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Scientific Publications

Boehringer Ingelheim offers an overview of scientific publications on the following pages. This overview represents all publications of the last three years (YTD) where employees of Boehringer Ingelheim worldwide were involved.

74 publications regarding Clinical Studies
  • Author:
    Dahl OE; Kurth AA; Rosencher N; Noack H; Clemens A; Eriksson BI
    Title:
    Erratum to: Thromboprophylaxis in patients older than 75 years or with moderate renal impairment undergoing knee or hip relacement surgery. (International Orthopaedics (DOI: 10.1007/s00264-011-1393-5).
    Source:
    Int Orthop 36 (5), 1113 (2012)
  • Author:
    Zhu DL; Bays H; Gao P; Mattheus M; Voelker B; Ruilope LM
    Title:
    Efficacy and tolerability of initial therapy with single-pill combination telmisartan/hydrochlorothiazide 80/25 mg in patients with grade 2 or 3 hypertension: A multinational, randomized, double-blind, active-controlled trial.
    Source:
    Clin Ther 34 (7), 1613-1624 (2012)
    Abstract:
    Background: Patients with grade 2 or 3 hypertension may require high-dose combination therapy to achieve blood pressure (BP) targets in a timely manner. Objectives: This study compared the effectiveness and tolerability of a single-pill combination (SPC) of telmisartan/hydrochlorothiazide 80/25 mg (T80/H25) with T80 monotherapy. Methods: In a Phase IV, multinational, randomized, double-blind, double-dummy, active-controlled, parallel-group trial, 894 patients with mean seated trough cuff systolic BP [SBP] =160 mm Hg and diastolic BP [DBP] =100 mm Hg were randomly assigned in a 2:1 ratio to receive T40/H12.5 SPC or telmisartan 40 mg monotherapy for 1 week before the dose was uptitrated to T80/H25 SPC or T80, respectively, administered for 6 weeks. The primary efficacy measure was the change from baseline in mean seated cuff trough SBP. Adverse events (AEs) were recorded. Results: A total of 888 patients received treatment (294 and 594 patients in the T80/H25 and T80 groups, respectively) (mean age, 57.0 years; age =65 years, 25.7%; male, 53.8%; white, 68.0%); 61 patients prematurely discontinued. Mean baseline SBP/DBP values were 172.3/104.3 mm Hg (T80/H25) and 173.3/104.5 mm Hg (T80). After 7 weeks, SBP was changed by -37.0 and -28.5 mm Hg in the T80/H25 and T80 groups (P < 0.0001); DBP was changed by -18.6 and -15.4 mm Hg respectively (P < 0.0001). These differences were significant after 2 weeks at the higher dosage (P < 0.0001). BP target (SBP/DBP <140/<90 mm Hg) was achieved in 55.5% and 34.7% of patients in the T80/H25 and T80 groups (P < 0.0001). T80/H25 SPC and T80 had a similar frequency of overall AEs (16.0% vs 17.0%). The prevalences of treatment-related AEs with T80/H25 SPC and T80 were low (4.6% and 2.8%), as were the rates of AEs that led to discontinuation (1.0% and 2.8%). Conclusions: In these patients with grade 2 or 3 hypertension, initial therapy with T80/H25 was associated with a significantly greater reduction in mean seated cuff trough SBP compared with T80 alone, as well as with improved hypertension goal attainment rates. Both treatments appeared to be well tolerated. ClinicalTrials.gov identifier: NCT00926289
  • Author:
    Mross K; Dittrich C; Aulizky WE; Strumberg D; Schutte J; Schmid RM; Hollerbach S; Merger M; Munzert G; Fleischer F; Scheulen ME
    Title:
    A randomised phase II trial of the polo-like kinase inhibitor BI 2536 in chemo-nave patients with unresectable exocrine adenocarcinoma of the pancreas-a study within the Central European Society Anticancer Drug Research (CESAR) collaborative network.
    Source:
    Br J Cancer 107 (2), 280-286 (2012)
    Abstract:
    Background: BI 2536, a novel Polo-like kinase 1 inhibitor, was assessed in patients with unresectable advanced exocrine adenocarcinoma of the pancreas. Methods: The study employed a two-stage design. Randomised first-line patients received BI 2536 200 mg on day 1 (n=43) or 60 mg on days 1-3 (n=43) every 21 days. Recruitment of second-line patients was planned for a second stage dependent on an interim analysis demonstrating =2 responses in the first 18 evaluable patients following 12 weeks of treatment and/or tumour control =12 weeks in 5 patients per schedule. Primary end point was objective response rate (ORR). Results: By independent review, ORR was 2.3% (all partial) and 24.4% had stable disease as confirmed best response. The second stage was not initiated. Median overall and progression-free survivals were 149 (95% confidence interval (CI), 91-307) and 46 days (95% CI, 44-56). Most common drug-related adverse events were neutropenia (37.2%), leukopenia (29.1%), fatigue (29.1%) and nausea (22.1%); most common grade 3/4-related events were neutropenia (36.0%), leukopenia (27.9%) and thrombocytopenia (8.1%). Conclusion: Given the low ORR and poor survival, further development of BI 2536 monotherapy is not warranted in this population
  • Author:
    Healey JS; Eikelboom J; Douketis J; Wallentin L; Oldgren J; Yang S; Themeles E; Heidbuchle H; Avezum A; Reilly P; Connolly SJ; Yusuf S; Ezekowitz M
    Title:
    Periprocedural bleeding and thromboembolic events with dabigatran compared with warfarin: Results from the randomized evaluation of long-term anticoagulation therapy (RE-LY) randomized trial.
    Source:
    Circulation 126 (3), 343-348 (2012)
    Abstract:
    Background-Dabigatran reduces ischemic stroke in comparison with warfarin; however, given the lack of antidote, there is concern that it might increase bleeding when surgery or invasive procedures are required. Methods and Results-The current analysis was undertaken to compare the periprocedural bleeding risk of patients in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial treated with dabigatran and warfarin. Bleeding rates were evaluated from 7 days before until 30 days after invasive procedures, considering only the first procedure for each patient. A total of 4591 patients underwent at least 1 invasive procedure: 24.7% of patients received dabigatran 110 mg, 25.4% received dabigatran 150 mg, and 25.9% received warfarin, P=0.34. Procedures included: pacemaker/defibrillator insertion (10.3%), dental procedures (10.0%), diagnostic procedures (10.0%), cataract removal (9.3%), colonoscopy (8.6%), and joint replacement (6.2%). Among patients assigned to either dabigatran dose, the last dose of study drug was given 49 (35-85) hours before the procedure on comparison with 114 (87-144) hours in patients receiving warfarin, P<0.001. There was no significant difference in the rates of periprocedural major bleeding between patients receiving dabigatran 110 mg (3.8%) or dabigatran 150 mg (5.1%) or warfarin (4.6%); dabigatran 110 mg versus warfarin: relative risk, 0.83; 95% CI, 0.59 to 1.17; P=0.28; dabigatran 150 mg versus warfarin: relative risk, 1.09; 95% CI, 0.80 to 1.49; P=0.58. Among patients having urgent surgery, major bleeding occurred in 17.8% with dabigatran 110 mg, 17.7% with dabigatran 150 mg, and 21.6% with warfarin: dabigatran 110 mg; relative risk, 0.82; 95% CI, 0.48 to 1.41; P=0.47; dabigatran 150 mg: relative risk, 0.82; 95% CI, 0.50 to 1.35; P=0.44. Conclusions- Dabigatran and warfarin were associated with similar rates of periprocedural bleeding, including patients having urgent surgery. Dabigatran facilitated a shorter interruption of oral anticoagulation. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00262600
  • Author:
    Gomis R; Owens DR; Taskinen M-R; Del Prato S; Patel S; Pivovarova A; Schlosser A; Woerle H-J
    Title:
    Long-term safety and efficacy of linagliptin as monotherapy or in combination with other oral glucose-lowering agents in 2121 subjects with type 2 diabetes: Up to 2 years exposure in 24-week phase II trials followed by a 78-week open-label extension.
    Source:
    Int J Clin Pract 66 (8), 731-740 (2012)
    Abstract:
    Aim: The aim of this study was to evaluate the long-term safety, tolerability and efficacy of the dipeptidyl peptidase-4 inhibitor linagliptin given either alone or in combination with other oral glucose-lowering agents in persons with type 2 diabetes. Methods: A 78-week open-label extension study evaluated subjects who participated in one of four preceding 24-week, randomised, double-blind, placebo-controlled parent trials and who received linagliptin, linagliptin + metformin, linagliptin + metformin + a sulphonylurea or linagliptin + pioglitazone (all with linagliptin administered orally once daily). Individuals receiving one of these treatments during a previous trial continued the same treatment (n = 1532) for up to a total of 102 weeks, whereas those previously receiving placebo were switched to linagliptin (n = 589). All 2121 participants received at least one dose of the trial medication and were included in the primary safety analysis. Results: In subjects previously receiving active treatment, the glycosylated haemoglobin A 1c reduction achieved during the 24-week parent trials was sustained through the 78-week extension period (change from baseline to week 102: -0.8%). Drug-related adverse events were experienced by 14.3% of participants. Hypoglycaemia occurred in 13.9% of participants and was similar between those previously receiving treatment (13.6%) and those switching from placebo to linagliptin (14.6%). Hypoglycaemia occurred most frequently with the use of metformin + a sulphonylurea background therapy (11%). Overall, no clinically relevant changes in body weight were observed. Conclusion: Long-term treatment with linagliptin was well tolerated with no change in the safety profile observed during the extension study. Sustained long-term glycaemic control was maintained for up to 102 weeks with either linagliptin monotherapy or linagliptin in combination with other oral glucose-lowering agents
  • Author:
    Eriksson BI; Smith JJ; Caprini J; Hantel S; Clemens A; Feuring M; Schnee J; Barsness GW
    Title:
    Evaluation of the acute coronary syndrome safety profile of dabigatran etexilate in patients undergoing major orthopedic surgery: Findings from four phase 3 trials.
    Source:
    Thromb Res 130 (3), 396-402 (2012)
    Abstract:
    Introduction: Several anticoagulants have been associated with a 'rebound effect' that potentially increases the risk of thrombosis and cardiovascular events following discontinuation. Four Phase 3 trials of dabigatran etexilate in major orthopedic surgery incorporated measures to assess the risk of acute coronary syndrome (ACS) events during and after treatment. Materials and methods: Patients in RE-MOBILIZE®, RE-MODEL™, RE-NOVATE®, and RENOVATE® II were randomized to dabigatran etexilate (150 mg or 220 mg once daily) or enoxaparin for 6-35 days, and followed for up to 90 days. ACS data were tabulated from investigator-reported serious adverse events using ACS-specific Medical Dictionary for Regulatory Authorities (MedDRA) lower-level terms. To ensure that all ACS events were identified in the initial three studies, RE-MOBILIZE®, RE-MODEL™, and RE-NOVATE®, a broader list of MedDRA terms was prespecified that would trigger treatment-blinded adjudication. Results: When pooling the four trials, patients receiving dabigatran etexilate 220 mg had the fewest treatment-emergent, investigator-reported ACS events (6 [0.16%] vs 14 [0.51%] for dabigatran 150 mg and 13 [0.35%] for enoxaparin). Corresponding post-treatment rates were 2 (0.06%), 1 (0.04%), and 4 (0.11%). Similarly, treatment-emergent centrally adjudicated definite or likely ACS events in the first three trials were fewer in patients on dabigatran 220 mg (16 [0.60%]) than dabigatran 150 mg (26 [0.95%]) and enoxaparin (20 [0.74%]). The corresponding numbers post treatment were 2, 2, and 7. None of these between-group differences were statistically significant. Conclusion: No increased ACS signal was detected with dabigatran etexilate compared with enoxaparin during or after treatment
  • Author:
    Aicher B; Peil H; Peil B; Diener H C
    Title:
    Responsiveness of efficacy endpoints in clinical trials with over the counter analgesics for headache
    Source:
    Cephalalgia 32 (13), 953-962 (2012)
    Abstract:
    Aim: To quantify and compare the responsiveness within the meaning of clinical relevance of efficacy endpoints in a clinical trial with over the counter (OTC) analgesics for headache. Efficacy endpoints and observed differences in clinical trials need to be clinically meaningful and mirror the change in the clinical status of a patient. This must be demonstrated for the specific disease indication and the particular patient population based on the application of treatments with proven efficacy. Methods: Patient's global efficacy assessment during two study phases (pre-phase and treatment phase) was used to classify patients as satisfied or non-satisfied with the efficacy of their medication. The analysis is based on 1734 patients included in the efficacy analysis of a randomized, placebo-controlled, double-blind, multi-centre parallel group trial with six treatment arms. Based on this classification and the pain intensity recorded by the patients on a 100mm visual analogue scale, group differences by assessment categories and receiver operating characteristic (ROC) curve methods were used to quantify responsiveness of the efficacy endpoints 'time to 50% pain relief', 'time until reduction of pain intensity to 10 mm', 'weighted sum of pain intensity difference' (%SPIDweighted), 'pain intensity difference (PID) relative to baseline at 2 hours', and 'pain-free at 2 hours'. Results: Clinically relevant differences between patients satisfied and non-satisfied with the treatment were observed for all efficacy endpoints. Patients with the highest rating of efficacy had the fastest and strongest pain relief. In comparison, patients assessing efficacy as 'less good' reached a 50% pain relief on average nearly an hour later than those scoring efficacy as at least 'good'. Simultaneously, their extent of pain relief was only half as great 2 hours after medication intake. Patients scoring efficacy as 'poor' experienced practically no pain relief within the 4 hour observation interval. ROC curve calculations confirmed an adequate responsiveness for all continuous endpoints. The following cut-off points for differentiating between satisfied and non-satisfied patients were deduced from the data in the pre- and treatment phase, respectively: 'time to 50% pain relief' 1:10 and 1:31 h:min, 'time until reduction of pain intensity to 10 mm' 2:40 and 3:00 h:min, '%SPIDweighted' 68 and 64%, 'PID at 2 hours' 35 and 35 mm. The sensitivity and specificity based on these cut-off points ranged from 70 to 79%. The binary endpoint 'pain-free at 2 hours' showed a clearly higher specificity (80 and 87%) than sensitivity (65 and 61%) in the pre- and treatment phase, respectively. Conclusions: When global assessment of efficacy by the patient was used as external criterion, ROC curve calculations confirmed a high responsiveness for all efficacy endpoints included in this study. Clinically relevant differences between patients satisfied and non-satisfied with the treatment were observed. The endpoint '%SPIDweighted' proved slightly but consistently superior to the other endpoints. SPID and %SPIDweighted are not easy to interpret and the time course of pain reduction is of high importance for the patients in the treatment of acute pain, including headache. The endpoint 'pain-free at 2 hours' showed the expected high specificity, but at the cost of a concurrently low sensitivity and clearly makes less use of the available information than the endpoint 'time to 50% pain reduction', which combines the highly relevant aspects of time course and extent of pain reduction. Responsiveness, the ability of an outcome measure to detect clinically important changes in a specific condition of a patient, should be added in future revisions of IHS guidelines for clinical trials in headache disorders. © 2012 International Headache Society.
  • Author:
    van de Werf F; Brueckmann M; Connolly SJ; Friedman J; Granger CB; Haertter S; Harper R; Kappetein AP; Lehr T; Mack MJ; Noack H; Eickelboom JW
    Title:
    A comparison of dabigatran etexilate with warfarin in patients with mechanical heart valves: The randomized, phase II study to evaluate the sAfety and pharmacokinetics of oraL dablGatran etexilate in patients after heart valve replacemeNt (RE-ALIGN).
    Source:
    Am Heart J 163 (6), 931-937.e1 (2012)
  • Author:
    Wagner C L; Visvanathan S; Elashoff M; Mcinnes I B; Mease P J; Krueger G G; Murphy F T; Papp K; Gomez-Reino JJ; Mack M; Beutler A; Gladman D; Kavanaugh A
    Title:
    Markers of inflammation and bone remodelling associated with improvement in clinical response measures in psoriatic arthritis patients treated with golimumab
    Source:
    Ann Rheum Dis 72 (1), 83-88 (2013)
    Abstract:
    Objective: To determine serum biomarker associations with clinical response to golimumab treatment in patients with psoriatic arthritis (PsA). Methods: GO-REVEAL was a randomised, placebo-controlled study of golimumab in patients with active PsA. Samples were collected from 100 patients at baseline, week 4 and week 14, and analysed for serum-based biomarkers and protein profiling (total 92 markers); data were correlated with clinical measures at week 14. Results: Serum levels of a subset of proteins (apolipoprotein C III, ENRAGE, IL-16, myeloperoxidase, vascular endothelial growth factor, pyridinoline, matrix metalloproteinase 3, C-reactive protein (CRP), carcinoembryonic antigen, intercellular adhesion molecule 1 and macrophage inflammatory protein 1?) at baseline or week 4 were strongly associated with American College of Rheumatology 20% improvement (ACR20) response and/or disease activity score in 28 joints (DAS28) at week 14. A smaller subset of proteins was significantly associated with a 75% improvement in the psoriasis area and severity index score (PASI75) at week 14, (adiponectin, apolipoprotein CIII, serum glutamic oxaloacetic transaminase, and tumour necrosis factor ?). Subsets of proteins were identified as potentially predictive of clinical response for each of the clinical measures, and the power of these biomarker panels to predict clinical response to golimumab treatment was stronger than for CRP alone. Conclusions: This analysis provides insight into several panels of markers that may have utility in identifying PsA patients likely to have ACR20, DAS28, or PASI75 responses following golimumab treatment. Copyright Article author (or their employer) 2012.
  • Author:
    Miller VA; Hirsh V; Cadranel J; Chen Y-M; Park K; Kim S-W; Zhou C; Su W-C; Wang M; Sun Y; Heo DS; Crino L; Tan E-H; Chao T-Y; Shahidi M; Cong XJ; Lorence RM; Yang JCH
    Title:
    Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): A phase 2b/3 randomised trial.
    Source:
    Lancet Oncol 13 (5), 528-538 (2012)
    Abstract:
    Background: Afatinib, an irreversible ErbB-family blocker, has shown preclinical activity when tested in EGFR mutant models with mutations that confer resistance to EGFR tyrosine-kinase inhibitors. We aimed to assess its efficacy in patients with advanced lung adenocarcinoma with previous treatment failure on EGFR tyrosine-kinase inhibitors. Methods: In this phase 2b/3 trial, we enrolled patients with stage IIIB or IV adenocarcinoma and an Eastern Cooperative Oncology Group performance (ECOG) performance score of 0-2 who had received one or two previous chemotherapy regimens and had disease progression after at least 12 weeks of treatment with erlotinib or gefitinib. We used a computer-generated sequence to randomly allocate patients (2:1) to either afatinib (50 mg per day) or placebo; all patients received best supportive care. Randomisation was done in blocks of three and was stratified by sex and baseline ECOG performance status (0-1 vs 2). Investigators, patients, and the trial sponsor were masked to treatment assignment. The primary endpoint was overall survival (from date of randomisation to death), analysed on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT00656136. Findings: Between May 26, 2008, and Sept 21, 2009, we identified 697 patients, 585 of whom were randomly allocated to treatment (390 to afatinib, 195 to placebo). Median overall survival was 10·8 months (95% CI 10·0-12·0) in the afatinib group and 12·0 months (10·2-14·3) in the placebo group (hazard ratio 1·08, 95% CI 0·86-1·35; p=0·74). Median progression-free survival was longer in the afatinib group (3·3 months, 95% CI 2·79-4·40) than it was in the placebo group (1·1 months, 0·95-1·68; hazard ratio 0·38, 95% CI 0·31-0·48; p<0·0001). No complete responses to treatment were noted; 29 (7%) patients had a partial response in the afatinib group, as did one patient in the placebo group. Subsequent cancer treatment was given to 257 (68%) patients in the afatinib group and 153 (79%) patients in the placebo group. The most common adverse events in the afatinib group were diarrhoea (339 [87%] of 390 patients; 66 [17%] were grade 3) and rash or acne (305 [78%] patients; 56 [14%] were grade 3). These events occurred less often in the placebo group (18 [9%] of 195 patients had diarrhoea; 31 [16%] had rash or acne), all being grade 1 or 2. Drug-related serious adverse events occurred in 39 (10%) patients in the afatinib group and one (<1%) patient in the placebo group. We recorded two possibly treatment-related deaths in the afatinib group. Interpretation: Although we recorded no benefit in terms of overall survival with afatinib (which might have been affected by cancer treatments given after progression in both groups), our findings for progression-free survival and response to treatment suggest that afatinib could be of some benefit to patients with advanced lung adenocarcinoma who have failed at least 12 weeks of previous EGFR tyrosine-kinase inhibitor treatment. Funding: Boehringer Ingelheim Inc. © 2012 Elsevier Ltd. |
  • Author:
    Yang JCH; Shih J-Y; Su W-C; Hsia T-C; Tsai C-M; Ou SHI; Yu C-J; Chang G-C; Hol C-L; Sequist LV; Dudek AZ; Shahidi M; Cong XJ; Lorence RM; Yang P-C; Miller VA
    Title:
    Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): A phase 2 trial.
