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Study to Evaluate the Pharmacokinetic (PK) Interactions Between GSK3640254 and Dolutegravir (DTG)

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ClinicalTrials.gov Identifier: NCT03816696
Recruitment Status : Completed
First Posted : January 25, 2019
Results First Posted : March 19, 2020
Last Update Posted : March 19, 2020
Sponsor:
Information provided by (Responsible Party):
ViiV Healthcare

Brief Summary:
This is an open-label, single-sequence, two-way drug interaction study to investigate the PK, safety and tolerability of GSK3640254 and DTG when administered alone or in combination in healthy subjects. Treatment of human immunodeficiency virus (HIV) infection frequently involves combination therapy. Data from this study will contribute to dosing recommendations when GSK3640254 and DTG are given in combination. The study will consist of a Screening period and 3 sequential treatment periods. Subjects will be administered DTG 50 milligrams (mg) once daily (QD) in Period 1 followed by GSK3640254 200 mg QD in Period 2. There will be a washout period of 4 days between Periods 1 and 2. In Period 3, subjects will be co-administered DTG 50 mg QD and GSK3640254 200 mg QD. The total duration of the study will be approximately 55 days, including Screening.

Condition or disease Intervention/treatment Phase
HIV Infections Drug: GSK3640254 Drug: DTG Phase 1

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 16 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-Label Two-way Interaction Clinical Trial to Evaluate the Pharmacokinetic Interactions Between GSK3640254 and Dolutegravir in Healthy Subjects
Actual Study Start Date : January 23, 2019
Actual Primary Completion Date : March 30, 2019
Actual Study Completion Date : April 10, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: DTG followed by GSK3640254 followed by DTG+GSK3640254
Subjects will receive DTG 50 mg QD on Days 1 through 5 in Period 1 followed by a wash-out period of 4 days. Subjects will then receive GSK3640254 200 mg QD on Days 1 through 7 in Period 2 followed by co-administration of DTG 50 mg QD with GSK3640254 200 mg QD on Days 1 through 7 in Period 3.
Drug: GSK3640254
GSK3640254 will be available as 100 mg capsules. Subjects will be administered GSK3640254 200 mg QD via the oral route.

Drug: DTG
DTG will be available as 50 mg tablets. Subjects will be administered DTG 50 mg QD via the oral route.




Primary Outcome Measures :
  1. Period 1: Area Under the Plasma Concentration-time Curve From Time 0 to the End of the Dosing (AUC[0 to Tau]) of Dolutegravir for Dolutegravir Arm [ Time Frame: Day 5: Pre-dose, 1, 1.5, 2, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of dolutegravir. The pharmacokinetic parameters were calculated by standard non-compartmental analysis. Pharmacokinetic Parameter Population consisted of all participants who underwent plasma pharmacokinetic sampling and had evaluable pharmacokinetic parameters estimated.

  2. Period 3: AUC(0 to Tau) of Dolutegravir for Dolutegravir + GSK3640254 Arm [ Time Frame: Day 7: Pre-dose, 1, 1.5, 2, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of dolutegravir. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.

  3. Period 1: Maximum Observed Concentration (Cmax) of Dolutegravir for Dolutegravir Arm [ Time Frame: Day 5: Pre-dose, 1, 1.5, 2, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of dolutegravir. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.

  4. Period 3: Cmax of Dolutegravir for Dolutegravir + GSK3640254 Arm [ Time Frame: Day 7: Pre-dose, 1, 1.5, 2, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of dolutegravir. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.

  5. Period 1: Plasma Concentration at the End of the Dosing Interval (Ctau) of Dolutegravir for Dolutegravir Arm [ Time Frame: Day 5: Pre-dose, 1, 1.5, 2, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of dolutegravir. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.

  6. Period 3: Ctau of Dolutegravir for Dolutegravir + GSK3640254 Arm [ Time Frame: Day 7: Pre-dose, 1, 1.5, 2, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of dolutegravir. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.

  7. Period 2: AUC(0 to Tau) of GSK3640254 for GSK3640254 Arm [ Time Frame: Day 7: Pre-dose, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of GSK3640254. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.

  8. Period 3: AUC(0 to Tau) of GSK3640254 for Dolutegravir + GSK3640254 Arm [ Time Frame: Day 7: Pre-dose, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of GSK3640254. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.

  9. Period 2: Cmax of GSK3640254 for GSK3640254 Arm [ Time Frame: Day 7: Pre-dose, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of GSK3640254. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.

  10. Period 3: Cmax of GSK3640254 for Dolutegravir + GSK3640254 Arm [ Time Frame: Day 7: Pre-dose, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of GSK3640254. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.

  11. Period 2: Ctau of GSK3640254 for GSK3640254 Arm [ Time Frame: Day 7: Pre-dose, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of GSK3640254. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.

  12. Period 3: Ctau of GSK3640254 for Dolutegravir + GSK3640254 Arm [ Time Frame: Day 7: Pre-dose, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of GSK3640254. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.


Secondary Outcome Measures :
  1. Number of Participants With Non-serious Adverse Events (Non-SAEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to Day 27 ]
    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, at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent disability/incapacity; is a congenital anomaly/birth defect; and other important medical events which may require medical or surgical intervention. Safety Population consisted of all participants who received at least 1 dose of study medication.

