A Phase 1 Bioavailability Study of Arbaclofen Placarbil Modified Release Formulations in Healthy Volunteers

NCT03058237 | Completed Phase 1

• 2 other identifiers: INDV-AP-1022016-003792-22
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

Part 1

• To evaluate the pharmacokinetic (PK) profile of Arbaclofen Placarbil (AP) and R-baclofen following dosing of Arbaclofen Placarbil Modified Release (MR) Prototype A Tablet and Arbaclofen Placarbil MR Prototype B Tablet in healthy subjects
• To determine the relative bioavailability of AP and R-baclofen following dosing of Arbaclofen Placarbil MR Prototype A Tablet and Arbaclofen Placarbil MR Prototype B Tablet compared to the reference Arbaclofen Placarbil Sustained Release (SR) Tablets (low dose)
• To determine the relative bioavailability and PK of AP and R-baclofen following dosing of the selected MR prototype formulation(s) in the presence of beverage
• To provide additional information on the safety and tolerability of single doses of AP Part 2
• To evaluate the PK profile of AP and R-baclofen following dosing of Arbaclofen Placarbil MR Prototype Tablets in healthy subjects
• To determine the relative bioavailability and PK of AP and R-baclofen following dosing of Arbaclofen Placarbil MR Prototype Tablets compared to the reference Arbaclofen Placarbil Immediate Release (IR) Capsule
• To provide additional information on the safety and tolerability of single doses of AP
• To determine the relative bioavailability and PK of AP and R-baclofen following dosing of a selected MR prototype formulation in the fed state (optional)
• To explore a possible in vitro in vivo correlation/relationship (IVIVC/IVIVR) for the Arbaclofen Placarbil MR Prototype Tablet Formulations Part 3
• To determine the relative bioavailability of the selected Arbaclofen Placarbil MR Prototype Tablet in the presence of either beverage or food and/or
• To evaluate the PK profile (dose proportionality) of AP and R-baclofen following dosing of the selected Arbaclofen Placarbil MR Prototype A + B Tablet at different dose levels in healthy subjects
• To provide additional information on the safety and tolerability of single doses of AP

Conditions

Healthy Volunteers

Outcome Measures

Primary Outcomes (1)

• Part 1: Time to Maximum Concentration (Tmax) of Arbaclofen Placarbil (AP) and R-baclofen in Low Dose Arbaclofen Placarbil Modified Release (MR) Prototypes A + B

  Part of the pharmacokinetic profile of arbaclofen placarbil (AP) and R-baclofen in low dose arbaclofen placarbil modified release (MR) prototypes A and B.

  Day 1 (pre-dose), post-dose up to 48 hours

Secondary Outcomes (75)

• Part 1: Maximum Observed Concentration (Cmax) of Arbaclofen Placarbil (AP) and R-baclofen in Low Dose Arbaclofen Placarbil Modified Release (MR) Prototypes A + B

  Day 1 (pre-dose), post-dose up to 48 hours

• Part 1: Concentrations at 12 Hours Post-dose (C12) of Arbaclofen Placarbil (AP) and R-baclofen in Low Dose Arbaclofen Placarbil Modified Release (MR) Prototypes A + B

  Day 1 (pre-dose), post-dose at 12 hours

• Part 1: Concentrations at 24 Hours Post-dose (C24) of Arbaclofen Placarbil (AP) and R-baclofen in Low Dose Arbaclofen Placarbil Modified Release (MR) Prototypes A + B

  Day 1 (pre-dose), post-dose at 24 hours

• Part 1: Area under the Concentration vs Time Curve From Time 0 to 12 Hours post-dose (AUC(0-12)) of Arbaclofen Placarbil (AP) and R-baclofen in Low Dose Arbaclofen Placarbil Modified Release (MR) Prototypes A + B

  Day 1 (pre-dose), post-dose up to 12 hours

• Part 1: Area under the Concentration vs Time Curve From Time 0 to 24 Hours post-dose (AUC(0-24)) of Arbaclofen Placarbil (AP) and R-baclofen in Low Dose Arbaclofen Placarbil Modified Release (MR) Prototypes A + B

  Day 1 (pre-dose), post-dose up to 24 hours

Study Arms (14)

Part 1: Regimen A

EXPERIMENTAL

One low dose Arbaclofen Placarbil MR Prototype A tablet taken under fasting conditions. Part 1 participants receive Regimens A, B, C, D and E in a sequential manner.

Drug: Arbaclofen Placarbil MR Prototype A

Part 1: Regimen B

EXPERIMENTAL

One low dose Arbaclofen Placarbil MR Prototype B tablet taken under fasting conditions. Part 1 participants receive Regimens A, B, C, D and E in a sequential manner.

