Once-daily simeprevir (TMC435) with pegylated interferon and ribavirin in treatment-naïve genotype 1 hepatitis C: The randomized PILLAR study

The phase IIb, double-blind, placebo-controlled PILLAR trial investigated the efficacy and safety of two different simeprevir (SMV) doses administered once-daily (QD) with pegylated interferon (Peg-IFN)-α-2a and ribavirin (RBV) in treatment-naïve patients with HCV genotype 1 infection. Patients were randomized to one of five treatments: SMV (75 or 150 mg QD) for 12 or 24 weeks or placebo, plus Peg-IFN and RBV. Patients in the SMV arms stopped all treatment at week 24 if response-guided therapy (RGT) criteria were met; patients not meeting RGT continued with Peg-IFN and RBV until week 48, as did patients in the placebo control group. Sustained virologic response (SVR) rates measured 24 weeks after the planned end of treatment (SVR24) were 74.7%-86.1% in the SMV groups versus 64.9% in the control group (P < 0.05 for all comparisons [SMV versus placebo], except SMV 75 mg for 24 weeks). Rapid virologic response (HCV RNA <25 IU/mL undetectable at week 4) was achieved by 68.0%-75.6% of SMV-treated and 5.2% of placebo control patients. According to RGT criteria, 79.2%-86.1% of SMV-treated patients completed treatment by week 24; 85.2%-95.6% of these subsequently achieved SVR24. The adverse event profile was generally similar across the SMV and placebo control groups, with the exception of mild reversible hyperbilirubinemia, without serum aminotransferase abnormalities, associated with higher doses of SMV

Pharmacotherapy of disruptive behavior and item changes on a standardized rating scale: pooled analysis of risperidone effects in children with subaverage IQ.

Contains fulltext : 49128.pdf (publisher's version ) (Open Access)BACKGROUND: Disruptive behavior disorders (DBDs), excluding attention deficit/hyperactivity disorder (ADHD), are characterized by a repetitive pattern of antisocial, aggressive, and defiant behavior involving major violations of age-appropriate norms, resulting in significant functional impairment. Risperidone is licensed for the treatment of DBDs in children, adolescents, and adults in several countries. The aim of this study was to determine the effect of risperidone in a clinical setting on the symptom items of the Nisonger Child Behavior Rating Form (N-CBRF), used for the assessment of DBD patients. METHOD: Data from two 6-week, randomized, double-blind, placebo-controlled trials of risperidone oral solution (0.02-0.06 mg/kg/day) in children with DBDs and subaverage IQ (mild, moderate mental retardation and borderline IQ) were pooled for analysis. RESULTS: Risperidone produced improvement in both the Social Competence and the Problem Behavior N-CBRF subscales. Risperidone reduced symptoms in the Problem Behavior subscales (e.g., Conduct Problem, Insecure/Anxious) but also improved positive behaviors on the Social Competence subscales. Unlike most problem-behavior items, certain items reflecting "Affective insecurity" (e.g., shy, timid; clings to adults; crying, tearful episodes) failed to improve. This was also true of social disinterest and certain rituals. No items showed any worsening of symptoms with active medication. CONCLUSION: Whereas most categories of problem behavior improved with risperidone, items reflecting "affective insecurity" and some infrequently endorsed items were unaffected in these children with DBDs and subaverage IQ. These data may provide a more refined knowledge of risperidone's therapeutic effects in such children

Cross-national cognitive assessment in schizophrenia clinical trials: a feasibility study

