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1.
Topics in Antiviral Medicine ; 31(2):287-288, 2023.
Article in English | EMBASE | ID: covidwho-2316560

ABSTRACT

Background: Immunocompromised persons are disproportionately affected by severe SARS-CoV-2 infection, but immune compromise is heterogenous, which may impact viral dynamics. We hypothesized that higher degrees of compromised immunity are associated with higher viral shedding and slower viral clearance in the absence of COVID-19 therapeutics. Method(s): Participants enrolled in ACTIV-2/A5401, a platform trial for COVID-19 therapeutics in non-hospitalized adults within 10 days of symptom onset, received either an active treatment or placebo between 8/2020 and 7/2021. Participants were categorized based on the extent of immunosuppression into none, mild, moderate and severe categories at enrollment (day 0). Longitudinal anterior nasal (AN) and plasma SARS-CoV-2 levels were measured with a quantitative PCR assay. Regression models assessed associations between immunocompromise severity and viral levels (VL) at day 0, and longitudinally among those on placebo with quantifiable RNA at day 0. Multivariate analyses adjusted for demographics and symptom duration and vaccination status at day 0. Result(s): Immunocompromised (mild 383, moderate 159, severe 35) and immunocompetent (1956) participants had comparable symptom durations at day 0 (median 6 days) and most were unvaccinated (~95%). AN VL at day 0 was higher in the moderate/severe group compared to the immunocompetent group (adjusted difference in means: 0.47 log10 copies/mL, 95% CI 0.12, 0.83). While AN VL decayed at similar rates among all groups from day 0 to 3, there was a trend towards higher cumulative AN VLs across the 28-day follow-up in the moderate/severe group compared to immunocompetent group (adjusted fold difference in VL AUC 1.63, 95%CI 0.95, 2.77). The mild group showed no differences in day 0 VL or AUC compared to the immunocompetent group. The frequency of detectable plasma SARS-CoV-2 RNA was similar at day 0 across all groups (overall 21%), but there appeared to be a higher proportion of immunocompromised participants with detectable plasma viral RNA at day 7 (moderate/severe 2/23 [9%], mild 5/44 [11%]) compared to the immunocompetent group (8/282, 3%). Conclusion(s): Before emergence of Omicron and widespread vaccination, moderate/severe immunocompromised status was associated with higher nasal viral levels at study enrollment and showed a trend towards higher cumulative AN viral load, and all immunocompromised groups appeared to have more persistent plasma viremia during follow-up.

2.
Topics in Antiviral Medicine ; 31(2):114, 2023.
Article in English | EMBASE | ID: covidwho-2315751

ABSTRACT

Background: Reliable biomarkers of COVID-19 severity and outcomes are critically needed for clinical and research applications. We evaluated associations between anti-Spike IgG and SARS-COV-2 nucleocapsid antigen (N Ag) in plasma with clinical outcomes in outpatients with COVID-19. Method(s): We used data from 229 non-hospitalized, US-based adults with COVID-19 who enrolled between January and July 2021 into the placebo arm of the ACTIV-2/A5401 platform trial within 10 days of symptom onset. Pretreatment (day 0) plasma was analyzed by the quantitative Simoa SARS-CoV-2 IgG antibody (anti-Spike) assay (lower limit of quantification [LLoQ] 0.77ug/ mL), and the quantitative Simoa SARS-CoV-2 N Protein Advantage (Quanterix) measuring N Ag (LLoQ 3pg/mL). In addition to analyses for < LLoQ vs >=LLoQ anti-Spike and N Ag, we categorized participants into five N Ag groups (< 3 pg/ml;3-< 100 pg/ml;100-< 1,000 pg/ml;1,000-< 2,500 pg/ml;>=2,500 pg/ ml). Associations between SARS-CoV-2 anti-Spike and N Ag levels and clinical outcomes (all-cause hospitalization/death through day 28 and time to symptom improvement or resolution for two consecutive days from day 0 status) were estimated using log-binomial and Cox regression models, respectively. Result(s): At day 0, 40% had anti-Spike levels >=LLoQ and 64% of participants had plasma N Ag levels >=LLoQ. Participants with anti-Spike levels < LLoQ compared to those who had quantifiable anti-Spike at day 0, had an increased risk of hospitalization/death (16% vs 2%, RR [95% confidence interval (CI)]: 7.3 [1.8, 30.1]), and a significantly longer time to symptom improvement (median [Q1, Q3] 14 days [8, >27] vs 9 days [4, 16], hazard ratio [HR]: 0.6 [95%: CI: 0.4, 0.8], p< 0.001). Participants with higher N Ag levels at day 0 had an increased risk of hospitalization or death, ranging from 1% for < 3 pg/ml to 70% for >=2500 pg/ml (Figure). Compared to individuals who had N Ag levels < LLoQ at day 0, those in the highest category of N Ag levels (>=2500 pg/mL) experienced a significantly longer time to symptom improvement (median [Q1, Q3]: 25 days [13, >27] vs 10 days [5, 20];HR: 0.4 [95% CI: 0.2, 0.7];p=0.04). Conclusion(s): At study entry, the absence of Spike antibodies and higher levels of plasma SARS-CoV-2 N Ag predicted hospitalizations and death in untreated outpatients with COVID-19. These parameters may serve as informative biomarkers for risk stratification in the evaluation of outpatients with COVID-19. (Figure Presented).

