Short-duration treatment for chronic hepatitis C virus with daclatasvir, asunaprevir, beclabuvir and sofosbuvir (FOURward study).

BACKGROUND & AIMS: The phase 2, FOURward study (NCT02175966) investigated short-duration therapy (4/6 weeks) with four direct-acting antivirals (DAAs) with distinct mechanisms of action in patients infected with hepatitis C virus (HCV) genotype-1. METHODS: Non-cirrhotic patients were randomized 1:1 to DCV-TRIO (fixed-dose daclatasvir 30 mg, asunaprevir 200 mg and beclabuvir 75 mg) twice-daily + sofosbuvir 400 mg once-daily for 4 or 6 weeks. The primary endpoint was sustained virological response at post-treatment Week 12 (SVR12). Patients without SVR12 were offered retreatment based on the DAA resistance profile at failure; patients with resistance to ≤1 DCV-TRIO component received DCV-TRIO + RBV for 12 weeks. RESULTS: Twenty-eight patients with HCV genotype-1 were enrolled; 79% had genotype-1a infection and median baseline HCV-RNA levels were high (9 × 106  IU/mL). Most patients had undetectable HCV-RNA at end of treatment (96% [n=27/28]); however, relapse occurred in 77% (n=10/13) and 43% (n=6/14) treated for 4 and 6 weeks, leading to SVR12 rates of 29% (n=4/14) and 57% (n=8/14) respectively. SVR12 was higher in patients with lower baseline HCV-RNA (<2 million IU/mL, 71% [n=5/7]; ≥2 million IU/mL, 33% [n=7/21]). None of the 16 non-SVR12 patients had NS3 or NS5B resistance-associated substitutions (RAS) detected at failure. All 15 patients retreated with DCV-TRIO + RBV for 12 weeks achieved SVR12. All regimens were well tolerated. CONCLUSIONS: Short-duration treatment with four DAAs with distinct mechanisms of action was insufficient for most patients with genotype-1 infection and high baseline viraemia. Non-SVR12 was not associated with emergence of NS3 or NS5B RAS and retreatment with DCV-TRIO + RBV for 12 weeks led to SVR in all patients.

All-oral daclatasvir plus asunaprevir for chronic hepatitis C virus (HCV) genotype 1b infection: a sub-analysis in Asian patients from the HALLMARK DUAL study.

BACKGROUND & AIMS: Daclatasvir plus asunaprevir (DCV + ASV) has demonstrated potent antiviral activity in patients with hepatitis C virus (HCV) genotype 1b (GT-1b) infection in the HALLMARK DUAL trial. This post hoc analysis was conducted to determine the efficacy and safety of this treatment in Asian patients. METHODS: Treatment-naive patients were randomly assigned (2:1; double-blinded) to receive DCV (60 mg once daily) plus ASV (100 mg twice daily) or placebo for 12 weeks. Subsequently, placebo patients entered another study, and the remaining patients continued treatment for an additional 12 weeks. Non-responders to peginterferon/ribavirin and ineligible/intolerant patients received dual therapy for 24 weeks. Sustained virological response at post-treatment Week 12 [sustained virological response (SVR)12] and safety outcomes were evaluated. RESULTS: This post hoc analysis included 186 Asian patients (Korean, 78; Taiwanese, 85; others, 23), of whom 32.3% were cirrhotic. SVR12 was observed in 92.3, 78.6 and 80.0% of treatment-naive, ineligible/intolerant and non-responder patients, respectively, and was comparable with non-Asian patients. SVR12 by baseline factors including age, viral load, interleukin-28B genotype and cirrhosis status was similar between the Asian sub-cohorts. Among 18 Asian patients with NS5A-Y93H or NS5A-L31M/V resistance-associated variants (RAVs), seven patients achieved SVR12. Multivariate regression analysis showed a significant influence of NS5A RAVs in both Asian and non-Asian cohorts. The incidence of serious adverse events in Asian patients was low (7.2%). Two Taiwanese patients had elevated alanine aminotransferase (≥5.1 × ULN); both achieved SVR12. CONCLUSIONS: All-oral dual therapy with DCV + ASV resulted in high SVR rates and was well tolerated in Asian patients with HCV GT-1b infection.

A phase 3, open-label study of daclatasvir plus asunaprevir in Asian patients with chronic hepatitis C virus genotype 1b infection who are ineligible for or intolerant to interferon alfa therapies with or without ribavirin.

