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Background The prevention of coronavirus disease 2019 (COVID-19) in vulnerable populations is a global health priority. EVADE was a phase 2/3 multicenter, double-blind, randomized, placebo-controlled trial of adintrevimab, an extended–half-life monoclonal antibody, for postexposure (PEP) and pre-exposure prophylaxis (PrEP) of symptomatic COVID-19. Methods Eligible participants (vaccine-naive, aged ≥12 years) were randomized 1:1 to receive a single 300-mg intramuscular injection of adintrevimab or placebo. Primary efficacy end points were reverse transcription polymerase chain reaction (RT-PCR)–confirmed symptomatic COVID-19 through day 28 in the PEP cohort (RT-PCR-negative at baseline) and through month 3 in the PrEP cohort (RT-PCR-negative and seronegative at baseline) among participants randomized before emergence of the severe acute respiratory syndrome coronavirus 2 Omicron variant (November 30, 2021). Safety was assessed through 6 months. Results Between April 27, 2021, and January 11, 2022, 2582 participants were randomized. In the primary efficacy analysis, RT-PCR-confirmed symptomatic COVID-19 occurred in 3/175 (1.7%) vs 12/176 (6.8%) adintrevimab- and placebo-treated PEP participants, respectively (74.9% relative risk reduction [RRR]; standardized risk difference, −5.0%; 95% CI, −8.87% to −1.08%; P =.0123) and in 12/752 (1.6%) vs 40/728 (5.5%) adintrevimab- and placebo-treated PrEP participants, respectively (71.0% RRR; standardized risk difference, −3.9%; 95% CI, −5.75% to −2.01%; P <.0001). In a prespecified exploratory analysis of 428 PrEP participants randomized after the emergence of Omicron, adintrevimab reduced RT-PCR-confirmed symptomatic COVID-19 by 40.6% (standardized risk difference −8.4%; 95% CI, −15.35% to −1.46%; nominal P =.0177) vs placebo. Adintrevimab was well tolerated, with no serious drug-related adverse events reported. Conclusions A single intramuscular injection of adintrevimab provided prophylactic efficacy against COVID-19 due to susceptible variants without safety concerns. Clinical trial registration. NCT04859517. [ABSTRACT FROM AUTHOR]

Background Safe and effective treatments are needed to prevent severe outcomes in individuals with coronavirus disease 2019 (COVID-19). We report results from STAMP, a phase 2/3, multicenter, double-blind, randomized, placebo-controlled trial of adintrevimab, an extended half-life monoclonal antibody, for treatment of high-risk ambulatory patients with mild to moderate COVID-19. Methods Nonhospitalized, unvaccinated participants aged ≥12 years with mild to moderate COVID-19 and ≥1 risk factor for disease progression were randomized to receive a single intramuscular injection of 300 mg adintrevimab or placebo. Enrollment was paused due to the global emergence of the Omicron BA.1/BA1.1 variants, against which adintrevimab showed reduced activity in vitro. The primary efficacy endpoint was COVID-19–related hospitalization or all-cause death through day 29 in participants with COVID-19 due to laboratory-confirmed or suspected non-Omicron severe acute respiratory syndrome coronavirus 2 variants. Results Between 8 August 2021 and 11 January 2022, 399 participants were randomized to receive adintrevimab (n = 198) or placebo (n = 201), including 336 with COVID-19 due to non-Omicron variants. COVID-19–related hospitalization or all-cause death through day 29 occurred in 8 of 169 (4.7%) participants in the adintrevimab group and 23 of 167 (13.8%) participants in the placebo group, a 66% relative risk reduction in favor of adintrevimab (standardized risk difference, −8.7% [95% confidence interval, −14.71% to −2.67%]; P =.0047). Incidence of treatment-emergent adverse events (TEAEs) was similar between treatment groups (33.9% for adintrevimab and 39.5% for placebo). No adintrevimab-related serious TEAEs were reported. Conclusions Treatment with a single intramuscular injection of adintrevimab provided protection against severe outcomes in high-risk ambulatory participants with COVID-19 due to susceptible variants, without safety concerns. Clinical Trial Registration. NCT04805671. [ABSTRACT FROM AUTHOR]

Introduction: Adintrevimab is a fully human immunoglobulin G1 extended half-life monoclonal antibody that was developed to have broad neutralization against SARS-CoV, SARS-CoV-2, and other SARS-like CoVs with pandemic potential. Here we report the safety, pharmacokinetics (PK), serum viral neutralizing antibody (sVNA) titers, and immunogenicity results of the first three cohorts evaluated in the first-in-human study of adintrevimab in healthy adults. Methods: This is a phase 1, randomized, placebo-controlled, single ascending-dose study of adintrevimab administered intramuscularly (IM) or intravenously (IV) to healthy adults aged ≥ 18–55 years with no current or prior SARS-CoV-2 infection. Participants were randomized 8:2 to adintrevimab or placebo in each of three dose cohorts: adintrevimab 300 mg IM (cohort 1), 500 mg IV (cohort 2), and 600 mg IM (cohort 3). Follow-up was 12 months. Blood samples were taken predose and at multiple time points postdose up to month 12 to assess sVNA, PK, and antidrug antibodies (ADAs). Results: Thirty participants received a single dose of adintrevimab (n = 24; 8 per cohort) or placebo (n = 6). All except one adintrevimab participant in cohort 1 completed the study. No participants in any treatment arm experienced a study drug-related adverse event. Across adintrevimab-treated participants, 11 (45.8%) experienced at least one TEAE. All but one TEAE were mild in severity, and all were either viral infection or respiratory symptoms. There were no serious adverse events, discontinuations due to adverse events, or deaths. Adintrevimab exhibited a linear and dose-proportional PK profile and extended serum half-life (mean 96, 89, and 100 days in cohorts 1, 2, and 3, respectively). Participants receiving adintrevimab demonstrated dose-dependent increased sVNA titers and breadth across multiple variants. Conclusion: Adintrevimab at doses of 300 mg IM, 500 mg IV, and 600 mg IM was well tolerated in healthy adults. Adintrevimab demonstrated dose-proportional exposure, rapid development of neutralizing antibody titers, and an extended half-life. [ABSTRACT FROM AUTHOR]

