A Study to Assess the Safety, Effects and Palatability of Sisunatovir in Healthy Adult Participants

Study Overview
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Brief Summary
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This study is seeking healthy participants who are: Aged 18 to 65 years of age. All fertile participants must agree to use a highly effective method of contraception. Male and female participants who are overtly healthy as determined by medical evaluation. This includes medical history, physical examination, blood pressure, pulse rate, standard 12-lead ECG (electrocardiogram), and laboratory tests. BMI (body mass index) of 17.5 to 35 kg/m2; and a total body weight >50 kg (110 lb). This study will consist of up to 2 cohorts (groups of participants).: Cohort 1 is a randomized, 2-part, crossover cohort. Part 1 has 3 periods. Periods 1 and 2 are to evaluate the safety and effects of sisunatovir. Participants will take sisunatovir tablets or placebo by mouth once every 12 hours. A placebo looks like the study medicine but does not contain any active medicine in it. Period 3 is an open label period to evaluate the food effect of the planned higher dose of sisunatovir. Participants will take the planned higher dose sisunatovir tablets every 12 hours. In Part 2, participants will take sisunatovir prepared in 4 different vehicles (water, infant formula, apple juice, and saline) to assess how palatable each form is. Participants will complete a questionnaire after tasting each form of sisunatovir. The palatability questionnaire will be completed for each vehicle, the questionnaire asks participants to assess each vehicle at 4 different time increments after tasting. At least 60 minutes will pass between tasting each vehicle. Period 4 may start after the last PK draw of Period 3. A minimum 7-day washout period will occur between the last dose of Periods 1 and 2 and the first dose of Periods 2 and 3. We will assess the safety of participants following each study period and doses and adjust the doses for subsequent study periods as needed. Cohort 2 is an optional cohort; the design of Cohort 2 is the same as Part 1 of Cohort 1. Dose levels studied in Cohort 2 will be determined after the completion of Cohort 1. Participants will take part in this study for approximately 2 months, excluding the screening period. During this time there are 3 separate 7-day in-patient stays at the study clinic and a follow-up phone call that takes place 28-35 days after the last dose of study medicine.

Official Title
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A PHASE 1, RANDOMIZED, SPONSOR OPEN, TWO-PART CROSSOVER STUDY TO ASSESS SAFETY, TOLERABILITY, PHARMACOKINETICS AND FOOD EFFECT OF MULTIPLE DOSES IN PART 1 AND PALATABILITY OF A SINGLE DOSE OF SISUNATOVIR IN PART 2, IN HEALTHY ADULT PARTICIPANTS

Conditions
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Respiratory Syncytial Viruses