Drug: Arbaclofen Placarbil MR Prototype B

Part 1: Regimen C

ACTIVE COMPARATOR

One low dose Arbaclofen Placarbil SR tablet taken under fasting conditions as the reference product. Part 1 participants receive Regimens A, B, C, D and E in a sequential manner.

Drug: Arbaclofen Placarbil SR

Part 1: Regimen D

EXPERIMENTAL

One low dose tablet of the selected Arbaclofen Placarbil MR Prototype administered with 0.6 g/kg of beverage in orange juice. Part 1 participants receive Regimens A, B, C, D and E in a sequential manner.

Drug: Arbaclofen Placarbil MR Prototype A; Drug: Arbaclofen Placarbil MR Prototype B

Part 1: Regimen E

EXPERIMENTAL

An optional regimen of one low dose tablet of the selected Arbaclofen Placarbil MR Prototype administered with 0.6 g/kg of beverage in orange juice. Part 1 participants receive Regimens A, B, C, D and E in a sequential manner.

Drug: Arbaclofen Placarbil MR Prototype A; Drug: Arbaclofen Placarbil MR Prototype B

Part 2: Regimen F

EXPERIMENTAL

One low dose Arbaclofen Placarbil MR prototype tablet (selected based on review of the data in Part 1) taken under fasting conditions. Part 2 participants receive Regimens F, G, H, I and J in a sequential manner.

Drug: Arbaclofen Placarbil MR Prototype A; Drug: Arbaclofen Placarbil MR Prototype B

Part 2: Regimen G

ACTIVE COMPARATOR

One low dose Arbaclofen Placarbil IR capsule taken under fasting conditions as the reference product. Part 2 participants receive Regimens F, G, H, I and J in a sequential manner.

Drug: Arbaclofen Placarbil IR

Part 2: Regimen H

EXPERIMENTAL

One low dose Arbaclofen Placarbil MR prototype tablet (selected based on review of the data in Part 1) taken under fasting conditions. Part 2 participants receive Regimens F, G, H, I and J in a sequential manner.

Drug: Arbaclofen Placarbil MR Prototype A; Drug: Arbaclofen Placarbil MR Prototype B

Part 2: Regimen I

EXPERIMENTAL

One low dose Arbaclofen Placarbil MR prototype tablet (selected based on review of the data in Part 1) taken under fasting conditions. Part 2 participants receive Regimens F, G, H, I and J in a sequential manner.

Drug: Arbaclofen Placarbil MR Prototype A; Drug: Arbaclofen Placarbil MR Prototype B

Part 2: Regimen J

EXPERIMENTAL

One low dose Arbaclofen Placarbil MR prototype tablet (selected based on review of the data in Part 1) taken under fasting conditions, or a previously dosed MR prototype in the fed state. Part 2 participants receive Regimens F, G, H, I and J in a sequential manner.

Drug: Arbaclofen Placarbil MR Prototype A; Drug: Arbaclofen Placarbil MR Prototype B

Part 3: Regimen K

EXPERIMENTAL

One low dose selected Arbaclofen Placarbil MR prototype tablet (selected based on review of the data in Part 2) taken under fasting conditions. Part 3 participants receive Regimens K and L in a randomised crossover manner as the first two treatments, followed by Regimens M and N in a sequential manner.

Drug: Arbaclofen Placarbil MR Prototype A; Drug: Arbaclofen Placarbil MR Prototype B

Part 3: Regimen L

EXPERIMENTAL

One low dose selected Arbaclofen Placarbil MR prototype tablet administered with 0.6 g/kg of beverage in orange juice or in the fed state, or one mid-low dose of the selected Arbaclofen Placarbil MR prototype tablet. Part 3 participants receive Regimens K and L in a randomised crossover manner as the first two treatments, followed by Regimens M and N in a sequential manner.

Drug: Arbaclofen Placarbil MR Prototype A; Drug: Arbaclofen Placarbil MR Prototype B

Part 3: Regimen M

EXPERIMENTAL

An optional regimen of one mid-low dose of the selected Arbaclofen Placarbil MR prototype tablet (if not previously dosed in Regimen L) or one mid-high dose of the selected Arbaclofen Placarbil MR prototype tablet taken under fasting conditions. Part 3 participants receive Regimens K and L in a randomised crossover manner as the first two treatments, followed by Regimens M and N in a sequential manner.