3.
Topics in Antiviral Medicine ; 31(2):69-70, 2023.
Article in English | EMBASE | ID: covidwho-2315656

ABSTRACT

Background: SARS-CoV-2 variants resistant to monoclonal antibodies, and drug-drug interactions and potential mutagenicity of direct acting antivirals, heightens the need for additional therapeutics to prevent progression to severe COVID-19. Exogenous interferon beta is a promising therapeutic option against SARS-CoV-2 given its broad-spectrum antiviral activity and data suggesting impaired endogenous IFN production in individuals with severe disease. Method(s): The safety and efficacy of orally inhaled nebulized interferon-beta1a (SNG001) was evaluated in a Phase II randomized controlled trial on the ACTIV-2/ A5401 platform (NCT04518410). Adult outpatients with confirmed SARS-CoV-2 infection within 10 days of symptom onset were randomized to SNG001 once daily for 14 days or blinded pooled placebo. Primary outcomes included treatment-emergent Grade >=3 adverse event (TEAE) through day 28;time to symptom improvement of 13 targeted COVID-19 symptoms collected by daily study diary through day 28;and SARS-CoV-2 RNA < lower limit of quantification (LLoQ) from nasopharyngeal (NP) swabs at days 3, 7, and 14. All-cause hospitalization or death through day 28 was a key secondary outcome. Result(s): Of 221 participants enrolled at 25 US sites between February and August 2021, 220 (110 SNG001, 110 placebo) initiated study intervention, with a median age of 40 years, 55% female, and 20% SARS-CoV-2 vaccinated. There was no significant difference between SNG001 and placebo in Grade >=3 TEAEs (4% vs 8%, Fisher's exact test p=0.25). Median time to symptom improvement was 13 days for SNG001 and 9 days for placebo (Gehan-Wilcoxon test p=0.17). There was no difference in the proportion of participants with SARS-CoV-2 RNA < LLoQ at day 3, 7 or 14 (SNG001 vs placebo, Day 3: 28% vs. 39%;Day 7: 65% vs. 66%;Day 10: 91% vs. 91%;joint Wald test p=0.41). There were fewer hospitalizations with SNG001 (n=1;1%) compared with placebo (n=7;6%), but this difference was not statistically significant (Fisher's exact test p=0.07;Figure). All hospitalizations were due to COVID-19 and occurred among unvaccinated participants without protocol-defined high-risk factors. Conclusion(s): Inhaled nebulized SNG001 was safe and well tolerated but did not reduce SARS-CoV-2 RNA levels in the nasopharynx nor decrease time to improvement of COVID-19 symptoms in outpatients with mild-to-moderate COVID-19. The non-statistically significant decrease in hospitalizations among SNG001 participants warrants further investigation in a phase 3 clinical trial. Cumulative incidence of hospitalization or death comparing SNG001 vs. placebo.

