No abstract

Background In the phase 1–2 portion of an adaptive trial, REGEN-COV, a combination of the monoclonal antibodies casirivimab and imdevimab, reduced the viral load and number of medical visits in patients with coronavirus disease 2019 (Covid-19). REGEN-COV has activity in vitro against current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern. Methods In the phase 3 portion of an adaptive trial, we randomly assigned outpatients with Covid-19 and risk factors for severe disease to receive various doses of intravenous REGEN-COV or placebo. Patients were followed through day 29. A prespecified hierarchical analysis was used to assess the end points of hospitalization or death and the time to resolution of symptoms. Safety was also evaluated. Results Covid-19–related hospitalization or death from any cause occurred in 18 of 1355 patients in the REGEN-COV 2400-mg group (1.3%) and in 62 of 1341 patients in the placebo group who underwent randomization concurrently (4.6%) (relative risk reduction [1 minus the relative risk], 71.3%; P<0.001); these outcomes occurred in 7 of 736 patients in the REGEN-COV 1200-mg group (1.0%) and in 24 of 748 patients in the placebo group who underwent randomization concurrently (3.2%) (relative risk reduction, 70.4%; P=0.002). The median time to resolution of symptoms was 4 days shorter with each REGEN-COV dose than with placebo (10 days vs. 14 days; P<0.001 for both comparisons). REGEN-COV was efficacious across various subgroups, including patients who were SARS-CoV-2 serum antibody–positive at baseline. Both REGEN-COV doses reduced viral load faster than placebo; the least-squares mean difference in viral load from baseline through day 7 was −0.71 log 10 copies per milliliter (95% confidence interval [CI], −0.90 to −0.53) in the 1200-mg group and −0.86 log 10 copies per milliliter (95% CI, −1.00 to −0.72) in the 2400-mg group. Serious adverse events occurred more frequently in the placebo group (4.0%) than in the 1200-mg group (1.1%) and the 2400-mg group (1.3%); infusion-related reactions of grade 2 or higher occurred in less than 0.3% of the patients in all groups. Conclusions REGEN-COV reduced the risk of Covid-19–related hospitalization or death from any cause, and it resolved symptoms and reduced the SARS-CoV-2 viral load more rapidly than placebo. (Funded by Regeneron Pharmaceuticals and others; ClinicalTrials.gov number, NCT04425629 .)

Background REGEN-COV (previously known as REGN-COV2), a combination of the monoclonal antibodies casirivimab and imdevimab, has been shown to markedly reduce the risk of hospitalization or death among high-risk persons with coronavirus disease 2019 (Covid-19). Whether subcutaneous REGEN-COV prevents severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and subsequent Covid-19 in persons at high risk for infection because of household exposure to a person with SARS-CoV-2 infection is unknown. Methods We randomly assigned, in a 1:1 ratio, participants (≥12 years of age) who were enrolled within 96 hours after a household contact received a diagnosis of SARS-CoV-2 infection to receive a total dose of 1200 mg of REGEN-COV or matching placebo administered by means of subcutaneous injection. At the time of randomization, participants were stratified according to the results of the local diagnostic assay for SARS-CoV-2 and according to age. The primary efficacy end point was the development of symptomatic SARS-CoV-2 infection through day 28 in participants who did not have SARS-COV-2 infection (as measured by reverse-transcriptase–quantitative polymerase-chain-reaction assay) or previous immunity (seronegativity). Results Symptomatic SARS-CoV-2 infection developed in 11 of 753 participants in the REGEN-COV group (1.5%) and in 59 of 752 participants in the placebo group (7.8%) (relative risk reduction [1 minus the relative risk], 81.4%; P<0.001). In weeks 2 to 4, a total of 2 of 753 participants in the REGEN-COV group (0.3%) and 27 of 752 participants in the placebo group (3.6%) had symptomatic SARS-CoV-2 infection (relative risk reduction, 92.6%). REGEN-COV also prevented symptomatic and asymptomatic infections overall (relative risk reduction, 66.4%). Among symptomatic infected participants, the median time to resolution of symptoms was 2 weeks shorter with REGEN-COV than with placebo (1.2 weeks and 3.2 weeks, respectively), and the duration of a high viral load (>10 4 copies per milliliter) was shorter (0.4 weeks and 1.3 weeks, respectively). No dose-limiting toxic effects of REGEN-COV were noted. Conclusions Subcutaneous REGEN-COV prevented symptomatic Covid-19 and asymptomatic SARS-CoV-2 infection in previously uninfected household contacts of infected persons. Among the participants who became infected, REGEN-COV reduced the duration of symptomatic disease and the duration of a high viral load. (Funded by Regeneron Pharmaceuticals and others; ClinicalTrials.gov number, NCT04452318 .)

Morphine (M) and hydromorphone (HM) are commonly used opioid analgesics for cancer pain. Opioid rotation is often necessary in the event of toxicity and/or inadequate analgesia. Equianalgesic reference tables based on single dose comparisons are possibly inadequate for patients on chronic treatment and developing tolerance. This retrospective study of opioid rotation involving M and HM sought to determine the equianalgesic dose ratio for 91 rotations in 74 consecutively evaluable cancer pain patients. Only rotations involving subcutaneous (s.c.-s.c.) and oral (p.o.-p.o.) routes were evaluated. There were 44 rotations from M-HM (34: s.c.-s.c., 10: p.o.-p.o.) and 47 rotations from HM-M (35: s.c.-s.c., 12: p.o.-p.o.). Expressing all ratios as M/HM, the median dose ratios (lower-upper quartiles) for s.c. and p.o. rotations were 4.92 (4.1-5.9) vs. 5.76 (4.9-5.8) for M-HM (P = 0.28, NS) and 4.0 (3.1-4.8) vs. 3.45 (2.8-4.2) for HM-M (P = 0.4, NS), respectively. Pain intensity, as measured on a visual analogue scale (VASP), showed no significant difference between mean values pre- and post-rotation. A unified overall median dose ratio of 4.29 (3.3-5.3, lower-upper quartiles) was calculated by expressing all of the HM-M dose ratios as M/HM and combining them with the dose ratios for all of the M-HM rotations. This suggests a potency ratio of approximately 4.3:1 between M and HM. When expressed as M/HM for dose ratio comparison, the median dose ratio for all HM-M rotations was 3.7 (2.9-4.5, lower-upper quartiles) vs. 5 (4.2-5.9) for M-HM rotations (P = 0.0001), suggesting that the opioid to which rotation is taking place is more potent than our proposed unified overall median dose ratio of 4.29:1 would predict. Our data suggests that HM is 5 times more potent than M when given second (M-HM), but is only 3.7 times more potent when given first (HM-M). We therefore recommend a ratio of 5 for M/HM in rotating from M to HM and ratio of 3.7 for M/HM when rotating from HM to M in patients exposed to chronic dosing of these opioids. There was no correlation observed between M-HM and HM-M dose ratios and the level of previous opioid dose, in contrast to HM to methadone rotation where the dose ratio was higher in patients receiving higher doses of HM.

CoV-2 treatments may be used to prevent progression from asymptomatic infection to symptomatic disease and to reduce viral carriage.OBJECTIVE To evaluate the effect of combination subcutaneous casirivimab and imdevimab on progression from early asymptomatic SARS-CoV-2 infection to symptomatic COVID-19.DESIGN, SETTING, AND PARTICIPANTS Randomized, double-blind, placebo-controlled, phase 3 trial of close household contacts of a SARS-CoV-2-infected index case at 112 sites in the US,