    Source:
    Lancet Oncol 13 (5), 539-548 (2012)
    Abstract:
    Background: Afatinib is an irreversible ErbB-family blocker with preclinical activity in non-small-cell lung cancer (NSCLC) with EGFR mutations. We aimed to assess the efficacy of afatinib in patients with lung adenocarcinoma and EGFR mutations. Methods: In this phase 2 study, we enrolled patients from 30 centres in Taiwan and the USA with lung adenocarcinoma (stage IIIb with pleural effusion or stage IV) with EGFR mutations, who had no more than one previous chemotherapy regimen for advanced disease, an Eastern Cooperative Oncology Group performance status of 0-2, and no previous treatment with EGFR tyrosine-kinase inhibitors. We tested two afatinib starting doses: 50 mg daily and subsequently 40 mg daily, introduced to establish whether tolerability could be improved with retention of anti-tumour activity. The primary endpoint was the proportion of patients with a confirmed objective response (complete response or partial response), on the basis of Response Evaluation Criteria in Solid Tumors 1.0 (independent review). This study is registered with ClinicalTrials.gov, number NCT00525148. Findings: 129 patients were treated with afatinib, 99 with a starting dose of 50 mg and 30 with a starting dose of 40 mg. 79 (61%) of 129 patients had an objective response (two complete responses, 77 partial responses). 70 (66%) of the 106 patients with the two common activating EGFR mutations (deletion 19 or L858R) had an objective response, as did nine (39%) of 23 patients with less common mutations. Similar proportions of patients had an objective response when analysed by starting dose (18 [60%] of 30 patients at 40 mg vs 61 [62%] of 99 patients at 50 mg). Of the two most common adverse events (diarrhoea and rash or acne), grade 3 events were more common in patients receiving a 50 mg starting dose (22 [22%] of 99 patients for diarrhoea and 28 [28%] of 99 patients for rash or acne) than they were in those receiving a 40 mg starting dose (two [7%] of 30 patients for both diarrhoea and rash or acne); possibly treatment-related serious adverse events were also less common in patients receiving a 40 mg starting dose (two of 30 patients vs 14 of 99 patients). We recorded one possibly drug-related death (interstitial lung disease). Interpretation: Afatinib shows activity in the treatment of patients with advanced lung adenocarcinoma with EGFR mutations, especially in patients with deletion 19 or L858R mutations. The efficacy of afatinib 40 mg should be compared with chemotherapy or other EGFR tyrosine-kinase inhibitors in EGFR-mutation-positive NSCLC. Funding: Boehringer Ingelheim Inc. © 2012 Elsevier Ltd
  • Author:
    Hart R G; Diener H-C; Yang S; Connolly S J; Wallentin L; Reilly P A; Ezekowitz M D; Yusuf S
    Title:
    Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with warfarin or dabigatran: The RE-LY trial.
    Source:
    Stroke 43 (6), 1511-1517 (2012)
    Abstract:
    Background and Purpose-: Intracranial hemorrhage is the most devastating complication of anticoagulation. Outcomes associated with different sites of intracranial bleeding occurring with warfarin versus dabigatran have not been defined. Methods-: Analysis of 18 113 participants with atrial fibrillation in the Randomized Evaluation of Long-term anticoagulant therapY (RE-LY) trial assigned to adjusted-dose warfarin (target international normalized ratio, 2-3) or dabigatran (150 mg or 110 mg, both twice daily). Results-: During a mean of 2.0 years of follow-up, 154 intracranial hemorrhages occurred in 153 participants: 46% intracerebral (49% mortality), 45% subdural (24% mortality), and 8% subarachnoid (31% mortality). The rates of intracranial hemorrhage were 0.76%, 0.31%, and 0.23% per year among those assigned to warfarin, dabigatran 150 mg, and dabigatran 110 mg, respectively (P<0.001 for either dabigatran dose versus warfarin). Fewer fatal intracranial hemorrhages occurred among those assigned dabigatran 150 mg and 110 mg (n=13 and n=11, respectively) versus warfarin (n=32; P<0.01 for both). Fewer traumatic intracranial hemorrhages occurred among those assigned to dabigatran (11 patients with each dose) compared with warfarin (24 patients; P<0.05 for both dabigatran doses versus warfarin). Independent predictors of intracranial hemorrhage were assignment to warfarin (relative risk, 2.9; P<0.001), aspirin use (relative risk, 1.6; P=0.01), age (relative risk, 1.1 per year; P<0.001), and previous stroke/transient ischemic attack (relative risk, 1.8; P=0.001). Conclusions-: The clinical spectrum of intracranial hemorrhage was similar for patients given warfarin and dabigatran. Absolute rates at all sites and both fatal and traumatic intracranial hemorrhages were lower with dabigatran than with warfarin. Concomitant aspirin use was the most important modifiable independent risk factor for intracranial hemorrhage. © 2012 American Heart Association, Inc
  • Author:
    Acrroll K J; Le Maulf F
    Title:
    Japanese Guideline on Global Clinical Trials: Statistical Implications and Alternative Criteria for Assessing Consistency
    Source:
    Drug Inf J 54 (5), 657-667 (2011)
    Abstract:
    The Japanese regulatory guideline "Basic Principles in Global Clinical Trials," issued in September 2007, serves to encourage the participation of Japan in international phase 3 clinical trials and, as such, is very much welcome, helping to avoid repeat, stand-alone trials in Japanese patients that are often underpowered. However, the guideline raises a concern regarding the consistency of outcomes in the subset of Japanese patients and the total trial population and offers two alternative criteria to determine the fraction of Japanese patients that should be recruited. The first criterion requires that sufficient Japanese patients are entered such that, if the treatment effects in the Japanese and overall populations are truly the same, there is an 80% chance that the effect in Japanese patients will be shown to be at least half of the effect in the total trial population. The second criterion requires that sufficient patients be entered per geographical region included in the trial such that, if there is a true effect in the overall population, the probability that each region (including Japan) will also show a positive effect is 80%. The purpose of this article is to explore the implications of these criteria in terms of overall power and the fraction of the Japanese patients that need to be recruited to satisfy them and to consider some potential alternative criteria that might offer advantages over those stated in the guideline. © 2011 Drug Information Association.
  • Author:
    Mancia G; Schumacher H
    Title:
    Incidence of adverse events with telmisartan compared with ACE inhibitors. Evidence from a pooled analysis of clinical trials.
  • Author:
    Lin NU; Winer EP; Wheatley D; Carey LA; Houston S; Mendelson D; Munster P; Frakes L; Kelly S; Garcia AA; Cleator S; Uttenreuther-Fischer M; Jones H; Wind S; Vinisko R; Hickish T
    Title:
    A phase II study of afatinib (BIBW 2992), an irreversible ErbB family blocker, in patients with HER2-positive metastatic breast cancer progressing after trastuzumab.
    Source:
    Breast Cancer Res Treat 133 (3), 1057-1065 (2012)
    Abstract:
    Afatinib is an oral, ErbB family blocker, which covalently binds and irreversibly blocks all kinase-compe-tent ErbB family members. This phase II, open-label, singlearm study explored afatinib activity in human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients progressing after trastuzumab treatment. Patients had stage IIIB/IV HER2-positive metastatic breast cancer, with progression following trastuzumab or trastuzumab intolerance and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Patients received 50 mg afatinib once-daily until disease progression. Primary endpoint was objective response rate (Response Evaluation Criteria in Solid Tumors 1.0), with tumor assessments every 8 weeks. Forty-one patients were treated. Patients had received a median of three prior chemotherapy lines (range, 0-15) and 68.3% had received trastuzumab for >1 year.Four patients (10% of 41 treated; 11% of evaluable patients) had partial response. Fifteen patients (37% of 41) had stable disease as best response and 19 (46% of 41) achieved clinical benefit. Median progression-free survival was 15.1 weeks (95% confidence interval [CI]: 8.1-16.7); median overall survival was 61.0 weeks (95% CI: 56.7-not evaluable). Most frequent common terminology criteria for adverse events grade 3 treatment-related adverse events were diarrhea (24.4%) and rash (9.8%). Afatinib monotherapy was associated with promising clinical activity in extensively pretreated HER2-positive breast cancer patients who had progressed following trastuzumab treatment.
  • Author:
    Dullweber F; Riedel A; Boehler S
    Title:
    Evaluation of paediartric study applications - Experiences of the members of the German Association of Research-Based Pharmaceutical Companies (vfa).
    Source:
    Monatsschr Kinderheilkd 160 (7), 6621-668 (2012)
    Abstract:
    The applications for paediatric clinical trials have to fulfil the high demands imposed by the legal requirements. A survey was sent to the members of the German Association of Research-Based Pharmaceutical Companies (vfa) to investigate the type and quantity of objections raised by Ethics Committees and the competent regulatory authorities. Most objections refer to the patient information and consent document, followed by objections to the trial protocol. Nearly 47% of all objections referred to special paediatric questions. The analysis of those objections was used to derive recommendations for the improvement of the applications: description of risk threshold and degree of distress as well as the concept of minimal risk and minimal burden with regard to the application; consideration of the pubertal maturity when describing types of contraception; design of consent documents for children in an age-appropriate language to enable the minor participants to take part in the decision-making process; addressing the principle of subsidiarity based on the approved paediatric investigation plan (PIP).
  • Author:
    Neldam S; Edwards C; Lang M; Jones R
    Title:
    Long-term tolerability and efficacy of single-pill combinations of telmisartan 40-80 mg plus amlodipine 5 or 10 mg in patients whose blood pressure was not initially controlled by amlodipine 5-10 mg: Open-label, long-term follow-ups of the TEAMSTA-5 and TEAMSTA-10 studies.
    Source:
    Curr Ther Res 73 (1-2), 65-84 (2012)
    Abstract:
    Background: Two 8-week, randomized, double-blind, controlled studies previously evaluated the efficacy and tolerability of single-pill combinations of telmisartan 40-80 mg/amlodipine 5-10 mg (T40-80/A5-10) in patients with hypertension not at diastolic blood pressure (DBP) goal (DBP <90 mm Hg) after 6 weeks of amlodipine 5 mg monotherapy (A5) (TEAMSTA-5) or amlodipine 10 mg monotherapy (A10) (TEAMSTA-10). The long-term (=6 months) tolerability and efficacy of single-pill combinations of T40-T80/A5-A10 have now been evaluated in 2 open-label studies in patients who had successfully completed either TEAMSTA-5 or TEAMSTA-10 (TEAMSTA-5 and TEAMSTA-10 Follow-Ups). Methods: In the TEAMSTA-5 Follow-Up, 976 patients whose blood pressure was not initially controlled by taking A5 received T40/A5 for 4 or 8 weeks, with consecutive uptitration to T80/A5 if DBP was =90 mm Hg. In TEAMSTA-10 Follow-Up, 838 patients not initially achieving blood pressure control using A10 received T40/A10 for 4 weeks before randomization to T40/A10 or T80/A10; after 4 weeks, patients randomized to T40/A10 with DBP =90 mm Hg were uptitrated to T80/A10. In both studies, add-on antihypertensive medication was allowed if DBP was not at goal. Results: Treatment compliance in both follow-up studies was =98.4%. Single-pill combinations of T40-T80/A5-A10 resulted in additional clinically relevant blood pressure reductions and 67% to 93% of patients achieved DBP goal (<90 mm Hg); only 1% to 19% of patients received additional medication for hypertension, of whom 29% to 76% achieved DBP goal. Long-term treatment with T40-T80/A5-A10 was well tolerated, with comparable adverse event profiles for all telmisartan/amlodipine combinations. The most common drug-related adverse events were peripheral edema (1.9%-3.9%) and dizziness (1.5% in the T80/A5 group only); these were consistent with the known tolerability profiles of telmisartan/amlodipine combinations. Overall treatment discontinuation rates due to adverse events were low (0.7%-1.5%). Conclusions: In patients not achieving DBP goal with either A5 or A10 monotherapy, the vast majority achieved DBP goal with single-pill combinations of T40-T80/A5-A10. Long-term treatment was well tolerated with high compliance, promoting treatment adherence regardless of telmisartan/amlodipine dose. . ClinicalTrials.gov identifiers: . NCT00614380 (TEAMSTA-5 Follow-up) and . NCT00624052 (TEAMSTA-10 Follow-up).
  • Author:
    Sharma AM; Bakris G; Neutel JM; Littlejohn TW; Kobe M; Ting N; Ley L
    Title:
    Single-pill combination of telmisartan/amlodipine versus amlodipine monotherapy in diabetic hypertensive patients. An 8-week randomized parallel-group, double-blind trial.
    Source:
    Clin Ther 34 (3), 537-551 (2012)
    Abstract:
    Background: Hypertensive patients with diabetes often require combination therapy to achieve a blood pressure (BP) goal, and evidence suggests that time to BP goal is crucial to decrease cardiovascular risk. Objective: The aim of the study was to investigate whether the single-pill combination of telmisartan and amlodipine was superior to amlodipine alone as initial antihypertensive therapy in patients with diabetes and hypertension. Methods: An 8-week, randomized, parallel-group, double-blind international trial comparing the once-daily single-pill combination of telmisartan 80 mg and amlodipine 10 mg (T/A; n = 352) with once-daily amlodipine 10 mg (A; n = 354) in patients with type 2 diabetes mellitus and stage 1 or 2 hypertension (systolic BP [SBP] >150 mm Hg). Results: Patient demographics were similar between treatment groups, with an mean (SD) age of 60.5 (10.1) years; 51.7% were male, the mean (SD) body mass index was 32.0 (6.1) and the mean (SD) duration of hypertension was 8.8 (7.9) years. After 8 weeks (primary end point) as well as after 1, 2, and 4 weeks (key secondary end points), significantly greater decreases in the in-clinic mean seated trough cuff SBP with T/A versus A were achieved (-29.0 mm Hg vs -22.9 mm Hg at 8 weeks; P < 0.0001). After 8 weeks, 71.4% versus 53.8% of patients achieved the BP goal (<140/90 mm Hg) with T/A versus A, with mean SBPs of 131.9 and 137.9 mm Hg, respectively. Similar results were observed in the obese (metabolic syndrome) subpopulation. The more stringent goal (<130/80 mm Hg) was achieved by 36.4% and 17.9% patients in the T/A and A groups, respectively. The most common adverse events were peripheral edema, headache, and dizziness. Conclusions: In this selected population of patients with diabetes and hypertension, T/A provided prompt and greater BP decreases compared with A monotherapy, with the majority of patients achieving the BP goal (<140/90 mm Hg).
  • Author:
    Neutel JM; Mancia G; Black HR; Dahloef B; Defeo H; Ley L; Vinisko R; Donova T; Gotcheva N; Milanov S; Mincheva V; Pencheva G; Zlatareva N; Raev D; Stoimenov S; Petranov S; Homy I; Jerabek O; Karen I; Kuchar JC; Krumlov Lorenc Z; Nagel J; Petenka M; Zidkova E; Barucq F; Queguiner A; Robin F; Touzet P; Bismuth M; Bourgoin M; Giraldi C; Breton M; Combet R; Venturini G; Causse P; Henriot F; Khennouf A; Lecaignard D; Cayron P; Chalaux P; Chaleon A; Chalvignac A; Forestier BD; Deme JC; Fivel C; Depoisier M; Dimon B; Flosi M; MacAgno A; Ripoll M; Geronimi O; Michalak B; Geoffray B; Hannoush E; Jacquet J-P; Jappy L; Jordan E; Lacoin F; Lefort D; Lemarie B; Martocq G; Michellier P; Nabedian E; Percheron C-A; Perrin B; Pouget M; Roger J-J; Rouviere G; Sacareau D; Taminau D; Vuong M-H; Zimmermann D; Andras V; Livia T; Ferenc P; Gabriella N; Laszloe I; Ibolya P; Judit S; Karoly Z; Judit R; Benedek I; Cristea M; Tatu-Chitoiu GP; Dragulescu S; Gaita D; Georgescu CA; Minescu B; Manitiu I; Matei A; Salajan M; Tyurina T; Vishnevsky A; Baek S-H; Kang S-M; Kwon H-M; Park C-G; Kim M-H; Lee M-Y; Yang JY; Gonsorcik J; Hojenova S; Hranai M; Kolikova V; Ruffini L; Zareczky P; Gil-Extremera B; Munoz J; Olivan J; Pont F; Tovar J-L; Faynyk A; Goloborodko B; Shatilo V; Sirenko Y; Svyshchenko Y; Vykhovanyuk I; Yena L; Karpenko O; Kononenko L; Zehnder B; Portnoy EB; Punzi HA; Ricci DR; Samson MB; Slabic S; Struble R; Tidman RE; Wayne J; Webster DE; Winer N; Jagminas L; Kanna B; Khronusova Y; Lane´PJ; Lewinson L; Marple R; Mello CJ; Patel NR; Paltron A; Pool JL; Korzh O; Kraiz I; Bittar N; Cheung DG; Crump K; Diaz JL; Eddy PL; Eyzaguirre RD; Graf RJ; Hill JM; Jack DB
    Title:
    Single-pill combination of telmisartan/amlodipine in patients with serve hypertension: Results from the TEAMSTA serve HTN study.
    Source:
    J Clin Hypertens 14 (4), 206-215 (2012)
    Abstract:
    Despite the well documented benefits conferred by adequate control of hypertension, the majority of hypertensive patients display suboptimal control and few patients achieve blood pressure (BP) levels <14090mmHg. As a consequence, combination therapy will be required in the majority of patients to achieve target BP. Fixed-dose combinations of antihypertensives not only simplify treatment regimens, contributing to enhanced patient adherence, they provide superior BP-lowering efficacy and an improved tolerability profile. Fixed-dose combinations have become the strategy of choice in high-risk patients or those with stage 23 hypertension. The combination of a renin-angiotensin system inhibitor (RASI) with a calcium channel blocker (CCB) is a first-line combination that, in addition to its antihypertensive efficacy, reduces oedema, the main adverse effect of the dihydropyridine CCB and the main factor limiting their use. In morbiditymortality studies, this fixed-dose combination has also demonstrated superiority over a RASI combined with a diuretic. The single-pill combination of telmisartan and amlodipine has been shown to produce a dose-dependent BP-lowering effect significantly greater than that of either agent administered as monotherapy. These findings have been confirmed by ambulatory BP monitoring in patients with stage 1 and 2 hypertension, which demonstrated that single-pill telmisartanamlodipine provides substantial 24-hour BP-lowering efficacy. A higher proportion of patients achieved 24-hour BP goals of <13080mmHg on combination therapy. The superior efficacy of combination therapy has been demonstrated across a broad range of patients, including those with moderate-to-severe hypertension, diabetes mellitus and obesity. Moreover, combined use of telmisartan and amlodipine reduces the incidence of amlodipine-induced oedema, making it a preferred combination for the treatment of hypertension. © 2011 Adis Data Information BV. All rights reserved
  • Author:
    Hijazi Z; Oldgren J; Andersson U; Connolly SJ; Ezekowitz MD; Hohnloser SH; Reilly PA; Vinereanu D; Siegbahn A; Yusuf S; Wallentin L
    Title:
    Cardiac biomarkers are associated with an increased risk of stroke and death in patients with atrial fibrillation: A randomized evaluation of long-termn anticoagulation therapy (RE-LY) substudy.
