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

Anna Turkova; Man K Chan; Cissy Kityo; Adeodata R Kekitiinwa; Philippa Musoke; Avy Violari; Ebrahim Variava; Moherndran Archary; Tim R Cressey; Suwalai Chalermpantmetagul; Kanokkorn Sawasdichai; Pradthana Ounchanum; Suparat Kanjanavanit; Sakulrat Srirojana; Ussanee Srirompotong; Steven Welch; Alasdair Bamford; Cristina Epalza; Clàudia Fortuny; Angela Colbers; Eleni Nastouli; Simon Walker; Dan Carr; Magda Conway; Moira J Spyer; Nazia Parkar; Iona White; Alessandra Nardone; Margaret J Thomason; Rashida A Ferrand; Carlo Giaquinto; Deborah Ford; D3 trial team

doi:10.1016/j.cct.2024.107540

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 Apr 16:142:107540. doi: 10.1016/j.cct.2024.107540. Online ahead of print.

Authors

Anna Turkova¹, Man K Chan², Cissy Kityo³, Adeodata R Kekitiinwa⁴, Philippa Musoke⁵, Avy Violari⁶, Ebrahim Variava⁶, Moherndran Archary⁷, Tim R Cressey⁸, Suwalai Chalermpantmetagul⁸, Kanokkorn Sawasdichai⁹, Pradthana Ounchanum¹⁰, Suparat Kanjanavanit¹¹, Sakulrat Srirojana¹², Ussanee Srirompotong¹³, Steven Welch¹⁴, Alasdair Bamford¹⁵, Cristina Epalza¹⁶, Clàudia Fortuny¹⁷, Angela Colbers¹⁸, Eleni Nastouli¹⁹, Simon Walker²⁰, Dan Carr²¹, Magda Conway²², Moira J Spyer²³, Nazia Parkar², Iona White², Alessandra Nardone²², Margaret J Thomason², Rashida A Ferrand²⁴, Carlo Giaquinto²⁵, Deborah Ford²; D3 trial team

Affiliations

¹ Medical Research Council Clinical Trials Unit at University College London, UK. Electronic address: a.turkova@ucl.ac.uk.
² Medical Research Council Clinical Trials Unit at University College London, UK.
³ Joint Clinical Research Centre, Kampala, Uganda.
⁴ Baylor College of Medicine, Kampala, Uganda.
⁵ Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda.
⁶ Perinatal HIV Research Unit, University of the Witwarsrand, Johannesburg, South Africa.
⁷ Department of Paediatrics and Children Health, King Edward VIII Hospital, Enhancing Care Foundation, University of KwaZulu-Natal, Durban, South Africa.
⁸ AMS-IRD PHPT Research Collaboration, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand.
⁹ Prapokklao Hospital, Chantaburi, Thailand.
¹⁰ Chiangrai Prachanukroh Hospital, Chiang Rai, Thailand.
¹¹ Nakornping Hospital, Chiang Mai, Thailand.
¹² Kalasin Hospital, Kalasin, Thailand.
¹³ Khon Kaen Hospital, Khon Kaen, Thailand.
¹⁴ Heartlands Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
¹⁵ Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK; University College London Great Ormond Street Institute of Child Health, London, UK.
¹⁶ Instituto de Investigación Sanitaria Hospital, 12 de Octubre (imas12), Madrid, Spain.
¹⁷ Infectious Diseases Department, Institut de Recerca Sant Joan de Déu, Sant Joan de Déu Children's Hospital, Barcelona, Spain; Department of Surgery and Medico-Surgical Specialties, Faculty of Medicine and Health Sciences, Universitat de Barcelona, Barcelona, Spain.
¹⁸ Department of Pharmacy, Radboud Institute for Medical InnovationHealth Sciences, Radboud University Medical Center, Nijmegen, Netherlands.
¹⁹ University College London Great Ormond Street Institute of Child Health, London, UK; University College London Hospitals NHS Trust, Advanced Pathogen Diagnostics Unit, London, UK.
²⁰ Centre for Health Economics, University of York, Heslington, York, UK.
²¹ Department of Molecular and Clinical Pharmacology, University of Liverpool, UK.
²² Fondazione Penta ETS, Padova, Italy.
²³ Medical Research Council Clinical Trials Unit at University College London, UK; University College London Great Ormond Street Institute of Child Health, London, UK.
²⁴ London School of Hygiene and Tropical Medicine, UK.
²⁵ Fondazione Penta ETS, Padova, Italy; University of Padova, Department of Women and Child Health, Padova, Italy.

PMID: 38636725
DOI: 10.1016/j.cct.2024.107540

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.

Associated data

ClinicalTrials.gov/NCT04337450