4.
Topics in Antiviral Medicine ; 31(2):286, 2023.
Article in English | EMBASE | ID: covidwho-2314388

ABSTRACT

Background: Whether early antiviral therapy reduces the risk of Long COVID is not known. The combination SARS-CoV-2 monoclonal antibodies amubarvimab+romlusevimab (A+R) were highly effective in reducing 28-day all-cause hospitalization/death among high-risk adults with mild-to-moderate COVID-19 in the randomized, placebo-controlled ACTIV-2/A5401 trial. We assessed the impact of A+R on late outcomes including Long COVID in ACTIV-2. Method(s): A long-term (LT) symptom diary and 2 health-related quality of life questionnaires (EQ-5D-5L and SF-36v2) were completed at week 36. The primary analysis compared the proportion of participants with the composite outcome of self-reported Long COVID (having any COVID-19 symptoms present on a global assessment question in LT diary) at week 36, or hospitalization or death by week 36 between A+R and placebo using regression models with inverse probability weighting to account for incomplete outcome data;supplemental analysis compared the proportion with Long COVID among those alive. Other analyses were restricted to observed data only. Result(s): 807 were randomized and received A+R (n=405) or placebo (n=402) from Jan-July 2021. At entry, median age was 49 years, 51% were female, >99% cis-gender, 17% Black/African American, 50% Hispanic/Latino, and 9% previously received COVID vaccination. 70 (17%) on A+R and 93 (23%) on placebo met the primary outcome;113 (14%) had incomplete data for determining the outcome (Figure 1). Accounting for incomplete data, weighted Risk Ratio [wRR]=0.74;95% CI: 0.56, 0.97;p=0.03. The difference was driven by fewer hospitalizations/deaths in the A+R arm (5%) than placebo arm (15%), particularly by day 28. Excluding 12 participants who died by week 36, frequency of Long COVID was similar in the arms, 16% for A+R and 14% for placebo (wRR=1.09;95%CI: 0.75, 1.58;p=0.64). There were no differences in the proportions reporting return to pre-COVID health (global assessment) or individual symptoms, or in number of symptoms reported or distribution of worst symptom severity. RRs favored the A+R arm on several EQ-5D-5L domains, but none met statistical significance. No differences were observed on SF-36v2 assessments. Conclusion(s): While A+R was highly effective in preventing all-cause hospitalizations and deaths in high-risk outpatients with mild-to-moderate COVID-19, there was no meaningful effect of treatment on measures of Long COVID at 36 weeks. Additional interventions are needed for Long COVID prevention. (Figure Presented).

5.
Topics in Antiviral Medicine ; 31(2):70, 2023.
Article in English | EMBASE | ID: covidwho-2314077

ABSTRACT

Background: Rebound of SARS-CoV-2 RNA and symptoms has been reported in people treated with nirmatrelvir/ritonavir. Since the natural course of viral and symptom trajectories during COVID-19 have not been well described, we evaluated the incidence of viral rebound and symptom relapse in untreated individuals with mild-to-moderate COVID-19. Method(s): This analysis included 563 participants randomized to placebo in the ACTIV-2/A5401 platform trial. Participants recorded the severity (scored as 0-3) of each of 13 targeted symptoms daily from days 0-28, with symptom score being the summed score (0-39). Symptom rebound was defined as >=4 point increase in symptom score between the maximum and the preceding minimum score. Anterior nasal (AN) swabs were collected for SARS-CoV-2 RNA testing on days 0-14 and 28. Viral rebound was defined as a >=0.5 log10 RNA copies/mL increase from the immediately preceding time point to a level >=3.0 log10 RNA copies/mL, with high-level rebound defined as an increase of >=0.5 log10 copies/mL to a level >=5.0 log10 RNA copies/mL. To mirror the timing of a 5-day nirmatrelvir/ritonavir course, a supportive analysis was conducted where participants were only classified as rebounders if their rebounds occurred on or after day 5. Result(s): Symptom rebound was identified in 26% of participants at a median [Q1, Q3] of 6 [4, 9] days after study entry and 11 [9, 14] days after initial symptom onset. Individuals with symptom rebound were more likely to be female, at high risk for progression to severe disease, have shorter time since symptom onset at study entry, and have higher symptom score and higher AN viral levels day 0. Viral rebound was detected in 32%, with high-level rebound in 13% of participants. Participants with viral rebound were older, more likely to be at low risk for progression to severe disease and had higher median AN viral level at day 0. Most symptom and viral rebound were transient with 89% of symptom rebound and 95% of viral rebound events occurring for only a single day before improving. The combination of symptom and high-level viral rebound was observed in 3% of participants. In the supportive analysis of rebound occurring >=5 days after study entry, 22% and 20% of participants met symptom and viral rebound criteria, respectively, but only 1.2% of participants met criteria for both symptom and high-level viral rebound. Conclusion(s): Symptom or viral rebound in the absence of antiviral treatment is common, but the combination of symptom and viral rebound is rare.

