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

An Open-Label Two-way Interaction Clinical Trial to Evaluate the Pharmacokinetic Interactions Between GSK3640254 and Dolutegravir in Healthy Subjects

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.

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: GSK3640254; Drug: DTG

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • Austin, Texas, United States, 78744
      • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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.	Day 5: Pre-dose, 1, 1.5, 2, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose
Period 3: AUC(0 to Tau) of Dolutegravir for Dolutegravir + GSK3640254 Arm	Blood samples were collected at the indicated time points for pharmacokinetic analysis of dolutegravir. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.	Day 7: Pre-dose, 1, 1.5, 2, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose
Period 1: Maximum Observed Concentration (Cmax) of Dolutegravir for Dolutegravir Arm	Blood samples were collected at the indicated time points for pharmacokinetic analysis of dolutegravir. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.	Day 5: Pre-dose, 1, 1.5, 2, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose
Period 3: Cmax of Dolutegravir for Dolutegravir + GSK3640254 Arm	Blood samples were collected at the indicated time points for pharmacokinetic analysis of dolutegravir. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.	Day 7: Pre-dose, 1, 1.5, 2, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose
Period 1: Plasma Concentration at the End of the Dosing Interval (Ctau) of Dolutegravir for Dolutegravir Arm	Blood samples were collected at the indicated time points for pharmacokinetic analysis of dolutegravir. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.	Day 5: Pre-dose, 1, 1.5, 2, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose
Period 3: Ctau of Dolutegravir for Dolutegravir + GSK3640254 Arm	Blood samples were collected at the indicated time points for pharmacokinetic analysis of dolutegravir. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.	Day 7: Pre-dose, 1, 1.5, 2, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose
Period 2: AUC(0 to Tau) of GSK3640254 for GSK3640254 Arm	Blood samples were collected at the indicated time points for pharmacokinetic analysis of GSK3640254. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.	Day 7: Pre-dose, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose
Period 3: AUC(0 to Tau) of GSK3640254 for Dolutegravir + GSK3640254 Arm	Blood samples were collected at the indicated time points for pharmacokinetic analysis of GSK3640254. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.	Day 7: Pre-dose, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose
Period 2: Cmax of GSK3640254 for GSK3640254 Arm	Blood samples were collected at the indicated time points for pharmacokinetic analysis of GSK3640254. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.	Day 7: Pre-dose, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose
Period 3: Cmax of GSK3640254 for Dolutegravir + GSK3640254 Arm	Blood samples were collected at the indicated time points for pharmacokinetic analysis of GSK3640254. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.	Day 7: Pre-dose, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose
Period 2: Ctau of GSK3640254 for GSK3640254 Arm	Blood samples were collected at the indicated time points for pharmacokinetic analysis of GSK3640254. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.	Day 7: Pre-dose, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose
Period 3: Ctau of GSK3640254 for Dolutegravir + GSK3640254 Arm	Blood samples were collected at the indicated time points for pharmacokinetic analysis of GSK3640254. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.	Day 7: Pre-dose, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Non-serious Adverse Events (Non-SAEs) and Serious Adverse Events (SAEs)	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.	Up to Day 27
Period 1: Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelet Count	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.	Baseline (Day -1) and at Day 9
Period 2: Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelet Count	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.	Baseline (Period 1 Day 9) and at Day 7
Period 3: Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelet Count	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.	Baseline (Period 2 Day 7) and at Days 4, 7 and 10
Period 1: Change From Baseline in Hematology Parameter: Hemoglobin	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.	Baseline (Day -1) and at Day 9
Period 2: Change From Baseline in Hematology Parameter: Hemoglobin	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.	Baseline (Period 1 Day 9) and at Day 7
Period 3: Change From Baseline in Hematology Parameter: Hemoglobin	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.	Baseline (Period 2 Day 7) and at Days 4, 7 and 10
Period 1: Change From Baseline in Hematology Parameter: Hematocrit	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.	Baseline (Day -1) and at Day 9
Period 2: Change From Baseline in Hematology Parameter: Hematocrit	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.	Baseline (Period 1 Day 9) and at Day 7
Period 3: Change From Baseline in Hematology Parameter: Hematocrit	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.	Baseline (Period 2 Day 7) and at Days 4, 7 and 10
