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

• Sponsor: F-star Therapeutics, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03493698
• Collaborator: PRA Health Sciences (Industry)
• Enrollment: 17
• Location: 1
• Arms: 3
• Actual Duration (Months): 3.7
• Patients Per Site Per Month: 4.6

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Drug Interaction Potentiation	Drug: Midazolam; Drug: Inarigivir	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 17 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: May 7, 2018
• Actual Primary Completion Date: Aug 27, 2018
• Actual Study Completion Date: Aug 27, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment A: Midazolam All subjects will receive a single oral dose of 2 mg Midazolam on Day 1	Drug: Midazolam; Midazolam
Experimental: Treatment B and C: Inarigivir All subjects will receive a single oral dose of 400 mg Inarigivir on Day 3, Day 6-18	Drug: Inarigivir; Inarigivir; Other Names: Inarigivir Soproxil, SB 9200
Experimental: Treatment D: Inarigivir with Midazolam 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; Midazolam; Drug: Inarigivir; Inarigivir; Other Names: Inarigivir Soproxil, SB 9200

Outcome Measures

Primary Outcome Measures

1. Effect of Steady-state Oral Inarigivir on the Single Dose Pharmacokinetics (PK) of Oral Midazolam in Healthy Subjects (Cmax) [Day 1 Treatment A and Day 19 Treatment D, respectively]

   Comparison of Cmax for midazolam between Treatments A and D.

2. Effect of Steady-state Oral Inarigivir on the Single Dose Pharmacokinetics (PK) of Oral Midazolam in Healthy Subjects (AUC0-t) [Day 1 Treatment A and Day 19 Treatment D, respectively]

   Comparison of AUC0-t for midazolam between Treatments A and D.

3. Effect of Steady-state Oral Inarigivir on the Single Dose Pharmacokinetics (PK) of Oral Midazolam in Healthy Subjects (AUC0-inf ) [Day 1 Treatment A and Day 19 Treatment D, respectively]

   Comparison of AUC0-inf for midazolam between Treatments A and D.

Secondary Outcome Measures

1. Number of Participants With Clinical Relevant Clinical Laboratory, Vital Signs, 12-lead ECG, or Physical Examination [Day -1 to Day 20 and Follow-up (5-9 days post-treatment)]

   Safety and tolerability were measured via clinical laboratory evaluations, vital signs, 12-lead ECG, or physical examination

2. PK of Inarigivir After Single and Multiple Oral Doses in Healthy Subjects (AUC) [Day 3 and Day 6 to 19]

   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)

3. PK of Inarigivir After Single and Multiple Oral Doses in Healthy Subjects (Cmax) [Day 3 and Day 6 to 19]

   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)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

1. Gender : male or female

2. Age : 18-55 years, inclusive, at screening

3. Body mass index (BMI) : 18.0-30.0 kg/m2, inclusive, at screening

4. Status : healthy subjects

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. Willing and able to sign the ICF

Exclusion Criteria:

1. Employee of PRA or the Sponsor

2. History of relevant drug and/or food allergies

3. Using tobacco products within 60 days prior to the first drug administration

4. History of alcohol abuse or drug addiction (including soft drugs like cannabis products)

5. 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

6. 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)

7. Positive screen for hepatitis B surface antigen (HBsAg), anti-HCV antibodies or anti-human immunodeficiency virus (HIV) 1 and 2 antibodies

8. 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

9. 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

10. 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University Medical Center Groningen	Groningen		Netherlands

Sponsors and Collaborators

• F-star Therapeutics, Inc.
• PRA Health Sciences

Investigators

• Principal Investigator: Jeroen van de Wetering, PRA Health Sciences

Study Documents (Full-Text)

• Study Protocol - Mar 6, 2018
• Statistical Analysis Plan - Jul 2, 2018

More Information

Publications

None provided.

