CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

668

AGILE CST-8 Phase I Trial of Combined Nirmatrelvir/r and Molnupiravir for Mild-Moderate COVID-19 Saye Khoo 1 , Richard J. Fitzgerald 1 , Shazaad Ahmad 2 , Chris Edwards 3 , Geoff Saunders 3 , Emma Knox 3 , Calley Middleton 3 , William Greenhalf 1 , Laura Else 1 , Victoria Shaw 1 , Thomas Fletcher 4 , Helen Reynolds 1 , Gareth Griffiths 3 , for the AGILE CST-8 Study Team 1 University of Liverpool, Liverpool, United Kingdom, 2 University of Manchester, Manchester, United Kingdom, 3 University of Southampton, Southampton, United Kingdom, 4 Liverpool School of Tropical Medicine, Liverpool, United Kingdom Background: AGILE (NCT04746183) is the UK platform for early-phase evaluation of COVID-19 antivirals. AGILE-CST-8 is a phase I, adaptive, dose de escalation study of combination nirmatrelvir/ritonavir plus molnupiravir Methods: Adults with a positive lateral flow test, within 5 days of mild moderate symptoms were randomised (2:1, open-label) to nirmatrelvir/ritonavir plus molnupiravir versus Standard of Care (SoC). Exclusions were oxygen saturation <92%, liver or renal impairment, drug interactions and pregnancy. The primary endpoint was dose-limiting-toxicities (DLT; AEs ≥ grade 3) up to day 11; safety review after each cohort (N=6) guided stepwise dose-reduction of molnupiravir from a starting dose of 800mg bd, reducing to 600mg or 400mg bd if required, with nirmatrelvir/ritonavir maintained at standard doses throughout. A Bayesian dose de-escalation model was used to estimate DLTs. We collected a combined throat/nose swab daily for 5 days, then at day 11 for virology, and measured antiviral concentrations in plasma, saliva, tears and nasal secretions. Results: Four cohorts totalling 24 participants (16 combination therapy, 8 SoC; 17 female) with median (range) age 35.5 years (20-70), and BMI 27 (20.2-40.2) were enrolled, at a median of 4 days (1-5) from symptom onset. No DLTs or SAEs were observed through to Day 29; all participants randomised to combination therapy received full doses of both drugs apart from one subject withdrawal on day 2 (Bayesian dose-toxicity model shown in Figure). AEs (Grade 1-2) were reported in 14/16 (87.5%, mainly gastrointestinal disorders and altered taste) of combination treatment versus 5/8 (62.5%) SoC participants. At baseline all but one (SoC arm) were SARS-CoV-2 PCR-positive. There was no evidence of differences between participants receiving combination antivirals versus SoC in baseline VL (median 5.2 vs 6.8 log 10 copies), or at any point across the first 5 days, or at day 11. The median reduction in VL at Day 5 was 5.0 vs 5.7 log 10 copies, with 11/16 (68.8%) of treated vs 5/8 (62.5%) of SoC participants achieving negative PCR. Nirmatrelvir concentrations in tears, nasal secretions, and saliva approximated to 86%, 70% and 18% that of plasma. Conclusion: This first report of combination nirmatrelvir/ritonavir with molnupiravir confirms safety and tolerability at full doses used in adults. The clinical and virological benefit of this combination should be tested in larger phase II studies.

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Molnupiravir vs Favipiravir: An RCT in Outpatients At-Risk for COVID-19 in Thailand Nicolas Salvadori 1 , Gonzague Jourdain 1 , Rungroj Krittayaphong 2 , Taweegrit Siripongboonsitti 3 , Subsai Kongsaengdao 4 , Parichart Sakulkonkij 5 , Nasikarn Angkasekwinai 2 , Sarunyou Chusri 6 , Tanavit Mekavuthikul 7 , Anucha Apisarnthanarak 8 , Sirawat Srichatrapimuk 9 , Suraphan Sangsawang 10 , Piya Hanvoravongchai 11 , Pra-ornsuda Sukrakanchana 1 , Prasert Auewarakul 2 1 Chiang Mai University, Chiang Mai, Thailand, 2 Mahidol University, Bangkok, Thailand, 3 Chulabhorn Royal Academy, Bangkok, Thailand, 4 Rajavithi Hospital, Bangkok, Thailand, 5 Lampang Hospital, Lampang, Thailand, 6 Prince of Songkla University Hospital, Songkhla, Thailand, 7 Samutsakhon Hospital, Samut Sakhon, Thailand, 8 Thammasat University Hospital, Pathum Thani, Thailand, 9 Ramathibodi Chakri Naruebodindra Hospital, Samut Prakan, Thailand, 10 Health Promotion Center Region 1 , Chiang Mai, Thailand, 11 National Health Foundation, Bangkok, Thailand Background: In December 2021, molnupiravir was granted a US FDA's emergency use authorization for patients with mild-to-moderate COVID-19 at high risk for progression to severe COVID-19 for whom alternative approved or authorized treatment options are not accessible or clinically appropriate. The efficacy of molnupiravir in a vaccinated population predominantly infected with the SARS-CoV-2 Omicron variant is unknown. Methods: In an open-label, parallel-group, multicenter trial in Thailand, outpatients with confirmed SARS-CoV-2 infection for ≤5 days, mild to moderate COVID-19 attributable signs/symptoms for ≤5 days (and ≥1 day before randomization) and ≥1 risk factor for severe COVID-19 were randomly assigned 1:1 to receive oral molnupiravir 800 mg BID for 5 days or oral favipiravir 1800 mg BID on Day 1 then 800 mg BID until Day 5, extended to Day 10 if clinical progression. Phone calls for remote symptom assessment were made on Days 6, 11 (if favipiravir extended), 15 and 29. Participants with worsening symptoms were instructed to return to the hospital. The primary endpoint was pulmonary involvement by Day 29, as evidenced by ≥2 of the following: dyspnea, oxygen saturation <92% or imaging. 465 evaluable participants per arm (930 overall) were needed to have 80% power to detect a difference in the percentage of participants with an endpoint event, assuming 3% in molnupiravir arm and 7% in favipiravir arm (1-sided α=0.024 for final analysis). Results: 977 participants (487 molnupiravir, 490 favipiravir) were enrolled from 8 July 2022 to 19 January 2023. 55% were female and median age was 56 years (interquartile range, 41-64). 98% had received ≥1 dose of COVID-19 vaccine and 83% ≥3 doses. The most common risk factors known to be associated with severity were hypertension (49%) and age ≥60 years (42%). By Day 29, pulmonary involvement occurred in 0% (0/483) in molnupiravir arm versus 1% (5/482) in favipiravir arm (-1.0%; Newcombe 95.2% CI: -2.4% to -0.0%; p=0.021); all-cause death in 0% (0/483) and <1% (1/482, from COVID-19 pneumonia); COVID-19 related hospitalization in <1% (1/483) and 1% (3/482); and treatment-related adverse event in 1% (5/483) and 1% (4/486). One participant prematurely discontinued molnupiravir on Day 4 due to rash. Conclusion: Rates of pulmonary involvement and of other adverse outcomes were much lower than anticipated in both arms in this population highly vaccinated and mostly infected with Omicron. Pulmonary involvement was less common with molnupiravir than with favipiravir.

Poster Abstracts

CROI 2024 192