A Randomised, Double-Blind, Placebo-Controlled, Dose Escalation, Safety, Tolerability and Pharmacokinetics Study of Single Ascending and Multiple Doses of GWP42006 in Healthy Volunteers
Overview
- Phase
- Phase 1
- Intervention
- GWP42006
- Conditions
- Epilepsy
- Sponsor
- Jazz Pharmaceuticals
- Enrollment
- 66
- Locations
- 1
- Primary Endpoint
- The incidence of adverse events as measure of subject safety
- Status
- Completed
- Last Updated
- 3 years ago
Overview
Brief Summary
The primary objective of this study is to evaluate the safety and tolerability of single ascending (increasing) and multiple doses of GWP42006 compared with placebo.
Detailed Description
This is a single-centre, randomised, double-blind, placebo-controlled, parallel group dose escalation, safety, tolerability and pharmacokinetic (PK) study of single escalating and multiple doses of GWP42006 in healthy volunteers. The study consists of 5 single dosing occasions, and a five day repeated dose period. Part 1 Single Dosing: Four parallel groups of 11 subjects will participate in the oral single dosing, dose escalation study phase. In each group, subjects will be randomly assigned so that eight subjects receive active and three subjects receive placebo. It is planned for Groups 1 and 2, that a staggered 'sentinel' dose design will be used, with two sub-groups: * The first will comprise of one placebo and one active subject. * In the second, seven subjects will receive active and two will receive placebo after a review of the 24 h post-dose safety data of the first group. Sentinel subject dosing will be performed in higher-dose groups if there is no measurable plasma GWP42006 in Group 1 or 2. One group within the single dosing part (Group 3/dose level 3) will then receive an intravenous administration of 5 mg GWP42006 to allow assessment of bioavailability. There will be a minimum of seven days between doses. Up to three further groups may be added for further evaluations, e.g. to assess additional dose levels or food effect. The need for additional groups will be based on a review of the safety, tolerability and PK data by the safety advisory committee. Dose Escalation: The planned dose levels are 25 mg (Group 1/dose level 1), 75 mg (Group 2/dose level 2), 200 mg (Group 3/dose level 3) and 400 mg (Group 4/dose level 4), with a maximum dose of 800 mg. Administration of each successive dose will be dependent on safety, tolerability and PK data of previous doses. Part 2 Multiple Dosing: The doses and dose regimens assessed in Part 2 will be selected based upon the safety, and PK data from Part 1 of the study. It is planned that one group of 11 subjects will participate in the multiple dose phase, and subjects will be randomly assigned so that eight subjects receive active and three receive matching placebo. Each subject will receive the selected dose of GWP42006 or placebo once, twice or three times daily for a total of five days, with the final dose administered on the morning of Day 5. Up to two further groups may be added for further evaluations, e.g. to assess a different dose level or a different dosing frequency. As for single dosing, the decision to include further groups will be taken based on safety, tolerability and PK data. All further groups would be added on blinded information.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Healthy females of non-childbearing potential or healthy males
- •Age 18 to 65 years, inclusive
- •Body mass index of 18 to 30 kg/m2 inclusive or, if outside the range, considered not clinically significant by the investigator
- •Must have no clinically significant abnormal findings on physical examination, vital signs, electrocardiogram, medical history, or clinical laboratory results during screening or Day -1 (admission)
- •Must be willing and able to communicate and participate in the whole study
- •Must provide written informed consent
- •Must be willing to allow his or her primary care practitioner and consultant, if appropriate, to be notified of participation in the study
- •Must agree to use an adequate method of contraception: Two or more of the following methods are acceptable and must include at least one barrier method:
- •Surgical sterilisation (i.e. bilateral tubal ligation, hysterectomy for female partners; vasectomy for males)
- •Placement of an intrauterine device or intrauterine system
Exclusion Criteria
- •Participation in a clinical research study/receiving an Investigational Medicinal Product within the 3 months prior to screening
- •Subjects who are study site employees, or immediate family members of a study site or sponsor employee
- •Subjects who have previously been randomised in this study
- •History of any drug or alcohol abuse in the past 2 years, or current habituation to any medications or illegal drugs
- •Regular alcohol consumption in males \>21 units per week and females \>14 units per week (1 unit = 0.5 pint beer, 25 mL of 40% spirit or a 125 mL glass of wine)
- •Tobacco product use in the previous 6 months. A breath carbon monoxide reading of greater than 10 ppm at screening
- •Subjects who do not have suitable veins for multiple venepunctures/cannulation as assessed by the investigator at screening
- •Clinically significant abnormal clinical chemistry, haematology or urinalysis as judged by the investigator
- •Positive drugs of abuse test result
- •Positive hepatitis B surface antigen, hepatitis C virus antibody or human immunodeficiency virus-1 and -2 results
Arms & Interventions
Group/dose level 1a
25 mg GWP42006 oral solution. As a safety precaution, subjects will be split into two sub-groups for sentinel dosing. On the first day of dosing , only two subjects will be dosed (randomisation schedule designed so that one placebo one active will be dosed on first day). Following a review of the safety data for the first set of subjects, the remaining subjects will be dosed.
