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2.
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.

3.
Topics in Antiviral Medicine ; 30(1 SUPPL):173, 2022.
Article in English | EMBASE | ID: covidwho-1880928

ABSTRACT

Background: The discovery and development of SARS-CoV-2 therapies remains a priority. SAB-185 is a Transchromosomic, bovine-derived, fully human polyclonal immunoglobulin product for SARS-CoV-2 being studied in ACTIV-2, randomized controlled platform trial evaluating the safety and efficacy of investigational agents for non-hospitalized adults with mild-moderate COVID-19 Methods: This Phase II trial was a superiority comparison of SAB-185 vs. placebo. Participants with confirmed SAR-CoV-2 infection received intravenous infusion of SAB-185 (3,840 Units/kg) or placebo. Primary outcome measures were proportion of participants with SARS-CoV-2 RNA < lower limit of quantification (LLoQ) in nasopharyngeal (NP) swab, time to improvement in targeted symptoms for 2 consecutive days after Day 0, and safety through Day 28. Secondary outcomes included quantitative NP RNA levels and all-cause hospitalizations and deaths. Antiviral or clinical efficacy and safety criteria for graduation to Phase III were pre-specified. Results: From April to August 2021, randomized participants from 42 sites in the US received SAB-185 (N=107) or placebo (N=106). Median age was 38 years (quartiles: 30,48), 54% female, >98% cis-gender, 7% Black/African-American, 50% Hispanic, and 11% were classified as high-risk for COVID-19 progression, with median 4 days (3,6) from symptom onset. Day 0 NP SARS-CoV-2 RNA levels were similar between SAB-185 and placebo: 4.80 vs 4.80 log10 copies/ml. No differences were observed in the proportion with NP SARS-CoV-2 RNA< lower limit of quantification (LLoQ) in nasopharyngeal (NP) swab, time to improvement in targeted symptoms for 2 consecutive days after Day 0, and safety through Day 28. Secondary outcomes included quantitative NP RNA levels and all-cause hospitalizations and deaths. Antiviral or clinical efficacy and safety criteria for graduation to phase 3 were pre-specified. Conclusion: SAB-185 was safe in this Phase II study. While no significant differences to placebo were seen in symptom duration and proportion of participants with NP SARS-CoV-2 RNA< lower limit of quantification (LLoQ) in nasopharyngeal (NP) swab, time to improvement in targeted symptoms for 2 consecutive days after Day 0, and safety through Day 28. Secondary outcomes included quantitative NP RNA levels and all-cause hospitalizations and deaths. Antiviral or clinical efficacy and safety criteria for graduation to phase 3 were pre-specified.

4.
Topics in Antiviral Medicine ; 30(1 SUPPL):41, 2022.
Article in English | EMBASE | ID: covidwho-1880388

ABSTRACT

Background: Camostat, a serine protease inhibitor, prevents activation of the SARS-CoV-2 spike protein and blocks SARS-CoV-2 infection in vitro. We studied the safety and antiviral and clinical efficacy of orally administered camostat in non-hospitalized adults with mild-moderate COVID-19. Methods: ACTIV-2/A5401 is a platform trial to evaluate therapies for non-hospitalized adults with mild-moderate COVID-19. In a Phase II portion of the study, participants were enrolled within 10 days of COVID-19 related symptom onset and randomized to camostat 200 mg orally every 6 hours for 7 days or the pooled placebo group. Objectives were to evaluate the safety and efficacy of camostat to reduce the duration of COVID-19 symptoms and increase the proportion of participants with SARS-CoV-2 RNA below the lower limit of quantification (LLoQ) from nasopharyngeal (NP) swabs on days 3, 7, and 14. Participants completed a study diary from day 0 to day 28 scoring COVID-19 symptoms as absent, mild, moderate, or severe. Results: Of the 224 participants enrolled from 54 US sites, 215 participants (108 camostat, 107 placebo) initiated study intervention and formed the modified intent-to-treat population. Fifty-four percent were female, >99% cis-gender, 85% White, 9% Black, and 51% Latinx. Median age was 37 years;47% reported ≤5 days of symptoms at study entry and 26% met the protocol definition of higher risk of progression to severe COVID-19. Most frequent symptoms on day 0 were cough (86%), fatigue (85%), nasal obstruction/congestion (71%) and body/muscle aches (71%). There was no significant difference between camostat and placebo arms in grade 3 or higher adverse events (7.4% vs. 6.5%, respectively). Median (Q1, Q3) time to symptom improvement was 9 days for both camostat (5, 20) and placebo (6, 19). There were no significant differences in the proportion of participants with NP SARS-CoV-2 RNA<="" div=""> Conclusion: Camostat was well-tolerated. Despite compelling in vitro data, camostat did not show evidence of antiviral or clinical efficacy in ACTIV-2/A5401. This highlights the critical importance of randomized controlled trials in the evaluation of therapies for COVID-19.

