A Study to Learn About the Drug-drug Interactions of Sisunatovir in Healthy Adult Participants

An Adaptive, Part Open-label, Part Randomised Phase 1 Clinical Trial in Healthy Volunteers to Study Drug Interactions With RV521 Including Those Mediated by CYP3A4 and P-glycoprotein

The purpose of this clinical trial is to learn about the interaction of sisunatovir with four medications (midazolam, itraconazole, rifampicin, and verapamil). These medications are known to have specific effects on enzymes and proteins that could influence drug absorption.

This study will be conducted in 4 Cohorts:

• Cohort 1 will receive midazolam and sisunatovir or placebo,
• Cohort 2 will receive Itraconazole and sisunatovir,
• Cohort 3 will receive verapamil and sisunatovir,
• Cohort 4 will receive rifampicin and sisunatovir. A placebo looks like sisunatovir but does not contain any active medicine in it.

This study is looking for health adult participants that meet the following criteria:

1. Caucasians age 18 to 45 years
2. All fertile participants must agree to the use of highly effective contraception
3. Body mass index (BMI) of 18-25.0 kg/m2
4. 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.

This study consists of 2 parts, Part A and Part B. Part A will enroll up to 104 participants. The design of Part B will be determined after the completion of Part A.

Study Overview

• Status: Completed
• Conditions: Respiratory Syncytial Virus Infections
• Intervention / Treatment: Drug: Midazolam; Drug: Itraconazole; Drug: RV521; Drug: Verapamil; Drug: Rifampicin; Drug: Placebo for RV521

• Study Type: Interventional
• Enrollment (Actual): 82
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, SE1 1YR
    • Richmond Pharmacology Ltd

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Age 18 to 45 years, inclusive
• Willing to comply with protocol defined contraception requirements
• In good health with no history of major medical conditions
• A body mass index (BMI) of 18 - 25 kg/m2

Exclusion Criteria:

• Evidence of any clinically significant or currently active major medical condition
• Positive test for Hepatitis B surface antigen (HBsAg), Hepatitis C antibody (HCV Ab), or human immunodeficiency virus antibody (HIV Ab)
• Not willing to comply with protocol defined restrictions for intake of drugs of abuse, alcohol, nicotine-containing products, medication (prescription, OTC, herbal, vitamins/minerals etc) and specified food and drink products

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Triple

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: RV521 plus Itraconazole; RV521 drug substance in capsule for oral administration, a single 200 mg dose administered on D1 and a single 200 mg dose administered on D7 plus Itraconazole 100 mg capsules for oral administration, a 200 mg dose administered once daily on D4 - D10, inclusive	Drug: Itraconazole; Itraconazole capsules; Drug: RV521; RV521 capsules
Experimental: RV521 plus Verapamil; RV521 drug substance in capsule for oral administration, a single 200 mg dose administered on D1 and a single 200 mg dose administered on D11 plus Verapamil, 80 mg tablets for oral administration, an 80 mg dose administered TDS daily on D4 - D14, inclusive	Drug: RV521; RV521 capsules; Drug: Verapamil; Verapamil tablets
Experimental: RV521 plus Rifampicin; RV521 drug substance in capsule for oral administration, a single 200 mg dose administered on D1 and a single 200 mg dose administered on D10 plus Rifadin, Rifampicin, 300 mg capsules for oral administration, a 600 mg dose administered once daily on D4 - D10, inclusive	Drug: RV521; RV521 capsules; Drug: Rifampicin; Rifampicin capsules; Other Names: Rifadin
Experimental: RV521 plus Midazolam; RV521 drug substance in capsule for oral administration, 200 mg dose administered BID on D2 - D15, inclusive plus Buccolam 10 mg oromucosal solution of midazolam, oral syringes, a single 10 mg dose administered on D1 and a single 200 mg dose administered on D15	Drug: Midazolam; Midazolam oromucosal solution; Other Names: Buccolam; Midazolam Prefilled Syringe; Drug: RV521; RV521 capsules
Placebo Comparator: Placebo plus Midazolam; Placebo for RV521 in capsule for oral administration, 200 mg dose administered BID on D2 - D15, inclusive plus Buccolam 10 mg oromucosal solution of midazolam, oral syringes, a single 10 mg dose administered on D1 and a single 200 mg dose administered on D15	Drug: Midazolam; Midazolam oromucosal solution; Other Names: Buccolam; Midazolam Prefilled Syringe; Drug: Placebo for RV521; Placebo for RV521 capsules