    Source:
    Circulation 125 (13), 1605-1616 (2012)
  • Author:
    Hohnloser SH; Oldgren J; Yang S; Wallentin L; Ezekowitz M; Reilly P; Eikelboom J; Brueckmann M; Yusuf S; Connolly SJ
    Title:
    Myocardial ischemic events in patients with atrial fibrillation treated with dabigatran or warfarin in the RE-LY (Randomized evaluation of long-term anticoagulation therapy) trial.
    Source:
    Circulation 125 (5), 669-676 (2012)
    Abstract:
    Background-There is a modest risk of myocardial infarction (MI) and myocardial ischemic events in patients with atrial fibrillation. Methods and Results-Data from the RE-LY study (Randomized Evaluation of Long-Term Anticoagulation Therapy) were used to report rates of MI, unstable angina, cardiac arrest, and cardiac death and the prespecified net clinical benefit and treatment effects of dabigatran versus warfarin. MI occurred at annual rates of 0.82% and 0.81% with dabigatran 110 or 150 mg BID compared with 0.64% with warfarin (hazard ratio [HR] 1.29, 95% confidence interval [CI] 0.96-1.75, P=0.09 for dabigatran 110 mg; HR 1.27, 95% CI 0.94-1.71, P=0.12 for dabigatran 150 mg). Annual rates of a composite of MI, unstable angina, cardiac arrest, and cardiac death were 3.16% per year with dabigatran 110 mg, 3.33% per year with dabigatran 150 mg, and 3.41% per year with warfarin (HR versus warfarin 0.93, 95% CI 0.80-1.06, P=0.28 for dabigatran 110 mg and HR 0.98, 95% CI 0.85-1.12, P=0.77 for dabigatran 150 mg). Events prespecified as "net clinical benefit" (all strokes, systemic embolism, MI, pulmonary embolism, major bleeding, and all-cause death) occurred at a rate of 7.34% per year with dabigatran 110 mg, 7.11% per year with dabigatran 150 mg, and 7.91% per year with warfarin (HR 0.92, 95% CI 0.84-1.01, P=0.09 for dabigatran 110 mg and HR 0.90, 95% CI 0.82-0.99, P=0.02 for dabigatran 150 mg). The relative effects of dabigatran versus warfarin on myocardial ischemic events were consistent in patients with or without a baseline history of MI or coronary artery disease. Conclusions-There was a nonsignificant increase in MI with dabigatran compared with warfarin, but other myocardial ischemic events were not increased. Treatment effects of dabigatran were consistent in patients at higher and lower risk of myocardial ischemic events. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT 00262600.
  • Author:
    Frost A; Mross K; Steinbild S; Hedborn S; Unger C; Kaiser R; Trommeshauser D; Munzert G
    Title:
    Phase I study of the Plk1 inhibitor BI 2536 administered intravenously on three consecutive days in advanced solid tumors.
    Source:
    Curr Oncol 19 (1), 28-35 (2012)
    Abstract:
    Background This open-label phase i study with an accelerated titration design was performed to determine the maximum tolerated dose of BI 2536, a potent, highly selective small-molecule polo-like kinase 1 (Plk1) inhibitor. Methods Patients with advanced solid tumours received a single 60-minute intravenous infusion of BI 2536 (50-70 mg) on days 1-3 of each 21-day treatment course. Recipients without disease progression or untenable toxicity could receive additional treatment courses. The maximum tolerated dose was determined based on dose-limiting toxicities. Other assessments included safety, pharmacokinetic profile, and antitumour activity according to the Response Evaluation Criteria in Solid Tumors. Results The study enrolled 21 patients. The maximum tolerated dose for BI 2536 was determined to be 60 mg for the study schedule. Dose-limiting toxicities included hematologic events, hypertension, elevated liver enzymes, and fatigue. The most frequently reported drug-related adverse events were mild-to-moderate fatigue, leukopenia, constipation, nausea, mucosal inflammation, anorexia, and alopecia. The pharmacokinetics of BI 2536 were linear within the dose range tested. Plasma concentration profiles exhibited multi compartmental pharmacokinetic behaviour, with a terminal elimination half-life of 20-30 hours. Conclusions In the present study, BI 2536 showed an acceptable safety profile warranting further investigation of Plk1 inhibitors in this patient population.
  • Author:
    Eikelboom JW; Connoly SJ; Healey JS; Yang s; Yusuf S; Wallentin L; Oldgren J; Ezekowitz M; Alings M; Kaatz S; Hohnloser SH; Diener H-C; Franzosi MG; Huber K; Reilly P; Varrone J
    Title:
    Reply to letters regarding article. "risk of bleeding with 2 doses of daigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term therapy (RE-LY) trial.
    Source:
    Circulation 125 (3), e293-e294 (2012)
    Abstract:
    no Abstract
  • Author:
    Derogatis LR; Komer L; Katz M; Moreau M; Kimura T; Garcia Jr. M; Wunderlich G; Pyke R
    Title:
    Treatment of hypoactive sexual desire disorder in premenopausal woman: Efficacy of flibanserin in the VIOLET study.
    Source:
    J Sex Med 9 (4), 1074-1085 (2012)
  • Author:
    Glomb P; Ring A
    Title:
    Delayed effects in the exposure-response analysis of clinical QTC trials.
    Source:
    J Biopharm Stat 22 (2), 387-400 (2012)
    Abstract:
    In clinical development, thorough QT interval/corrected QT interval (QT/QTc) studies are performed to demonstrate that new investigational drugs do not change cardiac repolarization. In addition to the analysis recommended by ICH E14, exposure-response modeling has recently gained increased scientific attention. A direct concentration-QTc relationship is usually assumed with this pharmacokinetics (PK) QT analysis. Consequently, unconsidered effect delays might lead to severe bias in estimation. Although literature and the Food and Drug Administration (FDA) recommend checking for hysteresis, little guidance is given for evaluating the presence of lagged effects. Based on simulated delay scenarios, we derive a metric that allows for the detection of relevant effect delays. With this, the necessity for refined modeling of lag times can be easily recognized.
  • Author:
    Thorp J; Simon J; Dattani D; Taylor L; Kimura T; Garcia Jr. M; Lesko L; Pyke R
    Title:
    Treatment of hypoactive sexual desire disorder in premenopausal women: Efficacy of flibanserin in the DAISY study.
    Source:
    J Sex Med 9 (3), 793-804 (2012)
    Abstract:
    Introduction. Hypoactive Sexual Desire Disorder (HSDD) is characterized by low sexual desire that causes marked distress or interpersonal difficulty. Aim. To assess the efficacy and tolerability of flibanserin, a postsynaptic 5-HT1A agonist/5-HT2A antagonist, in the treatment of premenopausal women with HSDD. Methods. North American premenopausal women with HSDD (mean age 35years) were randomized to 24weeks' treatment with flibanserin 25mg twice daily (N=396), 50mg twice daily (N=392), 100mg once daily at bedtime (N=395), or placebo (N=398). Main Outcome Measures. Co-primary endpoints were changed from baseline to study end in number of satisfying sexual events (SSE) and sexual desire score, measured daily using an eDiary. Secondary endpoints included change in Female Sexual Distress Scale-Revised (FSDS-R) total score and Item 13 score (distress due to low sexual desire), Female Sexual Function Index (FSFI) total and desire domain scores, and Patient's Global Impression of Improvement. Results. Flibanserin 100mg once daily was associated with an increase in SSE (P<0.01 vs. placebo) but the 25mg and 50mg twice daily doses were not. No group showed a significant increase in eDiary desire score vs. placebo. All flibanserin regimens improved FSDS-R total, FSDS-R Item 13, FSFI total, and FSFI desire domain scores vs. placebo (P<0.05, for all). More women receiving flibanserin 50mg twice daily and 100mg once daily considered their HSDD to have improved than women receiving placebo (44.1% and 47.0% vs. 30.3%, respectively) (P<0.000, 1 vs. placebo). The most frequently reported adverse events in women receiving flibanserin were somnolence (11.8%), dizziness (10.5%), and fatigue (10.3%). Conclusion. In premenopausal women with HSDD, flibanserin 100mg once daily was well tolerated and associated with statistically significant improvements in SSE, sexual desire (FSFI desire domain score but not eDiary desire score), sexual function, and decrease in sexual distress vs. placebo.
  • Author:
    Picchietti DL; Arbuckle RA; Abetz L; Durmer JS; Ivanenko A; Owens JA; Croenlein J; Allen RP; Walters AS
    Title:
    Pediatric restless legs syndrome: Analysis of symptom description and drawings.
    Source:
    J Child Neurol 26 (11), 1365-376 (2011)
  • Author:
    Mancia G; Schumacher H; Redon J; Verdecchia P; Schmieder R; Jennings G; Yusoff K; Ryden L; Liu GL; Teo K; Slight P; Yusuf S
    Title:
    Blood pressure targets recommended by guidelines and incidence of cardiovascular and renal events in the ongoing telmisartan alone and in combination with ramipril global endpoint trial (ONTARGET).
    Source:
    Circulation 124 (16), 1727-1736 (2011)
    Abstract:
    BACKGROUND-: Hypertension treatment guidelines recommend that blood pressure (BP) be lowered to <140/90 mm Hg, but that a reduction to <130/80 mm Hg be adopted in patients at high cardiovascular (CV) risk. We investigated the CV and renal benefits associated with these BP targets in the high-CV-risk population of the Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial (ONTARGET). METHODS AND RESULTS-: Patients were divided into 4 groups according to the proportion of in-treatment visits before the occurrence of an event (<25%->75%) in which BP was reduced to <140/90 or <130/80 mm Hg. After adjustment for demographic and clinical variables, a progressive increase in the proportion of visits in which BP was reduced to <140/90 or <130/80 mm Hg was associated with a progressive reduction in the risk of stroke, new onset of microalbuminuria or macroalbuminuria, and return to normoalbuminuria in albuminuric patients. An increased frequency of BP control to either target did not have any consistent effect on the adjusted risk of myocardial infarction and heart failure. The adjusted risk of CV events was reduced by increasing the frequency of BP control to <140/90 mm Hg, but not to <130/80 mm Hg. Similar findings were obtained for the achievement of the BP target in the visit preceding a CV event. CONCLUSION-: The more frequent achievement of the BP targets recommended by guidelines led to cerebrovascular and renal protection, but did not increase cardiac protection. Overall, CV protection was favorably affected by the less tight but not by the tighter BP target.
  • Author:
    Neldam St; Edwards C; Jones R
    Title:
    Switching patients with uncontrolled hypertension on amlodipine 10mg to single-pill combinations of telmisartan and amlodipine: Results of the TEAMSTA-10 study.
    Source:
    Curr Med Res Opin 27 (11), 2145-2153 (2011)
  • Author:
    Bleecker ER; Busse WW; Donohue JF; Garfinkel S; Lystig T; Manuel RC; Schlenker-Herceg R; Wise RA
    Title:
    Comparison of ipratropium bromide and albuterol sulfate chlorofluorocarbon metered-dose inhaler and albuterol hydrofluoroalkane metered-dose inhaler in crossover trial in patients with moderate-to-serve asthma.
    Source:
    J Allergy Clin Immunol 127 (2) (Supp.[S]), AB83 (2011)
  • Author:
    Dieterich D; Asselah T; Guyader D; Berg Th; Biermer M; Ceausu E; Preotescu L; Schuchmann M; Mauss St; Ratsiu V; Ferenci P; Larrey DG; Maieron A; Stern JO; Scherer J; Kubiak R; Boecher WO
    Title:
    SILEN-C3: treatment for 12 and 24 weeks with BI201335 combined with peginterferon alfa-2a and ribavirin (P/R) in treatment naive patients with chronic genotype-1 HCV infection.
    Source:
    Hepatology 54 (Supp.[1]), 378a (2011)
  • Author:
    Sulkowski MS; Asselah T; Ferenci P; Stern JO; Scherer J; Kukolj G; Boecher WO
    Title:
    Treatment with the second generation HCV protease inhibitor BI201355 results in high and consistent SVR rates - results from SILEN-C1 in treatment-naive patients across different baseline factors.
    Source:
    Hepatology 54 (Supp.[1]), 473A (2011)
  • Author:
    Zeuzem St; Asselah T; Angus PW; Zarski J-PH; Larrey DG; Mullhaupt B; Gane EJ; Schuchmann M; Lohse AW; Pol St; Moussalli J; Bronowicki J-P; Roberts SK; Arasteg K; Zoulim F; Stern JO; Mensa FJ; Nehmiz G; Haefner C; Boecher WO
    Title:
    High sustained virologic response following interferon-free treatment of chronic HCV GT1 infection for 4 weeks with HCV protease inhibitor BI201335, polymerase inhibitor BI207127 and ribavirin, followed by BI201335 and pegifn/ribavirin - the sound-C1 study.
    Source:
    Hepatology 54 (Suppl.[1), 486A-487A (2011)
  • Author:
    Diener HC; Peil H; Aicher B
    Title:
    The effiacy and tolerability of a fixed combination of acetylsalicylic acid, paracetamol and caffeine in patients with severe headache: A post-hoc subgroup analysis from a multicentre, randomized, double-blind, single-dose, placebo-controlled parallel group study.
    Source:
    Cephalalgia 31 (14), 1466-1476 (2011)
  • Author:
    Owens DR; Swallow R; Dugi KA; Woerle HJ
    Title:
    Efficacy and safety of linagliptin in persons with type 2 diabetes inadequately controlled by a combination of metformin and sulphonylurea: a 24-week randomized study(1).
    Source:
    Diabetic Med 28 (11), 1352-1361 (2011)
  • Author:
    Lehr Th; Yuan J; Hall D; Zimdahl-Gelling H; Schaerfer HG; Staab A; Macgregor ThR; Jayadev S
    Title:
    Integration of absorption, distribution, metabolism and elimination genotyping data into a population pharmacokinetic analysis of nevirapine.
    Source:
    Pharmacogenet Genomics 21 (11), 721-730 (2011)
    Abstract:
    OBJECTIVES: The aim of this analysis was to show the applicability of a newly developed algorithm to assess the influence of genetic variants and other covariates on nevirapineg€™s drug disposition. The algorithm combines high-throughput genotyping data and nonlinear mixed effects modeling methods. METHODS: Patients, who participated in the 2NN pharmacokinetic sub study, were reconsented and reenrolled into a clinical trial for genotyping analysis. Overall, 198 single nucleotide polymorphisms located in 45 absorption, distribution, metabolism, and elimination related genes were genotyped using the Illumina BeadArray technology. Data analysis was performed using NONMEM VI and SAS 9.1.3. RESULTS: Overall, 1260 nevirapine plasma concentrations were obtained from 271 genotyped patients. Plasma concentrationg^'time profiles of nevirapine were best described by a one-compartment model with auto-induced first-order elimination process. Nevirapine clearance was 19.4% reduced in Asian/Black patients, compared with Caucasian/Hispanic patients. For single nucleotide polymorphism rs3745274 (CYP2B6 516G>T) heterozygous patients (GT) showed a 15.3% reduced clearance; patients with homozygous CYP2B6 516TT alleles showed a 30.6% reduced clearance compared to patients with homozygous 516GG alleles. Patients carrying the homozygote genotype of rs12768009 (CYP2C19 8403AA), highly linked to rs4244285 (CYP2C19*2), showed a 26.8% reduced clearance compared with patients with CYP2C19 8403 AG and GG alleles. CONCLUSION: By integration of high-throughput genotyping data into a pharmacometric analysis of nevirapine, the impact of the CYP2B6 516G>T polymorphism on nevirapineg€™s exposure was confirmed and quantified. In addition, a new hypothesis with regard to CYP2C19 involvement in nevirapine metabolism has been generated. The analysis presented might help to optimize and individualize the therapy for patients treated with nevirapine to add to their therapeutic benefit.
  • Author:
    Kesten St; Celli B; Decramer M; Liu D; Tashkin D
    Title:
    Adverse helth consequences in COPD patients with rapid decline in FEV1 - evidence from the UPLIFT trial.
    Source:
    Respir Res 12, 129 (2011)
  • Author:
    Ledermann JA; Hackshaw A; Kaye S; Jayson G; Gabra H; McNeish I; Earl H; Perren T; Gore M; Persic M; Adams M; James L; Temple G; Merger M; Rustin G
    Title:
    Randomized phase II placebo-controlled trial of maintenance therapy using the oral triple angiokinase inhibitor BIBF 1120 after chemotherapy for relapsed ovarian cancer
    Source:
    J Clin Oncol 29 (28), 3798-3804 (2011)
    Abstract:
    Purpose: Inhibiting angiogenesis is one of the most promising avenues for new therapies for ovarian cancer. We investigated the efficacy and safety of a novel agent, BIBF 1120, a triple angiokinase inhibitor, after chemotherapy for relapsed disease. Patients and Methods: We conducted a randomized, double-blind, controlled phase II trial in 83 patients who had just completed chemotherapy for relapsed ovarian cancer, with evidence of response, but at high risk of further early recurrence. The patients were randomly assigned to receive maintenance therapy using BIBF 1120 250 mg or placebo, twice per day, continuously for 36 weeks. End points were progression-free survival (PFS), toxicity, and overall survival. Results: Thirty-six-week PFS rates were 16.3% and 5.0% in the BIBF 1120 and placebo groups, respectively (hazard ratio, 0.65; 95% CI, 0.42 to 1.02; P =.06). Four patients continued on BIBF 1120, including two patients for another year or more. The proportion of patients with any grade 3 or 4 adverse events was similar between the groups (34.9% for BIBF 1120 v 27.5% for placebo; P =.49; mostly grade 3). However, more patients on BIBF 1120 experienced diarrhea, nausea, or vomiting (mainly grade 1 or 2 and no grade 4). There was a higher rate of grade 3 or 4 hepatotoxicity in patients on BIBF 1120 (51.2%) compared with patients on placebo (7.5%; P < .001), but this was rarely of clinical significance, and patients continued with the trial treatment. A single-level dose reduction to 150 mg was made in 15 patients, all on active drug. Conclusion: BIBF 1120 is well tolerated and associated with a potential improvement in PFS. The observed treatment effect is sufficient to justify further study within a large phase III trial.
  • Author:
    Dahl OE; Kurth AA; Rosencher N; Noack H; Clemens A; Eriksson BI
    Title:
    Thromboprophylaxis with dabigatran etexilate in patients over seventy-five years of age with moderate renal impairment undergoing or knee replacement.
