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's 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 < .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.).

Novel 1 L polyethylene glycol-based bowel preparation NER1006 for overall and right-sided colon cleansing: a randomized controlled phase 3 trial versus trisulfate.

BACKGROUND AND AIMS: NER1006 is the first 32 fluid ounce (1 L) polyethylene glycol-based bowel preparation. This randomized, multicenter, colonoscopist/central reader-blinded phase 3 non-inferiority trial assessed the efficacy, safety, and tolerability of NER1006 versus trisulfate for bowel cleansing. METHODS: Patients undergoing colonoscopy were randomized (1:1) to receive NER1006 or trisulfate, using evening/morning split-dosing administration. Blinded central readers used the validated Harefield Cleansing Scale to evaluate 2 alternative primary endpoints: overall bowel-cleansing success and high-quality cleansing of the ascending colon/cecum. Secondary endpoints included lesion detection, Boston Bowel Preparation Scale (BBPS) assessment, and adherence. The non-inferiority margin was 10% and the significance threshold was P < .025. RESULTS: Of 621 patients randomized (NER1006, n=310; trisulfate, n=311), 556 were evaluated for efficacy (NER1006, n=276; trisulfate, n=280). NER1006 achieved non-inferiority versus trisulfate for both primary endpoints of overall bowel-cleansing success (85.1% vs 85.0%; difference, 0.14%; one-sided 97.5% lower confidence limit [LCL], -8.15%; P = .528) and high-quality cleansing of the ascending colon/cecum (35.9% versus 29.3%; difference, 6.58%; LCL, -1.69%; P = .059). BBPS assessments supported overall bowel-cleansing success rates. Lesion detection rates were similar between the groups. The percentage of patients with treatment-related adverse events was 14.9% with NER1006 and 9.4% with trisulfate. Both bowel preparations showed similar overall tolerability and safety profiles. Adherence was very high in both arms. CONCLUSIONS: With evening/morning split dosing, NER1006 was as effective as trisulfate for overall bowel and right-sided colon cleansing. Adverse event rates were slightly higher with NER1006 than trisulfate, but did not compromise tolerability, adherence, or efficacy. (Clinical trial registration number: NCT02254486.).

Randomized clinical trial: efficacy and safety of plecanatide in the treatment of chronic idiopathic constipation.

BACKGROUND: Plecanatide, with the exception of a single amino acid replacement, is identical to human uroguanylin and is approved in the United States for adults with chronic idiopathic constipation (CIC). This double-blind, placebo-controlled, phase III study evaluated the efficacy and safety of plecanatide versus placebo in CIC. METHODS: Adults meeting modified Rome III CIC criteria were randomized to plecanatide 3 mg (n = 443), 6 mg (n = 449), or placebo (n = 445). Patients recorded bowel movement (BM) characteristics [including spontaneous BMs (SBMs) and complete SBMs (CSBMs)] and rated CIC symptoms in daily electronic diaries. The primary endpoint was the percentage of durable overall CSBM responders (weekly responders for ⩾9 of 12 treatment weeks, including ⩾3 of the last 4 weeks). Weekly responders had ⩾3 CSBMs/week and an increase of ⩾1 CSBM from baseline for the same week. RESULTS: A significantly greater percentage of durable overall CSBM responders resulted with each plecanatide dose compared with placebo (3 mg = 20.1%; 6 mg = 20.0%; placebo = 12.8%; p = 0.004 each dose). Over the 12 weeks, plecanatide significantly improved stool consistency and stool frequency. Significant increases in mean weekly SBMs and CSBMs began in week 1 and were maintained through week 12 in plecanatide-treated patients. Adverse events were mostly mild/moderate, with diarrhea being the most common (3 mg = 3.2%; 6 mg = 4.5%; placebo = 1.3%). CONCLUSIONS: Plecanatide resulted in a significantly greater percentage of durable overall CSBM responders and improved stool frequency and secondary endpoints. Plecanatide was well tolerated; the most common AE, diarrhea, occurred in a small number of patients.[ClinicalTrials.gov identifier: NCT02122471].

Evaluation of drug-drug interaction between daclatasvir and methadone or buprenorphine/naloxone.