Multiple studies of vaccinated and convalescent cohorts have demonstrated that serum neutralizing antibody (nAb) titers correlate with protection against coronavirus disease 2019 (COVID-19). However, the induction of multiple layers of immunity after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure has complicated the establishment of nAbs as a mechanistic correlate of protection (CoP) and hindered the definition of a protective nAb threshold. Here, we show that a half-life–extended monoclonal antibody (adintrevimab) provides about 50% protection against symptomatic COVID-19 in SARS-CoV-2–naïve adults at serum nAb titers on the order of 1:30. Vaccine modeling results support a similar 50% protective nAb threshold, suggesting that low titers of serum nAbs protect in both passive antibody prophylaxis and vaccination settings. Extrapolation of adintrevimab pharmacokinetic data suggests that protection against susceptible variants could be maintained for about 3 years. The results provide a benchmark for the selection of next-generation vaccine candidates and support the use of broad, long-acting monoclonal antibodies as alternatives or supplements to vaccination in high-risk populations. Correlating protection: Monoclonal antibodies have become an essential component of the SARS-CoV-2 treatment toolkit. However, the serum neutralizing titers necessary for these antibodies to confer protection against symptomatic infection have not been determined. Here, Schmidt et al. studied the protection conferred by a half-life extended monoclonal antibody, adintrevimab, in SARS-CoV-2–naive adults. Serum neutralizing antibody titers of 1:30 were sufficient to confer 50% protection against symptomatic infection in these individuals. These data, in combination with pharmacokinetics studies in humans, suggested that adintrevimab could confer protection against susceptible variants for up to 3 years. Together, these results support the use of half-life extended monoclonal antibodies for SARS-CoV-2 prophylaxis, especially in high-risk populations. —CM [ABSTRACT FROM AUTHOR]

Objective To determine whether baseline nausea or prior triptan treatment for migraine impact the effectiveness of diclofenac potassium for oral solution in treating acute migraine. Background A great deal of variability exists in patients' response to migraine medications. Migraine-associated nausea is common and debilitating and can reduce the effectiveness of oral medications. It may cause patients to delay taking oral medications, which is known to diminish therapeutic outcomes, or to avoid taking them altogether. Gastroparesis, which may be associated with nausea, also inhibits drug absorption, resulting in lower bioavailability. Studies have shown that having nausea at the time of drug administration predicts a poorer response to triptan treatment. It is of interest to understand how effective other migraine medications are in patients with a poor response to triptans. Methods Data from two randomized, double-blind, placebo controlled trials were pooled and post hoc subgroup analyses were performed in patients with and without nausea at baseline, and in patients with and without prior triptan treatment. Efficacy assessments included the percentage of patients who, at 2 hours postdosing, were headache pain-free (2hPF, primary endpoint), without photophobia, without phonophobia, without nausea, or without a severe degree of disability. A Cochran-Mantel-Haenszel test, stratified by analysis center was used to evaluate treatment effect. Effects of nausea or prior triptan use were determined using logistic regression with factors of treatment group, analysis center, nausea or prior triptan use at time of dosing, and interaction of treatment group by nausea or prior triptan use at time of dosing. Results The modified intent to treat population consisted of 1272 patients, 644 on active drug and 628 on placebo. The majority of patients (85%) were female. At the time of dosing, 783 (62%) patients reported nausea with the treated attack. Prior triptan use was recorded in 570 (45%). For headache pain, nausea, photophobia, and phonophobia, patients in the active treatment group had a statistically significantly better response than those receiving placebo, regardless of whether they had nausea at baseline. In logistic regression analysis only treatment group predicted a response for these parameters with no detectable group interaction. Baseline nausea, as well as treatment group, predicted whether patients recorded severe disability at 2 hours. While patients in the active treatment group were significantly more likely to be headache pain-free at 2 hours after dosing, whether or not they had previously been treated with triptan, more triptan-naïve patients (30%) than triptan-experienced patients (20%) were headache pain-free. Interestingly, in the placebo groups, triptan-naïve patients were also more likely to be PF (14% vs 7%). In the logistic regression analysis, treatment group predicted a headache pain response, triptan use predicted a lack of response, and there was no interaction between the two. Prior triptan use did not predict any of the other outcome measures. Conclusions Nausea at the time of dosing does not diminish the effectiveness of diclofenac potassium for oral solution. The rapid absorption profile may enhance the effectiveness in patients with nausea. Prior triptan use predicted poorer headache response at 2 hours postdose, suggesting the possibility of a subset of patients who are more likely to be refractory to both triptans and diclofenac. Diclofenac potassium for oral solution is effective in triptan-naïve patients but no reliable inference can be made from this study as to about how to order treatment. [ABSTRACT FROM AUTHOR]