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| Name | Class |
|---|---|
| Clinical Unit at Cambridge (Addenbrooks) | UNKNOWN |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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 |
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| 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. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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 |
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| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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 | PK parameters for GSK2982772 will include area under the blood drug concentration versus time curve from time zero (pre-dose) to last time of quantifiable concentration within a subject across all treatments (AUC [0-t]), area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUC [0-infinity]), maximum observed blood drug concentration (Cmax), time to maximum observed blood drug concentration (Tmax), and terminal half-life (t1/2) following single (fed and fasted) doses, where data allow |
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Inclusion Criteria:
Exclusion Criteria:
Part B Specific Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| GSK Clinical Trials | GlaxoSmithKline | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| GSK Investigational Site | Cambridge | CB2 0GG | United Kingdom |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 29226626 | Derived | 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. |
| Label | URL |
|---|---|
| Results for study 200975 can be found on the GSK Clinical Study Register. | View source |
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| 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 |
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| 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 |
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| 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. |
|
| 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. |
|
| 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. |
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| 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 |
|
| 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 |
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| Placebo capsule | Drug | Size 00 White Opaque capsule containing Placebo as white to almost white solid |
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| Up to approximately 105 days |
| 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 | Derived blood PK parameters for GSK2982772 will include AUC(0-t), AUC(0-infinity), area under the concentration-time curve over the dosing interval (AUC [0-tau]), Cmax, Tmax and t1/2, following single and 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 | Ro will be calculated as the ratio of AUC(0-24) (Repeat Dose) to AUC(0-24) (Single Dose). Day 14 (Repeat Dose) will be compared with Day 1 (Single Dose) in order to estimate the accumulation ratio for each dose level | Up to Day 14 of Part B |
| Ratio of Plasma 4beta-hydroxycholesterol to cholesterol during pre-treatment and following repeat dosing of GSK2982772 | A comparison will be made between the ratio of 4beta-hydroxycholesterol: cholesterol at baseline and on Day 14 to assess potential changes in cytochrome P450 isoform 3A4(CYP3A4) enzyme activity following GSK2982772 treatment. | 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 |
| ID | Term |
|---|---|
| D015212 | Inflammatory Bowel Diseases |
| ID | Term |
|---|---|
| D005759 | Gastroenteritis |
| D005767 | Gastrointestinal Diseases |
| D004066 | Digestive System Diseases |
| D007410 | Intestinal Diseases |
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| ID | Term |
|---|---|
| C000708951 | GSK2982772 |
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