TY - JOUR
T1 - D3/Penta 21 clinical trial design
T2 - 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
AU - D3 trial team
AU - Turkova, Anna
AU - Chan, Man K
AU - Kityo, Cissy
AU - Kekitiinwa, Adeodata R
AU - Musoke, Philippa
AU - Violari, Avy
AU - Variava, Ebrahim
AU - Archary, Moherndran
AU - Cressey, Tim R
AU - Chalermpantmetagul, Suwalai
AU - Sawasdichai, Kanokkorn
AU - Ounchanum, Pradthana
AU - Kanjanavanit, Suparat
AU - Srirojana, Sakulrat
AU - Srirompotong, Ussanee
AU - Welch, Steven
AU - Bamford, Alasdair
AU - Epalza, Cristina
AU - Fortuny, Clàudia
AU - Colbers, Angela
AU - Nastouli, Eleni
AU - Walker, Simon
AU - Carr, Dan
AU - Conway, Magda
AU - Spyer, Moira J
AU - Parkar, Nazia
AU - White, Iona
AU - Nardone, Alessandra
AU - Thomason, Margaret J
AU - Ferrand, Rashida A
AU - Giaquinto, Carlo
AU - Ford, Deborah
N1 - © 2024 Published by Elsevier Inc. This is an author-produced version of the published paper. Uploaded in accordance with the University’s Research Publications and Open Access policy.
PY - 2024/7/1
Y1 - 2024/7/1
N2 - 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.
AB - 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.
U2 - 10.1016/j.cct.2024.107540
DO - 10.1016/j.cct.2024.107540
M3 - Article
C2 - 38636725
SN - 1551-7144
VL - 142
JO - Contemporary Clinical Trials
JF - Contemporary Clinical Trials
M1 - 107540
ER -