First Time in Human (FTIH) Safety and Pharmacokinetics (PK) Study of GSK3036656 in Healthy Subjects

NCT03075410 | Completed Phase 1 Results

• 2 other identifiers: 2010402015-003654-41
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 2

Brief Summary

GSK3036656 is being developed by GSK for the treatment of tuberculosis (TB). This is the FTIH study for GSK3036656 to evaluate the safety, tolerability and PK of single ascending and repeat oral doses of GSK3036656 in healthy adult subjects. The results of this study are intended to be used to identify appropriate and well-tolerated doses of GSK3036656 to be used in further studies. A food effect assessment will also be undertaken to investigate the influence of food on the PK of GSK3036656. The study will be conducted in two parts: Part A (single dose) and Part B (repeat dose). Up to two cohorts will be included in Part A. 9 healthy adult subjects will be included in each cohort. Each cohort will participate in up to 4 treatment (dosing) periods including a food effect treatment period. During each treatment period, GSK3036656 will be administered to 6 subjects and placebo will be administered to 3 subjects. The starting dose in Part A will be 5 milligrams (mg), and the maximum dose will be 1500 mg. The two cohorts in Part A will be dosed sequentially (i.e., dosing in Cohort 2 starts after dosing in Cohort 1 is completed). Initially, there will be a 14 day wash out period for individual subjects between each dose level. Study progression to Part B from Part A will be based on an acceptable safety, tolerability and PK profile in Part A. Part B will comprise up to 4 cohorts (Cohorts 3, 4, 5, and 6) each containing 10 (8 active: 2 placebo) healthy adult subjects to examine the safety, tolerability and PK of a repeated daily dose of GSK3036656 over a period of up to 14 days. Appropriate doses and dose regimens for Part B will be selected based on available safety, tolerability and PK data from Part A and/or any preceding repeat dose cohorts from Part B. Dividing the total daily dose into 2 or 3 smaller doses may be done in both Part A and Part B. Up to 18 subjects will be enrolled into Part A and up to 40 subjects will be enrolled into Part B. The total duration of the study for each subject recruited into Part A and Part B will be approximately 12 weeks and 8 weeks, respectively.

Conditions

Tuberculosis

Keywords

ascending dose; Pharmacokinetics; GSK3036656; FTIH; Safety

Outcome Measures

Primary Outcomes (30)

• Number of Participants With Non-serious Adverse Events (nSAE) and Serious Adverse Events (SAEs) for Part A

  An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. An SAE is defined as any untoward medical occurrence that results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, other situations judged by physician, such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in the above. Safety Population comprised of all randomized participants who received at least one dose of study medication.

  Up to 12 weeks

• Number of Participants With nSAE and SAEs for Part B

  An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. An SAE is defined as any untoward medical occurrence that results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, other situations judged by physician, such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in the above.

  Up to 8 weeks

• Number of Participants With Abnormal Electrocardiogram (ECG) Findings for Part A

  12-lead ECGs were collected during the study using an ECG machine that automatically calculated the heart rate and measures PR, QRS, QT, and QT interval corrected for heart rate using Fridericia's formula (QTcF) intervals. At each time point at which triplicate ECGs were required, three individual ECG tracings were obtained as closely as possible in succession, but no more than 2 to 5 minutes apart. ECG findings were categorized as normal, abnormal not clinically significant (A-NCS) and abnormal clinically significant (A-CS). Only A-NCS and A-CS worst case post-Baseline values have been presented. Only those participants with data available at the indicated time point were analyzed.

  Up to 6 weeks

• Number of Subjects With Clinically Relevant Changes in ECG in Part B

  12-lead ECGs were collected during the study using an ECG machine that automatically calculated the heart rate and measured PR, QRS, QT interval and QTcF intervals. At each time point at which triplicate ECGs were required, three individual ECG tracings were obtained as closely as possible in succession, but no more than 2 to 5 minutes apart. ECG findings were categorized as normal, A-NCS and A-CS. Only A-NCS and A-CS worst case post-Baseline values have been presented.