  2. Period 1: Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelet Count [ Time Frame: Baseline (Day -1) and at Day 9 ]
    Blood samples were collected to analyze the hematology parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils and Platelet count. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first treatment in Period 1. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  3. Period 2: Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelet Count [ Time Frame: Baseline (Period 1 Day 9) and at Day 7 ]
    Blood samples were collected to analyze the hematology parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils and Platelet count. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first treatment in Period 2. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  4. Period 3: Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelet Count [ Time Frame: Baseline (Period 2 Day 7) and at Days 4, 7 and 10 ]
    Blood samples were collected to analyze the hematology parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils and Platelet count. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first treatment in Period 3. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  5. Period 1: Change From Baseline in Hematology Parameter: Hemoglobin [ Time Frame: Baseline (Day -1) and at Day 9 ]
    Blood samples were collected to analyze the hematology parameter: hemoglobin. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first treatment in Period 1. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  6. Period 2: Change From Baseline in Hematology Parameter: Hemoglobin [ Time Frame: Baseline (Period 1 Day 9) and at Day 7 ]
    Blood samples were collected to analyze the hematology parameter: hemoglobin. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first treatment in Period 2. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  7. Period 3: Change From Baseline in Hematology Parameter: Hemoglobin [ Time Frame: Baseline (Period 2 Day 7) and at Days 4, 7 and 10 ]
    Blood samples were collected to analyze the hematology parameter: hemoglobin. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first treatment in Period 3. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  8. Period 1: Change From Baseline in Hematology Parameter: Hematocrit [ Time Frame: Baseline (Day -1) and at Day 9 ]
    Blood samples were collected to analyze the hematology parameter: hematocrit. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first treatment in Period 1. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  9. Period 2: Change From Baseline in Hematology Parameter: Hematocrit [ Time Frame: Baseline (Period 1 Day 9) and at Day 7 ]
    Blood samples were collected to analyze the hematology parameter: hematocrit. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first treatment in Period 2. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  10. Period 3: Change From Baseline in Hematology Parameter: Hematocrit [ Time Frame: Baseline (Period 2 Day 7) and at Days 4, 7 and 10 ]
    Blood samples were collected to analyze the hematology parameter: hematocrit. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first treatment in Period 3. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  11. Period 1: Change From Baseline in Hematology Parameter: Erythrocytes [ Time Frame: Baseline (Day -1) and at Day 9 ]
    Blood samples were collected to analyze the hematology parameter: erythrocytes. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first treatment in Period 1. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  12. Period 2: Change From Baseline in Hematology Parameter: Erythrocytes [ Time Frame: Baseline (Period 1 Day 9) and at Day 7 ]
    Blood samples were collected to analyze the hematology parameter: erythrocytes. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first treatment in Period 2. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  13. Period 3: Change From Baseline in Hematology Parameter: Erythrocytes [ Time Frame: Baseline (Period 2 Day 7) and at Days 4, 7 and 10 ]
    Blood samples were collected to analyze the hematology parameter: erythrocytes. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first treatment in Period 3. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  14. Period 1: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Volume [ Time Frame: Baseline (Day -1) and at Day 9 ]
    Blood samples were collected to analyze the hematology parameter: erythrocytes mean corpuscular volume. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first treatment in Period 1. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  15. Period 2: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Volume [ Time Frame: Baseline (Period 1 Day 9) and at Day 7 ]
    Blood samples were collected to analyze the hematology parameter: erythrocytes mean corpuscular volume. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first treatment in Period 2. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  16. Period 3: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Volume [ Time Frame: Baseline (Period 2 Day 7) and at Days 4, 7 and 10 ]
    Blood samples were collected to analyze the hematology parameter: erythrocytes mean corpuscular volume. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first treatment in Period 3. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  17. Period 1: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin [ Time Frame: Baseline (Day -1) and at Day 9 ]
    Blood samples were collected to analyze the hematology parameter: erythrocytes mean corpuscular hemoglobin. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first treatment in Period 1. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  18. Period 2: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin [ Time Frame: Baseline (Period 1 Day 9) and at Day 7 ]
    Blood samples were collected to analyze the hematology parameter: erythrocytes mean corpuscular hemoglobin. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first treatment in Period 2. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  19. Period 3: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin [ Time Frame: Baseline (Period 2 Day 7) and at Days 4, 7 and 10 ]
    Blood samples were collected to analyze the hematology parameter: erythrocytes mean corpuscular hemoglobin. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first treatment in Period 3. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  20. Period 1: Change From Baseline in Chemistry Parameters: Glucose, Cholesterol, Triglycerides, Anion Gap, Calcium, Carbon Dioxide, Chloride, Phosphate, Potassium, Sodium, Blood Urea Nitrogen [ Time Frame: Baseline (Day -1) and at Day 9 ]
    Blood samples were collected to analyze the chemistry parameters: glucose, cholesterol, triglycerides, anion gap, calcium, carbon dioxide, chloride, phosphate, potassium, sodium and blood urea nitrogen. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first treatment in Period 1. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  21. Period 2: Change From Baseline in Chemistry Parameters: Glucose, Cholesterol, Triglycerides, Anion Gap, Calcium, Carbon Dioxide, Chloride, Phosphate, Potassium, Sodium, Blood Urea Nitrogen [ Time Frame: Baseline (Period 1 Day 9) and at Day 7 ]
    Blood samples were collected to analyze the chemistry parameters: glucose, cholesterol, triglycerides, anion gap, calcium, carbon dioxide, chloride, phosphate, potassium, sodium and blood urea nitrogen. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first treatment in Period 2. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  22. Period 3: Change From Baseline in Chemistry Parameters: Glucose, Cholesterol, Triglycerides, Anion Gap, Calcium, Carbon Dioxide, Chloride, Phosphate, Potassium, Sodium, Blood Urea Nitrogen [ Time Frame: Baseline (Period 2 Day 7) and at Days 4, 7 and 10 ]
    Blood samples were collected to analyze the chemistry parameters: glucose, cholesterol, triglycerides, anion gap, calcium, carbon dioxide, chloride, phosphate, potassium, sodium and blood urea nitrogen. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first treatment in Period 3. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  23. Period 1: Change From Baseline in Chemistry Parameters: Creatine Kinase, Lactate Dehydrogenase, Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST), Gamma-glutamyl Transferase [ Time Frame: Baseline (Day -1) and at Day 9 ]
