Introduction
The randomized, placebo-controlled, double-blind MOVe-OUT trial demonstrated molnupiravir (800 mg every 12 h for 5 days) as safe and effective for outpatient treatment of ...mild-to-moderate COVID-19, significantly reducing the risk of hospitalization/death in high-risk adults. At the time of that report, virologic assessments from the trial were partially incomplete as a result of their time-intensive nature. Here we present final results from all prespecified virology endpoints in MOVe-OUT based on the full trial dataset.
Methods
Nasopharyngeal swabs were collected at baseline (day 1, prior to first dose) and days 3, 5 (end-of-treatment visit), 10, 15, and 29. From these samples, change from baseline in SARS-CoV-2 RNA titers (determined by quantitative PCR), detection of infectious SARS-CoV-2 (by plaque assay), and SARS-CoV-2 viral error induction (determined by whole genome next-generation sequencing) were assessed as exploratory endpoints.
Results
Molnupiravir was associated with greater mean reductions from baseline in SARS-CoV-2 RNA than placebo (including 50% relative reduction at end-of-treatment) through day 10. Among participants with infectious virus detected at baseline (
n
= 96 molnupiravir,
n
= 97 placebo) and evaluable post-baseline samples, no molnupiravir-treated participant had infectious SARS-CoV-2 by day 3, whereas infectious virus was recovered from 21% of placebo-arm participants on day 3 and 2% at end-of-treatment. Consistent with molnupiravir’s mechanism of action, sequence analysis demonstrated that molnupiravir was associated with an increased number of low-frequency transition errors randomly distributed across the SARS-CoV-2 RNA genome compared with placebo (median 143.5 molnupiravir, 15 placebo), while transversion errors were infrequent overall (median 2 in both arms). Outcomes were consistent regardless of baseline SARS-CoV-2 clade, presence of SARS-CoV-2-specific immune response, or viral load.
Conclusions
A 5-day course of orally administered molnupiravir demonstrated a consistently greater virologic effect than placebo, including rapidly eliminating infectious SARS-CoV-2, in high-risk outpatients with mild-to-moderate COVID-19.
Trial Registration
ClinicalTrials.gov, NCT04575597.
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.)
Oral outpatient treatment for Covid-19 is needed. In this phase 3, double-blind, randomized, controlled trial, molnupiravir, a small-molecule antiviral, was studied in unvaccinated patients with less ...than 5 days of Covid-19 illness. By day 29, hospitalization for progression of Covid-19 was lower with molnupiravir (6.8%) than with placebo (9.7%).
Abstract
Background
The β-lactamase inhibitor relebactam can restore imipenem activity against imipenem-nonsusceptible gram-negative pathogens. We evaluated imipenem/relebactam for treating ...imipenem-nonsusceptible infections.
Methods
Randomized, controlled, double-blind, phase 3 trial. Hospitalized patients with hospital-acquired/ventilator-associated pneumonia, complicated intraabdominal infection, or complicated urinary tract infection caused by imipenem-nonsusceptible (but colistin- and imipenem/relebactam-susceptible) pathogens were randomized 2:1 to 5–21 days imipenem/relebactam or colistin+imipenem. Primary endpoint: favorable overall response (defined by relevant endpoints for each infection type) in the modified microbiologic intent-to-treat (mMITT) population (qualifying baseline pathogen and ≥1 dose study treatment). Secondary endpoints: clinical response, all-cause mortality, and treatment-emergent nephrotoxicity. Safety analyses included patients with ≥1 dose study treatment.