Period 1: Change From Baseline in Hematology Parameter: Erythrocytes	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.	Baseline (Day -1) and at Day 9
Period 2: Change From Baseline in Hematology Parameter: Erythrocytes	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.	Baseline (Period 1 Day 9) and at Day 7
Period 3: Change From Baseline in Hematology Parameter: Erythrocytes	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.	Baseline (Period 2 Day 7) and at Days 4, 7 and 10
Period 1: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Volume	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.	Baseline (Day -1) and at Day 9
Period 2: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Volume	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.	Baseline (Period 1 Day 9) and at Day 7
Period 3: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Volume	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.	Baseline (Period 2 Day 7) and at Days 4, 7 and 10
Period 1: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin	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.	Baseline (Day -1) and at Day 9
Period 2: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin	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.	Baseline (Period 1 Day 9) and at Day 7
Period 3: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin	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.	Baseline (Period 2 Day 7) and at Days 4, 7 and 10
Period 1: Change From Baseline in Chemistry Parameters: Glucose, Cholesterol, Triglycerides, Anion Gap, Calcium, Carbon Dioxide, Chloride, Phosphate, Potassium, Sodium, Blood Urea Nitrogen	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.	Baseline (Day -1) and at Day 9
Period 2: Change From Baseline in Chemistry Parameters: Glucose, Cholesterol, Triglycerides, Anion Gap, Calcium, Carbon Dioxide, Chloride, Phosphate, Potassium, Sodium, Blood Urea Nitrogen	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.	Baseline (Period 1 Day 9) and at Day 7
Period 3: Change From Baseline in Chemistry Parameters: Glucose, Cholesterol, Triglycerides, Anion Gap, Calcium, Carbon Dioxide, Chloride, Phosphate, Potassium, Sodium, Blood Urea Nitrogen	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.	Baseline (Period 2 Day 7) and at Days 4, 7 and 10
Period 1: Change From Baseline in Chemistry Parameters: Creatine Kinase, Lactate Dehydrogenase, Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST), Gamma-glutamyl Transferase	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.	Baseline (Day -1) and at Day 9
Period 2: Change From Baseline in Chemistry Parameters: Creatine Kinase, Lactate Dehydrogenase, ALT, ALP, AST, Gamma-glutamyl Transferase	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.	Baseline (Period 1 Day 9) and at Day 7
Period 3: Change From Baseline in Chemistry Parameters: Creatine Kinase, Lactate Dehydrogenase, ALT, ALP, AST, Gamma-glutamyl Transferase	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.	Baseline (Period 2 Day 7) and at Days 4, 7 and 10
Period 1: Change From Baseline in Chemistry Parameters: Urate, Creatinine, Bilirubin, Direct Bilirubin	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.	Baseline (Day -1) and at Day 9
Period 2: Change From Baseline in Chemistry Parameters: Urate, Creatinine, Bilirubin, Direct Bilirubin	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.	Baseline (Period 1 Day 9) and at Day 7
Period 3: Change From Baseline in Chemistry Parameters: Urate, Creatinine, Bilirubin, Direct Bilirubin	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.	Baseline (Period 2 Day 7) and at Days 4, 7 and 10
Period 1: Change From Baseline in Chemistry Parameters: Albumin, Globulin, Protein	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.	Baseline (Day -1) and at Day 9
Period 2: Change From Baseline in Chemistry Parameters: Albumin, Globulin, Protein	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.	Baseline (Period 1 Day 9) and at Day 7
Period 3: Change From Baseline in Chemistry Parameters: Albumin, Globulin, Protein	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.	Baseline (Period 2 Day 7) and at Days 4, 7 and 10
Period 1: Change From Baseline in Chemistry Parameters: Amylase, Lipase	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.	Baseline (Day -1) and at Day 9
Period 2: Change From Baseline in Chemistry Parameters: Amylase, Lipase	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.	Baseline (Period 1 Day 9) and at Day 7
Period 3: Change From Baseline in Chemistry Parameters: Amylase, Lipase	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.	Baseline (Period 2 Day 7) and at Days 4, 7 and 10
Period 1: Change From Baseline in Urinalysis Parameter: Specific Gravity	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.	Baseline (Day -1) and at Day 9
Period 2: Change From Baseline in Urinalysis Parameter: Specific Gravity	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.	Baseline (Period 1 Day 9) and at Day 7
Period 3: Change From Baseline in Urinalysis Parameter: Specific Gravity	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.	Baseline (Period 2 Day 7) and at Days 4, 7 and 10
Period 1: Change From Baseline in Urinalysis Parameter: Urobilinogen	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.	Baseline (Day -1) and at Day 9
Period 2: Change From Baseline in Urinalysis Parameter: Urobilinogen	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.	Baseline (Period 1 Day 9) and at Day 7