• Responsible Party: F-star Therapeutics, Inc.
• ClinicalTrials.gov Identifier: NCT03493698
• Other Study ID Numbers: SBP-9200-HBV-202; 2018-000607-16
• First Posted: Apr 10, 2018
• Last Update Posted: Oct 8, 2020
• Last Verified: Sep 1, 2020

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Midazolam

Study Results

Participant Flow

Pre-assignment Detail	Each subject was expected to complete treatment groups A, B, C and D; sequentially.

Arm/Group Title	Sequential Single, Multi-day & Combo Midazolam and Inarigivir
Arm/Group Description	A: All subjects will receive a single oral dose of 2 mg Midazolam on Day 1 B: All subjects will receive a single oral dose of 400 mg Inarigivir on Day 3 C: All subjects receive oral dose of 400 mg Inarigivir once daily from Day 6 to Day 18 D: All subjects will receive a single oral dose of 400 mg Inarigivir coadministered with a single oral dose of 2 mg Midazolam on Day 19
Period Title: Treatment Period A
STARTED	17
COMPLETED	17
NOT COMPLETED	0
Period Title: Treatment Period A
STARTED	17
COMPLETED	17
NOT COMPLETED	0
Period Title: Treatment Period A
STARTED	17
COMPLETED	15
NOT COMPLETED	2
Period Title: Treatment Period A
STARTED	15
COMPLETED	15
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Sequential Single, Multi-day & Combo Midazolam and Inarigivir
Arm/Group Description	A: All subjects will receive a single oral dose of 2 mg Midazolam on Day 1 B: All subjects will receive a single oral dose of 400 mg Inarigivir on Day 3 C: All subjects receive oral dose of 400 mg Inarigivir once daily from Day 6 to Day 18 D: All subjects will receive a single oral dose of 400 mg Inarigivir coadministered with a single oral dose of 2 mg Midazolam on Day 19
Overall Participants	17
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	30 (9)
Sex: Female, Male (Count of Participants)
Female	4 23.5%
Male	13 76.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	17 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 5.9%
Asian	2 11.8%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	11 64.7%
More than one race	3 17.6%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
Netherlands	17 100%
BMI (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	25.5 (3.1)

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

All subjects who received at least one dose of midazolam and had sufficient concentration-time data to reliably estimate PK parameters

Arm/Group Title	Treatment A: Midazolam	Treatment B and C: Inarigivir	Treatment D: Inarigivir With Midazolam
Arm/Group Description	All subjects will receive a single oral dose of 2 mg Midazolam on Day 1 Midazolam: Midazolam	B: All subjects will receive a single oral dose of 400 mg Inarigivir on Day 3 C: All subjects receive oral dose of 400 mg Inarigivir once daily from Day 6 to Day 18 Inarigivir: Inarigivir	All subjects will receive a single oral dose of 400 mg Inarigivir coadministered with a single oral dose of 2 mg Midazolam on Day 19 Midazolam: Midazolam Inarigivir: Inarigivir
Measure Participants	17	0	15
Mean (Full Range) [ng/mL]	12.4	13.0

2. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

This outcome measure was prespecified for treatment groups A and D only.

Arm/Group Title	Treatment A: Midazolam	Treatment B and C: Inarigivir	Treatment D: Inarigivir With Midazolam
Arm/Group Description	All subjects will receive a single oral dose of 2 mg Midazolam on Day 1 Midazolam: Midazolam	B: All subjects will receive a single oral dose of 400 mg Inarigivir on Day 3 C: All subjects receive oral dose of 400 mg Inarigivir once daily from Day 6 to Day 18 Inarigivir: Inarigivir	All subjects will receive a single oral dose of 400 mg Inarigivir coadministered with a single oral dose of 2 mg Midazolam on Day 19 Midazolam: Midazolam Inarigivir: Inarigivir
Measure Participants	17	0	15
Mean (Full Range) [h.ng/ml]	29.9	28.7

3. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

This outcome measure was prespecified for treatment groups A and D only.