INTRODUCTION: Daclatasvir (DCV) is a potent hepatitis C virus (HCV) NS5A replication complex inhibitor with pangenotypic (1-6) activity in vitro. Methadone (MET) and buprenorphine (BUP) are opioid medications used to treat opioid addiction; patients on HCV therapy may require MET or BUP treatment. The effect of DCV on the pharmacokinetics (PK) of MET or BUP/naloxone (NLX) was assessed in subjects on stable MET or BUP. MATERIALS AND METHODS: An open-label, two-part study assessed the effect of steady-state oral administration of DCV on the PK of MET (Part 1, P1) or BUP/NAL (Part 2, P2). Safety/tolerability and pharmacodynamics (PD, opioid withdrawal scales/overdose assessment) were also assessed. Subjects (P1, N=14; P2, N=11) received daily single-dose oral MET (40-120mg) or BUP/NLX (8/2-24/6mg) based on their prescribed stable dose throughout, in addition to DCV (60mg QD) on Days 2-9. Serial PK sampling occurred predose and postdose till 24 hours on Day 1 (MET/BUP) and Day 10 (MET/BUP/DCV). Noncompartmental PK were derived. Geometric mean ratios (GMR) and 90% confidence intervals (90% CI) for MET/BUP/norBUP Cmax and AUCTAU were derived from linear mixed effects models. RESULTS: Subjects were aged 19-39 years, mostly white (P1, 93%; P2, 100%) and male (P1, 71%; P2, 91%). All subjects completed the study. No clinically meaningful effect was demonstrated as the GMR and 90% CIs fell within the prespecified interval (P1, 0.7-1.4; P2, 0.5-2.0: see Table 1). DCV coadministration was well-tolerated: overall, six (43%) subjects had adverse events (AEs) (all mild and resolved without treatment). DCV had no clinically significant effect on the PD of MET or BUP/NLX. CONCLUSIONS: Steady-state administration of DCV 60mg QD had no clinically meaningful effect on the PK of MET or BUP/NLX and was generally well-tolerated, suggesting that no dose adjustments will be required.

Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial.

BACKGROUND: The uridine nucleotide analogue sofosbuvir is a selective inhibitor of hepatitis C virus (HCV) NS5B polymerase. We assessed the safety and efficacy of sofosbuvir in combination with pegylated interferon alfa-2a (peginterferon) and ribavirin in non-cirrhotic treatment-naive, patients with HCV. METHODS: For this open-label, randomised phase 2 trial, we recruited patients from 42 centres in the USA and Puerto Rico between March 23, 2011, and Sept 21, 2011. Patients were eligible for inclusion if they had chronic HCV infection (genotypes 1, 4, 5, or 6), were aged 18 years or older, and had not previously received treatment for HCV infection. Using a computer-generated randomisation sequence, we randomly assigned patients with HCV genotype-1 to one of three cohorts (A, B, and C; in a 1:2:3 ratio), with randomisation stratified by IL28B (CC vs non-CC allele) and HCV RNA (<800,000 IU/mL vs ≥800,000 IU/mL). Patients received sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks (cohort A) or for 24 weeks (cohort B), or 12 weeks of sofosbuvir plus peginterferon and ribavirin followed by 12 weeks of either sofosbuvir monotherapy or sofosbuvir plus ribavirin (cohort C). We enrolled patients with all other eligible genotypes in cohort B. The primary efficacy endpoint was sustained virological response at post-treatment week 24 (SVR24) by intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT01329978. RESULTS: We enrolled 316 patients with HCV genotype-1: 52 to cohort A, 109 to cohort B, and 155 to cohort C. We assigned 11 patients with HCV genotype-4 and five patients with genotype-6 to cohort B (we detected no patients with genotype 5). In patients with HCVgenotype-1, SVR24 was achieved by 46 patients (89%, 95% CI 77-96) in cohort A, 97 patients (89%, 82-94) in cohort B, and by 135 (87%, 81-92) in cohort C. We detected no difference in the proportion of patients achieving SVR24 in cohort A compared with cohort B (p=0·94), or in cohort C (p=0·78). Nine (82%) of 11 patients with genotype-4 and all five with genotype-6 achieved SVR24. Seven patients, all with genotype-1 infection, relapsed after completion of assigned treatment. The most common adverse events that led to the discontinuation of any study drug--anaemia and neutropenia--were associated with peginterferon and ribavirin treatment. Three (6%) patients in cohort A, 18 (14%) patients in cohort B, and three (2%) patients in cohort C discontinued treatment because of an adverse event. INTERPRETATION: Our findings suggest that sofosbuvir is well tolerated and that there is no additional benefit of extending treatment beyond 12 weeks, but these finding will have to be substantiated in phase 3 trials. These results lend support to the further assessment of a 12 week sofosbuvir regimen in a broader population of patients with chronic HCV genotype-1 infection, including those with cirrhosis. FUNDING: Gilead Sciences.

A Phase I, randomized, placebo-controlled, 3-day, ascending-dose study of GS-9451, an NS3/4A protease inhibitor, in genotype 1 hepatitis C patients.