6.
Topics in Antiviral Medicine ; 31(2):69, 2023.
Article in English | EMBASE | ID: covidwho-2313700

ABSTRACT

Background: Amubarvimab and romlusevimab are anti-SARS-CoV-2 monoclonal antibodies (mAbs) that significantly reduced the risk of hospitalizations or death in the ACTIV-2/A5401 trial. SARS-CoV-2 variants (e.g., Delta, Epsilon, Lambda) harbor mutations against romlusevimab. We evaluated viral kinetics and resistance emergence in individuals treated with mono versus dual-active mAbs. Method(s): The study population included 789 non-hospitalized participants at high risk of progression to severe COVID-19 enrolled in the ACTIV-2/ A5401 platform trial (NCT04518410) and received either placebo (n=400) or amubarvimab plus romlusevimab (n=389). Anterior nasal (AN) swabs were collected for SARS-CoV-2 RNA testing on days 0-14, and 28. Spike (S) gene nextgeneration sequencing were performed on samples collected at study entry and the last sample with viral load >=2 log10 SARS-CoV-2 RNA copies per ml. We compared viral load kinetics and resistance emergence with single versus dual-active mAbs by categorizing participants as harboring variants sensitive to amubarvimab alone (Delta, Epsilon, Lambda, Mu) versus those sensitive to both mAbs (Alpha, Beta, Gamma, Others). Result(s): Study participants receiving single and dual-active mAbs had similar demographics, baseline AN viral load, baseline symptom score and duration since symptom onset. The most common SARS-CoV-2 variant in the study population was Delta (26%) followed by Gamma (19%), Alpha (12%), and Epsilon (10%). In those with successful sequencing, 37% (N=111) were infected with a variant sensitive to amubarvimab alone and 63% (N=188) were infected with a variant sensitive to both mAbs. Compared to treatment with a singleactive mAb, treatment with dual-active mAbs led to faster viral load decline at study day 3 (p=0.0001) and day 7 (p=0.003). Treatment-emergent resistance mutations were significantly more likely to be detected after amubarvimab plus romlusevimab treatment than placebo (2.6% vs 0%, P=0.0008). mAb resistance was also more frequently detected in the setting of single-active mAb treatment compared to dual-active mAb treatment (7.2% vs 1.1%, p=0.007). Participants with emerging mAb resistance had significantly higher pretreatment SARS-CoV-2 nasal viral RNA levels. Conclusion(s): Compared to single-active mAb therapy, dual-active mAb therapy led to significantly faster viral load decline and lower risk of emerging mAb resistance. Combination mAb therapy should be prioritized for the next generation of mAb therapeutics.