  Up to 8 weeks

• Number of Participants With Abnormal Cardiac Telemetry Findings for Part A

  Continuous cardiac telemetry was performed from approximately 1 hour pre-dose to 24 hours post dosing . Number of participants who had abnormal findings upon cardiac telemetry assessment have been presented.

  25 hours for each period

• Number of Participants With Abnormal Cardiac Telemetry Findings for Part B

  Continuous cardiac telemetry was performed from approximately 1 hour pre-dose to 24 hours post dosing . Number of participants who had abnormal findings upon cardiac telemetry assessment have been presented.

  25 hours for each period

• Number of Participants With Vital Sign Parameters Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) of Potential Clinical Importance (PCI) for Part A

  SBP and DBP were assessed in supine position with a completely automated device. Measurements were preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions (e.g., television, cell phones). The PCI range for SBP was less than 85 mmHg (lower) and greater than 160 mmHg (upper) while that for DBP was less than 45 mmHg (lower) and greater than 100 mmHg (upper).

  Up to 6 weeks

• Number of Participants With Vital Sign Parameters SBP and DBP of PCI for Part B

  SBP and DBP were assessed in supine position with a completely automated device. Measurements were preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions (e.g., television, cell phones). The PCI range for SBP was less than 85 mmHg (lower) and greater than 160 mmHg (upper) while that for DBP was less than 45 mmHg (lower) and greater than 100 mmHg (upper).

  Up to 8 weeks

• Number of Participants With Vital Sign Parameter Heart Rate of PCI for Part A

  Heart rate was assessed in supine position with a completely automated device. Measurements were preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions (e.g., television, cell phones). The PCI range for heart was less than 40 bpm (lower) and greater than 110 bpm (upper).

  Up to 6 weeks

• Number of Participants With Vital Sign Parameter Heart Rate of PCI for Part B

  Heart rate was assessed in supine position with a completely automated device. Measurements were preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions (e.g., television, cell phones). The PCI range for heart was less than 40 bpm (lower) and greater than 110 bpm (upper).

  Up to 8 weeks

• Number of Participants With Vital Sign Parameter Temperature of PCI for Part A

  Number of participants with temperature data of PCI have been presented.

  Up to 6 weeks

• Number of Participants With Vital Sign Parameter Temperature of PCI for Part B

  Number of participants with temperature data of PCI have been presented.

  Up to 8 weeks

• Number of Participants With Clinical Chemistry Parameters of PCI for Part A

  Blood samples were collected for the assessment of clinical chemistry parameters namely blood urea nitrogen (BUN), creatinine, glucose, cholesterol, potassium, sodium, calcium, aspartate amino transferase (AST), alanine amino transferase (ALT), alkaline phosphatase, triglycerides, total and direct bilirubin, total protein, albumin and troponin. Only categories with PCI values have been presented, therefore only AST is presented.

  Up to 12 weeks

• Number of Participants With Clinical Chemistry Parameters of PCI for Part B

  Blood samples were collected for the assessment of clinical chemistry parameters namely BUN, creatinine, glucose, cholesterol, potassium, sodium, calcium, AST, ALT, alkaline phosphatase, triglycerides, total and direct bilirubin, total protein, albumin and troponin. Only categories with PCI values have been presented.

  Up to 8 weeks

• Number of Participants With Hematology Parameters of PCI for Part A

  Blood samples were collected for the assessment of hematology parameters platelet count, red blood cell count, hemoglobin, hematocrit, reticulocytes, mean corpuscle volume, mean corpuscular hemoglobin, neutrophils, lymphocytes, monocytes, basophils and eosinophils. Only categories with PCI values have been presented.

