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

Abstract

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) log₁₀ 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.

Fig. 1

Study design. C1 Cohort 1, C2 Cohort 2, RSV respiratory syncytial virus. ^aStudy sites were located in Argentina, Belgium, Brazil, Bulgaria, France, Germany, Hungary, Italy, Japan, Malaysia, Mexico, Poland, Russia, Taiwan, Thailand, South Africa, South Korea, Spain, Sweden, Turkey, UK, and the USA. ^bScreening and treatment could have occurred on the same day. ^cThe original estimated sample size for C2 was N = 150, or 50 patients per treatment group. The sample size in C2 was allowed to be increased to a maximum of 300 (100 per treatment group) based on a pre-planned sample size re-estimation after interim analysis 3. ^dPrior to Protocol Amendment 4, study treatment was administered once daily. After Protocol Amendment 4, study treatment was administered twice daily, with the total daily dose remaining unmodified. ^eRilematovir dosing and volume of placebo were based on weight (mg/kg) and age group for both cohorts. ^fC1 after discharge and C2. ^gIn case of ongoing adverse event(s)

Fig. 2

Patient disposition. ITT-i intent-to-treat-infected, LLOQ lower limit of quantification, RSV respiratory syncytial virus. ^aDefined as all randomized patients who received one or more doses of study treatment and who had an RSV RNA viral load of ≥1 log₁₀ copies/mL above the LLOQ of the RSV quantitative real-time reverse transcription polymerase chain reaction assay at baseline. ^bSponsor’s decision leading to discontinuation of study treatment was because of the non-safety-related strategic decision of premature study termination

Fig. 3

Change in respiratory syncytial virus (RSV) RNA viral load (mean ± standard error [SE]) from baseline to day 8 in the intent-to-treat-infected population for Cohort 1 and Cohort 2 combined (A) overall, (B) in patients with ≤ 3 days since symptom onset, and (C) in patients with > 3 to ≤ 5 days since symptom onset. SD standard deviation

Fig. 4

Time to first confirmed undetectable respiratory syncytial virus RNA viral load in the intent-to-treat-infected analysis population for Cohort 1 and Cohort 2 combined. CI confidence interval, + indicates censoring

Fig. 5

Time to resolution of key respiratory syncytial virus symptoms (Pediatric Respiratory Syncytial Virus Electronic Severity and Outcome Rating System observer-reported outcome) in the intent-to-treat-infected analysis population for Cohorts 1 and 2. CI confidence interval, + indicates censoring. ^aDefined as the time (hours) from the first dose of study treatment until the first time at which all key respiratory syncytial virus symptoms were scored as not present or mild (i.e., “resolved”) after being free of oxygen, hydration, and feeding supplementation for at least 24 hours

Fig. 6

Time to A hospital discharge and B end of oxygen supplementation for patients in Cohort 1^a. CI confidence interval, + indicates censoring. ^aThe graph in B represents time to the end of oxygen supplementation up to 72 h from first hospital discharge (i.e., excluding oxygen supplementation received during re-hospitalizations that occurred > 72 h after initial hospital discharge)