    Source:
    Int Orthop 36 (4), 741-748 (2012)
    Abstract:
    Purpose: Prospective, double-blind studies in orthopaedic patients have been conducted using the direct thrombin inhibitor dabigatran etexilate (hereafter referred to as dabigatran), with two doses investigated and approved for adults (220 mg and 150 mg once daily) to prevent venous thromboembolism (VTE). The European Medicines Agency decided that in major joint orthopaedic surgery, the lower dose should be used in elderly patients (aged over 75 years) and those with reduced renal function (creatinine clearance between 30 and 50 ml/min). Our objective was to understand the efficacy and bleeding data for the lower dose in this subpopulation. Methods: We extracted and analysed data from the elderly or from moderately renally impaired patients (n 632 of = 5,539) from the orthopaedic clinical development programme of dabigatran. Results: Dabigatran 150 mg once daily was as effective as the standard European enoxaparin regimen, with numerically fewer major bleeding events. Rates of major VTE were 4.3% vs 6.4% of patients, respectively. Major bleeding events occurred in four (1.3%) vs 11 (3.3%), which shows a trend towards lower bleeding with dabigatran 150 mg [odds ratio (OR) 0.40; 95% confidence interval (CI) 0.13-1.25; p = 0.110]. Mean volume of blood loss was 395 vs 417 ml, and transfused units were 2.4 vs 2.5, respectively. Other safety parameters, including the incidence of wound infections and complications, were similar for 150 mg once daily dabigatran and enoxaparin. Conclusion: For patients at higher risk of bleeding, dabigatran 150 mg once daily is as effective as enoxaparin following major orthopaedic surgery and is associated with a favourable bleeding rate.
  • Author:
    Stopfer P; Marzin K; Narjes H; Gansser D; Shahidi M; Uttenreuther-Fischer M; Ebner T
    Title:
    Afatinib pharmacokinetics and metabolism after oral administration to healthy male volunteers.
    Source:
    Cancer Chemother Pharmacol 69 (4), 1051-1061 (2012)
    Abstract:
    Purpose: To investigate the pharmacokinetics, metabolism and tolerability of afatinib (BIBW 2992), an oral irreversible ErbB family blocker, in healthy male volunteers. Methods: In this open-label, single-center study, 8 healthy male volunteers received a single oral dose of 15 mg [14C]-radiolabeled afatinib (equivalent to 22.2 mg of the dimaleinate salt) as a solution. Blood, urine and fecal samples were collected for at least 96 hours (h) after dosing. Plasma and urine concentrations of afatinib were analyzed using high-performance liquid chromatography-tandem mass spectrometry. [14C]-radioactivity levels in plasma, whole blood, urine and feces were measured by liquid scintillation counting methods. Metabolite patterns were assessed by high-performance liquid chromatography. Results: [14C]-radioactivity was mainly excreted via feces (85.4%). Overall recovery of [14C]-radioactivity was 89.5%, indicative of a complete mass balance. Afatinib was slowly absorbed, with maximum plasma concentrations achieved at a median of 6 h after dosing, declining thereafter in a biexponential manner. The geometric mean terminal half-life of afatinib was 33.9 h in plasma and longer for [14C]-radioactivity in plasma and whole blood. Apparent total body clearance for afatinib was high (geometric mean 1,530 mL/min). The high volume of distribution (4,500 L) in plasma may indicate a high tissue distribution. Afatinib was metabolized to only a minor extent, with the main metabolite afatinib covalently bound to plasma proteins. Oxidative metabolism mediated via cytochrome P-450 was of negligible importance for the elimination of afatinib. Afatinib was well tolerated. Conclusions: Afatinib displayed a complete mass balance with the main route of excretion via feces. Afatinib undergoes minimal metabolism.
  • Author:
    Redon J; Mancia G; Sleight P; Schumacher H; Gao P; Pogue J; Fagard R; Verdecchia P; Weber M; Boehm M; Williams B; Yusoff K; Teo K; Yusuf S
    Title:
    Safety and efficacy of low blood pressures among patients with diabetes. Subgroup analyses from the ontarget (ongoing telmisartan alone and in combination with ramipril global trial endpoint).
    Source:
    J Am Coll Cardiol 59 (1), 74-83 (2012)
    Abstract:
    We sought to determine whether the blood pressure (BP) levels at which cardiovascular (CV) protection is achieved differ between diabetic and nondiabetic patients from the ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial). Greater absolute benefits of BP reductions have been claimed for diabetic as compared with nondiabetic patients. A total of 25,584 patients (9,603 diabetic), older than 55 years, at high CV risk were randomized to ramipril, telmisartan, or both and observed for 4.6 years. We pooled the treatment arms to examine the relationships between BP and the primary composite outcome (CV death, nonfatal myocardial infarction or stroke, or hospitalized heart failure) and its components. The primary outcome occurred in 1,938 (20.2%) diabetic patients and in 2,276 (14.2%) nondiabetic patients. Compared with nondiabetic patients, diabetic patients had a significantly higher risk for the primary endpoint (hazard ratio [HR]: 1.48; 95% confidence interval [CI]: 1.38 to 1.57) and CV death (HR: 1.56; 95% CI: 1.42 to 1.71); myocardial infarction (HR: 1.30 (95% CI: 1.17 to 1.46); stroke (HR: 1.39; 95% CI: 1.23 to 1.56); and congestive heart failure hospitalization (HR: 2.06; 95% CI: 1.82 to 2.32). The CV risk was significantly higher in diabetic than in nondiabetic patients regardless of the systolic BP changes during treatment. In both diabetic and nondiabetic patients, progressively greater systolic BP reductions were accompanied by reduced risk for the primary outcome only if baseline systolic BP levels ranged from 143 to 155 mm Hg; except for stroke, there was no benefit in fatal or nonfatal CV outcomes by reducing systolic BP below 130 mm Hg. The relationship between BP and overall CV risk had a similar pattern in diabetic and nondiabetic patients over a wide range of baseline and in-treatment BP values although, for the same systolic BP, a higher risk is observed in diabetic patients. (Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial [ONTARGET]; NCT00153101)
  • Author:
    Elgadi MM; Piliero PJ
    Title:
    Boosted tipranavir versus darunavir in treatment-experienced patients: Observational data from the randomized potent trial.
    Source:
    Drugs Res Dev 11 (4), 295-302 (2011)
    Abstract:
    tipranavir/ritonavir (TPV/r) to darunavir/ritonavir (DRV/r), each with an optimized background regimen (OBR) in triple-class experienced HIV-1-infected patients with resistance to more than one protease inhibitor (PI). MethodologyPrincipal Findings: POTENT was a prospective, open-label study of triple-class (PI, non-nucleoside reverse transcriptase inhibitors [NNRTI], nucleoside reverse transcriptase inhibitors [NRTI]), treatment-experienced, HIV-positive patients. Subjects were randomized to either TPV/r (500/200 mg twice daily) or DRV/r (600/100 mg twice daily) on a genotype-guided, investigator-selected OBR. CD4+ counts and HIV viral loads were assayed at key timepoints. The primary endpoint was time to virologic failure (viral load .gtoreq.500copies/mL). POTENT was prematurely terminated due to slow enrollment. Thirty-nine patients were treated with either TPV/r (n = 19) or DRV/r (n = 20); 82% were male, 77% White, with mean age of 43.6 years. Mean baseline HIV RNA was 3.9 log(10) copies/mL. Median prior antiretrovirals was 11, with no prior raltegravir or maraviroc exposure. Raltegravir was the most common novel class agent in the OBRs (n = 14 TPV/r; n = 12 DRV/r). In both groups, patients achieved mean viral load decreases .gtoreq.2 log(10) copies/mL by week 8, and by week 12 mean CD4+ counts rose by 40-50 cells/mm3. Total observation time was 32 weeks. Drug-related adverse events were reported in 21% (TPV/r) and 25% (DRV/r) of patients. ConclusionsSignificance: TPV/r- and DRV/r-based regimens showed similar short-term safety and efficacy. These data support the use of next-generation PIs such as tipranavir or darunavir with novel class antiretroviral agents (integrase inhibitors, CCR5 antagonists, or fusion inhibitors). Trial Registration: Clinicaltrials.gov NCT00517192. .COPYRGT. 2011 Elgadi & Piliero, publisher and licensee Adis Data Information BV. This is an open access article published under the terms of the Creative Commons License "Attribution-NonCommercial-NoDerivative 3.0" (http://creativecommons.org/licenses/by-nc-nd/3.0/) which permits non-commercial use, distribution, and reproduction, provided the original work is properly cited and not altered.
  • Author:
    DeJesus E; Mills A; Bhatti L; Conner C; Storfer S
    Title:
    A randomised comparison of safety and efficacy of nevirapine vs. atazanavir/ritonavir combined with tenofovir/emtricitabine in treatment-naive patients.
    Source:
    Int J Clin Pract 65 (12), 1240-1249 (2011)
    Abstract:
    ABSTRACT: Background: We report data from NEWART, a randomised phase 4 clinical trial comparing virologic efficacy and safety of nevirapine (NVP) vs. ritonavir-boosted atazanavir (ATV/r) on a background of tenofovir/emtricitabine (TDF/FTC) in HIV-1-infected treatment-naive patients. This study enrolled patients according to CD4-based initiation criteria for NVP (<250 cells/mm3 for women and <400 cells/mm3 for men), to reduce the likelihood of symptomatic hepatic events. NEWART was designed to support and confirm results from ARTEN, an international trial with similar design and study endpoints. Methods: A total of 152 patients were randomised 1 : 1 to open-label NVP 200 mg twice daily or ATV/r (300/100 mg) once daily, plus once daily TDF/FTC (300/200 mg). All participants met CD4(+) guidelines at entry. The primary endpoint for non-inferiority was virologic response prior to and at week 48 (confirmed HIV plasma viral load <50 copies/ml, without rebound or change in ARVs). Safety data, including plasma lipids, were recorded throughout the study. Results: The primary endpoint was achieved in 46/75 (61.3%) and 50/77 (64.9%) of patients taking NVP and ATV/r, respectively. Frequency of adverse events (AEs) was similar between arms, with 88.0% of NVP-treated patients and 94.8% of ATV/r-treated patients experiencing at least one AE. Nine patients (12%) in each arm experienced an AE that led to discontinuation. At week 48, a significantly greater increase was seen in mean plasma HDL cholesterol (HDL-C) in the NVP arm (9.6 mg/dl) vs. the ATV/r arm (3.5 mg/dl); p = 0.016. Also, total cholesterol (TC): HDL-C ratio on-treatment was -0.38 and -0.02 for the NVP and ATV/r arms, respectively (p = 0.038). Conclusions: Efficacy results were consistent with the ARTEN study demonstrating that NVP was non-inferior to ATV/r when taken in combination with TDF/FTC. Rates of AEs were similar between the two arms, whereas HDL-C increased and TC: HDL-C decreased significantly more in patients taking NVP than ATV/r.
  • Author:
    Barzilay JI; Gao P; Ryden L; Schumacher H; Probstfield J; Commerford P; Dans A; Ferreira R; Keltai M; Paolasso E; Yusuf S; Teo K
    Title:
    Effects of telmisartan on glucose levels in people at high risk for cardiovascular disease but free from diabetes the transcend study.
    Source:
    Diabetes Care 34 (9), 1902-1907 (2011)
    Abstract:
    OBJECTIVE-Several large clinical trials suggest that ACE inhibitors may reduce the incidence of diabetes. Less is known about the effects of angiotensin receptor blockers (ARBs) on reducing incident diabetes or leading to regression of impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) to normoglycemia. RESEARCH DESIGN AND METHODS-Participants were 3,488 adults at high risk for cardiovascular disease but free from diabetes (mean age 67 years; 61% male) in the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease (TRANSCEND) study. The participants were randomized to the ARB telmisartan 80 mg (n = 1,726) or placebo (n = 1,762) in addition to usual care. RESULTS-During a median 56 months, 21.8% of participants treated with telmisartan and 22.4% of those on placebo developed diabetes (relative ratio 0.95 [95% CI 0.83-1.10]; P = 0.51). Participants originally diagnosed with IFG and/or IGT were equally likely to regress to normoglycemia (26.9 vs. 24.5%) or to progress to incident diabetes (20.1 vs. 21.1%; P = 0.59) on telmisartan or placebo. CONCLUSIONS-There was no evidence that addition of the ARB telmisartan to usual care prevents incident diabetes or leads to regression of IFG or IGT in people at high risk for cardiovascular disease but free from diabetes.
  • Author:
    Battegay M; Arasteh K; Plettenberg A; Bogner JR; Livrozet JM; Witt MD; Mossdorf E; Yong C-L; Zhang W; Macha S; Berger F; Stern J; Robinson P; Quinson A-M
    Title:
    Bioavailability of extended-release nevirapine 400 and 300 mg in HIV-1: A multicenter, open-label study.
    Source:
    Clin Ther 33 (9), 1308-1320 (2011)
    Abstract:
    Background: Nevirapine (NVP) is a widely used non-nucleoside reverse transcriptase inhibitor. A once-daily extended-release (XR) formulation would potentially increase adherence and thus efficacy. Objective: The aim of this study was to investigate the steady-state bioavailability of 2 once-daily tablet formulations of NVP XR (containing 25% or 20% hypromellose; NVP XR25 and NVP XR20, respectively) in 400- or 300-mg tablets compared with twice-daily immediate-release (IR) NVP 200-mg tablets. Methods: This Phase Ib multinational, multicenter, open-label trial was conducted in patients aged 18 to 60 years, infected with HIV-1 (viral load, ?50 copies/mL), and treated for ?12 weeks with twice-daily NVP IR 200 mg. Patients were switched to NVP XR25 400 or 300 mg or NVP XR20 400 or 300 mg for 19 days. Plasma samples were collected over 24-hour periods at steady state. Primary end points were AUC0-24,ss, Cmax,ss, and Cmin,ss, analyzed using an ANOVA statistical model on the logarithmic scale and 2-sided 90% CI. Sample size was determined assuming an intrasubject %CV of 20% for Cmax. Adverse events (AEs) and viral loads were monitored. Results: Ninety-two patients were enrolled (NVP XR25 400 mg, 24 patients; NVP XR20 400 mg, 24; NVP XR25 300 mg, 21; NVP XR20 300 mg, 23). Compared with NVP IR, the AUC0-24,ss values of the NVP XR formulations were lower (test/reference ratios: 79.5% [90% CI, 73.0-86.7; P = 0.544], 71.0% [90% CI, 63.3-79.7; P = 0.956], 90.3% [90% CI, 80.4-101.4; P = 0.044], and 83.7% [90% CI, 77.9-89.9; P = 0.148] with NVP XR25 400 mg, NVP XR20 400 mg, NVP XR25 300 mg, and NVP XR20 300 mg, respectively). The relative bioavailability of NVP XR25 was greater compared with that of NVP XR20. Cmax,ss values were lower with all NVP XR formulations compared with NVP IR. For Cmin,ss, NVP XR25 400 and 300 mg were not significantly different from NVP IR, with 90% CIs within the range of 80% to 125% (P = 0.039 and P = 0.017, respectively). All AEs were mild or moderate, with no significant differences between treatment groups. No virologic failures (viral load, &gt;50 copies/mL over 2 consecutive readings) were observed. Conclusions: Extent of bioavailability was lower and tmax,ss was delayed with all NVP XR formulations compared with NVP IR. The bioavailability of the NVP XR25 formulations was greater than that of the NVP XR20 formulations. Cmin,ss with NVP XR25 was similar to that with NVP IR. All of the NVP XR formulations were well tolerated. The 400-mg NVP XR25 formulation was selected for further development.
  • Author:
    Brecht St; Desaiah D; Marechal ES; Santini AM; Podhorna J; Guelfi JD
    Title:
    Efficacy and safety of duloxetine 60 mg and 120 mg daily in patients hospitalized for serve depression: a double-blind randomized trial.
    Source:
    J Clin Psychiatry 72 (8), 1086-1094 (2011)
    Abstract:
    OBJECTIVE: To assess whether hospitalized patients with severe depression and potential suicidal ideation/behavior have earlier and better response to duloxetine 120 mg daily than 60 mg daily. METHOD: Adults from 34 sites in 4 countries with severe major depressive disorder, defined by DSM-IV criteria, who were demonstrating Montgomery-Asberg Depression Rating Scale (MADRS) scores .gtoreq. 30, 6-item Hamilton Depression Rating Scale (HDRS-6) scores .gtoreq. 12, and Clinical Global Impressions-Severity of Illness scale (CGI-S) .gtoreq. 4 and hospitalized .gtoreq. 2 weeks underwent double-blind treatment with either duloxetine 60 mg (n = 167) or 120 mg (n = 171) daily for 8 weeks. Patients treated with 60 mg/d who did not respond had their doses titrated up to 120 mg/d. Primary outcome was the difference in baseline to week 4 change in MADRS scores between the groups. Secondary outcomes were baseline to week 8 changes in MADRS and HDRS-6 scores, response and remission, CGI-S scores, CGI-Improvement scores, Patient Global Impressions-Improvement, Hamilton Anxiety Rating Scale scores, and Reasons For Living inventory results. Safety was also assessed. The study was conducted between February 9, 2007, and August 26, 2008. RESULTS: There was no significant difference in mean baseline to week 4 MADRS score change between the 60-mg (-20.1) and 120-mg (-19.9) groups (P = .88). At week 4, 96/166 (60 mg) and 106/170 (120 mg) patients responded and maintained responses at week 8 by further decreasing mean MADRS scores to 5.8 (60 mg) and 5.6 (120 mg). At week 8, 226/336 (67.3%) patients achieved remission, with no difference demonstrated between groups. Most secondary efficacy measures were significantly reduced from baseline to week 8 within each group and did not differ between groups. Treatment-emergent adverse events observed with > 10% frequency in both groups were headache and nausea. CONCLUSIONS: Duloxetine 60-mg and 120-mg doses were equally effective and demonstrated no significant differences in treating severe depressive symptoms in hospitalized patients. The safety and tolerability profile of duloxetine in both dosages did not differ and was similar to those reported in previous duloxetine studies.
  • Author:
    Girman CJ; Ibia E; Menjoge S; Mak C; Chen J; Binkowitz B; Agarwal A
    Title:
    Impact of different regulatory requirements for trial endpoints in multiregional clinical trials.
    Source:
    Drug Inf J 45 (5), 587-594 (2011)
    Abstract:
    Regulatory agencies in different parts of the world may have different requirements for endpoints, which significantly affects the design and conduct of registrational multiregional clinical trials (MRCT). In particular, different health authorities may request or require different endpoints as primary or key secondary hypotheses in phase 3 MRCTs. In addition, differences between regions may involve the time point considered primary, patient populations analyzed, study design, or noninferiority margins. No guidance exists on how pharmaceutical companies should handle such regional differences, and harmonized guidance across regions would be useful. Initial steps in any global program should involve attempts to reach consistency in an MRCT. We review scenarios involving different health authority requirements for endpoints and other study design features and recommend approaches to handling differing health authority requirements within a global program, when a consistent global approach is not acceptable to all regulatory authorities.
  • Author:
    Menjoge Sh; Chen J; Quan H; Gallo P; Luo X; Tanaka Y; Li G; Ouyang SP; Binkowitz B; Ibia E; Talerico St; Ikeda K
    Title:
    Consistency of treatment effect across regions and multiregional clinical trials. Part 1: Design considerations
    Source:
    Drug Inf J 45 (5), 595-602 (2011)
    Abstract:
    Assessment of consistency of treatment effect across regions is often a key issue in a multiregional clinical trial (MRCT) because of differences in intrinsic and extrinsic factors. Careful consideration of consistency assessment of treatment effect across regions is necessary at the design stage. This article is part 1 of a cross-industry PhRMA team's effort to provide perspective and recommendations on the issue of regional consistency, with primary focus on design considerations. We argue that given the premise of an MRCT that there is no or limited regional variation, choices of appropriate consistency criteria for assessing regional consistency need to reflect this a priori belief and should not add an additional burden of proving regional consistency in addition to meeting the primary study objectives. The total sample size of the MRCT should be mainly driven by the primary objectives and hypotheses. Appropriate sample size partitioning and distribution across regions may be considered to achieve a target "assurance probability" based upon predefined consistency criteria such as modified PMDA (Pharmaceutical and Medical Devices Agency) methods. Prespecification and documentation of the plan for regional assessment in the protocol are important for interpreting the results. We also encourage communication with health authorities, and acknowledge negotiation may be necessary to reach an agreement, especially when there are region or country-specific interests.
