Drug-drug Interaction (DDI) Study of GSK3640254 With Darunavir/Ritonavir (DRV/RTV) and Etravirine (ETR)

HIV Infections Clinical Trial

Official title:

Open-Label, Single-Sequence Study to Evaluate the Effects of Darunavir/Ritonavir and/or Etravirine on the Pharmacokinetics of GSK3640254 and the Effects of GSK3640254 on the Pharmacokinetics of Darunavir/Ritonavir and/or Etravirine in Heathy Adults

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04630002
• Other study ID #: 213054
• Status: Completed
• Phase: Phase 1
• Start date: October 28, 2020
• Est. completion date: October 2, 2021

Study information

• Verified date: September 2022
• Source: ViiV Healthcare
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is an open-label, single-sequence, multiple-dose, 3 cohort study to investigate the effects of DRV/RTV and/or ETR on the pharmacokinetics (PK) of GSK3640254 and the effects of GSK3640254 on the PK of DRV/RTV and/or ETR. This study will aid in understanding these interactions and resulting changes in exposure (if any) when given in combination with GSK3640254.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 54
• Est. completion date: October 2, 2021
• Est. primary completion date: October 2, 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 50 Years

Eligibility

Inclusion criteria:

• Participant must be 18 to 50 years of age inclusive, at the time of signing the informed consent.

• Participants who are overtly healthy as determined by investigator or medically qualified designee based on a medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring (history and screening ECG).

• Body weight more than or equal to (>=)50.0 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 participants:

1. Male participants should not engage in intercourse while confined in the study site. There is no need for an extended period of double barrier use or prolonged abstinence after study discharge.

2. Female participants:

(i) A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: Is not a woman of childbearing potential (WOCBP) OR Is a WOCBP and using a non-hormonal contraceptive method that is highly effective, with a failure rate of less than (<)1 percent (%) for 28 days before intervention, during the intervention period, and for at least 28 days after the last dose of study intervention. The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention.

(ii) A WOCBP must have a negative highly sensitive serum or urine pregnancy test at screening and check-in (Day -1).

• Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the Informed consent form (ICF) and in this protocol.

Exclusion criteria:

• Participants with 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 (for example [e.g.], gastroesophageal reflux disease, gastric ulcers, gastritis) or hepatic and/or renal function that could interfere with the absorption, metabolism, and/or excretion of the study intervention or render the participant unable to take oral study intervention.

• Prior cholecystectomy surgery (prior appendectomy is acceptable).

• Clinically significant illness, including viral syndromes within 3 weeks of dosing.

• A participant with known or suspected active Coronavirus Disease-2019 (COVID-19) infection or contact with an individual with known COVID-19, within 14 days of study enrollment (World Health Organization [WHO] definitions).

• 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 (more than [>]6 months) outpatient treatment. Participants 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 Healthcare/GlaxoSmithKline (VH/GSK) 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 participant's ability to comply with the dosing schedule and protocol evaluations or which might compromise the safety of the participant.

• Medical history of cardiac arrhythmias, prior myocardial infarction in the past 3 months, or cardiac disease or a family or personal history of long QT syndrome.

• Presence of hepatitis B surface antigen 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.

• Positive Human immunodeficiency virus (HIV)-1 and -2 antigen/antibody immunoassay at screening.

• Alanine aminotransferase (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%). A single repeat of any laboratory abnormality is allowed within a single screening period to determine eligibility.

• 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), lipid abnormalities (e.g., total cholesterol, triglycerides), and ALT (described above), will exclude a participant from the study unless the investigator can provide a compelling explanation for the laboratory result(s) and has the assent of the sponsor. A single repeat of any laboratory abnormality is allowed within a single screening period to determine eligibility.

• Urine drug screen positive (showing presence of): amphetamines, barbiturates, cannabinoids, cocaine, or phencyclidine, or non-prescribed opiates, oxycodone, benzodiazepines, methadone, Methylenedioxymethamphetamine (MDMA), methamphetamines, or tricyclic antidepressants at screening or before the first dose of study intervention.

• Unable to refrain from the use of prescription or nonprescription drugs including vitamins, herbal and dietary supplements (including Saint [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 intervention 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).

• Prior exposure to GSK3640254 or prior intolerance to DRV/RTV or ETR in this or another clinical study.

