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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03075410
Recruitment Status : Completed
First Posted : March 9, 2017
Results First Posted : April 19, 2019
Last Update Posted : April 19, 2019
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

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.

Condition or disease Intervention/treatment Phase
Tuberculosis Drug: GSK3036656 Drug: Placebo Phase 1

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Double Blind, Placebo-controlled First Time in Human Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Single and Repeat Doses of GSK3036656 in Healthy Adult Volunteers
Actual Study Start Date : April 2, 2017
Actual Primary Completion Date : August 4, 2017
Actual Study Completion Date : August 4, 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Tuberculosis

Arm Intervention/treatment
Experimental: Cohort 1- GSK3036656 in Part A
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
GSK3036656 is available as capsules (for oral administration) containing 5 mg, 25 mg or 100 mg of GSK3036656 as free base equivalent.

Placebo Comparator: Cohort 1- Placebo in Part A
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
Placebo is a matching capsule containing Avicel PH (Suitable for Pharmaceutical Use) 102, for oral administration.

Experimental: Cohort 2- GSK3036656 in Part A
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
GSK3036656 is available as capsules (for oral administration) containing 5 mg, 25 mg or 100 mg of GSK3036656 as free base equivalent.

Placebo Comparator: Cohort 2- Placebo in Part A
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
Placebo is a matching capsule containing Avicel PH (Suitable for Pharmaceutical Use) 102, for oral administration.

Experimental: Cohort 3- GSK3036656 in Part B
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
GSK3036656 is available as capsules (for oral administration) containing 5 mg, 25 mg or 100 mg of GSK3036656 as free base equivalent.

Placebo Comparator: Cohort 3- Placebo in Part B
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
Placebo is a matching capsule containing Avicel PH (Suitable for Pharmaceutical Use) 102, for oral administration.

Experimental: Cohort 4- GSK3036656 in Part B
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
GSK3036656 is available as capsules (for oral administration) containing 5 mg, 25 mg or 100 mg of GSK3036656 as free base equivalent.

Placebo Comparator: Cohort 4- Placebo in Part B
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
Placebo is a matching capsule containing Avicel PH (Suitable for Pharmaceutical Use) 102, for oral administration.

Experimental: Cohort 5- GSK3036656 in Part B
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
GSK3036656 is available as capsules (for oral administration) containing 5 mg, 25 mg or 100 mg of GSK3036656 as free base equivalent.

Placebo Comparator: Cohort 5- Placebo in Part B
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
Placebo is a matching capsule containing Avicel PH (Suitable for Pharmaceutical Use) 102, for oral administration.

Experimental: Cohort 6- GSK3036656 in Part B
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
GSK3036656 is available as capsules (for oral administration) containing 5 mg, 25 mg or 100 mg of GSK3036656 as free base equivalent.

Placebo Comparator: Cohort 6- Placebo in Part B
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
Placebo is a matching capsule containing Avicel PH (Suitable for Pharmaceutical Use) 102, for oral administration.




Primary Outcome Measures :
  1. Number of Participants With Non-serious Adverse Events (nSAE) and Serious Adverse Events (SAEs) for Part A [ Time Frame: Up to 12 weeks ]
    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.

  2. Number of Participants With nSAE and SAEs for Part B [ Time Frame: Up to 8 weeks ]
    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.

  3. Number of Participants With Abnormal Electrocardiogram (ECG) Findings for Part A [ Time Frame: Up to 6 weeks ]
    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.

  4. Number of Subjects With Clinically Relevant Changes in ECG in Part B [ Time Frame: Up to 8 weeks ]
    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.

  5. Number of Participants With Abnormal Cardiac Telemetry Findings for Part A [ Time Frame: 25 hours for each period ]
    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.

  6. Number of Participants With Abnormal Cardiac Telemetry Findings for Part B [ Time Frame: 25 hours for each period ]
    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.

  7. Number of Participants With Vital Sign Parameters Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) of Potential Clinical Importance (PCI) for Part A [ Time Frame: Up to 6 weeks ]
    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).

  8. Number of Participants With Vital Sign Parameters SBP and DBP of PCI for Part B [ Time Frame: Up to 8 weeks ]
    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).

  9. Number of Participants With Vital Sign Parameter Heart Rate of PCI for Part A [ Time Frame: Up to 6 weeks ]
    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).

  10. Number of Participants With Vital Sign Parameter Heart Rate of PCI for Part B [ Time Frame: Up to 8 weeks ]
    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).

  11. Number of Participants With Vital Sign Parameter Temperature of PCI for Part A [ Time Frame: Up to 6 weeks ]
    Number of participants with temperature data of PCI have been presented.