  • Author:
    Tanaka Y; Gallo P; Chen J; Quan H; Menjoge S; Luo X; Li G; Ouyang SP; Binkowitz B; Ibia E; Talerico S; Ikeda K
    Title:
    Consistency of treatment effect across regions in multiregional clinical trials, Part 2: Monitoring, reporting and interpretation.
    Source:
    Drug Inf J 45 (5), 603-608 (2011)
    Abstract:
    The degree of consistency of treatment effects seen across regions within a multiregional clinical trial has important implications for all stakeholders. It can affect the ability of the trial results to be interpreted by the scientific community in an unambiguous manner and can have important ramifications for regulatory decision making. This article is part of a PhRMA team's effort to provide perspective and recommendations on this issue. A companion article from the same team focuses on relevant design considerations, while in this article the focus is on monitoring considerations specific to multiregional trials, on how the final trial results should be presented, and on thought processes that are relevant to how signals of inconsistency should be investigated and interpreted.
  • Author:
    Carroll KJ
    Title:
    Japanese guideline on global clinical trials: Statistical implications and alternative criteria for assessing consistency.
    Source:
    Drug Inf J 45 (5), 657-667 (2011)
    Abstract:
    The Japanese regulatory guideline "Basic Principles in Global Clinical Trials," issued in September 2007, serves to encourage the participation of Japan in international phase 3 clinical trials and, as such, is my much welcome, helping to avoid repeat, stand-alone trials in Japanese patients that are often underpowered. However, the guideline raises a concern regarding the consistency of outcomes in the subset of Japanese patients and the total trial population and offers two alternative criteria to determine the fraction of Japanese patients that should be recruited. The first criterion requires that sufficient Japanese patients are entered such that, if the treatment effects in the Japanese and overall populations are truly the same, there is an 80% chance that the effect in Japanese patients will be shown to be at least half of the effect in the total trial population. The second criterion requires that sufficient patients be entered per geographical region included in the trial such that, if there is a true effect in the overall population, the probability that each region (including Japan) will also show a positive effect is 80%. The purpose of this article is to explore the implications of these criteria in terms of overall power and the fraction of the Japanese patients that need to be recruited to satisfy them and to consider some potential alternative criteria that might offer advantages over those stated in the guideline.
  • Author:
    Poewe W; Rascokl O; Barone P; Hauser RA; Mizuno Y; Haaksma M; Salin L; Juhel N; Schapira AHV
    Title:
    Extended-release pramipexole in early Parkinson disease A 33-week randomized controlled trial.
    Source:
    Neurology 77 (8), 759-766 (2011)
    Abstract:
    Objective: To assess the clinical efficacy of a novel once-daily extended-release (ER) formulation of the dopamine agonist pramipexole as monotherapy in patients with early Parkinson disease (PD) and establish its noninferiority vs standard immediate-release (IR) pramipexole. Methods: This was a multicenter, double-blind, parallel study of patients with early PD not receiving levodopa or dopamine agonists, randomly assigned to pramipexole IR, pramipexole ER, or placebo. Seven-week flexible titration was followed by 26-week maintenance, with levodopa permitted as rescue medication. The primary analysis was to test pramipexole ER noninferiority to pramipexole IR based on a change in the Unified Parkinson's Disease Rating Scale (UPDRS) part II+III score at 33 weeks, with noninferiority predefined as a treatment group difference for which the lower bound of the 95% confidence interval (CI) did not exceed -3 points. Results: Among 213 ER and 207 IR recipients, the adjusted mean 33-week UPDRS II+III change (excluding levodopa rescue effects) was -8.2 for ER and -8.7 for IR, a difference of -0.5 with a 95% CI of -2.3 to 1.3. Compared with placebo (n = 103), pramipexole ER and pramipexole IR were significantly superior on UPDRS II+III score, all key secondary outcomes, and almost all other endpoints. On the 39-item Parkinson Disease Questionnaire, superiority of pramipexole ER failed to reach statistical significance. Both formulations were equally safe and well-tolerated. Conclusions: As monotherapy for early PD, pramipexole ER was noninferior to pramipexole IR and significantly more effective than placebo. Tolerability and safety did not differ between the formulations. - DERWENT Abstract - This phase 3, multicenter, double-blind, parallel, placebo-controlled, randomized study (NCT00479401) evaluated efficacy, safety and tolerability of new once-daily extended-release (ER) formulation of pramipexole (PX) as monotherapy in 539 patients with early Parkinson disease and established its non-inferiority vs. standard immediate release (IR) PX. Compared with placebo, PX ER and PX IR were superior on Unified Parkinson's Disease Rating Scale II + III score, all key secondary outcomes, and almost all other endpoints. On 39-item Parkinson Disease Questionnaire, superiority of PX ER failed to reach significance. Both formulations were equally safe and well-tolerated. Adverse events noted more frequently in PX were somnolence, nausea, constipation, dizziness and dry mouth. As monotherapy for early Parkinson disease, PX ER was non-inferior to PX IR and more effective than placebo. Methods 539 Patients with early Parkinson disease were randomly assigned in a 2:2:1 ratio to receive PX ER (0.375, 0.75, 1.5, 2.25, 3, 3.75, or 4.5 mg/day) (n=223, mean age 61.3 yr), PX IR (0.125, 0.25, 0.50, 0.75, 1, 1.25 or 1.5 mg t.i.d.) (n=213, mean age 61.7 yr) or matching placebo (n=103, mean age 62 yr) in a double-blind fashion. Results 98 Patients discontinued before completing 33 wk (11.7% in placebo, 22% in ER arm, and 17.4% in IR arm). At wk 33, 15/213 ER recipients and 9/207 IR recipients vs. 22/103 placebo recipients had received adjunct levodopa. The adjusted mean decrease in Unified Parkinson's Disease Rating Scale II + III score at 33 wk was -8.2 for ER and -8.7 for IR. Both PX formulations showed a significant difference from placebo on the adjusted mean changes in Unified Parkinson's Disease Rating Scale II + III score. Superiority of both formulations was also observed in all key secondary outcomes. The mean duration of exposure to study drug was 199 days for ER and 208.2 days for IR compared with 215.2 days for placebo. The final mean study medication dosage was 2.9 mg/day in PX ER group and 2.9 mg/day in PX IR group compared with 3.2 mg/day of matched placebo in placebo group. Overall, 88.3% of subjects in placebo, 78% of subjects in PX ER group and 82.6% in PX IR group completed the study. The percentages of patients with adverse events leading to discontinuation were 3.9% in placebo group, 10.8% in ER group and 9.4% in IR group. Adverse events reported more frequently in PX group than in placebo group were somnolence, nausea, constipation, dizziness and dry mouth. There were no reports of drug-induced dyskinesias or motor fluctuations.
  • Author:
    Schapira AHV; Barone P; Hauser RA; Mizuno Y; Rascol O; Busse M; Salin L; Juhel N; Poewe W
    Title:
    Extended-release pramipexole in advanced Parkinson disease a randomized controlled trial.
    Source:
    Neurology 77 (8), 767-774 (2011)
    Abstract:
    Background: In advanced Parkinson disease (PD), immediate-release pramipexole, taken 3 times daily, improves symptoms and quality of life. A once-daily extended-release formulation may be an effective and simple alternative therapy. Methods: For a multicenter randomized, double-blind, parallel trial of extended-and immediate-release pramipexole vs placebo, patients experiencing motor fluctuations while taking levodopa underwent flexible study drug titration and then maintenance at optimized dosage (0.375-4.5 mg/day). The primary endpoint was a change in the Unified Parkinson's Disease Rating Scale (UPDRS) part II+III score at 18 weeks, with further assessments at 33 weeks in a subset of patients. Adverse events were recorded throughout. Results: Among 507 patients in the 18-week analyses, UPDRS II+III scores decreased (from baseline means of 40.0-41.7) by an adjusted mean of -11.0 for extended-release pramipexole and -12.8 for immediate-release pramipexole vs -6.1 for placebo (p = 0.0001 and p < 0.0001) and off-time decreased (from baseline means of 5.8-6.0 hours/day) by an adjusted mean of -2.1 and -2.5 vs -1.4 hours/day (p = 0.0199 and p < 0.0001). Other outcomes were largely corroborative, including a significant improvement in early morning off symptoms. Among 249 pramipexole patients completing 33 weeks, UPDRS II+III and off-time findings showed <= 10.1% change from 18-week values. Both formulations were well-tolerated. Conclusions: Extended-release pramipexole significantly improved UPDRS score and off-time compared with placebo, with similar efficacy, tolerability, and safety of immediate-release pramipexole compared with placebo. Classification of evidence: This study provides Class I evidence that the extended-release form of pramipexole, taken once daily, is efficacious as an adjunct to levodopa in advanced PD. - DERWENT Abstract - This phase III, multicenter, randomized, placebo-controlled, double-blind, parallel study (NCT00466167) evaluated efficacy, safety and tolerability of extended-release (ER) pramipexole (PX, Sifrol, Mirapex, Mirapexin, Pexola, Boehr.Ingelheim) in 517 patients experiencing motor fluctuations with levodopa for advanced Parkinson disease, and compared it with immediate-release (IR) PX and placebo. Among 507/517 patients in efficacy analyses, UPDRS II + III score decreased for ER PX and IR PX vs. placebo. Other outcomes were largely corroborative, including improvement in early morning off symptoms. ER PX improved UPDRS II + III score and off-time compared with placebo, with similar efficacy, tolerability, and safety of IR PX compared with placebo. Adverse events noted were dyskinesia, somnolence, nausea, constipation, headache, hallucination, dizziness and vomiting. Methods 517 Patients experiencing motor fluctuations with levodopa for advanced Parkinson disease randomly received (in a 1:1: ratio) placebo (n=178, mean age 60.9 yr), ER PX (0.375, 0.75, 1.5, 2.25, 3, 3.75 or 4.5 mg once daily) (n=164, mean age 61.6 yr) and IR PX (0.125, 0.25, 0.50, 0.75, 1, 1.25 or 1.5 mg t.i.d.) (n=175, mean age 62 yr). Results Among them, 11.8% of placebo recipients, 11.6% of PX ER recipients and 6.9% of PX IR recipients discontinued before completing 18 wk, most often due to adverse events. Of 517 patients, 507 provided postbaseline data for the study's 18 wk efficacy analyses. In full-analysis set at 18 wk, the adjusted mean decrease in UPDRS II + III score was -11 for PX ER and -12.8 for PX IR vs. -6.1 for placebo. Off-time decreased by an adjusted mean -2.1 hr/day for PX ER and -2.5 hr/day for PX IR vs. -1.4 hr/day for placebo. Of 337 patients who completed the study up to 33 wk, 308 patients had an evaluable UPDRS II + III score, permitting descriptive evaluation of 33 wk mean change from baseline vs. 18 wk mean change from baseline with no use of last observation carried forward. Among all treated patients, the proportion reporting any adverse events while taking PX ER, as of wk 18, resembled the proportion for placebo (at 54.9% and 55.6%) and was lower than the proportion for PX IR (64%). The frequency of severe adverse events was similar in each PX group and the frequency of serious adverse events and adverse events leading to premature discontinuation was similar in all groups. Adverse events reported by the patients were dyskinesia, somnolence, nausea, constipation, headache, hallucination, dizziness, and vomiting.
  • Author:
    Horie Y; Kanada Sh; Watada H; Sarashina A; Taniguchi A; Hayashi N; Graefe-Mody EU; Woerle H-J; Dugi KA
    Title:
    Pharmacokinetic, pharmacodynamic and tolerability profiles of the dipeptidyl peptidase-4 inhibitor Linagliptin: A 4-week multicenter, randomized, double-blind, placebo-controlled phase IIa study in Japanese type 2 diabetes patients.
    Source:
    Clin Ther 33 (7), 973-989 (2011)
    Abstract:
    BACKGROUND: The dipeptidyl-peptidase-4 (DPP-4) inhibitor linagliptin is under clinical development for treatment of type 2 diabetes mellitus (T2DM). In previous studies in white populations it showed potential as a once-daily oral antidiabetic drug. OBJECTIVES: In compliance with regulatory requirements for new drugs intended for use in the Japanese population, this study investigated the pharmacokinetics, pharmacodynamics, and tolerability of multiple oral doses of linagliptin in Japanese patients with T2DM. METHODS: In this randomized, double-blind, placebo-controlled multiple dose study, 72 Japanese patients with T2DM were assigned to receive oral doses of linagliptin 0.5, 2.5, or 10 mg or placebo (1:1:1:1 ratio) once daily for 28 days. For analysis of pharmacokinetic properties, linagliptin concentrations were determined from plasma and urinary samples obtained throughout the treatment phase, with more intensive samplings on days 1 and 28. DPP-4 inhibition, glycosylated hemoglobin A1c (HbA(1c)) levels, and plasma glucose and glucagon-like peptide-1 (GLP-1) levels were compared by mixed effect model. Tolerability was assessed throughout the study by physical examination, including blood pressure and pulse rate measurements, 12-lead ECG, and laboratory analysis. RESULTS: Baseline demographic characteristics were well balanced across the 4 treatment groups (mean [SD] age, 59.7 [6.4] years in the placebo group, 60.8 [9.2] years in the 0.5 mg group, 60.2 [6.4] years in the 2.5 mg group, and 59.1 [8.6] years in the 10 mg group; mean [SD] weight, 67.2 [10.0] kg in the placebo group, 64.5 [9.0] kg in the 0.5 mg group, 69.6 [9.4] kg in the 2.5 mg group, and 63.5 [12.2] kg in the 10 mg group; mean [SD] duration of T2DM diagnosis, 5.1 [4.2] years in the placebo group, 5.2 [4.7] years in the 0.5 mg group, 5.9 [4.8] years in the 2.5 mg group, and 2.6 [2.3] years in the 10 mg group). The majority of the patients treated were male (76.4%). Use of previous antidiabetic medication was more common in the 2.5 mg linagliptin group (44%) than in the 0.5 or 10 mg linagliptin (15.8% and 22.2%, respectively) or placebo groups (35.3%). Total systemic exposure in terms of linagliptin AUC and C(max) (which occurred at 1.25-1.5 hours) increased in a less than dose-proportional manner. The terminal half-life was long (223-260 hours) but did not reflect the accumulation half-life (10.0-38.5 hours), resulting in a moderate accumulation ratio of <2.9 that decreased with increasing dose. Urinary excretion increased with linagliptin doses but was <7% at steady state for all dose groups. Inhibition of plasma DPP-4 at 24 hours after the last dose on day 28 was approximately 45.8%, 77.8%, and 89.7% after linagliptin 0.5, 2.5, and 10 mg, respectively. At steady state, linagliptin was associated with dose-dependent increases in plasma GLP-1 levels, and the postprandial GLP-1 response was enhanced. Statistically significant dose-dependent reductions were observed in fasting plasma glucose levels at day 29 for all linagliptin groups (-11.5, -13.6, and -25.0 mg/dL for the 0.5, 2.5, and 10 mg groups, respectively; P < 0.05 for all linagliptin groups). Linagliptin also produced statistically significant dose-dependent reductions from baseline for glucose area under the effect curve over 3 hours after meal tolerance tests (-29.0 to -68.1 mg .times. h/dL; P < 0.05 for all 3 linagliptin groups). For the 0.5 and 10 mg linagliptin-treated groups, there were statistically significant reductions in HbA(1c) from baseline compared with placebo, despite the relatively low baseline HbA(1c) (7.2%) and small sample size (P < 0.01 for both groups). The greatest reduction in HbA(1c) (-0.44%) was seen in the highest linagliptin dose group (10 mg). On dosing for up to 28 days, linagliptin was well tolerated with no reported serious adverse events or symptoms suggestive of hypoglycemia. Overall, fewer adverse events were reported by patients after linagliptin than after placebo (11 of 55 [20%] vs 6 of 17 [35%]). CONCLUSIONS: Linagliptin demonstrated a nonlinear pharmacokinetic profile in these Japanese patients with T2DM consistent with the findings of previous studies in healthy Japanese and white patients. Linagliptin treatment resulted in statistically significant and clinically relevant reductions in HbA(1c) as soon as 4 weeks after starting therapy in these Japanese patients with T2DM, suggesting that clinical studies of longer duration in Japanese T2DM patients are warranted. - DERWENT Abstract - This multicenter, randomized, double-blind, placebo-controlled, phase IIa study examined the pharmacokinetic, pharmacodynamic, and tolerability profiles of the dipeptidyl peptidase-4 (DPP-4) inhibitor p.o. linagliptin (LIN) in 72 Japanese patients with type 2 diabetes. Total systemic exposure in terms of AUC and Cmax increased in a less than dose-proportional manner. The terminal half-life was long but did not reflect the accumulation half-life. LIN dose-dependently inhibited DPP-4, increased plasma glucagon-like peptide (GLP)-1 levels, decreased glucose AUC over 3 hr after meal tolerance tests, and decreased HbA1c. LIN was well tolerated. These findings suggest that LIN has a nonlinear pharmacokinetic profile in these patients. 72 Japanese patients with type 2 diabetes randomly received p.o. LIN (0.5, 2.5, or 10.0 mg/day) (n=19, 18, and 18, mean age 60.8, 60.2, and 59.1 yr, 15, 14, and 13 male, respectively) or placebo (17, mean age 59.7 yr, 13 male) for 28 days. LIN was rapidly absorbed in all patients, with a Tmax of 1.5 hr across doses. A less than proportional increase of LIN Cmax was seen between 0.5 and 2.5 mg, while a dose-proportional increase of Cmax was seen between 2.5 and 10.0 mg. The total exposure on day 1 of LIN increased dose-dependently, but less than dose proportionally from 0.5 to 2.5 mg and from 2.5 to 10.0 mg. In the statistical analysis for dose proportionally using a power model for the pharmacokinetic parameters AUC after the 1st dose, AUC at steady-state, Cmax after the 1st dose, and Cmax at steady-state of LIN, none of these parameters showed dose proportionality. LIN oral clearance at steady-state and Vd increased with dose. The renal excretion of the parent compound appeared to be only a minor route of elimination. The terminal half-life was long (223-260 hr) but did not reflect the accumulation half-life (10.0-38.5 hr). LIN resulted in 45.8%, 77.8%, and 89.7% inhibition of plasma DPP-4 at 24 hr after the last dose on day 28. LIN dose-dependently decreased fasting plasma glucose at day 29, being -11.5, -13.6, and -25.0 mg/l for the 0.5, 2.5, and 10.0 mg groups, respectively. LIN dose-dependently decreased glucose AUC over 3 hr after meal tolerance tests (-29.0 to -68.1 mg x hr/dl). The greatest reduction in HbA1c was seen with LIN (10.0 mg) (-0.44%). LIN was well tolerated. Overall, fewer adverse events were seen with LIN than with placebo (20% vs. 35%).
  • Author:
    Kerstjens HAM; Disse B; Schroeder-Babo W; Bantje TA; Gahlemann M; Sigmund R; Engel M; van Noord JA
    Title:
    Tiotropium improves lung function in patients with severe uncontrolled asthma: A randomized controlled trial.