  Up to 12 weeks

• Number of Participants With Hematology Parameters of PCI for Part B

  Blood samples were collected for the assessment of hematology parameters platelet count, red blood cell count, hemoglobin, hematocrit, reticulocytes, mean corpuscle volume, mean corpuscular hemoglobin, neutrophils, lymphocytes, monocytes, basophils and eosinophils. Only categories with PCI values have been presented.

  Up to 8 weeks

• Number of Participants With Abnormal Urinalysis Parameters for Part A

  Urinalysis included dipstick urine test which was used to screen for glucose, ketones, occult blood and protein up to 72 hours post dose. The dipstick test gives results in a semi-quantitative manner, and results for urinalysis parameters of urine glucose, ketones, occult blood and protein can be read as negative, trace, trace-intact, trace-lysed,1+ and 2+ indicating proportional concentrations in the urine sample. Only categories with non-negative values have been presented. Only those participants with data available the indicated time points were analyzed.

  Up to 72 hours post-dose

• Urine Potential of Hydrogen (pH) Analysis by Dipstick Method for Part A

  Urinary pH measurement is a routine part of urinalysis. Urine pH is an acid-base measurement. pH is measured on a numeric scale ranging from 0 to 14; values on the scale refer to the degree of alkalinity or acidity. A pH of 7 is neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. Normal urine has a slightly acid pH (5.0 - 6.0). Urine samples were collected for the measurement of urine pH by method up to 72 hours in Part A. Only those participants with data available at the indicated time points were analyzed.

  Up to 72 hours post-dose

• Number of Participants With Abnormal Urinalysis Parameters for Part B

  Urinalysis included dipstick urine test which was used to screen for glucose, ketones, occult blood and protein up to 14 days post dose The dipstick test gives results in a semi-quantitative manner, and results for urinalysis parameters of urine glucose, ketones, occult blood and protein can be read as negative, trace, trace-intact, trace-lysed, 1+ and 2+ indicating proportional concentrations in the urine sample. Only categories with non-negative values have been presented. Only those participants available at the specified time points were analyzed represented by n=x in the category titles. Period 1 = Cohort 1 in Part B, Period 2 = Cohort 2 in Part B.

  Up to 8 weeks

• Urine pH Analysis by Dipstick Method for Part B

  Urinary pH measurement is a routine part of urinalysis. Urine pH is an acid-base measurement. pH is measured on a numeric scale ranging from 0 to 14; values on the scale refer to the degree of alkalinity or acidity. A pH of 7 is neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. Normal urine has a slightly acid pH (5.0 - 6.0). Urine samples were collected for the measurement of urine pH by method up to 8 weeks in Part B. Only those participants available at the specified time points were analyzed represented by n=x in the category titles. Period 1 = Cohort 1 in Part B, Period 2 = Cohort 2 in Part B.

  Up to 8 weeks

• Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to the Time of Last Quantifiable Concentration (AUC[0-t]) Following Single Dose Administration of GSK3036656 for Part A

  Blood samples for plasma PK analysis of GSK3036656 was collected into K3 Ethylenediaminetetraacetic acid (EDTA) tubes at Pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 1 in each period. The actual date and time of each blood sample collection was recorded. PK population comprised of participants in the Safety population who administered at least one dose of active treatment and had at least one evaluable PK sample.

  Pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 1 in each period

• AUC From Time Zero Extrapolated to Infinite Time (AUC[0-infinity]) of GSK3036656 Following Single Dose Administration for Part A

  Cmax will be derived from the PK samples collected at the indicated time points Blood samples for plasma PK analysis of GSK3036656 was collected into K3 EDTA tubes at Pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 1 in each period. The actual date and time of each blood sample collection was recorded.

  Pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 1 in each period

• Maximum Observed Plasma Drug Concentration (Cmax) of GSK3036656 Following Single Dose Administration for Part A

  Blood samples for plasma PK analysis of GSK3036656 was collected into K3 EDTA tubes at Pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 1 in each period. The actual date and time of each blood sample collection was recorded.

  Pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 1 in each period

• Time to Maximum Observed Plasma Drug Concentration (Tmax) of GSK3036656 Following Single Dose Administration for Part A

  Blood samples for plasma PK analysis of GSK3036656 was collected into K3 EDTA tubes at Pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 1 in each period. The actual date and time of each blood sample collection was recorded.

  Pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 1 in each period

• Apparent Terminal Half-life (t1/2) of GSK3036656 Following Single Dose Administration for Part A

  Blood samples for plasma PK analysis of GSK3036656 was collected into K3 EDTA tubes at Pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 1 in each period. The actual date and time of each blood sample collection was recorded.

  Pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 1 in each period

• AUC[0-t] Following Repeated Dose Administration of GSK3036656 for Part B

  Blood samples for plasma PK analysis of GSK3036656 was collected into K3 EDTA tubes at Pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 1. The actual date and time of each blood sample collection was recorded. Results presented are for Day 1.

  Pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 1

• AUC From Time Zero During a Dosing Interval of Duration Tau (AUC[0-tau]) of GSK3036656 Following Repeated Dose Administration for Part B

  Blood samples for plasma PK analysis of GSK3036656 was collected into K3 EDTA tubes at Pre-dose and at pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 14The actual date and time of each blood sample collection was recorded. Results presented are for Day 14.

  Pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 14

• Cmax of GSK3036656 Following Repeated Dose Administration for Part B

  Blood samples for plasma PK analysis of GSK3036656 was collected into K3 EDTA tubes at Pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 1; at pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 14; and at pre-dose on Days 12 and 13. The actual date and time of each blood sample collection was recorded.

  Pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 1; at pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 14; and at pre-dose on Days 12 and 13

• Tmax of GSK3036656 Following Repeat Dose Administration for Part B

  Blood samples for plasma PK analysis of GSK3036656 was collected into K3 EDTA tubes at Pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 1; at pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 14; and at pre-dose on Days 12 and 13. The actual date and time of each blood sample collection was recorded.

  Pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 1; at pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 14; and at pre-dose on Days 12 and 13

• t1/2 of GSK3036656 Following Repeated Dose Administration for Part B

  Blood samples for plasma PK analysis of GSK3036656 was collected into K3 EDTA tubes pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 14. The actual date and time of each blood sample collection was recorded. Results presented are for Day 14.

  Pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 14.

Secondary Outcomes (14)

• AUC (0-t) of GSK3036656 Following Single Dose Administration in Fed Condition in Part A

  Pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 1 in each period

• AUC (0-infinity) of GSK3036656 Following Single Dose Administration in Fed Condition in Part A

  Pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 1 in each period

• Cmax of GSK3036656 Following Single Dose Administration in Fed Condition in Part A

  Pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 1 in each period

• t1/2 of GSK3036656 Following Single Dose Administration in Fed Condition in Part A

  Pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 1 in each period

• Tmax of GSK3036656 Following Single Dose Administration in Fed Condition in Part A

  Pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 hour post-dose on Day 1 in each period

Study Arms (12)

Cohort 1- GSK3036656 in Part A

EXPERIMENTAL

During Part A (Cohort 1), Subjects will receive a single dose of GSK3036656 in the morning on Day 1 in each of the 4 treatment (dosing) periods after an overnight fast of at least 8 hours. Dosing with food may also be done in Part A once results from the food effect analysis are available. The total daily dose for the treatment (dosing) period may also be divided into 2 or 3 smaller doses administered within 24 hours on discretion of the GSK study team and the principal investigator. The starting dose in Part A will be 5 mg and will then be escalated up to a dose no higher than 1500 mg. One of the 4 dosing periods will be food effect group which will be determined based on from previous cohorts. For the food effect assessment, the selected dose will be given with a high fat meal. There will be a 2 week washout between doses initially but the washout period may be modified depending on emerging data from previous cohorts. Subjects will be followed up to 2 weeks from the last dose.