BACKGROUND AND AIM: Daclatasvir plus asunaprevir has demonstrated efficacy and safety in patients with chronic hepatitis C virus genotype 1b infection. This study focused on evaluating daclatasvir plus asunaprevir in interferon (±ribavirin)-ineligible or -intolerant Asian patients with genotype 1b infection from mainland China, Korea, and Taiwan. METHODS: Interferon (±ribavirin)-ineligible and -intolerant patients with genotype 1b infection received daclatasvir 60 mg tablets once daily plus asunaprevir 100 mg soft capsules twice daily for 24 weeks. The primary endpoint was sustained virologic response at post-treatment week 24 (SVR24). RESULTS: Of the 159 patients treated, 89.3% were Chinese, 65.4% were female, and 73.6% were interferon-intolerant. Cirrhosis was present in 32.7% of patients, and 40.3% had IL28B non-CC genotypes. SVR24 was achieved by 145/159 (91.2%) patients (100% concordance with SVR12) and was similarly high in cirrhotic patients (47/52, 90.4%). SVR24 was higher in patients without baseline NS5A (L31M or Y93H) resistance-associated variants (RAVs) (137/139, 98.6%), including those with cirrhosis (43/44, 97.7%). Prevalence of baseline NS5A RAVs was low (19/159, 11.9%), particularly in mainland China (10/127, 7.9%). One death (0.6%), five serious adverse events (3.1%), and three grade 4 laboratory abnormalities (1.9%) occurred on treatment; none were considered related to study drugs. Two patients (1.3%) discontinued because of adverse events. Treatment was generally well tolerated regardless of cirrhosis status. CONCLUSIONS: Daclatasvir plus asunaprevir achieved a SVR24 rate of 91.2%, rising to 98.6% in patients without baseline NS5A RAVs, and was generally well tolerated in interferon (±ribavirin)-ineligible or -intolerant patients with genotype 1b infection from mainland China, Korea, and Taiwan.

Assessment of the Efficacy and Safety of BMS-820836 in Patients With Treatment-Resistant Major Depression: Results From 2 Randomized, Double-Blind Studies.

Two phase 2B, randomized, double-blind studies assessed the efficacy and safety of fixed or flexible dose of triple monoamine uptake inhibitor BMS-820836 in patients with treatment-resistant depression to demonstrate whether switching to BMS-820836 was superior to the continuation of standard antidepressant treatment. Patients with a history of inadequate response to 1 to 3 adequate trials of antidepressant therapies were prospectively treated with duloxetine 60 mg/d for 8 weeks (CN162-006) or duloxetine 60 mg/d or escitalopram 20 mg/d for 7 weeks (CN162-007). Inadequate responders were randomized to continue their prospective phase treatment or switch to flexible-dose (0.5-2 mg/d; CN162-006) or fixed-dose (0.25, 0.5, 1, or 2 mg/d; CN162-007) BMS-820836 for 6 weeks. The primary end point in both studies was mean change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from randomization to study end point. BMS-820836 flexible (0.5-2 mg/d) or fixed dose of 1 mg/d or greater showed efficacy similar to the continuation of antidepressant treatment, with no statistically significant or clinically meaningful differences. In the CN162-006 study, the adjusted mean (SE) change in MADRS total score was -8.7 (0.661) and -8.1 (0.656) for BMS-820836 and duloxetine, respectively (P = 0.526). In the CN162-007 study, the adjusted mean (SE) change in MADRS total score was -7.3 (0.830) and -6.6 (0.842) for BMS-820836 of 1 and 2 mg, respectively, and -6.9 (0.602) for the continuation group (P = 0.910). Thus, BMS-820836 was well tolerated, with no evidence of dose-dependent discontinuations due to adverse events, but it failed to demonstrate superiority to the continuation of an existing antidepressant in patients with treatment-resistant depression.

Aripiprazole monotherapy in acute mania: 12-week randomised placebo- and haloperidol-controlled study.

BACKGROUND: Well-tolerated and effective therapies for bipolar mania are required. AIMS: To evaluate the efficacy and tolerability of aripiprazole as acute and maintenance of effect therapy in patients with bipolar I disorder experiencing manic or mixed episodes. METHOD: Patients were randomised to double-blind aripiprazole (15 or 30 mg/day; n=167), placebo (n=153) or haloperidol (5-15 mg/day, n=165) for 3 weeks (trial registration NCT00097266). Aripiprazole- and haloperidol-treated patients remained on masked treatment for 9 additional weeks. RESULTS: Mean change in Young Mania Rating Scale Total score (primary end-point) at week 3 was significantly greater with aripiprazole (-12.0; P<0.05) and haloperidol (-12.8; P<0.01) than with placebo (-9.7). Improvements were maintained to week 12 for aripiprazole (-17.2) and haloperidol (-17.8). Aripiprazole was well tolerated. Extrapyramidal adverse events were more frequent with haloperidol than aripiprazole (53.3% v. 23.5%). CONCLUSIONS: Clinical improvements with aripiprazole were sustained to week 12. Aripiprazole was generally well tolerated.

Safety of Abatacept Versus Placebo in Rheumatoid Arthritis: Integrated Data Analysis of Nine Clinical Trials.

