HIV Infections
Conditions
Keywords
Dolutegravir, Human immunodeficiency virus, Sequential study, Dispersible tablet, Suspension, Liquid solution
Brief summary
This is an open-label, single-center, single dose, non-randomized, sequential, fixed-sequence study, which will evaluate pharmacokinetics (PK) of dolutegravir (DTG) in healthy adult subjects. The study will contain 6 periods with five prototype liquid formulations for evaluation in fasted state. In period 1, 2 and 3 single reference dose of 2 dispersible tablets of 5 milligram DTG will be administered and at least 2 liquid prototype DTG formulations (containing a target total dose of 10mg DTG). There will be a wash-out period of 7 days between each period. In period 4 through 6, there would be options to evaluate additional prototype liquid formulations. The total duration of study will be up to 17 weeks. DTG has been found to be safe and effective in adults infected with human immunodeficiency virus (HIV). DTG dispersible tablets have been developed primarily for use in children from 4 weeks to 6 years of age, and a DTG liquid formulation are is being developed to study the appropriate dose needed for the HIV-exposed and infected neonatal population in the first four weeks of life. Approximately 18 subjects will be enrolled in this study.
Interventions
DTG will be available as an oral tablet with dosing strength of 5 mg 2 tablet will be dispersed in water will be administered orally for prescribed regimen.
DRUGDolutegravir oral suspension
DTG will be available as an oral suspension with dosing strength of 5 mg per milliliter (ml) or 2 mg per ml with miglyol 812N or ethyl cellulose in miglyol 812N as vehicle for suspension administered orally for prescribed regimen.
DRUGDolutegravir oral solution
DTG will be available as an oral solution with dosing strength of 2 mg per ml will be administered orally for prescribed regimen.
Sponsors
ViiV Healthcare
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
The study is non-randomized 6 period, 6 way fixed sequential design.
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Subject must be 18 to 55 years of age inclusive, at the time of signing the informed consent. * Subjects who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and cardiac evaluation. * Body weight \>= 50 kg (110 pounds \[lbs\]) for men and \>=45 kg (99 lbs) for women and body mass index (BMI) within the range 18.5-31.0 kilogram per meter square (kg/m\^2) (inclusive). * Male and female subjects will be part of study. A female subject is eligible to participate if she is not pregnant or breastfeeding, and is not a woman of childbearing potential (WOCBP). * Additional requirements for pregnancy testing, if needed, during and after study intervention; The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy. * Subject should be capable of giving signed informed consent as which includes compliance with the requirements and restrictions listed in the informed consent form (ICF).
Exclusion criteria
* History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study intervention; or interfering with the interpretation of data. * Abnormal blood pressure as determined by the investigator. * Alanine transaminase (ALT) \>1.5 times upper limit of normal (ULN). * Bilirubin \>1.5times ULN (isolated bilirubin \>1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%). * Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). * QT correction using Fridericia Formula (QTcF) \>450 millisecond (msec) * Past or intended use of over-the-counter or prescription medication (including herbal medications) within 7 days prior to dosing. Paracetamol. * History of allergy or sensitivity to DTG. * Participation in the study would result in loss of blood or blood products in excess of 500 mL within 56 days. * Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day. * Current enrollment or past participation within the last 30 days before signing of consent in this or any other clinical study involving an investigational study intervention or any other type of medical research. * Presence of Hepatitis B surface antigen (HBsAg), or a positive hepatitis B core antibody with a negative hepatitis B surface antibody at screening. * Positive Hepatitis C antibody test result at screening: Subjects with positive Hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative Hepatitis C ribonucleic acid (RNA) test is obtained. * Positive Hepatitis C RNA test result at screening or within 3 months prior to first dose of study intervention. * Positive pre-study drug/alcohol screen. * Positive HIV antibody test. * Regular use of known drugs of abuse. * Regular alcohol consumption within one month prior to the study defined as: For the United Kingdom an average weekly intake of \>14 units for males or females. One unit is equivalent to 8 gram (g) of alcohol: a half-pint (\ 240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits. * Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products (e.g. nicotine patches or vaporizing devices) within 6 months prior to screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration Time Curve From Time Zero to the Last Quantifiable Time Point (AUC[0-t]) for DTG | Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3,3.5, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose | Blood samples were collected at indicated time points and pharmacokinetic (PK) analysis was performed. PK parameters were determined by non-compartmental methods. |
