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.

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.

A pilot phase 2a, randomized, double-blind, placebo-controlled study to explore the antiviral activity, clinical outcomes, safety, and tolerability of rilematovir at two dose levels in non-hospitalized adults with respiratory syncytial virus infection.

OBJECTIVES: To assess the antiviral effect, clinical outcomes, and safety of the respiratory syncytial virus (RSV) fusion inhibitor rilematovir in non-hospitalized RSV-infected adults. METHODS: This phase 2a, double-blind, multicentre study randomly assigned RSV-positive adult outpatients ≤5 days from symptom onset 1:1:1 to receive rilematovir 500 mg, 80 mg, or placebo once-daily for 7 days. Antiviral effect was assessed by RSV RNA viral load (VL), measured by quantitative RT-PCR, and Kaplan-Meier (KM) estimates of time to undetectable VL. Clinical course was assessed by KM estimates of median time to resolution of key RSV symptoms assessed through patient-reported outcomes. RESULTS: RSV-positive patients (n = 72) were randomly assigned; 66 had confirmed RSV infection and received rilematovir 500 mg (n = 23), 80 mg (n = 21) or placebo (n = 22). Differences versus placebo in mean RSV RNA VL area under the curve (90% CI) through days 3, 5 and 8, respectively, were 0.09 (-0.837; 1.011), -0.10 (-2.171; 1.963), and -1.03 (-4.746; 2.682) log10 copies.day/mL for rilematovir 500 mg, and 1.25 (0.291; 2.204), 2.53 (0.430; 4.634), and 3.85 (0.097; 7.599) log10 copies.day/mL for rilematovir 80 mg. KM estimates of median (90% CI) time-to-first confirmed undetectable VL were 5.9 (3.85; 6.90), 8.0 (6.86; 12.80) and 7.0 (6.62; 10.88) days and 5.7 (2.93; 7.01), 8.1 (6.74; 12.80) and 7.9 (6.62; 11.74) days in patients with symptom onset ≤3 days, for rilematovir 500 mg, 80 mg, and placebo, respectively. KM estimates of median (90% CI) time to resolution of key RSV symptoms were 7.1 (5.03; 11.43), 7.6 (5.93; 8.32), and 9.6 (5.95; 14.00) days for rilematovir 500 mg, 80 mg, and placebo, respectively; and in patients with symptom onset ≤3 days, median 8.0, 7.6, and 11.8 days, respectively. DISCUSSION: Rilematovir use, initiated early, suggests a potential clinical benefit in RSV-infected adults, with data supporting development of RSV therapeutic options. TRIAL REGISTRATION: This study is registered with clinicaltrials.gov (NCT03379675).

Systematic literature review of the signs and symptoms of respiratory syncytial virus.

Respiratory syncytial virus (RSV) is responsible for over 30 million lower respiratory tract infections (LRTIs) and 3 million hospitalizations worldwide each year. Despite the risk RSV poses to young children, older adults, and individuals with comorbidities or suppressed immunity, there is limited understanding of RSV symptom presentation across these at-risk groups, and there is no vaccine for RSV. We conducted two systematic literature reviews (SLRs) of studies that document signs and symptoms (S&S) of RSV in (1) children aged ≤5 years and (2) immunocompromised adolescents and adults, and adults at high risk for severe RSV due to age or comorbidities. Symptom duration and hospital length of stay (LOS) were explored. Electronic database searches were performed following PRISMA guidelines. Studies captured RSV S&S across community and hospital settings. Clinicians and caregivers reported (n = 25 studies) nasal discharge/congestion, cough, shortness of breath, feeding abnormalities, and fever in ≥40% of children across studies and settings. Median hospital stays for children ranged from 2 days in the United States to 7.5 days in China. High-risk adults with RSV (n = 6 studies) commonly (≥40% of adults) reported cough, sputum, dyspnea, and fever/feverishness. Median length of hospital stay in adults ranged from 6 to 15 days across studies. Caregivers and clinicians reported similar RSV S&S in young children, including upper and lower respiratory and systemic symptoms. In high-risk and immunocompromised adults, the most frequent (in multiple publications) and commonly reported RSV S&S were primarily LRTI symptoms. RSV symptoms could last for weeks and are variable based on geography.