5.
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.

6.
Open Forum Infectious Diseases ; 8(SUPPL 1):S27-S28, 2021.
Article in English | EMBASE | ID: covidwho-1746801

ABSTRACT

Background. Remdesivir (RDV) reduced time to recovery and mortality in some subgroups of hospitalized patients in the NIAID ACTT-1 RCT compared to placebo. Comparative effectiveness data in clinical practice are limited. Methods. Using the Premier Healthcare Database, we compared survival for adult non-mechanically ventilated hospitalized COVID-19 patients between Aug-Nov 2020 and treated with RDV within 2 days of hospitalization vs. those who did not receive RDV. Preferential within-hospital propensity score matching with replacement was used. Patients were matched on baseline O2 and 2-month admission period and were excluded if discharged within 3 days of RDV initiation (to exclude anticipated discharges/transfers within 72 hrs consistent with ACTT-1 study). Time to 14- and 28-day mortality was examined separately for patients on high-flow/non-invasive ventilation (NIV), low-flow, and no supplemental O2 using Cox Proportional Hazards models. Results. RDV patients (n=27,559) were matched to unique non-RDV patients (n=15,617) (Fig 1). The two groups were balanced;median age 66 yrs and 73% white (RDV);68 yrs and 74% white (non-RDV), and 55% male. At baseline, 21% required high-flow O2, 50% low-flow O2, and 29% no O2, overall. Mortality in RDV patients was 9.6% and 13.8% on days 14 and 28, respectively. For non-RDV patients, mortality was 14.0% and 17.3% on days 14 and 28, respectively. Kaplan-Meier curves for time to mortality are shown in Fig 2. After adjusting for baseline and clinical covariates, RDV patients on no O2 and low-flow O2 had a significantly lower risk of death within 14 days (no O2, HR: 0.69, 95% CI: 0.57-0.83;low-flow, HR: 0.67, 95% CI: 0.59-0.77) and 28 days (no O2, HR: 0.80, 95% CI: 0.68-0.94;low-flow, HR: 0.76, 95% CI: 0.68-0.86). Additionally, RDV patients on high-flow O2/NIV had a significantly lower risk of death within 14 days (HR: 0.81, 95% CI: 0.70-0.93);but not at 28 days (Fig 3). Conclusion. In this large study of patients in clinical care hospitalized with COVID-19, we observed a significant reduction of mortality in RDV vs. non-RDV treated patients in those on no O2 or low-flow O2. Mortality reduction was also seen in patients on high-flow O2 at day 14, but not day 28. These data support the use of RDV early in the course of COVID-19 in hospitalized patients.

7.
Open Forum Infectious Diseases ; 8(SUPPL 1):S807-S808, 2021.
Article in English | EMBASE | ID: covidwho-1746276

ABSTRACT

Background. SARS-CoV-2 continues to spread and the development of safe and effective therapeutics for the prevention of severe disease remains a priority. BRII-196 and BRII-198 are non-competing anti-SARS-CoV-2 mAbs with YTE triple amino acid substitution in Fc to extend half-life and reduce receptor binding, that are being studied for treatment of COVID-19 in the ACTIV-2 Trial, sponsored by NIAID and led by ACTG. Methods. ACTIV-2 evaluates safety/efficacy of investigational agents for treatment of non-hospitalized adults with mild-moderate COVID-19 under a randomized, blinded, controlled adaptive platform. BRII-196/BRII-198 (1000 mg each) as a single dose given as sequential infusions, or placebo to those at high risk of clinical progression (i.e., age ≥ 60 years or presence of other medical conditions) within 10 days of symptom onset and positive test for SARS-CoV-2. The primary endpoint was hospitalization and/or death through day 28. We report Phase 3 BRII-196/BRII-198 trial results per DSMB recommendation following an interim analysis. Results. Between January and July 2021, 837 participants (418 active, 419 placebo) from sites in the US (66%), Brazil, South Africa, Mexico, Argentina and the Philippines were randomized and received study product at time of emerging variants. Median age 49 years (Q1, Q3: 39, 58), 51% female, 17% Black/African-American and 49% Hispanic/Latino, with median 6 days from symptom onset. At interim analysis 71% and 97% had a day 28 and 7 visit, respectively. For all available data at interim review, BRII-196/BRII-198 compared to placebo had fewer hospitalizations (12 vs. 45) and deaths (1 vs. 9). At day 28 of follow-up, there was an estimated 78% reduction in hospitalization and/or death (2.4 vs. 11.1%), relative risk 0.22 (95% CI: 0.05, 0.86), P=0.00001 (nominal one-sided). Grade 3 or higher adverse events (AEs) were observed less frequently among BRII-196/BRII-198 participants than placebo (3.8% vs. 13.4%) with no severe infusion reactions or drug related serious AEs. Conclusion. BRII-196/BRII-198 was safe, well-tolerated, and demonstrated significant reduction compared to placebo in the risk of hospitalization and/or death among adults with mild-moderate COVID-19 at high risk for progression to severe disease.