| AUC From Time Zero to Infinity (AUC[0-inf]) for DTG | Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3,3.5, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose | Blood samples were collected at indicated time points and PK analysis was performed. PK parameters were determined by non-compartmental methods. |
| Maximum Observed Concentration (Cmax) for DTG | Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3,3.5, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose | Blood samples were collected at indicated time points and PK analysis was performed. PK parameters were determined by non-compartmental methods. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Elimination Half-life (t½) Following Administration of DTG | Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3,3.5, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose | Blood samples were collected at indicated time points and PK analysis was performed. PK parameters were determined by non-compartmental methods. |
| Apparent Elimination Rate Constant (Lambda z) Following Administration of DTG | Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose | Blood samples were collected at indicated time points and PK analysis was performed. PK parameters were determined by non-compartmental methods. |
| Percentage of AUC(0-inf) Extrapolated (%AUCex) Following Administration of DTG | Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3,3.5, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose | Blood samples were collected at indicated time points and PK analysis was performed. PK parameters were determined by non-compartmental methods. |
| AUC From Time Zero to 24 Hours (AUC[0-24]) Following Administration of DTG | Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3,3.5, 4, 5, 6, 8, 12, 16, and 24 hours post-dose | Blood samples were collected at indicated time points and PK analysis was performed. PK parameters were determined by non-compartmental methods. |
| AUC From Time Zero to 72 Hours (AUC[0-72]) Following Administration of DTG | Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 48 and 72 hours post-dose | Blood samples were collected at indicated time points and PK analysis was performed. PK parameters were determined by non-compartmental methods. |
| Apparent Oral Clearance (CL/F) Following Administration of DTG | Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3,3.5, 4, 5, 6, 8, 12, 16, 24, 48 and 72 hours post-dose | Blood samples were collected at indicated time points and PK analysis was performed. PK parameters were determined by non-compartmental methods. |
| Last Quantifiable Concentration (Ct) Following Administration of DTG | Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3,3.5, 4, 5, 6, 8, 12, 16, 24, 48 and 72 hours post-dose | Blood samples were collected at indicated time points and PK analysis was performed. PK parameters were determined by non-compartmental methods. |
| Absorption Lag Time (Tlag) Following Administration of DTG | Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3,3.5, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose | Blood samples were collected at indicated time points and PK analysis was performed. PK parameters were determined by non-compartmental methods. |
| Concentration at 24hours Post-dose (C24) Following Administration of DTG | 24 hours | Blood samples were collected at indicated time points and PK analysis was performed. PK parameters were determined by non-compartmental methods. |
| Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | Baseline (Day -1) and Day 4 | SBP and DBP was measured in a supine position after at least 5 minutes of rest for the participant in a quiet setting without any distractions using a completely automated device. Day -1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specific time point value. |
| Change From Baseline in Pulse Rate | Baseline (Day -1) and Day 4 | Pulse rate was measured in a supine position after at least 5 minutes of rest for the participant in a quiet setting without any distractions using a completely automated device. Day -1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specific time point value. |
| Number of Participants With Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs) | Up to Week 11 | 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. A 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, any other situation according to medical or scientific judgement. |
| Number of Participants With Clinically Significant Hematology Parameters | Baseline (Day -1) | Blood samples were collected to analyze the following hematology parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets, hemoglobin, hematocrit, mean corpuscular hemoglobin (MCH), mean corpuscular volume (MCV), percentage reticulocytes and red blood cell count. Data for clinically significant abnormal hematology parameters have been presented. Clinically significant abnormal laboratory 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. |