BACKGROUND: GS-9451 is a novel inhibitor of the HCV NS3/4A protease and demonstrates potent in vitro suppression of HCV genotype 1 replicons. METHODS: The safety, pharmacokinetics and antiviral efficacy of GS-9451 were evaluated in a Phase I study in treatment-naive, HCV genotype-1-infected patients. Patients were randomized to 3 days of once-daily dosing with placebo (n=8) or GS-9451 60 mg (n=8 genotype 1a), 200 mg (n=8 genotype 1a; n=8 genotype 1b) or 400 mg (n=9 genotype 1a). Plasma samples were collected up to and on day 14 for pharmacokinetic evaluation, serum HCV RNA quantitation and NS3 sequencing. RESULTS: No patients interrupted or discontinued dosing because of an adverse event. The median (range) maximal HCV RNA reductions from baseline were -0.88 (-1.24- -0.64), -3.19 (-3.31- -2.94) and -3.64 (-4.08- -3.54) log10 IU/ml in genotype 1a patients receiving 60, 200 and 400 mg/day GS-9451, respectively, and -3.48 (-3.54- -3.03) log10 IU/ml in genotype 1b patients receiving GS-9451 200 mg/day. Median half-life ranged from 14 to 17 h. Day 3 mean concentration at the end of dosing interval was 5.5- and 17-fold above protein-binding adjusted mean 50% effective inhibitory concentration in 200 mg and 400 mg cohorts, respectively. No resistance mutations were detected with GS-9451 60 mg/day. In the 200 mg/day or 400 mg/day groups, predominant mutations were NS3 R155 (R155K) in genotype 1a patients and D168 (D168E, D168V and D168G) in genotype 1b patients. CONCLUSIONS: GS-9451 was well-tolerated. During 3 days of monotherapy, GS-9451 200 mg/day or 400 mg/day demonstrated potent antiviral activity in both HCV genotype 1a- and 1b-infected patients. GS-9451 is currently being evaluated in combination regimens with and without pegylated interferon-α.

Single- and multiple-ascending-dose studies of the NS3 protease inhibitor asunaprevir in subjects with or without chronic hepatitis C.

Hepatitis C virus (HCV) protease inhibitors combined with pegylated alfa interferon-ribavirin have demonstrated improved efficacy compared with pegylated alfa interferon-ribavirin alone for the treatment of chronic hepatitis C. Asunaprevir (BMS-650032), a novel HCV NS3 protease inhibitor in clinical development, was evaluated for safety, antiviral activity, and resistance in four double-blind, placebo-controlled, sequential-panel, single- and multiple-ascending-dose (SAD and MAD) studies in healthy subjects or subjects with chronic HCV genotype 1 infection. In SAD studies, subjects (healthy or with chronic HCV infection) were randomized to receive asunaprevir in dose groups of 10 to 1,200 mg or a placebo. In MAD studies, healthy subjects were randomized to receive asunaprevir in dose groups of 10 to 600 mg twice daily or a placebo for 14 days; subjects with HCV infection received asunaprevir in dose groups of 200 to 600 mg twice daily, or a placebo, for 3 days. Across all four studies, headache and diarrhea were the most frequent adverse events in asunaprevir recipients. Asunaprevir at doses of 200 to 600 mg resulted in rapid HCV RNA decreases from the baseline; maximal mean changes in HCV RNA over time were 2.7 and 3.5 log(10) IU/ml in the SAD and MAD studies, respectively. No enrichment of signature asunaprevir-resistant viral variants was detected. In conclusion, the novel NS3 protease inhibitor asunaprevir, when administered at single or multiple doses of 200 to 600 mg twice daily, is generally well tolerated, achieving rapid and substantial decreases in HCV RNA levels in subjects chronically infected with genotype 1 HCV.

Multiple ascending dose study of BMS-790052, a nonstructural protein 5A replication complex inhibitor, in patients infected with hepatitis C virus genotype 1.

UNLABELLED: The antiviral activity, resistance profile, pharmacokinetics (PK), safety, and tolerability of BMS-790052, a nonstructural protein 5A (NS5A) replication complex inhibitor, were evaluated in a double-blind, placebo-controlled, sequential panel, multiple ascending dose study. Thirty patients with chronic hepatitis C virus (HCV) genotype 1 infection were randomized to receive a 14-day course of BMS-790052 (1, 10, 30, 60, or 100 mg once daily or 30 mg twice daily) or placebo in a ratio of 4:1. The mean maximum decline from baseline in HCV RNA ranged from 2.8 to 4.1 log(10) IU/mL; the placebo group showed no evidence of antiviral activity. Most patients experienced viral rebound on or before day 7 of treatment with BMS-790052 monotherapy; viral rebound was associated with viral variants that had been previously implicated in resistance development in the in vitro replicon system. The PK profile was supportive of once-daily dosing with median peak plasma concentrations at 1-2 hours postdose and mean terminal half-life of 12-15 hours. Steady state was achieved following 3-4 days of daily dosing. BMS-790052 was well tolerated in all dose groups, with adverse events occurring with a similar frequency in BMS-790052- and placebo-treated groups. There were no clinically relevant changes in vital signs, laboratory, or electrocardiogram parameters. CONCLUSION: BMS-7590052 is the first NS5A replication complex inhibitor with multiple dose proof-of-concept in clinic. At doses of 1-100 mg daily, BMS-790052 was well tolerated, had a PK profile supportive of once-daily dosing, and produced a rapid and substantial decrease in HCV-RNA levels in patients chronically infected with HCV genotype 1.