    Source:
    J Allergy Clin Immunol 128 (2), 308-314 (2011)
    Abstract:
    Background: Some patients with severe asthma remain symptomatic and obstructed despite maximal recommended treatment. Tiotropium, a long-acting inhaled anticholinergic agent, might be an effective bronchodilator in such patients. Objective: We sought to compare the efficacy and safety of 2 doses of tiotropium (5 and 10 ?g daily) administered through the Respimat inhaler with placebo as add-on therapy in patients with uncontrolled severe asthma (Asthma Control Questionnaire score, ?1.5; postbronchodilator FEV1, ?80% of predicted value) despite maintenance treatment with at least a high-dose inhaled corticosteroid plus a long-acting ?2-agonist. Methods: This was a randomized, double-blind, crossover study with three 8-week treatment periods. The primary end point was peak FEV1 at the end of each treatment period. Results: Of 107 randomized patients (54% female patients; mean, 55 years of age; postbronchodilator FEV1, 65% of predicted value), 100 completed all periods. Peak FEV1 was significantly higher with 5 ?g (difference, 139 mL; 95% CI, 96-181 mL) and 10 ?g (difference, 170 mL; 95% CI, 128-213 mL) of tiotropium than with placebo (both P &lt; .0001). There was no significant difference between the active doses. Trough FEV1 at the end of the dosing interval was higher with tiotropium (5 ?g: 86 mL [95% CI, 41-132 mL]; 10 ?g: 113 mL [95% CI, 67-159 mL]; both P &lt; .0004). Daily home peak expiratory flow measurements were higher with both tiotropium doses. There were no significant differences in asthma-related health status or symptoms. Adverse events were balanced across groups except for dry mouth, which was more common on 10 ?g of tiotropium. Conclusion: The addition of once-daily tiotropium to asthma treatment, including a high-dose inhaled corticosteroid plus a long-acting ?2-agonist, significantly improves lung function over 24 hours in patients with inadequately controlled, severe, persistent asthma. - DERWENT Abstract - This randomized, controlled study evaluated the efficacy and safety of inhaled tiotropium in 107 patients with uncontrolled severe asthma. Peak FEV1 was higher with 5 and 10 ug of tiotropium than with placebo. There was no difference between the active doses. Trough FEV1 at the end of the dosing interval was higher with tiotropium (5 ug). Daily home peak expiratory flow measurements were higher with both tiotropium doses. There were no differences in asthma-related health status or symptoms. Adverse events were balanced across groups except for dry mouth, which was more common on 10 ug tiotropium. Thus, the addition of once-daily tiotropium to asthma treatment improves lung function over 24 hr in patients with inadequately controlled, severe, persistent asthma.
  • Author:
    Reck M; Kaiser R; Eschbach C; Stefanic M; Love J; Gatzemeier U; Stopfer P; von Pawel J
    Title:
    A phase II double-blind study to investigate efficacy and safety of two doses of the triple angiokinase inhibitor BIBF 1120 in patients with relapsed advanced non-small-cell lung cancer.
    Source:
    Ann Oncol 22 (6), 1374-1381 (2011)
    Abstract:
    Background: To assess the efficacy, safety, tolerability and pharmacokinetics of BIBF 1120 in patients with stage IIIB/IV non-small-cell lung cancer (NSCLC). Methods: Patients with locally advanced or metastatic relapsed NSCLC in whom first- or second-line platinumbased chemotherapy failed were randomly allocated to daily 250 mg BIBF 1120 b.i.d. or 150 mg BIBF 1120 b.i.d. Primary end points were progression-free survival (PFS) and objective tumour response (RECIST). Incidence and severity of adverse events (AEs) were reported. Results: Seventy-three patients received BIBF 1120. Median PFS was 6.9 weeks, with no significant difference between treatment arms. Median overall survival (OS) was 21.9 weeks. Eastern Cooperative Oncology Group (ECOG) 0-1 patients (n = 56) had a median PFS of 11.6 weeks and a median OS of 37.7 weeks. Tumour stabilisation was achieved in 46% of patients (ECOG 0-1 patients: 59%), with one confirmed partial response (250 mg b.i.d.). Most commonly reported drug-related AEs were nausea (57.5%), diarrhoea (47.9%), vomiting (42.5%), anorexia (28.8%), abdominal pain (13.7%) and reversible alanine transaminase (13.7%) and aspartate aminotransferase elevations (9.6%). BIBF 1120 displayed dose-linear pharmacokinetic characteristics. Conclusion: Continuous treatment with BIBF 1120 was well tolerated, with no difference in efficacy between treatment arms. PFS and objective response with single-agent treatment in advanced disease warrants further exploration. - DERWENT ABstract - This phase II double-blind, randomized study assessed the efficacy, safety, tolerability and pharmacokinetics of BIBF 1120 in 73 patients with locally advanced or metastatic relapsed NSCLC whom failed 1st- or 2nd-line platinum-based chemotherapy. Median PFS was 6.9 wk. Median overall survival (OS) was 21.9 wk. Eastern Cooperative Oncology Group (ECOG) 0-1 patients had a median PFS of 11.6 wk, and a median OS of 37.7 wk. Tumor stabilization was achieved in 46% of patients with 1 confirmed PR. Most commonly reported drug-related adverse events were nausea, diarrhea, vomiting, anorexia, abdominal pain, and reversible ALT and AST elevations. Continuous treatment with BIBF 1120 is well tolerated, with no difference in efficacy between treatment arms, PFS and objective response with single-agent treatment in advanced disease warrants further exploration. Methods 73 Patients with locally advanced or metastatic relapsed NSCLC whom failed 1st- or 2nd-line platinum-based chemotherapy were randomized to receive BIBF 1120 at 250 mg b.i.d. (n = 36, 26 male, mean age 62.7 yr) or 150 mg b.i.d. (n = 37, 18 male, mean age 62.4 yr). Results Median PFS for all patients was 6.9 wk. Median OS for all patients was 21.9 wk. PFS was longer in patients with baseline ECOG 0-1 than in those with ECOG 2. Patients with ECOG 0-1 had a median OS of 37.7 wk. Tumor stabilization was achieved in 46% of all patients and 59% in patients with ECOG 0-1. 1 Confirmed PR was observed in patients treated with BIBF 1120 at 250 mg. 4 Patients achieved a maximum decrease of at least 25% in tumor size. Among patients with ECOG 0-1, both doses (150 and 250 mg) of BIBF 1120 had comparable efficacy with 16 and 17 patients in BIBF 1120 at 150 mg and 200 mg experiencing clinical benefit. Adverse events were nausea, diarrhea, vomiting, anorexia, abdominal pain, ALT and AST elevations, dyspnea, hemoptysis, pulmonary bleeding, gamma glutamyl transferase elevation, elevated hepatic enzymes, increased bilirubin, hemorrhage, fatigue, weight decrease, constipation, dysgeusia, and peripheral sensory neuropathy. Within the BIBF 1120 at 150 mg b.i.d. dose group, BIBF 1120 plasma levels increased, with geometric mean BIBF 1120 values of 12.3, 13.2, and 18.2 ng/ml at 1, 2 and 3 hr after drug administration. Within the BIBF 1120 at 150 mg b.i.d. dose group, BIBF 1120 plasma levels increased within the 1st 3 hr after the 1st drug administration, with geometric mean BIBF 1120 values of 18.4, 28.1, 27.8 ng/ml at 1, 2 and 3 hr after drug administration.
  • Author:
    Uchiyama S; Ikeda Y; Urano Y; Horie Y; Yamaguchi T
    Title:
    The Japanese aggrenox (extended-release dipyridamole plus aspirin) stroke prevention versus aspirin programme (JASAP) study: A randomized, double-blind, controlled trial.
    Source:
    Cerebrovasc Dis 31 (6), 601-613 (2011)
    Abstract:
    Background: Despite improvements in treatment, stroke still carries a high death toll and disability in Asia. Extended-release dipyridamole (ER-DP) plus acetylsalicylic acid (ASA) has consistently been shown to be superior over conventional platelet inhibition by ASA. ER-DP plus ASA is well established in the secondary prevention of stroke in a lot of countries including the USA and Europe. DP has an established benefit in the treatment of heart disease in Japan; however, for the prevention of stroke, the fixed-dose combination of ER-DP plus ASA has only been investigated in a small number of patients in Japan. Methods: The aim of this double-blind, randomized clinical trial was to investigate the efficacy and safety of ER-DP plus ASA versus 81 mg ASA over 1 year. The primary end point of this study was the event rate of recurrent ischemic stroke (fatal or nonfatal) using the Kaplan-Meier method and Cox regression analysis. Results: Of the 1,294 enrolled patients, the primary end point was analyzed in 652 patients in the ER-DP plus ASA group and 639 in the ASA group. The incidence of ischemic stroke was 6.9% for ER-DP plus ASA and 5.0% for ASA with a hazard ratio of 1.47 (95% confidence interval 0.93-2.31) for the primary end point. The ASA treatment group was found to have a lower than expected yearly event rate, compared to other studies in Japanese stroke patients. Noninferiority of ER-DP plus ASA versus ASA could not be shown. The risks of major bleeding events and intracranial hemorrhage were found to be similar between the treatment arms. There were 4 deaths (0.6%) in the ER-DP plus ASA group and 10 (1.6%) in the ASA group. Conclusions: The results of the study are inconclusive. Noninferiority of ER-DP plus ASA versus ASA could not be established, a difference between treatments could not be shown for the primary end point. Possible reasons for this result include a small sample size, low event rates and too short a treatment duration. - DERWENT Abstract - This Japanese Aggrenox (Extended-Release (ER) Dipyridamole (DP) + Aspirin) Stroke Prevention versus Aspirin Programme (JASAP), a phase III, randomized, double-blind, parallel-group, active, controlled comparative study evaluated the efficacy and safety of extended-release dipyridamole + aspirin vs. aspirin over 1 yr in 1294 patients with stroke. The incidence of ischemic stroke was 6.9% for extended-release dipyridamole + aspirin-and 5.0% for aspirin-treated patients with a hazard ratio of 1.47 for the primary end point. The aspirin treatment group was lower than expected yearly event rate. The risks of major bleeding events and intracranial hemorrhage were found to be similar between the treatment arms. Noninferiority of extended-release dipyridamole + aspirin vs. aspirin could not be established, a difference between treatments could not be shown for the primary end point. Methods 1294 Patients (925 male, mean age 66.1 yr) with stroke were treated with extended-release dipyridamole (200 mg b.i.d.) + aspirin (25 mg b.i.d.; both p.o.) or aspirin (81 mg/day). Results Recurrent ischemic stroke occurred in 45/652 patients in the extended-release dipyridamole + aspirin group, and in 32/639 patients in the aspirin group. Non-inferiority of extended-release dipyridamole + aspirin vs. aspirin was not shown. The event rate of stroke was significantly higher for extended-release dipyridamole + aspirin vs. aspirin. There was no significant difference between treatment groups for the other secondary end points (cerebral hemorrhage, subarachnoid hemorrhage, transient ischemic attack, acute coronary syndromes, other vascular events, ischemic vascular composite end point, and stroke). Higher modified Rankin Scale values and established end organ damage at baseline had a deleterious effect on the primary outcome, whereas the concomitant therapy with statins had a beneficial effect. There were 4 and 10 deaths in the extended-release dipyridamole + aspirin group in the aspirin group. Adverse events were nasopharyngitis, metabolism and nutrition disorders, headache, eye disorders, vascular disorders, respiratory, thoracic and mediastinal disorders, GI disorders, diarrhea, skin and subcutaneous tissue disorders, musculoskeletal and connective tissue disorders, injury, poisoning and procedural complications, fall, and ischemic stroke.
  • Author:
    Kurlan R; Crespi G; Koval S; Coffey B; Mueller-Vahl K; Wunderlich G
    Title:
    A multicenter randomized placebo-controlled clinical trial of pramipexole for tourette's syndrome.
    Source:
    Mov Disord 26 (5), II-III (2011)
    Abstract:
    Background: Dopamine agonists could theoretically normalize the suspected central dopamine hypersensitivity in Tourette's syndrome. Methods: There was a multicenter randomized, placebo-controlled, double-blind clinical trial of pramipexole given for 6 weeks in 63 children and adolescents with Tourette's syndrome. Results: There were no significant differences in the adjusted mean change in the Total Tic Score of the Yale Global Tic Severity Scale for patients treated with pramipexole (-7.16) and placebo (-7.17). There were no significant treatment effects on change from baseline in the Global Severity score of the Yale Scale and parent- and investigator-scored Clinical Global Impression of Improvement. In patients with attention deficit hyperactivity disorder, there was improvement in DuPaul ADHD scale scores for patients receiving pramipexole compared with placebo. Conclusions: There was no evidence that pramipexole has efficacy in suppressing tics. Pramipexole may decrease symptoms of associated attention deficit hyperactivity disorder.
  • Author:
    Gomis R; Espadero R-M; Jones R; Woerele H-J; Dugi KA
    Title:
    Efficacy and safety of initial combination therapy with linagliptin and pioglitazone in patients with inadequately controlled type 2 diabetes: A randomized, double-blind, placebo-controlled study.
    Source:
    Diabetes Obes Metab 13 (7), 653-661 (2011)
    Abstract:
    Aims: To compare the efficacy, safety and tolerability of linagliptin or placebo administered for 24 weeks in combination with pioglitazone in patients with type 2 diabetes mellitus (T2DM) exhibiting insufficient glycaemic control (HbA1c 7.5-11.0%). Methods: Patients were randomized to receive the initial combination of 30 mg pioglitazone plus 5 mg linagliptin (n = 259) or pioglitazone plus placebo (n = 130), all once daily. The primary endpoint was change from baseline in HbA1c after 24 weeks of treatment, adjusted for baseline HbA1c and prior antidiabetes medication. Results: After 24 weeks of treatment, the adjusted mean change (.+-.s.e.) in HbA1c with the initial combination of linagliptin plus pioglitazone was -1.06% (.+-.0.06), compared with -0.56% (.+-.0.09) for placebo plus pioglitazone. The difference in adjusted mean HbA1c in the linagliptin group compared with placebo was -0.51% (95% confidence interval [CI] -0.71, -0.30; p < 0.0001). Reductions in fasting plasma glucose (FPG) were significantly greater for linagliptin plus pioglitazone than with placebo plus pioglitazone; -1.8 and -1.0 mmol/l, respectively, equating to a treatment difference of -0.8 mmol/l (95% CI -1.2, -0.4; p < 0.0001). Patients taking linagliptin plus pioglitazone, compared with those receiving placebo plus pioglitazone, were more likely to achieve HbA1c of <7.0% (42.9 vs. 30.5%, respectively; p = 0.0051) and reduction in HbA1c of .gtoreq.0.5% (75.0 vs. 50.8%, respectively; p < 0.0001). .beta.-cell function, exemplified by the ratio of relative change in adjusted mean HOMA-IR and disposition index, improved. The proportion of patients that experienced at least one adverse event was similar for both groups. Hypoglycaemic episodes (all mild) occurred in 1.2% of the linagliptin plus pioglitazone patients and none in the placebo plus pioglitazone group. Conclusion: Initial combination therapy with linagliptin plus pioglitazone was well tolerated and produced significant and clinically meaningful improvements in glycaemic control. This combination may offer a valuable additive initial treatment option for T2DM, particularly where metformin either is not well tolerated or is contraindicated, such as in patients with renal impairment. - DERWENT Abstract - This randomized, double-blind, placebo-controlled study evaluated the efficacy, safety, and tolerability of initial combination therapy with linagliptin (LIN) and pioglitazone (PIO) in 389 patients with inadequately controlled type 2 diabetes. After 24 wk of treatment, the adjusted mean change in HbA1c with the initial combination of LIN (5 mg) + PIO (30 mg) was -1.06% compared with -0.56% for placebo + PIO. Reductions in fasting plasma glucose were greater for LIN + PIO than with placebo + PIO. Beta-cell function improved. The proportion of patients that experienced at least 1 adverse event was similar for both groups. Hypoglycemic episodes occurred in 1.2% of the LIN + PIO patients and none in the placebo + PIO group. Thus, initial combination therapy with LIN + PIO was well tolerated and produced meaningful improvements in glycemic control.
  • Author:
    Eikelboom JW; Wallentin L; Connolly SJ; Ezekowitz M; Healey JS; Oldgren J; Yang S; Alings M; Kaatz S; Hohnloser SH; Diener HC; Franzosi MG; Huber K; Reilly P; Varrone J; Yusuf S
    Title:
    Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial.
    Source:
    Circulation 123 (21), 2363-NIL-72 (2011)
    Abstract:
    ABSTRACT: Background-Dabigatran 150 and 110 mg twice a day and warfarin are effective for stroke prevention in atrial fibrillation. The purpose of this study was to compare their risks of bleeding in the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial. Methods and Results-The RE-LY trial randomized 18 113 patients to receive dabigatran 110 or 150 mg twice a day or warfarin dose adjusted to an international normalized ratio of 2.0 to 3.0 for a median follow-up of 2.0 years. Compared with warfarin, dabigatran 110 mg twice a day was associated with a lower risk of major bleeding (2.87% versus 3.57%; P=0.002), whereas dabigatran 150 mg twice a day was associated with a similar risk of major bleeding (3.31% versus 3.57%; P=0.32). There was a significant treatment-by-age interaction, such that dabigatran 110 mg twice a day compared with warfarin was associated with a lower risk of major bleeding in patients aged <75 years (1.89% versus 3.04%; P<0.001) and a similar risk in those aged >= 75 years (4.43% versus 4.37%; P=0.89; P for interaction <0.001), whereas dabigatran 150 mg twice a day compared with warfarin was associated with a lower risk of major bleeding in those aged <75 years (2.12% versus 3.04%; P<0.001) and a trend toward higher risk of major bleeding in those aged >= 75 years (5.10% versus 4.37%; P=0.07; P for interaction <0.001). The interaction with age was evident for extracranial bleeding, but not for intracranial bleeding, with the risk of the latter being consistently reduced with dabigatran compared with warfarin irrespective of age. Conclusions-In patients with atrial fibrillation at risk for stroke, both doses of dabigatran compared with warfarin have lower risks of both intracranial and extracranial bleeding in patients aged <75 years. In those aged >= 75 years, intracranial bleeding risk is lower but extracranial bleeding risk is similar or higher with both doses of dabigatran compared with warfarin. - DERWENT Abstract - The Authors compared the risks of bleeding in the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial involving 18113 patients with atrial fibrillation at risk for stroke who received dabigatran 110 or 150 mg b.i.d. or warfarin dose adjusted to an international normalized ratio of 2.0 to 3.0 for a median follow-up of 2 yr. Both doses of dabigatran exhibited lower risks of both intracranial and extracranial bleeding in patients younger than 75 yr compared with warfarin. Intracranial bleeding risk was lower but extracranial bleeding risk was similar or higher with both doses of dabigatran compared with warfarin in those 75 yr or older. Methods 18113 Patients with atrial fibrillation at risk for stroke were randomized to receive dabigatran 110 mg b.i.d. (n=6015, mean age 71.4 yr, 3865 male), dabigatran 150 mg b.i.d. (n=6076, mean age 71.5 yr, 3840 male) or warfarin dose adjusted to an international normalized ratio of 2.0 to 3.0 (n=6022, mean age 71.6 yr, 3809 male) for a median follow-up of 2 yr. Results Compared with warfarin, dabigatran 110 mg b.i.d. was associated with a lower risk of major bleeding (2.87% vs. 3.57%), whereas dabigatran 150 mg b.i.d. was associated with a similar risk of major bleeding (3.31% vs. 3.57%). There was a treatment-by-age interaction, such that dabigatran 110 mg b.i.d. compared with warfarin was associated with a lower risk of major bleeding in patients younger than 75 yr (1.89% vs. 3.04%) and a similar risk in those 75 yr or older (4.43% vs. 4.37%), whereas dabigatran 150 mg b.i.d. was associated with a lower risk of major bleeding in those younger than 75 yr (2.12% vs. 3.04%) and a trend toward higher risk of major bleeding in those 75 yr or older (5.10% vs. 4.37%) compared with warfarin. The interaction with age was evident for extracranial bleeding, but not the intracranial bleeding, with the risk of the latter being consistently reduced with dabigatran compared with warfarin irrespective of age.