| Number of Participants With Clinically Significant Chemistry Parameters | Baseline (Day -1) | Blood samples were collected to analyze the following clinical chemistry parameters: Potassium, calcium, sodium, creatinine, glucose, alkaline phosphatase, Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), Blood urea nitrogen (BUN), total and direct bilirubin, total protein and creatine kinase. Data for clinically significant abnormal clinical chemistry parameters have been presented. Clinically significant abnormal laboratory 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. |
| Number of Participants With Clinically Significant Urine Parameters | Baseline (Day -1) | Urine samples were collected to analyze the following urinalysis parameters: specific gravity, potential of hydrogen (pH). Clinically significant abnormal laboratory 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. |
| Apparent Oral Volume of Distribution (Vz/F) Following Administration of DTG | Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3,3.5, 4, 5, 6, 8, 12, 16, 24, 48 and 72 hours post-dose | Blood samples were collected at indicated time points and PK analysis was performed. PK parameters were determined by non-compartmental methods. |
| Time of Maximum Observed Concentration (Tmax) Following Administration of DTG | Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose | Blood samples were collected at indicated time points and PK analysis was performed. PK parameters were determined by non-compartmental methods. |
| Time of Last Quantifiable Concentration (Tlast) Following Administration of DTG | Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose | Blood samples were collected at indicated time points and PK analysis was performed. PK parameters were determined by non-compartmental methods. |
Countries
United Kingdom
Participant flow
Recruitment details
This was a Phase 1, open-label, non-randomized, single dose study in healthy adult participants conducted at a single center in the United Kingdom (UK) to assess the prototype liquid fomulations of dolutegravir (DTG) versus DTG dispersible tablets (reference).
Pre-assignment details
A total of 22 participants were enrolled in the study. The washout time between dosing in consecutive study periods was a minimum of 7 days.
Participants by arm
| Arm | Count |
|---|---|
| Prototype A/DTG Reference/Prototype B Participants were administered a single oral dose of 5 milligrams (mg) per milliliter (mL) DTG sodium oral suspension (Prototype A), for a total of 10 mg in Period 1 followed by a single oral dose of two 5 mg DTG dispersible tablets dispersed in water (DTG reference) in Period 2. Participants further received a single oral dose of 2 mg/mL DTG sodium oral liquid (Prototype B) in Period 3, also receiving a total dose of 10 mg. There was a minimum washout of 7 days between doses. | 22 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Period 2 (4 Days) | Withdrawal by Subject | 3 |
| Period 3 (4 Days) | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Prototype A/DTG Reference/Prototype B |
|---|---|
| Age, Continuous | 31.3 Years STANDARD_DEVIATION 7.93 |
| Race/Ethnicity, Customized BLACK OR AFRICAN AMERICAN | 2 Participants |
| Race/Ethnicity, Customized CENTRAL/SOUTH ASIAN HERITAGE | 1 Participants |
| Race/Ethnicity, Customized WHITE/CAUCASIAN/EUROPEAN HERITAGE | 19 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 18 | 0 / 19 | 0 / 22 |
| other Total, other adverse events | 3 / 18 | 3 / 19 | 4 / 22 |
| serious Total, serious adverse events | 0 / 18 | 0 / 19 | 0 / 22 |
Outcome results
Primary
Area Under the Plasma Concentration Time Curve From Time Zero to the Last Quantifiable Time Point (AUC[0-t]) for DTG
Blood samples were collected at indicated time points and pharmacokinetic (PK) analysis was performed. PK parameters were determined by non-compartmental methods.
Time frame: Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3,3.5, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose
Population: PK Population comprised of participants in the 'All Participants' (who were randomized and received at least one dose of study medication)' population for whom a PK sample was obtained and had evaluable PK assay results. Only those participants with data available at the specified data points were analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Prototype A | Area Under the Plasma Concentration Time Curve From Time Zero to the Last Quantifiable Time Point (AUC[0-t]) for DTG | 11.9968 Hours*micrograms per milliliter | Geometric Coefficient of Variation 22.7 |
| Prototype B | Area Under the Plasma Concentration Time Curve From Time Zero to the Last Quantifiable Time Point (AUC[0-t]) for DTG | 13.7921 Hours*micrograms per milliliter | Geometric Coefficient of Variation 20.5 |
| DTG Reference | Area Under the Plasma Concentration Time Curve From Time Zero to the Last Quantifiable Time Point (AUC[0-t]) for DTG | 12.1944 Hours*micrograms per milliliter | Geometric Coefficient of Variation 22.7 |
90% CI: [0.91, 1.03]
90% CI: [1.05, 1.2]
Primary
AUC From Time Zero to Infinity (AUC[0-inf]) for DTG
Blood samples were collected at indicated time points and PK analysis was performed. PK parameters were determined by non-compartmental methods.
