UNIVERSAL2: Pharmacokinetics Safety and Acceptability of DRV/r for Children Living With HIV

Sponsor

PENTA Foundation (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT06139796

Collaborator

AMS-PHPT Research Collaboration (Other), Institut National de la Santé Et de la Recherche Médicale, France (Other), Centre Mère et Enfant de la Fondation Chantal Biya (Other), Centre Hospitalier National d'Enfants Albert Royer (Other), University of Zimbabwe Clinical Research Centre (UZCRC) (Other), Baylor College of Medicine (Other)

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

The UNIVERSAL2 study is a research project designed to evaluate a newly developed formulation of an approved drug for children living with HIV aged over 3 years and weighing between 10 and 25 kg. The aim of UNIVERSAL2 is to determine the right dosage of this new formulation.

Condition or Disease	Intervention/Treatment	Phase
HIV Infections	Drug: DRV/r FDC (120/20mg)	Phase 1/Phase 2

Detailed Description

It is a combination of two anti-HIV medicines called darunavir (DRV) and ritonavir (RTV). The DRV/RTV combination is well known and has been used for a long time in adults and children to treat HIV infection but there is no combined pediatric formulation that has been adapted to the needs of children ("child friendly" formulation).

The new combination has been developed in the form of fixed-dose combination tablets with a dose of 120 mg of DRV and 20 mg of RTV (DRV/RTV 120/20) in each tablet. Depending on their weight and the need to take the medication once or twice a day, children may receive 2, 3 or 4 DRV/RTV 120/20 tablets at any given time.

The aim of UNIVERSAL2 is to determine the correct dosage and to assess the safety and acceptability of the new drug for children living with HIV.

The study will focus on two groups of children.

Group A will include children with one or two specific viral genetic mutations linked to DRV resistance and will receive DRV/RTV twice daily.
Group B will include children without DRV resistance viral gene mutations who will receive DRV/RTV once daily.

All children will start taking the DRV/r at the beginning of the study. After two weeks, participants will be invited to stay at the clinic for blood samples to be taken at different times of the day in order to understand how the drug is absorbed, metabolised and excreted in the body (pharmacokinetic tests). They will then continue to be monitored at the clinic several times over a 24-week period, with additional blood tests to be sure children are tolerating the drug well and that it helps to control HIV replication. Participants and their carers will also be asked to answer some questions to determine how acceptable the new tablets are to children and carers.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

50 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Intervention Model Description:

Open-label, multi-centre, single-arm, phase I/II studyOpen-label, multi-centre, single-arm, phase I/II study

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Pharmacokinetics, Safety and Acceptability of a Solid Paediatric Fixed-dose Combination of Darunavir/Ritonavir (DRV/r) 120/20 mg for Children Living With HIV

Anticipated Study Start Date :

Jun 1, 2024

Anticipated Primary Completion Date :

Jan 1, 2025

Anticipated Study Completion Date :

Jun 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort A Twice daily DRV/r twice daily (BID): 30 children with 1 or 2 DRV RAM* weighing 10 to <25 kg (10 per weight band: 10-13.9kg, 14-19.9kg, 20-24.9kg)	Drug: DRV/r FDC (120/20mg) Initiation of DRV/r FDC (120/20mg) as part of antiretroviral therapy (ART) with an Optimized Background Therapy (OBT)
Experimental: Cohort B Once daily DRV/r once daily (OD): 20 children with no DRV RAM* weighing 10 to <20 kg (10 per weight band: 10-13.9kg, 14-19.9kg) *DRV RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V	Drug: DRV/r FDC (120/20mg) Initiation of DRV/r FDC (120/20mg) as part of antiretroviral therapy (ART) with an Optimized Background Therapy (OBT)

Arm

Intervention/Treatment

Experimental: Cohort A Twice daily

DRV/r twice daily (BID): 30 children with 1 or 2 DRV RAM* weighing 10 to <25 kg (10 per weight band: 10-13.9kg, 14-19.9kg, 20-24.9kg)

