A Single-centre, Randomized, Double-blind (Sponsor Unblinded), Placebo-controlled Two-part Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of GSK2982772, in Single (in Both Fed and Fasted States) and Repeat Oral Doses in Healthy Male Subjects
Overview
- Phase
- Phase 1
- Intervention
- GSK2982772 solution
- Conditions
- Inflammatory Bowel Diseases
- Sponsor
- GlaxoSmithKline
- Enrollment
- 79
- Locations
- 1
- Primary Endpoint
- Safety and tolerability of GSK2982772 as assessed by clinical monitoring and reporting of adverse events (AE) and serious adverse events (SAE)
- Status
- Completed
- Last Updated
- 8 years ago
Overview
Brief Summary
This study is the first administration of GSK2982772 in humans. The study will evaluate the safety, tolerability, pharmacokinetics (PK), and exploratory pharmacodynamics (PD) of single and repeat oral doses of up to 14 days with GSK2982772 in healthy male subjects.
This study is planned to include approximately 52 subjects and will consist of 2 parts: Part A - single ascending dose, randomized, placebo controlled, 4 way crossover. In addition to the crossover treatment periods, up to 8 subjects in cohort 2 will participate in an additional treatment period and receive GSK2982772 with a high-fat meal. Part B - repeat dose, randomized, placebo controlled, sequential-group. In both cohorts of Part A (Cohorts 1 and 2), subjects will be randomized equally (1:1:1:1) to one of 4 treatment sequences. Within each period, allocation of active to placebo treatment will be 3:1.
In all cohorts in Part B (Cohorts 3, 4 and 5) subjects will be randomized to GSK2982772 or placebo in a 3:1 ratio. If required, subjects in the additional cohorts in Part A (Cohort 6) and Part B (Cohort 7) will be randomized to GSK2982772 or placebo in a 1:1:1:1 and 3:1 ratio, respectively. The study duration, including screening and follow-up, is not expected to exceed 105 days for any subject in the study.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Male subjects between 18 and 65 years of age inclusive, at the time of signing the informed consent.
- •Healthy as determined by the Investigator or medically qualified designee based on a medical evaluation including medical history, physical examination, neurological examination, laboratory tests and cardiac monitoring. A subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or exclusion criteria, outside the reference range for the population being studied may be included only if the Investigator in consultation with the Medical Monitor agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures. Note: Screened subjects with laboratory values outside of the normal range may be repeated once for inclusion into the study at the discretion of the Investigator.
- •Body weight \>= 50 kilogram (kg) and body mass index (BMI) within the range 19 - 30 (kilogram/squared meter) kg/m\^2 (inclusive).
- •Male subjects with female partners of child bearing potential must comply with the following contraception requirements from the time of first dose of study medication until at least five half-lives of study medication after the last dose of study medication or the follow-up visit, whichever is longer. a. Abstinence, defined as sexual inactivity consistent with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception; b. Vasectomy with documentation of azoospermia; c. Male condom plus partner use of one of the contraceptive options: Contraceptive subdermal implant that meets the standard operation procedure (SOP) effectiveness criteria including a \<1% rate of failure per year, as stated in the product label; Intrauterine device or intrauterine system that meets the SOP effectiveness criteria including a \<1% rate of failure per year, as stated in the product label; Oral Contraceptive, either combined or progestogen alone. Injectable progestogen; Contraceptive vaginal ring; Percutaneous contraceptive patches; Occlusive cap (female diaphragm or cervical/vault cap) with a vaginal spermicide (foam, gel, cream or suppository). These allowed methods of contraception are only effective when used consistently, correctly and in accordance with the product label. The Investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception.
- •Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the consent form and as explained by the investigator.
Exclusion Criteria
- •Alanine aminotransferase (ALT) and bilirubin \>1.5x Upper limit of normal (ULN) (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
- •Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
- •History of active infections within 14 days of receiving study medication.
- •Average QT duration corrected for heart rate by Fridericia's formula (QTcF) \> 450 milliseconds (msec) of three measures taken at least 5 minutes apart in the semi-supine position.