Time frame: Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3,3.5, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose
Population: PK Population. Only those participants with data available at the specified data points were analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Prototype A | AUC From Time Zero to Infinity (AUC[0-inf]) for DTG | 12.8297 Hours*micrograms per milliliter | Geometric Coefficient of Variation 23 |
| Prototype B | AUC From Time Zero to Infinity (AUC[0-inf]) for DTG | 14.8099 Hours*micrograms per milliliter | Geometric Coefficient of Variation 21.8 |
| DTG Reference | AUC From Time Zero to Infinity (AUC[0-inf]) for DTG | 13.0715 Hours*micrograms per milliliter | Geometric Coefficient of Variation 23.8 |
90% CI: [0.91, 1.03]
90% CI: [1.06, 1.2]
Primary
Maximum Observed Concentration (Cmax) for DTG
Blood samples were collected at indicated time points and PK analysis was performed. PK parameters were determined by non-compartmental methods.
Time frame: Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3,3.5, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose
Population: PK Population. Only those participants with data available at the specified data points were analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Prototype A | Maximum Observed Concentration (Cmax) for DTG | 0.9200 Micrograms per milliliter | Geometric Coefficient of Variation 14.4 |
| Prototype B | Maximum Observed Concentration (Cmax) for DTG | 0.9993 Micrograms per milliliter | Geometric Coefficient of Variation 17.6 |
| DTG Reference | Maximum Observed Concentration (Cmax) for DTG | 0.8200 Micrograms per milliliter | Geometric Coefficient of Variation 26.1 |
90% CI: [1.01, 1.19]
90% CI: [1.13, 1.33]
Secondary
Absorption Lag Time (Tlag) Following Administration of DTG
Blood samples were collected at indicated time points and PK analysis was performed. PK parameters were determined by non-compartmental methods.
Time frame: Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3,3.5, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose
Population: PK Population. Only those participants with data available at the specified data points were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Prototype A | Absorption Lag Time (Tlag) Following Administration of DTG | 0.0 Hours |
| Prototype B | Absorption Lag Time (Tlag) Following Administration of DTG | 0.0 Hours |
| DTG Reference | Absorption Lag Time (Tlag) Following Administration of DTG | 0.0 Hours |
Secondary
Apparent Elimination Rate Constant (Lambda z) Following Administration of DTG
Blood samples were collected at indicated time points and PK analysis was performed. PK parameters were determined by non-compartmental methods.
Time frame: Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose
Population: PK Population. Only those participants with data available at the specified data points were analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Prototype A | Apparent Elimination Rate Constant (Lambda z) Following Administration of DTG | 0.0508 Per hour | Geometric Coefficient of Variation 17.5 |
| Prototype B | Apparent Elimination Rate Constant (Lambda z) Following Administration of DTG | 0.0475 Per hour | Geometric Coefficient of Variation 19.1 |
| DTG Reference | Apparent Elimination Rate Constant (Lambda z) Following Administration of DTG | 0.0510 Per hour | Geometric Coefficient of Variation 20.9 |
Secondary
Apparent Oral Clearance (CL/F) Following Administration of DTG
Blood samples were collected at indicated time points and PK analysis was performed. PK parameters were determined by non-compartmental methods.
Time frame: Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3,3.5, 4, 5, 6, 8, 12, 16, 24, 48 and 72 hours post-dose
Population: PK Population. Only those participants with data available at the specified data points were analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Prototype A | Apparent Oral Clearance (CL/F) Following Administration of DTG | 0.7794 Liters per hour | Geometric Coefficient of Variation 23 |
| Prototype B | Apparent Oral Clearance (CL/F) Following Administration of DTG | 0.6752 Liters per hour | Geometric Coefficient of Variation 21.8 |
| DTG Reference | Apparent Oral Clearance (CL/F) Following Administration of DTG | 0.7650 Liters per hour | Geometric Coefficient of Variation 23.8 |
Secondary
Apparent Oral Volume of Distribution (Vz/F) Following Administration of DTG
Blood samples were collected at indicated time points and PK analysis was performed. PK parameters were determined by non-compartmental methods.