7.
Topics in Antiviral Medicine ; 31(2):225-226, 2023.
Article in English | EMBASE | ID: covidwho-2312979

ABSTRACT

Background: Within the ACTIV-2/A5401 platform (NCT04518410), the safety and efficacy of tixagevimab/cilgavimab (T/C), an anti-SARS-CoV-2 monoclonal antibody combination, was studied in outpatients with COVID-19. Intravenous (IV) and intramuscular (IM) administration of T/C were assessed. Method(s): Non-hospitalized adults >=18 years enrolled within 10 days of positive SARS-CoV-2 test and symptom onset. Participants at higher risk of disease progression were eligible for IV T/C 300mg (150mg each component) or placebo;all were eligible for IM T/C 600mg (300mg each) administered to the lateral thigh or placebo. Co-primary outcomes were: time to symptom improvement through day 28;nasopharyngeal (NP) SARS-CoV-2 RNA below lower limit of quantification (LLoQ) on days 3, 7 or 14;and treatment emergent Grade >=3 adverse events. Result(s): Between February and May 2021, 223 participants (106 T/C, 117 placebo) initiated study intervention and were included in the IM analysis and 114 participants (58 T/C, 56 placebo) in the IV analysis;the IV study was stopped early for administrative reasons. Both studies enrolled 45% Latinx;the IM and IV populations included 12% and 19% Black participants, 49% and 59% female sex at birth, and median age was 39 and 44 years, respectively, all of which were balanced between active vs placebo for each. Median (IQR) days from symptom onset at enrollment was 6 (4, 7). There were no differences in time to symptom improvement comparing IM T/C to placebo (median 8 (IQR 7, 12) vs 10 (8, 13) days;p=0.35) or IV T/C to placebo (11 (9, 15) vs 10 (7, 15) days;p=0.71). A significantly greater proportion (80%) in the IM T/C arm had NP SARS-CoV-2 RNA below LLoQ at day 7 compared to placebo (65%), but not days 3 or 14, overall p=0.003 across visits. Secondary and post-hoc analyses revealed antiviral effects within the smaller IV study. There was no difference in Grade >=3 AEs with either administration route. Fewer participants were hospitalized who received T/C vs placebo (4 vs 7 in IM group;0 vs 4 in IV group), neither group reaching statistical significance. Conclusion(s): Tixagevimab/cilgavimab administered IM or IV was well-tolerated and demonstrated antiviral activity and a trend towards fewer hospitalizations, but did not change time to symptom improvement in mild-to-moderate COVID-19 compared to placebo. Monoclonal antibodies administered intramuscularly to the thigh may present a valuable alternative for early SARSCoV-2 infection. Virologic Outcomes of Tixagevimab/Cilgavimab treatment 600mg IM (panels A and B) or 300mg IV (panels C and D) versus placebo.

8.
Open Forum Infectious Diseases ; 9(Supplement 2):S449, 2022.
Article in English | EMBASE | ID: covidwho-2189718

ABSTRACT

Background. Predictors of SARS-CoV-2 RNA levels and changes over time during early COVID-19 are not well characterized. Methods. ACTIV-2 is a phase II/III randomized, placebo-controlled, platform trial to evaluate investigational agents for treatment of COVID-19 in non-hospitalized adults. Participants enrolled within 10 days of symptom onset. Nasopharyngeal samples were collected for SARS-CoV-2 RNA testing on Days 0, 3, 7, 14 and 28;RNA was quantified with qPCR assay. SARS-CoV-2 seropositivity was defined as detectable IgG to any of nucleocapsid, receptor binding domain, S1 and S2 antigens by Bio-Plex multiplex assay. Censored linear regression and repeated measures Poisson models evaluated predictors of RNA including age, sex, race, ethnicity, risk of severe COVID-19, diabetes, BMI, obesity (BMI > 35 kg/m2) and serostatus. Results. The study enrolled 537 participants from Aug 2020 to July 2021 at US sites. Median age was 48 years;49% were female sex, >99% cis-gender, 83% white, 29% Hispanic/Latino, and 21% had BMI > 35 kg/m2. At Day 0, median symptom duration was 6 days, 50% were seropositive (2 were vaccinated) and 17% had RNA below the lower limit of quantification (LLoQ). Higher Day 0 RNA was associated with shorter symptom duration (Spearman correlation = -0.40, p< 0.001), as well as older age, white race, lower BMI and seronegativity, even when adjusting for symptom duration (all p< 0.03). Among the 203 on placebo with Day 0 RNA >= LLoQ, female sex had larger decreases in RNA at Day 3 vs male sex (difference in mean change: -0.8 log10 copies/mL (95% CI: -1.2, -0.4), p< 0.001) when adjusted for symptom duration and Day 0 RNA;this difference was also observed when evaluating the proportion with RNA < LLoQ at Day 3 (Risk Ratio (95% CI): 2.38 (1.11, 5.09)). Seropositivity at Day 0 was associated with higher probability of RNA < LLoQ at Days 3 and 7 (p< 0.001) in adjusted models. Seropositivity at Day 0 did not differ by sex. Conclusion. In this well characterized clinical trial cohort, shorter symptom duration, older age, white race, lower BMI and seronegativity were associated with higher RNA in early infection. Female sex and seropositivity were associated with earlier viral clearance. Further research is needed to determine if viral decay differences mediated by these host factors influence clinical outcomes.