OBJECTIVE: To assess the safety of abatacept treatment in rheumatoid arthritis (RA) using integrated data from multiple clinical trials. METHODS: Data from nine double-blind, placebo-controlled studies of abatacept treatment (seven intravenous, two subcutaneous) in patients with RA were pooled, focusing on safety events in the double-blind treatment period of each study. Incidence rates (IRs) of adverse events (AEs) per 100 patient-years of exposure were calculated for abatacept- and placebo-treated patients. AEs in abatacept-treated patients were combined regardless of dose and formulation. RESULTS: In total, 2653 patients received abatacept and 1485 received placebo, with 2357 and 1254 patient-years of exposure, respectively. The mean (SD) durations of exposure in the abatacept and placebo groups were 10.8 (3.3) and 10.3 (3.5) months, respectively. The IRs (95% confidence interval [CI]) for serious AEs were 14.8 (13.3, 16.5) and 14.6 (12.5, 17.0) in the abatacept and placebo groups, respectively. Death occurred in 12 (0.5%) and 12 (0.8%) patients in the abatacept and placebo groups, respectively, and was most commonly caused by cardiac disorders. Malignancies were observed in 31 patients (1.2%) treated with abatacept (IR: 1.32 [95% CI: 0.90, 1.87]) versus 14 (0.9%; IR: 1.12 [0.61, 1.88]) who received placebo. Solid organ tumor was the most frequent malignancy reported in both groups (abatacept: 1.0%; IR: 1.11 [95% CI: 0.72, 1.62]; placebo: 0.8%; 0.96 [0.50, 1.67]). CONCLUSION: In this integrated analysis, the IRs of safety events in the abatacept and placebo groups were similar with no new safety concerns identified.

Effectiveness of long-term aripiprazole therapy in patients with acutely relapsing or chronic, stable schizophrenia: a 52-week, open-label comparison with olanzapine.

OBJECTIVE: To compare the long-term efficacy and safety of aripiprazole with olanzapine in patients with either acute relapsing or chronic, stable schizophrenia. MATERIALS AND METHODS: A 52-week, open-label extension to a 26-week, multicenter, randomized, double-blind, placebo-controlled trial in patients with chronic schizophrenia. Patients who completed the initial treatment or who met the protocol definition of relapse after > or =2 weeks of double-blind treatment were randomized to aripiprazole (15-30 mg/day, n = 104) or olanzapine (10-20 mg/day, n = 110) for 52 weeks. RESULTS: Sixty-nine percent of patients completed the study. Efficacy improvements were similar between groups at endpoint, mean reductions in Positive and Negative Syndrome Scale (PANSS) Total scores from baseline for patients completing the study (observed cases) were similar in chronic stable patients (aripiprazole, -7.94; olanzapine, -7.36) and in patients with acute relapse (aripiprazole, -31.19; olanzapine, -29.55). Olanzapine-treated patients reported more extrapyramidal symptoms (EPS)-related adverse events (18%) than aripiprazole-treated patients (10%). No significant differences in EPS were seen between treatments at endpoint. Olanzapine was associated with significantly greater weight gain than aripiprazole at all time points (week 52 [LOCF]: +2.54 vs +0.04 kg; p < 0.001). Changes in fasting glucose and lipid levels at endpoint favored aripiprazole over olanzapine, with significant differences observed for total cholesterol, low- and high-density lipoprotein. While differences observed for changes in fasting glucose and triglycerides favored aripiprazole, they were not statistically significant. CONCLUSION: Aripiprazole showed similar efficacy to olanzapine for long-term treatment of acutely psychotic and chronic, stable schizophrenia patients, with a lower liability for weight gain or increased lipid levels.

Aripiprazole for the prevention of relapse in stabilized patients with chronic schizophrenia: a placebo-controlled 26-week study.

BACKGROUND: Aripiprazole is a novel antipsychotic for the management of schizophrenia. This study investigated the efficacy, safety, and tolerability of aripiprazole in preventing relapse in adult chronic schizophrenia patients experiencing ongoing stable symptomatology. METHOD: In this 26-week, randomized, double-blind, placebo-controlled, parallel-group, multi-center study, 310 patients with DSM-IV schizophrenia (mean Positive and Negative Syndrome Scale [PANSS] total score = 82) were randomly assigned to receive a once-daily fixed dose of aripiprazole, 15 mg, or placebo. The primary outcome measure was time to relapse following randomization. Secondary objectives were to assess the efficacy, safety, and tolerability of aripiprazole, 15 mg, compared with placebo, in the study population. The study was conducted between Dec. 21, 2000, and Aug. 20, 2001. RESULTS: The time to relapse following randomization was significantly (p < .001) longer for aripiprazole compared with placebo. More patients relapsed with placebo (N = 85; 57%) than aripiprazole (N = 50; 34%); the relative risk of relapse for the aripiprazole group was 0.59 (p < .001). Aripiprazole was significantly superior to placebo from baseline to endpoint in PANSS total, PANSS positive, PANSS-derived Brief Psychiatric Rating Scale, and Clinical Global Impressions-Severity of Illness scale (CGI-S) scores and demonstrated significantly better mean Clinical Global Impressions-Global Improvement scale scores (p < or = .01 for all comparisons except CGI-S: .01 < p < or = .05). Aripiprazole was well tolerated, with no evidence of marked sedation and no evidence of hyperprolactinemia or prolonged heart rate-corrected QT interval (QTc). Extrapyramidal symptoms were comparable in the aripiprazole and placebo groups. Modest mean weight loss at endpoint was evident in both groups. CONCLUSION: Aripiprazole, 15 mg once daily, is an effective, well-tolerated treatment for prevention of relapse in patients with chronic, stable schizophrenia.