• Prior intolerance to any other study medications: DRV/RTV or ETR.

• Where participation in the study would result in donation of blood or blood products in excess of 500 milliliters (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).

• Systolic blood pressure <100 millimeters of mercury (mm Hg). Up to 2 repeats are allowed for confirmation.

• Any significant arrhythmia or ECG finding (e.g., prior myocardial infarction in the past 3 months, symptomatic bradycardia, non-sustained or sustained atrial arrhythmias, non-sustained or sustained ventricular tachycardia, any degree of atrioventricular block, or conduction abnormality) which, in the opinion of the investigator or VH/GSK medical monitor, will interfere with the safety for the individual participant.

• Exclusion criteria for screening ECG (a single repeat is allowed for eligibility determination):

1. Heart rate: <50 or >100 beats per minute (bpm).

2. PR interval >200 milliseconds (ms).

3. Corrected QT interval (QTc) >450 ms.

• 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 (g) of alcohol: a half-pint (approximately 240 mL) of beer, 1 glass (125 mL) of wine, or 1 (25 mL) measure of spirits.

• Unable to refrain from 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.

Related Conditions & MeSH terms

• HIV Infections

Intervention

Drug:
• GSK3640254
GSK3640254 will be available as oral tablets.
• Darunavir/Ritonavir (DRV/RTV)
DRV/RTV will be available as oral tablets.
• Etravirine (ETR)
ETR will be available as oral tablets.

Locations

Country	Name	City	State
United States	GSK Investigational Site	Austin	Texas

Sponsors (1)