Period 3: Change From Baseline in Urinalysis Parameter: Urobilinogen	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.	Baseline (Period 2 Day 7) and at Days 4, 7 and 10
Period 1: Change From Baseline in Urinalysis Parameter: Potential of Hydrogen (pH)	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.	Baseline (Day -1) and at Day 9
Period 2: Change From Baseline in Urinalysis Parameter: pH	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.	Baseline (Period 1 Day 9) and at Day 7
Period 3: Change From Baseline in Urinalysis Parameter: pH	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.	Baseline (Period 2 Day 7) and at Days 4, 7 and 10
Period 1: Number of Participants With Urinalysis Dipstick Results	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.	Day 9
Period 2: Number of Participants With Urinalysis Dipstick Results	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.	Day 7
Period 3: Number of Participants With Urinalysis Dipstick Results	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.	Days 4, 7 and 10
Period 1: Change From Baseline in PR Interval, QRS Duration, QT Interval, Fridericia QT Correction Formula (QTcF), Bazett's QT Correction Formula (QTcB)	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.	Baseline, Day 1: 2 hours, 4 hours; Day 5: Pre-dose, 2 hours and 4 hours
Period 2: Change From Baseline in PR Interval, QRS Duration, QT Interval, QTcF, QTcB	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.	Baseline; Day 1: 2 hours, 4 hours; Day 5: Pre-dose, 2 hours and 4 hours
Period 3: Change From Baseline in PR Interval, QRS Duration, QT Interval, QTcF, QTcB	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.	Baseline; Day 1: 2 hours, 4 hours; Days 4, 5 and 7: Pre-dose, 2 hours and 4 hours; Day 10
Period 1: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)	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.	Baseline (Day 1, Pre-dose), Days 2, 3, 4 and 5
Period 2: Change From Baseline in SBP and DBP	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.	Baseline (Day 1, Pre-dose), Days 2, 3, 4, 5, 6 and 7
Period 3: Change From Baseline in SBP and DBP	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.	Baseline (Day 1, Pre-dose), Days 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11
Period 1: Change From Baseline in Pulse Rate	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.	Baseline (Day 1, Pre-dose), Days 2, 3, 4 and 5
Period 2: Change From Baseline in Pulse Rate	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.	Baseline (Day 1, Pre-dose), Days 2, 3, 4, 5, 6 and 7
Period 3: Change From Baseline in Pulse Rate	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.	Baseline (Day 1, Pre-dose), Days 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11
Period 1: Change From Baseline in Respiratory Rate	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.	Baseline (Day 1, Pre-dose), Days 2, 3, 4 and 5
Period 2: Change From Baseline in Respiratory Rate	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.	Baseline (Day 1, Pre-dose), Days 2, 3, 4, 5, 6 and 7
Period 3: Change From Baseline in Respiratory Rate	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.	Baseline (Day 1, Pre-dose), Days 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11
Period 1: Change From Baseline in Body Temperature	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.	Baseline (Day 1, Pre-dose), Days 2, 3, 4 and 5
Period 2: Change From Baseline in Body Temperature	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.	Baseline (Day 1, Pre-dose), Days 2, 3, 4, 5, 6 and 7
Period 3: Change From Baseline in Body Temperature	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.	Baseline (Day 1, Pre-dose), Days 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11
Period 1: Absolute Values for Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelet Count	Blood samples were collected to analyze the hematology parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils and Platelet count.	Day 9
Period 2: Absolute Values for Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelet Count	Blood samples were collected to analyze the hematology parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils and Platelet count.	Day 7
Period 3: Absolute Values for Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelet Count	Blood samples were collected to analyze the hematology parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils and Platelet count.	Days 4, 7 and 10
Period 1: Absolute Values for Hematology Parameter: Hemoglobin	Blood samples were collected to analyze the hematology parameter: hemoglobin.	Day 9
Period 2: Absolute Values for Hematology Parameter: Hemoglobin	Blood samples were collected to analyze the hematology parameter: hemoglobin.	Day 7
Period 3: Absolute Values for Hematology Parameter: Hemoglobin	Blood samples were collected to analyze the hematology parameter: hemoglobin.	Days 4, 7 and 10
Period 1: Absolute Values for Hematology Parameter: Hematocrit	Blood samples were collected to analyze the hematology parameter: hematocrit.	Day 9
Period 2: Absolute Values for Hematology Parameter: Hematocrit	Blood samples were collected to analyze the hematology parameter: hematocrit.	Day 7
Period 3: Absolute Values for Hematology Parameter: Hematocrit	Blood samples were collected to analyze the hematology parameter: hematocrit.	Days 4, 7 and 10