Results
Thirty-one patients received imipenem/relebactam and 16 colistin+imipenem. Among mITT patients (n = 21 imipenem/relebactam, n = 10 colistin+imipenem), 29% had Acute Physiology and Chronic Health Evaluation II scores >15, 23% had creatinine clearance <60 mL/min, and 35% were aged ≥65 years. Qualifying baseline pathogens: Pseudomonas aeruginosa (77%), Klebsiella spp. (16%), other Enterobacteriaceae (6%). Favorable overall response was observed in 71% imipenem/relebactam and 70% colistin+imipenem patients (90% confidence interval CI for difference, –27.5, 21.4), day 28 favorable clinical response in 71% and 40% (90% CI, 1.3, 51.5), and 28-day mortality in 10% and 30% (90% CI, –46.4, 6.7), respectively. Serious adverse events (AEs) occurred in 10% of imipenem/relebactam and 31% of colistin+imipenem patients, drug-related AEs in 16% and 31% (no drug-related deaths), and treatment-emergent nephrotoxicity in 10% and 56% (P = .002), respectively.
Conclusions
Imipenem/relebactam is an efficacious and well-tolerated treatment option for carbapenem-nonsusceptible infections.
Clinical Trials Registration
NCT02452047.
Imipenem/relebactam (IMI/REL) is a suitable treatment option for serious gram-negative infections, including those caused by carbapenem-nonsusceptible pathogens in high-risk patients. IMI/REL may be preferable to colistin-based therapy, given comparable efficacy but IMI/REL’s significantly lower nephrotoxicity and improved overall tolerability.
The β-lactamase inhibitor relebactam can restore imipenem activity against imipenem non-susceptible pathogens.
To explore relebactam's safety, tolerability and efficacy, we conducted a randomized ...(1:1:1), controlled, Phase 2 trial comparing imipenem/cilastatin+relebactam 250 mg, imipenem/cilastatin+relebactam 125 mg and imipenem/cilastatin alone in adults with complicated urinary tract infections (cUTI) or acute pyelonephritis, regardless of baseline pathogen susceptibility. Treatment was administered intravenously every 6 h for 4-14 days, with optional step-down to oral ciprofloxacin. The primary endpoint was favourable microbiological response rate (pathogen eradication) at discontinuation of intravenous therapy (DCIV) in the microbiologically evaluable (ME) population. Non-inferiority of imipenem/cilastatin+relebactam over imipenem/cilastatin alone was defined as lower bounds of the 95% CI for treatment differences being above -15%.
At DCIV, 71 patients in the imipenem/cilastatin + 250 mg relebactam, 79 in the imipenem/cilastatin + 125 mg relebactam and 80 in the imipenem/cilastatin-only group were ME; 51.7% had cUTI and 48.3% acute pyelonephritis. Microbiological response rates were 95.5%, 98.6% and 98.7%, respectively, confirming non-inferiority of both imipenem/cilastatin + relebactam doses to imipenem/cilastatin alone. Clinical response rates were 97.1%, 98.7% and 98.8%, respectively. All 23 ME patients with imipenem non-susceptible pathogens had favourable DCIV microbiological responses (100% in each group). Among all 298 patients treated, 28.3%, 29.3% and 30.0% of patients, respectively, had treatment-emergent adverse events. The most common treatment-related adverse events across groups (1.0%-4.0%) were diarrhoea, nausea and headache.
Imipenem/cilastatin + relebactam (250 or 125 mg) was as effective as imipenem/cilastatin alone for treatment of cUTI. Both relebactam-containing regimens were well tolerated. (NCT01505634).
Abstract
Background
Imipenem combined with the β-lactamase inhibitor relebactam has broad antibacterial activity, including against carbapenem-resistant gram-negative pathogens. We evaluated efficacy ...and safety of imipenem/cilastatin/relebactam in treating hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP).
Methods
This was a randomized, controlled, double-blind phase 3 trial. Adults with HABP/VABP were randomized 1:1 to imipenem/cilastatin/relebactam 500 mg/500 mg/250 mg or piperacillin/tazobactam 4 g/500 mg, intravenously every 6 hours for 7–14 days. The primary endpoint was day 28 all-cause mortality in the modified intent-to-treat (MITT) population (patients who received study therapy, excluding those with only gram-positive cocci at baseline). The key secondary endpoint was clinical response 7–14 days after completing therapy in the MITT population.
Results
Of 537 randomized patients (from 113 hospitals in 27 countries), the MITT population comprised 264 imipenem/cilastatin/relebactam and 267 piperacillin/tazobactam patients; 48.6% had ventilated HABP/VABP, 47.5% APACHE II score ≥15, 24.7% moderate/severe renal impairment, 42.9% were ≥65 years old, and 66.1% were in the intensive care unit. The most common baseline pathogens were Klebsiella pneumoniae (25.6%) and Pseudomonas aeruginosa (18.9%). Imipenem/cilastatin/relebactam was noninferior (P < .001) to piperacillin/tazobactam for both endpoints: day 28 all-cause mortality was 15.9% with imipenem/cilastatin/relebactam and 21.3% with piperacillin/tazobactam (difference, −5.3% 95% confidence interval {CI}, −11.9% to 1.2%), and favorable clinical response at early follow-up was 61.0% and 55.8%, respectively (difference, 5.0% 95% CI, −3.2% to 13.2%). Serious adverse events (AEs) occurred in 26.7% of imipenem/cilastatin/relebactam and 32.0% of piperacillin/tazobactam patients; AEs leading to treatment discontinuation in 5.6% and 8.2%, respectively; and drug-related AEs (none fatal) in 11.7% and 9.7%, respectively.
Conclusions
Imipenem/cilastatin/relebactam is an appropriate treatment option for gram-negative HABP/VABP, including in critically ill, high-risk patients.
Clinical Trials Registration
NCT02493764.
Imipenem/cilastatin/relebactam was noninferior to piperacillin/tazobactam for treating hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP), with a comparable tolerability profile. Imipenem/cilastatin/relebactam is an efficacious treatment option for nosocomial pneumonia, including HABP/VABP in mechanically ventilated and critically ill, high-risk patients.
Abstract
Background
Molnupiravir is an orally administered antiviral authorized for COVID-19 treatment in adults at high risk of progression to severe disease. Here, we report secondary and post hoc ...analyses of participants’ self-reported symptoms in the MOVe-OUT trial, which evaluated molnupiravir initiated within 5 days of symptom onset in nonhospitalized, unvaccinated adults with mild-to-moderate, laboratory-confirmed COVID-19.
Methods
Eligible participants completed a 15-item symptom diary daily from day 1 (randomization) through day 29, rating symptom severity as “none,” “mild,” “moderate,” or “severe”; loss of smell and loss of taste were rated as “yes” or “no.” Time to sustained symptom resolution/improvement was defined as the number of days from randomization to the first of 3 consecutive days of reduced severity, without subsequent relapse. Time to symptom progression was defined as the number of days from randomization to the first of 2 consecutive days of worsening severity. The Kaplan-Meier method was used to estimate event rates at various time points. The Cox proportional hazards model was used to estimate the hazard ratio between molnupiravir and placebo.
Results
For most targeted COVID-19 symptoms, sustained resolution/improvement was more likely, and progression was less likely, in the molnupiravir versus placebo group through day 29. When evaluating 5 distinctive symptoms of COVID-19, molnupiravir participants had a shorter median time to first resolution (18 vs 20 d) and first alleviation (13 vs 15 d) of symptoms compared with placebo.
Conclusions
Molnupiravir treatment in at-risk, unvaccinated patients resulted in improved clinical outcomes for most participant-reported COVID-19 symptoms compared with placebo.
Clinical Trials Registration. ClinicalTrials.gov: NCT04575597.
Secondary and post hoc analyses of patient-reported outcome data from the phase 3 component of MOVe-OUT demonstrated improved clinical outcomes with molnupiravir treatment—both for sustained resolution/improvement and progression—for most targeted COVID-19 symptoms compared with placebo.
Graphical abstract
Graphical Abstract
In a placebo-controlled, phase 2–3 trial, one dose of mRNA-1345 led to a lower incidence of RSV disease among adults 60 years of age or older. Solicited local and systemic adverse reactions occurred ...more often with the vaccine.
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