Drug: GSK3036656

Cohort 1- Placebo in Part A

PLACEBO COMPARATOR

During Part A (Cohort 1), Subjects will receive a single matching placebo in morning on Day 1 in each of the 4 treatment (dosing) periods after an overnight fast of at least 8 hours. Dosing with food may also be done in Part A once results from the food effect analysis are available. Placebo for the treatment (dosing) period may also be divided into 2 or 3 smaller doses administered within 24 hours in a similar manner if divided for subjects receiving active treatment in the same period. One of the 4 dosing periods will be food effect group which will be determined based on from previous cohorts. For the food effect assessment, placebo will be given with a high fat meal. There will be a 2 week washout between doses initially but the washout period may be modified depending on emerging data from previous cohorts. Subjects will be followed up to 2 weeks from the last dose.

Drug: Placebo

Cohort 2- GSK3036656 in Part A

EXPERIMENTAL

During Part A (Cohort 2), Subjects will receive a single dose of GSK3036656 in morning on Day 1 in each period after an overnight fast of at least 8 hours. Dosing with food may also be done once results from the food effect analysis are available. The total dose for the treatment period may also be divided into 2 or 3 smaller doses administered within 24 hours on discretion of the GSK study team and the principal investigator. The dose will be selected on basis of safety, tolerability and PK data from the previous treatment period or cohort and will then be escalated up to a dose no higher than 1500 mg. One of the 4 dosing periods will be food effect group, determined based on from previous cohorts, where the selected dose will be given with a high fat meal. There will be a 2 week washout between doses initially but the washout period may be modified depending on emerging data from previous cohorts. Subjects will be followed up to 2 weeks from the last dose.

Drug: GSK3036656

Cohort 2- Placebo in Part A

PLACEBO COMPARATOR

During Part A (Cohort 2), Subjects will receive a single matching placebo in morning on Day 1 in each of the 4 treatment (dosing) periods after an overnight fast of at least 8 hours. Dosing with food may also be done once results from the food effect analysis are available. Placebo for the treatment period may also be divided into 2 or 3 smaller doses administered within 24 hours in a similar manner if divided for subjects receiving active treatment in the same period. One of the 4 dosing periods will be food effect group, determined based on from previous cohorts, where the placebo will be given with a high fat meal. There will be a 2 week washout between doses initially but the washout period may be modified depending on emerging data from previous cohorts. Subjects will be followed up to 2 weeks from the last dose.

Drug: Placebo

Cohort 3- GSK3036656 in Part B

EXPERIMENTAL

During Part B (Cohort 3), Subjects will receive a single dose of GSK3036656 once daily in morning on Day 1 after an overnight fast of at least 8 hours. Subjects will receive repeat single dose of GSK3036656 once daily over a period of 14 days. Dosing with food may also be done if there are PK or tolerability reasons making it preferable to dose in a fed state (dose will be given with a high fat meal.). The total dose may also be divided into 2 or 3 smaller doses administered within 24 hours on discretion of the GSK study team and the principal investigator. Appropriate dose and dose regimen will be selected on available safety, tolerability and PK data from Part A. Subjects will be followed up to 2 weeks from the last dose.

Drug: GSK3036656

Cohort 3- Placebo in Part B

PLACEBO COMPARATOR

During Part B (Cohort 3), Subjects will receive a single matching placebo once daily in morning on Day 1 after an overnight fast of at least 8 hours. Subjects will receive a placebo once daily over a period of 14 days. Dosing with food may also be done if the active treatment is given in a fed state (dose will be given with a high fat meal.). The total dose may also be divided into 2 or 3 smaller doses administered within 24 hours in a similar manner if divided for subjects receiving active treatment in the same cohort. Subjects will be followed up to 2 weeks from the last dose.