Drug: Arbaclofen Placarbil MR Prototype A; Drug: Arbaclofen Placarbil MR Prototype B

Part 3: Regimen N

EXPERIMENTAL

An optional regimen of one mid-high dose of the selected Arbaclofen Placarbil MR prototype tablet (if not previously dosed in Regimen M) or two mid-low dose of the selected Arbaclofen Placarbil MR prototype tablets. Part 3 participants receive Regimens K and L in a randomised crossover manner as the first two treatments, followed by Regimens M and N in a sequential manner.

Drug: Arbaclofen Placarbil MR Prototype A; Drug: Arbaclofen Placarbil MR Prototype B

Interventions

Arbaclofen Placarbil SR DRUG

One low dose oral tablet of Arbaclofen Placarbil sustained release (SR) in the fasted state.

Part 1: Regimen C

Arbaclofen Placarbil MR Prototype A DRUG

One low dose oral tablet pf Arbaclofen Placarbil modified release (MR) Prototype A in the fasted state; this formulation may also be tested with 0.6 g/kg beverage diluted in orange juice

Part 1: Regimen A; Part 1: Regimen D; Part 1: Regimen E; Part 2: Regimen F; Part 2: Regimen H; Part 2: Regimen I; Part 2: Regimen J; Part 3: Regimen K; Part 3: Regimen L; Part 3: Regimen M; Part 3: Regimen N

Arbaclofen Placarbil MR Prototype B DRUG

One low dose oral tablet of Arbaclofen Placarbil modified release (MR) Prototype B; this formulation may also be tested with 0.6 g/kg beverage diluted in orange juice

Part 1: Regimen B; Part 1: Regimen D; Part 1: Regimen E; Part 2: Regimen F; Part 2: Regimen H; Part 2: Regimen I; Part 2: Regimen J; Part 3: Regimen K; Part 3: Regimen L; Part 3: Regimen M; Part 3: Regimen N

Arbaclofen Placarbil IR DRUG

One low dose oral capsule of Arbaclofen Placarbil immediate release (IR) in the fasted state.

Part 2: Regimen G

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy males
• Non-pregnant, non-lactating healthy females
• Body mass index of 18.0 to 30.0 kg/m\^2 or, if outside the range, considered not clinically significant by the investigator
• Must be willing and able to communicate and participate in the whole study
• Must provide written informed consent prior to any study-specific procedures
• Must agree to use an adequate method of contraception

You may not qualify if:

• Subjects who have received any IMP in a clinical research study within the previous 3 months
• Subjects who are study site employees, or immediate family members of a study site or sponsor employee
• Subjects who have previously been enrolled in this study
• History of any clinically significant drug/substance or alcohol abuse or disorders in the past 2 years
• Regular alcohol consumption in males \>21 units per week and females \>14 units per week (1 unit = ½ pint beer, 25 mL of 40% spirit or a 125 mL glass of wine)
• Regular alcohol consumption \<5 units per week on average
• Current smokers and those who have smoked within the last 12 months. A breath carbon monoxide reading of greater than 10 ppm at screening and each admission
• Current smokers of e-cigarettes and nicotine replacement products and those who have smoked these products within the last 12 months
• Females of childbearing potential who are pregnant or lactating (female subjects must have a negative urine pregnancy test). A woman is considered of childbearing potential unless she is permanently sterile (hysterectomy, bilateral salpingectomy or bilateral oophorectomy) or is postmenopausal (had no menses for 12 months without an alternative medical cause and a serum follicle-stimulating hormone \[FSH\] concentration ≥40 IU/L)
• Subjects who do not have suitable veins for multiple venepunctures/cannulation as assessed by the investigator at screening
• Clinically significant abnormal biochemistry, haematology or urinalysis as judged by the investigator
• Clinically significant abnormal ECG as judged by the investigator, including a QT interval corrected using Fridericia's formula of \>450 msec in males and \>470 msec in females
• Positive drugs of abuse test result at screening and each admission (drugs of abuse tests are listed in the protocol)
• Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) results
• Evidence of renal impairment at screening, as indicated by an estimated creatinine clearance of \<70 mL/min using the Cockcroft-Gault equation

Sponsors & Collaborators

• Indivior Inc.: lead

Study Sites (1)

Quotient Clinical

Ruddington, Nottingham, NG11 6JS, United Kingdom

Location

Study Officials

• Global Director, Clinical Development

  Indivior Inc.

  STUDY DIRECTOR

Study Design

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

Model Details: The Clinical Trial Authorisation application for this study describes a flexible protocol design using the formulation design space concept to allow decision-making in response to interim PK observations

Study Record Dates

• First Submitted: February 9, 2017
• First Posted: February 20, 2017
• Study Start: January 24, 2017
• Primary Completion: July 5, 2017
• Study Completion: July 5, 2017
• Last Updated: January 17, 2018

Record last verified: 2018-01

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)