Intervention: GWP42006
Group/dose level 1b
Matching placebo for Group/dose level 1a. As a safety precaution, subjects will be split into two sub-groups for sentinel dosing. On the first day of dosing , only two subjects will be dosed (randomisation schedule designed so that one placebo one active will be dosed on first day). Following a review of the safety data for the first set of subjects, the remaining subjects will be dosed.
Intervention: Placebo
Group/dose level 2a
75 mg GWP42006 oral solution. As a safety precaution, subjects will be split into two sub-groups for sentinel dosing. On the first day of dosing , only two subjects will be dosed (randomisation schedule designed so that one placebo one active will be dosed on first day). Following a review of the safety data for the first set of subjects, the remaining subjects will be dosed.
Intervention: GWP42006
Group/dose level 2b
Matching placebo for Group/dose level 2a. As a safety precaution, subjects will be split into two sub-groups for sentinel dosing. On the first day of dosing , only two subjects will be dosed (randomisation schedule designed so that one placebo one active will be dosed on first day). Following a review of the safety data for the first set of subjects, the remaining subjects will be dosed.
Intervention: Placebo
Group/dose level 3a
200 mg GWP42006 oral solution (single dose) followed by an intravenous administration of 5 mg GWP42006 after the oral dose
Intervention: GWP42006
Group/dose level 3b
Matching placebo for Group/dose level 3a
Intervention: Placebo
Group/dose level 4a
400 mg GWP42006 oral solution
Intervention: GWP42006
Group/dose level 4b
Matching placebo for Group/dose level 4a
Intervention: Placebo
GWP42006 1, 2, or 3 times daily
Subjects will receive the selected dose of GWP42006 once, twice or three times daily (the number of daily doses and actual dose will be decided upon based on results from Part 1 of the study) for a total of 5 days, with the final dose given on the morning of Day 5.
Intervention: GWP42006
Placebo 1, 2, or 3 times daily
Subjects will receive placebo once, twice or three times daily (the number of daily doses and actual dose will be decided upon based on results from Part 1 of the study) for a total of 5 days, with the final dose given on the morning of Day 5.
Intervention: Placebo
Outcomes
Primary Outcomes
The incidence of adverse events as measure of subject safety
Time Frame: Day 0 - Day 10
The number of subjects who experienced an adverse event during each arm of the study is presented.
Secondary Outcomes
- To investigate cognitive function following single ascending and multiples doses of GWP42006(Admission (Day -1) and 2 h post-dose)
- To investigate gene expression following multiple doses of GWP42006(Pre-dose on multiple dose Days 1-4 then 2 h post-dose on multiple dose Day 5)
- To determine the plasma concentration time curves for GWP42006, 7-hydroxy-GWP42006 and 6-hydroxy-GWP42006 compounds, following escalating single doses and multiple doses of pure GWP42006.(Pre-dose then 0, 0.04, 0.08, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 36, 48 h post-dose)