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
Trial Snapshot
- Phase
- Phase 1
- Status
- Completed
- Sponsor
- Pfizer
- Enrollment
- 12
- Locations
- 1
- Primary Endpoint
- Number of Participants With Treatment Emergent Adverse Events (TEAEs)
Study Overview
Brief Summary
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Crossover
- Primary Purpose
- Basic Science
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- 18 Years to 65 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- Yes
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.
Arms & Interventions
Group A: Higher dose sisunatovir
higher dose of sisunatovir dosed every 12 hours
Intervention: sisunatovir (Drug)
Group B: Lower dose sisunatovir
Lower dose of sisunatovir dosed every 12 hours
Intervention: sisunatovir (Drug)
Group C: Placebo
Placebo for sisunatovir dosed every 12 hours
Intervention: Placebo (Drug)
Group D: Higher dose of sisunatovir
Higher dose of sisunatovir dosed every 12 hours under fasted conditions
Intervention: sisunatovir (Drug)
Group E: sisunatovir palatability
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.
Intervention: sisunatovir (Drug)
Outcomes
Primary Outcomes
Number of Participants With Treatment Emergent Adverse Events (TEAEs)
Time Frame: From start of treatment to 28-35 days after last dose (maximum upto 66 days)
An adverse event (AE) is any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. TEAEs were any AEs that occurred following start of treatment.
Number of Participants With Clinical Laboratory Abnormalities: Part 1
Time Frame: Up to Day 5
Laboratory tests included haematology (Monocytes \[10\^9/L\] increase: \> 1.2\* upper limit of normal \[ULN\] and Monocytes/Leukocytes \[percentage\] {%}:\> 1.2\* ULN); clinical chemistry (serum) included Alanine Aminotransferase (units per liter \[U/L\]):\> 3.0\* ULN and Bicarbonate (milliequivalents per liter) (mEq/L): \>1.1\* ULN and in urinalysis (urine Hemoglobin (Scalar) more than equal to (\>=) 1, urine Bilirubin (Scalar) \>= 1, Hyaline Casts (/Low power field \[LPF\]) \>= 1. Number of participants with any clinical laboratory abnormalities is reported in this outcome.
Number of Participants With Newly Occurring Notable Abnormal Vital Signs: Part 1
Time Frame: Up to Day 5
Supine blood pressure (BP) was measured with the participant's arm supported at the level of the heart and recorded after approximately 5 minutes of rest. Pulse rate was measured in the brachial/radial artery. Notable abnormal vital sign categories included: Systolic BP: \<90 millimeter of mercury \[mmHg\]; Systolic BP change from baseline: maximum increase and decrease \>=30 mmHg; Diastolic BP \<50 mmHg; Diastolic BP change from baseline: maximum decrease and increase ≥20 mmHg; pulse rate \<40 and \>120 beats per minute. Number of participants with newly occurring notable abnormal vital sign (i.e. change in supine systolic BP \>=30 millimeter of mercury \[mmHg\] increase) is reported in this outcome measure.
Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Findings: Part 1
Time Frame: Up to Day 7
Standard 12-lead ECGs utilizing limb leads were used to measure PR interval, QT interval, QTc corrected using Fridericia's formula (QTcF), and QRS complex. ECG was performed after the participant had rested quietly for at least 5 minutes in a supine position. Clinical significance was determined by the investigator.
Secondary Outcomes
- Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) for Day 1: Part 1(Pre-dose, 1, 2, 3, 4, 5, 6, 8 and 12 hours post-dose on Day 1)
- Dose Normalized AUCtau (AUCtau [dn]) for Day 1: Part 1(Pre-dose, 1, 2, 3, 4, 5, 6, 8 and 12 hours post-dose on Day 1)
- Maximum Observed Plasma Concentration (Cmax) for Day 1: Part 1(Pre-dose, 1, 2, 3, 4, 5, 6, 8 and 12 hours post-dose on Day 1)
- Dose Normalized Maximum Plasma Concentration (Cmax [dn]) for Day 1: Part 1(Pre-dose, 1, 2, 3, 4, 5, 6, 8 and 12 hours post-dose on Day 1)
- Time to Reach Maximum Observed Plasma Concentration (Tmax) for Day 1: Part 1(Pre-dose, 1, 2, 3, 4, 5, 6, 8 and 12 hours post-dose on Day 1)
- Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) for Day 5: Part 1(Pre-dose, 1, 2, 3, 4, 5, 6, 8 and 12 hours post-dose on Day 5)
- AUCtau(dn) for Day 5: Part 1(Pre-dose, 1, 2, 3,4, 5, 6, 8 and 12 hours post-dose on Day 5)
- Maximum Observed Plasma Concentration (Cmax) for Day 5: Part 1(Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36 and 48 hours post-dose on Day 5)
- Cmax(dn) for Day 5: Part 1(Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36 and 48 hours post-dose on Day 5)
- Time to Reach Maximum Observed Plasma Concentration (Tmax) for Day 5: Part 1(Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36 and 48 hours post-dose on Day 5)
- Apparent Clearance (CL/F) for Day 5: Part 1(Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36 and 48 hours post-dose on Day 5)
- Observed Accumulation Ratio (Rac) for AUC for Day 5: Part 1(Pre-dose, 1, 2, 3, 4, 5, 6, 8 and 12 hours post-dose on Day 1 and Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12 hours post-dose on Day 5)
- Observed Accumulation Ratio for Maximum Observed Plasma Concentration (Rac,Cmax) for Day 5: Part 1(Pre-dose, 1, 2, 3, 4, 5, 6, 8 and 12 hours post-dose on Day 1 and Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36 and 48 hours post-dose on Day 5)
- Plasma Decay Half-Life (t1/2) for Day 5: Part 1(Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36 and 48 hours post-dose on Day 5)
- Apparent Volume of Distribution (Vz/F) for Day 5: Part 1(Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36 and 48 hours post-dose on Day 5)
- AUCtau for Day 5: Evaluation of Food Effect (Sisunatovir 200 mg Fed Versus Fasted): Part 1(Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12 hours post-dose on Day 5)
- Cmax for Day 5: Evaluation of Food Effect (Sisunatovir 200 mg Fed Versus Fasted): Part 1(Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36 and 48 hours post-dose on Day 5)
- Assessment of Overall Liking Based on Palatability Assessment Questionnaire: Part 2(1 minute (immediately following dose), 5,10 and 20 minutes after tasting dose in each vehicle)
- Assessment of Mouth Feel Based on Palatability Assessment Questionnaire: Part 2(1 minute (immediately following dose), 5,10 and 20 minutes after tasting dose in each vehicle)
- Assessment of Bitterness Based on Palatability Assessment Questionnaire: Part 2(1 minute (immediately following dose), 5,10 and 20 minutes after tasting dose in each vehicle)
- Assessment of Tongue/Mouth Burn Based on Palatability Assessment Questionnaire: Part 2(1 minute (immediately following dose), 5,10 and 20 minutes after tasting dose in each vehicle)
- Assessment of Sourness Based on Palatability Assessment Questionnaire: Part 2(1 minute (immediately following dose), 5,10 and 20 minutes after tasting dose in each vehicle)
- Assessment of Saltiness Based on Palatability Assessment Questionnaire: Part 2(1 minute (immediately following dose), 5,10 and 20 minutes after tasting dose in each vehicle)
- Assessment of Sweetness on Palatability Assessment Questionnaire: Part 2(1 minute (immediately following dose), 5,10 and 20 minutes after tasting dose in each vehicle)