  • Author:
    Desmond A; Stanton A; Maher V; Crean P; Feely J; Sullivan P
    Title:
    A survey of patients attitudes to clinical research.
    Source:
    Ir Med J 104 (4), 117-119 (2011)
    Abstract:
    Every year hundreds of patients voluntarily participate in clinical trials across Ireland. However, little research has been done as to how patients find the experience. This survey was conducted in an attempt to ascertain clinical trial participants views on their experience of participating in a clinical trial and to see and how clinical trial participation can be improved. One hundred and sixty-six clinical trial participants who had recently completed a global phase IV cardiovascular endpoint clinical trial were sent a 3-page questionnaire. Ninety-one (91%) respondents found the experience of participating in a clinical trial a good one with 85 (84.16%) respondents saying they would recommend participating in a clinical trial to a friend or relative and eighty-five (87.63%) respondents feeling they received better healthcare because they had participated in a clinical trial.
  • Author:
    Decramer M; Molenberghs G; Liu D; Celli B; Kesten S; Lystig T; Tashkin DP
    Title:
    Premature discontinuation during the UPLIFT study.
    Source:
    Respir Med 105 (10), 1523-1530 (2011)
    Abstract:
    Rationale: Placebo-controlled clinical trials on COPD are characterized by premature discontinuation. At present, no clear insight into this phenomenon is available. Objective: To obtain better insight into the phenomenon of premature discontinuation. Methods: We analyzed the pattern of discontinuation in the UPLIFT-trial. Measurements and main results: Premature discontinuation was substantial and greater in the placebo than in the tiotropium group (45 vs. 37%, p &lt; 0.001). Patients discontinuing were characterized by more severe COPD (p &lt; 0.0001), greater number of pack years (p &lt; 0.002), smaller pre-bronchodilator and post-bronchodilator FEV1 (p &lt; 0.0001 for both), and worse SGRQ scores (p &lt; 0.0001). Rates of decline of FEV1 and SGRQ were greater in non-completers (p &lt; 0.0001 for both). The latter differences increased over time indicating that the evolution of variables in time was related to trial completion. The risks of exacerbations and hospitalizations were greater in non-completers. In logistic regression analysis BMI, post-bronchodilator FEV1, male gender and treatment with tiotropium were positively related to trial completion, whereas age, worse SGRQ, female gender, current smoking and assignment to the placebo group were negatively related. Conclusion: Assignment to the control group is related to premature discontinuation. Discontinuation was important and selective in this large trial. Pulmonary function, health-related quality of life and smoking are the most important other variables related to discontinuation. The evolution of variables during the trial is also related to discontinuation. Complete follow-up of discontinued patients may provide better insight into the efficacy of medication in future trials.
  • Author:
    Zalewski J; Bogaerts K; Desmet W; Sinnaeve P; Berger P; Grines C; Danays T; Armstrong P; Van de Werf F
    Title:
    Intraluminal thrombus in facilitated versus primary percutaneous coronary intervention an angiographic substudy of the ASSENT-4 PCI (Assessment of the safety and efficacy of a new treatment strategy with percutaneous coronary intervention) trial.
    Source:
    J Am Coll Cardiol 57 (19), 1867-1873 (2011)
    Abstract:
    Objectives: This study investigated the occurrence of intraluminal thrombus and its potential implications with facilitated percutaneous coronary interventions (fPCIs). Background: The effect of fPCI on the presence and consequences of intraluminal thrombus is unknown. Methods: Thrombolysis In Myocardial Infarction (TIMI) flow grade, frame count, and thrombus grade; distal embolization; and slow flow in the infarct-related artery were assessed in a blinded fashion on coronary angiograms in 1,342 patients from the ASSENT-4 PCI (Assessment of the Safety and Efficacy of a New Treatment Strategy With Percutaneous Coronary Intervention) trial. Residual TIMI thrombus grade <2 and/or distal embolization and/or slow flow, reflecting thrombus burden (TB), following PCI were correlated with ST-segment resolution, epicardial blood flow, and clinical outcome. The clinical composite endpoint was death, congestive heart failure, or shock. Results: In the fPCI group, more TIMI flow grade 2/3 in the infarct-related artery at the first angiogram (73.7% vs. 33.4%, p < 0.001) and a higher TB following PCI (19.7% vs. 13.4%, p = 0.002) were found in comparison with the primary PCI group. Post-PCI TIMI thrombus grade was significantly associated with ST-segment resolution (p < 0.001) and TIMI frame count (p < 0.0001) in both groups. In the fPCI group, the presence of post-PCI thrombus was associated with a significantly worse outcome at 90 days (clinical composite endpoint: 32.1% vs. 18.6%, p = 0.023). Multivariable logistic regression showed that facilitation with tenecteplase (p = 0.005) and TB (odds ratio: 2.43, 95% confidence interval: 1.30 to 4.51, p = 0.0052) were independent predictors of 90-day mortality. Conclusions: In ASSENT-4 PCI, despite more patency, residual TB was significantly higher in fPCI patients and was associated with less efficient tissue reperfusion and worse clinical outcomes. (A Trial Evaluating the Efficacy and Safety of Tenecteplase Together With Unfractionated Heparin Prior to Early Percutaneous Coronary Intervention [PCI] as Compared to Standard Primary PCI in Patients With Acute Myocardial Infarction [ASSENT-4 PCI]; NCT00168792). - DERWENT Abstract - This study (NCT00168792) examined the occurrence of intraluminal thrombus and its potential implications with facilitated percutaneous coronary intervention (fPCI) in 1342 patients from the ASSENT-4 PCI trial. The patients were assigned to either fPCI (group A, GA) or primary PCI (pPCI) (GB). Post-PCI Thrombolysis in MI (TIMI) thrombus grade (TTG) was associated with ST-segment resolution (STR) and TIMI frame count in both groups. In GA, the presence of post-PCI thrombus was associated with worse outcome at 90 days. Facilitation with tenecteplase and TB were identified as independent predictors of 90-day mortality in a multivariate analysis. In ASSENT-4 PCI, despite more patency, residual TB was higher in fPCI patients and was associated with less efficient tissue reperfusion and worse clinical outcomes. Methods The occurrence of intraluminal thrombus and its potential implications with fPCI were investigated in 1342 patients from the ASSENT-4 PCI trial. The patients were assigned to either fPCI (GA, n=656, mean age 60.8 yr, 497 male) or pPCI (GB, n=686, mean age 59.9 yr, 527 male). Results A clopidogrel loading dose after the procedure and glycoprotein IIb/IIIa inhibitors before and after PCI were more frequent in GB vs. GA. The clinical composite endpoint (death, CHF, or shock 90 days postrandomization) and reinfarction rates were higher in GA at 30 and 90 days, and by 90 days, there was also a tendency for excess death, CHF, and shock in GA. After fibrinolytic therapy, higher rates of TTG 0 to 3 were seen in GA, and more frequent TTG 5 was present in GB. During PCI, more patent vessels without thrombosis were found in GA, while more arteries with medium-size thrombus (TTG 2/3) were present in GB. After PCI, no significant differences in TTG were present. However, trends toward more distal embolization and large (TTG 2 or greater) residual thrombus were seen in GA. The calculated TB was greater in GA (19.7% vs. 13.%, GB). The relationship between post-PCI TTG and TIMI frame counts was significant in GA vs. GB but different between the groups. GA had higher STR at 60 min (38.6% vs. 28.6%), while STR at 180 min was similar in the 2 groups (71.4% vs. 71.2%). Compared to GB, in GA, post-PCI TTG 1 to 5 was associated with a higher risk of combined clinical endpoint and TTG 0 with a higher risk of reinfarction. Multivariable logistic regression showed that facilitation with tenecteplase and TB were independent predictors of 90-day mortality.
  • Author:
    Podzamczer D; Andrade-Villanueva J; Clotet B; Taylor S; Rockstroh J; Reiss P; Domingo P; Gellermann H; de Rossi L; Cairns V; Soriano V
    Title:
    Lipid profiles for nevirapine vs. atazanavir/ritonavir, both combined with tenofovir disoproxil fumarate and emtricitabine over 48 weeks, in treatment naive HIV-1-infected patients (the ARTEN study).
    Source:
    HIV Med 12 (6), 374-382 (2011)
    Abstract:
    The Authors evaluated lipid profiles for nevirapine (NVP) vs. atazanavir/ritonavir (ATZ/r), both combined with tenofovir disoproxil fumarate and emtricitabine over 48 wk, in an ongoing multinational, multicenter, randomized, open-label, prospective study of 569 antiretroviral (ARV) treatment-naive HIV-1-infected patients. NVP showed a potentially less atherogenic lipid profile compared with ATZ/r in ARV-naive patients with low cardiovascular risk (CR) at the outset. Methods 569 ARV treatment-naive HIV-1-infected patients received ritonavir-boosted atazanavir (ATZ/r) 300 mg/100 mg once/day (qd) with immediate-release NVP 200 mg b.i.d. or 400 mg/day, each combined with fixed-dose tenofovir 300 mg/emtricitabine 200 mg qd. Lipid profiles and CR from baseline to wk 48 were reported. Changes from baseline to wk 48 in fasting plasma levels of total cholesterol (TC), HDL cholesterol, LDL cholesterol, TC:HDL cholesterol ratio, apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), and total triglycerides (TG) were determined. Results At wk 48, NVP treatment resulted in significantly greater mean increases from baseline in TC (24.4 mg/dl vs. 19.6 mg/dl), HDL cholesterol (9.7 m/dl vs. 3.9 mg/dl), LDL cholesterol (15.0 mg/dl vs. 10.4 mg/dl) and ApoA1 (0.18 g/l vs. 0.08 g/l) but not ApoB (0.02 g/l vs. 0.02 g/l) compared with ATZ/r treatment. ATZ/r use was associated with higher mean TG increases (27.80 mg/dl vs. 0.02 mg/dl). Significantly greater mean decreases in TC:HDL cholesterol and ApoB/ApoA ratios were observed with NVP vs. ATZ/r. Framingham CR scores were low and comparable between the arms, with only a slight mean increase from baseline to wk 48 of 0.70 for NVP and 0.80 for ATZ/r (difference -0.069).
  • Author:
    Eriksson BI; Dahl OE; Huo MH; Kurth AA; Hantel S; Hermansson K; Schnee JM; Friedman RJ
    Title:
    Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (re-novate II) a randomised, double-blind, non-inferiority trial.
    Source:
    Thromb Haemost 105 (4), 721-7289 (2011)
    Abstract:
    This trial compared the efficacy and safety of oral dabigatran, a direct thrombin inhibitor, versus subcutaneous enoxaparin for extended thromboprophylaxis in patients undergoing total hip arthroplasty. A total of 2,055 patients were randomised to 28-35 days treatment with oral dabigatran, 220 mg once-daily, starting with a half-dose 1-4 hours after surgery, or subcutaneous enoxaparin 40 mg once-daily, starting the evening before surgery. The primary efficacy outcome was a composite of total venous thromboembolism [VTE] (venographic or symptomatic) and death from all-causes. The main secondary composite outcome was major VTE (proximal deep-vein thrombosis or non-fatal pulmonary embolism) plus VTE-related death. The main safety outcome was major bleeding. In total, 2,013 were treated, of whom 1,577 operated patients were included in the primary efficacy analysis. The primary efficacy outcome occurred in 7.7% of the dabigatran group versus 8.8% of the enoxaparin group, risk difference (RD) -1.1% (95%CI - 3.8 to 1.6%); p<0.0001 for the pre-specified non-inferiority margin. Major VTE plus VTE-related death occurred in 2.2% of the dabigatran group versus 4.2% of the enoxaparin group, RD -1.9% (-3.6% to -0.2%); p=0.03. Major bleeding occurred in 1.4% of the dabigatran group and 0.9% of the enoxaparin group (p=0.40). The incidence of adverse events, including liver enzyme elevations and cardiac events, during treatment was similar between the groups. Extended prophylaxis with oral dabigatran 220 mg once-daily was as effective as subcutaneous enoxaparin 40 mg once-daily in reducing the risk of VTE after total hip arthroplasty, and superior to enoxaparin for reducing the risk of major VTE. The risk of bleeding and safety profiles were similar.
  • Author:
    Graefe-Mody U; Rose P; Ring A; Zander K; Iovino M; Woerle H-J
    Title:
    Assessment of the pharmacokinetic interaction between the novel DPP-4 inhibitor linagliptin in a sulfonylurea, glyburide, in healthy subjects.
    Source:
    Drug Metab Pharmacokinet 26 (2), 123-129 (2011)
    Abstract:
    The aim of this study was to investigate the effect of the dipeptidyl peptidase-4 inhibitor linagliptin on the pharmacokinetics of glyburide (a CYP2C9 and CYP3A4 substrate) and vice versa. This randomized, open-label, three-period, two-way crossover study examined the effects of co-administration of multiple oral doses of linagliptin (5 mg/day .times. 6 days) and single doses of glyburide (1.75 mg/day .times. 1 day) on the relative bioavailability of either compound in healthy subjects (n = 20, age 18-55 years). Coadministration of glyburide did not alter the steady-state pharmacokinetics of linagliptin. Geometric mean ratios (GMRs) [90% CI] for (linagliptin + glyburide)/linagliptin AUC(.tau.,ss) and C(max,ss) were 101.7% [97.7-105.8%] and 100.8% [89.0-114.3%], respectively. For glyburide, there was a slight reduction in exposure of .apprx.14% when coadministered with linagliptin (GMRs [90% CI] for (glyburide + linagliptin)/glyburide AUC(0-.infin.) and C(max) were 85.7% [79.8-92.1%] and 86.2% [79.6-93.3%], respectively). However, this was not seen as clinically relevant due to the absence of a reliable dose-response relationship and the known large pharmacokinetic interindividual variability of glyburide. These results further support the assumption that linagliptin is not a clinically relevant inhibitor of CYP2C9 or CYP3A4 in vivo. Coadministration of linagliptin and glyburide had no clinically relevant effect on the pharmacokinetics of linagliptin or glyburide. Both agents were well tolerated and can be administered together without the need for dosage adjustments.
  • Author:
    Diener H-Ch; Barbanti P; Dahloef C; Reuter U; Habeck J; Padhorna J
    Title:
    BI 44370 TA, an oral CGRP antagonist for the treatment of acute migraine attacks: Results from a phase II study.
    Source:
    Cephalalgia 31 (5), 573-584 (2011)
    Abstract:
    Methods: Four hundred and sixty-one adult subjects with migraine were randomised to one of five treatments, the oral antagonist at the calcitonin gene-related peptide (CGRP) receptor BI 44370 TA (50 mg, 200 mg, 400 mg), active comparator eletriptan 40 mg or placebo. The analysis included 341 subjects who took study medication. Results: The primary endpoint, pain-free after two hours, was reached by significantly more subjects in the BI 44370 TA 400 mg (20/73=27.4%) and eletriptan 40 mg (24/69=34.8%) groups compared to placebo (6/70=8.6%, p=.0016), but not by subjects in the BI 44370 TA 200 mg group (14/65=21.5%). The effect of 50 mg BI 44370 TA (5/64=7.8%) was similar to that of placebo. Analysis of secondary endpoints supported the conclusion from the primary analysis. The frequency of adverse events was low in all groups. Conclusion: Efficacy of BI 44370 TA was shown in a dose-dependent manner in the treatment of acute migraine attacks. - DERWENT Avstract - 2011-18683 DRUGU T S <<LOGINID:SSSWISFTS:20110610>> AB This randomized, double-blind, double-dummy, placebo- and active-controlled, parallel-group, outpatient, phase II study (NCT00751803) investigated the efficacy and safety of p.o. BI-44370TA, a calcitonin gene-related peptide antagonist, in 341 adult subjects with migraine. The highest dose of BI-44370TA tested as well as the active control p.o. eletriptan (ELE) resulted in more subjects being pain-free at 2 hr vs. placebo. The overall incidence of adverse events was low in all groups. The most common adverse events were fatigue and diarrhea. These findings suggest that the efficacy of BI-44370TA is dose-dependent in this patient population. Methods 341 Adult subjects (mean age 40.2 yr, 284 female) with migraine were randomized to either p.o. BI-44370TA (50, 200, or 400 mg) (n=64, 65, and 73, respectively), p.o. ELE (40 mg) (n=69), or placebo (n=70). Results Pain-free after 2 hr was reached by more subjects given BI-44370TA (400 mg) (20/73, 27.4%) and ELE (40 mg) (24/69, 34.8%) groups vs. placebo (6/70, 8.6%), but not by subjects in the BI-44370TA (200 mg) group (14/65, 21.5%). The effect of BI-44370TA (50 mg) was similar to that of placebo. The frequency of adverse events was low in all groups. No adverse event occurred with an incidence of greater than 5% during the treatment period. Overall, 42/341 subjects (12.3%) experienced at least 1 adverse event. The highest overall incidence (5/341, 1.5%) was found for diarrhea and fatigue. No dose-dependent increase of adverse event frequency was observed for treatment with BI-44370TA. No changes of clinical relevance were noted during the trial for ECG results, mean pulse rate, and B.P. Abnormalities of laboratory value were rare and there were no clinically relevant differences among treatment groups.
  • Author:
    Fliri AF; Loging WT; Volkmann RA
    Title:
    Analysis of information flows in interaction networks: implication drug discovery and pharmacological research.
    Source:
    Discov Med 11 (57), 133-143 (2011)
    Abstract:
    Frequent failures of experimental medicines in clinical trials question current concepts for predicting drug-effects in the human body. Improving the probability for success in drug discovery requires a better understanding of cause-effect relationships at the organism, organ, tissue, cellular, and molecular levels, each having a different degree of complexity. Despite the longstanding realization that clinical and preclinical drug-effect information needs to be integrated for generating more accurate forecasts of drug-effects, a road map for linking these disparate sources of information currently does not exist. This review focuses on a possible approach for obtaining these relationships by analyzing causes and effects on the basis of the topology of network interaction systems that process information at the cellular and organ system levels.
  • Author:
    Huang F; Scholl P; Huang DB; Macgregor ThR; Taub ME; Vinisko R; Castles MA; Robinson P
    Title:
    Concomitant administration of BILR 355/r with emtricitabine/tenofovir disoproxil fumarate increases exposure to emtricitabine and tenofovir: A randomized, open-label, prospective study.
