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A Two-part Study to Compare a Tablet and Capsule Formulation of GSK2838232 With and Without Food, and to Assess the Safety and Drug Levels of Repeated Once-daily Doses of GSK2838232 Without Ritonavir

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: NCT03234036
Recruitment Status : Completed
First Posted : July 31, 2017
Results First Posted : March 7, 2019
Last Update Posted : March 7, 2019
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Brief Summary:
This study will be conducted in two Parts to confirm the acceptability/selection of a tablet formulation for future clinical development of GSK2838232. Part 1 of the study will assess single ritonavir (RTV)-boosted doses of a new tablet formulation given with food (containing approximately 30% fat) against the reference capsule formulation also given with food and then will assess the impact of fasted conditions on the tablet performance. In Part 2, non-boosted GSK2838232 will be given as once-daily tablet doses for 11 days in a separate group of subjects, assuming the tablet performance is considered acceptable from Part 1. Approximately 16 healthy subjects will be enrolled to provide at least 12 evaluable subjects through the three study periods in Part 1. 10 healthy subjects will be enrolled to provide at least 8 evaluable subjects through the single study period in Part 2. The maximum duration of study participation will be approximately 9 to 10 weeks for Part 1; and 8 to 9 weeks for Part 2.

Condition or disease Intervention/treatment Phase
Infection, Human Immunodeficiency Virus Drug: GSK2838232 100 mg tablet Drug: GSK2838232 50 mg capsule Drug: Ritonavir 100 mg tablets Drug: Placebo for GSK2838232 tablets Phase 1

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 26 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: The randomization number will determine the allocation of treatment sequences (ABC or BAC) for Part 1, and of treatment (GSK2838232 without RTV or placebo) for Part 2. Allocation to treatment for Part 1A or Part 1B (with Part 2 being fixed) will be according to a predetermined random order.
Masking: Double (Participant, Investigator)
Masking Description: Part 1 of the study will be open label and thus not be blinded. Part 2 of the study will be single blinded because of the unavailability of matching placebo tablets. The Principal Investigator and the subject will be completely blinded to specific treatment assignment.
Primary Purpose: Treatment
Official Title: A Two Part Study to Assess i) the Relative Bioavailability and Food Effect of a Novel Tablet Formulation of Boosted-GSK2838232 Compared to Capsule and ii) the Safety and Pharmacokinetics of Repeated Once-Daily Doses of Non-boosted GSK2838232
Actual Study Start Date : August 2, 2017
Actual Primary Completion Date : November 10, 2017
Actual Study Completion Date : November 10, 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS
Drug Information available for: Ritonavir

Arm Intervention/treatment
Experimental: Treatment sequence ABC: Part 1

A single dose of GSK2838232 200 mg (as 4 x 50 mg) capsule formulation will be administered under fed conditions (treatment A) in period 1 in Part 1A.

A single dose of GSK2838232 200 mg (as 2 x 100 mg) tablet formulation will be administered under fed conditions (treatment B) in period 2 in Part 1A.

Both these treatments in Part 1A will be administered with RTV in fed state with a washout of 10 days.

A single dose of GSK2838232 200 mg (as 2 x 100 mg) tablet formulation (with RTV) will be administered under fasted conditions (treatment C) in period 3 in Part 1B.

There will be a wash out of 15 days between Part 1A and Part 1B.

Drug: GSK2838232 100 mg tablet
It is a white to slightly colored tablet. It will be supplied as prefilled tablets in bulk for dispensing to subjects at the site according to the treatment code.

Drug: GSK2838232 50 mg capsule
It is a pink unmarked capsule. It will be supplied as prefilled capsules in bulk for dispensing to subjects at the site according to the treatment code.

Drug: Ritonavir 100 mg tablets
It is a white film-coated ovaloid tablets.

Experimental: Treatment sequence BAC: Part 1

A single dose of GSK2838232 200 mg (as 2 x 100 mg) tablet formulation will be administered under fed conditions (treatment B) in period 1 in Part 1A.

A single dose of GSK2838232 200 mg (as 4 x 50 mg) capsule formulation will be administered under fed conditions (treatment A) in period 2 in Part 1A.

A single dose of GSK2838232 200 mg (as 2 x 100 mg) tablet formulation (with RTV) will be administered under fasted conditions (treatment C) in period 3 in Part 1B.

There will be a wash out of 15 days between Part 1A and Part 1B.