8.
PubMed; 2021.
Preprint in English | PubMed | ID: ppcovidwho-330094

ABSTRACT

Background: Few prospective studies of SARS-CoV-2 transmission within households have been reported from the United States, where COVID-19 cases are the highest in the world and the pandemic has had disproportionate impact on communities of color. Methods and Findings: This is a prospective observational study. Between April-October 2020, the UNC CO-HOST study enrolled 102 COVID-positive persons and 213 of their household members across the Piedmont region of North Carolina, including 45% who identified as Hispanic/Latinx or non-white. Households were enrolled a median of 6 days from onset of symptoms in the index case. Secondary cases within the household were detected either by PCR of a nasopharyngeal (NP) swab on study day 1 and weekly nasal swabs (days 7, 14, 21) thereafter, or based on seroconversion by day 28. After excluding household contacts exposed at the same time as the index case, the secondary attack rate (SAR) among susceptible household contacts was 60% (106/176, 95% CI 53%-67%). The majority of secondary cases were already infected at study enrollment (73/106), while 33 were observed during study follow-up. Despite the potential for continuous exposure and sequential transmission over time, 93% (84/90, 95% CI 86%-97%) of PCR-positive secondary cases were detected within 14 days of symptom onset in the index case, while 83% were detected within 10 days. Index cases with high NP viral load (>10

9.
PubMed; 2021.
Preprint in English | PubMed | ID: ppcovidwho-329391

ABSTRACT

Background: Easily distributed oral antivirals are urgently needed to treat coronavirus disease-2019 (COVID-19), prevent progression to severe illness, and block transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We report the results of a Phase 2a trial evaluating the safety, tolerability, and antiviral efficacy of molnupiravir in the treatment of COVID-19 ( ClinicalTrials.gov NCT04405570 ). Methods: Eligible participants included outpatients with confirmed SARS-CoV-2 infection and symptom onset within 7 days. Participants were randomized 1:1 to 200 mg molnupiravir or placebo, or 3:1 to molnupiravir (400 or 800 mg) or placebo, twice-daily for 5 days. Antiviral activity was assessed as time to undetectable levels of viral RNA by reverse transcriptase polymerase chain reaction and time to elimination of infectious virus isolation from nasopharyngeal swabs. Results: Among 202 treated participants, virus isolation was significantly lower in participants receiving 800 mg molnupiravir (1.9%) versus placebo (16.7%) at Day 3 (p = 0.02). At Day 5, virus was not isolated from any participants receiving 400 or 800 mg molnupiravir, versus 11.1% of those receiving placebo (p = 0.03). Time to viral RNA clearance was decreased and a greater proportion overall achieved clearance in participants administered 800 mg molnupiravir versus placebo (p = 0.01). Molnupiravir was generally well tolerated, with similar numbers of adverse events across all groups. Conclusions: Molnupiravir is the first oral, direct-acting antiviral shown to be highly effective at reducing nasopharyngeal SARS-CoV-2 infectious virus and viral RNA and has a favorable safety and tolerability profile.

10.
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.

