Phase 2/3 Trial of Molnupiravir for Treatment of Covid-19 in Nonhospitalized Adults.

BACKGROUND: Safe and effective oral treatments are needed to improve clinical outcomes for nonhospitalized patients with Covid-19. Molnupiravir is an orally administered, small-molecule ribonucleoside prodrug shown to inhibit replication of severe acute respiratory syndrome coronavirus 2 in vitro and in animal models. METHODS: MOVe-OUT is an ongoing, phase 2/3, randomized, placebo-controlled, double-blind study evaluating the safety, efficacy, and pharmacokinetics of molnupiravir in nonhospitalized adults. In the phase 2 component, participants had mild or moderate, laboratory-confirmed Covid-19 with sign/symptom onset up to (and including) 7 days before randomization. Participants were randomly assigned 1:1:1:1 to receive 200, 400, or 800 mg of molnupiravir or placebo twice daily for 5 days, stratified by time since sign/symptom onset and by being at increased risk for severe illness from Covid-19. The primary efficacy end point was the proportion of participants who were hospitalized and/or died through day 29. RESULTS: The phase 2 component randomly assigned 302 participants to treatment; baseline characteristics were comparable across treatment groups. Molnupiravir had no apparent dose-related effect on adverse events, and no clinically meaningful abnormalities in laboratory test results were observed in relation to dose or treatment. Eleven participants were hospitalized or died through day 29. Of 225 participants in the combined molnupiravir group, 7 (3.1%) were hospitalized or died, compared with 4 of 74 participants (5.4%) in the placebo group. Subgroup analyses suggested lower incidences of hospitalization and/or death in the molnupiravir versus placebo groups in participants older than 60 years of age, those with increased risk for severe illness, those with symptom onset up to (and including) 5 days before randomization, and those with both symptom onset up to (and including) 5 days before randomization and increased risk for severe illness. CONCLUSIONS: These interim study results support further evaluation of molnupiravir as a potential treatment to reduce hospitalizations and/or death in nonhospitalized patients with Covid-19. (Funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.; ClinicalTrials.gov number, NCT04575597.)

Sugammadex efficacy for reversal of rocuronium- and vecuronium-induced neuromuscular blockade: A pooled analysis of 26 studies.

STUDY OBJECTIVE: To summarize and compare efficacy of sugammadex with neostigmine or placebo for reversal of rocuronium- or vecuronium-induced neuromuscular blockade (NMB), and to demonstrate consistency of sugammadex results across various patient populations. DESIGN: Pooled analysis on data from 26 multicenter, randomized, Phase II and III studies. SETTING: Operating room. PATIENTS: 1855 adults undergoing surgery under general anesthesia and receiving rocuronium or vecuronium for NMB. INTERVENTIONS: Sugammadex (2.0mg/kg at second twitch reappearance [T2; moderate NMB], 4.0mg/kg at 1-2 post-tetanic counts [PTC; deep NMB] or 16.0mg/kg at 3min after rocuronium 1.2mg/kg), neostigmine or placebo. MEASUREMENTS: Time to recovery of the train-of-four (TOF) ratio to 0.9. MAIN RESULTS: Geometric mean (95% CI) times to recovery to TOF ratio of 0.9 were 1.9 (1.8-2.0) min following sugammadex 2.0mg/kg and 10.6 (9.8-11.6) min following neostigmine administration at T2 after rocuronium, and 2.9 (2.5-3.4) min and 17.4 (13.4-22.6) min, respectively, after vecuronium. Recovery times were 2.2 (2.1-2.3) min following sugammadex 4.0mg/kg and 19.0 (14.8-24.6) min following neostigmine administered at a target of 1-2 PTC after rocuronium, and 3.8 (3.0-5.0) min and 67.6 (56.3-81.2) min after vecuronium. Sugammadex administered 3min after rocuronium 1.2mg/kg resulted in rapid recovery (1.7 [1.5-2.0] min). Modest increases in mean recovery time were associated with vecuronium use (+1.6min [78%; (61%-98%)] versus rocuronium), mild-to-moderate renal impairment (+0.4min [20%; (9%-32%)] versus normal renal function) and geographic location (+1.0min [38%; (25%-52%)] in subjects in USA/Canada versus Europe/Japan). CONCLUSIONS: Sugammadex administered at recommended doses provides rapid and predictable reversal of rocuronium and vecuronium-induced moderate and deep NMB, and effective reversal 3min after rocuronium 1.2mg/kg. Robust recovery was seen across various patient factors, providing further confirmation of labeled dose recommendations.

Deep Neuromuscular Blockade Improves Laparoscopic Surgical Conditions: A Randomized, Controlled Study.