- •History or diagnosis of obstructive sleep apnoea.
- •History of a significant respiratory disorder.
- •History or current evidence of febrile seizures, epilepsy, convulsions, significant head injury, or other significant neurologic conditions.
- •Unable to refrain from prescription or non-prescription drugs, including agents active in the central nervous system, vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication and throughout the study, unless in the opinion of the Investigator and/or GlaxoSmithKline Medical Monitor (if needed) the medication will not interfere with the study procedures or compromise subject safety.
- •History of regular alcohol consumption within 6 months of the study, defined as: For United Kingdom (UK) - an average weekly intake of \>21 units for males. One unit is equivalent to 8 gram(g) of alcohol: a half-pint (approximately 240 millilitre \[mL\]) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
- •Current use or history of regular tobacco- or nicotine-containing product use within 6 months of screening. Subject must have urinary cotinine levels indicative of non-smoking status at screening visit.
Arms & Interventions
Cohort 1: GSK2982772 Single Ascending Dose (Part A) (0.1-10mg)
Eight subjects will be randomized equally (1:1:1:1) to one of the 4 placebo-controlled dose sequences with 2 subjects in each sequence and each subject having four dose periods (3 active dose of GSK2982772 + 1 placebo dose). The subjects will fast overnight from Day -1 to Day 1 of the treatment period. Two of the 8 subjects will be randomized to the dosing on Day 1 as sentinel dosing. Assuming adequate safety in the judgment of the Principal Investigator (e.g., vital signs, ECGs, and adverse events) through approximately 24 hours; the remaining 6 subjects may be randomized to dosing on the following day. Subjects will receive single planned doses of GSK2982772 as 0.1, 0.5, 2.5, and 10mg. A sequential design will be used including approximately weekly dose escalations while allowing for a sufficient washout period. The proposed doses may be adjusted based on emerging safety and PK
Intervention: GSK2982772 solution
Cohort 1: GSK2982772 Single Ascending Dose (Part A) (0.1-10mg)
Eight subjects will be randomized equally (1:1:1:1) to one of the 4 placebo-controlled dose sequences with 2 subjects in each sequence and each subject having four dose periods (3 active dose of GSK2982772 + 1 placebo dose). The subjects will fast overnight from Day -1 to Day 1 of the treatment period. Two of the 8 subjects will be randomized to the dosing on Day 1 as sentinel dosing. Assuming adequate safety in the judgment of the Principal Investigator (e.g., vital signs, ECGs, and adverse events) through approximately 24 hours; the remaining 6 subjects may be randomized to dosing on the following day. Subjects will receive single planned doses of GSK2982772 as 0.1, 0.5, 2.5, and 10mg. A sequential design will be used including approximately weekly dose escalations while allowing for a sufficient washout period. The proposed doses may be adjusted based on emerging safety and PK
Intervention: GSK2982772 capsule
Cohort 1: GSK2982772 Single Ascending Dose (Part A) (0.1-10mg)
