Efficacy of Sofosbuvir, Velpatasvir, and GS-9857 in Patients With Hepatitis C Virus Genotype 2, 3, 4, or 6 Infections in an Open-Label, Phase 2 Trial

Background & Aims Studies are needed to determine the optimal regimen for patients with chronic hepatitis C virus (HCV) genotype 2, 3, 4, or 6 infections whose prior course of antiviral therapy has failed, and the feasibility of shortening treatment duration. We performed a phase 2 study to determine the efficacy and safety of the combination of the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the NS3/4A protease inhibitor GS-9857 in these patients. Methods We performed a multicenter, open-label trial at 32 sites in the United States and 2 sites in New Zealand from March 3, 2015 to April 27, 2015. Our study included 128 treatment-naïve and treatment-experienced patients (1 with HCV genotype 1b; 33 with HCV genotype 2; 74 with HCV genotype 3; 17 with genotype HCV 4; and 3 with HCV genotype 6), with or without compensated cirrhosis. All patients received sofosbuvir-velpatasvir (400 mg/100 mg fixed-dose combination tablet) and GS-9857 (100 mg) once daily for 6–12 weeks. The primary end point was sustained virologic response 12 weeks after treatment (SVR12). Results After 6 weeks of treatment, SVR12s were achieved by 88% of treatment-naïve patients without cirrhosis (29 of 33; 95% confidence interval, 72%–97%). After 8 weeks of treatment, SVR12s were achieved by 93% of treatment-naïve patients with cirrhosis (28 of 30; 95% CI, 78%–99%). After 12 weeks of treatment, SVR12s were achieved by all treatment-experienced patients without cirrhosis (36 of 36; 95% CI, 90%–100%) and 97% of treatment-experienced patients with cirrhosis (28 of 29; 95% CI, 82%–100%). The most common adverse events were headache, diarrhea, fatigue, and nausea. Three patients (1%) discontinued treatment due to adverse events. Conclusions In a phase 2 open-label trial, we found sofosbuvir-velpatasvir plus GS-9857 (8 weeks in treatment-naïve patients or 12 weeks in treatment-experienced patients) to be safe and effective for patients with HCV genotype 2, 3, 4, or 6 infections, with or without compensated cirrhosis

A phase III study evaluating the efficacy and safety of remimazolam (CNS 7056) compared with placebo and midazolam in patients undergoing colonoscopy.

BACKGROUND AND AIMS: Remimazolam is an ultrashort-acting benzodiazepine. METHODS: We performed a randomized double-blind comparison of remimazolam to placebo for outpatient colonoscopy. This study design was a requirement of the U.S. Food and Drug Administration. An additional group was randomized to open-label midazolam administered according to its package insert instructions (the randomization ratio for remimazolam:placebo:midazolam was 30:6:10). Study medications were administered under the supervision of the endoscopist, without any involvement of an anesthesia specialist. Patients were given 50 to 75 μg of fentanyl before receiving study medications. Patients who failed to achieve adequate sedation in any arm were rescued with midazolam dosed at the investigator\u27s discretion. The primary endpoint was a composite that required 3 criteria be met: completion of the colonoscopy, no need for rescue medication, and ≤5 doses of remimazolam or placebo in any 15-minute interval (≤3 doses of midazolam in any 12-minute interval in the open-label midazolam arm). RESULTS: There were 461 randomized patients in 12 U.S. sites. The primary endpoint was met for remimazolam, placebo, and midazolam in 91.3%, 1.7%, and 25.2% of patients, respectively (P \u3c .0001 for remimazolam vs placebo). Patients administered remimazolam received less fentanyl, had faster recovery of neuropsychiatric function, were ready for discharge earlier, and felt back to normal sooner than patients with both placebo and midazolam. Hypotension was less frequent with remimazolam, and hypoxia occurred in 1% of patients with remimazolam or midazolam. There were no treatment-emergent serious adverse events. CONCLUSION: Remimazolam can be administered safely under the supervision of endoscopists for outpatient colonoscopy, and it allows faster recovery of neuropsychiatric function compared with placebo (midazolam rescue) and midazolam. (Clinical trial registration number: NCT02290873.)