Drug: GSK2838232 100 mg tablet
It is a white to slightly colored tablet. It will be supplied as prefilled tablets in bulk for dispensing to subjects at the site according to the treatment code.

Drug: GSK2838232 50 mg capsule
It is a pink unmarked capsule. It will be supplied as prefilled capsules in bulk for dispensing to subjects at the site according to the treatment code.

Drug: Ritonavir 100 mg tablets
It is a white film-coated ovaloid tablets.

Experimental: GSK2838232 tablet without RTV: Part 2
In Part 2, subjects will receive non-RTV boosted GSK2838232 500 mg, given as single daily doses for 11 days. The dose will not exceed 500 mg (as 5 x 100 mg tablets) once daily (QD).
Drug: GSK2838232 100 mg tablet
It is a white to slightly colored tablet. It will be supplied as prefilled tablets in bulk for dispensing to subjects at the site according to the treatment code.

Placebo Comparator: Placebo without RTV: Part 2
In Part 2, subjects will receive a Placebo given as single daily doses for 11 days.
Drug: Placebo for GSK2838232 tablets
It is a white to slightly colored tablet. The placebo tablets supplied will not be identical to GSK2838232 tablets. It will be administered by site staff via an opaque card or paper tube.




Primary Outcome Measures :
  1. Part 1: Area Under the Concentration-time Curve From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUC [0-infinity]) Following Administration of GSK2838232 Tablet and Capsule Formulation in Fed State [ Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96, and 120 hours post-dose in treatment periods 1 and 2 of Part 1 ]
    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232 given as tablet and capsule formulation in fed state. Pharmacokinetic parameters were determined using standard non-compartmental methods. Pharmacokinetic Population comprised of all participants in the Safety Population who had at least 1 non-missing pharmacokinetic assessment (Non-quantifiable [NQ] values were considered as non-missing values).

  2. Part 1: Maximum Observed Concentration (Cmax) Following Administration of GSK2838232 Tablet and Capsule Formulation in Fed State [ Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96, and 120 hours post-dose in treatment periods 1 and 2 of Part 1 ]
    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232 given as tablet and capsule formulation in fed state. Pharmacokinetic parameters were determined using standard non-compartmental methods.

  3. Part 1: AUC (0-infinity) Following Administration of GSK2838232 Tablet in Fasted and Fed State [ Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96, and 120 hours post-dose in treatment periods 1, 2 and 3 of Part 1 ]
    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232 given as tablet formulation in fed and fasted state. Pharmacokinetic parameters were determined using standard non-compartmental methods.

  4. Part 1: Cmax Following Administration of GSK2838232 Tablet in Fasted and Fed State [ Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96, and 120 hours post-dose in treatment periods 1, 2 and 3 of Part 1 ]
    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232 given as tablet formulation in fed and fasted state. Pharmacokinetic parameters were determined using standard non-compartmental methods.

  5. Part 1: Time of Occurrence of Cmax (Tmax) Following Administration of GSK2838232 Tablet in Fasted and Fed State [ Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96, and 120 hours post-dose in treatment periods 1, 2 and 3 of Part 1 ]
    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232 given as tablet formulation in fed and fasted state. Pharmacokinetic parameters were determined using standard non-compartmental methods.

  6. Part 2: Number of Participants With Serious Adverse Events (SAEs) and Non-SAEs [ Time Frame: Up to 25 days ]
    An adverse event (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. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/ birth defect, is associated with liver injury or impaired liver function or any other situations as per medical or scientific judgment. Safety Population comprised of all participants who received at least 1 dose of the study treatment (including placebo) with at least 1 post-Baseline safety assessment. Number of participants with SAEs and common non-SAEs (>=5%) are presented.

  7. Part 2: Number of Participants With Worst Case Hematology Results to Potential Clinical Importance (PCI) Criteria [ Time Frame: Up to 25 days ]
    Blood samples were collected from participants for analysis of following hematology parameters; hematocrit, hemoglobin, leukocytes, lymphocytes, neutrophils and platelets. PCI ranges were < 0.075 or >0.54 proportion of red blood cells in blood for hematocrit, <25 or >180 grams per liter (g/L) for hemoglobin, < 3 or >20 cells per liter (cells/L) for leukocytes, 0.8 x10^9 cells/L for lymphocytes, 1.5 x10^9 cells/L for neutrophils, and <100 or >550 cells/L for platelets. Participants were counted in the worst case category that their value changes to (low, within range or no change, or high), unless there is no change in their category. Participants whose laboratory value category was unchanged (example given [e.g.], High to High), or whose value became within range, were recorded in the "To within Range or No Change" category.