  12. Number of Participants With Vital Sign Parameter Temperature of PCI for Part B [ Time Frame: Up to 8 weeks ]
    Number of participants with temperature data of PCI have been presented.

  13. Number of Participants With Clinical Chemistry Parameters of PCI for Part A [ Time Frame: Up to 12 weeks ]
    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.

  14. Number of Participants With Clinical Chemistry Parameters of PCI for Part B [ Time Frame: Up to 8 weeks ]
    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.

  15. Number of Participants With Hematology Parameters of PCI for Part A [ Time Frame: Up to 12 weeks ]
    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.

  16. Number of Participants With Hematology Parameters of PCI for Part B [ Time Frame: Up to 8 weeks ]
    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.

  17. Number of Participants With Abnormal Urinalysis Parameters for Part A [ Time Frame: Up to 72 hours post-dose ]
    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.

  18. Urine Potential of Hydrogen (pH) Analysis by Dipstick Method for Part A [ Time Frame: Up to 72 hours post-dose ]
    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.

  19. Number of Participants With Abnormal Urinalysis Parameters for Part B [ Time Frame: Up to 8 weeks ]
    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.

  20. Urine pH Analysis by Dipstick Method for Part B [ Time Frame: Up to 8 weeks ]
    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.

  21. 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 [ Time Frame: 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 ]
    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.

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

  23. Maximum Observed Plasma Drug Concentration (Cmax) of GSK3036656 Following Single Dose Administration for Part A [ Time Frame: 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 ]
    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.

  24. Time to Maximum Observed Plasma Drug Concentration (Tmax) of GSK3036656 Following Single Dose Administration for Part A [ Time Frame: 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 ]
    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.

  25. Apparent Terminal Half-life (t1/2) of GSK3036656 Following Single Dose Administration for Part A [ Time Frame: 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 ]
    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.

  26. AUC[0-t] Following Repeated Dose Administration of GSK3036656 for Part B [ Time Frame: 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 ]
    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.

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

  28. Cmax of GSK3036656 Following Repeated Dose Administration for Part B [ Time Frame: 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 ]
    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.

  29. Tmax of GSK3036656 Following Repeat Dose Administration for Part B [ Time Frame: 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 ]
    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.

  30. t1/2 of GSK3036656 Following Repeated Dose Administration for Part B [ Time Frame: 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. ]
    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.


Secondary Outcome Measures :
  1. AUC (0-t) of GSK3036656 Following Single Dose Administration in Fed Condition in Part A [ Time Frame: 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 ]
    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. For the food effect assessment, the selected dose was given with a high fat meal.

  2. AUC (0-infinity) of GSK3036656 Following Single Dose Administration in Fed Condition in Part A [ Time Frame: 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 ]
    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. For the food effect assessment, the selected dose was given with a high fat meal.

  3. Cmax of GSK3036656 Following Single Dose Administration in Fed Condition in Part A [ Time Frame: 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 ]
    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. For the food effect assessment, the selected dose was given with a high fat meal.

  4. t1/2 of GSK3036656 Following Single Dose Administration in Fed Condition in Part A [ Time Frame: 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 ]
    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. For the food effect assessment, the selected dose was given with a high fat meal.

  5. Tmax of GSK3036656 Following Single Dose Administration in Fed Condition in Part A [ Time Frame: 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 ]
    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. For the food effect assessment, the selected dose was given with a high fat meal.

  6. Observed Accumulation Ratio Based on AUC (AUC [Ro]) of GSK3036656 in Part B [ Time Frame: 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 ]
    AUC Ro was calculated as Day 14 AUC(0-tau)/Day 1 AUC(0-t), where t and tau= 24 hours.

  7. Observed Accumulation Ratio Based on Cmax (RCmax) of GSK3036656 in Part B [ Time Frame: 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 ]
    Rcmax was calculated as Day 14 Cmax/Day 1 Cmax. Statistics has been presented on geometric least square means.

  8. Steady State Ratio (Rss) of GSK3036656 in Part B [ Time Frame: 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 ]
    Rss was calculated as Day 14 AUC (0-tau)/Day 1 AUC (0-inf). It was not possible to calculate AUC(0-inf) on Day 1 for the repeat dosing period, therefore it was not possible to calculate the (Rss).Na indicates data was not available.