Evaluation of a new, rapid test for detecting HCV infection, suitable for use with blood or oral fluid.

The availability of a highly accurate, rapid, point-of-care test for hepatitis C virus (HCV) may be useful in addressing the problem of under-diagnosis of HCV, by increasing opportunities for testing outside of traditional clinical settings. A new HCV rapid test device (OraQuick® HCV Rapid Antibody Test), approved recently in Europe for use with venous blood, fingerstick blood, serum, plasma, or oral fluid was evaluated in a multi-center study and performance compared to established laboratory-based tests for detection of HCV. The HCV rapid test was evaluated in prospective testing of subjects with signs and/or symptoms of hepatitis, or who were at risk for hepatitis C using all 5 specimen types. Performance was assessed relative to HCV serostatus established by laboratory methods (EIA, RIBA and PCR) approved in Europe for diagnosis of hepatitis C infection. Sensitivity to antibody in early infection was also compared to EIA in 27 seroconversion panels. In addition, the reliability of the oral fluid sample for accurate detection of anti-HCV was assessed by studying the impact of various potentially interfering conditions of oral health, use of oral care products and consumption of food and drink. In this large study of at-risk and symptomatic persons, the overall specificities of the OraQuick® HCV Rapid Antibody Test were equivalent (99.6-99.9%) for all 5 specimen types and the 95% CIs substantially overlapped. Overall sensitivities were virtually identical for venous blood, fingerstick blood, serum and plasma (99.7-99.9%). Observed sensitivity was slightly lower for oral fluid at 98.1% though the upper CI (99.0%) was equal to the lower CI for venous blood and fingerstick blood. Most of the HCV positive subjects which gave nonreactive results in oral fluid had serological and virological results consistent with resolved infection. Sensitivity for anti-HCV in early seroconversion was virtually identical between the HCV rapid test and EIA. Detection of anti-HCV in oral fluid appeared generally robust to conditions of oral health, consumption of food and drink and use of oral care products. The OraQuick® HCV Rapid Antibody Test demonstrated clinical performance that was equivalent to current laboratory-based EIA. This new, HCV rapid test appears suitable as an aid in the diagnosis of HCV infection and may increase testing opportunities due to its simplicity and flexibility to use multiple specimen types, including fingerstick blood and oral fluid.

Residue-free sodium phosphate tablets (OsmoPrep) versus Visicol for colon cleansing: a randomized, investigator-blinded trial.

BACKGROUND: The bowel purgative Visicol contains microcrystalline cellulose (MCC) residue, which may impair full visibility during a colonoscopy. An MCC residue-free sodium phosphate (RF-NaP; OsmoPrep) tablet was developed. OBJECTIVE: To investigate appropriate RF-NaP dosing. DESIGN: Phase 2, randomized, investigator-blinded study. SETTING: Six research centers in the United States. PATIENTS AND INTERVENTIONS: Patients undergoing a colonoscopy received Visicol (n = 34) or 1 of 6 RF-NaP regimens administered as either split (S) dosing (the evening before and the day of colonoscopy) or evening-only (E) dosing. Dosing regimens for RF-NaP were 40 tablets S, 3 every 15 minutes (n = 33); 40 tablets S, 4 every 15 minutes (n = 34); 32 tablets E, 4 every 15 minutes (n = 34); 32 tablets S, 4 every 15 minutes (n = 36); 28 tablets E, 4 every 15 minutes (n = 34); 28 tablets S, 4 every 15 minutes (n = 34). Visicol was administered as 40 tablets S, 3 every 15 minutes. MAIN OUTCOME MEASURE: Overall colon cleansing (OCC) was assessed by a physician questionnaire (4-point scale, based on colonic contents). An OCC rating of "excellent" or "good" was considered a response. Safety measures were also monitored. RESULTS: Split dosing with RF-NaP was associated with high OCC and achieved response rates of 90%, 97%, and 100% for 28, 32, and 40 tablets, respectively, compared with 86% for Visicol. In addition, RF-NaP evening-only regimen response rates were 90% (32 tablets) and 72% (28 tablets). Transient shifts in electrolyte levels were reduced, and GI adverse events were less common with lower RF-NaP dose regimens. CONCLUSIONS: Administration of RF-NaP retains the benefits of a tablet purgative but eliminates MCC issues. Split dosing and 32-tablet evening-only dosing of RF-NaP tablets were efficacious and well tolerated, and split dosing of RF-NaP tablets is recommended.