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

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: HIV Infections
• Intervention / Treatment: Drug: DRV/r FDC (120/20mg)

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Alessandra Nardone; Phone Number: 0039 049 716 9822; Email: alessandra.nardone@pentafoundation.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

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, …).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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)

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: PENTA Foundation
• Collaborators: Baylor College of Medicine; Institut National de la Santé Et de la Recherche Médicale, France; Centre Mère et Enfant de la Fondation Chantal Biya; AMS-PHPT Research Collaboration; University of Zimbabwe Clinical Research Centre (UZCRC); Centre Hospitalier National d'Enfants Albert Royer
• Investigators: Study Chair: Albert Faye, Hôpital Robert Debré and Université Paris Cité

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2024
• Primary Completion (Estimated): January 1, 2025
• Study Completion (Estimated): June 1, 2026

Study Registration Dates

• First Submitted: November 7, 2023
• First Submitted That Met QC Criteria: November 15, 2023
• First Posted (Actual): November 18, 2023

Study Record Updates

• Last Update Posted (Actual): November 18, 2023
• Last Update Submitted That Met QC Criteria: November 15, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: HIV; Ritonavir; Darunavir; Paediatrics; new formulation
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Urogenital Diseases; Genital Diseases; HIV Infections
• Other Study ID Numbers: UNIVERSAL2

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No