Adaption of an ongoing clinical trial to quickly respond to gaps in changing international recommendations: the experience of D2EFT

Papot, Emmanuelle and Jacoby, Simone and Arlinda, Dona and Avihingsanon, Anchalee and Azwa, Iskandar and Borok, Margaret and Brown, Dannae and Cissé, Mohamed and Dao, Sounkalo and Eriobu, Nnakelu and Kaplan, Richard and Karyana, Muhammad and Kumarasamy, Nagalingeswaran and Lee, Johnnie and Losso, Marcelo H. and Matthews, Gail V. and Perelis, Leonardo and Perez-Casas, Carmen and Ruxrungtham, Kiat and Watkins, Melynda and Lane, H. Clifford and Kelleher, Anthony and Law, Matthew and Polizzotto, Mark N. (2022) Adaption of an ongoing clinical trial to quickly respond to gaps in changing international recommendations: the experience of D2EFT. HIV Research and Clinical Practice, 23 (1). 37 -46. ISSN 2578-7489, DOI

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A rapidly changing landscape of antiretrovirals and their procurement at scale has permitted the evaluation of new optimised second-line antiretroviral therapy (ART) in low- and middle-income countries. D2EFT is an open-label randomised controlled non-inferiority phase IIIB/IV trial in people living with HIV-1 (PWH) whose first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART is failing. At inception, it compared a standard of care of boosted darunavir with two nucleos(t)ide reverse transcriptase inhibitors (NRTIs) to the novel NRTI-sparing regimen of boosted darunavir with dolutegravir. Implemented in 2017, participating sites were across Africa, Asia and Latin America. Around the time of implementation, the World Health Organization updated its treatment guidelines and recommended scaling up tenofovir disoproxil fumarate-lamivudine-dolutegravir (TLD). This situation pushed D2EFT investigators to consider the impact of the roll-out of TLD on the D2EFT research question. The protocol team agreed it was important to study TLD in second-line when an NNRTI regimen was failing, and focused on options to expedite the work by studying the question within the existing trial and network. All key issues (statistical, programmatic and financial) were reviewed to assess the benefits and risks of adding a third arm to the ongoing study, as opposed to developing a new randomised clinical trial with the same control arm and within the same network. The development of a new trial was deemed to be longer than adding a third arm, and to create a challenging situation with two competing clinical trials at the same sites which would slow down recruitment and impair both trials. On the other hand, adding a third arm would be demanding in terms of operationalisation, increased sample size and statistical biases to control. The optimal strategy was deemed to be the addition of a third arm, arriving retrospectively at a simplified multi-arm multi-stage clinical trial design to achieve statistical validity. The D2EFT study maintains additional value in a quickly evolving second-line ART strategy allowed by the progress in global access to ART. © 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

Item Type: Article
Funders: Ennie Chidziva-Chikuse, Margaret Borok, ViiV Healthcare and Janssen donation, National Institutes of Health [Grant No: 18Q065, 19Q120], Gilead Sciences, ViiV Healthcare, Cilag, National Health and Medical Research Council [Grant No: APP1104610]
Uncontrolled Keywords: Anti-HIV Agents; Darunavir; Drug Therapy, Combination; HIV Infections; Humans; Retrospective Studies; Reverse Transcriptase Inhibitors; Viral Load; darunavir; darunavir plus ritonavir; dolutegravir; dolutegravir plus lamivudine plus tenofovir disoproxil; emtricitabine plus tenofovir disoproxil; lamivudine plus tenofovir disoproxil; lopinavir plus ritonavir; raltegravir; anti human immunodeficiency virus agent; darunavir; RNA directed DNA polymerase inhibitor; adaptive clinical trial; advisory committee; antiretroviral therapy; Article; funding; human; Human immunodeficiency virus infected patient; Human immunodeficiency virus infection; multicenter study (topic); phase 3 clinical trial (topic); phase 4 clinical trial (topic); practice guideline; program feasibility; protocol compliance; randomized controlled trial (topic); sample size; World Health Organization; clinical trial; combination drug therapy; controlled study; Human immunodeficiency virus infection; phase 3 clinical trial; randomized controlled trial; retrospective study; virus load
Subjects: R Medicine > R Medicine (General)
Divisions: Faculty of Medicine > Medicine Department
Depositing User: Ms. Juhaida Abd Rahim
Date Deposited: 28 Dec 2023 06:38
Last Modified: 28 Dec 2023 06:38

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