  8. Part 2: Number of Participants With Worst Case Clinical Chemistry Results to PCI Criteria [ Time Frame: Up to 25 days ]
    Blood samples were collected from participants for analysis of following clinical chemistry parameters; glucose, alanine aminotransferase (ALT), albumin, alkaline phosphatase, aspartate aminotransferase (AST), bilirubin, calcium, potassium and sodium. PCI ranges were <30 g/L for albumin, <2 or >2.75 millimoles per liter (mmol/L) for calcium, <3 or >9 mmol/L for glucose, >=2 times Upper limit of Normal (ULN) units per liter (U/L) for ALT, >=2 times ULN U/L for alkaline phosphatase, >=2 times ULN U/L for AST, >=1.5 times ULN micromoles per liter (µmol/L) for bilirubin, <3 or >5.5 mmol/L for potassium, and <130 or >150 mmol/L for sodium. Participants were counted in the worst case category that their value changes to (low, within range or no change,or high), unless there is no change in their category. Participants whose laboratory value category was unchanged (e.g., High to High), or whose value became within range, were recorded in the "To within Range or No Change" category.

  9. Part 2: Number of Participants With Worst Case Urinalysis Results Relative to Normal Range Criteria [ Time Frame: Up to 25 days ]
    Urine samples were collected from participants for analysis of following urinalysis parameters; specific gravity, potential of hydrogen (pH), presence of glucose, protein, occult blood, ketones in urine analyzed by dipstick method. The dipstick test gives results in a semi-quantitative manner. Urine specific gravity is a measure of the concentration of solutes in the urine and provides information on the kidney's ability to concentrate urine. The reference range is 1.002-1.030. Urine pH is an acid-base measurement. Normal urine has a slightly acid pH (5.0 - 6.0). Participants were counted in the worst case category that their value changes to (low, normal or high), unless there is no change in their category. Participants whose laboratory value category was unchanged (e.g., High to High), or whose value became normal, were recorded in the "To Normal or No Change" category.

  10. Part 2: Blood Pressure at Indicated Time Points [ Time Frame: Day -1; Pre-dose, 1, 4 hours on Day 1; 24 hours (Day 2); 48 hours (Day 3); 72 hours (Day 4), Days 5, 6, 7, 8, 9, 10; Pre-dose, 1, 4 , 24, 48, 72 hours on Day 11; Follow-up (Day 25) ]
    Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured in supine position after 10 minutes rest for the participants at indicated time points.

  11. Part 2: Change From Baseline in Blood Pressure [ Time Frame: Baseline (Day -1) and 1, 4 hours on Day 1; 24 hours (Day 2); 48 hours (Day 3); 72 hours (Day 4), Days 5, 6, 7, 8, 9, 10; Pre-dose, 1, 4 , 24, 48, 72 hours on Day 11; Follow-up (Day 25) ]
    SBP and DBP were measured in supine position after 10 minutes rest for participants at indicated time points. Baseline was defined as the latest pre-dose assessment, including those from unscheduled visits. Change from Baseline was defined as any visit value minus Baseline value.

  12. Part 2: Pulse Rate at Indicated Time Points [ Time Frame: Day -1; Pre-dose, 1, 4 hours on Day 1; 24 hours (Day 2); 48 hours (Day 3); 72 hours (Day 4), Days 5, 6, 7, 8, 9, 10; Pre-dose, 1, 4 , 24, 48, 72 hours on Day 11; Follow-up (Day 25) ]
    Pulse rate of participants was measured in supine position after 10 minutes rest at indicated time points.

  13. Part 2: Change From Baseline in Pulse Rate [ Time Frame: Baseline (Day -1) and 1, 4 hours on Day 1; 24 hours (Day 2); 48 hours (Day 3); 72 hours (Day 4), Days 5, 6, 7, 8, 9, 10; Pre-dose, 1, 4 , 24, 48, 72 hours on Day 11; Follow-up (Day 25) ]
    Pulse rate was measured in supine position after 10 minutes rest at indicated time points. Baseline was defined as the latest pre-dose assessment, including those from unscheduled visits. Change from Baseline was defined as any visit value minus Baseline value.