Arm/Group Title	Treatment A: Midazolam	Treatment B and C: Inarigivir	Treatment D: Inarigivir With Midazolam
Arm/Group Description	All subjects will receive a single oral dose of 2 mg Midazolam on Day 1 Midazolam: Midazolam	B: All subjects will receive a single oral dose of 400 mg Inarigivir on Day 3 C: All subjects receive oral dose of 400 mg Inarigivir once daily from Day 6 to Day 18 Inarigivir: Inarigivir	All subjects will receive a single oral dose of 400 mg Inarigivir coadministered with a single oral dose of 2 mg Midazolam on Day 19 Midazolam: Midazolam Inarigivir: Inarigivir
Measure Participants	17	0	15
Mean (Full Range) [h.ng/ml]	31.5	30.5

4. Secondary Outcome

Title	Number of Participants With Clinical Relevant Clinical Laboratory, Vital Signs, 12-lead ECG, or Physical Examination
Description	Safety and tolerability were measured via clinical laboratory evaluations, vital signs, 12-lead ECG, or physical examination
Time Frame	Day -1 to Day 20 and Follow-up (5-9 days post-treatment)

Outcome Measure Data

Analysis Population Description

All participants analyzed

Arm/Group Title	Treatment A: Midazolam	Treatment B: Inarigivir	Treatment C: Inarigivir	Treatment D: Inarigivir With Midazolam
Arm/Group Description	All subjects will receive a single oral dose of 2 mg Midazolam on Day 1 Midazolam: Midazolam	B: All subjects will receive a single oral dose of 400 mg Inarigivir on Day 3 Inarigivir: Inarigivir	C: All subjects receive oral dose of 400 mg Inarigivir once daily from Day 6 to Day 18 Inarigivir: Inarigivir	All subjects will receive a single oral dose of 400 mg Inarigivir coadministered with a single oral dose of 2 mg Midazolam on Day 19 Midazolam: Midazolam Inarigivir: Inarigivir
Measure Participants	17	15	15	15
Count of Participants [Participants]	0 0%	0 NaN	0 NaN	0 NaN

5. Secondary Outcome

Title	PK of Inarigivir After Single and Multiple Oral Doses in Healthy Subjects (AUC)
Description	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)
Time Frame	Day 3 and Day 6 to 19

Outcome Measure Data

Analysis Population Description

All subjects in treatment arms B and D who received inarigivir and had sufficient concentration-time data to reliably estimate PK parameters

Arm/Group Title	Treatment B: Inarigivir	Treatment D: Inarigivir With Midazolam
Arm/Group Description	B: All subjects will receive a single oral dose of 400 mg Inarigivir on Day 3 Inarigivir: Inarigivir	All subjects will receive a single oral dose of 400 mg Inarigivir coadministered with a single oral dose of 2 mg Midazolam on Day 19 Midazolam: Midazolam Inarigivir: Inarigivir
Measure Participants	17	15
Day 3 AUC0-t (h.ng/mL)	0.914
Day 3AUC0-inf (h.ng/mL)	1.19
Day 19 AUC0-t (h.ng/mL)	0.951

6. Secondary Outcome

Title	PK of Inarigivir After Single and Multiple Oral Doses in Healthy Subjects (Cmax)
Description	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)
Time Frame	Day 3 and Day 6 to 19

Outcome Measure Data

Analysis Population Description

All subjects in treatment arms B and D who received inarigivir and had sufficient concentration-time data to reliably estimate PK parameters

Arm/Group Title	Treatment B: Inarigivir	Treatment D: Inarigivir With Midazolam
Arm/Group Description	B: All subjects will receive a single oral dose of 400 mg Inarigivir on Day 3 Inarigivir: Inarigivir	All subjects will receive a single oral dose of 400 mg Inarigivir coadministered with a single oral dose of 2 mg Midazolam on Day 19 Midazolam: Midazolam Inarigivir: Inarigivir
Measure Participants	17	15
Mean (Full Range) [ng/mL]	0.886	0.991