    Source:
    Basic Clin Pharmacol Toxicol 108 (3), 163-170 (2011)
    Abstract:
    The objective of this study was to evaluate the pharmacokinetic interaction of ritonavir-boosted BILR 355 (BILR 355/r) with emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF). This was an open-label, prospective study. For Group A, 26 healthy subjects were given FTC/TDF (200/300 mg) once daily (QD) for 7 days and then co-administered with BILR 355/r (150/100 mg) twice daily (bid) for an additional 7 days. Pharmacokinetics assessments were performed at days 7 and 14. For Group B, eight subjects were given BILR 355/r (150/100 mg) bid for 7 days. The pharmacokinetic data from Group B were also pooled with Group B subjects from other similar studies performed in parallel to this study. After co-administration with BILR 355/r, the geometric mean ratio (GMR, %) and 90% confidence interval (CI, %) of combined versus alone treatment for FTC AUC(0-24,ss) , C(max,ss) and C(0-12,ss) were 160 (154-166), 128 (121-136) and 223 (206-241), respectively; and for tenofovir AUC(0-24,ss) , C(max,ss) and C(24,ss) were 126 (121-132), 131 (117-146) and 132 (124-140), respectively. Co-administration with FTC/TDF resulted in an 18% increase in AUC(0-12,ss) , 14% increase in C(max,ss) and 19% increase in C(12,ss) for BILR 355. BILR 355 was well tolerated in this study. There was no evidence of increased risk of TFV or FTC toxicity upon co-administration of FTC/TDF with BILR 355/r. - DERWENT Abstract - This randomized, open-label, prospective study evaluated the pharmacokinetic interaction of ritonavir-boosted BILR 355 (BILR 355/r) with emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) in 34 healthy subjects. Co-administration with p.o. FTC/TDF resulted in an 18% increase in AUC0-12,ss, 14% increase in Cmax,ss and 19% increase in C(12,ss) for BILR 355. BILR 355 was well tolerated in this study. There was no evidence of increased risk of TFV or FTC toxicity upon co-administration of FTC/TDF with BILR 355/r. Methods 34 Healthy subjects were evaluated in this randomized study. For Group A, 26 healthy subjects (mean age 36.3 yr, 13 male) were given FTC/TDF (200/300 mg) once daily (QD) for 7 days and then co-administered with BILR 355/r (150/100 mg) b.i.d. for an additional 7 days. Pharmacokinetics assessments were performed at days 7 and 14. For Group B, 8 subjects (mean age 35.6 yr, 4 male) were given BILR 355/r (150/100 mg) b.i.d. for 7 days. The pharmacokinetic data from Group B were also pooled with Group B subjects from other similar studies performed in parallel to this study. Results All 34 subjects received at least 1 dose of study medication. After co-administration with BILR 355/r, the geometric mean ratio (GMR, %) and 90% confidence interval (CI, %) of combined vs. alone treatment for FTC AUC0-24,ss, Cmax,ss and C0-12,ss were 160 (154-166), 128 (121-136) and 223 (206-241), respectively; and for tenofovir AUC0-24,ss, Cmax,ss, and C24,ss were 126 (121-132), 131 (117-146) and 132 (124-140), respectively. The mean half-life of BILR 355 was modestly shortened from 18.5 to 15.8 hr in the presence of FTC/TDF. P.o. clearance of tenofovir was significantly decreased after co-administration of FTC/TDF with BILR 355/r. The overall adverse events rate was similar among the 3 treatment regimens in this study, with 57.7%, 52.0%, and 62.5% of subjects in the FTC/TDF, FTC/TDF + BILR 355/r and BILR 355/r groups. No subjects experienced adverse events that were severe in intensity.
  • Author:
    Hanania NA; Sharafkhaneh A; Celli B; Decramer M; Lystig T; Kesten S; Tashkin D
    Title:
    Acute bronchodilator responsiveness and health outcomes in COPD patients in the UPLIFT trial - art. no. 6
    Source:
    Respir Res 12, 6 (2011)
    Abstract:
    Background: Debate continues as to whether acute bronchodilator responsiveness (BDR) predicts long-term outcomes in COPD. Furthermore, there is no consensus on a threshold for BDR. Methods: At baseline and during the 4-year Understanding Potential Long-term Improvements in Function with Tiotropium (UPLIFT (R)) trial, patients had spirometry performed before and after administration of ipratropium bromide 80 mcg and albuterol 400 mcg. Patients were split according to three BDR thresholds: >= 12% + >= 200 mL above baseline (criterion A), >= 15% above baseline (criterion B); and >= 10% absolute increase in percent predicted FEV1 values (criterion C). Several outcomes (pre-dose spirometry, exacerbations, St. George's Respiratory Questionnaire [SGRQ] total score) were assessed according to presence or absence of BDR in the treatment groups. Results: 5783 of 5993 randomized patients had evaluable pre- and post-bronchodilator spirometry at baseline. Mean age (SD) was 64 (8) years, with 75% men, mean post-bronchodilator FEV1 1.33 +/- 0.44 L (47.6 +/- 12.7% predicted) and 30% current smokers. At baseline, 52%, 66%, and 39% of patients had acute BDR using criterion A, B, and C, respectively. The presence of BDR was variable at follow-up visits. Statistically significant improvements in spirometry and health outcomes occurred with tiotropium regardless of the baseline BDR or criterion used. Conclusions: A large proportion of COPD patients demonstrate significant acute BDR. BDR in these patients is variable over time and differs according to the criterion used. BDR status at baseline does not predict long-term response to tiotropium. Assessment of acute BDR should not be used as a decision-making tool when prescribing tiotropium to patients with COPD.
  • Author:
    Fernandez L; Kesten St; Liu D; Decramer M; Tashkin D; Celli B; Fukuchi Y
    Title:
    Efficacy of tiotropium in COPD patients from ASIA: A subgroup analysis from the UPLIFT trial.
    Source:
    Respirology 16 (5), 825-835 (2011)
    Abstract:
    This subgroup analysis of a 4-yr, placebo-controlled study (Uplift) evaluated the efficacy of tiotropium (TIO) in 362 COPD patients. In TIO treated patients, discontinuations were less when compared to the placebo group. Pre-bronch forced expiratory volume in 1 sec (lung airflow measure; FEV1) increased at all timepoints. Higher annual FEV1 decline was observed in TIO treated patients when compared to the placebo group. Thus, in COPD patients, tiotropium improves lung function, improves health-related quality of life, and reduces exacerbations over 4 yr of treatment. Methods 362 COPD patients (median age 66 yr; males 95%) were randomized to receive TIO (n=184) or placebo (n=178). The outcomes evaluated were the rate of FEV1 decline, changes in FEV1 and forced vital capacity (lung function test; FVC), St. Georges respiratory questionnaire (SGRQ), exacerbations, and mortality. Results Discontinuations were 38% in the TIO group and 47% in the placebo group. Annual FEV1 decline (TIO vs. placebo) were 20 vs. 18 ml/yr (pre-bronch) and 26 vs. 31 ml/yr (post-bronch). Pre-bronch FEV1 increased by 63-120 ml at all timepoints. Mean pre-bronch FEV1 over time: SGRQ total score improved by 1.5-6.1 units for mth 6, 12, 42, and 48. Number of exacerbations were reduced with TIO vs. placebo (0.68/patient-yr vs. 0.92/patient-yr). Death occurred in 34 (TIO) and 42 (placebo) patients during planned treatment (vital status to day 1440).
  • Author:
    Del Prato S; Barnett AH; Huisman H; Neubacher D; Woerle H-J; Dugi KA
    Title:
    Effect of linagliptin monotherapy on glycaemic control and markers of beta-cell function in patients with inadequately controlled type 2 diabetes: A randomized controlled trial
    Source:
    Diabetes Obes Metab 13 (3), 258-267 (2011)
    Abstract:
    Aim: To assess the safety and efficacy of the potent and selective dipeptidyl peptidase-4 inhibitor linagliptin 5 mg when given for 24 weeks to patients with type 2 diabetes who were either treatment-naive or who had received one oral antidiabetes drug (OAD). Methods: This multicentre, randomized, parallel group, phase III study compared linagliptin treatment (5 mg once daily, n = 336) with placebo (n = 167) for 24 weeks in type 2 diabetes patients. Before randomization, patients pretreated with one OAD underwent a washout period of 6 weeks, which included a placebo run-in period during the last 2 weeks. Patients previously untreated with an OAD underwent a 2-week placebo run-in period. The primary endpoint was the change in HbA1c from baseline after 24 weeks of treatment. Results: Linagliptin treatment resulted in a placebo-corrected change in HbA1c from baseline of -0.69% (p < 0.0001) at 24 weeks. In patients with baseline HbA1c ? 9.0%, the adjusted reduction in HbA1c was 1.01% (p < 0.0001). Patients treated with linagliptin were more likely to achieve a reduction in HbA1c of ?0.5% at 24 weeks than those in the placebo arm (47.1 and 19.0%, respectively; odds ratio, OR = 4.2, p < 0.0001). Fasting plasma glucose improved by -1.3 mmol/l (p < 0.0001) with linagliptin vs. placebo, and linagliptin produced an adjusted mean reduction from baseline after 24 weeks in 2-h postprandial glucose of -3.2 mmol/l (p < 0.0001). Statistically significant and relevant treatment differences were observed for proinsulin/insulin ratio (p = 0.025), Homeostasis Model Assessment-%B (p = 0.049) and disposition index (p = 0.0005). There was no excess of hypoglycaemic episodes with linagliptin vs. placebo and no patient required third-party intervention. Mild or moderate renal impairment did not influence the trough plasma levels of linagliptin. Conclusions: Monotherapy with linagliptin produced a significant, clinically meaningful and sustained improvement in glycaemic control, accompanied by enhanced parameters of ?-cell function. The safety profile of linagliptin was comparable with that of placebo. - DERWENT Abstract - Methods: This multicentre, randomized, parallel group, phase III study compared linagliptin treatment (5 mg once daily, n = 336) with placebo (n = 167) for 24 weeks in type 2 diabetes patients. Before randomization, patients pretreated with one OAD underwent a washout period of 6 weeks, which included a placebo run-in period during the last 2 weeks. Patients previously untreated with an OAD underwent a 2-week placebo run-in period. The primary endpoint was the change in HbA1c from baseline after 24 weeks of treatment. Results: Linagliptin treatment resulted in a placebo-corrected change in HbA1c from baseline of -0.69% (p < 0.0001) at 24 weeks. In patients with baseline HbA1c >= 9.0%, the adjusted reduction in HbA1c was 1.01% (p < 0.0001). Patients treated with linagliptin were more likely to achieve a reduction in HbA1c of >= 0.5% at 24 weeks than those in the placebo arm (47.1 and 19.0%, respectively; odds ratio, OR = 4.2, p < 0.0001). Fasting plasma glucose improved by -1.3 mmol/l (p < 0.0001) with linagliptin vs. placebo, and linagliptin produced an adjusted mean reduction from baseline after 24 weeks in 2-h postprandial glucose of -3.2 mmol/l (p < 0.0001). Statistically significant and relevant treatment differences were observed for proinsulin/insulin ratio (p = 0.025), Homeostasis Model Assessment-%B (p = 0.049) and disposition index (p = 0.0005). There was no excess of hypoglycaemic episodes with linagliptin vs. placebo and no patient required third-party intervention. Mild or moderate renal impairment did not influence the trough plasma levels of linagliptin. Conclusions: Monotherapy with linagliptin produced a significant, clinically meaningful and sustained improvement in glycaemic control, accompanied by enhanced parameters of beta-cell function. The safety profile of linagliptin was comparable with that of placebo. - DERWENT Abstract - This multicenter, randomized, parallel group, phase III study assessed the safety and efficacy of the potent and selective dipeptidyl peptidase-4 inhibitor linagliptin 5 mg when given for 24 wk to 503 patients with type 2 diabetes who were either treatment-naive or who had received 1 p.o. antidiabetes drug (OAD). Linagliptin treatment resulted in a placebo-corrected change in HbA1c from baseline of -0.69% at 24 wk. There was no excess of hypoglycemic episodes with linagliptin vs. placebo and no patient required third-party intervention. Mild or moderate renal impairment did not influence the trough plasma levels of linagliptin. Thus, linagliptin monotherapy produced a significant, clinically meaningful and sustained improvement in glycemic control, accompanied by enhanced parameters of beta-cell function. The safety profile of linagliptin was comparable with that of placebo. Methods 503 Patients (mean age 55.7 yr, 243 male) with type 2 diabetes who were either treatment-naive or who had received 1 OAD were studied. Linagliptin treatment (5 mg once daily, n=336) was compared with placebo (n=167) for 24 wk in type 2 diabetes patients. Before randomization, patients pretreated with one OAD underwent a washout period of 6 wk, which included a placebo run-in period during the last 2 wk. Patients previously untreated with an OAD underwent a 2-wk placebo run-in period. The primary endpoint was the change in HbA1c from baseline after 24 wk of treatment. Results The geometric mean trough plasma concentrations of linagliptin remained constant over time: 6.4 and 6.5 nM at Wk 12 and 24, respectively. Linagliptin treatment resulted in a placebo-corrected change in HbA1c from baseline of -0.69% at 24 wk. In patients with baseline HbA1c at least 9.0%, the adjusted reduction in HbA1c was 1.01%. Patients treated with linagliptin were more likely to achieve a reduction in HbA1c of at least 0.5% at 24 wk than those in the placebo arm (47.1% and 19.0%, respectively). Fasting plasma glucose improved by -1.3 mM with linagliptin vs. placebo, and linagliptin produced an adjusted mean reduction from baseline after 24 wk in 2-h postprandial glucose of -3.2 mM. Statistically significant and relevant treatment differences were noted for proinsulin/insulin ratio, Homeostasis Model Assessment-%B and disposition index. There was no excess of hypoglycemic episodes with linagliptin vs. placebo and no patient required 3rd-party intervention. Mild or moderate renal impairment did not influence the trough plasma levels of linagliptin.
  • Author:
    Rabe E; Stuecker M; Esperester A; Schaefer E; Ottillinger B
    Title:
    Efficacy and tolerability of a red-vine-leaf extract in patients: Suffering from chronic venous insufficiency - results of a double-blind placebo-controlled study.
    Source:
    Eur J Vasc Endovasc Surg 41 (4), 540-547 (2011)
    Abstract:
    Objectives: The aim of this study was to investigate the effect of a red-vine-leaf extract (AS195, Antistax<sup>®</sup>, Boehringer Ingelheim Pharma GmbH &amp; Co. KG, Ingelheim, Germany) on the volume of the leg and clinical symptoms in patients with chronic venous insufficiency (CVI). Design, materials and methods: A multicentre, randomised, double-blind and placebo-controlled study was carried out with 720 mg AS195 per day over 12 weeks in CVI patients (CEAP Grades 3-4a) and moderate-to-severe clinical symptoms. Efficacy endpoints were changes in limb volume determined by water displacement volumetry, clinical CVI symptoms assessed on a 10-cm visual analogue scale and global efficacy evaluations. Results: The full-analysis set included 248 patients (placebo: n = 122; AS195: n = 126). After 12 weeks, AS195 significantly reduced lower limb volume by a mean of 19.9 standard error (SE) 8.9 ml over placebo (95% confidence interval (CI): -37.5, -2.3; p = 0.0268; analysis of covariance, ANCOVA). The standardised effect size of 0.28 for volume reduction indicates a clinically relevant effect. On Day 84, the symptom of 'pain in the legs' assessed by visual analogue scale decreased in the AS195 group compared with the placebo group: mean difference -6.6 SD 3.3 mm (95% CI: -13.1,-0.1; p = 0.047). Other symptoms showed no significant change. The tolerability of AS195 was similar to that of placebo. Conclusions: AS195 treatment for 84 days resulted in an approximately 20 ml reduction of limb volume in the active treatment group compared with the placebo group. Patients reported subjective improvement following treatment with AS195 compared with placebo. However, patients' overall rating of efficacy did not correlate well with measured reductions in limb volume. Trial Registration: ClinicalTrials.gov NCT00855179.
  • Author:
    Inoue Y; Kagimra T; Kuroda K; Hirata K; Uchimura N; Shimizu T
    Title:
    Efficacy, safety and dose response of pramipexole in Japanese patients with primary restless legs syndrome: randomized trial.
    Source:
    Neuropsychobiology 63 (1), 35-42 (2011)
    Abstract:
    Aims: To assess the safety and efficacy of pramipexole in Japanese patients with restless legs syndrome (RLS) and to investigate factors predictive of early treatment response. Methods: Patients with primary RLS and the International Restless Legs Syndrome Study Group rating scale (IRLS) total score of >15 were randomized to receive pramipexole 0.25, 0.5 or 0.75 mg/day for 6 weeks. Results: A total of 154 patients were recruited. Following treatment, the mean adjusted change in IRLS score in the 0.25, 0.5 and 0.75 mg/day groups was -12.3, -12.5 and -11.8, respectively. The proportion of IRLS responders at week 2, when all patients were receiving pramipexole at a dose of 0.25 mg/day, was 34.0-37.7%. At 6 weeks, when the patients were on 0.25, 0.5 or 0.75 mg/day, IRLS responders defined as those having a >= 50% reduction in IRLS score accounted for 60.4, 58.5 and 49.1%, respectively. Older age above the median value (>= 55 years) and low IRLS score at baseline (<21.5 points) were significantly associated with early response to low-dose pramipexole therapy. The type and frequency of adverse events were consistent with the known safety profile for dopamine agonists in RLS. Conclusions: Pramipexole at 0.25-0.75 mg/day is efficacious, safe and well tolerated in Japanese patients with primary RLS.
  • Author:
    Anderson C; Teo K; Gao P; Arima H; Dans A; Unger T; Commerford P; Dyal L; Schumacher H; Pogue J; Paolasso E; Holwerda N; Chazova I; Binbrek A; Young J; Yusuf B
    Title:
    Renin-angiotensin system blockade and cognitive function in patients at high risk of cardiovascular disease: analysis of data from the ONTARGET and TRANSCEND studies.
    Source:
    Lancet Neurol 10 (1), 43-53 (2011)
    Abstract:
    Background: Cardiovascular risk factors are associated with dementia and cognitive decline. We investigated the effects of renin-angiotensin system blockade on cognitive function in patients aged 55 years and older with established atherosclerotic cardiovascular disease or diabetes with end-organ damage in two clinical trials. Methods: In the main study, ONTARGET, a double-blind, double-dummy, randomised controlled trial, the effects on cardiovascular outcomes of standard doses of an angiotensin-converting enzyme (ACE) inhibitor (ramipril), an angiotensin-receptor blocker (telmisartan), and a combination of the drugs were evaluated in 25 620 participants. In the parallel TRANSCEND trial, the effects of telmisartan were compared with those of placebo in 5926 participants intolerant to ACE inhibitors. Secondary outcomes included cognitive impairment (defined by investigator-reported diagnosis of dementia or significant cognitive dysfunction, or a score of ?23 on the Mini-Mental State Examination [MMSE]) and cognitive decline (a decrease of ?3 points on the MMSE from baseline during follow-up). Analyses were by intention to treat. We pooled data from these studies to identify baseline predictors of cognitive impairment and its frequency according to mean systolic blood pressure during follow-up. These studies were registered with ClinicalTrials.gov, number NCT00153101. Findings: During a median duration of 56 months (IQR 51-64) of follow-up in ONTARGET, cognitive impairment occurred in 652 (8%) of 7865 patients allocated ramipril, 584 (7%) of 7797 allocated telmisartan, and 618 (8%) of 7807 allocated combination treatment (combination vs ramipril, odds ratio [OR] 0·95, 95% CI 0·85-1·07, p=0·39; telmisartan vs ramipril, OR 0·90, 0·80-1·01, p=0·06). Corresponding figures for cognitive decline were 1314 (17%), 1279 (17%), and 1240 (17%) in each of the groups, respectively (telmisartan vs ramipril, OR 0·97, 0·89-1·06, p=0·53; combination vs ramipril, OR 0·95, 0·88-1·04, p=0·28). In TRANSCEND, cognitive impairment occurred in 239 (9%) of 2694 participants allocated telmisartan compared with 245 (9%) of 2689 allocated placebo (OR 0·97, 0·81-1·17, p=0·76). The corresponding figures for cognitive decline were 454 (17%) and 412 (16%; OR 1·10, 0·95-1·27, p=0·22). Interpretation: In patients with cardiovascular disease or diabetes, different approaches to blocking of the renin-angiotensin system had no clear effects on cognitive outcomes. Although patients with the lowest systolic blood pressure had the greatest preservation of cognitive function, meta-regression analyses did not show any benefits of blood-pressure lowering on cognition over several years of treatment. Funding: Boehringer-Ingelheim.
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