  14. Part 2: Number of Participants With Abnormal Electrocardiogram (ECG) Findings [ Time Frame: Day -1; 1, 4, 12 hours on Day 1; Days 2, 3, 5, 8; 1, 4, 12, 24 Hours on Day 11; Follow-up (Day 25) ]
    Single and triplicate 12-lead ECG's were obtained at least 5 minutes apart in the supine position after 10 minutes of rest at indicated time points 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. Clinically significant (CS) and not clinically significant (NCS) abnormal ECG findings have been presented. CS abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition.

  15. Part 2: Change From Baseline in Mean Heart Rate Values as ECG Parameter [ Time Frame: Baseline (Day -1) and 1, 4, 12 hours on Day 1; Days 2, 3 5, 8; Pre-dose, 1, 4, 12, 24 hours Day 11; Follow-up (Day 25) ]
    Single and triplicate 12-lead ECG's were obtained at least 5 minutes apart in the supine position after 10 minutes of rest at indicated time points using an ECG machine that automatically calculates the heart rate. Baseline was defined as the latest pre-dose assessment, including those from unscheduled visits. Change from Baseline was defined as any visit value minus Baseline value.

  16. Part 2: Change From Baseline in PR Interval, QRS, QT Interval, and QTcF Interval as ECG Parameters [ Time Frame: Baseline (Day -1) and 1, 4, 12 hours on Day 1; Days 2, 3 5, 8; Pre-dose, 1, 4, 12, 24 hours Day 11; Follow-up (Day 25) ]
    Single and triplicate 12-lead ECG's were obtained at least 5 minutes apart in the supine position after 10 minutes of rest at indicated time points using an ECG machine that automatically calculates measures PR, QRS, QT and QTcF intervals. Baseline was defined as the latest pre-dose assessment, including those from unscheduled visits. Change from Baseline was defined as any visit value minus Baseline value.

  17. Part 2: Area Under the Plasma Drug Concentration Time Curve From Pre-dose to the End of the Dosing Interval at Steady State (AUC[0-tau]) Following Administration of Non-boosted Once-daily Doses of GSK2838232 Tablet in Fed State [ Time Frame: Pre-dose, 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12 and 24 hours post-dose on Day 1; Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96 and 120 hours post-dose on Day 11 in Part 2 ]
    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232 given as a non-boosted once-daily dosing tablet in fed state. Pharmacokinetic parameters were determined using standard non-compartmental methods.

  18. Part 2: Cmax Following Administration of Non-boosted Once-daily Doses of GSK2838232 Tablet in Fed State [ Time Frame: Pre-dose, 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12 and 24 hours post-dose on Day 1; Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96 and 120 hours post-dose on Day 11 in Part 2 ]
    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232 given as a non-boosted once-daily dosing tablet in fed state. Pharmacokinetic parameters were determined using standard non-compartmental methods.

  19. Part 2: Observed Concentration at the End of the Dosing Interval (Ctau) Following Administration of Non-boosted Once-daily Doses of GSK2838232 Tablet in Fed State [ Time Frame: Pre-dose, 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12 and 24 hours post-dose on Day 1; Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96 and 120 hours post-dose on Day 11 in Part 2 ]
    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232 given as a non-boosted once-daily dosing tablet in fed state. Pharmacokinetic parameters were determined using standard non-compartmental methods.

  20. Part 2: Tmax Following Administration of Non-boosted Once-daily Doses of GSK2838232 Tablet in Fed State [ Time Frame: Pre-dose, 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12 and 24 hours post-dose on Day 1; Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96 and 120 hours post-dose on Day 11 in Part 2 ]
    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232 given as a non-boosted once-daily dosing tablet in fed state. Pharmacokinetic parameters were determined using standard non-compartmental methods.

  21. Part 2: Lag-time (Tlag) Following Administration of Non-boosted Once-daily Doses of GSK2838232 Tablet in Fed State on Day 1 [ Time Frame: Pre-dose, 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12 and 24 hours post-dose on Day 1 in Part 2 ]
    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232 given as a non-boosted once-daily dosing tablet in fed state. Tlag is a time delay between drug administration and first observed concentration. Pharmacokinetic parameters were determined using standard non-compartmental methods.

  22. Part 2: AUC(0-infinity) Following Administration of Non-boosted Once-daily Doses of GSK2838232 Tablet in Fed State on Day 11 [ Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96 and 120 hours post-dose on Day 11 in Part 2 ]
    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232 given as a non-boosted once-daily dosing tablet in fed state. Pharmacokinetic parameters were determined using standard non-compartmental methods.