Lead Sponsor	Collaborator
ViiV Healthcare

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Cohort 1: Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval at Steady State (AUC[0-tau]) of GSK3640254	Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.	Pre-dose and 0.5 Hours, 1 Hour, 1.5 Hours, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 16 Hours, 24 Hours post-dose in Treatment Periods 1 and 3
Primary	Cohort 1: Maximum Observed Concentration (Cmax) of GSK3640254	Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.	Pre-dose and 0.5 Hours, 1 Hour, 1.5 Hours, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 16 Hours, 24 Hours post-dose in Treatment Periods 1 and 3
Primary	Cohort 1: AUC(0-tau) of DRV	Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.	Pre-dose and 0.5 Hours, 1 Hour, 1.5 Hours, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours post-dose in Treatment Periods 2 and 3
Primary	Cohort 1: Cmax of DRV	Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.	Pre-dose and 0.5 Hours, 1 Hour, 1.5 Hours, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours post-dose in Treatment Periods 2 and 3
Primary	Cohort 1: AUC(0-tau) of RTV	Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.	Pre-dose and 0.5 Hours, 1 Hour, 1.5 Hours, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours post-dose in Treatment Periods 2 and 3
Primary	Cohort 1: Cmax of RTV	Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.	Pre-dose and 0.5 Hours, 1 Hour, 1.5 Hours, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours post-dose in Treatment Periods 2 and 3
Primary	Cohort 2: AUC(0-tau) of GSK3640254	Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.	Pre-dose and 0.5 Hours, 1 Hour, 1.5 Hours, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 16 Hours, 24 Hours post-dose in Treatment Periods 1 and 3
Primary	Cohort 2: Cmax of GSK3640254	Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.	Pre-dose and 0.5 Hours, 1 Hour, 1.5 Hours, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 16 Hours, 24 Hours post-dose in Treatment Periods 1 and 3
Primary	Cohort 2: AUC(0-tau) of ETR	Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.	Pre-dose and 0.5 Hours, 1 Hour, 1.5 Hours, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours post-dose in Treatment Periods 2 and 3
Primary	Cohort 2: Cmax of ETR	Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.	Pre-dose and 0.5 Hours, 1 Hour, 1.5 Hours, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours post-dose in Treatment Periods 2 and 3
Primary	Cohort 3: AUC(0-tau) of GSK3640254	Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.	Pre-dose and 0.5 Hours, 1 Hour, 1.5 Hours, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 16 Hours, 24 Hours post-dose in Treatment Periods 1 and 2
Primary	Cohort 3: Cmax of GSK3640254	Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.	Pre-dose and 0.5 Hours, 1 Hour, 1.5 Hours, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 16 Hours, 24 Hours post-dose in Treatment Periods 1 and 2
Secondary	Cohort 1: Plasma Concentration at the End of the Dosing Interval (Ctau) of DRV	Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.	Pre-dose and 0.5 Hours, 1 Hour, 1.5 Hours, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours post-dose in Treatment Periods 2 and 3
Secondary	Cohort 1: Time of Maximum Observed Concentration (Tmax) of DRV	Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.	Pre-dose and 0.5 Hours, 1 Hour, 1.5 Hours, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours post-dose in Treatment Periods 2 and 3
Secondary	Cohort 1: Ctau of RTV	Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.	Pre-dose and 0.5 Hours, 1 Hour, 1.5 Hours, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours post-dose in Treatment Periods 2 and 3
Secondary	Cohort 1: Tmax of RTV	Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.	Pre-dose and 0.5 Hours, 1 Hour, 1.5 Hours, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours post-dose in Treatment Periods 2 and 3
Secondary	Cohort 1: Ctau of GSK3640254	Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.	Pre-dose and 0.5 Hours, 1 Hour, 1.5 Hours, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 16 Hours, 24 Hours post-dose in Treatment Periods 1 and 3