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect of RV521 on Cmax of Midazolam	The specified pharmacokinetic parameter will be summarised using descriptive statistics	Baseline to study day 17
Effect of RV521 on tmax of Midazolam	The specified pharmacokinetic parameter will be summarised using descriptive statistics	Baseline to study day 17
Effect of RV521 on t1/2 of Midazolam	The specified pharmacokinetic parameter will be summarised using descriptive statistics	Baseline to study day 17
Effect of RV521 on AUC of Midazolam	The specified pharmacokinetic parameter will be summarised using descriptive statistics	Baseline to study day 17
Effect of RV521 on CL/F of Midazolam	The specified pharmacokinetic parameter will be summarised using descriptive statistics	Baseline to study day 17
Effect of itraconazole on Cmax of RV521	The specified pharmacokinetic parameter will be summarised using descriptive statistics	Baseline to study day 12
Effect of itraconazole on tmax of RV521	The specified pharmacokinetic parameter will be summarised using descriptive statistics	Baseline to study day 12
Effect of itraconazole on t1/2 of RV521	The specified pharmacokinetic parameter will be summarised using descriptive statistics	Baseline to study day 12
Effect of itraconazole on AUC of RV521	The specified pharmacokinetic parameter will be summarised using descriptive statistics	Baseline to study day 12
Effect of itraconazole on CL/F of RV521	The specified pharmacokinetic parameter will be summarised using descriptive statistics	Baseline to study day 12
Effect of verapamil on Cmax of RV521	The specified pharmacokinetic parameter will be summarised using descriptive statistics	Baseline to study day 16
Effect of verapamil on tmax of RV521	The specified pharmacokinetic parameter will be summarised using descriptive statistics	Baseline to study day 16
Effect of verapamil on t1/2 of RV521	The specified pharmacokinetic parameter will be summarised using descriptive statistics	Baseline to study day 16
Effect of verapamil on AUC of RV521	The specified pharmacokinetic parameter will be summarised using descriptive statistics	Baseline to study day 16
Effect of verapamil on CL/F of RV521	The specified pharmacokinetic parameter will be summarised using descriptive statistics	Baseline to study day 16
Effect of rifampicin on Cmax of RV521	The specified pharmacokinetic parameter will be summarised using descriptive statistics	Baseline to study day 15
Effect of rifampicin on tmax of RV521	The specified pharmacokinetic parameter will be summarised using descriptive statistics	Baseline to study day 15
Effect of rifampicin on t1/2 of RV521	The specified pharmacokinetic parameter will be summarised using descriptive statistics	Baseline to study day 15
Effect of rifampicin on AUC of RV521	The specified pharmacokinetic parameter will be summarised using descriptive statistics	Baseline to study day 15
Effect of rifampicin on CL/F of RV521	The specified pharmacokinetic parameter will be summarised using descriptive statistics	Baseline to study day 15

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of subjects with treatment-related adverse events as assessed by NCI CTCAE V5.0	The number of subjects with treatment-related adverse events will be summarised by treatment group using descriptive statistics	Screening to final study visit (performed at 7 days following the last dose of any intervention)
Number of subjects with QT/QTc interval changes relative to baseline who received RV521 (monotherapy), Midazolam (monotherapy) or RV521 and Midazolam (combination therapy)	Descriptive statistics will be given by time point and dose-group for absolute values and change from baseline. Results will be tabulated and for QTc, the difference to time matched placebo will also be displayed	Baseline to to final study visit (performed at 7 days following the last dose of any intervention)

Collaborators and Investigators

• Sponsor: Pfizer
• Investigators: Study Director: Pfizer CT.gov Call Center, Pfizer

Publications and helpful links

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start (Actual): November 7, 2018
• Primary Completion (Actual): March 17, 2019
• Study Completion (Actual): March 17, 2019

Study Registration Dates

• First Submitted: December 5, 2018
• First Submitted That Met QC Criteria: December 18, 2018
• First Posted (Actual): December 20, 2018

Study Record Updates

• Last Update Posted (Actual): April 22, 2024
• Last Update Submitted That Met QC Criteria: April 18, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Paramyxoviridae Infections; Mononegavirales Infections; Pneumovirus Infections; Respiratory Syncytial Virus Infections; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Vasodilator Agents; Anti-Infective Agents; Central Nervous System Depressants; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Hormones, Hormone Substitutes, and Hormone Antagonists; Anti-Bacterial Agents; Tranquilizing Agents; Psychotropic Drugs; Membrane Transport Modulators; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Leprostatic Agents; Hormone Antagonists; Cytochrome P-450 Enzyme Inducers; Calcium-Regulating Hormones and Agents; Antifungal Agents; Steroid Synthesis Inhibitors; Calcium Channel Blockers; Cytochrome P-450 CYP3A Inducers; Antitubercular Agents; 14-alpha Demethylase Inhibitors; Antibiotics, Antitubercular; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C8 Inducers; Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C9 Inducers; Midazolam; Rifampin; Itraconazole; Verapamil
• Other Study ID Numbers: REVC004; 2018-003256-21 (EudraCT Number); C5241004 (Other Identifier: Alias Study Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No