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

被引：5

作者：

Turkova, Anna ^{[1
]}

Chan, Man K. ^{[1
]}

Kityo, Cissy ^{[2
]}

Kekitiinwa, Adeodata R. ^{[3
]}

Musoke, Philippa ^{[4
]}

Violari, Avy ^{[5
]}

Variava, Ebrahim ^{[5
]}

Archary, Moherndran ^{[6
]}

Cressey, Tim R. ^{[7
]}

Chalermpantmetagul, Suwalai ^{[7
]}

Sawasdichai, Kanokkorn ^{[8
]}

Ounchanum, Pradthana ^{[9
]}

Kanjanavanit, Suparat ^{[10
]}

Srirojana, Sakulrat ^{[11
]}

Srirompotong, Ussanee ^{[12
]}

Welch, Steven ^{[13
]}

Bamford, Alasdair ^{[14
,15
]}

Epalza, Cristina ^{[16
]}

Fortuny, Claudia ^{[17
,18
]}

Colbers, Angela ^{[19
]}

Nastouli, Eleni ^{[15
,20
]}

Walker, Simon ^{[21
]}

Carr, Dan ^{[22
]}

Conway, Magda ^{[23
]}

Spyer, Moira J. ^{[1
,15
]}

Parkar, Nazia ^{[1
]}

White, Iona ^{[1
]}

Nardone, Alessandra ^{[23
]}

Thomason, Margaret J. ^{[1
]}

Ferrand, Rashida A. ^{[24
]}

Giaquinto, Carlo ^{[23
,25
]}

Ford, Deborah ^{[1
]}

机构：

[1] UCL, Med Res Council Clin Trials Unit, London, England

[2] Joint Clin Res Ctr, Kampala, Uganda

[3] Baylor Coll Med, Kampala, Uganda

[4] Makerere Univ, Johns Hopkins Univ Res Collaborat, Kampala, Uganda

[5] Univ Witwarsrand, Perinatal HIV Res Unit, Johannesburg, South Africa

[6] Univ KwaZulu Natal, King Edward VIII Hosp, Enhancing Care Fdn, Dept Paediat & Children Hlth, Durban, South Africa

[7] Chiang Mai Univ, Fac Associated Med Sci, AMS IRD PHPT Res Collaborat, Chiang Mai, Thailand

[8] Prapokklao Hosp, Chanthaburi, Thailand

[9] Chiangrai Prachanukroh Hosp, Chiang Rai, Thailand

[10] Nakornping Hosp, Chiang Mai, Thailand

[11] Kalasin Hosp, Kalasin, Thailand

[12] Khon Kaen Hosp, Khon Kaen, Thailand

[13] Univ Hosp Birmingham NHS Fdn Trust, Heartlands Hosp, Birmingham, England

[14] Great Ormond St Hosp Children NHS Fdn Trust, London, England

[15] UCL, Inst Child Hlth, Great Ormond St, London, England

[16] Inst Invest Sanitaria Hosp, 12 Octubre imas12, Madrid, Spain

[17] Sant Joan de Deu Childrens Hosp, Inst Recerca Sant Joan de Deu, Infect Dis Dept, Barcelona, Spain

[18] Univ Barcelona, Fac Med & Hlth Sci, Dept Surg & Med Surg Specialties, Barcelona, Spain

[19] Radboud Univ Nijmegen, Radboud Inst Med Innovat Hlth Sci, Dept Pharm, Med Ctr, Nijmegen, Netherlands

[20] Univ Coll London Hosp NHS Trust, Adv Pathogen Diagnost Unit, London, England

[21] Univ York, Ctr Hlth Econ, York, England

[22] Univ Liverpool, Dept Mol & Clin Pharmacol, Liverpool, England

[23] Fdn Penta ETS, Padua, Italy

[24] London Sch Hyg & Trop Med, London, England

[25] Univ Padua, Dept Women & Child Hlth, Padua, Italy

来源：

CONTEMPORARY CLINICAL TRIALS | 2024年 / 142卷

基金：

英国医学研究理事会;

关键词：

Randomised control trial; HIV; Children; Adolescents; Dolutegravir/lamivudine; Two-drug therapy; ANTIRETROVIRAL THERAPY; PLUS LAMIVUDINE; EFFICACY; ADULTS;

D O I：

10.1016/j.cct.2024.107540

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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 noninferiority 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.

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