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1.
Nat Commun ; 13(1):4931, 2022.
Article in English | PubMed | ID: covidwho-2000888

ABSTRACT

Anti-SARS-CoV-2 monoclonal antibodies are mainstay COVID-19 therapeutics. Safety, antiviral, and clinical efficacy of bamlanivimab were evaluated in the randomized controlled trial ACTIV-2/A5401. Non-hospitalized adults were randomized 1:1 within 10 days of COVID-19 symptoms to bamlanivimab or blinded-placebo in two dose-cohorts (7000 mg, n = 94;700 mg, n = 223). No differences in bamlanivimab vs placebo were observed in the primary outcomes: proportion with undetectable nasopharyngeal SARS-CoV-2 RNA at days 3, 7, 14, 21, and 28 (risk ratio = 0.82-1.05 for 7000 mg [p(overall) = 0.88] and 0.81-1.21 for 700 mg [p(overall) = 0.49]), time to symptom improvement (median 21 vs 18.5 days [p = 0.97], 7000 mg;24 vs 20.5 days [p = 0.08], 700 mg), or grade 3+ adverse events. However, bamlanivimab was associated with lower day 3 nasopharyngeal viral levels and faster reductions in inflammatory markers and viral decay by modeling. This study provides evidence of faster reductions in nasopharyngeal SARS-CoV-2 RNA levels but not shorter symptom durations in non-hospitalized adults with early variants of SARS-CoV-2.

2.
Topics in Antiviral Medicine ; 30(1 SUPPL):246, 2022.
Article in English | EMBASE | ID: covidwho-1880203

ABSTRACT

Background: Randomized COVID-19 trials provide opportunities to describe post-acute sequelae of SARS-CoV-2 (PASC)-related symptom burden longitudinally and assess the impact of early use of antivirals on PASC prevalence. Methods: ACTIV-2 evaluates safety and efficacy of investigational agents for non-hospitalized adults with mild to moderate COVID-19 in a Phase II/III trial. In Phase II, participants were randomized within 10 days of symptom onset and a positive SARS-CoV-2 virologic test to receive bamlanivimab (BAM) or placebo as a single infusion at 7000mg (n=94) or 700mg (n=225). In a subsequent single-arm open-label study, 1059 participants received 700mg BAM. Participants completed a 13-symptom daily diary from enrollment through Day 28. A long-term (LT) diary (14 additional symptoms) introduced after the study was underway was completed by a subset of individuals every 12 weeks. We report Week 24 findings. Results: Between Aug 2020 to Feb 2021 605 participants enrolled and completed LT diary at Week 24 [Phase II: 7000mg vs. placebo (n=25);700mg vs. placebo (n=68);single-arm open-label cohort: 700mg (n=512)]. Median age was 50 years, 51% female sex, 99% identified as cis-gender, 5% Black/African American, and 35% Hispanic/Latino. At enrollment, 53% reported ≥1 high-risk comorbidity and 0.3% were vaccinated against COVID-19. By Week 24, 14% (87/605) had not returned to their pre-COVID-19 health by self-report, with 57% (50/87) reporting ≥3 PASC symptoms. The most common symptoms were fatigue (45% of 87), smell disorder (36%), breathing difficulties (30%), taste disorders (25%), musculoskeletal pain (26%) or weakness (23%), and cognitive complaints: difficulty concentrating/thinking (30%), difficulty reasoning and solving problems (21%), memory loss (25%) and insomnia (23%). Most reported symptoms as "mild". Participants who reported acute viral illness symptoms between Days 22-28 were more likely to report PASC symptoms at Week 24 than those who did not report symptoms at Days 22-28 [51% (164/320) vs. 27% (76/285);p<0.0001]. Conclusion: In outpatients with mild to moderate COVID-19, 14% had not returned to pre-COVID-19 health by 24 weeks post infection, with generally mild but multiple symptoms. Presence of acute viral illness symptoms at 3-4 weeks was associated with an increased risk of PASC symptoms months later. Larger placebo-controlled studies within ACTIV-2 will assess the potential for early antiviral therapies to mitigate or prevent PASC.

3.
MEDLINE;
Preprint in English | MEDLINE | ID: ppcovidwho-326686

ABSTRACT

Resistance mutations to monoclonal antibody (mAb) therapy has been reported, but in the non-immunosuppressed population, it is unclear if in vivo emergence of SARS-CoV-2 resistance mutations alters either viral replication dynamics or therapeutic efficacy. In ACTIV-2/A5401, non-hospitalized participants with symptomatic SARS-CoV-2 infection were randomized to bamlanivimab (700mg or 7000mg) or placebo. Treatment-emergent resistance mutations were significantly more likely detected after bamlanivimab 700mg treatment than placebo (7% of 111 vs 0% of 112 participants, P=0.003). There were no treatment-emergent resistance mutations among the 48 participants who received bamlanivimab 7000mg. Participants with emerging mAb resistant virus had significantly higher pre-treatment nasopharyngeal and anterior nasal viral load. Intensive respiratory tract viral sampling revealed the dynamic nature of SARS-CoV-2 evolution, with evidence of rapid and sustained viral rebound after emergence of resistance mutations, and worsened symptom severity. Participants with emerging bamlanivimab resistance often accumulated additional polymorphisms found in current variants of concern/interest and associated with immune escape. These results highlight the potential for rapid emergence of resistance during mAb monotherapy treatment, resulting in prolonged high level respiratory tract viral loads and clinical worsening. Careful virologic assessment should be prioritized during the development and clinical implementation of antiviral treatments for COVID-19.

6.
Jama-Journal of the American Medical Association ; 326(1):46-55, 2021.
Article in English | Web of Science | ID: covidwho-1330273

ABSTRACT

Importance Preventive interventions are needed to protect residents and staff of skilled nursing and assisted living facilities from COVID-19 during outbreaks in their facilities. Bamlanivimab, a neutralizing monoclonal antibody against SARS-CoV-2, may confer rapid protection from SARS-CoV-2 infection and COVID-19. Objective To determine the effect of bamlanivimab on the incidence of COVID-19 among residents and staff of skilled nursing and assisted living facilities. Design, Setting, and Participants Randomized, double-blind, single-dose, phase 3 trial that enrolled residents and staff of 74 skilled nursing and assisted living facilities in the United States with at least 1 confirmed SARS-CoV-2 index case. A total of 1175 participants enrolled in the study from August 2 to November 20, 2020. Database lock was triggered on January 13, 2021, when all participants reached study day 57. Interventions Participants were randomized to receive a single intravenous infusion of bamlanivimab, 4200 mg (n = 588), or placebo (n = 587). Main Outcomes and Measures The primary outcome was incidence of COVID-19, defined as the detection of SARS-CoV-2 by reverse transcriptase-polymerase chain reaction and mild or worse disease severity within 21 days of detection, within 8 weeks of randomization. Key secondary outcomes included incidence of moderate or worse COVID-19 severity and incidence of SARS-CoV-2 infection. Results The prevention population comprised a total of 966 participants (666 staff and 300 residents) who were negative at baseline for SARS-CoV-2 infection and serology (mean age, 53.0 [range, 18-104] years;722 [74.7%] women). Bamlanivimab significantly reduced the incidence of COVID-19 in the prevention population compared with placebo (8.5% vs 15.2%;odds ratio, 0.43 [95% CI, 0.28-0.68];P < .001;absolute risk difference, -6.6 [95% CI, -10.7 to -2.6] percentage points). Five deaths attributed to COVID-19 were reported by day 57;all occurred in the placebo group. Among 1175 participants who received study product (safety population), the rate of participants with adverse events was 20.1% in the bamlanivimab group and 18.9% in the placebo group. The most common adverse events were urinary tract infection (reported by 12 participants [2%] who received bamlanivimab and 14 [2.4%] who received placebo) and hypertension (reported by 7 participants [1.2%] who received bamlanivimab and 10 [1.7%] who received placebo). Conclusions and Relevance Among residents and staff in skilled nursing and assisted living facilities, treatment during August-November 2020 with bamlanivimab monotherapy reduced the incidence of COVID-19 infection. Further research is needed to assess preventive efficacy with current patterns of viral strains with combination monoclonal antibody therapy. This randomized clinical trial assesses the effect of a single intravenous infusion of bamlanivimab vs placebo on incidence of COVID-19 among residents and staff of skilled nursing and assisted living facilities. Question Among residents and staff of skilled nursing and assisted living facilities with high risk of SARS-CoV-2 exposure, what is the effect of bamlanivimab on the incidence of COVID-19? Findings This randomized phase 3 clinical trial included 966 participants who were residents and staff at US skilled nursing and assisted living facilities with at least 1 confirmed SARS-CoV-2 index case and who were negative at baseline for SARS-CoV-2 infection and serology, enrolled from August to November 2020. The incidence of COVID-19 infection among those treated with bamlanivimab vs placebo was 8.5% vs 15.2%, respectively, a difference that was statistically significant. Meaning Bamlanivimab monotherapy compared with placebo reduced the risk of COVID-19 in residents and staff of skilled nursing and assisted living facilities.