Intervention / Treatment
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* Drug: sisunatovir
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants aged 18 to 65 years of age, inclusive, at the time of signing of the informed consent document (ICD). • All fertile participants must agree to use a highly effective method of contraception. Male and female participants who are overtly healthy as determined by medical evaluation including medical history, physical examination, including blood pressure, pulse rate, standard 12-lead electrocardiogram (ECG), and laboratory tests. Body mass index (BMI) of 17.5 to 35 kg/m2; and a total body weight >50 kg (110 lb). Exclusion Criteria: Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at the time of dosing). Other medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality, or other conditions or situations related to Coronavirus Disease 2019 (COVID-19) pandemic that may increase the risk of study participation or, in the investigator's judgment, make the participant inappropriate for the study. Use of prescription or nonprescription drugs and dietary and herbal supplements within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study intervention with the exception of moderate/strong CYP3A inducers or time dependent inhibitors which are prohibited within 14 days plus 5 half lives prior to the first dose of study intervention. A positive urine drug test, confirmed by a repeat test, if deemed necessary. Screening supine blood pressure (BP) ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), following at least 5 minutes of supine rest. If BP is ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), the BP should be repeated 2 more times and the average of the 3 BP values should be used to determine the participant's eligibility. Standard 12 lead ECG that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results. Participants with ANY of the following abnormalities in clinical laboratory tests at screening, as assessed by the study specific laboratory and confirmed by a single repeat test, if deemed necessary: glomerular filtration rate (GFR) <60 mL/min/1.73m2 based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation; Aspartate Aminotransferase (AST) or Alanine Transaminase (ALT) level ≥1.5 x upper limit of normal (ULN); Gamma-glutamyl transferase (Gamma-GT)> ULN; Alkaline phosphatase > ULN; Total bilirubin level ≥1.5 × ULN; participants with a history of Gilbert's syndrome may have direct bilirubin measured and would be eligible for this study provided the direct bilirubin level is ≤ ULN.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A: Higher dose sisunatovir<br>higher dose of sisunatovir dosed every 12 hours | Drug: sisunatovir<br>* Sisunatovir is an orally administered RSV F-protein inhibitor being developed to target viral-host cell fusion for the treatment of adult and pediatric patients with RSV<br>|
| Experimental: Group B: Lower dose sisunatovir<br>Lower dose of sisunatovir dosed every 12 hours | Drug: sisunatovir<br>* Sisunatovir is an orally administered RSV F-protein inhibitor being developed to target viral-host cell fusion for the treatment of adult and pediatric patients with RSV<br>|
| Placebo Comparator: Group C: Placebo<br>Placebo for sisunatovir dosed every 12 hours | Drug: Placebo<br>* Placebo for sisunatovir<br>|
| Experimental: Group D: Higher dose of sisunatovir<br>Higher dose of sisunatovir dosed every 12 hours under fasted conditions | Drug: sisunatovir<br>* Sisunatovir is an orally administered RSV F-protein inhibitor being developed to target viral-host cell fusion for the treatment of adult and pediatric patients with RSV<br>|
| Experimental: Group E: sisunatovir palatability<br>Sisunatovir in 4 vehicles (water, saline, apple juice, infant formula) to assess the palatability of sisunatovir in each vehicle. sisunatovir will not be swallowed, participants will swirl and spit to assess various aspects of the taste. | Drug: sisunatovir<br>* Sisunatovir is an orally administered RSV F-protein inhibitor being developed to target viral-host cell fusion for the treatment of adult and pediatric patients with RSV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment Emergent Treatment-Related Adverse Events (AEs) | Treatment-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to Y days after last dose that were absent before treatment or that worsened relative to pretreatment state. Relatedness to Drug X was assessed by the investigator (Yes/No). Participants with multiple occurrences of an AE within a category were counted once within the category. | Baseline (Day 0) up to 35 days after last dose of study medication | 
| Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities | Laboratory parameters included: hematology (hemoglobin, hematocrit, red blood cell, platelet and white blood cell count, neutrophils, eosinophils, monocytes, basophils and lymphocytes), chemistry (blood urea nitrogen, creatinine, sodium, potassium, aspartate aminotransferase, alanine aminotransferase, total bilirubin, alkaline phosphatase, albumin, total protein and serum pregnancy test [for all female participants]) and urine (urine pregnancy test [for all female participants]). Clinical significance of laboratory parameters was determined at the investigator's discretion. | Baseline up to Day 7 | 
| Number of Participants With Clinically Significant Change From Baseline in Vital Signs | Vital signs (temperature, respiratory rate, pulse, systolic and diastolic blood pressure) were obtained with participant in the seated position, after having sat calmly for at least 5 minutes. Clinical significance of vital signs was determined at the investigator's discretion. | Baseline up to Day 7 | 
| Number of Participants With Notable Electrocardiogram (ECG) Values from baseline | Criteria for notable ECG values were as follow: QT interval (in millisecond [msec]) new (newly occurring post-baseline value) greater than (>) 450, 480, 500, increase from baseline >30, increase from baseline >60; corrected QT interval by Fredericia formula (QTcF) in msec new (newly occurring post-baseline value) > 450, 480, 500, increase from baseline >30, increase from baseline >60; corrected QT interval by Bazett's formula (QTcB) in msec new (newly occurring post-baseline value) > 450, 480, 500, increase from baseline >30, increase from baseline >60; heart rate in bpm new (newly occurring post-baseline value) <60 and >100. | Baseline up to Day 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve from Time Zero to end of dosing interval (AUCtau) | AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. | 0, 1, 2, 3, 4, 5, 6, 8, 12, 16, and 24 hours after the first dose | 
| Maximum Observed Plasma Concentration (Cmax) |  | 0, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48 hours after the last dose. | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) |  | 0, 1, 2, 3, 4, 5, 6, 8, 12, 16, and 24 hours after the first dose | 
| Area Under the Curve from Time Zero to end of dosing interval (AUCtau) | AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. | 0, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48 hours after the last dose. | 
| Maximum Observed Plasma Concentration (Cmax) |  | 0, 1, 2, 3, 4, 5, 6, 8, 12, 16, and 24 hours after the first dose | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) |  | 0, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48 hours after the last dose. | 
| Apparent Oral Clearance (CL/F) | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. | 0, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48 hours after the last dose. | 
| Accumulation Ratio (Rac) | Accumulation ratio was calculated as, Rac obtained from Area Under the Concentration Time Curve (AUC) from time 0-t (Day X) divided by AUC from time 0-t (Day 1). | 0, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48 hours after the last dose. | 
| Accumulation Ratio for Maximum Observed Plasma Concentration (Rac,Cmax) | Accumulation ratio based on maximum plasma concentration (Cmax) was calculated as: Rac,Cmax = Cmax at steady state (ss) divided by Cmax at first dose. | 0, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48 hours after the last dose. | 
| Plasma Decay Half-Life (t1/2) | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. | 0, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48 hours after the last dose. | 
| Apparent Volume of Distribution (Vz/F) | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed. | 0, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48 hours after the last dose. | 
| Palatability evaluation using Oral Solution or Suspension Palatability Questionnaire (Sisunatovir in Water) | evaluation of the mouth feel (grittiness, stickiness, waxiness), bitterness, sweetness, sourness, saltiness, tongue/mouth burn, and overall liking of the drug. evaluated with a validated color bar with a scale from 0 to 100. Outcomes will be summarized using descriptive statistics. | 1, 5, 10, and 20 minutes after dose | 
| Palatability evaluation using Oral Solution or Suspension Palatability Questionnaire (Sisunatovir in Saline) | evaluation of the mouth feel (grittiness, stickiness, waxiness), bitterness, sweetness, sourness, saltiness, tongue/mouth burn, and overall liking of the drug. evaluated with a validated color bar with a scale from 0 to 100. Outcomes will be summarized using descriptive statistics. | 1, 5, 10, and 20 minutes after dose | 
| Palatability evaluation using Oral Solution or Suspension Palatability Questionnaire (Sisunatovir in Infant Formula) | evaluation of the mouth feel (grittiness, stickiness, waxiness), bitterness, sweetness, sourness, saltiness, tongue/mouth burn, and overall liking of the drug. evaluated with a validated color bar with a scale from 0 to 100. Outcomes will be summarized using descriptive statistics. | 1, 5, 10, and 20 minutes after dose | 
| Palatability evaluation using Oral Solution or Suspension Palatability Questionnaire (Sisunatovir in Apple Juice) | evaluation of the mouth feel (grittiness, stickiness, waxiness), bitterness, sweetness, sourness, saltiness, tongue/mouth burn, and overall liking of the drug. evaluated with a validated color bar with a scale from 0 to 100. Outcomes will be summarized using descriptive statistics. | 1, 5, 10, and 20 minutes after dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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RSV, respiratory syncytial virus