Dolutegravir Pediatric Liquid Formulation Study

Phase 1

Completed

• Conditions: HIV Infections
• Interventions: Drug: Dolutegravir dispersible tablet; Drug: Dolutegravir oral suspension; Drug: Dolutegravir oral solution

• Registration Number: NCT03921723
• Lead Sponsor: ViiV Healthcare

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2019-04-17
• Study First Submitted QC: 2019-04-17
• Study First Posted: 2019-04-19
• Study Start: 2019-05-07
• Primary Completion: 2019-07-25
• Study Completion: 2019-07-25
• Status Verified: 2020-07
• Results First Submitted: 2020-07-09
• Results First Submitted QC: 2020-07-09
• Last Update Submitted: 2020-07-09
• Results First Posted: 2020-07-31
• Last Update Posted: 2020-07-31

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 22

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).

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Subject receiving Dolutegravir 10 mg	Dolutegravir oral suspension	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.
Subject receiving Dolutegravir 10 mg	Dolutegravir dispersible tablet	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.
Subject receiving Dolutegravir 10 mg	Dolutegravir oral solution	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.

Primary Outcome Measures

Name	Time	Method
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.
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.

Secondary Outcome Measures

Name	Time	Method
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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 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.

Trial Locations

Locations (1)

GSK Investigational Site; 🇬🇧 Nottingham, United Kingdom