Study of the Relative Oral Bioavailability of AL-3778 Tablets and Drug Interaction With Entecavir or Tenofovir Disoproxil Fumarate in Healthy Volunteers

NCT03032536 | Terminated Phase 1 FDA Drug

• 2 other identifiers: AL-3778-1002U1111-1187-4391
• Study Type: interventional
• Target: 54
• Locations: 1 country
• Sites: 2

Brief Summary

This is an open-label, randomized, multi-part study to evaluate the relative oral bioavailability of a tablet formulation of AL-3778 (formerly NVR 3-778) administered under fasted and fed conditions (Parts 1 and 2) and the drug-drug interaction between AL-3778 and entecavir or tenofovir disoproxil fumarate (Part 3).

Conditions

Hepatitis B; Chronic Hepatitis B; Viral Hepatitis B

Outcome Measures

Primary Outcomes (7)

• AL-3778, entecavir, tenofovir: Maximum observed plasma concentration (Cmax)

  At 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 hours after dosing on Day 1 and 14 and once per day on Day 8, 10, 12, and 22

• AL-3778, entecavir, tenofovir: Area under the plasma concentration-time curve from time 0 to last measurable concentration (AUClast)

  At 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 hours after dosing on Day 1 and 14 and once per day on Day 8, 10, 12, and 22

• AL-3778, entecavir, tenofovir: Area under the plasma concentration-time curve from time 0 to extrapolated to infinity (AUC∞)

  At 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 hours after dosing on Day 1 and 14 and once per day on Day 8, 10, 12, and 22

• AL-3778, entecavir, tenofovir: Maximum observed plasma concentration on Day 1 (Cmax. Day 1)

  At 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 hours after dosing on Day 1

• AL-3778, entecavir, tenofovir: Minimum observed plasma concentration on Day 1 (Cmin, Day 1)

  At 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 hours after dosing on Day 1

• AL-3778, entecavir, tenofovir: Area under the plasma concentration-time curve from time 0 to dosing interval on Day 1 (AUC0-Τ, Day 1)

  At 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 hours after dosing on Day 1

• AL-3778, entecavir, tenofovir: Minimum observed plasma concentration (C_min)

  At 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 hours after dosing on Day 1 and 14 and once per day on Day 8, 10, 12, and 22

Secondary Outcomes (15)

• AL-3778, entecavir, tenofovir: Predose plasma concentrations (C_0-h)

  At 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 hours after dosing on Day 1 and 14 and once per day on Day 8, 10, 12, and 22

• AL-3778, entecavir, tenofovir: Last observed plasma concentration (C_last)

  At 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 hours after dosing on Day 1 and 14 and once per day on Day 8, 10, 12, and 22

• AL-3778, entecavir, tenofovir: Time of the maximum observed plasma concentration (T_max)

  At 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 hours after dosing on Day 1 and 14 and once per day on Day 8, 10, 12, and 22

• AL-3778, entecavir, tenofovir: Time to last measurable plasma concentration (T_last)

  At 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 hours after dosing on Day 1 and 14 and once per day on Day 8, 10, 12, and 22

• AL-3778, entecavir, tenofovir: Apparent oral clearance (CL/F)

  At 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 hours after dosing on Day 1 and 14 and once per day on Day 8, 10, 12, and 22

Study Arms (7)

Treatments A, B, C

EXPERIMENTAL

Part 1: Cross-Over * Treatment A: AL-3778 6 x 100-mg capsules (fasted) once. * Treatment B: AL-3778 2 x 300-mg tablets (fasted) once * Treatment C: AL-3778 2 x 300-mg tablets (high-fat meal) once.

Drug: AL-3778

Treatments D, E, F

EXPERIMENTAL

Part 2 (optional): Cross-Over * Treatment D: AL-3778 2×300-mg tablets (fasted) once. * Treatment E: AL-3778 tablet Dose (fasted) once. Dose will match Treatment F dose and will be: * 1000mg: 2 x 500-mg OR * 800mg: 1 x 300-mg + 1 x 500-mg OR * 700mg: 1 x 200-mg + 1 x 500-mg * Treatment F: AL-3778 tablet Dose (high-fat meal) once. Dose will match Treatment E dose and will be: * 1000mg: 2 x 500-mg OR * 800mg: 1 x 300-mg + 1 x 500-mg OR * 700mg: 1 x 200-mg + 1 x 500-mg

Drug: AL-3778

Treatment G

EXPERIMENTAL

Part 3: AL-3778 twice daily administered under fasted conditions for 14 days. Dose will be determined by Part 1 and/or Part 2 and will be one of the following tablet dosages: * 600mg: 2 x 300-mg OR * 1000mg: 2 x 500-mg OR * 800mg: 1 x 300-mg + 1 x 500-mg OR * 700mg: 1 x 200-mg + 1 x 500-mg

Drug: AL-3778

Treatment H

ACTIVE COMPARATOR

Part 3: Entecavir 0.5 mg once daily administered under fasted conditions for 14 days

Drug: Entecavir

Treatment I

EXPERIMENTAL

Part 3: AL-3778 twice daily with entecavir 0.5 mg once daily both administered under fasted conditions for 14 days. AL-3778 dose will be determined by Part 1 and/or Part 2 and will be one of the following tablet dosages: * 600mg: 2 x 300-mg OR * 1000mg: 2 x 500-mg OR * 800mg: 1 x 300-mg + 1 x 500-mg OR * 700mg: 1 x 200-mg + 1 x 500-mg

Drug: AL-3778; Drug: Entecavir

Treatment J

ACTIVE COMPARATOR

Part 3: Tenofovir disoproxil fumarate 300 mg once daily administered under fasted conditions for 14 days

