Dolutegravir Pediatric Liquid Formulation Study

Study Overview
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Brief Summary
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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.

Official Title
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Non-randomized, Sequential, Fixed-sequence Evaluation of Prototype Dolutegravir Liquid Formulations Versus 5mg Dolutegravir Dispersible Tablets Following Single-dose Fasted-state Administrations to Normal Healthy Adult Participants

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Dolutegravir dispersible tablet
* Drug: Dolutegravir oral suspension
* Drug: Dolutegravir oral solution


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: The study is non-randomized 6 period, 6 way fixed sequential design.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Subject receiving Dolutegravir 10 mg<br>Subject will receive a prototype equivalent to DTG 10 mg liquid formulation in period 1, a prototype equivalent to DTG 10 mg liquid formulation in period 2, a DTG 10 mg dispersible tablet in Period 3, each period will be separated by washout period of >= 7 days, if required a prototype equivalent to DTG 10 mg liquid formulation in period 4, a prototype equivalent to DTG 10 mg liquid formulation in period 5, and a prototype equivalent to DTG 10 mg liquid formulation in period 6 will be evaluated. | Drug: Dolutegravir dispersible tablet<br>* 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.<br>Drug: Dolutegravir oral suspension<br>* 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.<br>Drug: Dolutegravir oral solution<br>* DTG will be available as an oral solution with dosing strength of 2 mg per ml will be administered orally for prescribed regimen.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 24 hours | 
| 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. | Baseline (Day -1) and Day 4 | 
| 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. | Baseline (Day -1) and Day 4 | 
| 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. | Up to Week 11 | 
| 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. | Baseline (Day -1) | 
| 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. | Baseline (Day -1) | 
| 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. | Baseline (Day -1) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dolutegravir, Human immunodeficiency virus, Sequential study, Dispersible tablet, Suspension, Liquid solution