Time frame: Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3,3.5, 4, 5, 6, 8, 12, 16, 24, 48 and 72 hours post-dose
Population: PK Population. Only those participants with data available at the specified data points were analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Prototype A | Apparent Oral Volume of Distribution (Vz/F) Following Administration of DTG | 15.3369 Liters | Geometric Coefficient of Variation 13.8 |
| Prototype B | Apparent Oral Volume of Distribution (Vz/F) Following Administration of DTG | 14.2222 Liters | Geometric Coefficient of Variation 15 |
| DTG Reference | Apparent Oral Volume of Distribution (Vz/F) Following Administration of DTG | 14.9889 Liters | Geometric Coefficient of Variation 19.1 |
Secondary
AUC From Time Zero to 24 Hours (AUC[0-24]) Following Administration of DTG
Blood samples were collected at indicated time points and PK analysis was performed. PK parameters were determined by non-compartmental methods.
Time frame: Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3,3.5, 4, 5, 6, 8, 12, 16, and 24 hours post-dose
Population: PK Population. Only those participants with data available at the specified data points were analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Prototype A | AUC From Time Zero to 24 Hours (AUC[0-24]) Following Administration of DTG | 9.2541 Hours*micrograms per milliliter | Geometric Coefficient of Variation 16.4 |
| Prototype B | AUC From Time Zero to 24 Hours (AUC[0-24]) Following Administration of DTG | 10.2918 Hours*micrograms per milliliter | Geometric Coefficient of Variation 15.8 |
| DTG Reference | AUC From Time Zero to 24 Hours (AUC[0-24]) Following Administration of DTG | 9.2356 Hours*micrograms per milliliter | Geometric Coefficient of Variation 18.7 |
Secondary
AUC From Time Zero to 72 Hours (AUC[0-72]) Following Administration of DTG
Blood samples were collected at indicated time points and PK analysis was performed. PK parameters were determined by non-compartmental methods.
Time frame: Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 48 and 72 hours post-dose
Population: PK Population. Only those participants with data available at the specified data points were analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Prototype A | AUC From Time Zero to 72 Hours (AUC[0-72]) Following Administration of DTG | 12.2645 Hours*micrograms per milliliter | Geometric Coefficient of Variation 22 |
| Prototype B | AUC From Time Zero to 72 Hours (AUC[0-72]) Following Administration of DTG | 14.1062 Hours*micrograms per milliliter | Geometric Coefficient of Variation 20.8 |
| DTG Reference | AUC From Time Zero to 72 Hours (AUC[0-72]) Following Administration of DTG | 12.5289 Hours*micrograms per milliliter | Geometric Coefficient of Variation 21.9 |
Secondary
Change From Baseline in Pulse Rate
Pulse rate was measured in a supine position after at least 5 minutes of rest for the participant in a quiet setting without any distractions using a completely automated device. Day -1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specific time point value.
Time frame: Baseline (Day -1) and Day 4
Population: Safety Population. Only those participants with data available at the specified data points were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Prototype A | Change From Baseline in Pulse Rate | 6.1 Beats per minute | Standard Deviation 11.06 |
| Prototype B | Change From Baseline in Pulse Rate | 6.8 Beats per minute | Standard Deviation 8.54 |
| DTG Reference | Change From Baseline in Pulse Rate | 4.1 Beats per minute | Standard Deviation 11.38 |
Secondary
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
SBP and DBP was measured in a supine position after at least 5 minutes of rest for the participant in a quiet setting without any distractions using a completely automated device. Day -1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specific time point value.
