D3/Penta 21 clinical trial design: A randomised non-inferiority trial with nested drug licensing substudy to assess dolutegravir and lamivudine fixed dose formulations for the maintenance of virological suppression in children with HIV-1 infection, aged 2 to 15 years

Contemp Clin Trials. 2024 Jul:142:107540. doi: 10.1016/j.cct.2024.107540. Epub 2024 Apr 16.

Abstract

Background: There is increasing interest in utilising two-drug regimens for HIV treatment with the goal of reducing toxicity and improve acceptability. The D3 trial evaluates the efficacy and safety of DTG/3TC in children and adolescents and includes a nested pharmacokinetics(PK) substudy for paediatric drug licensing.

Methods: D3 is an ongoing open-label, phase III, 96-week non-inferiority randomised controlled trial(RCT) conducted in South Africa, Spain, Thailand, Uganda and the United Kingdom. D3 has enrolled 386 children aged 2- < 15 years, virologically suppressed for ≥6 months, with no prior treatment failure. Participants were randomised 1:1 to receive DTG/3TC or DTG plus two nucleoside reverse transcriptase inhibitors(NRTIs), stratified by region, age (2- < 6, 6- < 12, 12- < 15 years) and DTG use at enrolment (participants permitted to start DTG at enrolment). The primary outcome is confirmed HIV-1 RNA viral rebound ≥50 copies/mL by 96-weeks. The trial employs the Smooth Away From Expected(SAFE) non-inferiority frontier, which specifies the non-inferiority margin and significance level based on the observed event risk in the control arm. The nested PK substudy evaluates WHO weight-band-aligned dosing in the DTG/3TC arm.

Discussion: D3 is the first comparative trial evaluating DTG/3TC in children and adolescents. Implications of integrating a PK substudy and supplying data for prompt regulatory submission, were carefully considered to ensure the integrity of the ongoing trial. The trial uses an innovative non-inferiority frontier for the primary analysis to allow for a lower-than-expected confirmed viral rebound risk in the control arm, while ensuring interpretability of results and maintaining the planned sample size in an already funded trial.

Trial registration: International Standard Randomised Clinical Trial Number Register: ISRCTN17157458. European Clinical Trials Database: 2020-001426-57.

Clinicaltrials: gov: NCT04337450.

Keywords: Adolescents; Children; Dolutegravir/lamivudine; HIV; Randomised control trial; Two-drug therapy.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Adolescent
  • Anti-HIV Agents / administration & dosage
  • Anti-HIV Agents / pharmacokinetics
  • Anti-HIV Agents / therapeutic use
  • Child
  • Child, Preschool
  • Drug Combinations
  • Drug Therapy, Combination
  • Equivalence Trials as Topic
  • Female
  • HIV Infections* / drug therapy
  • HIV-1* / drug effects
  • Heterocyclic Compounds, 3-Ring* / administration & dosage
  • Heterocyclic Compounds, 3-Ring* / pharmacokinetics
  • Heterocyclic Compounds, 3-Ring* / therapeutic use
  • Humans
  • Lamivudine* / administration & dosage
  • Lamivudine* / therapeutic use
  • Male
  • Oxazines* / administration & dosage
  • Oxazines* / therapeutic use
  • Piperazines* / administration & dosage
  • Pyridones* / administration & dosage
  • Pyridones* / pharmacokinetics
  • Pyridones* / therapeutic use
  • RNA, Viral
  • Reverse Transcriptase Inhibitors / administration & dosage
  • Reverse Transcriptase Inhibitors / pharmacokinetics
  • Reverse Transcriptase Inhibitors / therapeutic use
  • Viral Load

Substances

  • Anti-HIV Agents
  • dolutegravir
  • Drug Combinations
  • Heterocyclic Compounds, 3-Ring
  • Lamivudine
  • Oxazines
  • Piperazines
  • Pyridones
  • Reverse Transcriptase Inhibitors
  • RNA, Viral

Associated data

  • ClinicalTrials.gov/NCT04337450