Secondary	Cohort 1: Tmax of GSK3640254	Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.	Pre-dose and 0.5 Hours, 1 Hour, 1.5 Hours, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 16 Hours, 24 Hours post-dose in Treatment Periods 1 and 3
Secondary	Cohort 2: Ctau of ETR	Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.	Pre-dose and 0.5 Hours, 1 Hour, 1.5 Hours, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours post-dose in Treatment Periods 2 and 3
Secondary	Cohort 2: Tmax of ETR	Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.	Pre-dose and 0.5 Hours, 1 Hour, 1.5 Hours, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours post-dose in Treatment Periods 2 and 3
Secondary	Cohort 2: Ctau of GSK3640254	Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.	Pre-dose and 0.5 Hours, 1 Hour, 1.5 Hours, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 16 Hours, 24 Hours post-dose in Treatment Periods 1 and 3
Secondary	Cohort 2: Tmax of GSK3640254	Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.	Pre-dose and 0.5 Hours, 1 Hour, 1.5 Hours, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 16 Hours, 24 Hours post-dose in Treatment Periods 1 and 3
Secondary	Cohort 1: Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs)	An adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An SAE is defined as any untoward medical occurrence that, at any dose that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or other situations as per medical or scientific judgment. Adverse events which were not Serious were considered as Non-Serious adverse events.	Up to Day 35
Secondary	Cohort 2: Number of Participants With SAEs and Non-SAEs	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An SAE is defined as any untoward medical occurrence that, at any dose that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or other situations as per medical or scientific judgment. Adverse events which were not Serious were considered as Non-Serious adverse events.	Up to Day 36
Secondary	Cohort 3: Number of Participants With SAEs and Non-SAEs	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An SAE is defined as any untoward medical occurrence that, at any dose that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or other situations as per medical or scientific judgment. Adverse events which were not Serious were considered as Non-Serious adverse events.	Up to Day 26
Secondary	Cohort 1: Number of Participants With AEs Leading to Discontinuations and Deaths	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. Number of participants with AEs leading to discontinuations and deaths were reported.	Up to Day 35
Secondary	Cohort 2: Number of Participants With AEs Leading to Discontinuations and Deaths	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. Number of participants with AEs leading to discontinuations and deaths were reported.	Up to Day 36
Secondary	Cohort 3: Number of Participants With AEs Leading to Discontinuations and Deaths	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. Number of participants with AEs leading to discontinuations and deaths were reported.	Up to Day 26
Secondary	Cohort 1: Number of Participants With Grade Increase Post-Baseline Relative to Baseline in Hematology Parameters	Blood samples were collected for analysis of hematology parameters. Laboratory abnormalities were graded according to Division of Acquired Immunodeficiency Syndrome (DAIDS) grading table Version 2.1. For Hemoglobin Low, Grade 3: 7.0 to <9.0 Grams per deciliter (g/dL) (males) and 6.5 to <8.5 g/dL (females),Grade 4: <7.0 g/dL (males) and <6.5 g/dL (females); Leukocytes Low, Grade 3: 1000 to 1499 cells per cubic millimeter (cells/mm^3),Grade 4: <1000 cells/mm^3; Lymphocytes Low, Grade 3: 350 to <500 cells per liter (cells/L),Grade 4: <350 cells/L; Neutrophils Low, Grade 3: 400 to 599 cells/mm^3, Grade 4: <400 cells/mm^3; Platelets Low, Grade 3: 25,000 to <50,000 cells/mm^3, Grade 4: <25,000 cells/mm^3. Baseline was defined as latest pre-dose assessment with a non-missing value, including those from unscheduled visits. An increase is defined as an increase in DAIDS grade relative to Baseline grade.	Baseline (Pre-dose, Day-1) and up to Day 35
Secondary	Cohort 2: Number of Participants With Grade Increase Post-Baseline Relative to Baseline in Hematology Parameters	Blood samples were collected for analysis of hematology parameters. Laboratory abnormalities were graded according to DAIDS grading table Version 2.1. For Hemoglobin Low, Grade 3: 7.0 to <9.0 g/dL (males) and 6.5 to <8.5 g/dL (females),Grade 4: <7.0 g/dL (males) and <6.5 g/dL (females); Leukocytes Low, Grade 3: 1000 to 1499 cells/mm^3,Grade 4: <1000 cells/mm^3; Lymphocytes Low, Grade 3: 350 to <500 cells/L,Grade 4: <350 cells/L; Neutrophils Low, Grade 3: 400 to 599 cells/mm^3, Grade 4: <400 cells/mm^3; Platelets Low, Grade 3: 25,000 to <50,000 cells/mm^3, Grade 4: <25,000 cells/mm^3. Baseline was defined as latest pre-dose assessment with a non-missing value, including those from unscheduled visits. An increase is defined as an increase in DAIDS grade relative to Baseline grade.	Baseline (Pre-dose, Day-1) and up to Day 36
Secondary	Cohort 3: Number of Participants With Grade Increase Post-Baseline Relative to Baseline in Hematology Parameters	Blood samples were collected for analysis of hematology parameters. Laboratory abnormalities were graded according to DAIDS grading table Version 2.1. For Hemoglobin Low, Grade 3: 7.0 to <9.0 g/dL (males) and 6.5 to <8.5 g/dL (females),Grade 4: <7.0 g/dL (males) and <6.5 g/dL (females); Leukocytes Low, Grade 3: 1000 to 1499 cells/mm^3,Grade 4: <1000 cells/mm^3; Lymphocytes Low, Grade 3: 350 to <500 cells/L,Grade 4: <350 cells/L; Neutrophils Low, Grade 3: 400 to 599 cells/mm^3, Grade 4: <400 cells/mm^3; Platelets Low, Grade 3: 25,000 to <50,000 cells/mm^3, Grade 4: <25,000 cells/mm^3. Baseline was defined as latest pre-dose assessment with a non-missing value, including those from unscheduled visits. An increase is defined as an increase in DAIDS grade relative to Baseline grade.	Baseline (Pre-dose, Day-1) and up to Day 26
Secondary	Cohort 1: Number of Participants With Grade Increase Post-Baseline Relative to Baseline in Clinical Chemistry Parameters: Alanine Aminotransferase, Albumin, Alkaline Phosphatase, Amylase, Aspartate Aminotransferase, Bilirubin and Direct Bilirubin	Blood samples were collected for analysis of clinical chemistry parameters. Laboratory abnormalities were graded according to DAIDS grading table Version 2.1. For Alanine Aminotransferase High; Grade 3: 5.0 to <10.0 times (×) Upper Limit Normal (ULN), Grade 4: >=10.0 × ULN; Albumin Low, Grade 3: <2.0 grams per deciliter (g/dL), Grade 4: Not Applicable; Alkaline Phosphatase High, Grade 3: 5.0 to <10.0 × ULN, Grade 4: >=10.0 × ULN; Amylase High, Grade 3: 3.0 to <5.0 × ULN, Grade 4: >=5.0 × ULN; Aspartate Aminotransferase High, Grade 3: 5.0 to <10.0 × ULN, Grade 4: >=10.0 × ULN; Bilirubin High, Grade 3: 2.6 to<5.0 × ULN, Grade 4: >=5.0 × ULN and Direct Bilirubin High, Grade 3: >ULN with other signs and symptoms of hepatotoxicity, Grade 4: >ULN with life-threatening consequences. Baseline was defined as latest pre-dose assessment with a non-missing value, including those from unscheduled visits. An increase is defined as an increase in DAIDS grade relative to Baseline grade.	Baseline (Pre-dose, Day-1) and up to Day 35
Secondary	Cohort 1: Number of Participants With Grade Increase Post-Baseline Relative to Baseline in Clinical Chemistry Parameters: Calcium, Creatine Kinase, Creatinine, Phosphate, Potassium and Sodium	Blood samples were collected for analysis of clinical chemistry parameters. Laboratory abnormalities were graded according to DAIDS grading table Version 2.1. For Calcium High, Grade 3: 12.5 to <13.5 milligrams/deciliter (mg/dL), Grade 4: >=13.5 mg/dL; Calcium Low, Grade 3: 6.1 to <7.0 mg/dL, Grade 4: <6.1 mg/dL; Creatine Kinase High, Grade 3: 10 to <20 × ULN, Grade 4: >=20 × ULN; Creatinine High, Grade 3: >1.8 to <3.5 ULN, Grade 4: >=3.5 × ULN; Phosphate Low, Grade 3: 1.0 to <1.4 mg/dL, Grade 4: <1.0 mg/dL; Potassium High, Grade 3: 6.5 to <7.0 Milliequivalents per liter (mEq/L),Grade 4: >=7.0 mEq/L; Potassium Low, Grade 3: 2.0 to <2.5 mEq/L, Grade 4: <2.00 mEq/L; Sodium High, Grade 3: 154 to <160 mEq/L, Grade 4:>=160 mEq/L; Sodium Low, Grade 3: 121 to <125 mEq/L, Grade 4:<=120 mEq/L. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. An increase is defined as an increase in DAIDS grade relative to Baseline grade.	Baseline (Pre-dose, Day-1) and up to Day 35
Secondary	Cohort 1: Number of Participants With Grade Increase Post-Baseline Relative to Baseline in Clinical Chemistry Parameters: Glucose, Triglycerides, Lipase, Urate and Cholesterol	Blood samples were collected for analysis of clinical chemistry parameters. Laboratory abnormalities were graded according to DAIDS grading table Version 2.1. For Glucose High, Grade 3: >250 to 500 mg/dL, Grade 4: >=500 mg/dL, Glucose Low, Grade 3: 30 to<40 mg/dL, Grade 4:<30 mg/dL; Triglycerides High, Grade 3: >500 to <1.000 mg/dL, Grade 4:>1000 mg/dL; Lipase High, Grade 3: 3.0 to <5.0×ULN, Grade 4:>=5.0×ULN; Urate High, Grade 3: 12.0 to <15.0 mEq/L, Grade 4:>=15.0 mEq/L; Cholesterol High, Grade 3: >=300 mg/dL, Grade 4: Not Applicable. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. An increase is defined as an increase in DAIDS grade relative to Baseline grade.	Baseline (Pre-dose, Day-1) and up to Day 35
Secondary	Cohort 2: Number of Participants With Grade Increase Post-Baseline Relative to Baseline in Clinical Chemistry Parameters: Alanine Aminotransferase, Albumin, Alkaline Phosphatase, Amylase, Aspartate Aminotransferase, Bilirubin and Direct Bilirubin	Blood samples were collected for analysis of clinical chemistry parameters. Laboratory abnormalities were graded according to DAIDS grading table Version 2.1. For Alanine Aminotransferase High; Grade 3: 5.0 to <10.0 × ULN, Grade 4: >=10.0 × ULN; Albumin Low, Grade 3: <2.0 g/dL, Grade 4: Not Applicable; Alkaline Phosphatase High, Grade 3: 5.0 to <10.0 × ULN, Grade 4: >=10.0 × ULN; Amylase High, Grade 3: 3.0 to <5.0 × ULN, Grade 4: >=5.0 × ULN; Aspartate Aminotransferase High, Grade 3: 5.0 to <10.0 × ULN, Grade 4: >=10.0 × ULN; Bilirubin High, Grade 3: 2.6 to<5.0 × ULN, Grade 4: >=5.0 × ULN and Direct Bilirubin High, Grade 3: >ULN with other signs and symptoms of hepatotoxicity, Grade 4: >ULN with life-threatening consequences. Baseline was defined as latest pre-dose assessment with a non-missing value, including those from unscheduled visits. An increase is defined as an increase in DAIDS grade relative to Baseline grade.	Baseline (Pre-dose, Day-1) and up to Day 36
Secondary	Cohort 2: Number of Participants With Grade Increase Post-Baseline Relative to Baseline in Clinical Chemistry Parameters: Calcium, Creatine Kinase, Creatinine, Phosphate, Potassium and Sodium	Blood samples were collected for analysis of clinical chemistry parameters. Laboratory abnormalities were graded according to DAIDS grading table Version 2.1. For Calcium High, Grade 3: 12.5 to <13.5 mg/dL, Grade 4: >=13.5 mg/dL; Calcium Low, Grade 3: 6.1 to <7.0 mg/dL, Grade 4: <6.1 mg/dL; Creatine Kinase High, Grade 3: 10 to <20 × ULN, Grade 4: >=20 × ULN; Creatinine High, Grade 3: >1.8 to <3.5 ULN, Grade 4: >=3.5 × ULN; Phosphate Low, Grade 3: 1.0 to <1.4 mg/dL, Grade 4: <1.0 mg/dL; Potassium High, Grade 3: 6.5 to <7.0 mEq/L,Grade 4: >=7.0 mEq/L; Potassium Low, Grade 3: 2.0 to <2.5 mEq/L, Grade 4: <2.00 mEq/L; Sodium High, Grade 3: 154 to <160 mEq/L, Grade 4:>=160 mEq/L; Sodium Low, Grade 3: 121 to <125 mEq/L, Grade 4:<=120 mEq/L. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. An increase is defined as an increase in DAIDS grade relative to Baseline grade.	Baseline (Pre-dose, Day-1) and up to Day 36
Secondary	Cohort 2: Number of Participants With Grade Increase Post-Baseline Relative to Baseline in Clinical Chemistry Parameters: Glucose, Triglycerides, Lipase, Urate and Cholesterol	Blood samples were collected for analysis of clinical chemistry parameters. Laboratory abnormalities were graded according to DAIDS grading table Version 2.1. For Glucose High, Grade 3: >250 to 500 mg/dL, Grade 4: >=500 mg/dL, Glucose Low, Grade 3: 30 to<40 mg/dL, Grade 4:<30 mg/dL; Triglycerides High, Grade 3: >500 to <1.000 mg/dL, Grade 4:>1000 mg/dL; Lipase High, Grade 3: 3.0 to <5.0×ULN, Grade 4:>=5.0×ULN; Urate High, Grade 3: 12.0 to <15.0 mEq/L, Grade 4:>=15.0 mEq/L; Cholesterol High, Grade 3: >=300 mg/dL, Grade 4: Not Applicable. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. An increase is defined as an increase in DAIDS grade relative to Baseline grade.	Baseline (Pre-dose, Day-1) and up to Day 36
Secondary	Cohort 3: Number of Participants With Grade Increase Post-Baseline Relative to Baseline in Clinical Chemistry Parameters: Alanine Aminotransferase, Albumin, Alkaline Phosphatase, Amylase, Aspartate Aminotransferase, Bilirubin and Direct Bilirubin	Blood samples were collected for analysis of clinical chemistry parameters. Laboratory abnormalities were graded according to DAIDS grading table Version 2.1. For Alanine Aminotransferase High; Grade 3: 5.0 to <10.0 × ULN, Grade 4: >=10.0 × ULN; Albumin Low, Grade 3: <2.0 g/dL, Grade 4: Not Applicable; Alkaline Phosphatase High, Grade 3: 5.0 to <10.0 × ULN, Grade 4: >=10.0 × ULN; Amylase High, Grade 3: 3.0 to <5.0 × ULN, Grade 4: >=5.0 × ULN; Aspartate Aminotransferase High, Grade 3: 5.0 to <10.0 × ULN, Grade 4: >=10.0 × ULN; Bilirubin High, Grade 3: 2.6 to<5.0 × ULN, Grade 4: >=5.0 × ULN and Direct Bilirubin High, Grade 3: >ULN with other signs and symptoms of hepatotoxicity, Grade 4: >ULN with life-threatening consequences. Baseline was defined as latest pre-dose assessment with a non-missing value, including those from unscheduled visits. An increase is defined as an increase in DAIDS grade relative to Baseline grade.	Baseline (Pre-dose, Day-1) and up to Day 26
Secondary	Cohort 3: Number of Participants With Grade Increase Post-Baseline Relative to Baseline in Clinical Chemistry Parameters: Calcium, Creatine Kinase, Creatinine, Phosphate, Potassium and Sodium	Blood samples were collected for analysis of clinical chemistry parameters. Laboratory abnormalities were graded according to DAIDS grading table Version 2.1. For Calcium High, Grade 3: 12.5 to <13.5 mg/dL, Grade 4: >=13.5 mg/dL; Calcium Low, Grade 3: 6.1 to <7.0 mg/dL, Grade 4: <6.1 mg/dL; Creatine Kinase High, Grade 3: 10 to <20 × ULN, Grade 4: >=20 × ULN; Creatinine High, Grade 3: >1.8 to <3.5 ULN, Grade 4: >=3.5 × ULN; Phosphate Low, Grade 3: 1.0 to <1.4 mg/dL, Grade 4: <1.0 mg/dL; Potassium High, Grade 3: 6.5 to <7.0 mEq/L,Grade 4: >=7.0 mEq/L; Potassium Low, Grade 3: 2.0 to <2.5 mEq/L, Grade 4: <2.00 mEq/L; Sodium High, Grade 3: 154 to <160 mEq/L, Grade 4:>=160 mEq/L; Sodium Low, Grade 3: 121 to <125 mEq/L, Grade 4:<=120 mEq/L. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. An increase is defined as an increase in DAIDS grade relative to Baseline grade.	Baseline (Pre-dose, Day-1) and up to Day 26
Secondary	Cohort 3: Number of Participants With Grade Increase Post-Baseline Relative to Baseline in Clinical Chemistry Parameters: Glucose, Triglycerides, Lipase, Urate and Cholesterol	Blood samples were collected for analysis of clinical chemistry parameters. Laboratory abnormalities were graded according to DAIDS grading table Version 2.1. For Glucose High, Grade 3: >250 to 500 mg/dL, Grade 4: >=500 mg/dL, Glucose Low, Grade 3: 30 to<40 mg/dL, Grade 4:<30 mg/dL; Triglycerides High, Grade 3: >500 to <1.000 mg/dL, Grade 4:>1000 mg/dL; Lipase High, Grade 3: 3.0 to <5.0×ULN, Grade 4:>=5.0×ULN; Urate High, Grade 3: 12.0 to <15.0 mEq/L, Grade 4:>=15.0 mEq/L; Cholesterol High, Grade 3: >=300 mg/dL, Grade 4: Not Applicable. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. An increase is defined as an increase in DAIDS grade relative to Baseline grade.	Baseline (Pre-dose, Day-1) and up to Day 26
Secondary	Cohort 1: Number of Participants With Grade Increase Post-Baseline Relative to Baseline in Urinalysis Parameters	Urine samples were collected for urinalysis parameters. Laboratory abnormalities were graded according to DAIDS grading table Version 2.1. For Erythrocytes High, Grade 3: Gross, with or without clots OR with Red Blood Cells (RBC) casts OR intervention indicated, Grade 4: Life-threatening consequences; Glucose High, Grade 3: >2+ (proportionate concentration by dipstick test) or >500 mg, Grade 4: >500 mg; Protein High, Grade 3: 3+ (proportionate concentration by dipstick test) or higher, Grade 4: Not Applicable. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. An increase is defined as an increase in DAIDS grade relative to Baseline grade.	Baseline (Pre-dose, Day-1) and up to Day 35
Secondary	Cohort 2: Number of Participants With Grade Increase Post-Baseline Relative to Baseline in Urinalysis Parameters	Urine samples were collected for urinalysis parameters. Laboratory abnormalities were graded according to DAIDS grading table Version 2.1. For Erythrocytes High, Grade 3: Gross, with or without clots OR with RBC casts OR intervention indicated, Grade 4: Life-threatening consequences; Glucose High, Grade 3: >2+ (proportionate concentration by dipstick test) or >500 mg, Grade 4: >500 mg; Protein High, Grade 3: 3+ (proportionate concentration by dipstick test) or higher, Grade 4: Not Applicable. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. An increase is defined as an increase in DAIDS grade relative to Baseline grade.	Baseline (Pre-dose, Day-1) and up to Day 36
Secondary	Cohort 3: Number of Participants With Grade Increase Post-Baseline Relative to Baseline in Urinalysis Parameters	Urine samples were collected for urinalysis parameters. Laboratory abnormalities were graded according to DAIDS grading table Version 2.1. For Erythrocytes High, Grade 3: Gross, with or without clots OR with RBC casts OR intervention indicated, Grade 4: Life-threatening consequences; Glucose High, Grade 3: >2+ (proportionate concentration by dipstick test) or >500 mg, Grade 4: >500 mg; Protein High, Grade 3: 3+ (proportionate concentration by dipstick test) or higher, Grade 4: Not Applicable. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. An increase is defined as an increase in DAIDS grade relative to Baseline grade.	Baseline (Pre-dose, Day-1) and up to Day 26
Secondary	Cohort 1: Number of Participants With Vital Sign Values of Potential Clinical Importance (PCI) Criteria	Vital signs including systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse rate were measured in a supine position after atleast 5 minutes of rest. The PCI ranges for vitals were as follows; for SBP <85 or >140 millimeters of mercury (mmHg), for DBP <45 or >90 mmHg, for pulse rate <40 or >100 beats per minute. The number of participants with vital signs of PCI were presented.	Up to Day 35
Secondary	Cohort 2: Number of Participants With Vital Sign Values of PCI Criteria	Vital signs including SBP, DBP and pulse rate were measured in a supine position after atleast 5 minutes of rest. The PCI ranges for vitals were as follows; for SBP <85 or >140 mmHg, for DBP <45 or >90 mmHg, for pulse rate <40 or >100 beats per minute. The number of participants with vital signs of PCI were presented.	Up to Day 36
Secondary	Cohort 3: Number of Participants With Vital Sign Values of PCI Criteria	Vital signs including SBP, DBP and pulse rate were measured in a supine position after atleast 5 minutes of rest. The PCI ranges for vitals were as follows; for SBP <85 or >140 mmHg, for DBP <45 or >90 mmHg, for pulse rate <40 or >100 beats per minute. The number of participants with vital signs of PCI were presented.	Up to Day 26
Secondary	Cohort 1: Number of Participants With Clinically Significant Abnormal Electrocardiogram (ECG) Findings	A 12-lead ECG was recorded with the participant in a supine position using an automated ECG machine. Clinically significant abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition. Data for number of participants with clinically significant abnormal ECG findings were reported. Data has been presented for the participants with respect to the actual treatment received in respective treatment periods.	Day 1 (2,4,6 Hours), Day 7 and Day 11 in Treatment Period 1; Day 12 (2,4,6 Hours), Day 21 in Treatment Period 2; Day 22 (2,4,6 Hours), Day 26 and Day 35 in Treatment Period 3
Secondary	Cohort 2: Number of Participants With Clinically Significant Abnormal ECG Findings	A 12-lead ECG was recorded with the participant in a supine position using an automated ECG machine. Clinically significant abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition. Data for number of participants with clinically significant abnormal ECG findings were reported. Data has been presented for the participants with respect to the actual treatment received in respective treatment periods.	Day 1 (2,4,6 Hours), Day 7 and Day 11 in Treatment Period 1; Day 12 (2,4,6 Hours), Day 21 in Treatment Period 2; Day 22 (2,4,6 Hours), Day 26 and Day 36 in Treatment Period 3
Secondary	Cohort 3: Number of Participants With Clinically Significant Abnormal ECG Findings	A 12-lead ECG was recorded with the participant in a supine position using an automated ECG machine. Clinically significant abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition. Data for number of participants with clinically significant abnormal ECG findings were reported. Data has been presented for the participants with respect to the actual treatment received in respective treatment periods.	Day 1 (2,4,6 Hours) in Treatment Period 1; Day 8 (2,4,6 Hours), Day 9 (2,4,6 Hours), Day 26 in Treatment Period 2