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1.
Topics in Antiviral Medicine ; 30(1 SUPPL):175, 2022.
Article in English | EMBASE | ID: covidwho-1880389

ABSTRACT

Background: Camostat, an oral protease inhibitor, blocks entry and replication of SARS-CoV-1 and SARS-CoV-2 in vitro. It is approved for therapy of recurrent pancreatitis in several countries. Camostat has an excellent safety profile and repurposing for COVID-19 treatment was proposed. Methods: We conducted a Phase II randomized, placebo-controlled trial of camostat in adult outpatients with confirmed COVID-19 and one or more risk factors for severe disease (including age ≥65 years, severe obesity, hypertension, diabetes, chronic lung, heart or liver disease). Participants were randomized 2:1 to oral camostat 200 mg or matching placebo four times a day for 14 days. Exclusion criteria were end-stage liver disease, severe renal impairment, oxygen saturation ≤94% on room air, and experimental treatment for COVID-19. The primary efficacy endpoint was hospitalization or death within 28 days. Secondary efficacy included positivity for SARS-CoV-2 by PCR on mid-nasal turbinate swabs on days 7 and 15 compared to baseline. Results: We enrolled 295 participants, 57.3% were female, 15.6% Black and 60% Latinx. Mean age was 51 years (18-93 years). Most (75.3%) were randomized ≤5 days after symptom onset. Common risk factors were hypertension (63.4%), chronic lung disease (33.2%) and diabetes (25.4%), with 46.8% having >1 risk factor. With a lower than anticipated event rate, the primary endpoint of hospitalization or death was not significantly different in the camostat (5.3%, 10/194) and placebo groups (6.1%, 6/99;p=0.78). In the intention-to-treat population, there was a trend towards a lower proportion of PCR positivity in the camostat compared to the placebo group at day 7 (65.2% vs. 75.7%, p=0.12) and day 15 (22.0% vs. 34.3%, p=0.06). Similarly, in a post hoc as treated population, fewer participants in the camostat than in the placebo group remained PCR positive at day 7 (64.7%, 88/136 vs. 76.8%, 53/96;p=0.077) and day 15 (21.8%, 29/133, vs. 34.8%, 23/66;p=0.05). Adverse events occurred in 13% of participants in the placebo and 9% in the camostat group. All severe adverse events (5% in both groups) were related to COVID-19. Conclusion: With a low overall event rate, we did not observe a decrease in risk of hospitalization or death in camostat treated outpatients with COVID-19 at risk for severe disease. SARS-CoV-2 PCR turned negative faster on camostat treatment. Camostat was well tolerated.

2.
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.

3.
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.

5.
Francis, J. M.; Leistritz-Edwards, D.; Dunn, A.; Tarr, C.; Lehman, J.; Dempsey, C.; Hamel, A.; Rayon, V.; Liu, G.; Wang, Y.; Wille, M.; Durkin, M.; Hadley, K.; Sheena, A.; Roscoe, B.; Ng, M.; Rockwell, G.; Manto, M.; Gienger, E.; Nickerson, J.; Moarefi, A.; Noble, M.; Malia, T.; Bardwell, P. D.; Gordon, W.; Swain, J.; Skoberne, M.; Sauer, K.; Harris, T.; Goldrath, A. W.; Shalek, A. K.; Coyle, A. J.; Benoist, C.; Pregibon, D. C.; Jilg, N.; Li, J.; Rosenthal, A.; Wong, C.; Daley, G.; Golan, D.; Heller, H.; Sharpe, A.; Abayneh, B. A.; Allen, P.; Antille, D.; Armstrong, K.; Boyce, S.; Braley, J.; Branch, K.; Broderick, K.; Carney, J.; Chan, A.; Davidson, S.; Dougan, M.; Drew, D.; Elliman, A.; Flaherty, K.; Flannery, J.; Forde, P.; Gettings, E.; Griffin, A.; Grimmel, S.; Grinke, K.; Hall, K.; Healy, M.; Henault, D.; Holland, G.; Kayitesi, C.; LaValle, V.; Lu, Y.; Luthern, S.; Schneider, J. M.; Martino, B.; McNamara, R.; Nambu, C.; Nelson, S.; Noone, M.; Ommerborn, C.; Pacheco, L. C.; Phan, N.; Porto, F. A.; Ryan, E.; Selleck, K.; Slaughenhaupt, S.; Sheppard, K. S.; Suschana, E.; Wilson, V.; Carrington, M.; Martin, M.; Yuki, Y.; Alter, G.; Balazs, A.; Bals, J.; Barbash, M.; Bartsch, Y.; Boucau, J.; Carrington, M.; Chevalier, J.; Chowdhury, F.; DeMers, E.; Einkauf, K.; Fallon, J.; Fedirko, L.; Finn, K.; Garcia-Broncano, P.; Ghebremichael, M. S.; Hartana, C.; Jiang, C.; Judge, K.; Kaplonek, P.; Karpell, M.; Lai, P.; Lam, E. C.; Lefteri, K.; Lian, X.; Lichterfeld, M.; Lingwood, D.; Liu, H.; Liu, J.; Ly, N.; Hill, Z. M.; Michell, A.; Millstrom, I.; Miranda, N.; O'Callaghan, C.; Osborn, M.; Pillai, S.; Rassadkina, Y.; Reissis, A.; Ruzicka, F.; Seiger, K.; Sessa, L.; Sharr, C.; Shin, S.; Singh, N.; Sun, W.; Sun, X.; Ticheli, H.; Trocha-Piechocka, A.; Walker, B.; Worrall, D.; Yu, X. G.; Zhu, A..
Sci Immunol ; : eabk3070, 2021.
Article in English | PubMed | ID: covidwho-1519187

ABSTRACT

[Figure: see text].

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