  23. Part 2: Apparent Terminal Phase Half-life (T1/2) Following Administration of Non-boosted Once-daily Doses of GSK2838232 Tablet in Fed State on Day 11 [ Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96 and 120 hours post-dose on Day 11 in Part 2 ]
    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232 given as a non-boosted once-daily dosing tablet in fed state. Pharmacokinetic parameters were determined using standard non-compartmental methods.

  24. Part 2: Time of Last Quantifiable Concentration (Tlast) Following Administration of Non-boosted Once-daily Doses of GSK2838232 Tablet in Fed State on Day 11 [ Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96 and 120 hours post-dose on Day 11 in Part 2 ]
    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232 given as a non-boosted once-daily dosing tablet in fed state. Pharmacokinetic parameters were determined using standard non-compartmental methods.


Secondary Outcome Measures :
  1. Part 1: Number of Participants With SAEs and Non-SAEs [ Time Frame: Up to 60 days ]
    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. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/ birth defect, is associated with liver injury or impaired liver function or any other situations as per medical or scientific judgment. Number of participants with SAEs and common non-SAEs (>=5%) are presented.

  2. Part 1: Number of Participants With Worst Case Hematology Results to PCI Criteria [ Time Frame: Up to 60 days ]
    Blood samples were collected from participants for analysis of following hematology parameters; hematocrit, hemoglobin, leukocytes, lymphocytes, neutrophils and platelets. PCI ranges were >0.54 as proportion of red blood cells in blood for hematocrit, >180 g/L for hemoglobin, < 3 or >20 cells/L for leukocytes, 0.8 x10^9 cells/L for lymphocytes, 1.5 x10^9 cells/L for neutrophils, and <100 or >550 cells/L for platelets. Participants were counted in the worst case category that their value changes to (low, within range or no change, or high), unless there is no change in their category. Participants whose laboratory value category was unchanged (e.g., High to High), or whose value became within range, were recorded in the "To within Range or No Change" category.

  3. Part 1: Number of Participants With Worst Case Clinical Chemistry Results to PCI Criteria [ Time Frame: Up to 60 days ]
    Blood samples were collected from participants for analysis of following clinical chemistry parameters; glucose, ALT, albumin, alkaline phosphatase, AST, bilirubin, calcium, potassium and sodium. PCI ranges were <30 g/L for albumin, <2 or 2.75 mmol/L for calcium, <3 or >9 mmol/L for glucose, >=2 times ULN U/L for ALT, >=2 times ULN U/L for alkaline phosphatase, >=2 times ULN U/L for AST, >=1.5 times ULN µmol/L for bilirubin, <3 or >5.5 mmol/L for potassium, and <130 or >150 mmol/L for sodium. Participants were counted in the worst case category that their value changes to (low, within range or no change,or high), unless there is no change in their category. Participants whose laboratory value category was unchanged (e.g., High to High), or whose value became within range, were recorded in the "To within Range or No Change" category.

  4. Part 1: Number of Participants With Worst Case Urinalysis Results Relative to Normal Range Criteria [ Time Frame: Up to 60 days ]
    Urine samples were collected from participants for analysis of following urinalysis parameters; specific gravity, pH, presence of glucose, protein, occult blood, ketones in urine analyzed by dipstick method. The dipstick test gives results in a semi-quantitative manner. Urine specific gravity is a measure of the concentration of solutes in the urine and provides information on the kidney's ability to concentrate urine. The reference range is 1.002-1.030. Urine pH is an acid-base measurement. Normal urine has a slightly acid pH (5.0 - 6.0). Participants were counted in the worst case category that their value changes to (low, normal or high), unless there is no change in their category. Participants whose laboratory value category was unchanged (e.g., High to High), or whose value became normal, were recorded in the "To Normal or No Change" category.

  5. Part 1: Blood Pressure at Indicated Time Points [ Time Frame: Day -2; Day -1; Pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72 Hours on Day 1 ]
    SBP and DBP of participants were measured in supine position after 10 minutes rest at indicated time points.

  6. Part 1: Change From Baseline in Blood Pressure [ Time Frame: Baseline (Day -1) and 1, 2, 4, 6, 8, 12, 24, 48, 72 Hours on Day 1 ]
    SBP and DBP were measured in supine position after 10 minutes rest for the participant at indicated time points. Baseline was defined as the latest pre-dose assessment, including those from unscheduled visits. Change from Baseline was defined as any visit value minus Baseline value.

  7. Part 1: Pulse Rate at Indicated Time Points [ Time Frame: Day -2; Day -1; Pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72 Hours on Day 1 ]
    Pulse rate was measured in supine position after 10 minutes rest for the participant at indicated time points.

