Molnupiravir for the treatment of COVID-19 in immunocompromised participants: efficacy, safety, and virology results from the phase 3 randomized, placebo-controlled MOVe-OUT trial.

PURPOSE: Immunocompromised patients have a potentially increased risk for progression to severe COVID-19 and prolonged replication of SARS-CoV-2. This post hoc analysis examined outcomes among immunocompromised participants in the MOVe-OUT trial. METHODS: In phase 3 of MOVe-OUT, non-hospitalized at-risk adults with mild-to-moderate COVID-19 were randomized to receive molnupiravir 800 mg or placebo twice daily for 5 days. Immunocompromised participants were identified based on prior/concomitant medications and/or medical history. All-cause hospitalization/death, adverse events, SARS-CoV-2 titers, infectivity, and RNA sequences were compared between immunocompromised participants who received molnupiravir or placebo and with non-immunocompromised participants. RESULTS: Fifty-five of 1408 participants were considered immunocompromised. Compared to placebo, fewer molnupiravir-treated immunocompromised participants were hospitalized/died through Day 29 (22.6% [7/31] vs. 8.3% [2/24]), with fewer adverse events (45.2% [14/31] vs. 25.0% [6/24]). A larger mean change from baseline in SARS-CoV-2 RNA was observed with molnupiravir compared to placebo in non-immunocompromised participants (least squares mean [LSM] difference Day 5: - 0.31, 95% confidence interval [CI] - 0.47 to - 0.15), while the mean change was comparable between treatment groups in immunocompromised participants (LSM difference Day 5: 0.23, 95% CI - 0.71 to 1.17). Molnupiravir treatment was associated with increased clearance of infectious virus. Increased errors in viral nucleotide sequences in post-baseline samples compared to placebo support molnupiravir's mechanism of action and were not associated with observation of novel treatment-emergent amino acid substitutions in immunocompromised participants. CONCLUSION: Although the study population was small, these data suggest that molnupiravir treatment for mild-to-moderate COVID-19 in non-hospitalized immunocompromised adults is efficacious and safe and quickly reduces infectious SARS-CoV-2. GOV REGISTRATION NUMBER: NCT04575597.

Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients.

BACKGROUND: New treatments are needed to reduce the risk of progression of coronavirus disease 2019 (Covid-19). Molnupiravir is an oral, small-molecule antiviral prodrug that is active against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: We conducted a phase 3, double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of treatment with molnupiravir started within 5 days after the onset of signs or symptoms in nonhospitalized, unvaccinated adults with mild-to-moderate, laboratory-confirmed Covid-19 and at least one risk factor for severe Covid-19 illness. Participants in the trial were randomly assigned to receive 800 mg of molnupiravir or placebo twice daily for 5 days. The primary efficacy end point was the incidence hospitalization or death at day 29; the incidence of adverse events was the primary safety end point. A planned interim analysis was performed when 50% of 1550 participants (target enrollment) had been followed through day 29. RESULTS: A total of 1433 participants underwent randomization; 716 were assigned to receive molnupiravir and 717 to receive placebo. With the exception of an imbalance in sex, baseline characteristics were similar in the two groups. The superiority of molnupiravir was demonstrated at the interim analysis; the risk of hospitalization for any cause or death through day 29 was lower with molnupiravir (28 of 385 participants [7.3%]) than with placebo (53 of 377 [14.1%]) (difference, -6.8 percentage points; 95% confidence interval [CI], -11.3 to -2.4; P = 0.001). In the analysis of all participants who had undergone randomization, the percentage of participants who were hospitalized or died through day 29 was lower in the molnupiravir group than in the placebo group (6.8% [48 of 709] vs. 9.7% [68 of 699]; difference, -3.0 percentage points; 95% CI, -5.9 to -0.1). Results of subgroup analyses were largely consistent with these overall results; in some subgroups, such as patients with evidence of previous SARS-CoV-2 infection, those with low baseline viral load, and those with diabetes, the point estimate for the difference favored placebo. One death was reported in the molnupiravir group and 9 were reported in the placebo group through day 29. Adverse events were reported in 216 of 710 participants (30.4%) in the molnupiravir group and 231 of 701 (33.0%) in the placebo group. CONCLUSIONS: Early treatment with molnupiravir reduced the risk of hospitalization or death in at-risk, unvaccinated adults with Covid-19. (Funded by Merck Sharp and Dohme; MOVe-OUT ClinicalTrials.gov number, NCT04575597.).

