A Study to Learn About the Effects of Sisunatovir in Infants With Respiratory Syncytial Virus Lower Respiratory Tract Infection.

Study Overview
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Brief Summary
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The purpose of this clinical trial is to learn about the safety and effects of the study medicine (sisunatovir). Sisunatovir is developed as potential treatment of Respiratory Syncytial Virus (RSV) infections. This study will assess sisunatovir as compared to placebo in infants aged 1 month to 36 months who are hospitalized with RSV lower respiratory tract infection (LRTI). A placebo looks like the study medicine but does not contain any active medicine in it. This study will be conducted in 3 parts: In Part A participants aged 6 months to 3 years will be given a single dose of 2.5 mg/kg of sisunatovir in Cohort 1. In Cohort 2, participants age 1 month to 6 months will receive a single dose of 2 mg/kg of sisunatovir only after the completion of Cohort 1. 12-24 participants will be enrolled in Part A In Part B participants age 1 month to 36 months will receive sisunatovir or placebo dosed every 12 hours for 5 days. Doses for part B will be determined after the completion of Part A. 24-40 participants will be enrolled in Part B. The dose regimen for Part C will be determined after the completion of Part B. Approximately 120 participants age 1 month to 36 months will receive either sisunatovir or placebo. To participate in this study participants must meet the following criteria: Age 1 month to 36 months Weight ≥ 3.5 kg Diagnosis of LRTI Diagnosis of RSV Hospitalization due to RSV LRTI

Detailed Description
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This is a multicentre, 3-part study to evaluate safety, tolerability, PK, PD, and antiviral effect of single and multiple dosing of RV521 in infants hospitalised due to RSV LRTI. The clinical study consists of 3 parts, the third part (Part C) is optional: Part A is an open-label, multicentre, single dose study in infants hospitalised with RSV LRTI (Cohorts 1 & 2) Part B is a randomised, double-blind, placebo-controlled, multicentre multiple dose study in infants hospitalised with RSV LRTI (Cohorts 3, 4 & 5) Part C is a randomised 1:1, double-blind, placebo-controlled, multicentre, multiple-dose study in infants hospitalised with RSV LRTI I The number of subjects enrolled in Parts A and B of the study will depend on the safety and PK data from the group of subjects enrolled in specified age cohorts and the subsequent recommendation of the Data Safety Monitoring Committee (DSMC). The DSMC may recommend a dose adjustment (either a reduction or an escalation) and/or regimen adjustment (Part B only) for subsequent subjects because of the observation of an unexpected safety/tolerability profile and/or differences between the observed and predicted exposure resulting from a specified dose of RV521.

Official Title
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A Phase 2 Open-Label Study in Infants With REspiratory Syncytial VIRus Lower RespirAtory Tract Infection, Followed by a DoubLe-blind, Placebocontrolled Part, to Evaluate the Safety, Tolerability, Pharmacokinetics and Antiviral Effect of RV521 (REVIRAL 1)

Conditions
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Respiratory Syncytial Virus (RSV), Lower Resp Tract Infection

Intervention / Treatment
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* Drug: RV521
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female ≥ 1 month and ≤ 36 months of age Weight ≥ 3.5 kg Clinical diagnosis of LRTI A positive RSV diagnostic test Hospitalised because of RSV LRTI Symptoms of LRTI must be present for no more than 1 week (Part B) and no more than 5 days (Part C) before the Screening Visit Expected to remain in hospital for a minimum of 3 days The parent(s)/legal guardian(s) of the subject have provided written informed consent for the subject to participate and are able and willing to comply with the study protocol Exclusion Criteria: Premature (gestational age less than 37 weeks) AND <1 year of post-natal age Known to have significant comorbidities that would limit the ability to administer study drug or evaluate the safety or clinical response to study drug. Any clinically significant ECG abnormalities. Known to be immunocompromised. High risk of having developing asthma. Suspected of having a clinically significant bacterial infection. History of renal failure. Clinical evidence of hepatic decompensation History of epilepsy or seizures, including febrile seizures Allergy to test medication or constituents Has received 1 or more doses of palivizumab at any time before Screening or received treatment with antiviral therapy for RSV (eg, ribavirin or intravenous [IV] immunoglobulin) within 3 months before the Screening Visit.