Time frame: Baseline (Day -1) and Day 4
Population: Safety Population. All participants who were randomized and received at least one dose of study medication were part of Safety Population. Only those participants with data available at the specified data points were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Prototype A | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | SBP, Day 4 | 0.3 Millimeters of mercury | Standard Deviation 10.5 |
| Prototype A | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | DBP, Day 4 | -0.7 Millimeters of mercury | Standard Deviation 6.83 |
| Prototype B | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | SBP, Day 4 | 4.9 Millimeters of mercury | Standard Deviation 10.97 |
| Prototype B | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | DBP, Day 4 | 1.8 Millimeters of mercury | Standard Deviation 6.07 |
| DTG Reference | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | SBP, Day 4 | 7.3 Millimeters of mercury | Standard Deviation 9.59 |
| DTG Reference | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | DBP, Day 4 | 7.8 Millimeters of mercury | Standard Deviation 7.05 |
Secondary
Concentration at 24hours Post-dose (C24) Following Administration of DTG
Blood samples were collected at indicated time points and PK analysis was performed. PK parameters were determined by non-compartmental methods.
Time frame: 24 hours
Population: PK Population. Only those participants with data available at the specified data points were analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Prototype A | Concentration at 24hours Post-dose (C24) Following Administration of DTG | 0.1763 Micrograms per milliliter | Geometric Coefficient of Variation 28.5 |
| Prototype B | Concentration at 24hours Post-dose (C24) Following Administration of DTG | 0.2167 Micrograms per milliliter | Geometric Coefficient of Variation 21.7 |
| DTG Reference | Concentration at 24hours Post-dose (C24) Following Administration of DTG | 0.1917 Micrograms per milliliter | Geometric Coefficient of Variation 22.7 |
Secondary
Elimination Half-life (t½) Following Administration of DTG
Blood samples were collected at indicated time points and PK analysis was performed. PK parameters were determined by non-compartmental methods.
Time frame: Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3,3.5, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose
Population: PK Population. Only those participants with data available at the specified data points were analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Prototype A | Elimination Half-life (t½) Following Administration of DTG | 13.6389 Hours | Geometric Coefficient of Variation 17.5 |
| Prototype B | Elimination Half-life (t½) Following Administration of DTG | 14.5997 Hours | Geometric Coefficient of Variation 19.1 |
| DTG Reference | Elimination Half-life (t½) Following Administration of DTG | 13.5807 Hours | Geometric Coefficient of Variation 20.9 |
Secondary
Last Quantifiable Concentration (Ct) Following Administration of DTG
Blood samples were collected at indicated time points and PK analysis was performed. PK parameters were determined by non-compartmental methods.
Time frame: Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3,3.5, 4, 5, 6, 8, 12, 16, 24, 48 and 72 hours post-dose
Population: PK Population. Only those participants with data available at the specified data points were analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Prototype A | Last Quantifiable Concentration (Ct) Following Administration of DTG | 0.0398 Micrograms per milliliter | Geometric Coefficient of Variation 35.4 |
| Prototype B | Last Quantifiable Concentration (Ct) Following Administration of DTG | 0.0412 Micrograms per milliliter | Geometric Coefficient of Variation 53.2 |
| DTG Reference | Last Quantifiable Concentration (Ct) Following Administration of DTG | 0.0421 Micrograms per milliliter | Geometric Coefficient of Variation 39.9 |
Secondary
Number of Participants With Clinically Significant Chemistry Parameters
Blood samples were collected to analyze the following clinical chemistry parameters: Potassium, calcium, sodium, creatinine, glucose, alkaline phosphatase, Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), Blood urea nitrogen (BUN), total and direct bilirubin, total protein and creatine kinase. Data for clinically significant abnormal clinical chemistry parameters have been presented. Clinically significant abnormal laboratory 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.
Time frame: Baseline (Day -1)
Population: Safety Population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Prototype A | Number of Participants With Clinically Significant Chemistry Parameters | 0 Participants |
| Prototype B | Number of Participants With Clinically Significant Chemistry Parameters | 0 Participants |
| DTG Reference | Number of Participants With Clinically Significant Chemistry Parameters | 0 Participants |
Secondary
Number of Participants With Clinically Significant Hematology Parameters
Blood samples were collected to analyze the following hematology parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets, hemoglobin, hematocrit, mean corpuscular hemoglobin (MCH), mean corpuscular volume (MCV), percentage reticulocytes and red blood cell count. Data for clinically significant abnormal hematology parameters have been presented. Clinically significant abnormal laboratory 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.