    Blood samples were collected to analyze the chemistry parameters: creatine kinase, lactate dehydrogenase, ALT, ALP, AST and gamma-glutamyl transferase. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first treatment in Period 1. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  24. Period 2: Change From Baseline in Chemistry Parameters: Creatine Kinase, Lactate Dehydrogenase, ALT, ALP, AST, Gamma-glutamyl Transferase [ Time Frame: Baseline (Period 1 Day 9) and at Day 7 ]
    Blood samples were collected to analyze the chemistry parameters: creatine kinase, lactate dehydrogenase, ALT, ALP, AST and gamma-glutamyl transferase. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first treatment in Period 2. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  25. Period 3: Change From Baseline in Chemistry Parameters: Creatine Kinase, Lactate Dehydrogenase, ALT, ALP, AST, Gamma-glutamyl Transferase [ Time Frame: Baseline (Period 2 Day 7) and at Days 4, 7 and 10 ]
    Blood samples were collected to analyze the chemistry parameters: creatine kinase, lactate dehydrogenase, ALT, ALP, AST and gamma-glutamyl transferase. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first treatment in Period 3. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  26. Period 1: Change From Baseline in Chemistry Parameters: Urate, Creatinine, Bilirubin, Direct Bilirubin [ Time Frame: Baseline (Day -1) and at Day 9 ]
    Blood samples were collected to analyze the chemistry parameters: urate, creatinine, bilirubin and direct bilirubin. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first treatment in Period 1. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  27. Period 2: Change From Baseline in Chemistry Parameters: Urate, Creatinine, Bilirubin, Direct Bilirubin [ Time Frame: Baseline (Period 1 Day 9) and at Day 7 ]
    Blood samples were collected to analyze the chemistry parameters: urate, creatinine, bilirubin and direct bilirubin. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first treatment in Period 2. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  28. Period 3: Change From Baseline in Chemistry Parameters: Urate, Creatinine, Bilirubin, Direct Bilirubin [ Time Frame: Baseline (Period 2 Day 7) and at Days 4, 7 and 10 ]
    Blood samples were collected to analyze the chemistry parameters: urate, creatinine, bilirubin and direct bilirubin. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first treatment in Period 3. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  29. Period 1: Change From Baseline in Chemistry Parameters: Albumin, Globulin, Protein [ Time Frame: Baseline (Day -1) and at Day 9 ]
    Blood samples were collected to analyze the chemistry parameters: albumin, globulin and protein. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first treatment in Period 1. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  30. Period 2: Change From Baseline in Chemistry Parameters: Albumin, Globulin, Protein [ Time Frame: Baseline (Period 1 Day 9) and at Day 7 ]
    Blood samples were collected to analyze the chemistry parameters: albumin, globulin and protein. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first treatment in Period 2. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  31. Period 3: Change From Baseline in Chemistry Parameters: Albumin, Globulin, Protein [ Time Frame: Baseline (Period 2 Day 7) and at Days 4, 7 and 10 ]
    Blood samples were collected to analyze the chemistry parameters: albumin, globulin and protein. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first treatment in Period 3. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  32. Period 1: Change From Baseline in Chemistry Parameters: Amylase, Lipase [ Time Frame: Baseline (Day -1) and at Day 9 ]
    Blood samples were collected to analyze the chemistry parameters: amylase and lipase. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first treatment in Period 1. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  33. Period 2: Change From Baseline in Chemistry Parameters: Amylase, Lipase [ Time Frame: Baseline (Period 1 Day 9) and at Day 7 ]
    Blood samples were collected to analyze the chemistry parameters: amylase and lipase. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first treatment in Period 2. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  34. Period 3: Change From Baseline in Chemistry Parameters: Amylase, Lipase [ Time Frame: Baseline (Period 2 Day 7) and at Days 4, 7 and 10 ]
    Blood samples were collected to analyze the chemistry parameters: amylase and lipase. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first treatment in Period 3. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  35. Period 1: Change From Baseline in Urinalysis Parameter: Specific Gravity [ Time Frame: Baseline (Day -1) and at Day 9 ]
    Urine samples were collected to analyze the urinalysis parameter: specific gravity. 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. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first treatment in Period 1. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  36. Period 2: Change From Baseline in Urinalysis Parameter: Specific Gravity [ Time Frame: Baseline (Period 1 Day 9) and at Day 7 ]
    Urine samples were collected to analyze the urinalysis parameter: specific gravity. 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. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first treatment in Period 2. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  37. Period 3: Change From Baseline in Urinalysis Parameter: Specific Gravity [ Time Frame: Baseline (Period 2 Day 7) and at Days 4, 7 and 10 ]
    Urine samples were collected to analyze the urinalysis parameter: specific gravity. 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. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first treatment in Period 3. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  38. Period 1: Change From Baseline in Urinalysis Parameter: Urobilinogen [ Time Frame: Baseline (Day -1) and at Day 9 ]
    Urine samples were collected to analyze the urinalysis parameter: urobilinogen. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first treatment in Period 1. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  39. Period 2: Change From Baseline in Urinalysis Parameter: Urobilinogen [ Time Frame: Baseline (Period 1 Day 9) and at Day 7 ]
    Urine samples were collected to analyze the urinalysis parameter: urobilinogen. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first treatment in Period 2. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  40. Period 3: Change From Baseline in Urinalysis Parameter: Urobilinogen [ Time Frame: Baseline (Period 2 Day 7) and at Days 4, 7 and 10 ]
    Urine samples were collected to analyze the urinalysis parameter: urobilinogen. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first treatment in Period 3. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  41. Period 1: Change From Baseline in Urinalysis Parameter: Potential of Hydrogen (pH) [ Time Frame: Baseline (Day -1) and at Day 9 ]
    Urine samples were collected to analyze the urinalysis parameter: pH. 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). Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first treatment in Period 1. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  42. Period 2: Change From Baseline in Urinalysis Parameter: pH [ Time Frame: Baseline (Period 1 Day 9) and at Day 7 ]
    Urine samples were collected to analyze the urinalysis parameter: pH. 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). Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first treatment in Period 2. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  43. Period 3: Change From Baseline in Urinalysis Parameter: pH [ Time Frame: Baseline (Period 2 Day 7) and at Days 4, 7 and 10 ]
    Urine samples were collected to analyze the urinalysis parameter: pH. 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). Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first treatment in Period 3. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  44. Period 1: Number of Participants With Urinalysis Dipstick Results [ Time Frame: Day 9 ]
    Urine samples were collected at indicated time points to analyze parameters including glucose, protein, occult blood, ketones, nitrite, bilirubin and leukocyte esterase levels by dipstick. The dipstick test gives results in a semi-quantitative manner, and results for urinalysis parameters can be read as negative, Trace, 1+ (low concentrations present) and 2+ (moderate concentrations present) indicating proportional concentrations in the urine sample.

  45. Period 2: Number of Participants With Urinalysis Dipstick Results [ Time Frame: Day 7 ]
    Urine samples were collected at indicated time points to analyze parameters including glucose, protein, occult blood, ketones, nitrite, bilirubin and leukocyte esterase levels by dipstick. The dipstick test gives results in a semi-quantitative manner, and results for urinalysis parameters can be read as negative, Trace, 1+ (low concentrations present), and 2+ (moderate concentrations present) indicating proportional concentrations in the urine sample.

  46. Period 3: Number of Participants With Urinalysis Dipstick Results [ Time Frame: Days 4, 7 and 10 ]
    Urine samples were collected at indicated time points to analyze parameters including glucose, protein, occult blood, ketones, nitrite, bilirubin and leukocyte esterase levels by dipstick. The dipstick test gives results in a semi-quantitative manner, and results for urinalysis parameters can be read as negative, Trace, 1+ (low concentrations present), and 2+ (moderate concentrations present)indicating proportional concentrations in the urine sample.

  47. Period 1: Change From Baseline in PR Interval, QRS Duration, QT Interval, Fridericia QT Correction Formula (QTcF), Bazett's QT Correction Formula (QTcB) [ Time Frame: Baseline, Day 1: 2 hours, 4 hours; Day 5: Pre-dose, 2 hours and 4 hours ]
    Twelve-lead electrocardiograms (ECG) were obtained to measure PR Interval, QRS Duration, QT Interval, QTcF Interval and QTcB Interval. Twelve-lead ECGs were performed with the participant in a supine or semi-supine position after a rest of at least 10 minutes. Baseline was defined as the average of the triplicate pre-dose assessments on Day 1 of Period 1. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  48. Period 2: Change From Baseline in PR Interval, QRS Duration, QT Interval, QTcF, QTcB [ Time Frame: Baseline; Day 1: 2 hours, 4 hours; Day 5: Pre-dose, 2 hours and 4 hours ]
    Twelve-lead ECG were obtained to measure PR Interval, QRS Duration, QT Interval, QTcF Interval and QTcB Interval. Twelve-lead ECGs were performed with the participant in a supine or semi-supine position after a rest of at least 10 minutes. Baseline was defined as the average of the triplicate pre-dose assessments on Day 1 of Period 2. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  49. Period 3: Change From Baseline in PR Interval, QRS Duration, QT Interval, QTcF, QTcB [ Time Frame: Baseline; Day 1: 2 hours, 4 hours; Days 4, 5 and 7: Pre-dose, 2 hours and 4 hours; Day 10 ]
    Twelve-lead ECG were obtained to measure PR Interval, QRS Duration, QT Interval, QTcF Interval and QTcB Interval. Twelve-lead ECGs were performed with the participant in a supine or semi-supine position after a rest of at least 10 minutes. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, in Period 3. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  50. Period 1: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) [ Time Frame: Baseline (Day 1, Pre-dose), Days 2, 3, 4 and 5 ]
    SBP and DBP were measured in the semi-recumbent position with a completely automated device. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, in Period 1. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  51. Period 2: Change From Baseline in SBP and DBP [ Time Frame: Baseline (Day 1, Pre-dose), Days 2, 3, 4, 5, 6 and 7 ]
    SBP and DBP were measured in the semi-recumbent position with a completely automated device. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, in Period 2. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  52. Period 3: Change From Baseline in SBP and DBP [ Time Frame: Baseline (Day 1, Pre-dose), Days 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11 ]
    SBP and DBP were measured in the semi-recumbent position with a completely automated device. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, in Period 3. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  53. Period 1: Change From Baseline in Pulse Rate [ Time Frame: Baseline (Day 1, Pre-dose), Days 2, 3, 4 and 5 ]
    Pulse rate was measured in the semi-recumbent position with a completely automated device. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, in Period 1. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  54. Period 2: Change From Baseline in Pulse Rate [ Time Frame: Baseline (Day 1, Pre-dose), Days 2, 3, 4, 5, 6 and 7 ]
    Pulse rate was measured in the semi-recumbent position with a completely automated device. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, in Period 2. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  55. Period 3: Change From Baseline in Pulse Rate [ Time Frame: Baseline (Day 1, Pre-dose), Days 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11 ]
    Pulse rate was measured in the semi-recumbent position with a completely automated device. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, in Period 3. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  56. Period 1: Change From Baseline in Respiratory Rate [ Time Frame: Baseline (Day 1, Pre-dose), Days 2, 3, 4 and 5 ]
    Respiratory rate was measured in the semi-recumbent position after at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, in Period 1. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  57. Period 2: Change From Baseline in Respiratory Rate [ Time Frame: Baseline (Day 1, Pre-dose), Days 2, 3, 4, 5, 6 and 7 ]
    Respiratory rate was measured in the semi-recumbent position after at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, in Period 2. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  58. Period 3: Change From Baseline in Respiratory Rate [ Time Frame: Baseline (Day 1, Pre-dose), Days 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11 ]
    Respiratory rate was measured in the semi-recumbent position after at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, in Period 3. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  59. Period 1: Change From Baseline in Body Temperature [ Time Frame: Baseline (Day 1, Pre-dose), Days 2, 3, 4 and 5 ]
    Body temperature was measured in the semi-recumbent position after at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, in Period 1. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  60. Period 2: Change From Baseline in Body Temperature [ Time Frame: Baseline (Day 1, Pre-dose), Days 2, 3, 4, 5, 6 and 7 ]
    Body temperature was measured in the semi-recumbent position after at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, in Period 2. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  61. Period 3: Change From Baseline in Body Temperature [ Time Frame: Baseline (Day 1, Pre-dose), Days 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11 ]
    Body temperature was measured in the semi-recumbent position after at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, in Period 3. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.

  62. Period 1: Absolute Values for Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelet Count [ Time Frame: Day 9 ]
    Blood samples were collected to analyze the hematology parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils and Platelet count.

  63. Period 2: Absolute Values for Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelet Count [ Time Frame: Day 7 ]
    Blood samples were collected to analyze the hematology parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils and Platelet count.

  64. Period 3: Absolute Values for Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelet Count [ Time Frame: Days 4, 7 and 10 ]
    Blood samples were collected to analyze the hematology parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils and Platelet count.

  65. Period 1: Absolute Values for Hematology Parameter: Hemoglobin [ Time Frame: Day 9 ]
    Blood samples were collected to analyze the hematology parameter: hemoglobin.

  66. Period 2: Absolute Values for Hematology Parameter: Hemoglobin [ Time Frame: Day 7 ]
    Blood samples were collected to analyze the hematology parameter: hemoglobin.

  67. Period 3: Absolute Values for Hematology Parameter: Hemoglobin [ Time Frame: Days 4, 7 and 10 ]
    Blood samples were collected to analyze the hematology parameter: hemoglobin.

  68. Period 1: Absolute Values for Hematology Parameter: Hematocrit [ Time Frame: Day 9 ]
    Blood samples were collected to analyze the hematology parameter: hematocrit.

  69. Period 2: Absolute Values for Hematology Parameter: Hematocrit [ Time Frame: Day 7 ]
    Blood samples were collected to analyze the hematology parameter: hematocrit.

  70. Period 3: Absolute Values for Hematology Parameter: Hematocrit [ Time Frame: Days 4, 7 and 10 ]
    Blood samples were collected to analyze the hematology parameter: hematocrit.

  71. Period 1: Absolute Values for Hematology Parameter: Erythrocytes [ Time Frame: Day 9 ]
    Blood samples were collected to analyze the hematology parameter: erythrocytes.

  72. Period 2: Absolute Values for Hematology Parameter: Erythrocytes [ Time Frame: Day 7 ]
    Blood samples were collected to analyze the hematology parameter: erythrocytes.

  73. Period 3: Absolute Values for Hematology Parameter: Erythrocytes [ Time Frame: Days 4, 7 and 10 ]
    Blood samples were collected to analyze the hematology parameter: erythrocytes.

  74. Period 1: Absolute Values for Hematology Parameter: Erythrocytes Mean Corpuscular Volume [ Time Frame: Day 9 ]
    Blood samples were collected to analyze the hematology parameter: erythrocytes mean corpuscular volume.

  75. Period 2: Absolute Values for Hematology Parameter: Erythrocytes Mean Corpuscular Volume [ Time Frame: Day 7 ]
    Blood samples were collected to analyze the hematology parameter: erythrocytes mean corpuscular volume.

  76. Period 3: Absolute Values for Hematology Parameter: Erythrocytes Mean Corpuscular Volume [ Time Frame: Days 4, 7 and 10 ]
    Blood samples were collected to analyze the hematology parameter: erythrocytes mean corpuscular volume.

  77. Period 1: Absolute Values for Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin [ Time Frame: Day 9 ]
    Blood samples were collected to analyze the hematology parameter: erythrocytes mean corpuscular hemoglobin.

  78. Period 2: Absolute Values for Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin [ Time Frame: Day 7 ]
    Blood samples were collected to analyze the hematology parameter: erythrocytes mean corpuscular hemoglobin.

  79. Period 3: Absolute Values for Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin [ Time Frame: Days 4, 7 and 10 ]
    Blood samples were collected to analyze the hematology parameter: erythrocytes mean corpuscular hemoglobin.

  80. Period 1: Absolute Values for Chemistry Parameters: Glucose, Cholesterol, Triglycerides, Anion Gap, Calcium, Carbon Dioxide, Chloride, Phosphate, Potassium, Sodium, Blood Urea Nitrogen [ Time Frame: Day 9 ]
    Blood samples were collected to analyze the chemistry parameters: glucose, cholesterol, triglycerides, anion gap, calcium, carbon dioxide, chloride, phosphate, potassium, sodium and blood urea nitrogen.

  81. Period 2: Absolute Values for Chemistry Parameters: Glucose, Cholesterol, Triglycerides, Anion Gap, Calcium, Carbon Dioxide, Chloride, Phosphate, Potassium, Sodium, Blood Urea Nitrogen [ Time Frame: Day 7 ]
    Blood samples were collected to analyze the chemistry parameters: glucose, cholesterol, triglycerides, anion gap, calcium, carbon dioxide, chloride, phosphate, potassium, sodium and blood urea nitrogen.

