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

NCT ID: NCT03058237

Last Updated: 2018-01-17

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 40 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-01-24
• Study Completion Date: 2017-07-05

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

Detailed Description

For Parts 1, 2 and 3, participants will attend the clinical unit for a screening visit up to 28 days before dosing. For each treatment period, eligible subjects will be admitted to the clinical unit on the evening before dosing (Day -1). Participants will receive each regimen in the morning of Day 1 and will remain on site until 48 h post-dose. There will be a minimum washout period of 7 days between administration of each regimen. Where interim decisions occur, the interval between periods will be sufficient to permit the decision process.

Arbaclofen Placarbil MR Prototype Tablets will be administered in Part 1 and one prototype will be selected for development in Part 2 where the release rate of modified release (MR) prototype formulations will be optimised using a design space concept (at a fixed low dose).

A selected MR prototype formulation from Part 2 may be administered in Part 3 at up to 4 different dose levels (low, mid-low, mid-high, high). The suggested doses in Part 3 may be modified based on emerging safety and PK data from Part 2 of the study.

In Parts 2 and 3, there will be an option to dose selected Arbaclofen Placarbil MR Prototype Tablets in the fed state.

Conditions

Healthy Volunteers

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

Part 1: Regimen A

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.

Group Type: EXPERIMENTAL

Arbaclofen Placarbil MR Prototype A

Intervention Type: 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 B

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.

Group Type: EXPERIMENTAL

Arbaclofen Placarbil MR Prototype B

Intervention Type: 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 C

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.

Group Type: ACTIVE_COMPARATOR

Arbaclofen Placarbil SR

Intervention Type: DRUG

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

Part 1: Regimen D

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.

Group Type: EXPERIMENTAL

Arbaclofen Placarbil MR Prototype A

Intervention Type: 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

Arbaclofen Placarbil MR Prototype B

Intervention Type: 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 E

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.

Group Type: EXPERIMENTAL

Arbaclofen Placarbil MR Prototype A

Intervention Type: 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

Arbaclofen Placarbil MR Prototype B

Intervention Type: 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 2: Regimen F

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.

Group Type: EXPERIMENTAL

Arbaclofen Placarbil MR Prototype A

Intervention Type: 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

Arbaclofen Placarbil MR Prototype B

Intervention Type: 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 2: Regimen G

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.

Group Type: ACTIVE_COMPARATOR

Arbaclofen Placarbil IR

Intervention Type: DRUG

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

Part 2: Regimen H

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.

Group Type: EXPERIMENTAL

Arbaclofen Placarbil MR Prototype A

Intervention Type: 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

Arbaclofen Placarbil MR Prototype B

Intervention Type: 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 2: Regimen I

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.

Group Type: EXPERIMENTAL

Arbaclofen Placarbil MR Prototype A

Intervention Type: 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

Arbaclofen Placarbil MR Prototype B

Intervention Type: 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 2: Regimen J

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.

Group Type: EXPERIMENTAL

Arbaclofen Placarbil MR Prototype A

Intervention Type: 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

Arbaclofen Placarbil MR Prototype B

Intervention Type: 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 3: Regimen K

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.

Group Type: EXPERIMENTAL

Arbaclofen Placarbil MR Prototype A

Intervention Type: 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

Arbaclofen Placarbil MR Prototype B

Intervention Type: 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 3: Regimen L

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.

Group Type: EXPERIMENTAL

Arbaclofen Placarbil MR Prototype A

Intervention Type: 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

Arbaclofen Placarbil MR Prototype B

Intervention Type: 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 3: Regimen M

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.

Group Type: EXPERIMENTAL

Arbaclofen Placarbil MR Prototype A

Intervention Type: 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

Arbaclofen Placarbil MR Prototype B

Intervention Type: 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 3: Regimen N

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.

Group Type: EXPERIMENTAL

Arbaclofen Placarbil MR Prototype A

Intervention Type: 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

Arbaclofen Placarbil MR Prototype B

Intervention Type: 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

Interventions

Arbaclofen Placarbil SR

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

Intervention Type: DRUG

Arbaclofen Placarbil MR Prototype A

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

Intervention Type: DRUG

Arbaclofen Placarbil MR Prototype B

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

Intervention Type: DRUG

Arbaclofen Placarbil IR

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

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• 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

Exclusion Criteria

• 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
• History of cardiovascular, renal, hepatic, chronic respiratory or gastrointestinal disease or psychiatric disorder, as judged by the investigator
• History of surgical procedures involving the brain or meninges, encephalitis, meningitis, degenerative central nervous system disorder (eg, Alzheimer's or Parkinson's Disease), epilepsy, mental retardation, or any other disease/procedure/accident/intervention associated with significant injury to or malfunction of the central nervous system, or a history of significant head trauma within the past 2 years, or currently receiving anticonvulsant therapy for any reason
• Serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients
• Presence or history of clinically significant allergy requiring treatment, as judged by the investigator. Hayfever is allowed unless it is active
• Donation or loss of greater than 400 mL of blood within the previous 3 months
• Subjects who are taking, or have taken, any prescribed or over-the-counter drug (other than 4 g per day paracetamol, hormone replacement therapy and hormonal contraceptives) or herbal remedies in the 14 days before IMP administration. Exceptions may apply on a case by case basis, if considered not to interfere with the objectives of the study, as agreed by the PI and sponsor's medical monitor.
• Failure to satisfy the investigator of fitness to participate for any other reason

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 55 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Indivior Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Global Director, Clinical Development

Role: STUDY_DIRECTOR

Indivior Inc.

Locations

Quotient Clinical

Ruddington, Nottingham, United Kingdom

Countries

United Kingdom

Other Identifiers

2016-003792-22

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

INDV-AP-102

Identifier Type: -

Identifier Source: org_study_id