  8. Part 1: Change From Baseline in Pulse Rate [ Time Frame: Baseline (Day -1) and 1, 2, 4, 6, 8, 12, 24, 48, 72 Hours on Day 1 ]
    Pulse rate was measured in supine position after 10 minutes rest for the participant at indicated time points. Baseline was defined as the latest pre-dose assessment, including those from unscheduled visits. Change from Baseline was defined as any visit value minus Baseline value.

  9. Part 1: Number of Participants With Abnormal ECG Findings [ Time Frame: Day -2, Day -1; 1, 2, 4, 6, 8, , 12, 24, 48, 72 hours on Day 1 ]
    Single and triplicate 12-lead ECG's were obtained at least 5 minutes apart in the supine position after 10 minutes of rest at indicated time points using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT and QTcF intervals. CS and NCS abnormal ECG findings have been presented. CS abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition.

  10. Part 1: Change From Baseline in Mean Heart Rate Values as ECG Parameter [ Time Frame: Baseline (Day -1) and 1, 2, 4, 6, 8, 12, 24, 48, 72 hours on Day 1 ]
    Single and triplicate 12-lead ECG's were obtained at least 5 minutes apart in the supine position after 10 minutes of rest at indicated time points using an ECG machine that automatically calculates the heart rate. Baseline was defined as the latest pre-dose assessment, including those from unscheduled visits. Change from Baseline was defined as any visit value minus Baseline value.

  11. Part 1: Change From Baseline in PR Interval, QRS, QT Interval, and QTcF Interval as ECG Parameters [ Time Frame: Baseline (Day -1) and 1, 2, 4, 6, 8, 12, 24, 48, 72 hours on Day 1 ]
    Single and triplicate 12-lead ECG's were obtained at least 5 minutes apart in the supine position after 10 minutes of rest at indicated time points using an ECG machine that automatically calculates measures PR, QRS, QT and QTcF intervals. Baseline was defined as the latest pre-dose assessment, including those from unscheduled visits. Change from Baseline was defined as any visit value minus Baseline value.

  12. Part 1: Tlag Following Administration of GSK2838232 Tablet and Capsule Formulation in Fed State and Tablet Formulation in Fasted State [ Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96, and 120 hours post-dose in treatment periods 1, 2 and 3 of Part 1 ]
    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232 given as capsule and tablet formulation in fed state as well as tablet formulation in fasted state. Tlag is a time delay between drug administration and first observed concentration. Pharmacokinetic parameters were determined using standard non-compartmental methods.

  13. Part 1: Tmax Following Administration of GSK2838232 Tablet and Capsule Formulation in Fed State and Tablet Formulation in Fasted State [ Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96, and 120 hours post-dose in treatment periods 1, 2 and 3 of Part 1 ]
    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232 given as capsule and tablet formulation in fed state as well as tablet formulation in fasted state. Pharmacokinetic parameters were determined using standard non-compartmental methods.

  14. Part 1: T1/2 Following Administration of GSK2838232 Tablet and Capsule Formulation in Fed State and Tablet Formulation in Fasted State [ Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96, and 120 hours post-dose in treatment periods 1, 2 and 3 of Part 1 ]
    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232 given as capsule and tablet formulation in fed state as well as tablet formulation in fasted state. Pharmacokinetic parameters were determined using standard non-compartmental methods.

  15. Part 1: Tlast Following Administration of GSK2838232 Tablet and Capsule Formulation in Fed State and Tablet Formulation in Fasted State [ Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96, and 120 hours post-dose in treatment periods 1, 2 and 3 of Part 1 ]
    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232 given as capsule and tablet formulation in fed state as well as tablet formulation in fasted state. Pharmacokinetic parameters were determined using standard non-compartmental methods.

  16. Part 1: Plasma Drug Concentration at 24 Hours (C24) Following Administration of GSK2838232 Tablet and Capsule Formulation in Fed State and Tablet Formulation in Fasted State [ Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96, and 120 hours post-dose in treatment periods 1, 2 and 3 of Part 1 ]
    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232 given as capsule and tablet formulation in fed state as well as tablet formulation in fasted state. Pharmacokinetic parameters were determined using standard non-compartmental methods.

  17. Part 1: AUC(0-t) Following Administration of GSK2838232 Tablet and Capsule Formulation in Fed State and Tablet Formulation in Fasted State [ Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96, and 120 hours post-dose in treatment periods 1, 2 and 3 of Part 1 ]
    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK2838232 given as capsule and tablet formulation in fed state as well as tablet formulation in fasted state. Pharmacokinetic parameters were determined using standard non-compartmental methods.