Ages Eligible for Study
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Minimum Age: 1 Month
Maximum Age: 36 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: This is a multicentre, 3-part study to evaluate safety, tolerability, PK, PD, and antiviral effect of single and multiple dosing of RV521 in infants hospitalised due to RSV LRTI. Due to the adaptive study design, the number of enrolled subjects may vary depending on the obtained PK and safety profiles. The clinical study consists of 3 parts: Part A is an open-label, multicentre, single dose study in infants hospitalised with RSV LRTI (Cohorts 1 & 2) Part B is a randomised, double-blind, placebo-controlled, multicentre multiple dose study in infants hospitalised with RSV LRTI (Cohorts 3, 4 & 5) Part C is a randomised 1:1, double-blind, placebo-controlled, multicentre, multiple-dose study in infants hospitalised with RSV LRTI
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RV521<br>sisunatovir is formulated as a dry powder blend of RV521 drug substance with mannitol as excipient. The RV521 dry powder blend will be supplied in capsules containing 10, 20, or 50 mg RV521. The Investigational Medicinal Product (IMP) will be dispersed in a defined volume of suspending diluent prior to oral administration on a mg/kg basis. Instructions for opening the capsule(s) and dispersing the contents in a fixed volume of suspending diluent prior to administration will be provided in the Pharmacy Manual. The proposed dosing regimen for Part A is a single open label dose of RV521. Part B and C is RV521 or placebo administered BID, 12 hours apart, for a period of 5 consecutive days with a total of 10 doses. However, this is subject to the recommendation of the DSMC. | Drug: RV521<br>* RV521 is an RSV F protein inhibitor administered orally<br>* Other names: sisunatovir;|
| Placebo Comparator: Placebo<br>The placebo capsules administered in Part B and C will contain mannitol and microcrystalline cellulose (vehicle). The placebo dry powder will be dispersed in suspending diluent and given orally BID. Instructions for opening the capsule(s) and dispersing the contents in a fixed volume of suspending diluent prior to administration will be provided in the Pharmacy Manual. | Drug: Placebo<br>* vehicle administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the safety and tolerability of single (Part A) and multiple (Part B) oral doses of RV521 in infants hospitalised with RSV LRTI by assessing incidence of AEs, TEAEs, SAEs, and withdrawals due to TEAEs. | Summary tables of AEs will be based on TEAEs, defined as events starting, or worsening, after the first dose of IMP. | 48 hours post dose 1 (Part A) and 48 hours post dose 10 (Part B) | 
| To evaluate the safety and tolerability of single (Part A) and multiple (Part B) oral doses of RV521 in infants hospitalised with RSV LRTI by assessing changes in physical examinations. | Results at each visit will be summarised using the statistics: n (number of observations), mean, SD, median, minimum and maximum. | 48 hours post dose 1 (Part A) and 48 hours post dose 10 (Part B) | 
| To evaluate the safety and tolerability of single (Part A) and multiple (Part B) oral doses of RV521 in infants hospitalised with RSV LRTI by assessing systolic BP (vital sign parameters) and changes from baseline | Baseline characteristics will be summarized descriptively by treatment. Quantitative variables will be summarized used the statistics n, mean, standard deviation, median, minimum and maximum. | 48 hours post dose 1 (Part A) and 48 hours post dose 10 (Part B) | 
| To evaluate the safety and tolerability of single (Part A) and multiple (Part B) oral doses of RV521 in infants hospitalised with RSV LRTI by assessing diastolic BP (vital sign parameters) and changes from baseline | Baseline characteristics will be summarized descriptively by treatment. Quantitative variables will be summarized used the statistics n, mean, standard deviation, median, minimum and maximum. | 48 hours post dose 1 (Part A) and 48 hours post dose 10 (Part B) | 
| To evaluate the safety and tolerability of single (Part A) and multiple (Part B) oral doses of RV521 in infants hospitalised with RSV LRTI by assessing body temperature (vital sign parameters) and changes from baseline | Baseline characteristics will be summarized descriptively by treatment. Quantitative variables will be summarized used the statistics n, mean, standard deviation, median, minimum and maximum. | 48 hours post dose 1 (Part A) and 48 hours post dose 10 (Part B) | 
| To evaluate the safety and tolerability of single (Part A) and multiple (Part B) oral doses of RV521 in infants hospitalised with RSV LRTI by assessing respiration rate (vital sign parameters) and changes from baseline | Baseline characteristics will be summarized descriptively by treatment. Quantitative variables will be summarized used the statistics n, mean, standard deviation, median, minimum and maximum. | 48 hours post dose 1 (Part A) and 48 hours post dose 10 (Part B) | 
| To evaluate the safety and tolerability of single (Part A) and multiple (Part B) oral doses of RV521 in infants hospitalised with RSV LRTI by assessing heart rate (vital sign parameters) and changes from baseline | Baseline characteristics will be summarized descriptively by treatment. Quantitative variables will be summarized used the statistics n, mean, standard deviation, median, minimum and maximum. | 48 hours post dose 1 (Part A) and 48 hours post dose 10 (Part B) | 
| To evaluate the safety and tolerability of single (Part A) and multiple (Part B) oral doses of RV521 in infants hospitalised with RSV LRTI by assessing pulse oximetry (vital sign parameters) and changes from baseline | Baseline characteristics will be summarized descriptively by treatment. Quantitative variables will be summarized used the statistics n, mean, standard deviation, median, minimum and maximum. | 48 hours post dose 1 (Part A) and 48 hours post dose 10 (Part B) | 
| Number of participants with changes in haematology/clinical chemistry/urinalysis laboratory values (laboratory tests read by a central lab) from baseline in Part A and Part B. | Results at each visit will be summarised using the statistics n, mean, standard deviation, median, minimum and maximum. Also, change from baseline will also be summarised by post baseline visits. | 48 hours post dose 1 (Part A) and 48 hours post dose 10 (Part B) | 
| Number of participants with changes in ECG measurements from baseline in Part A and Part B | Parameters collected will be: Ventricular Heart Rate (bpm) PR Interval (msec) QRS Interval (msec) QT Interval (msec) QTcB Interval (msec) Results at each visit will be summarised using the statistics: n (number of observations), mean, SD, median, minimum and maximum. | 48 hours post dose 1 (Part A) and 48 hours post dose 10 (Part B) | 
| Part C: Evaluate the effect of RV521, compared to placebo, on the clinical course of RSV LRTI using the RSV Clinical Scoring System and the Adapted Version of ReSVinet Scale to show time to resolution of symptoms. | Overall time to resolution of RSV-related signs and symptoms will be calculated from the time of randomization to the time that they are no longer present (absent or severity =0), and will be summarized and analysed as Time to Improvement. | up to 48 hours post dose 10 | 
| Part C: Evaluate the effect (efficacy) of RV521, compared to placebo, on the clinical course of RSV LRTI using the RSV Clinical Scoring System and the Adapted Version of ReSVinet Scale to assess time to change of symptoms. | Time to change in symptoms will be calculated for RSV-related signs and symptoms that are classified as moderate or severe during the course of the study and will be defined as the time from randomization until no longer present (absent or severity=0) or mild (scores ≤ 5). | up to 48 hours post dose 10 | 
| Part C: Evaluate the effect (efficacy) of RV521, compared to placebo, on the clinical course of RSV LRTI using the RSV Clinical Scoring System and the Adapted Version of ReSVinet Scale to assess change in severity of symptoms | Change in severity of symptoms by RV521, compared to placebo, will be measured by a composite score over time. | up to 48 hours post dose 10 | 