Period 1: Absolute Values for Hematology Parameter: Erythrocytes	Blood samples were collected to analyze the hematology parameter: erythrocytes.	Day 9
Period 2: Absolute Values for Hematology Parameter: Erythrocytes	Blood samples were collected to analyze the hematology parameter: erythrocytes.	Day 7
Period 3: Absolute Values for Hematology Parameter: Erythrocytes	Blood samples were collected to analyze the hematology parameter: erythrocytes.	Days 4, 7 and 10
Period 1: Absolute Values for Hematology Parameter: Erythrocytes Mean Corpuscular Volume	Blood samples were collected to analyze the hematology parameter: erythrocytes mean corpuscular volume.	Day 9
Period 2: Absolute Values for Hematology Parameter: Erythrocytes Mean Corpuscular Volume	Blood samples were collected to analyze the hematology parameter: erythrocytes mean corpuscular volume.	Day 7
Period 3: Absolute Values for Hematology Parameter: Erythrocytes Mean Corpuscular Volume	Blood samples were collected to analyze the hematology parameter: erythrocytes mean corpuscular volume.	Days 4, 7 and 10
Period 1: Absolute Values for Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin	Blood samples were collected to analyze the hematology parameter: erythrocytes mean corpuscular hemoglobin.	Day 9
Period 2: Absolute Values for Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin	Blood samples were collected to analyze the hematology parameter: erythrocytes mean corpuscular hemoglobin.	Day 7
Period 3: Absolute Values for Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin	Blood samples were collected to analyze the hematology parameter: erythrocytes mean corpuscular hemoglobin.	Days 4, 7 and 10
Period 1: Absolute Values for Chemistry Parameters: Glucose, Cholesterol, Triglycerides, Anion Gap, Calcium, Carbon Dioxide, Chloride, Phosphate, Potassium, Sodium, Blood Urea Nitrogen	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.	Day 9
Period 2: Absolute Values for Chemistry Parameters: Glucose, Cholesterol, Triglycerides, Anion Gap, Calcium, Carbon Dioxide, Chloride, Phosphate, Potassium, Sodium, Blood Urea Nitrogen	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.	Day 7
Period 3: Absolute Values for Chemistry Parameters: Glucose, Cholesterol, Triglycerides, Anion Gap, Calcium, Carbon Dioxide, Chloride, Phosphate, Potassium, Sodium, Blood Urea Nitrogen	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.	Days 4, 7 and 10
Period 1: Absolute Values for Chemistry Parameters: Creatine Kinase, Lactate Dehydrogenase, ALT, ALP, AST, Gamma-glutamyl Transferase	Blood samples were collected to analyze the chemistry parameters: creatine kinase, lactate dehydrogenase, ALT, ALP, AST and gamma-glutamyl transferase.	Day 9
Period 2: Absolute Values for Chemistry Parameters: Creatine Kinase, Lactate Dehydrogenase, ALT, ALP, AST, Gamma-glutamyl Transferase	Blood samples were collected to analyze the chemistry parameters: creatine kinase, lactate dehydrogenase, ALT, ALP, AST and gamma-glutamyl transferase.	Day 7
Period 3: Absolute Values for Chemistry Parameters: Creatine Kinase, Lactate Dehydrogenase, ALT, ALP, AST, Gamma-glutamyl Transferase	Blood samples were collected to analyze the chemistry parameters: creatine kinase, lactate dehydrogenase, ALT, ALP, AST and gamma-glutamyl transferase.	Days 4, 7 and 10
Period 1: Absolute Values for Chemistry Parameters: Urate, Creatinine, Bilirubin, Direct Bilirubin	Blood samples were collected to analyze the chemistry parameters: urate, creatinine, bilirubin and direct bilirubin.	Day 9
Period 2: Absolute Values for Chemistry Parameters: Urate, Creatinine, Bilirubin, Direct Bilirubin	Blood samples were collected to analyze the chemistry parameters: urate, creatinine, bilirubin and direct bilirubin.	Day 7
Period 3: Absolute Values for Chemistry Parameters: Urate, Creatinine, Bilirubin, Direct Bilirubin	Blood samples were collected to analyze the chemistry parameters: urate, creatinine, bilirubin and direct bilirubin.	Days 4, 7 and 10
Period 1: Absolute Values for Chemistry Parameters: Albumin, Globulin, Protein	Blood samples were collected to analyze the chemistry parameters: albumin, globulin and protein.	Day 9
Period 2: Absolute Values for Chemistry Parameters: Albumin, Globulin, Protein	Blood samples were collected to analyze the chemistry parameters: albumin, globulin and protein.	Day 7
Period 3: Absolute Values for Chemistry Parameters: Albumin, Globulin, Protein	Blood samples were collected to analyze the chemistry parameters: albumin, globulin and protein.	Days 4, 7 and 10
Period 1: Absolute Values for Chemistry Parameters: Amylase, Lipase	Blood samples were collected to analyze the chemistry parameters: amylase and lipase.	Day 9
Period 2: Absolute Values for Chemistry Parameters: Amylase, Lipase	Blood samples were collected to analyze the chemistry parameters: amylase and lipase.	Day 7
Period 3: Absolute Values for Chemistry Parameters: Amylase, Lipase	Blood samples were collected to analyze the chemistry parameters: amylase and lipase.	Days 4, 7 and 10
Period 1: Absolute Values for Urinalysis Parameter: Specific Gravity	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.	Day 9
Period 2: Absolute Values for Urinalysis Parameter: Specific Gravity	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.	Day 7
Period 3: Absolute Values for Urinalysis Parameter: Specific Gravity	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.	Days 4, 7 and 10
Period 1: Absolute Values for Urinalysis Parameter: Urobilinogen	Urine samples were collected to analyze the urinalysis parameter: urobilinogen.	Day 9