Evaluation of Neural Tube Defects (NTDs) After Exposure to Raltegravir During Pregnancy.

OBJECTIVE: To evaluate the risk of neural tube defects (NTDs) after exposure to raltegravir during pregnancy. METHODS: Exposures to raltegravir during pregnancy reported cumulatively through May 31, 2018, to the company safety database were reviewed to identify cases of NTDs. This database includes all reports of pregnancy from Merck-sponsored clinical trials, spontaneous postmarketing reports, and non-interventional data sources, including the Antiretroviral Pregnancy Registry (APR). Reports were classified as prospective (before knowledge of pregnancy outcome) or retrospective (after knowledge of pregnancy outcome). We also reviewed data from 2 ongoing pregnancy cohorts. RESULTS: A total of 2426 pregnancies with reported outcomes were identified among women exposed to raltegravir: 1238 from the Merck database and 1188 from United Kingdom/Ireland and French pregnancy cohorts. Among all 2426 reports, 1991 were prospective. No cases of NTDs were identified among the prospective pregnancy reports, of which 767 were first trimester, including 456 in the periconception period (at or within 28 days after conception). Among the 435 retrospective reports, 3 NTD cases per APR criteria were identified (anencephaly, and 2 meningomyelocele), of which only one (meningomyelocele) was among exposures in the periconception period. Given the inherent limitations and bias of retrospective reports, it is not appropriate to calculate an incidence rate. CONCLUSIONS: Prospectively collected pregnancy outcome data do not suggest an association between raltegravir exposure in the periconception period and NTDs. The current data support the updated DHHS and EACS treatment guidelines for use of raltegravir as a preferred integrase inhibitor in all stages of pregnancy.

Use of an active surveillance system by the FDA to observe patterns of quinine sulfate use and adverse hematologic outcomes in CMS Medicare data.

PURPOSE: In 2005, the Food and Drug Administration approved Qualaquin (quinine) for treatment of malaria and later ordered unapproved quinine formulations off the market. In 2009, labeling for Qualaquin added a warning for use for leg cramps, as serious hematologic reactions could occur. We examined quinine use trends among Medicare beneficiaries focusing on indications for use and associations with adverse hematologic outcomes. METHODS: Medicare beneficiaries, aged 65 years and older, in 2006-2012, were included in incident quinine or comparator, diltiazem, cohorts if 183 days prior to dispensing, they were enrolled in Medicare, had no dispensing of quinine, diltiazem, ticlodipine, clopidogrel, and sulfonamide drugs, and had no diagnoses of thrombocytopenia, immune thrombocytopenic purpura (ITP), thrombotic microangiopathy (TMA), or hemolytic-uremic syndrome (HUS). Diagnoses of malaria or leg cramps were observed during 183 days prior to index dispensing. Outcomes of ITP, TMA, or HUS in inpatient or emergency room settings were then observed during drug use. RESULTS: Prevalent use of quinine decreased by 99%, from 419 675 to 6036 users during 2006-2012. Of 88 066 quinine users, 9 had diagnoses of malaria and 36 218 had leg cramps. Incidence rates (per 1000 person-years) for ITP were quinine 1.67 and diltiazem 0.40 [incidence rate ratio 4.2 (95% confidence interval 2.5, 6.5)], for TMA were quinine 0.23 and diltiazem 0.03 [incidence rate ratio 6.9 (95% confidence interval 1.3, 24.0)], and for HUS were quinine 0 and diltiazem 0.01. CONCLUSIONS: Use of quinine decreased substantially, although diagnoses of leg cramps persist. To our knowledge, this is the first demonstration of an association for quinine and ITP and TMA in claims data.

Scientific and regulatory reasons for delay and denial of FDA approval of initial applications for new drugs, 2000-2012.