Clinical trials for the treatment of schizophrenia now often include cognitive assessments in addition to clinical ratings of symptoms. Recently, these trials have included cross-national assessments. It is not clear if translated psychological tests produce consistent results across different languages. This paper presents the results of a study of the comparability of the results of cognitive assessments in different English-speaking countries and a number of countries where tests were translated into other languages. Performance on tests of executive functioning, verbal and visuo-spatial learning and memory, language skills, psychomotor speed, and vigilance was compared across the first episode patients with schizophrenia ( n=301) assessed in six different languages (English, French, Finnish, German, Hebrew, and Afrikaans), including two different countries where patients were assessed in English and other languages: Canada (French) and South Africa (Afrikaans). The variance in performance across the sites tested in English was as large as the variance between English and non-English speakers when all tests were considered. Performance differences across English and other languages were found only for executive functions, vigilance, and psychomotor speed, with executive functioning differences nonsignificant when education was considered. No differences were found between English and non-English speakers in Canada. These results suggest that the translation of tests of memory and verbal skills can lead to consistent results across translated versions of the tests. Differences between countries were greater than differences between languages, suggesting the need to consider representativeness of patient samples in terms of local educational attainment. In general, these data support the validity of cross-national neuropsychological assessments

Virologic response and characterisation of HCV genotype 2-6 in patients receiving TMC435 monotherapy (study TMC435-C202).

TMC435 is a potent, once-daily, investigational hepatitis C virus (HCV) NS3/4A protease inhibitor in phase III clinical development. In the phase II trial TMC435-C202 (NCT00812331), TMC435 displayed potent activity in genotype 4, 5 and 6 patients and in 3/6 genotype 2 patients, whereas no activity was observed with genotype 3.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Antiviral activity of TMC435 monotherapy in patients infected with HCV genotypes 2-6: TMC435-C202, a phase IIa, open-label study.

TMC435 is an investigational, once-daily, oral NS3/4A protease inhibitor currently in phase III development for the treatment of hepatitis C virus (HCV) infection. Phase I and II studies in patients infected with HCV genotype 1 have demonstrated that TMC435 is generally well tolerated, has a pharmacokinetic profile that supports once daily dosing, and demonstrates potent antiviral activity. This phase IIa study (TMC435-C202; NCT00812331) was conducted to investigate the antiviral activity, safety, tolerability, and pharmacokinetics of TMC435 in treatment-naїve patients infected with HCV genotypes 2-6.Clinical Trial, Phase IIJournal ArticleMulticenter StudySCOPUS: ar.jinfo:eu-repo/semantics/publishe

Efficacy and safety of etravirine in treatment-experienced, HIV-1 patients: pooled 48 week analysis of two randomized, controlled trials

OBJECTIVE: To evaluate the efficacy, safety and virologic resistance profile of etravirine (TMC125), a next-generation nonnucleoside reverse transcriptase inhibitor, over 48 weeks in treatment-experienced adults infected with HIV-1 strains resistant to a nonnucleoside reverse transcriptase inhibitor and other antiretrovirals. DESIGN: DUET-1 (NCT00254046) and DUET-2 (NCT00255099) are two identically designed, randomized, double-blind phase III trials. METHODS: Patients received twice-daily etravirine 200 mg or placebo, each plus a background regimen of darunavir/ritonavir, investigator-selected nucleoside/nucleotide reverse transcriptase inhibitors and optional enfuvirtide. Eligible patients had documented nonnucleoside reverse transcriptase inhibitor resistance, at least three primary protease inhibitor mutations at screening and were on a stable but virologically failing regimen for at least 8 weeks, with plasma viral load more than 5000 copies/ml. Pooled 48-week data from the two trials are presented. RESULTS: Patients (1203) were randomized and treated (n = 599, etravirine; n = 604, placebo). Significantly more patients in the etravirine than in the placebo group achieved viral load less than 50 copies/ml at week 48 (61 vs. 40%, respectively; P < 0.0001). Significantly fewer patients in the etravirine group experienced at least one confirmed or probable AIDS-defining illness/death (6 vs. 10%; P = 0.0408). Safety and tolerability in the etravirine group was comparable to the placebo group. Rash was the only adverse event to occur at a significantly higher incidence in the etravirine group (19 vs. 11%, respectively, P < 0.0001), occurring primarily in the second week of treatment. CONCLUSION: At 48 weeks, treatment-experienced patients receiving etravirine plus background regimen had statistically superior and durable virologic responses (viral load less than 50 copies/ml) than those receiving placebo plus background regimen, with comparable tolerability and no new safety signals reported since week 2

