CROCuS, a Phase II Study Evaluating the Antiviral Activity, Clinical Outcomes, and Safety of Rilematovir in Children Aged ≥ 28 Days and ≤ 3 Years with Acute Respiratory Tract Infection Due to Respiratory Syncytial Virus

• Published in: Paediatric drugs Vol. 26; no. 4; pp. 411 - 427
• Main Authors: Ferrero, Fernando, Lin, Chien-Yu, Liese, Johannes, Luz, Kleber, Stoeva, Tatyana, Nemeth, Agnes, Gijón, Manuel, Calvo, Cristina, Natalini, Silvina, Toh, Teck-Hock, Deleu, Sofie, Chen, Bohang, Rusch, Sarah, Sánchez, Beatriz López, Leipoldt, Illse, Vijgen, Leen, Huntjens, Dymphy, Baguet, Tristan, Bertzos, Kristi, Gamil, Mohamed, Stevens, Marita
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.07.2024; Springer Nature B.V
• Subjects: Antiviral Agents - administration & dosage; Antiviral Agents - adverse effects; Antiviral Agents - pharmacokinetics; Antiviral Agents - therapeutic use; Child, Preschool; Clinical outcomes; Cyanosis; Dose-Response Relationship, Drug; Double-Blind Method; FDA approval; Female; Hospitalization; Humans; Infant; Infant, Newborn; Infections; Internal Medicine; Male; Medicine; Medicine & Public Health; Monoclonal antibodies; NCT; NCT03656510; Original; Original Research Article; Pediatrics; Pharmacotherapy; Pneumonia; Proteins; Respiratory syncytial virus; Respiratory Syncytial Virus Infections - drug therapy; Respiratory Tract Infections - drug therapy; Respiratory Tract Infections - virology; Treatment Outcome; Viral Load - drug effects; United States > US
• ISSN: 1174-5878; 1179-2019
• DOI: 10.1007/s40272-024-00625-x

Background Respiratory syncytial virus (RSV) causes significant morbidity and mortality in children aged ≤ 5 years and adults aged ≥ 60 years worldwide. Despite this, RSV-specific therapeutic options are limited. Rilematovir is an investigational, orally administered inhibitor of RSV fusion protein-mediated viral entry. Objective To establish the antiviral activity, clinical outcomes, safety, and tolerability of rilematovir (low or high dose) in children aged ≥ 28 days and ≤ 3 years with RSV disease. Methods CROCuS was a multicenter, international, double-blind, placebo-controlled, randomized, adaptive phase II study, wherein children aged ≥ 28 days and ≤ 3 years with confirmed RSV infection who were either hospitalized (Cohort 1) or treated as outpatients (Cohort 2) were randomized (1:1:1) to receive rilematovir (low or high dose) or placebo. Study treatment was administered daily as an oral suspension from days 1 to 7, with dosing based on weight and age groups. The primary objective was to establish antiviral activity of rilematovir by evaluating the area under the plasma concentration–time curve of RSV viral load in nasal secretions from baseline through day 5. Severity and duration of RSV signs and symptoms and the safety and tolerability of rilematovir were also assessed through day 28 (± 3). Results In total, 246 patients were randomized, treated, and included in the safety analysis population (Cohort 1: 147; Cohort 2: 99). Of these, 231 were included in the intent-to-treat-infected analysis population (Cohort 1: 138; Cohort 2: 93). In both cohorts, demographics were generally similar across treatment groups. In both cohorts combined, the difference (95% confidence interval) in the mean area under the plasma concentration–time curve of RSV RNA viral load through day 5 was - 1.25 (- 2.672, 0.164) and - 1.23 (- 2.679, 0.227) log 10 copies∙days/mL for the rilematovir low-dose group and the rilematovir high-dose group, respectively, when compared with placebo. The estimated Kaplan–Meier median (95% confidence interval) time to resolution of key RSV symptoms in the rilematovir low-dose, rilematovir high-dose, and placebo groups of Cohort 1 was 6.01 (4.24, 7.25), 5.82 (4.03, 8.18), and 7.05 (5.34, 8.97) days, respectively; in Cohort 2, estimates were 6.45 (4.81, 9.70), 6.26 (5.41, 7.84), and 5.85 (3.90, 8.27) days, respectively. A similar incidence of adverse events was reported in patients treated with rilematovir and placebo in Cohort 1 (rilematovir: 61.9%; placebo: 58.0%) and Cohort 2 (rilematovir: 50.8%; placebo: 47.1%), with most reported as grade 1 or 2 and none leading to study discontinuation. The study was terminated prematurely, as the sponsor made a non-safety-related strategic decision to discontinue rilematovir development prior to full recruitment of Cohort 2. Conclusions Data from the combined cohort suggest that rilematovir has a small but favorable antiviral effect of indeterminate clinical relevance compared with placebo, as well as a favorable safety profile. Safe and effective therapeutic options for RSV in infants and young children remain an unmet need. Clinical Trial Registration EudraCT Number: 2016-003642-93; ClinicalTrials.gov Identifier: NCT03656510. First posted date: 4 September, 2018.