Drug: Placebo

Cohort 4- GSK3036656 in Part B

EXPERIMENTAL

During Part B (Cohort 4), Subjects will receive a single dose of GSK3036656 once daily in morning on Day 1 after an overnight fast of at least 8 hours. Subjects will receive repeat single dose of GSK3036656 once daily over a period of 14 days. Dosing with food may also be done if there are PK or tolerability reasons making it preferable to dose in a fed state (dose will be given with a high fat meal.). The total dose may also be divided into 2 or 3 smaller doses administered within 24 hours on discretion of the GSK study team and the principal investigator. Appropriate dose and dose regimen will be selected on available safety, tolerability and PK data from preceding repeat dose cohorts from Part B. Subjects will be followed up to 2 weeks from the last dose.

Drug: GSK3036656

Cohort 4- Placebo in Part B

PLACEBO COMPARATOR

During Part B (Cohort 4), Subjects will receive a single matching placebo once daily in morning on Day 1 after an overnight fast of at least 8 hours. Subjects will receive a placebo once daily over a period of 14 days. Dosing with food may also be done if the active treatment is given in a fed state (dose will be given with a high fat meal.). The total dose may also be divided into 2 or 3 smaller doses administered within 24 hours in a similar manner if divided for subjects receiving active treatment in the same cohort. Subjects will be followed up to 2 weeks from the last dose.

Drug: Placebo

Cohort 5- GSK3036656 in Part B

EXPERIMENTAL

During Part B (Cohort 5), Subjects will receive a single dose of GSK3036656 once daily in morning on Day 1 after an overnight fast of at least 8 hours. Subjects will receive repeat single dose of GSK3036656 once daily over a period of 14 days. Dosing with food may also be done if there are PK or tolerability reasons making it preferable to dose in a fed state (dose will be given with a high fat meal.). The total dose may also be divided into 2 or 3 smaller doses administered within 24 hours on discretion of the GSK study team and the principal investigator. Appropriate dose and dose regimen will be selected on available safety, tolerability and PK data from preceding repeat dose cohorts from Part B. Subjects will be followed up to 2 weeks from the last dose.

Drug: GSK3036656

Cohort 5- Placebo in Part B

PLACEBO COMPARATOR

During Part B (Cohort 5), Subjects will receive a single matching placebo once daily in morning on Day 1 after an overnight fast of at least 8 hours. Subjects will receive a placebo once daily over a period of 14 days. Dosing with food may also be done if the active treatment is given in a fed state (dose will be given with a high fat meal.). The total dose may also be divided into 2 or 3 smaller doses administered within 24 hours in a similar manner if divided for subjects receiving active treatment in the same cohort. Subjects will be followed up to 2 weeks from the last dose.

Drug: Placebo

Cohort 6- GSK3036656 in Part B

EXPERIMENTAL

During Part B (Cohort 6), Subjects will receive a single dose of GSK3036656 once daily in morning on Day 1 after an overnight fast of at least 8 hours. Subjects will receive repeat single dose of GSK3036656 once daily over a period of 14 days. Dosing with food may also be done if there are PK or tolerability reasons making it preferable to dose in a fed state (dose will be given with a high fat meal.). The total dose may also be divided into 2 or 3 smaller doses administered within 24 hours on discretion of the GSK study team and the principal investigator. Appropriate dose and dose regimen will be selected on available safety, tolerability and PK data from preceding repeat dose cohorts from Part B. Subjects will be followed up to 2 weeks from the last dose.

Drug: GSK3036656

Cohort 6- Placebo in Part B

PLACEBO COMPARATOR

During Part B (Cohort 6), Subjects will receive a single matching placebo once daily in morning on Day 1 after an overnight fast of at least 8 hours. Subjects will receive a placebo once daily over a period of 14 days. Dosing with food may also be done if the active treatment is given in a fed state (dose will be given with a high fat meal.). The total dose may also be divided into 2 or 3 smaller doses administered within 24 hours in a similar manner if divided for subjects receiving active treatment in the same cohort. Subjects will be followed up to 2 weeks from the last dose.

Drug: Placebo

Interventions

GSK3036656 DRUG

GSK3036656 is available as capsules (for oral administration) containing 5 mg, 25 mg or 100 mg of GSK3036656 as free base equivalent.