Period 2: Absolute Values for Urinalysis Parameter: Urobilinogen	Urine samples were collected to analyze the urinalysis parameter: urobilinogen.	Day 7
Period 3: Absolute Values for Urinalysis Parameter: Urobilinogen	Urine samples were collected to analyze the urinalysis parameter: urobilinogen.	Days 4, 7 and 10
Period 1: Absolute Values for Urinalysis Parameter: pH	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).	Day 9
Period 2: Absolute Values for Urinalysis Parameter: pH	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).	Day 7
Period 3: Absolute Values for Urinalysis Parameter: pH	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).	Days 4, 7 and 10
Period 1: Absolute Values for ECG Parameters: PR Interval, QRS Duration, QT Interval, QTcF, QTcB	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.	Day 1: 2 hours, 4 hours; Day 5: Pre-dose, 2 hours and 4 hours
Period 2: Absolute Values for ECG Parameters: PR Interval, QRS Duration, QT Interval, QTcF, QTcB	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.	Day 1: 2 hours, 4 hours; Day 5: Pre-dose, 2 hours and 4 hours
Period 3: Absolute Values for ECG Parameters: PR Interval, QRS Duration, QT Interval, QTcF, QTcB	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.	Day 1: 2 hours, 4 hours; Days 4, 5 and 7: Pre-dose, 2 hours and 4 hours; Day 10
Period 1: Absolute Values for SBP and DBP	SBP and DBP were measured in the semi-recumbent position with a completely automated device.	Days 2, 3, 4 and 5
Period 2: Absolute Values for SBP and DBP	SBP and DBP were measured in the semi-recumbent position with a completely automated device.	Days 2, 3, 4, 5, 6 and 7
Period 3: Absolute Values for SBP and DBP	SBP and DBP were measured in the semi-recumbent position with a completely automated device.	Days 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11
Period 1: Absolute Values for Pulse Rate	Pulse rate was measured in the semi-recumbent position with a completely automated device.	Days 2, 3, 4 and 5
Period 2: Absolute Values for Pulse Rate	Pulse rate was measured in the semi-recumbent position with a completely automated device.	Days 2, 3, 4, 5, 6 and 7
Period 3: Absolute Values for Pulse Rate	Pulse rate was measured in the semi-recumbent position with a completely automated device.	Days 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11
Period 1: Absolute Values for Respiratory Rate	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.	Days 2, 3, 4 and 5
Period 2: Absolute Values for Respiratory Rate	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.	Days 2, 3, 4, 5, 6 and 7
Period 3: Absolute Values for Respiratory Rate	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.	Days 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11
Period 1: Absolute Values for Body Temperature	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.	Days 2, 3, 4 and 5
Period 2: Absolute Values for Body Temperature	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.	Days 2, 3, 4, 5, 6 and 7
Period 3: Absolute Values for Body Temperature	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.	Days 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11
Period 2: Time of Maximum Observed Concentration (Tmax) of GSK3640254 for GSK3640254 Arm	Blood samples were collected at the indicated time points for pharmacokinetic analysis of GSK3640254. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.	Day 7: Pre-dose, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose
Period 3: Tmax of GSK3640254 for Dolutegravir + GSK3640254 Arm	Blood samples were collected at the indicated time points for pharmacokinetic analysis of GSK3640254. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.	Day 7: Pre-dose, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose
Period 2: Apparent Terminal Phase Half-life (T1/2) of GSK3640254 for GSK3640254 Arm	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.	Day 7: Pre-dose, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose
Period 3: T1/2 of GSK3640254 for Dolutegravir + GSK3640254 Arm	Blood samples were collected at the indicated time points for pharmacokinetic analysis of GSK3640254. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.	Day 7: Pre-dose, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose
Period 1: Tmax of Dolutegravir for Dolutegravir Arm	Blood samples were collected at the indicated time points for pharmacokinetic analysis of dolutegravir. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.	Day 5: Pre-dose, 1, 1.5, 2, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose
Period 3: Tmax of Dolutegravir for Dolutegravir + GSK3640254 Arm	Blood samples were collected at the indicated time points for pharmacokinetic analysis of dolutegravir. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.	Day 7: Pre-dose, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose
Period 1: T1/2 of Dolutegravir for Dolutegravir Arm	Blood samples were collected at the indicated time points for pharmacokinetic analysis of dolutegravir. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.	Day 5: Pre-dose, 1, 1.5, 2, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose
Period 3: T1/2 of Dolutegravir for Dolutegravir + GSK3640254 Arm	Blood samples were collected at the indicated time points for pharmacokinetic analysis of dolutegravir. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.	Day 7: Pre-dose, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose

Collaborators and Investigators

• Sponsor: ViiV Healthcare

Publications and helpful links

General Publications

• Pene Dumitrescu T, Joshi SR, Xu J, Greene TJ, Johnson M, Butcher L, Zimmerman E, Webster L, Pham TT, Lataillade M, Min S. Phase I evaluation of pharmacokinetics and tolerability of the HIV-1 maturation inhibitor GSK3640254 and dolutegravir in healthy adults. Br J Clin Pharmacol. 2021 Sep;87(9):3501-3507. doi: 10.1111/bcp.14759. Epub 2021 Mar 4.

Study record dates

Study Major Dates

• Study Start (Actual): January 23, 2019
• Primary Completion (Actual): March 30, 2019
• Study Completion (Actual): April 10, 2019

Study Registration Dates

• First Submitted: January 22, 2019
• First Submitted That Met QC Criteria: January 22, 2019
• First Posted (Actual): January 25, 2019

Study Record Updates

• Last Update Posted (Actual): March 19, 2020
• Last Update Submitted That Met QC Criteria: March 4, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: GSK3640254, dolutegravir, healthy subjects, two-way interaction, HIV
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections
• Other Study ID Numbers: 209712

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: IPD for this study will be made available via the Clinical Study Data Request site.
• IPD Sharing Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints of the study.
• IPD Sharing 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No