  18. Part 2: Slope of Pre-dose Concentration of GSK2838232 Administered as Non-boosted Once-daily Doses of a Tablet Formulation to Assess Achievement of Steady State [ Time Frame: Pre-dose on Day 3, Day 4, Day 5, Day 6, Day 7, Day 8, Day 9, Day 10 and Day 11 in Part 2 ]
    Blood sample were collected at indicated time points to assess pre-dose concentration of GSK2838232 when administered as non-boosted once-daily doses of a tablet formulation for 11 days in Part 2. Slope and 90 percent confidence interval have been presented.

  19. Part 2: Accumulation Ratio Calculated From AUC(0-tau) Following Administration of GSK2838232 as Non-boosted Once-daily Doses of a Tablet Formulation [ Time Frame: Pre-dose, 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12 and 24 hours post-dose on Day 1; Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96 and 120 hours post-dose on Day 11 in Part 2 ]
    Blood sample were collected at indicated time points to calculate accumulation ratio from AUC(0-tau) following administration of GSK2838232 as non-boosted once-daily doses of a tablet formulation. Accumulation ratio of GSK2838232 was evaluated by Day 11, AUC (0-tau) divided by Day 1, AUC (0-tau).

  20. Part 2: Accumulation Ratio Calculated From Cmax Following Administration of GSK2838232 as Non-boosted Once-daily Doses of a Tablet Formulation [ Time Frame: Pre-dose, 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12 and 24 hours post-dose on Day 1; Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96 and 120 hours post-dose on Day 11 in Part 2 ]
    Blood sample were collected at indicated time points to calculate accumulation ratio from Cmax following administration of GSK2838232 as non-boosted once-daily doses of a tablet formulation. Accumulation ratio of GSK2838232 was evaluated by Day 11, Cmax divided by Day 1, Cmax.

  21. Part 2: Accumulation Ratio Calculated From Ctau Following Administration of GSK2838232 as Non-boosted Once-daily Doses of a Tablet Formulation [ Time Frame: Pre-dose, 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12 and 24 hours post-dose on Day 1; Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96 and 120 hours post-dose on Day 11 in Part 2 ]
    Blood sample were collected at indicated time points to calculate accumulation ratio from Ctau following administration of GSK2838232 as non-boosted once-daily doses of a tablet formulation. Accumulation ratio of GSK2838232 was evaluated by Day 11, Ctau divided by Day 1, Ctau.



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, and 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.
  • A creatinine clearance (CLcr) > 80 milliliter per minute (mL/min) as determined by Cockcroft-Gault equation: CLcr = (140 minus age) multiplied by weight divided by (72 multiplied by serum creatinine) (times 0.85 if female) where age is in years, weight in kilogram (kg), and serum creatinine is in units of milligram per deciliter (mg/dL).
  • Body weight >=50.0 kg (110 pounds [lbs.]) for men and >=45.0 kg (99 lbs) for women and body mass index (BMI) within the range 18.5 to 31.0 kg/meter (m)^2 (inclusive).
  • Males or females.
  • A female subject is eligible to participate if she is not pregnant (as confirmed by a negative serum human chorionic gonadotrophin [hCG] test), not lactating, and of non-reproductive potential which is defined as:

Reproductive potential:

There is no definitive drug-drug interaction (DDI) information with GSK2838232 and an interaction with oral contraceptives is possible, so other (barrier, inter-uterine device etc.) methods of contraception will be required. Females of reproductive potential may only be enrolled if they are using two forms of complementary contraception, which must include at least one barrier method. They will be counseled on safer sex practices. Fertile females, who have an established, long-term lifestyle of sexual abstinence, or only same sex partners, require no other means of birth control.

Non-reproductive potential:

  • Pre-menopausal females with one of the following: Documented tubal ligation; documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion; hysterectomy; documented Bilateral Oophorectomy.
  • Postmenopausal defined as 12 months of spontaneous amenorrhea in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels consistent with menopause. Females on hormone replacement therapy (HRT) must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment.

    • 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 one week after the last dose of study medication.
  • Vasectomy with documentation of azoospermia.
  • Male condom plus partner use of one of the contraceptive options below: Contraceptive subdermal implant with a <1 percent rate of failure per year; intrauterine device or intrauterine system with a <1 percent rate of failure per year; oral contraceptive, either combined or progestogen alone or injectable progestogen; contraceptive vaginal ring; percutaneous contraceptive patches.