INTRODUCTION: Sustained deep neuromuscular blockade (NMB) during laparoscopic surgery may facilitate optimal surgical conditions. This exploratory study assessed whether deep NMB improves surgical conditions and, in doing so, allows use of lower insufflation pressures during laparoscopic cholecystectomy. We further assessed whether use of low insufflation pressure improves patient pain scores after surgery. METHODS: This randomized, controlled, blinded study (NCT01728584) compared use of deep (1-2 post-tetanic-counts) or moderate (train-of-four ratio 10%) NMB, and lower (8 mmHg) or higher (12 mmHg; 'standard') insufflation pressure in a 2 × 2 factorial design. Primary endpoint was surgeon's overall satisfaction with surgical conditions, rated at end of surgery using an 11-point numerical scale. Post-operative pain scores were also evaluated. Data were analyzed using analysis of covariance. RESULTS: Of 127 randomized patients, 120 had evaluable data for the primary endpoint. Surgeon's score of overall satisfaction with surgical conditions was significantly higher with deep versus moderate NMB indicated by a least-square mean difference of 1.1 points (95% confidence interval 0.1-2.0; P = 0.026). Furthermore, strong evidence of an effect was observed for standard versus low pressure: least-square mean difference of 3.0 points (95% confidence interval 2.1-4.0; P < 0.001). No significant difference was observed in average pain scores within 24 h post-surgery for low versus standard pressure [0.17 (95% confidence interval -0.67 to +0.33); P = 0.494]. CONCLUSIONS: Although associated with significantly improved surgical conditions, deep NMB alone was insufficient to promote use of low insufflation pressure during laparoscopic cholecystectomy. Furthermore, low insufflation pressure did not result in reduced pain, compared with standard pressure. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01728584. FUNDING: Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

A randomized trial assessing dorzolamide in patients with glaucoma who are younger than 6 years.

OBJECTIVE: To evaluate dorzolamide hydrochloride in patients younger than 6 years who have an elevated intraocular pressure or glaucoma. DESIGN: A 3-month, controlled, randomized, double-masked, multicenter, clinical trial. Patients were randomized to 2% dorzolamide 3 times daily or timolol maleate gel-forming solution (0.25% for patients <2 years and 0.5% for patients > or =2 but <6 years) once daily plus placebo twice daily. If the intraocular pressure was not controlled through monotherapy, younger patients received concomitant dorzolamide 3 times daily and 0.25% timolol gel-forming solution once daily and older patients received a fixed combination of 2% dorzolamide and 0.5% timolol twice daily. The primary safety variable was the proportion of patients who discontinued therapy for a drug-related adverse experience. Intraocular pressure reduction was a secondary measure. RESULTS: One younger patient (1.8%) of 56 randomized to dorzolamide discontinued concomitant therapy because of bradycardia. Two older patients (3.0%) of 66 discontinued dorzolamide because of ocular adverse experiences. The most frequent ocular adverse experiences were discharge and ocular hyperemia (younger cohort) and ocular hyperemia and burning/stinging (older cohort). At week 12, the mean change in intraocular pressure for dorzolamide was statistically significant from baseline (-7.3 mm Hg [-20.6%] and -7.1 mm Hg [-23.3%]) in the younger and older cohorts, respectively; P<.001 for both. CONCLUSION: Dorzolamide was generally well tolerated and demonstrated efficacy for up to 3 months in patients younger than 6 years.

Intravenous and subcutaneous weight-based dosing of the low molecular weight heparin tinzaparin (Innohep) in end-stage renal disease patients undergoing chronic hemodialysis.

BACKGROUND: Patients with end-stage renal disease are subject to a broad range of thrombotic complications. Low molecular weight heparins (LMWHs) are effective antithrombotic agents; however, they are cleared largely by renal mechanisms, raising uncertainty about their use in renally impaired patients. METHODS: Twelve chronic hemodialysis subjects were administered two single doses of the LMWH tinzaparin, 75 IU/kg, 2 weeks apart: subcutaneously (SC) on an off-dialysis day and intravenously (IV) just before dialysis. RESULTS: Mean maximal anti-factor Xa (anti-Xa) activity was 0.33 IU/mL 4.0 hours after SC administration and 1.33 IU/mL 0.25 hours after IV administration. Anti-Xa half-lives were 3.89 and 2.31 hours, respectively. Anti-Xa activity returned to baseline within 24 hours of administration by either route. Consistent with population pharmacokinetic analyses of clinical study subjects with severe renal impairment, anti-Xa clearance after tinzaparin administration was reduced 28% relative to subjects with normal renal function. All 12 study subjects completed hemodialysis without requiring additional anticoagulation. One subject had minimal clotting in the dialyzer drip chamber, and one subject had mild prolonged bleeding at the vascular access site after dialysis needle removal. No major bleeding events occurred. CONCLUSION: Tinzaparin, 75 IU/kg, SC on an off-dialysis day and IV just before dialysis is well tolerated in chronic hemodialysis patients. The weight-based regimen of 75 IU/kg IV just before dialysis provides adequate anticoagulation. SC weight-based dosing on off-dialysis days is a feasible regimen for further clinical thromboprophylaxis efficacy studies in hemodialysis patients. The risk for clinical overdose in severely renally impaired patients using this weight-based regimen of tinzaparin is unlikely.

Dosing in heavy-weight/obese patients with the LMWH, tinzaparin: a pharmacodynamic study.

This pharmacodynamic study examined weight-based dosing of the low molecular weight heparin (LMWH), tinzaparin, in heavyweight/obese subjects. Single doses (175 and 75 IU/kg) were administered subcutaneously (SC) to 37 healthy heavy-weight subjects (101-165 kg; 26-61 kg/m2). AUA and Amax values of anti-Xa and anti-IIa activities were consistent over these body weight and body mass index (BMI) ranges, indicating that tinzaparin pharmacodynamics are not influenced by body weight or BMI. The range of AUA and Amax values in the study population overlapped that of historical control normal-weight subjects (<100 kg), indicating that weight-adjusted tinzaparin dosing yields a predictable response regardless of body weight or BMI. Tinzaparin was well tolerated, although injection site bruising was commonly reported. SC tinzaparin dosing in heavy or obese patients is appropriate based on body weight alone; the dose need not be capped at a maximal absolute dose.