UNIVERSAL 1: Pharmacokinetic Study of a Novel DTG/FTC/TAF Dose Ratio for Children

Study Overview
=================
Brief Summary
-----------------
This study aims to find out whether treating children living with HIV with three anti-HIV medicines, dolutegravir (DTG), emtricitabine (FTC) and tenofovir alafenamide (TAF), with a novel dose ratio will achieve adequate drug concentrations and is safe. The optimal DTG/FTC/TAF dose ratio will be used for the development of a fixed-dose combination dispersible tablet.

Detailed Description
-----------------
Dolutegravir (DTG), Emtricitabine (FTC) and Tenofovir alafenamide (TAF) are anti-HIV medicines. DTG works very well, can be taken once-daily and has few side effects. In international treatment guidelines, DTG is one of the most recommended medicines for adults and young people. Emtricitabine is also one of the preferred medicines in anti-HIV treatment for adults and children. Tenofovir alafenamide (TAF) is not yet recommended in children <25 kg, however TAF could potentially be used safely and effectively in children. Combining DTG, FTC and TAF in a specific dose ratio may offer treatment that is safe and effective. If so, a combination dispersible tablet containing these three medicines can be developed and this will allow the same HIV medicines to be used across children and adults. This study will include 50 children aged 28 days to less than 10 years old who are living with HIV. All participants will receive the same treatment with DTG, FTC and TAF. Depending on their weight, participants will receive a certain number of tablets that can be dispersed and taken once a day. All children in the study will have clinical assessments. Blood tests will be performed to make sure that the medicines are safe and, at some visits, participants and carers will also be asked to answer some questions on taking medicine and how medicine tastes. All children will be followed up for 24 weeks.

Official Title
-----------------
Pharmacokinetic Study of an Optimized Dose Ratio of Dolutegravir/Emtricitabine/Tenofovir Alafenamide Fumarate: Expediting a UNIVERSAL First Line Regimen for All Children Living With HIV in Africa

Conditions
-----------------
HIV Infection

Intervention / Treatment
-----------------
* Drug: dolutegravir (DTG)/emtricitabine (FTC)/tenofovir alafenamide (TAF) regimen


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age between 28 days and 10 years old Weighing 3 to <25 kg Confirmed HIV-1 infection (local, molecular methods) A parent or legal guardian is willing and able to give informed consent on behalf of the child as per national legislation and willing to adhere to the protocol Participant is willing to give informed assent if the trial site clinician deems them old enough and able to understand the age-appropriate information about participation in the study Girls who have reached menarche must have a negative pregnancy test at screening Subject is willing to start DTG/FTC/TAF regimen in the novel dose ratio for HIV treatment Subjects already on a DTG-based ART regimen should be virologically suppressed at screening Exclusion Criteria: Age between 28 days and 10 years old Weighing 3 to <25 kg Confirmed HIV-1 infection (local, molecular methods) A parent or legal guardian is willing and able to give informed consent on behalf of the child as per national legislation and willing to adhere to the protocol Participant is willing to give informed assent if the trial site clinician deems them old enough and able to understand the age-appropriate information about participation in the study Girls who have reached menarche must have a negative pregnancy test at screening Subject is willing to start DTG/FTC/TAF regimen in the novel dose ratio for HIV treatment Subjects already on a DTG-based ART regimen should be virologically suppressed at screening History or presence of known allergy to DTG, FTC or TAF Alanine aminotransferase (ALT) ≥5 times the upper limit of normal (ULN), OR ALT ≥3xULN AND bilirubin ≥2xULN Patients with severe hepatic impairment or unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, or persistent jaundice), known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones) Current or anticipated need for TB therapy during the study Use of rifampicin-based therapy within 4 weeks before start trial Presence of comedication known to interact with trial medications Known resistance to INSTI or NRTI

Ages Eligible for Study
-----------------
Minimum Age: 28 Days
Maximum Age: 10 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: An interventional, phase I/II, multicenter, single-arm study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: dolutegravir (DTG)/emtricitabine (FTC)/tenofovir alafenamide (TAF) regimen<br>Switch or start dolutegravir (DTG)/emtricitabine (FTC)/tenofovir alafenamide (TAF) regimen with a novel dose ratio for HIV treatment | Drug: dolutegravir (DTG)/emtricitabine (FTC)/tenofovir alafenamide (TAF) regimen<br>* Switch or start dolutegravir (DTG)/emtricitabine (FTC)/tenofovir alafenamide (TAF) regimen with a novel dose ratio for HIV treatment<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary endpoints for DTG: | - Geometric mean Ctrough concentration | From enrollment to the end of treatment at 24 weeks | 
| Primary endpoints for DTG: | Percentage of individual Ctrough concentrations below the 90% effective concentration (EC90) (0.32 mg/L) | From enrollment to the end of treatment at 24 weeks | 
| Primary endpoints for DTG: | - Geometric mean DTG Ctrough, Cmax, and AUC | From enrollment to the end of treatment at 24 weeks | 
| Primary safety endpoints | - Occurrence of serious adverse events | From enrollment to the end of treatment at 24 weeks | 
| Primary safety endpoints | - Occurrence of new clinical and laboratory grade 3 and 4 adverse events | From enrollment to the end of treatment at 24 weeks | 
| Primary safety endpoints | Occurrence of adverse events (of any grade) leading to treatment modification | From enrollment to the end of treatment at 24 weeks | 
| Primary endpoints for FTC/TAF: | - Geometric mean Ctrough, Cmax, and AUC | From enrollment to the end of treatment at 24 weeks | 
| Primary endpoints for FTC/TAF: | Intracellular tenofovir diphosphate (TDP) levels at 24 hours acquired through dried blood spot analysis | From enrollment to the end of treatment at 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy endpoints | - Viral load (VL) <400 c/ml at 24 weeks | From enrollment to the end of treatment at 24 weeks | 
| Efficacy endpoints | Occurrence of new or recurrent WHO clinical stage 3 or 4 event | From enrollment to the end of treatment at 24 weeks |