  82. Period 3: Absolute Values for Chemistry Parameters: Glucose, Cholesterol, Triglycerides, Anion Gap, Calcium, Carbon Dioxide, Chloride, Phosphate, Potassium, Sodium, Blood Urea Nitrogen [ Time Frame: Days 4, 7 and 10 ]
    Blood samples were collected to analyze the chemistry parameters: glucose, cholesterol, triglycerides, anion gap, calcium, carbon dioxide, chloride, phosphate, potassium, sodium and blood urea nitrogen.

  83. Period 1: Absolute Values for Chemistry Parameters: Creatine Kinase, Lactate Dehydrogenase, ALT, ALP, AST, Gamma-glutamyl Transferase [ Time Frame: Day 9 ]
    Blood samples were collected to analyze the chemistry parameters: creatine kinase, lactate dehydrogenase, ALT, ALP, AST and gamma-glutamyl transferase.

  84. Period 2: Absolute Values for Chemistry Parameters: Creatine Kinase, Lactate Dehydrogenase, ALT, ALP, AST, Gamma-glutamyl Transferase [ Time Frame: Day 7 ]
    Blood samples were collected to analyze the chemistry parameters: creatine kinase, lactate dehydrogenase, ALT, ALP, AST and gamma-glutamyl transferase.

  85. Period 3: Absolute Values for Chemistry Parameters: Creatine Kinase, Lactate Dehydrogenase, ALT, ALP, AST, Gamma-glutamyl Transferase [ Time Frame: Days 4, 7 and 10 ]
    Blood samples were collected to analyze the chemistry parameters: creatine kinase, lactate dehydrogenase, ALT, ALP, AST and gamma-glutamyl transferase.

  86. Period 1: Absolute Values for Chemistry Parameters: Urate, Creatinine, Bilirubin, Direct Bilirubin [ Time Frame: Day 9 ]
    Blood samples were collected to analyze the chemistry parameters: urate, creatinine, bilirubin and direct bilirubin.

  87. Period 2: Absolute Values for Chemistry Parameters: Urate, Creatinine, Bilirubin, Direct Bilirubin [ Time Frame: Day 7 ]
    Blood samples were collected to analyze the chemistry parameters: urate, creatinine, bilirubin and direct bilirubin.

  88. Period 3: Absolute Values for Chemistry Parameters: Urate, Creatinine, Bilirubin, Direct Bilirubin [ Time Frame: Days 4, 7 and 10 ]
    Blood samples were collected to analyze the chemistry parameters: urate, creatinine, bilirubin and direct bilirubin.

  89. Period 1: Absolute Values for Chemistry Parameters: Albumin, Globulin, Protein [ Time Frame: Day 9 ]
    Blood samples were collected to analyze the chemistry parameters: albumin, globulin and protein.

  90. Period 2: Absolute Values for Chemistry Parameters: Albumin, Globulin, Protein [ Time Frame: Day 7 ]
    Blood samples were collected to analyze the chemistry parameters: albumin, globulin and protein.

  91. Period 3: Absolute Values for Chemistry Parameters: Albumin, Globulin, Protein [ Time Frame: Days 4, 7 and 10 ]
    Blood samples were collected to analyze the chemistry parameters: albumin, globulin and protein.

  92. Period 1: Absolute Values for Chemistry Parameters: Amylase, Lipase [ Time Frame: Day 9 ]
    Blood samples were collected to analyze the chemistry parameters: amylase and lipase.

  93. Period 2: Absolute Values for Chemistry Parameters: Amylase, Lipase [ Time Frame: Day 7 ]
    Blood samples were collected to analyze the chemistry parameters: amylase and lipase.

  94. Period 3: Absolute Values for Chemistry Parameters: Amylase, Lipase [ Time Frame: Days 4, 7 and 10 ]
    Blood samples were collected to analyze the chemistry parameters: amylase and lipase.

  95. Period 1: Absolute Values for Urinalysis Parameter: Specific Gravity [ Time Frame: Day 9 ]
    Urine samples were collected to analyze the urinalysis parameter: specific gravity. 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.

  96. Period 2: Absolute Values for Urinalysis Parameter: Specific Gravity [ Time Frame: Day 7 ]
    Urine samples were collected to analyze the urinalysis parameter: specific gravity. 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.

  97. Period 3: Absolute Values for Urinalysis Parameter: Specific Gravity [ Time Frame: Days 4, 7 and 10 ]
    Urine samples were collected to analyze the urinalysis parameter: specific gravity. 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.

  98. Period 1: Absolute Values for Urinalysis Parameter: Urobilinogen [ Time Frame: Day 9 ]
    Urine samples were collected to analyze the urinalysis parameter: urobilinogen.

  99. Period 2: Absolute Values for Urinalysis Parameter: Urobilinogen [ Time Frame: Day 7 ]
    Urine samples were collected to analyze the urinalysis parameter: urobilinogen.

  100. Period 3: Absolute Values for Urinalysis Parameter: Urobilinogen [ Time Frame: Days 4, 7 and 10 ]
    Urine samples were collected to analyze the urinalysis parameter: urobilinogen.

  101. Period 1: Absolute Values for Urinalysis Parameter: pH [ Time Frame: Day 9 ]
    Urine samples were collected to analyze the urinalysis parameter: pH. 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).

  102. Period 2: Absolute Values for Urinalysis Parameter: pH [ Time Frame: Day 7 ]
    Urine samples were collected to analyze the urinalysis parameter: pH. 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).

  103. Period 3: Absolute Values for Urinalysis Parameter: pH [ Time Frame: Days 4, 7 and 10 ]
    Urine samples were collected to analyze the urinalysis parameter: pH. 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).

  104. Period 1: Absolute Values for ECG Parameters: PR Interval, QRS Duration, QT Interval, QTcF, QTcB [ Time Frame: Day 1: 2 hours, 4 hours; Day 5: Pre-dose, 2 hours and 4 hours ]
    Twelve-lead ECG were obtained to measure PR Interval, QRS Duration, QT Interval, QTcF Interval and QTcB Interval. Twelve-lead ECGs were performed with the participant in a supine or semi-supine position after a rest of at least 10 minutes.

