A Drug-Drug Interaction Study to Evaluate the Effect of Vapendavir on the Pharmacokinetics of Midazolam in Healthy Male and Female Volunteers

Study Overview
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Brief Summary
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The primary aim of this Phase 1 study is to evaluate the effect of vapendavir daily doses of 528 mg daily (QD) and 264 mg twice daily (BID) on the pharmacokinetic (PK) profile of midazolam, a cytochrome (CYP) 3A4 substrate. Additionally, the effect of midazolam on the PK profile of vapendavir, a PK profile comparison of vapendavir in males and females, as well as the safety of vapendavir will also be assessed.

Official Title
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A Phase 1, Randomized, Open-Label Study to Evaluate the Effect of Vapendavir (BTA798) on the Pharmacokinetics of Orally Administered Midazolam, a CYP3A4 Substrate, in Healthy Male and Female Volunteers

Conditions
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Drug-Drug Interaction Healthy Volunteers

Intervention / Treatment
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* Drug: Midazolam 5mg Syrup
* Drug: Vapendavir 264 mg BID
* Drug: Vapendavir 528 mg QD


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must be male or female between 18 and 55 years of age (inclusive) with BMI between 18 and 30 kg/m2 (inclusive), and weight ≥50 kg at the time of screening; Capable of giving written informed consent; Subject is able to understand and comply with the protocol requirements, instructions and restrictions; Healthy on the basis of physical examination, medical history, medication usage, vital signs (VS), electrocardiograms (ECGs), and clinical laboratory tests; Female subjects who are not post-menopausal for at least 2 years or surgically sterile with complete hysterectomy or bilateral oophorectomy and male subjects who are not surgically sterile via vasectomy, must agree to use a double barrier method of birth control, such as a condom plus spermicidal agent (foam/gel/film/cream/suppository); and Female subjects must not be breastfeeding or pregnant. Exclusion Criteria: Positive results for Hepatitis B, Hepatitis C, or HIV; Frequent use (defined as > 5 times/day) of tobacco products, including cigarettes, cigars, chewing tobacco; A medical history of significant hematological, gastrointestinal, respiratory, renal, hepatic, cerebrovascular, immunologic, psychiatric or cardiovascular disease or event; Current or recent respiratory infection (defined as within 14 days of first study visit participation) Presence or history of significant allergy; Clinically significant abnormalities noted on ECG; Screening vital signs representing sustained elevated systolic blood pressure <90 mmHg or >140 mmHg, and/or diastolic blood pressure <55 mmHg or >90 mmHg. Presence of significant gastrointestinal abnormalities such as diarrhea or constipation; Safety laboratory abnormalities noted at screening which are clinically significant Current or defined history of abuse of alcohol or illicit drugs; A positive pregnancy test at screening; Poor vein access or fear of venipuncture or sight of blood; and Regular consumption of alcohol defined as either > 2 units (glass or shot) of alcoholic beverages per day or > 14 units per week.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: Other
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vapendavir 528 mg QD<br>Twelve subjects (6 male and 6 female) will receive 528 mg vapendavir (achieved with four 132 mg vapendavir capsules) QD in the morning for seven days | Drug: Midazolam 5mg Syrup<br>* All twenty four subjects will receive 5 mg midazolam syrup at four different time points during the study for a total of four non-subsequent dosing days. On Study Days 0 and 12, subjects will receive only 5 mg midazolam syrup dosed in the morning. On Study Days 6 and 9, subjects will have 5 mg midazolam syrup co-administered with their assigned dose of vapendavir in the morning. Co-administration of midazolam will not occur at the time of the evening dose for Group B.<br>Drug: Vapendavir 528 mg QD<br>* Twelve subjects (6 male and 6 female) will receive 528 mg vapendavir (achieved with four 132 mg vapendavir capsules) QD in the morning for seven days<br>|
| Experimental: Vapendavir 264 mg BID<br>Twelve subjects (6 male and 6 female) will receive 264 mg vapendavir (achieved with two 132 mg vapendavir capsules) BID daily as divided dose given in the morning and evening 12 hours apart for seven days. | Drug: Midazolam 5mg Syrup<br>* All twenty four subjects will receive 5 mg midazolam syrup at four different time points during the study for a total of four non-subsequent dosing days. On Study Days 0 and 12, subjects will receive only 5 mg midazolam syrup dosed in the morning. On Study Days 6 and 9, subjects will have 5 mg midazolam syrup co-administered with their assigned dose of vapendavir in the morning. Co-administration of midazolam will not occur at the time of the evening dose for Group B.<br>Drug: Vapendavir 264 mg BID<br>* Twelve subjects (6 male and 6 female) will receive 264 mg vapendavir (achieved with two 132 mg vapendavir capsules) BID daily as divided dose given in the morning and evening 12 hours apart for seven days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Effect of Vapendavir on the PK Profile of Midazolam | To evaluate the effect of vapendavir daily dose of 264 mg BID on the PK profile of midazolam, a CYP3A4 substrate. The primary outcome will be evaluated through a series of analyses of PK parameters including: for midazolam including maximum observed plasma concentration (Cmax) time at which Cmax was observed (Tmax) plasma concentration at the end of the dosing interval (Ctau) area under the plasma concentration-time curve from time 0 to the last measurable plasma concentration (AUC0-last) area under the plasma concentration-time curve from time 0 to the end of the dosing interval (AUC0-tau) area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC0-inf) elimination half-life (t1/2) apparent oral clearance (CL/F) apparent oral volume of distribution (Vz/F). | End of Study (up to 46 weeks in duration) | 
| The Effect of Vapendavir on the PK Profile of Midazolam | To evaluate the effect of vapendavir daily dose of 528 mg QD on the PK profile of midazolam, a CYP3A4 substrate. The primary outcome will be evaluated through a series of analyses of PK parameters including: for midazolam including maximum observed plasma concentration (Cmax) time at which Cmax was observed (Tmax) plasma concentration at the end of the dosing interval (Ctau) area under the plasma concentration-time curve from time 0 to the last measurable plasma concentration (AUC0-last) area under the plasma concentration-time curve from time 0 to the end of the dosing interval (AUC0-tau) area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC0-inf) elimination half-life (t1/2) apparent oral clearance (CL/F) apparent oral volume of distribution (Vz/F). | End of Study (up to 46 weeks in duration) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess Whether PK Profile of Vapendavir is Affected by Presence of Midazolam | To evaluate whether the PK profile of vapendavir, is affected by the presence of midazolam, a strong CYP3A4 substrate. This outcome will be evaluated through a series of analyses of PK parameters for vapendavir including: maximum observed plasma concentration (Cmax) time at which Cmax was observed (Tmax) plasma concentration at the end of the dosing interval (Ctau) area under the plasma concentration-time curve from time 0 to the last measurable plasma concentration (AUC0-last) area under the plasma concentration-time curve from time 0 to the end of the dosing interval (AUC0-tau) area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC0-inf) elimination half-life (t1/2) apparent oral clearance (CL/F) apparent oral volume of distribution (Vz/F). | End of Study (up to 46 weeks in duration) | 
| Assess the Safety of Vapendavir | To evaluate the safety of vapendavir. This will be accomplished by assessing adverse events, clinical laboratory tests (including blood chemistry, hematology with differential and urinalysis), physical exams, ECG assessments, vital sign assessments and concomitant medications. | End of Study (up to 46 weeks in duration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Aviragen Therapeutics, Inc., Aviragen Therapeutics, Aviragen