11.
Value in Health ; 25(1):S27, 2022.
Article in English | EMBASE | ID: covidwho-1650257

ABSTRACT

Objectives: In this comparative effectiveness study, we compare the survival outcomes for hospitalized COVID-19 patients treated with remdesivir (RDV) upon admission vs. those not treated with RDV. Methods: We used the Premier Healthcare Database to examine patients hospitalized between Aug-Nov 2020 and treated with RDV within 2 days of hospitalization vs. those who did not receive RDV during their hospitalization. Preferential within-hospital propensity score matching with replacement was used. Patients were matched on baseline oxygen requirement and 2-month admission period and were excluded if discharged within 3 days of RDV initiation (to exclude anticipated discharges/transfers within 72 hrs consistent with ACTT-1 study). Cox Proportional Hazards models were used to examine 14- and 28-day mortality overall and for patients on no supplemental oxygen (NSO), low-flow oxygen (LFO), high-flow oxygen/non-invasive ventilation (HFO/NIV) and invasive mechanical ventilation/ECMO (IMV/ECMO) separately. Results: RDV patients (n=28,855) were matched to unique non-RDV patients (n=16,687). The two groups were balanced. At baseline, 28% required NSO, 48% LFO, 20% HFO/NIV and 4% IMV/ECMO. Mortality in RDV patients was 10.6% and 15.4% on days 14 and 28, respectively. For non-RDV patients, mortality was 15.4% and 19.1% on days 14 and 28, respectively. After adjusting for baseline and clinical covariates, RDV patients had significantly lower risk of mortality at 14-days (HR[95% CI]: 0.76[0.70−0.83]) and 28-days (0.89[0.82−0.96]). This mortality benefit was also seen for NSO, LFO and IMV/ECMO patients at 14-days (NSO: 0.69[0.57−0.83], LFO: 0.68[0.80−0.77], IMV/ECMO: 0.70[0.58−0.84]) and 28-days (NSO: 0.80[0.68−0.94], LFO: 0.77[0.68−0.86], IMV/ECMO: 0.81[0.69−0.94]). Additionally, HFO/NIV RDV patients had a significantly lower risk of mortality at 14-days (0.81[0.70−0.93]);but not at 28-days. Conclusions: In this observational study, treatment with RDV was associated with statistically significant reduction in mortality among hospitalized COVID-19 patients. These results complement the findings from the ACTT-1 and contribute to the growing body of evidence on the survival benefits of RDV.

13.
Pharmacoepidemiology and Drug Safety ; 30:239-239, 2021.
Article in English | Web of Science | ID: covidwho-1381741
14.
Hum Reprod ; 36(9): 2506-2513, 2021 08 18.
Article in English | MEDLINE | ID: covidwho-1345732

ABSTRACT

STUDY QUESTION: Does the immune response to coronavirus disease 2019 (COVID-19) infection or the BNT162b2 mRNA vaccine involve the ovarian follicle, and does it affect its function? SUMMARY ANSWER: We were able to demonstrate anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgG in follicular fluid (FF) from both infected and vaccinated IVF patients, with no evidence for compromised follicular function. WHAT IS KNOWN ALREADY: No research data are available yet. STUDY DESIGN, SIZE, DURATION: This is a cohort study, composed of 32 consecutive IVF patients, either infected with COVID-19, vaccinated or non-exposed, conducted between 1 February and 10 March 2021 in a single university hospital-based IVF clinic. PARTICIPANTS/MATERIALS, SETTING, METHODS: A consecutive sample of female consenting patients undergoing oocyte retrieval was recruited and assigned to one of the three study groups: recovering from confirmed COVID-19 (n = 9); vaccinated (n = 9); and uninfected, non-vaccinated controls (n = 14). Serum and FF samples were taken and analyzed for anti-COVID IgG as well as estrogen, progesterone and heparan sulfate proteoglycan 2 concentration, as well as the number and maturity of aspirated oocytes and day of trigger estrogen and progesterone measurements. Main outcome measures were follicular function, including steroidogenesis, follicular response to the LH/hCG trigger, and oocyte quality biomarkers. MAIN RESULTS AND THE ROLE OF CHANCE: Both COVID-19 and the vaccine elicited anti-COVID IgG antibodies that were detected in the FF at levels proportional to the IgG serum concentration. No differences between the three groups were detected in any of the surrogate parameters for ovarian follicle quality. LIMITATIONS, REASONS FOR CAUTION: This is a small study, comprising a mixed fertile and infertile population, and its conclusions should be supported and validated by larger studies. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study to examine the impact of SARS-Cov-2 infection and COVID-19 vaccination on ovarian function and these early findings suggest no measurable detrimental effect on function of the ovarian follicle. STUDY FUNDING/COMPETING INTEREST(S): The study was funded out of an internal budget. There are no conflicts of interest for any of the authors. TRIAL REGISTRATION NUMBER: CinicalTrials.gov registry number NCT04822012.


Subject(s)
COVID-19 , Ovarian Follicle , SARS-CoV-2 , COVID-19 Vaccines , Cohort Studies , Female , Fertilization in Vitro , Humans , Ovarian Follicle/physiopathology , RNA, Messenger , Vaccination
15.
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.