Cohort 1- GSK3036656 in Part A; Cohort 2- GSK3036656 in Part A; Cohort 3- GSK3036656 in Part B; Cohort 4- GSK3036656 in Part B; Cohort 5- GSK3036656 in Part B; Cohort 6- GSK3036656 in Part B

Placebo DRUG

Placebo is a matching capsule containing Avicel PH (Suitable for Pharmaceutical Use) 102, for oral administration.

Cohort 1- Placebo in Part A; Cohort 2- Placebo in Part A; Cohort 3- Placebo in Part B; Cohort 4- Placebo in Part B; Cohort 5- Placebo in Part B; Cohort 6- Placebo in Part B

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Between 18 and 55 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, laboratory tests and cardiac monitoring.

You may not qualify if:

• Body weight \>=60 kilograms (kg) and body mass index (BMI) within the range 19 to 29.9 kg/meter\^2 inclusive.
• Male
• Female subjects of non-child bearing potential are eligible to participate. Non-child bearing potential is defined as:
• Pre-menopausal females with one of the following: documented tubal ligation; documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion or documented bilateral salpingectomy; hysterectomy; documented bilateral oophorectomy.
• Postmenopausal defined as 12 months of spontaneous amenorrhea. Post-menopausal status will be confirmed by a simultaneous follicle stimulating hormone (FSH) and estradiol levels test.
• 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 90 days after the last dose of study treatment (i.e. one sperm cycle).
• Vasectomy with documentation of azoospermia.
• Male condom plus partner use of one of the contraceptive options as follows: contraceptive subdermal implant; intrauterine device or intrauterine system; highly effective oral contraceptive, either combined or progestogen alone (provided it is associated with inhibition of ovulation); injectable progestogen; contraceptive vaginal ring; percutaneous contraceptive patches.
• 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.
• The subject is able to understand and comply with protocol requirements, instructions and protocol-stated restrictions.
• Alanine aminotransferase (ALT) and bilirubin \>1.5 times of upper limit of normal (ULN) (isolated bilirubin \>1.5 times of ULN may be acceptable, after consultation with the GlaxoSmithKline (GSK) medical monitor, if bilirubin is fractionated and direct bilirubin \<35 percent)
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• QTcF \>450 milliseconds.
• Presence of moderate or severe valve disorder or any other clinically significant abnormality.
• Subjects with a history of photosensitivity.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (2)

GSK Investigational Site

London, NW10 7EW, United Kingdom

Location

GSK Investigational Site

London, NW10 7, United Kingdom

Location

Related Publications (1)

• Tenero D, Derimanov G, Carlton A, Tonkyn J, Davies M, Cozens S, Gresham S, Gaudion A, Puri A, Muliaditan M, Rullas-Trincado J, Mendoza-Losana A, Skingsley A, Barros-Aguirre D. First-Time-in-Human Study and Prediction of Early Bactericidal Activity for GSK3036656, a Potent Leucyl-tRNA Synthetase Inhibitor for Tuberculosis Treatment. Antimicrob Agents Chemother. 2019 Jul 25;63(8):e00240-19. doi: 10.1128/AAC.00240-19. Print 2019 Aug.

  PMID: 31182528 DERIVED

MeSH Terms

Conditions

Tuberculosis

Interventions

GSK656

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

• GSK Clinical Trials

  GlaxoSmithKline (for GlaxoSmithKline; Human Genome Sciences Inc., a GSK Company; Sirtris, a GSK Company; Stiefel, a GSK Company; ViiV Healthcare)

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

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

Study Record Dates

• First Submitted: March 6, 2017
• First Posted: March 9, 2017
• Study Start: April 2, 2017
• Primary Completion: August 4, 2017
• Study Completion: August 4, 2017
• Last Updated: April 19, 2019
• Results First Posted: April 19, 2019

Record last verified: 2019-01

Locations

GB (2)