Time frame: Baseline (Day -1)
Population: Safety Population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Prototype A | Number of Participants With Clinically Significant Hematology Parameters | 0 Participants |
| Prototype B | Number of Participants With Clinically Significant Hematology Parameters | 0 Participants |
| DTG Reference | Number of Participants With Clinically Significant Hematology Parameters | 0 Participants |
Secondary
Number of Participants With Clinically Significant Urine Parameters
Urine samples were collected to analyze the following urinalysis parameters: specific gravity, potential of hydrogen (pH). Clinically significant abnormal laboratory 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.
Time frame: Baseline (Day -1)
Population: Safety Population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Prototype A | Number of Participants With Clinically Significant Urine Parameters | 0 Participants |
| Prototype B | Number of Participants With Clinically Significant Urine Parameters | 0 Participants |
| DTG Reference | Number of Participants With Clinically Significant Urine Parameters | 0 Participants |
Secondary
Number of Participants With Non-serious Adverse Events (AEs) 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 intervention, whether or not considered related to the study intervention. A 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, any other situation according to medical or scientific judgement.
Time frame: Up to Week 11
Population: Safety Population.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Prototype A | Number of Participants With Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs) | Non-serious AEs | 3 Participants |
| Prototype A | Number of Participants With Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 Participants |
| Prototype B | Number of Participants With Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs) | Non-serious AEs | 3 Participants |
| Prototype B | Number of Participants With Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 Participants |
| DTG Reference | Number of Participants With Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs) | Non-serious AEs | 4 Participants |
| DTG Reference | Number of Participants With Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 Participants |
Secondary
Percentage of AUC(0-inf) Extrapolated (%AUCex) Following Administration of DTG
Blood samples were collected at indicated time points and PK analysis was performed. PK parameters were determined by non-compartmental methods.
Time frame: Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3,3.5, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose
Population: PK Population. Only those participants with data available at the specified data points were analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Prototype A | Percentage of AUC(0-inf) Extrapolated (%AUCex) Following Administration of DTG | 6.1049 Percentage of AUCex | Geometric Coefficient of Variation 36.8 |
| Prototype B | Percentage of AUC(0-inf) Extrapolated (%AUCex) Following Administration of DTG | 5.8582 Percentage of AUCex | Geometric Coefficient of Variation 57.1 |
| DTG Reference | Percentage of AUC(0-inf) Extrapolated (%AUCex) Following Administration of DTG | 6.3086 Percentage of AUCex | Geometric Coefficient of Variation 36.3 |
Secondary
Time of Last Quantifiable Concentration (Tlast) Following Administration of DTG
Blood samples were collected at indicated time points and PK analysis was performed. PK parameters were determined by non-compartmental methods.
Time frame: Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose
Population: PK Population. Only those participants with data available at the specified data points were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Prototype A | Time of Last Quantifiable Concentration (Tlast) Following Administration of DTG | 48.0000 Hours |
| Prototype B | Time of Last Quantifiable Concentration (Tlast) Following Administration of DTG | 48.0333 Hours |
| DTG Reference | Time of Last Quantifiable Concentration (Tlast) Following Administration of DTG | 48.0000 Hours |
Secondary
Time of Maximum Observed Concentration (Tmax) Following Administration of DTG
Blood samples were collected at indicated time points and PK analysis was performed. PK parameters were determined by non-compartmental methods.
Time frame: Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose
Population: PK Population. Only those participants with data available at the specified data points were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Prototype A | Time of Maximum Observed Concentration (Tmax) Following Administration of DTG | 1.50 Hours |
| Prototype B | Time of Maximum Observed Concentration (Tmax) Following Administration of DTG | 0.50 Hours |
| DTG Reference | Time of Maximum Observed Concentration (Tmax) Following Administration of DTG | 0.75 Hours |