Adverse Events

Time Frame	20 days
Arm/Group Title	Treatment A: Midazolam		Treatment B: Inarigivir		Treatment C: Inarigivir		Treatment D: Inarigivir With Midazolam
Arm/Group Description	All subjects will receive a single oral dose of 2 mg Midazolam on Day 1 Midazolam: Midazolam		B: All subjects will receive a single oral dose of 400 mg Inarigivir on Day 3 Inarigivir: Inarigivir		C: All subjects receive oral dose of 400 mg Inarigivir once daily from Day 6 to Day 18 Inarigivir: Inarigivir		All subjects will receive a single oral dose of 400 mg Inarigivir coadministered with a single oral dose of 2 mg Midazolam on Day 19 Midazolam: Midazolam Inarigivir: Inarigivir
All Cause Mortality
	Treatment A: Midazolam		Treatment B: Inarigivir		Treatment C: Inarigivir		Treatment D: Inarigivir With Midazolam
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/17 (0%)		0/17 (0%)		0/15 (0%)		0/15 (0%)
Serious Adverse Events
	Treatment A: Midazolam		Treatment B: Inarigivir		Treatment C: Inarigivir		Treatment D: Inarigivir With Midazolam
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/17 (0%)		0/17 (0%)		0/15 (0%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	Treatment A: Midazolam		Treatment B: Inarigivir		Treatment C: Inarigivir		Treatment D: Inarigivir With Midazolam
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/17 (23.5%)		4/17 (23.5%)		7/17 (41.2%)		2/15 (13.3%)
Eye disorders
Dry eye	0/17 (0%)		0/17 (0%)		1/17 (5.9%)		0/15 (0%)
Gastrointestinal disorders
Aphthous Ulcer	0/17 (0%)		1/17 (5.9%)		0/17 (0%)		0/15 (0%)
Diarrhea	1/17 (5.9%)		0/17 (0%)		1/17 (5.9%)		0/15 (0%)
Dry Mouth	0/17 (0%)		0/17 (0%)		1/17 (5.9%)		0/15 (0%)
Flatulence	0/17 (0%)		0/17 (0%)		1/17 (5.9%)		0/15 (0%)
General disorders
Fatigue	1/17 (5.9%)		2/17 (11.8%)		0/17 (0%)		0/15 (0%)
Influenza Like Illness	0/17 (0%)		0/17 (0%)		1/17 (5.9%)		0/15 (0%)
Sensation of Foreign Body	0/17 (0%)		0/17 (0%)		1/17 (5.9%)		0/15 (0%)
Infections and infestations
Nasopharyngitis	0/17 (0%)		0/17 (0%)		2/17 (11.8%)		0/15 (0%)
Musculoskeletal and connective tissue disorders
Muscle spasms	1/17 (5.9%)		0/17 (0%)		0/17 (0%)		1/15 (6.7%)
Musculoskeletal stiffness	0/17 (0%)		0/17 (0%)		1/17 (5.9%)		0/15 (0%)
Nervous system disorders
Headache	0/17 (0%)		1/17 (5.9%)		1/17 (5.9%)	2	0/15 (0%)	2
Psychiatric disorders
Affect Lability	0/17 (0%)		0/17 (0%)		0/17 (0%)		1/15 (6.7%)
Renal and urinary disorders
Pollakiuria	0/17 (0%)		0/17 (0%)		1/17 (5.9%)		0/15 (0%)
Respiratory, thoracic and mediastinal disorders
Laryngeal Discomfort	1/17 (5.9%)		0/17 (0%)		0/17 (0%)		0/15 (0%)
Skin and subcutaneous tissue disorders
Pruritus	1/17 (5.9%)		0/17 (0%)		0/17 (0%)		0/15 (0%)
Acne	0/17 (0%)		0/17 (0%)		1/17 (5.9%)		0/15 (0%)
Skin Fissures	0/17 (0%)		0/17 (0%)		1/17 (5.9%)		0/15 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.