  105. Period 2: Absolute Values for ECG Parameters: PR Interval, QRS Duration, QT Interval, QTcF, QTcB [ Time Frame: Day 1: 2 hours, 4 hours; Day 5: Pre-dose, 2 hours and 4 hours ]
    Twelve-lead ECG were obtained to measure PR Interval, QRS Duration, QT Interval, QTcF Interval and QTcB Interval. Twelve-lead ECGs were performed with the participant in a supine or semi-supine position after a rest of at least 10 minutes.

  106. Period 3: Absolute Values for ECG Parameters: PR Interval, QRS Duration, QT Interval, QTcF, QTcB [ Time Frame: Day 1: 2 hours, 4 hours; Days 4, 5 and 7: Pre-dose, 2 hours and 4 hours; Day 10 ]
    Twelve-lead ECG were obtained to measure PR Interval, QRS Duration, QT Interval, QTcF Interval and QTcB Interval. Twelve-lead ECGs were performed with the participant in a supine or semi-supine position after a rest of at least 10 minutes.

  107. Period 1: Absolute Values for SBP and DBP [ Time Frame: Days 2, 3, 4 and 5 ]
    SBP and DBP were measured in the semi-recumbent position with a completely automated device.

  108. Period 2: Absolute Values for SBP and DBP [ Time Frame: Days 2, 3, 4, 5, 6 and 7 ]
    SBP and DBP were measured in the semi-recumbent position with a completely automated device.

  109. Period 3: Absolute Values for SBP and DBP [ Time Frame: Days 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11 ]
    SBP and DBP were measured in the semi-recumbent position with a completely automated device.

  110. Period 1: Absolute Values for Pulse Rate [ Time Frame: Days 2, 3, 4 and 5 ]
    Pulse rate was measured in the semi-recumbent position with a completely automated device.

  111. Period 2: Absolute Values for Pulse Rate [ Time Frame: Days 2, 3, 4, 5, 6 and 7 ]
    Pulse rate was measured in the semi-recumbent position with a completely automated device.

  112. Period 3: Absolute Values for Pulse Rate [ Time Frame: Days 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11 ]
    Pulse rate was measured in the semi-recumbent position with a completely automated device.

  113. Period 1: Absolute Values for Respiratory Rate [ Time Frame: Days 2, 3, 4 and 5 ]
    Respiratory rate was measured in the semi-recumbent position after at least 5 minutes of rest for the participant in a quiet setting without distractions.

  114. Period 2: Absolute Values for Respiratory Rate [ Time Frame: Days 2, 3, 4, 5, 6 and 7 ]
    Respiratory rate was measured in the semi-recumbent position after at least 5 minutes of rest for the participant in a quiet setting without distractions.

  115. Period 3: Absolute Values for Respiratory Rate [ Time Frame: Days 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11 ]
    Respiratory rate was measured in the semi-recumbent position after at least 5 minutes of rest for the participant in a quiet setting without distractions.

  116. Period 1: Absolute Values for Body Temperature [ Time Frame: Days 2, 3, 4 and 5 ]
    Body temperature was measured in the semi-recumbent position after at least 5 minutes of rest for the participant in a quiet setting without distractions.

  117. Period 2: Absolute Values for Body Temperature [ Time Frame: Days 2, 3, 4, 5, 6 and 7 ]
    Body temperature was measured in the semi-recumbent position after at least 5 minutes of rest for the participant in a quiet setting without distractions.

  118. Period 3: Absolute Values for Body Temperature [ Time Frame: Days 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11 ]
    Body temperature was measured in the semi-recumbent position after at least 5 minutes of rest for the participant in a quiet setting without distractions.

  119. Period 2: Time of Maximum Observed Concentration (Tmax) of GSK3640254 for GSK3640254 Arm [ Time Frame: Day 7: Pre-dose, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of GSK3640254. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.

  120. Period 3: Tmax of GSK3640254 for Dolutegravir + GSK3640254 Arm [ Time Frame: Day 7: Pre-dose, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of GSK3640254. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.

  121. Period 2: Apparent Terminal Phase Half-life (T1/2) of GSK3640254 for GSK3640254 Arm [ Time Frame: Day 7: Pre-dose, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of GSK3640254. The pharmacokinetic parameters were calculated by standard non-compartmental analysis. Data could not be determined due to limited sampling points after final dosing (during elimination phase). An accurate determination of GSK3640254 half-life would require sampling up to 3 times half-life (3 * approximately 24 hours). However sampling in Period 2 was performed up to only 24 hours post-dose.

  122. Period 3: T1/2 of GSK3640254 for Dolutegravir + GSK3640254 Arm [ Time Frame: Day 7: Pre-dose, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of GSK3640254. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.

  123. Period 1: Tmax of Dolutegravir for Dolutegravir Arm [ Time Frame: Day 5: Pre-dose, 1, 1.5, 2, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of dolutegravir. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.

  124. Period 3: Tmax of Dolutegravir for Dolutegravir + GSK3640254 Arm [ Time Frame: Day 7: Pre-dose, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of dolutegravir. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.

  125. Period 1: T1/2 of Dolutegravir for Dolutegravir Arm [ Time Frame: Day 5: Pre-dose, 1, 1.5, 2, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of dolutegravir. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.

  126. Period 3: T1/2 of Dolutegravir for Dolutegravir + GSK3640254 Arm [ Time Frame: Day 7: Pre-dose, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of dolutegravir. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.



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.