    • Capable of giving signed informed consent.

Exclusion Criteria:

  • ALT >1.5 times upper limit of normal (ULN)
  • Bilirubin >1.5 times ULN (isolated bilirubin >1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin <35 percent).
  • Current or chronic history of liver disease, or known hepatic or biliary abnormalities.
  • Subjects who have asthma or a history of asthma.
  • Medical history of cardiac arrhythmias or cardiac disease or a family or personal history of long QT syndrome.
  • Unable to refrain from the use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and GlaxoSmithKline medical monitor, the medication will not interfere with the study procedures or compromise participant safety.
  • History of regular alcohol consumption (within 6 months prior to screening or unable to refrain from alcohol use from 5 days prior to admission through the last blood sample collected) defined as:

    • For United States sites: an average weekly intake of >14 drinks for males or >7 drinks for females. One drink is equivalent to 12 gram of alcohol: 12 ounces (360 mL) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.

  • Regular use of tobacco- or nicotine- containing products within 6 months prior to screening. Unable to refrain from smoking from the Screening Visit through the last blood sample collected. As confirmed by a urine cotinine test.
  • 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), or positive hepatitis C virus (HCV) test result at screening or within 3 months prior to first dose of study treatment.
  • Screening or Baseline cardiac troponin I greater than the 99 percent cutoff (>0.045 nanogram [ng]/mL by the Dimension Vista cTnI assay) for a given assay.
  • A positive pre-study drug/alcohol screen.
  • A positive test for human immunodeficiency virus (HIV) antibody.
  • Where participation in the study would result in donation of blood or blood products in excess of 500 mL within 56 days.
  • 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: 30 days, 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.
  • Exclusion Criteria for 24-hour Screening Holter:

    • Any symptomatic arrhythmia (except isolated extra systoles).
    • Sustained cardiac arrhythmias (such as atrial fibrillation or flutter, supraventricular tachycardia (>= 10 consecutive beats), complete heart block).
    • Non-sustained or sustained ventricular tachycardia (defined as >=3 consecutive ventricular ectopic beats).
    • Any conduction abnormality (including but not specific to left or right incomplete or complete bundle branch block, atrioventricular (AV) block [2nd degree or higher], Wolff Parkinson White (WPW) syndrome etc.).
    • Sinus Pauses >3 seconds.
    • 300 or more supraventricular ectopic beats in 24 hours.
    • 250 or more ventricular ectopic beats in 24 hours.
  • Any clinically significant abnormal echocardiogram finding.
  • Exclusion criteria for screening ECG (a single repeat is allowed for eligibility determination):

    • Heart rate <45 or >100 beats per minute (bpm) for males; <50 or >100 bpm for females
    • PR interval <120 or >220 milliseconds (msec)
    • QRS duration <70 or >120 msec
    • QTc interval (Fridericia's) >450 msec
    • Evidence of previous myocardial infarction (does not include ST segment changes associated with re-polarization).
    • Any conduction abnormality (including but not specific to left or right complete bundle branch block, AV block [2nd degree or higher], WPW syndrome).
    • Sinus Pauses >3 seconds.
    • Any significant arrhythmia which, in the opinion of the Investigator or GSK medical monitor, will interfere with the safety for the individual subject.
    • Non-sustained or sustained ventricular tachycardia (>=3 consecutive ventricular ectopic beats).

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): NCT03234036


Locations
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United States, Maryland
GSK Investigational Site
Baltimore, Maryland, United States, 21225
Sponsors and Collaborators
GlaxoSmithKline
Investigators
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Study Director: GSK Clinical Trials GlaxoSmithKline
  Study Documents (Full-Text)

Documents provided by GlaxoSmithKline:
Study Protocol  [PDF] July 18, 2017
Statistical Analysis Plan  [PDF] December 7, 2017

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Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT03234036    
Other Study ID Numbers: 205820
First Posted: July 31, 2017    Key Record Dates
Results First Posted: March 7, 2019
Last Update Posted: March 7, 2019
Last Verified: November 2018

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by GlaxoSmithKline:
GSK2838232
safety
food effect
capsule
healthy
PK
tablet
Additional relevant MeSH terms:
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Acquired Immunodeficiency Syndrome
HIV Infections
Immunologic Deficiency Syndromes
Immune System Diseases
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Slow Virus Diseases
Ritonavir
GSK2838232
HIV Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors