A Safety and Tolerability Study of GSK2982772, in Single (in Both Fed and Fasted States) and Repeat Oral Doses in Healthy Male Subjects

NCT02302404 | Completed Phase 1

• 1 other identifier: 200975
• Study Type: interventional
• Target: 79
• Locations: 1 country
• Sites: 1

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.

Conditions

Inflammatory Bowel Diseases

Keywords

FTIH; pharmacodynamics; pharmacokinetics; GSK2982772; safety; Repeat dose; tolerability

Outcome Measures

Primary Outcomes (5)

• Safety and tolerability of GSK2982772 as assessed by clinical monitoring and reporting of adverse events (AE) and serious adverse events (SAE)

  AEs and SAEs will be collected from the start of Study Treatment until the follow-up contact

  Up to approximately 105 days

• Change in laboratory values after single (fed and fasted) and repeat doses of GSK2982772

  Laboratory assessments will include analysis of hematology parameters, clinical chemistry, routine urinalysis, lipid panel (Part B Only) and other screening Tests

  Up to approximately 105 days

• Electrocardiogram (ECG) assessment after single (fed and fasted) and repeat doses of GSK2982772

  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).

  Up to approximately 105 days

• Change in vital signs after single (fed and fasted) and repeat doses of GSK2982772

  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)

  Up to approximately 105 days

• Summary of physical examinations after single (fed and fasted) and repeat doses of GSK2982772

  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

  Up to approximately 105 days

Secondary Outcomes (5)

• 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

Study Arms (7)

Cohort 1: GSK2982772 Single Ascending Dose (Part A) (0.1-10mg)

EXPERIMENTAL

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

Drug: GSK2982772 solution; Drug: GSK2982772 capsule; Drug: Placebo solution; Drug: Placebo capsule

Cohort 2: GSK2982772 Single Ascending Dose (Part A) (40-240mg)

EXPERIMENTAL

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.

Drug: GSK2982772 capsule; Drug: Placebo capsule

Cohort 3: GSK2982772 Repeat Dose (Part B)

EXPERIMENTAL

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

Drug: GSK2982772 capsule; Drug: Placebo capsule

Cohort 4: GSK2982772 Repeat Dose (Part B)

EXPERIMENTAL

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

Drug: GSK2982772 capsule; Drug: Placebo capsule

Cohort 5: GSK2982772 Repeat Dose (Part B)

EXPERIMENTAL

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.

Drug: GSK2982772 capsule; Drug: Placebo capsule

Cohort 6: GSK2982772 Single Ascending Dose (Part A)

EXPERIMENTAL

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.

Drug: GSK2982772 capsule; Drug: Placebo capsule

Cohort 7: GSK2982772 Repeat Dose (Part B)

EXPERIMENTAL

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.

Drug: GSK2982772 capsule; Drug: Placebo capsule

Interventions

GSK2982772 solution DRUG

Clear, colorless solution containing GSK2982772 in water with 5% ethanol (0.1mg/mL). Administered orally in required volumes for dosing less than 5mg

Cohort 1: GSK2982772 Single Ascending Dose (Part A) (0.1-10mg)

GSK2982772 capsule DRUG

Size 00 White Opaque capsule containing GSK2982772 as white to almost white solid. Administered orally with water for dosing from 5 to 120 mg

Cohort 1: GSK2982772 Single Ascending Dose (Part A) (0.1-10mg); Cohort 2: GSK2982772 Single Ascending Dose (Part A) (40-240mg); Cohort 3: GSK2982772 Repeat Dose (Part B); Cohort 4: GSK2982772 Repeat Dose (Part B); Cohort 5: GSK2982772 Repeat Dose (Part B); Cohort 6: GSK2982772 Single Ascending Dose (Part A); Cohort 7: GSK2982772 Repeat Dose (Part B)

Placebo solution DRUG

Clear, colorless solution containing placebo in water with 5% ethanol (0.1mg/mL). Administered orally in required volumes for dosing less than 5mg

Cohort 1: GSK2982772 Single Ascending Dose (Part A) (0.1-10mg)

Placebo capsule DRUG

Size 00 White Opaque capsule containing Placebo as white to almost white solid

Cohort 1: GSK2982772 Single Ascending Dose (Part A) (0.1-10mg); Cohort 2: GSK2982772 Single Ascending Dose (Part A) (40-240mg); Cohort 3: GSK2982772 Repeat Dose (Part B); Cohort 4: GSK2982772 Repeat Dose (Part B); Cohort 5: GSK2982772 Repeat Dose (Part B); Cohort 6: GSK2982772 Single Ascending Dose (Part A); Cohort 7: GSK2982772 Repeat Dose (Part B)

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male subjects between 18 and 65 years of age inclusive, at the time of signing the informed consent.

You may not qualify if:

• 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.
• 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.
• Unwilling or unable to swallow multiple size 00 capsules as part of study participation
• History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the Investigator and/or Medical Monitor (if appropriate), contraindicates their participation.

Sponsors & Collaborators

• GlaxoSmithKline: lead
• Clinical Unit at Cambridge (Addenbrooks): collaborator

Study Sites (1)

GSK Investigational Site

Cambridge, CB2 0GG, United Kingdom

Location

Related Publications (1)

• Weisel K, Scott NE, Tompson DJ, Votta BJ, Madhavan S, Povey K, Wolstenholme A, Simeoni M, Rudo T, Richards-Peterson L, Sahota T, Wang JG, Lich J, Finger J, Verticelli A, Reilly M, Gough PJ, Harris PA, Bertin J, Wang ML. Randomized clinical study of safety, pharmacokinetics, and pharmacodynamics of RIPK1 inhibitor GSK2982772 in healthy volunteers. Pharmacol Res Perspect. 2017 Dec;5(6):e00365. doi: 10.1002/prp2.365.

  PMID: 29226626 DERIVED

Related Links

• Results for study 200975 can be found on the GSK Clinical Study Register.

MeSH Terms

Conditions

Inflammatory Bowel Diseases

Interventions

GSK2982772

Condition Hierarchy (Ancestors)

Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Intestinal Diseases

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 27, 2014
• First Posted: November 27, 2014
• Study Start: January 6, 2015
• Primary Completion: March 5, 2016
• Study Completion: March 5, 2016
• Last Updated: May 9, 2017

Record last verified: 2017-05

Locations

GB (1)