9.
Open Forum Infectious Diseases ; 9(Supplement 2):S46, 2022.
Article in English | EMBASE | ID: covidwho-2189513

ABSTRACT

Background. Symptoms during acute COVID-19 can limit daily activities and delay return to work and school. Little is known about the association between SARS-CoV-2 burden in either the upper airway or plasma and the duration of COVID-19 symptoms. Methods. ACTIV-2/A5401 is a platform trial for COVID-19 treatments in nonhospitalized symptomatic adults enrolled within 10 days of symptom onset. We included participants randomized to placebo from August 2020 to July 2021. Participants self-reported severity of 13 symptoms daily from day 0 (baseline) to 28 as Absent 0, Mild 1, Moderate 2, Severe 3;total symptom score was calculated as the sum of all scores. Anterior nasal (AN) and plasma SARS-CoV-2 RNA levels at day 0 were measured with a quantitative qPCR assay. The relationship between day 0 RNA and time to symptom improvement or resolution (first of 2 consecutive days of all symptoms improved or resolved from day 0, respectively) was evaluated using proportional hazards regression adjusted for time from symptom onset. Time to resolution of distinct symptoms was also assessed. Results. Among 570 participants randomized to placebo, median age was 48 years, 51% were female, and median time since symptom onset at baseline was 6 days;7% had prior COVID-19 vaccination. At day 0, AN RNA was detectable in 80% with a median of 4.1 log10 copies/ml (n=533, quartiles: 1.7, 6.0) and plasma RNA was detectable in 19% (91/476). Detectable plasma RNA at day 0, but not AN RNA, was associated with more severe symptoms at day 0 (2.4-point higher mean total symptom score, P=0.001). Both high AN (>=6 vs < 2 log10 copies/ml, adjusted hazard ratio [aHR] 0.63, P=0.001) and detectable plasma RNA (aHR 0.74, P=0.03) at day 0 predicted delayed symptom improvement. High AN RNA at day 0 also predicted a delay in symptom resolution (aHR 0.59, P=0.001). Both high AN RNA and detectable plasma RNA levels predicted delays in the resolution of cough and shortness of breath. Detectable plasma RNA also predicted delayed body pain resolution.