| Part C: Evaluate the effect (efficacy) of RV521, compared to placebo, on the clinical course of RSV LRTI using the RSV Clinical Scoring System and the Adapted Version of ReSVinet Scale to assess use of supplemental oxygen. | Duration and maximum level of O2 provided will be assessed. | up to 48 hours post dose 10 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To characterise the pharmacokinetics (PK) of single (Part A) and multiple (Part B) oral doses of RV521 in infants hospitalised with RSV LRTI by assessing time to maximum plasma concentration (tmax). | Pharmacokinetic analysis will include listings and summaries of PK concentrations by time point, derived PK, parameters and analysis of relationship with dose and body weight. | 48 hours post dose 1 (Part A) | 
| To characterise the pharmacokinetics (PK) of single (Part A) and multiple (Part B) oral doses of RV521 in infants hospitalised with RSV LRTI by assessing maximum observed plasma concentration (Cmax). | Pharmacokinetic analysis will include listings and summaries of PK concentrations by time point, derived PK, parameters and analysis of relationship with dose and body weight. | 48 hours post dose 1 (Part A) | 
| To characterise the pharmacokinetics (PK) of single (Part A) and multiple (Part B) oral doses of RV521 in infants hospitalised with RSV LRTI by assessing area under the plasma concentration time curve from time zero to 12 hours (AUC0-12). | Pharmacokinetic analysis will include listings and summaries of PK concentrations by time point, derived PK, parameters and analysis of relationship with dose and body weight. | 48 hours post dose 1 (Part A) | 
| To characterise the PK of single (Part A) and multiple (Part B) oral doses of RV521 in infants hospitalised with RSV LRTI by assessing the area under the plasma concentration time curve from time zero to last measurable plasma concentration (AUC0 t). | Pharmacokinetic analysis will include listings and summaries of PK concentrations by time point, derived PK, parameters and analysis of relationship with dose and body weight. | 48 hours post dose 1 (Part A) | 
| To characterise the pharmacokinetics (PK) of single (Part A) and multiple (Part B) oral doses of RV521 in infants hospitalised with RSV LRTI by assessing terminal half-life (t1/2). | Pharmacokinetic analysis will include listings and summaries of PK concentrations by time point, derived PK, parameters and analysis of relationship with dose and body weight. | 48 hours post dose 1 (Part A) | 
| To characterise the pharmacokinetics (PK) of single (Part A) and multiple (Part B) oral doses of RV521 in infants hospitalised with RSV LRTI by assessing area under the plasma concentration time curve from time zero to infinity (AUC0-∞). | Pharmacokinetic analysis will include listings and summaries of PK concentrations by time point, derived PK, parameters and analysis of relationship with dose and body weight. | 48 hours post dose 1 (Part A) | 
| To characterise the pharmacokinetics (PK) of single (Part A) and multiple (Part B) oral doses of RV521 in infants hospitalised with RSV LRTI by assessing predicted plasma clearance. | Pharmacokinetic analysis will include listings and summaries of PK concentrations by time point, derived PK, parameters and analysis of relationship with dose and body weight. | 48 hours post dose 1 (Part A) | 
| To characterise the pharmacokinetics (PK) of single (Part A) and multiple (Part B) oral doses of RV521 in infants hospitalised with RSV LRTI by assessing apparent volume of distribution of the drug after extravascular administration (V/F). | Pharmacokinetic analysis will include listings and summaries of PK concentrations by time point, derived PK, parameters and analysis of relationship with dose and body weight. | 48 hours post dose 1 (Part A) | 
| To characterise the pharmacokinetics (PK) of single (Part A) and multiple (Part B) oral doses of RV521 in infants hospitalised with RSV LRTI by assessing trough concentration at the end of first dosing interval (C12) (data permitting). | Pharmacokinetic analysis will include listings and summaries of PK concentrations by time point, derived PK, parameters and analysis of relationship with dose and body weight. | 48 hours post dose 1 (Part A) | 