IMPORTANCE: Some new drug applications fail because of inadequate drug performance and others are not approved because the information submitted to the US Food and Drug Administration (FDA) is unsatisfactory to make that determination. Resubmission of failed applications is costly, delaying marketing approval and the availability of new drugs to patients. OBJECTIVE: To identify the reasons that FDA marketing approval for new drugs was delayed or denied. DESIGN, SETTING, AND PARTICIPANTS: A retrospective review of FDA documents and extraction of data were performed. We examined all drug applications first submitted to the FDA between 2000 and 2012 for new molecular entities (NMEs), which are active ingredients never before marketed in the United States in any form. Using FDA correspondence and reviews, we investigated the reasons NMEs failed to obtain FDA approval. MAIN OUTCOMES AND MEASURES: Reasons for delayed FDA approval or nonapproval of NME applications. RESULTS: Of the 302 identified NME applications, 151 (50%) were approved when first submitted and 222 (73.5%) were ultimately approved. Seventy-one applications required 1 or more resubmissions before approval, with a median delay to approval of 435 days following the first unsuccessful submission. Of the unsuccessful first-time applications, 24 (15.9%) included uncertainties related to dose selection, 20 (13.2%) choice of study end points that failed to adequately reflect a clinically meaningful effect, 20 (13.2%) inconsistent results when different end points were tested, 17 (11.3%) inconsistent results when different trials or study sites were compared, and 20 (13.2%) poor efficacy when compared with the standard of care. The frequency of safety deficiencies was similar among never-approved drugs compared with those with delayed approval (43 of 80 never approved [53.8%] vs 37 of 71 eventually approved [52.1%]; difference, 1.7% [95% CI, -14.86% to 18.05%]; P = .87). However, efficacy deficiencies were significantly more frequent among the never-approved drugs than among those with delayed approvals (61 of 80 never approved [76.3%] vs 28 of 71 eventually approved [39.4%]; difference, 36.9% [95% CI, 20.25% to 50.86%]; P < .001). CONCLUSIONS AND RELEVANCE: Several potentially preventable deficiencies, including failure to select optimal drug doses and suitable study end points, accounted for significant delays in the approval of new drugs. Understanding the reasons for previous failures is helpful to improve the efficiency of clinical development for new drugs.

Treatment approaches to prosthetic joint infections: results of an Emerging Infections Network survey.

We report the results of an Emerging Infections Network survey of 994 infectious disease consultants (IDCs) regarding their participation in the medical management of prosthetic joint infections and observations of adverse effects associated with antibiotic-impregnated materials (response rate, 54.8%). There was general agreement about when a prosthesis can be retained, but substantial variability in the duration of suppressive antibiotics was recommended, with 36% supporting life-long suppression. For 2-stage procedures, 95% recommended a minimum of 4 weeks of systemic antibiotics after the first stage. However, there was little agreement regarding the duration of an antibiotic-free period before reimplantation. Eleven percent of IDCs reported adverse events related to antibiotic-impregnated materials, ranging from skin reactions to renal failure. Further studies to address the substantial variability in the duration of antibiotic suppressive therapy for retained joints and for the duration of antibiotic-free period before reimplantation are needed.

Systemic blastomycosis with osseous involvement of the foot: case report.

We report a patient who presented with three months of foot pain, lytic bone lesions in the foot, and a painless ipsilateral leg skin ulcer. Bone and skin biopsies revealed organisms compatible with Blastomyces. Systemic blastomycosis is rare, especially with bone involvement in the foot.

Sternoclavicular septic arthritis: review of 180 cases.

We review 170 previously reported cases of sternoclavicular septic arthritis, and report 10 new cases. The mean age of patients was 45 years; 73% were male. Patients presented with chest pain (78%) and shoulder pain (24%) after a median duration of symptoms of 14 days. Only 65% were febrile. Bacteremia was present in 62%. Common risk factors included intravenous drug use (21%), distant site of infection (15%), diabetes mellitus (13%), trauma (12%), and infected central venous line (9%). No risk factor was found in 23%. Serious complications such as osteomyelitis (55%), chest wall abscess or phlegmon (25%), and mediastinitis (13%) were common. Staphylococcus aureus was responsible for 49% of cases, and is now the major cause of sternoclavicular septic arthritis in intravenous drug users. Pseudomonas aeruginosa infection in injection drug users declined dramatically with the end of an epidemic of pentazocine abuse in the 1980s. Sternoclavicular septic arthritis accounts for 1% of septic arthritis in the general population, but 17% in intravenous drug users, for unclear reasons. Bacteria may enter the sternoclavicular joint from the adjacent valves of the subclavian vein after injection of contaminated drugs into the upper extremity, or the joint may become infected after attempted drug injection between the heads of the sternocleidomastoid muscle. Computed tomography or magnetic resonance imaging should be obtained routinely to assess for the presence of chest wall phlegmon, retrosternal abscess, or mediastinitis. If present, en-bloc resection of the sternoclavicular joint is indicated, possibly with ipsilateral pectoralis major muscle flap. Empiric antibiotic therapy may need to cover methicillin-resistant Staphylococcus aureus (MRSA).