Pharmacokinetic and pharmacodynamic study of the concomitant administration of methadone and TMC125 in HIV-negative volunteers

TMC125 is a nonnucleoside reverse transcriptase inhibitor (NNRTI) with potent in vitro activity against wild-type and NNRTI-resistant HIV-1. TMC125 is an inducer of CYP3A and an inhibitor of CYP2C. This trial evaluated the effect of TMC125 on the pharmacokinetics and pharmacodynamics of methadone. In an open-label, add-on, 1-way interaction trial, 16 male HIV-negative volunteers on stable methadone maintenance therapy received 100 mg TMC125 bid for 14 days. Plasma concentrations and pharmacokinetic parameters of R- and S-methadone isomers were determined on days -1, 7, and 14 and of TMC125 on days 7 and 14. Safety and tolerability were assessed. The LSmeans ratios (90% confidence interval) for AUC(24h), C(max), and C(min) of the pharmacologically active R-methadone were 1.08 (1.02-1.13), 1.03 (0.97-1.09), and 1.12 (1.05-1.19), respectively, on day 7 and 1.06 (0.99-1.13), 1.02 (0.96-1.09), and 1.10 (1.02-1.19), respectively, on day 14 compared with methadone alone. No withdrawal symptoms were observed; dose adjustment of methadone was not required. The concomitant administration of TMC125 and methadone was generally safe and well tolerated. TMC125 has no clinically relevant effect on the pharmacokinetics or pharmacodynamics of methadone. No dose adjustment for methadone is anticipated when coadministered with TMC12

Efficacy and safety of etravirine in treatment-experienced, HIV-1 patients: pooled 48 week analysis of two randomized, controlled trials.

peer reviewedOBJECTIVE: To evaluate the efficacy, safety and virologic resistance profile of etravirine (TMC125), a next-generation nonnucleoside reverse transcriptase inhibitor, over 48 weeks in treatment-experienced adults infected with HIV-1 strains resistant to a nonnucleoside reverse transcriptase inhibitor and other antiretrovirals. DESIGN: DUET-1 (NCT00254046) and DUET-2 (NCT00255099) are two identically designed, randomized, double-blind phase III trials. METHODS: Patients received twice-daily etravirine 200 mg or placebo, each plus a background regimen of darunavir/ritonavir, investigator-selected nucleoside/nucleotide reverse transcriptase inhibitors and optional enfuvirtide. Eligible patients had documented nonnucleoside reverse transcriptase inhibitor resistance, at least three primary protease inhibitor mutations at screening and were on a stable but virologically failing regimen for at least 8 weeks, with plasma viral load more than 5000 copies/ml. Pooled 48-week data from the two trials are presented. RESULTS: Patients (1203) were randomized and treated (n = 599, etravirine; n = 604, placebo). Significantly more patients in the etravirine than in the placebo group achieved viral load less than 50 copies/ml at week 48 (61 vs. 40%, respectively; P < 0.0001). Significantly fewer patients in the etravirine group experienced at least one confirmed or probable AIDS-defining illness/death (6 vs. 10%; P = 0.0408). Safety and tolerability in the etravirine group was comparable to the placebo group. Rash was the only adverse event to occur at a significantly higher incidence in the etravirine group (19 vs. 11%, respectively, P < 0.0001), occurring primarily in the second week of treatment. CONCLUSION: At 48 weeks, treatment-experienced patients receiving etravirine plus background regimen had statistically superior and durable virologic responses (viral load less than 50 copies/ml) than those receiving placebo plus background regimen, with comparable tolerability and no new safety signals reported since week 24