Drug: DRV/r FDC (120/20mg)

Initiation of DRV/r FDC (120/20mg) as part of antiretroviral therapy (ART) with an Optimized Background Therapy (OBT)

Experimental: Cohort B Once daily

DRV/r once daily (OD): 20 children with no DRV RAM* weighing 10 to <20 kg (10 per weight band: 10-13.9kg, 14-19.9kg) *DRV RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V

Drug: DRV/r FDC (120/20mg)

Initiation of DRV/r FDC (120/20mg) as part of antiretroviral therapy (ART) with an Optimized Background Therapy (OBT)

Outcome Measures

Primary Outcome Measures

Pharmacokinetics Darunavir [From enrollment to the end of treatment at 24 weeks]
area under the concentration-time curve (AUC0-12) (Cohort A)
Pharmacokinetics Darunavir [From enrollment to the end of treatment at 24 weeks]
area under the concentration-time curve (AUC0-24) (Cohort B)
Pharmacokinetics Darunavir [From enrollment to the end of treatment at 24 weeks]
maximum plasma concentration (Cmax)
Pharmacokinetics Darunavir [From enrollment to the end of treatment at 24 weeks]
12 hours or 24 hours post dose concentrations (C12 or C24)
Safety events [From enrollment to the end of treatment at 24 weeks]
serious adverse events (SAEs)
Safety events [From enrollment to the end of treatment at 24 weeks]
adverse events (AEs) of Grade 3 or higher
Safety events [From enrollment to the end of treatment at 24 weeks]
treatment related AEs
Safety events [From enrollment to the end of treatment at 24 weeks]
AEs leading to treatment discontinuation or modification

Secondary Outcome Measures

Acceptability [From enrollment to the end of treatment at 24 weeks]
Questionnaire
Efficacy of treatment [From enrollment to the end of treatment at 24 weeks]
HIV-1 RNA <50 c/mL and <400 c/mL
Efficacy of treatment [From enrollment to the end of treatment at 24 weeks]
Occurrence of a new or recurrent WHO clinical stage 3 or 4 event
Efficacy of treatment [From enrollment to the end of treatment at 24 weeks]
Change in CD4 cell count and percentage from baseline to week 24
Pharmacokinetics Ritonavir [From enrollment to the end of treatment at 24 weeks]
RTV PK parameters and DRV unbound concentrations

Eligibility Criteria

Criteria

Ages Eligible for Study:

3 Years to 17 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

• Confirmed HIV-1 infection
Aged ≥ 3 years
With unsuppressed viral load (HIV-1 RNA viral load > 1000 c/mL) on ART-regimen and eligible to switch to new DRV/r 120/20 mg-based regimen per investigator's judgement
Able to swallow the 120/20 mg DRV/r tablets
Willing to receive the 120/20 mg DRV/r tablets
Parents or guardians, and children where appropriate, willing and able to give informed consent and to adhere to the protocol
Cohort-specific inclusion criteria:

Cohort A:

Have 1 or 2 DRV resistance-associated mutations (RAMs)*
Weigh 10 to <25 kg at screening

Cohort B:

Have no DRV RAMs*
Weigh 10 to <20 kg at screening. *DRV RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V

Exclusion Criteria:

Presence of >2 darunavir RAMs*
Failure of protease genotypic resistance testing at baseline, except if treatment history indicates that it is very unlikely
Resistance to all NRTI available in the country or impossibility to define an OBT
Intercurrent illness (enrolment can take place after the illness resolves)
Creatinine ≥ 1.8 Upper Limit of Normal (ULN) or ALT ≥ 5 ULN or (ALT ≥ 3 ULN and bilirubin ≥2 ULN) at screening.
Severe hepatic impairment or unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, oesophageal or gastric varices, or persistent jaundice), or known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)
History or presence of known allergy or other contraindication to DRV/r or their components as described in the Summary of Product Characteristics (SmPC)
Concomitant medications that may interact with the current antiretroviral treatment, in particular TB drugs (i.e: rifampicin, rifabutin, rifapentine, …).