Drug: Tenofovir disoproxil fumarate

Treatment K

EXPERIMENTAL

Part 3: AL-3778 twice daily and tenofovir disoproxil fumarate 300 mg once daily both administered under fasted conditions for 14 days. AL-3778 dose will be determined by Part 1 and/or Part 2 and will be one of the following tablet dosages: * 600mg: 2 x 300-mg OR * 1000mg: 2 x 500-mg OR * 800mg: 1 x 300-mg + 1 x 500-mg OR * 700mg: 1 x 200-mg + 1 x 500-mg

Drug: AL-3778; Drug: Tenofovir disoproxil fumarate

Interventions

AL-3778 DRUG

AL-3778 tablets or capsules

Also known as: NVR 3-778, JNJ-63595948, ALS-003778

Treatment G; Treatment I; Treatment K; Treatments A, B, C; Treatments D, E, F

Entecavir DRUG

Entecavir once daily for 14 days

Treatment H; Treatment I

Tenofovir disoproxil fumarate DRUG

Tenofovir disoproxil fumarate once daily for 14 days

Also known as: Viread

Treatment J; Treatment K

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Subject has provided written consent.
• In the investigator's opinion, the subject is able to understand and comply with protocol requirements, instructions, and study restrictions and is likely to complete the study as planned.
• Subject is in good health as deemed by the investigator, based on the totality of findings following a medical evaluation, including medical history, physical examination, laboratory tests and ECG.
• Male or female, 18-60 years of age.
• Body mass index 18-30 kg/m2, inclusive. The minimum weight is 50 kg.
• A female subject is eligible to participate in this study if she is of non-childbearing potential (defined as females with a documented tubal ligation, bilateral oophorectomy or hysterectomy) or postmenopausal (defined as 12 months of spontaneous amenorrhea and follicle stimulating hormone level within the laboratory's reference range for postmenopausal females). A post-menopausal female receiving hormone replacement therapy who is willing to discontinue hormone therapy 28 days before study drug dosing and agrees to remain off hormone replacement therapy for the duration of the study may be eligible for study participation.
• If male, subject is surgically sterile or practicing required forms of birth control until 6 months after the last dose of the study drug(s). Males must agree to refrain from sperm donation from check-in through 6 months after the last dose of the study drug(s).
• Subject has been a nonsmoker and has not used nicotine or nicotine-containing products for at least 6 months.

You may not qualify if:

• Subject is mentally or legally incapacitated, has significant emotional problems at the time of prestudy (screening) visit or expected during the conduct of the study or has a history of a clinically significant psychiatric disorder over the last 5 to 10 years.
• Subject has a history of any illness that, in the opinion of the investigator, would confound the objectives or results of the study or poses an additional risk to the subject by their participation in the study.
• Subject has an estimated creatinine clearance of ≤80 mL/min based on the Cockcroft-Gault equation; An actual creatinine clearance, as determined by a 24-hour urine collection, may be used in place of, or in conjunction with, the Cockcroft-Gault equation; subjects who have an actual or estimated creatinine clearance within 10% of 80 mL/min may be enrolled in the study at the discretion of the investigator.
• Pregnant or nursing (lactating) females, confirmed by a positive human chorionic gonadotropin laboratory test or females contemplating pregnancy. Men whose female partners are pregnant or contemplating pregnancy from the date of screening until 6 months after their last dose of study drugs.
• Clinically significant cardiovascular, respiratory, skeletal, renal, gastrointestinal, hematologic, hepatic, immunological, neurologic, endocrine, genitourinary abnormalities or disease or any other medical illness as determined by the investigator or Sponsor's Medical Monitor.
• Subject has a history of malignancy except completely excised basal cell carcinoma or squamous cell carcinoma of the skin.
• Subject lacks or has poor peripheral venous access.
• Positive screening result for hepatitis B, hepatitis C and/or HIV serology.
• Any condition that, in the opinion of the investigator, would compromise the study's objectives or the well-being of the subject or prevent the subject from meeting the study requirements.
• Clinically significant abnormal ECG findings. Particularly, a history or family history of prolonged QT syndrome (eg, torsade de pointes) or sudden cardiac death.
• ECG with PR \>200 ms, QRS \>120 ms, QTcF \>450 ms, as assessed by triplicate 12-lead ECG at the screening visit.
• Subject has had major surgery, or clinically significant blood loss or elective blood donation of significant volume (ie, \>500 mL) within 60 days of first dose of study drug; \>1 unit of plasma within 7 days of first dose of study drug.
• Abnormal heart rate, respiratory rate, temperature or blood pressure values outside of the normal range (evaluated in a semi-recumbent or recumbent position after 5 minutes of rest). One repeat measurement after an additional 5 minutes of rest is permitted.
• Evidence of active infection.
• Unwilling to abstain from alcohol for at least 48 hours prior to the start of dosing through the study completion visit.

Sponsors & Collaborators

• Alios Biopharma Inc.: lead

Study Sites (2)

Auckland Clinical Studies

Auckland, 1010, New Zealand

Location

Christchurch Clinical Studies Trust

Christchurch, 8011, New Zealand

Location

MeSH Terms

Conditions

Hepatitis B; Hepatitis B, Chronic

Interventions

NVR 3-778; entecavir; Tenofovir

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Hepadnaviridae Infections; DNA Virus Infections; Virus Diseases; Hepatitis, Viral, Human; Hepatitis; Liver Diseases; Digestive System Diseases; Hepatitis, Chronic; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Adenine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• William D Kennedy, MD

  Alios Biopharma Inc.

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 24, 2017
• First Posted: January 26, 2017
• Study Start: January 31, 2017
• Primary Completion: June 28, 2017
• Study Completion: June 28, 2017
• Last Updated: October 16, 2017

Record last verified: 2017-10

Data Sharing

• IPD Sharing: Will share

Locations

NZ (2)