Clinical trial NCT03921723: Dolutegravir Pediatric Liquid Formulation Study
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: HIV Infections
Keywords: Dolutegravir
Human immunodeficiency virus
Sequential study
Dispersible tablet
Suspension
Liquid solution
Lead sponsor: ViiV Healthcare
Sponsor class: INDUSTRY
First posted: 2019-04-19
Enrollment: 22
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: The study is non-randomized 6 period, 6 way fixed sequential design.
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Area Under the Plasma Concentration Time Curve From Time Zero to the Last Quantifiable Time Point (AUC[0-t]) for DTG
timeFrame: 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
measure: AUC From Time Zero to Infinity (AUC[0-inf]) for DTG
timeFrame: 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
measure: Maximum Observed Concentration (Cmax) for DTG
timeFrame: 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 outcomes:
measure: Absorption Lag Time (Tlag) Following Administration of DTG
timeFrame: 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
measure: Time of Maximum Observed Concentration (Tmax) Following Administration of DTG
timeFrame: 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
measure: Time of Last Quantifiable Concentration (Tlast) Following Administration of DTG
timeFrame: 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
measure: Elimination Half-life (t½) Following Administration of DTG
timeFrame: 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
measure: Apparent Elimination Rate Constant (Lambda z) Following Administration of DTG
timeFrame: 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
measure: Percentage of AUC(0-inf) Extrapolated (%AUCex) Following Administration of DTG
timeFrame: 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
measure: AUC From Time Zero to 24 Hours (AUC[0-24]) Following Administration of DTG
timeFrame: 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
measure: AUC From Time Zero to 72 Hours (AUC[0-72]) Following Administration of DTG
timeFrame: 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
measure: Apparent Oral Clearance (CL/F) Following Administration of DTG
timeFrame: 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
measure: Last Quantifiable Concentration (Ct) Following Administration of DTG
timeFrame: 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
measure: Apparent Oral Volume of Distribution (Vz/F) Following Administration of DTG
timeFrame: 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
measure: Concentration at 24hours Post-dose (C24) Following Administration of DTG
timeFrame: 24 hours
measure: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
timeFrame: Baseline (Day -1) and Day 4
measure: Change From Baseline in Pulse Rate
timeFrame: Baseline (Day -1) and Day 4
measure: Number of Participants With Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Up to Week 11
measure: Number of Participants With Clinically Significant Hematology Parameters
timeFrame: Baseline (Day -1)
measure: Number of Participants With Clinically Significant Chemistry Parameters
timeFrame: Baseline (Day -1)
measure: Number of Participants With Clinically Significant Urine Parameters
timeFrame: Baseline (Day -1)
Other outcomes:
Locations:
city: Nottingham
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: ViiV Healthcare
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: