Drug Interaction Study With RV521 in Healthy Volunteer Subjects

Study Overview
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Brief Summary
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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

Official Title
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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

Conditions
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Respiratory Syncytial Virus Infections

Intervention / Treatment
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* Drug: Itraconazole
* Drug: Verapamil
* Drug: Rifampicin
* Drug: Midazolam
* Drug: Placebo for RV521
* Drug: RV521


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RV521 plus Itraconazole<br>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<br>* Itraconazole capsules<br>Drug: RV521<br>* RV521 capsules<br>|
| Experimental: RV521 plus Verapamil<br>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: Verapamil<br>* Verapamil tablets<br>Drug: RV521<br>* RV521 capsules<br>|
| Experimental: RV521 plus Rifampicin<br>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: Rifampicin<br>* Rifampicin capsules<br>* Other names: Rifadin;Drug: RV521<br>* RV521 capsules<br>|
| Experimental: RV521 plus Midazolam<br>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<br>* Midazolam oromucosal solution<br>* Other names: Buccolam;Drug: RV521<br>* RV521 capsules<br>|
| Placebo Comparator: Placebo plus Midazolam<br>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<br>* Midazolam oromucosal solution<br>* Other names: Buccolam;Drug: Placebo for RV521<br>* Placebo for RV521 capsules<br>|

What is the study measuring?
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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) |