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

Inclusion Criteria:

  • Subject must be 18 to 55 years of age inclusive, at the time of signing the informed consent.
  • Subjects who are 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 (history and ECG).
  • Body weight >=50 kilograms (kg) (110 pounds [lbs]) for men and >=45.0 kg (99 lbs) for women and body mass index within the range 18.5 to 31.0 kilograms per square meter (kg/m^2) (inclusive).
  • Male or female subjects can participate. A female subject is eligible to participate if she is not pregnant, not breastfeeding, and not a woman of childbearing potential (WOCBP).
  • Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and protocol.

Exclusion Criteria:

  • Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
  • A pre-existing condition interfering with normal gastrointestinal (GI) anatomy or motility (e.g., gastroesophageal reflux disease, gastric ulcers, gastritis), hepatic and/or renal function, that could interfere with the absorption, metabolism, and/or excretion of the study drugs or render the subject unable to take oral study intervention.
  • Any history of significant underlying psychiatric disorder, including but not limited to schizophrenia, bipolar disorder with or without psychotic symptoms, other psychotic disorders, or schizotypal (personality) disorder.
  • Any history of major depressive disorder with or without suicidal features, or anxiety disorders, that required medical intervention (pharmacologic or not) such as hospitalization or other inpatient treatment and/or chronic (>6 months) outpatient treatment. Subjects with other conditions such as adjustment disorder or dysthymia that have required shorter term medical therapy (<6 months) without inpatient treatment and are currently well-controlled clinically or resolved may be considered for entry after discussion and agreement with the ViiV Medical Monitor.
  • Any pre-existing physical or other psychiatric condition (including alcohol or drug abuse), which, in the opinion of the investigator (with or without psychiatric evaluation), could interfere with the subject's ability to comply with the dosing schedule and protocol evaluations or which might compromise the safety of the subject.
  • Medical history of cardiac arrhythmias or cardiac disease or a family or personal history of long QT syndrome.
  • Presence of Hepatitis B surface antigen (HBsAg) at Screening or within 3 months prior to starting study intervention.
  • Positive Hepatitis C antibody test result at Screening or within 3 months prior to starting study intervention and positive on reflex to Hepatitis C ribonucleic acid (RNA).
  • Positive HIV-1 and -2 antigen/antibody immunoassay at Screening.
  • ALT >1.5 times upper limit of normal (ULN). A single repeat of ALT is allowed within a single screening period to determine eligibility.
  • Bilirubin >1.5 times ULN (isolated bilirubin >1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin <35 percent).
  • Any acute laboratory abnormality at Screening which, in the opinion of the investigator, should preclude participation in the study of an investigational compound.
  • Any Grade 2 to 4 laboratory abnormality at Screening, with the exception of creatine phosphokinase (CPK) and lipid abnormalities (e.g., total cholesterol, triglycerides), and ALT (described above), will exclude a subject from the study unless the investigator can provide a compelling explanation for the laboratory results and has the assent of the sponsor. A single repeat of any laboratory abnormality is allowed within a single screening period to determine eligibility.
  • A positive test result for drugs of abuse (including marijuana), alcohol, or cotinine (indicating active current smoking) at Screening or before the first dose of study intervention.
  • 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 and for the duration of the study.
  • Treatment with any vaccine within 30 days prior to receiving study intervention.
  • Unwillingness to abstain from excessive consumption of any food or drink containing grapefruit and grapefruit juice, Seville oranges, blood oranges, or pomelos or their fruit juices within 7 days prior to the first dose of study intervention(s) until the end of the study.
  • Participation in another concurrent clinical study or prior clinical study (with the exception of imaging trials) 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 study intervention (whichever is longer).
  • Where participation in the study would result in donation of blood or blood products in excess of 500 milliliter (mL) within 56 days.
  • Any positive (abnormal) response confirmed by the investigator on a screening clinician- or qualified designee-administered Columbia Suicide Severity Rating Scale (C-SSRS).
  • Any significant arrhythmia or ECG finding (e.g., prior myocardial infarction, sinoatrial pauses, bundle branch block, or conduction abnormality) which, in the opinion of the investigator or ViiV Healthcare (VH)/GlaxoSmithKline (GSK) Medical Monitor, will interfere with the safety for the individual subject.
  • Exclusion criteria for screening ECG (a single repeat is allowed for eligibility determination): Heart rate (males: <45 or >100 beats per minute [bpm] and females: <50 or >100 bpm); PR interval (<120 or >200 milliseconds [msec]); QRS duration (<70 or >110 msec); QTcF interval (males: >450 msec and females: >470 msec).
  • History of regular alcohol consumption within 6 months of the study defined as: an average weekly intake of >14 units. One unit is equivalent to 8 grams of alcohol: a half-pint (equivalent to 240 mL) of beer, 1 glass (125 mL) of wine, or 1 (25 mL) measure of spirits.
  • Regular use of tobacco- or nicotine-containing products within 3 months prior to Screening.
  • 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.

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): NCT03816696


Locations
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United States, Texas
GSK Investigational Site
Austin, Texas, United States, 78744
Sponsors and Collaborators
ViiV Healthcare
Investigators
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Study Director: GSK Clinical Trials ViiV Healthcare
  Study Documents (Full-Text)

Documents provided by ViiV Healthcare:
Study Protocol  [PDF] December 12, 2018
Statistical Analysis Plan  [PDF] April 1, 2019

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: ViiV Healthcare
ClinicalTrials.gov Identifier: NCT03816696    
Other Study ID Numbers: 209712
First Posted: January 25, 2019    Key Record Dates
Results First Posted: March 19, 2020
Last Update Posted: March 19, 2020
Last Verified: February 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: IPD for this study will be made available via the Clinical Study Data Request site.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints of the study.
Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.
URL: http://clinicalstudydatarequest.com

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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 ViiV Healthcare:
GSK3640254, dolutegravir, healthy subjects, two-way interaction, HIV
Additional relevant MeSH terms:
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HIV Infections
Blood-Borne Infections
Communicable Diseases
Infections
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Immunologic Deficiency Syndromes
Immune System Diseases