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