| To characterise the pharmacokinetics (PK) of multiple (Part B) oral doses of RV521 in infants hospitalised with RSV LRTI by assessing accumulation ratio, percent fluctuation. | Pharmacokinetic analysis will include listings and summaries of PK concentrations by time point, derived PK, parameters and analysis of relationship with dose and body weight. | 48 hours post dose 10 | 
| To characterise the pharmacokinetics (PK) of multiple (Part B) oral doses of RV521 in infants hospitalised with RSV LRTI by assessing the area under the plasma concentration time curve from time zero to the end of last dosing interval (AUC0-tau). | Pharmacokinetic analysis will include listings and summaries of PK concentrations by time point, derived PK, parameters and analysis of relationship with dose and body weight. | 48 hours post dose 10 | 
| To characterise the pharmacokinetics (PK) of multiple (Part B) oral doses of RV521 in infants hospitalised with RSV LRTI by assessing average plasma concentration over dosing interval (Cave). | Pharmacokinetic analysis will include listings and summaries of PK concentrations by time point, derived PK, parameters and analysis of relationship with dose and body weight. | 48 hours post dose 10 | 
| To characterise the pharmacokinetics (PK) of multiple (Part B) oral doses of RV521 in infants hospitalised with RSV LRTI by assessing minimum observed plasma concentration (Cmin). | Pharmacokinetic analysis will include listings and summaries of PK concentrations by time point, derived PK, parameters and analysis of relationship with dose and body weight. | 48 hours post dose 10 | 
| To characterise the pharmacokinetics (PK) of multiple (Part B) oral doses of RV521 in infants hospitalised with RSV LRTI by assessing plasma trough concentration (Ctrough). | Pharmacokinetic analysis will include listings and summaries of PK concentrations by time point, derived PK, parameters and analysis of relationship with dose and body weight. | 48 hours post dose 10 | 
| Part B: To evaluate the antiviral effects of RV521 in infants hospitalised with RSV LRTI by RSV viral load measured in nasopharyngeal swabs by RT qPCR. | Pharmacodynamics analysis will include listing of results of viral load with summary statistics by dose level and time point. | up to 48 hours post dose 10 | 
| Part B: To evaluate the antiviral effects of RV521 in infants hospitalised with RSV LRTI by RSV viral load measured in nasopharyngeal swabs by CBIA. | Pharmacodynamics analysis will include listing of results of viral load with summary statistics by dose level and time point. | up to 48 hours post dose 10 | 
| Part B: Evaluate the effect of RV521 compared to placebo on the clinical course of RSV LRTI using the RSV Clinical Scoring System and the Adapted Version of ReSVinet Scale to assess time to resolution of symptoms. | Overall Time to Resolution of RSV-related signs and symptoms will be calculated from the time of randomization to the time that they are no longer present (absent or severity =0), and will be summarized and analysed as for Time to Improvement. | 48 hours post dose 10 | 
| Part B: Evaluate the effect of RV521 compared to placebo on the clinical course of RSV LRTI using the RSV Clinical Scoring System and the Adapted Version of ReSVinet Scale to assess time to improvement evaluated by change in severity of symptoms. | Time to improvement will be calculated for RSV-related signs and symptoms that are classified as moderate or severe during the course of the study and will be defined as the time from randomization until no longer present (absent or severity=0) or mild (scores ≤ 5). | 48 hours post dose 10 | 
| Part B: Evaluate the effect of RV521 compared to placebo on the clinical course of RSV LRTI using the RSV Clinical Scoring System and the Adapted Version of ReSVinet Scale to assess change in severity of symptoms. | Change in severity of symptoms by RV521, compared to placebo, will be measured by a composite score over time. | 48 hours post dose 10 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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RV521, Pediatrics, Children, LRTI, Wheezing, Rhinitis, Cough, sisunatovir