Drug Interaction Study With RV521 in Healthy Volunteer Subjects

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 main aim of this study is to determine whether RV521 interacts with any other medication using four licensed medicines (midazolam, itraconazole, rifampicin and verapamil) that are known to have specific effects on enzymes and transporter proteins that influence the absorption of drugs

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
• Genders Eligible for Study: All

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: Parallel 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: Principal Investigator: Lorch, MD, Richmond Pharmacology Limited

Study record dates

Study Major Dates

• Study Start (Actual): November 6, 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): May 23, 2019
• Last Update Submitted That Met QC Criteria: May 22, 2019
• Last Verified: May 1, 2019

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)

Drug and device information, study documents

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