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

Study Overview
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Brief Summary
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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.

Detailed Description
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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. 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.

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

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: DRV/r FDC (120/20mg)


Participation Criteria
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Eligibility Criteria
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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, …).

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

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: Single Group Assignment
Interventional Model Description: Open-label, multi-centre, single-arm, phase I/II study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A Twice daily<br>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)<br>* Initiation of DRV/r FDC (120/20mg) as part of antiretroviral therapy (ART) with an Optimized Background Therapy (OBT)<br>|
| Experimental: Cohort B Once daily<br>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)<br>* Initiation of DRV/r FDC (120/20mg) as part of antiretroviral therapy (ART) with an Optimized Background Therapy (OBT)<br>|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, Darunavir, Ritonavir, Paediatrics, new formulation