Eight subjects will be randomized equally (1:1:1:1) to one of the 4 placebo-controlled dose sequences with 2 subjects in each sequence and each subject having four dose periods (3 active dose of GSK2982772 + 1 placebo dose). The subjects will fast overnight from Day -1 to Day 1 of the treatment period. Two of the 8 subjects will be randomized to the dosing on Day 1 as sentinel dosing. Assuming adequate safety in the judgment of the Principal Investigator (e.g., vital signs, ECGs, and adverse events) through approximately 24 hours; the remaining 6 subjects may be randomized to dosing on the following day. Subjects will receive single planned doses of GSK2982772 as 0.1, 0.5, 2.5, and 10mg. A sequential design will be used including approximately weekly dose escalations while allowing for a sufficient washout period. The proposed doses may be adjusted based on emerging safety and PK
Intervention: Placebo solution
Cohort 1: GSK2982772 Single Ascending Dose (Part A) (0.1-10mg)
Eight subjects will be randomized equally (1:1:1:1) to one of the 4 placebo-controlled dose sequences with 2 subjects in each sequence and each subject having four dose periods (3 active dose of GSK2982772 + 1 placebo dose). The subjects will fast overnight from Day -1 to Day 1 of the treatment period. Two of the 8 subjects will be randomized to the dosing on Day 1 as sentinel dosing. Assuming adequate safety in the judgment of the Principal Investigator (e.g., vital signs, ECGs, and adverse events) through approximately 24 hours; the remaining 6 subjects may be randomized to dosing on the following day. Subjects will receive single planned doses of GSK2982772 as 0.1, 0.5, 2.5, and 10mg. A sequential design will be used including approximately weekly dose escalations while allowing for a sufficient washout period. The proposed doses may be adjusted based on emerging safety and PK
Intervention: Placebo capsule
Cohort 2: GSK2982772 Single Ascending Dose (Part A) (40-240mg)
Eight subjects will be randomized equally to one of the 4 placebo-controlled dose sequences with 2 subjects in each sequence and each subject having 4 dose periods (3 active dose of GSK2982772 +1 placebo dose). The subjects will fast overnight from Day -1 to Day 1 of the treatment period. Two of the 8 subjects will be randomized to the dosing on Day 1 as sentinel dosing. Assuming adequate safety in the judgment of the Principal Investigator (e.g., vital signs, ECGs, and adverse events) through 24 hours; the remaining 6 subjects may be randomized to dosing on the following day. Subjects will receive single planned doses of GSK2982772 as 40, 100, 180, and 240 mg. A sequential design with weekly dose escalations and sufficient washout period will be used. The proposed doses may be adjusted based on emerging safety and PK. After the completion of the fasted treatment periods, subjects will receive a high fat meal within 30 minutes of dosing with GSK2982772 during a final treatment period.
Intervention: GSK2982772 capsule
Cohort 2: GSK2982772 Single Ascending Dose (Part A) (40-240mg)
Eight subjects will be randomized equally to one of the 4 placebo-controlled dose sequences with 2 subjects in each sequence and each subject having 4 dose periods (3 active dose of GSK2982772 +1 placebo dose). The subjects will fast overnight from Day -1 to Day 1 of the treatment period. Two of the 8 subjects will be randomized to the dosing on Day 1 as sentinel dosing. Assuming adequate safety in the judgment of the Principal Investigator (e.g., vital signs, ECGs, and adverse events) through 24 hours; the remaining 6 subjects may be randomized to dosing on the following day. Subjects will receive single planned doses of GSK2982772 as 40, 100, 180, and 240 mg. A sequential design with weekly dose escalations and sufficient washout period will be used. The proposed doses may be adjusted based on emerging safety and PK. After the completion of the fasted treatment periods, subjects will receive a high fat meal within 30 minutes of dosing with GSK2982772 during a final treatment period.
Intervention: Placebo capsule
Cohort 3: GSK2982772 Repeat Dose (Part B)
Twelve subjects will be randomized to repeat doses of GSK2982772 or placebo in a 3:1 ratio. The subjects will fast overnight from Day -1 to Day 1 and overnight from Day 13 to Day 14. The selection of appropriate daily doses will be performed upon consideration of available safety and tolerability and PK data from Part A. Once-daily dosing is planned, but twice-daily dosing may be considered based upon the exposure observed in the Part A data
Intervention: GSK2982772 capsule
Cohort 3: GSK2982772 Repeat Dose (Part B)
Twelve subjects will be randomized to repeat doses of GSK2982772 or placebo in a 3:1 ratio. The subjects will fast overnight from Day -1 to Day 1 and overnight from Day 13 to Day 14. The selection of appropriate daily doses will be performed upon consideration of available safety and tolerability and PK data from Part A. Once-daily dosing is planned, but twice-daily dosing may be considered based upon the exposure observed in the Part A data
Intervention: Placebo capsule
Cohort 4: GSK2982772 Repeat Dose (Part B)
Twelve subjects will be randomized to repeat doses of GSK2982772 or placebo in a 3:1 ratio. The subjects will fast overnight from Day -1 to Day 1 and overnight from Day 13 to Day 14. The selection of appropriate daily doses will be performed upon consideration of available safety and tolerability and PK data from Part A and/or any preceding repeat dose cohorts in Part B. Once-daily dosing is planned, but twice-daily dosing may be considered based upon the exposure observed in Part A or any preceding repeat dose cohorts in Part B
Intervention: GSK2982772 capsule
Cohort 4: GSK2982772 Repeat Dose (Part B)
Twelve subjects will be randomized to repeat doses of GSK2982772 or placebo in a 3:1 ratio. The subjects will fast overnight from Day -1 to Day 1 and overnight from Day 13 to Day 14. The selection of appropriate daily doses will be performed upon consideration of available safety and tolerability and PK data from Part A and/or any preceding repeat dose cohorts in Part B. Once-daily dosing is planned, but twice-daily dosing may be considered based upon the exposure observed in Part A or any preceding repeat dose cohorts in Part B
Intervention: Placebo capsule
Cohort 5: GSK2982772 Repeat Dose (Part B)
Twelve subjects will be randomized to repeat doses of GSK2982772 or placebo in a 3:1 ratio. The subjects will fast overnight from Day -1 to Day 1 and overnight from Day 13 to Day 14. The selection of appropriate daily doses will be performed upon consideration of available safety and tolerability and PK data from Part A and/or any preceding repeat dose cohorts in Part B. Once-daily dosing is planned, but twice-daily dosing may be considered based upon the exposure observed in the Part A or any preceding repeat dose cohorts in Part B.
Intervention: GSK2982772 capsule
Cohort 5: GSK2982772 Repeat Dose (Part B)
Twelve subjects will be randomized to repeat doses of GSK2982772 or placebo in a 3:1 ratio. The subjects will fast overnight from Day -1 to Day 1 and overnight from Day 13 to Day 14. The selection of appropriate daily doses will be performed upon consideration of available safety and tolerability and PK data from Part A and/or any preceding repeat dose cohorts in Part B. Once-daily dosing is planned, but twice-daily dosing may be considered based upon the exposure observed in the Part A or any preceding repeat dose cohorts in Part B.
Intervention: Placebo capsule
Cohort 6: GSK2982772 Single Ascending Dose (Part A)
This additional cohort in Part A of the study will only be conducted to allow for evaluation of additional dose levels or repeated evaluation of a dose level already studied. Doses will be selected based on the safety, tolerability, and PK data from Part A and/or previous Part B cohorts. Eight subjects will be randomized equally (1:1:1:1) to one of the 4 placebo-controlled dose sequences with 2 subjects in each sequence and each subject having four dose periods (3 active dose of GSK2982772 + 1 placebo dose). The selection of appropriate daily doses will be performed upon consideration of available safety and tolerability and PK data from Part A and/or any preceding repeat dose cohorts in Part B.
Intervention: GSK2982772 capsule
Cohort 6: GSK2982772 Single Ascending Dose (Part A)
This additional cohort in Part A of the study will only be conducted to allow for evaluation of additional dose levels or repeated evaluation of a dose level already studied. Doses will be selected based on the safety, tolerability, and PK data from Part A and/or previous Part B cohorts. Eight subjects will be randomized equally (1:1:1:1) to one of the 4 placebo-controlled dose sequences with 2 subjects in each sequence and each subject having four dose periods (3 active dose of GSK2982772 + 1 placebo dose). The selection of appropriate daily doses will be performed upon consideration of available safety and tolerability and PK data from Part A and/or any preceding repeat dose cohorts in Part B.
Intervention: Placebo capsule
Cohort 7: GSK2982772 Repeat Dose (Part B)
This additional cohort in Part B of the study will only be conducted to allow for evaluation of additional dose levels or repeated evaluation of a dose level already studied Doses will be selected based on the safety, tolerability, and PK data from Part A and/or previous Part B cohorts. Twelve subjects will be randomized to repeat doses of GSK2982772 or placebo in a 3:1 ratio. The selection of appropriate daily doses will be performed upon consideration of available safety and tolerability and PK data from Part A and/or any preceding repeat dose cohorts in Part B.
Intervention: GSK2982772 capsule
Cohort 7: GSK2982772 Repeat Dose (Part B)
This additional cohort in Part B of the study will only be conducted to allow for evaluation of additional dose levels or repeated evaluation of a dose level already studied Doses will be selected based on the safety, tolerability, and PK data from Part A and/or previous Part B cohorts. Twelve subjects will be randomized to repeat doses of GSK2982772 or placebo in a 3:1 ratio. The selection of appropriate daily doses will be performed upon consideration of available safety and tolerability and PK data from Part A and/or any preceding repeat dose cohorts in Part B.
Intervention: Placebo capsule
Outcomes
Primary Outcomes
Safety and tolerability of GSK2982772 as assessed by clinical monitoring and reporting of adverse events (AE) and serious adverse events (SAE)
Time Frame: Up to approximately 105 days
AEs and SAEs will be collected from the start of Study Treatment until the follow-up contact
Change in laboratory values after single (fed and fasted) and repeat doses of GSK2982772
Time Frame: Up to approximately 105 days
Laboratory assessments will include analysis of hematology parameters, clinical chemistry, routine urinalysis, lipid panel (Part B Only) and other screening Tests
Electrocardiogram (ECG) assessment after single (fed and fasted) and repeat doses of GSK2982772
Time Frame: Up to approximately 105 days
12-lead ECGs will be obtained at each time point during the study using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QT duration corrected for heart rate by Fridericia's formula (QTcF) intervals. Triplicate 12-lead ECGs will be obtained pre-dose on Day 1 and Day 14 (Part B only).
Summary of physical examinations after single (fed and fasted) and repeat doses of GSK2982772
Time Frame: Up to approximately 105 days
A complete physical examination will include assessment of the Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. Weight will also be measured and recorded. A brief physical examination will include assessments of the skin, lungs, cardiovascular system, abdomen (liver and spleen), and assessment for lymphadenopathy
Change in vital signs after single (fed and fasted) and repeat doses of GSK2982772
Time Frame: Up to approximately 105 days
Vital signs will be measured in semi-supine position after short period of time (e.g., 5 to 10 minutes rest) and will include systolic and diastolic blood pressure, temperature, pulse rate, pulse oximetry (SpO2), and respiratory rate. Triplicate vital signs will be obtained pre-dose on Day 1 and Day 14 (Part B only)
Secondary Outcomes
- Composite of derived Pharmacokinetic (PK) parameters of GSK2982772 measured by AUC (0-t), AUC (0-infinity), Cmax, Tmax and t1/2,following single (fed and fasted) doses(Pre-dose, Days 1 (20 and 40 minutes, 1, 1.5, 2, 3, 5, 8, 10 and 12 hours), 2 and 3 post dose)
- Composite of derived blood PK parameters of GSK2982772 measured by AUC (0-t), AUC (0-infinity), AUC (0-tau), Cmax, Tmax and t1/2,following repeat doses(Pre-dose, Days 1 (20 and 40 minutes, 1, 1.5, 2, 3, 5, 8, 10 and 12 hours) , 2, 3, 4, 5, 6, 7, 14 (20 and 40 minutes, 1, 1.5, 2, 3, 5, 8, 10 and 12 hours), 15 and 16 post-dose)
- Estimation of accumulation ratio (Ro) of GSK2982772 following single and repeat doses(Up to Day 14 of Part B)
- Ratio of Plasma 4beta-hydroxycholesterol to cholesterol during pre-treatment and following repeat dosing of GSK2982772(Up to Day 14 of Part B)
- Ex-vivo GSK2982772 blood:plasma concentration ratio over a range of concentrations and % blood cell association.(Up to approximately 105 days)