10.
Open Forum Infectious Diseases ; 9(Supplement 2):S44, 2022.
Article in English | EMBASE | ID: covidwho-2189512

ABSTRACT

Background. Data are currently limited on the performance of SARS-CoV-2 RNA levels as predictors or surrogate markers for clinical outcomes in outpatients with mild-to-moderate COVID-19. Methods. This exploratory analysis used data from 2205 non-hospitalized adults who enrolled between August 2020 and July 2021 and participated in placebocontrolled evaluations of two monoclonal antibody (mAb) agents (bamlanivimab [n=317] or amubarvimab/romlusevimab [n=837]), and an open-label cohort of bamlanivimab recipients [n=1051] as part of the ACTIV-2/A5401 platform trial. SARS-CoV-2 RNA levels were measured in anterior nasal (AN) swabs and plasma at day 0 (pre-treatment) and AN at day 3. We fit regression models to estimate the association between RNA level or detection and subsequent hospitalization/death within 28 days of enrollment. Results. One-hundred four participants (53/571 [9%] on placebo and 51/ 1634 [3%] on mAb) died or were hospitalized through day 28. Median AN RNA levels were lower at day 3 compared to day 0 in both placebo (2.5 vs 4.0 log10 copies/mL [cp/mL]) and mAb (2.3 vs 4.9) groups. For placebo recipients, higher Day 0 AN RNA was associated with an increasing risk of hospitalization/ death, ranging from 3% to 16% for < 2 and >= 6 log10 cp/mL, respectively. Although only 1% had quantifiable plasma SARS-CoV-2 RNA, there was a similar trend for day 0 plasma RNA: 5% hospitalizations/death for undetectable RNA, 16% for detectable but not quantifiable RNA, and 80% for >= 2 log10 cp/mL. Among 485 placebo recipients with days 0 and 3 ANRNA results, the risk of subsequent hospitalization/death was highest among those with >= 5.0 log10 cp/mL at both days [8/78;10%] and lowest for those with unquantifiable levels at both days [0/124;0%]. Higher AN RNA at day 3 (adjusted for day 0 RNA) was associated with subsequent hospitalization/death among placebo recipients (relative risk (RR): 1.4 per log10 cp/mL;95%CI: 1.0, 2.1), but not mAb recipients (RR: 1.0;95%CI: 0.7, 1.6). Conclusion. These findings suggest that AN and plasma SARS-CoV-2 RNA levels are predictive of hospitalization/death in the natural history setting. However, different associations for mAb and placebo recipients raises concerns for using AN RNA as a surrogate for clinical outcomes in mAb trials. (Table Presented).

11.
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.

12.
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.

13.
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.

14.
Open Forum Infectious Diseases ; 8(SUPPL 1):S245-S246, 2021.
Article in English | EMBASE | ID: covidwho-1746713

ABSTRACT

Background. Previous studies demonstrated the adverse impact corticosteroids can have on blood glucose homeostasis in both diabetics and non-diabetics. This raises concern for corticosteroid use in severe COVID-19 where the population is enriched for those at highest risk of severe disease, such as diabetics and patients with obesity. Previous studies of dexamethasone in COVID-19 were limited by the inability to assess steroid-induced hyperglycemia or the impact of hyperglycemia on hospital resources. Objective. The study aimed to describe the clinical characteristics, management, and outcomes related to hyperglycemia, before and after dexamethasone therapy was used as the standard of care in patients with severe COVID-19. Methods. We performed a pre/post retrospective study of patients with severe COVID-19 pneumonia admitted from May to July 2020 to Harbor-UCLA Medical Center. 126 patients were evaluated. 64 received dexamethasone and 62 did not. To quantify the effect of dexamethasone on diabetic vs. non-diabetic patients, we documented the average blood glucoses and frequency of correctional insulin doses required by each patient group (diabetic with and without dexamethasone, non-diabetic with and without dexamethasone). Results. While dexamethasone was associated with higher median blood glucose and more frequent correctional insulin dosing in diabetic patients, there was minimal effect of dexamethasone on hyperglycemia in non-diabetic patients. Furthermore, while non-diabetic patients receiving dexamethasone required more doses of correctional insulin per day vs non-diabetic patients not receiving dexamethasone (0.3 doses per day vs 0.1 doses per day), the frequency of correctional insulin doses required by non-diabetics on dexamethasone remained low at 0.3 doses per day. Conclusion. NIH COVID-19 guidelines recommend administering dexamethasone only if the patient is in a monitored setting. Our data support the NIH concerns that outpatients with diabetes receiving steroids are at risk for hyperglycemic complications. However, contrary to the NIH guidelines, our data suggest that patients without diabetes receiving steroids are at low risk for complications due to hyperglycemia and a majority do not require monitoring.

15.
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.

17.
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).

18.
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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