Temporal Trends in the Detection of Right-Sided Colon Polyps: Summary Data of Large GI Practices

Although overall colorectal cancer incidence and mortality has decreased in those undergoing colonoscopy, there is still a concern regarding efficacy of colonoscopy in detection of right-sided colonic lesions and prevention of colon cancers on the right side. Quality measures in colonoscopy have traditionally looked at detecting adenomatous polyps from throughout the colon. Data regarding polyp detection and cancer prevention in the left vs. right side are sparse

Longitudinal Assessment of Colonoscopy Quality Indicators: A Report From the Gastroenterology Practice Management Group (GPMG)

BACKGROUND: There is increasing demand for colonoscopy quality measures for procedures performed in ambulatory surgery centers. Benchmarks such as adenoma detection rate (ADR) are traditionally reported as static, one-dimensional point estimates at a provider or practice level. OBJECTIVE: To evaluate 6-year variability of ADRs for 370 gastroenterologists from across the nation. DESIGN: Observational cross-sectional analysis. SETTING:Collaborative quality metrics database from 2007 to 2012. PATIENTS:Patients who underwent colonoscopies in ambulatory surgery centers. INTERVENTIONS: Colonoscopy. MAIN OUTCOME MEASUREMENTS: The number of colonoscopies with an adenomatous polyp divided by the total number of colonoscopies (ADR-T), inclusive of indication and patient\u27s sex. RESULTS: Data from 368,157 colonoscopies were included for analysis from 11 practices. Three practice sites (5, 8, and 10) were significantly above and 2 sites (3, 7) were significantly below mean ADR-T, with a 95% confidence interval (CI). High-performing sites had 9.0% higher ADR-T than sites belonging to the lowest quartile (P \u3c .001). The mean ADR-T remained stable for 9 of 11 sites. Regression analysis showed that the 2 practice sites where ADR-T varied had significant improvements in ADR-T during the 6-year period. For each, mean ADR-T improved an average of 0.5% per quarter for site 2 (P = .001) and site 3 (P = .021), which were average and low performers, respectively. LIMITATIONS: Summary-level data, which does not allow cross-reference of variables at an individual level. CONCLUSION: We found performance disparities among practice sites remaining relatively consistent over a 6-year period. The ability of certain sites to sustain their high-performance over 6 years suggests that further research is needed to identify key organizational processes and physician incentives that improve the quality of colonoscopy

Simeprevir plus sofosbuvir (12 and 8 weeks) in hepatitis C virus genotype 1-infected patients without cirrhosis: OPTIMIST-1, a phase 3, randomized study

Effective antiviral therapy is essential for achieving sustained virological response (SVR) in hepatitis C virus (HCV)-infected patients. The phase 2 COSMOS study reported high SVR rates in treatment-naive and prior null-responder HCV genotype (GT) 1-infected patients receiving simeprevir+sofosbuvir±ribavirin for 12 or 24 weeks. OPTIMIST-1 (NCT02114177) was a multicenter, randomized, open-label study assessing the efficacy and safety of 12 and 8 weeks of simeprevir+sofosbuvir in HCV GT1-infected treatment-naive and treatment-experienced patients without cirrhosis. Patients were randomly assigned (1:1; stratified by HCV GT/subtype and presence or absence of NS3 Q80K polymorphism [GT1b, GT1a with Q80K, GT1a without Q80K]), prior HCV treatment history, and IL28B GT [CC, non-CC]) to simeprevir 150 mg once daily+sofosbuvir 400 mg once daily for 12 or 8 weeks. The primary efficacy endpoint was SVR rate 12 weeks after end of treatment (SVR12). Superiority in SVR12 was assessed for simeprevir+sofosbuvir at 12 and 8 weeks versus a composite historical control SVR rate. Enrolled were 310 patients, who were randomized and received treatment (n = 155 in each arm). SVR12 with simeprevir+sofosbuvir for 12 weeks (97% [150/155; 95% confidence interval 94%-100%]) was superior to the historical control (87%). SVR12 with simeprevir+sofosbuvir for 8 weeks (83% [128/155; 95% confidence interval 76-89%]) was not superior to the historical control (83%). The most frequent adverse events were nausea, headache, and fatigue (12-week arm: 15% [23/155], 14% [22/155], and 12% [19/155]; 8-week arm: 9% [14/155], 17% [26/155], and 15% [23/155], respectively). No patients discontinued treatment due to an adverse event. One (1%, 12-week arm) and three (2%, 8-week arm) patients experienced a serious adverse event (all unrelated to study treatment). CONCLUSION: Simeprevir+sofosbuvir for 12 weeks is highly effective in the treatment of HCV GT1-infected patients without cirrhosis, including those with Q80K. (Hepatology 2016;64:370-380)