  9. Trough Plasma Concentrations at the End of the Dosing Interval (Ctau) of GSK3036656 Following Repeat Dose Administrations in Part B [ Time Frame: Day 1 (24 hours), Day 12 (Pre-dose ), Day 13 (Pre-dose ), Day 14 (Pre-dose), Day 14 (24 hours) ]
    Blood samples for the analysis of Ctau were collected at Day 1 (24 hours), Day 12 (Pre-dose ), Day 13 (Pre-dose ), Day 14 (Pre-dose), Day 14 (24 hours). Ctau samples collected were used to assess attainment of steady state. Statistics has been presented on geometric least square means.

  10. AUC (0-infinity) as a Measure of Dose Proportionality of GSK3036656 Following Single Dose Administrations for Part A [ Time Frame: 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 ]
    Blood samples for the analysis of AUC (0-infinity) were collected 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. AUC(0-infinity) following single doses was used for assessment of dose proportionality.

  11. AUC (0-t) as a Measure of Dose Proportionality of GSK3036656 Following Single Dose Administrations for Part A [ Time Frame: 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 ]
    Blood samples for the analysis of AUC (0-t) were collected 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. AUC(0-t) following single doses was used for assessment of dose proportionality.

  12. Cmax as a Measure of Dose Proportionality of GSK3036656 Following Single Dose Administrations for Part A [ Time Frame: 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 ]
    Blood samples for the analysis of Cmax were collected 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. Cmax following single doses was used for assessment of dose proportionality.

  13. AUC (0-tau) as a Measure of Dose Proportionality of GSK3036656 Following Repeat Dose Administrations for Part B [ Time Frame: 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 ]
    Blood samples for the assessment of AUC (0-tau) were collected 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. AUC (0-tau) following repeat doses was used for assessment of dose proportionality.

  14. Cmax as a Measure of Dose Proportionality of GSK3036656 Following Repeat Dose Administrations for Part B [ Time Frame: 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 ]
    Blood samples for the assessment of Cmax were collected 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. Cmax following repeat doses was used for assessment of dose proportionality.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • 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.
  • 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, if required, agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
  • 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.

Exclusion criteria:

  • 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.
  • Females of non-childbearing potential who are susceptible to heavy periods or vaginal bleeding or spotting.
  • Pregnant females. A human chorionic gonadotrophin (hCG) test will be performed on Day -1 of each treatment (dosing) period in Part A and Part B for women for whom post-menopausal status has not been confirmed by FSH/estradiol testing. No pregnancy tests will be required for female subjects confirmed as post-menopausal by FSH/estradiol testing.
  • Lactating females.
  • Use of prescription or non-prescription drugs, including high-dose vitamins, herbal and dietary supplements (including Saint 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, unless in the opinion of the investigator and sponsor, the medication will not interfere with the study procedures or compromise subject safety. Paracetamol for mild analgesia will be permitted.
  • Breath carbon monoxide test indicative of smoking or history of current use of tobacco- or nicotine-containing products.
  • Current regular alcohol consumption defined as an average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 8 grams (g) of alcohol: a half-pint (approximately 240 milliliter [mL]) of beer, 1 glass (125 ml) of wine or 1 (25 ml) measure of spirits.
  • Subjects must not sunbathe or use a tanning device whilst taking the study medication and until at least 2 weeks after their last dose. Subjects are to be advised that they should wear protective clothing (e.g. sun hat, long sleeves) and use a broad spectrum ultraviolet A/ ultraviolet B sunscreen (sun protection factor >=30) when outdoors.
  • History of sensitivity to heparin or heparin-induced thrombocytopenia.
  • 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 or medical monitor, contraindicates their participation.
  • Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment.
  • A positive test for human immunodeficiency virus (HIV) antibody.
  • A positive pre-study drug/alcohol screen.
  • The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 3 months, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
  • Exposure to more than four new chemical entities within 12 months prior to the first dosing day.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03075410


Locations
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United Kingdom
GSK Investigational Site
London, United Kingdom, NW10 7EW
GSK Investigational Site
London, United Kingdom, NW10 7
Sponsors and Collaborators
GlaxoSmithKline
Investigators
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Study Director: 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 Documents (Full-Text)

Documents provided by GlaxoSmithKline:
Study Protocol  [PDF] February 27, 2017
Statistical Analysis Plan  [PDF] March 28, 2017

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT03075410    
Other Study ID Numbers: 201040
2015-003654-41 ( EudraCT Number )
First Posted: March 9, 2017    Key Record Dates
Results First Posted: April 19, 2019
Last Update Posted: April 19, 2019
Last Verified: January 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by GlaxoSmithKline:
ascending dose
Pharmacokinetics
GSK3036656
FTIH
Safety
Additional relevant MeSH terms:
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Tuberculosis
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Bacterial Infections and Mycoses
Infections
GSK656
Anti-Bacterial Agents
Anti-Infective Agents