16.
Topics in Antiviral Medicine ; 29(1):210-211, 2021.
Article in English | EMBASE | ID: covidwho-1250023

ABSTRACT

Background: The relationship between nasopharyngeal (NP) SARS-CoV-2 RNA, demographics and symptom characteristics in non-hospitalized persons with COVID-19 is not well described. Methods: ACTIV-2 is a phase 2/3 adaptive platform trial testing antivirals for SARS-CoV-2 in symptomatic non-hospitalized adults. We analyzed associations between NP quantitative SARS-CoV-2 RNA (Abbott m2000sp/rt) and COVID-19 symptomatology in 284 participants with both a NP swab and symptom diary prior to study intervention. The diary included 13 targeted symptoms and questions about overall severity of COVID-19 symptoms, each scored as none, mild, moderate, or severe (and very severe for overall severity) and general physical health (scored as poor, fair, good, very good, excellent). Wilcoxon tests were used to compare NP RNA levels between pre-defined groups. Spearman correlations, Jonchkeere-Terpstra trend tests, and linear regressions evaluated associations between symptom measures and NP RNA. Results: Participants were 49% female, 82% white, 9% black, and 27% Latinx. Median age was 46 years and 50% met the protocol definition of higher risk for COVID-19 progression (age ≥55 years and/or protocol-defined comorbidities);32% reported moderate and 5% severe symptoms. Median (Q1, Q3) time from onset of symptoms to NP swab/symptom assessment was 6 (4, 8) days. NP RNA was above the lower limit of quantification in 85%;median (Q1, Q3) was 5.4 (3.5, 6.8) log10 copies/mL. Higher RNA levels were associated with shorter symptom duration (median 6.5 vs 4.7 log10 copies/mL for ≤5 vs >5 days) but not total symptom score (Figure). Controlling for symptom duration, higher NP RNA levels were associated with better general physical health (p=0.02) and more severe body/muscle pain (p=0.04). No associations were observed with symptom severity (sum of scores or overall severity) or any other symptoms. There was no association between NP RNA and age or risk category for COVID-19 progression. Conclusion: In symptomatic outpatients, NP SARS-CoV-2 RNA levels were higher in persons with more recent symptom onset, but were not associated with symptom severity or risk for disease progression. The range of viral RNA shedding was remarkably similar across the range of symptom severity, suggesting symptom severity may not correlate with transmission risk or the potential to respond to antiviral therapy. Outpatient trials aimed at evaluating antiviral activity of new agents should focus enrollment on participants with recent onset of symptoms. (Figure Presented).

17.
Topics in Antiviral Medicine ; 29(1):140-141, 2021.
Article in English | EMBASE | ID: covidwho-1250022

ABSTRACT

Background: Due to the substantial morbidity but low rates of hospitalization and death among outpatients with COVID-19, symptom outcome measures should be considered for primary efficacy assessment in phase 3 treatment trials. We analyzed potential measures utilizing the ACTIV-2 participant diary. Methods: Data from the first 95 participants in ACTIV-2 were included. All had symptomatic SARS-CoV-2 infection and received blinded bamlanivimab 7000 mg/placebo. The symptom diary was completed by participants prior to treatment (Day 0) and then daily for 28 days. It included 13 targeted symptoms scored as absent, mild, moderate, or severe, and a question about whether they had returned to pre-COVID-19 health. Without unblinding, 3 candidate symptom outcome measures were assessed: A) time to confirmed (2 consecutive days) absence of all targeted symptoms, B) time to all targeted symptoms confirmed to be mild or absent, and C) time to confirmed improvement in all targeted symptoms. Median time to outcome was estimated by Kaplan-Meier methods. Results: Of the 95 participants, 53% were female, 82% white, and 33% Latinx. Median age was 44 years;46% were age ≥55 years and/or had protocol-defined comorbidities. Median time from COVID-19 symptom onset to randomization was 6 days. Prevalence of each targeted symptom on Day 0 ranged from 6% vomiting to 87% fatigue. Candidate outcome B was met in median 2 days due to 29% of participants having only mild symptoms at Day 0. For candidate outcomes A and C, median time was 11 and 8 days, with 26% and 16%, respectively, not meeting the outcome by 28 days. These candidate outcomes (A and C) were associated with a participant's confirmed assessment of return to pre-COVID-19 health (Figure). For all measures, increasing the consecutive days required for confirmation from 2 to 3 or 4 had a modest impact on median time to the outcome being met, consistent with few participants experiencing relapsing symptoms. Conclusion: Outcomes based on symptom resolution (A) or improvement (C) are promising for evaluating COVID-19 treatment response, with good internal validity with self-assessment of return to pre-COVID-19 health. A valid symptom outcome measure may be preferred over hospitalization/death as a primary outcome for outpatient COVID-19 treatment trials as most participants achieve the outcome, increasing power to compare treatments, especially among participants who are at low risk for hospitalization/death.

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