7.
Topics in Antiviral Medicine ; 29(1):33, 2021.
Article in English | EMBASE | ID: covidwho-1250118

ABSTRACT

Background: Patients with underlying medical conditions have a greater risk of developing severe COVID-19. Unlike vaccine-derived immunity which develops over time, administration of neutralizing monoclonal antibodies is an immediate, passive humoral immunotherapy, with the potential to reduce disease progression, emergency room visits, hospitalizations, and death. Methods: In this phase 3 portion of the BLAZE-1 trial, a high-risk ambulatory cohort of 1035 patients with mild-to-moderate COVID-19 were randomly assigned 1:1 to receive a single intravenous infusion of a neutralizing monoclonal antibody combination treatment consisting of 2800mg bamlanivimab+2800mg etesevimab together, or placebo, within 3 days of laboratory diagnosis. The primary outcome was overall patient clinical status, measured by the proportion of patients who experienced COVID-19-related hospitalization or death by any cause by Day 29. Results: 1035 patients were randomized and infused (mean age [SD];53.8 years [16.8], female (52%)). A 70% reduction in COVID-19-related hospitalization and death by any cause by Day 29 was observed in patients who received the bamlanivimab+etesevimab combination treatment (11/518 arm total) compared to those who received placebo (36/517 arm total) (Δ[95% CI]=-4.8[-7.4,-2.3])(p=0.0004). No deaths were observed among patients who received the combination treatment, 10 deaths were reported in the placebo group, at least 8 designated COVID-19-related. A significantly greater reduction in log10(viral load) from baseline at Day 7 was observed amongst patients who received bamlanivimab+etesevimab compared to placebo (Δ[95% CI]=-1.20[-1.46,-0.94])(p<0.00000001). The median time to sustained symptom resolution was shorter for those who received the combination treatment (days [95% CI]=8[7.0,8.0]) compared to those who received placebo (days [95% CI]=9[8.0,10.0])(p=0.007). Similar rates of adverse events were observed between placebo (60/517,11.6%) and combination treatment groups (69/518,13.3%). Conclusion: 2800mg bamlanivimab+2800mg etesevimab neutralizing monoclonal antibody combination therapy significantly reduced COVID-19- related hospitalizations and deaths amongst high-risk ambulatory patients and accelerated the decline in viral load and disease symptoms over time. This study confirms that early intervention with bamlanivimab + etesevimab greatly improves the clinical outcomes for high-risk ambulatory patients, and links reduction in nasopharyngeal viral load to clinically meaningful benefits.

8.
Topics in Antiviral Medicine ; 29(1):32-33, 2021.
Article in English | EMBASE | ID: covidwho-1250038

ABSTRACT

Background: The COVID-19 pandemic has disproportionately affected residents of skilled nursing and assisted living facilities. Interventions are urgently needed to protect this vulnerable population. Bamlanivimab is a potent neutralizing monoclonal antibody that binds the receptor-binding domain of the spike protein of SARS-CoV-2. This study evaluates the safety and efficacy of bamlanivimab in preventing COVID-19. Methods: BLAZE-2 is a Phase 3, randomized, double-blind, placebo-controlled, single-dose study that enrolled residents and staff at skilled nursing and assisted living facilities reporting at least one confirmed SARS-CoV-2 case. Eligible participants received bamlanivimab (4200 mg) or placebo intravenously. Nasal swabs were collected at baseline and weekly through day 57 to determine SARS-CoV-2 infection status via reverse transcriptase polymerase chain reaction (RT-PCR). COVID-19-releated symptoms and signs were recorded daily. The primary analysis prevention population included participants negative at baseline for SARS-CoV-2 by RT-PCR and serology. The primary endpoint was incidence of mild or worse COVID-19 by day 57. Results: Of the 1175 participants dosed, 966 (82.2%) comprised the prevention population. The prevention population included 299 residents for whom the median age was 76 years (range 31-104), 234 (78.3%) were aged ≥65, and 178 (59.5%) were female. All were considered at high risk for development of severe COVID-19. The proportion of residents in the prevention population with mild or worse COVID-19 by day 57 was significantly lower in the bamlanivimab group compared with the placebo group (odds ratio [OR], 0.20;95% confidence interval [CI], 0.08 to 0.49;p<0.001)(Figure). For this same group, bamlanivimab was associated with significant reductions in the incidence of moderate or worse COVID-19 by day 57 (OR, 0.20;95% CI, 0.08 to 0.49;p<0.001) and incident SARS-CoV-2 infection by day 29 (OR, 0.23;CI, 0.11 to 0.48;p<0.001) compared with placebo. Of the 16 deaths reported during the study, all 5 that were attributed to COVID-19 were in the placebo group. The incidence of both adverse events and serious adverse events were balanced between the bamlanivimab and placebo group. Conclusion: Bamlanivimab was highly effective in reducing the incidence of symptomatic COVID-19 and SARS-CoV-2 infection and was well tolerated. These findings demonstrate the potential beneficial impact of bamlanivimab use on COVID-19 morbidity and mortality among skilled nursing facility residents.

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