A Fixed-Sequence, Drug-Drug Interaction Study Between Multiple Oral Doses of Inarigivir Soproxil and a Single Oral Dose of Midazolam in Healthy Subjects

Study Overview
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Brief Summary
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This is a single center, open-label, fixed sequence study to investigate the effect of multiple oral dosing of Inarigivir Soproxil and a single oral dose of Midazolam in Healthy Subjects

Official Title
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A Phase 1, Open-label, Fixed-Sequence, Drug-Drug Interaction Study Between Multiple Oral Doses of Inarigivir Soproxil and a Single Oral Dose of Midazolam in Healthy Subjects

Conditions
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Drug Interaction Potentiation

Intervention / Treatment
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* Drug: Midazolam
* Drug: Inarigivir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Gender : male or female Age : 18-55 years, inclusive, at screening Body mass index (BMI) : 18.0-30.0 kg/m2, inclusive, at screening Status : healthy subjects At screening, females must be non-pregnant and non-lactating, or of non-childbearing potential (either surgically sterilized or physiologically incapable of becoming pregnant, or at least 1 year post-menopausal [amenorrhoea duration of 12 consecutive months]); non-pregnancy will be confirmed for all females by a serum pregnancy test conducted at screening, and a urine pregnancy test at each admission and at follow-up Female subjects of childbearing potential, with a fertile male sexual partner, must agree to use adequate contraception from screening until 90 days after the follow-up visit. Adequate contraception is defined as using a non-hormonal intrauterine device combined with at least 1 of the following forms of contraception: a diaphragm or cervical cap, or a condom; please note that hormonal contraceptives are not allowed. Also, total abstinence, in accordance with the lifestyle of the subject, is acceptable Male subjects, if not surgically sterilized, must agree to use adequate contraception and not donate sperm from admission to the clinical research center until 90 days after the follow-up visit. Adequate contraception for the male subject (and his female partner) is defined as using hormonal contraceptives or an intrauterine device, combined with at least 1 of the following forms of contraception: a diaphragm or cervical cap, or a condom. Also, total abstinence, in accordance with the lifestyle of the subject is acceptable All prescribed medication, including hormonal contraceptives for female subjects, must have been stopped at least 30 days prior to admission to the clinical research center All over-the-counter medication, vitamin preparations and other food supplements, or herbal medications (eg, St. John's Wort) must have been stopped at least 14 days prior to admission to the clinical research center. An exception is made for paracetamol, which is allowed up to admission to the clinical research center Ability and willingness to abstain from alcohol, methylxanthine-containing beverages or food (coffee, tea, cola, chocolate, energy drinks) and grapefruit (juice) from 72 hours prior to admission to the clinical research center Good physical and mental health on the basis of medical history, physical examination, clinical laboratory, electrocardiogram (ECG) and vital signs, as judged by the PI Willing and able to sign the ICF Exclusion Criteria: Employee of PRA or the Sponsor History of relevant drug and/or food allergies Using tobacco products within 60 days prior to the first drug administration History of alcohol abuse or drug addiction (including soft drugs like cannabis products) Positive drug and alcohol screen (opiates, methadone, cocaine, amphetamines [including ecstasy], cannabinoids, barbiturates, benzodiazepines, tricyclic antidepressants and alcohol) at screening and admission to the clinical research center Average intake of more than 24 units of alcohol per week (1 unit of alcohol equals approximately 250 mL of beer, 100 mL of wine or 35 mL of spirits) Positive screen for hepatitis B surface antigen (HBsAg), anti-HCV antibodies or anti-human immunodeficiency virus (HIV) 1 and 2 antibodies Participation in a drug study within 60 days prior to the first drug administration in the current study. Participation in more than 4 other drug studies in the 12 months prior to the first drug administration in the current study Donation or loss of more than 100 mL of blood within 60 days prior to the first drug administration. Donation or loss of more than 1.5 liters of blood (for male subjects) / more than 1.0 liters of blood (for female subjects) in the 10 months prior to the first drug administration in the current study Significant and/or acute illness within 5 days prior to the first drug administration that may impact safety assessments, in the opinion of the PI

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: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment A: Midazolam<br>All subjects will receive a single oral dose of 2 mg Midazolam on Day 1 | Drug: Midazolam<br>* Midazolam<br>|
| Experimental: Treatment B and C: Inarigivir<br>All subjects will receive a single oral dose of 400 mg Inarigivir on Day 3, Day 6-18 | Drug: Inarigivir<br>* Inarigivir<br>* Other names: Inarigivir Soproxil, SB 9200;|
| Experimental: Treatment D: Inarigivir with Midazolam<br>All subjects will receive a single oral dose of 400 mg Inarigivir coa administered with a single oral dose of 2 mg Midazolam on Day 19 | Drug: Midazolam<br>* Midazolam<br>Drug: Inarigivir<br>* Inarigivir<br>* Other names: Inarigivir Soproxil, SB 9200;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of Steady-state Oral Inarigivir on the Single Dose Pharmacokinetics (PK) of Oral Midazolam in Healthy Subjects (Cmax) | Comparison of Cmax for midazolam between Treatments A and D. | Day 1 Treatment A and Day 19 Treatment D, respectively | 
| Effect of Steady-state Oral Inarigivir on the Single Dose Pharmacokinetics (PK) of Oral Midazolam in Healthy Subjects (AUC0-t) | Comparison of AUC0-t for midazolam between Treatments A and D. | Day 1 Treatment A and Day 19 Treatment D, respectively | 
| Effect of Steady-state Oral Inarigivir on the Single Dose Pharmacokinetics (PK) of Oral Midazolam in Healthy Subjects (AUC0-inf ) | Comparison of AUC0-inf for midazolam between Treatments A and D. | Day 1 Treatment A and Day 19 Treatment D, respectively | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Clinical Relevant Clinical Laboratory, Vital Signs, 12-lead ECG, or Physical Examination | Safety and tolerability were measured via clinical laboratory evaluations, vital signs, 12-lead ECG, or physical examination | Day -1 to Day 20 and Follow-up (5-9 days post-treatment) | 
| PK of Inarigivir After Single and Multiple Oral Doses in Healthy Subjects (AUC) | A summary of the main plasma PK parameters for inarigivir, Rp-SB 9000, Sp-SB 9000, and Rp-SB 9000 and Sp-SB 9000 combined after a single oral dose of 400 mg inarigivir on Day 3 (Treatment B) and after the last of 14 consecutive daily oral doses of 400 mg inarigivir from Day 6 to 19 (Treatment D) | Day 3 and Day 6 to 19 | 
| PK of Inarigivir After Single and Multiple Oral Doses in Healthy Subjects (Cmax) | A summary of the main plasma PK parameters for inarigivir, Rp-SB 9000, Sp-SB 9000, and Rp-SB 9000 and Sp-SB 9000 combined after a single oral dose of 400 mg inarigivir on Day 3 (Treatment B) and after the last of 14 consecutive daily oral doses of 400 mg inarigivir from Day 6 to 19 (Treatment D) | Day 3 and Day 6 to 19 |