Multi-arm, multi-stage randomised controlled trials for evaluating therapeutic HIV cure interventions

Moore, Christopher; Stöhr, Wolfgang; Crook, Angela M.; Richert, Laura; Pantaleo, Giuseppe; García, Felipe; Vella, Stefano; Lévy, Yves; Thiébaut, Rodolphe; McCormack, Sheena

doi:10.1016/s2352-3018(19)30082-7

Cited by 7 publications

(5 citation statements)

References 31 publications

(36 reference statements)

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“…We are aware of multiple further MAMS trials that are currently being considered or designed for the late-phase setting including, but not limited to, multiple sclerosis,52 Parkinson’s disease,53 HIV 54. We note that to date, there has been a lack of use for this design in areas such as cardiology.…”

Section: Discussionmentioning

confidence: 99%

“…We are aware of multiple further MAMS trials that are currently being considered or designed for the late-phase Open access but not limited to, multiple sclerosis, 52 Parkinson's disease, 53 HIV. 54 We note that to date, there has been a lack of use for this design in areas such as cardiology. However, given the number of potential new interventions, large population sizes and ongoing medical needs in the field of cardiology, it is likely that there would be many benefits from using an MAMS design in the late-phase setting for cardiovascular conditions.…”

Section: Considerations For the Futurementioning

confidence: 99%

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Uptake of the multi-arm multi-stage (MAMS) adaptive platform approach: a trial-registry review of late-phase randomised clinical trials

et al. 2022

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BackgroundFor medical conditions with numerous interventions worthy of investigation, there are many advantages of a multi-arm multi-stage (MAMS) platform trial approach. However, there is currently limited knowledge on uptake of the MAMS design, especially in the late-phase setting. We sought to examine uptake and characteristics of late-phase MAMS platform trials, to enable better planning for teams considering future use of this approach.DesignWe examined uptake of registered, late-phase MAMS platforms in the EU clinical trials register, Australian New Zealand Clinical Trials Registry, International Standard Randomised Controlled Trial Number registry, Pan African Clinical Trials Registry, WHO International Clinical Trial Registry Platform and databases: PubMed, Medline, Cochrane Library, Global Health Library and EMBASE. Searching was performed and review data frozen on 1 April 2021. MAMS platforms were defined as requiring two or more comparison arms, with two or more trial stages, with an interim analysis allowing for stopping of recruitment to arms and typically the ability to add new intervention arms.Results62 late-phase clinical trials using an MAMS approach were included. Overall, the number of late-phase trials using the MAMS design has been increasing since 2001 and been accelerated by COVID-19. The majority of current MAMS platforms were either targeting infectious diseases (52%) or cancers (29%) and all identified trials were for treatment interventions. 89% (55/62) of MAMS platforms were evaluating medications, with 45% (28/62) of the MAMS platforms having at least one or more repurposed medication as a comparison arm.ConclusionsHistorically, late-phase trials have adhered to long-established standard (two-arm) designs. However, the number of late-phase MAMS platform trials is increasing, across a range of different disease areas. This study highlights the potential scope of MAMS platform trials and may assist research teams considering use of this approach in the late-phase randomised clinical trial setting.PROSPERO registration numberCRD42019153910.

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Section: Discussionmentioning

confidence: 99%

Section: Considerations For the Futurementioning

confidence: 99%

Uptake of the multi-arm multi-stage (MAMS) adaptive platform approach: a trial-registry review of late-phase randomised clinical trials

et al. 2022

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“…This observation led our group to propose preexposure prophylaxis (PrEP) in our future HIV cure trial in France (28) and also at the European level (EHVA T02 trial; ClinicalTrials.gov registration no. NCT04120415 [29]). Although PrEP may mitigate the risk of secondary transmission, this strategy should be associated with strong counseling and additional measures of prevention because of the lack of clear data on the efficacy of PrEP against viral rebound to high levels of viremia following ATI.…”

Section: Discussionmentioning

confidence: 99%

A Randomized Placebo-Controlled Efficacy Study of a Prime Boost Therapeutic Vaccination Strategy in HIV-1-Infected Individuals: VRI02 ANRS 149 LIGHT Phase II Trial

Lévy

Lacabaratz

Lhomme

et al. 2021

J Virol

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In this placebo-controlled phase II randomized clinical trial, 103 HIV-1 infected patients under c-ART (combined antiretroviral treatment) were randomized 2:1 to receive 3 doses of DNA GTU-MultiHIV B (coding for Rev, Nef, Tat, Gag and gp160) at Week (W)0, W4 and W12 followed by 2 doses of LIPO-5 vaccine containing long peptides from Gag, Pol and Nef at W20 and W24 or placebos. Analytical treatment interruption (ATI) was performed between W36 to W48. At W28, vaccinees experienced an increase in functional CD4+ T cell responses measured (P<0.001 for each cytokine compared to W0) predominantly against Gag and Pol/Env and an increase in HIV-specific CD8+ T cells producing IL-2 and TNF-α (P=0.001 and 0.013, respectively), predominantly against Pol/Env and Nef. However, analysis of T cell subsets by mass cytometry in a subpopulation showed an increase of W28/W0 ratio for memory CD8+ T cells co-expressing exhaustion and senescence markers such as PD-1/TIGIT (P=0.004) and CD27/CD57 (P=0.044) in vaccinees compared to placebo. During ATI, all patients experienced viral rebound with a maximum observed HIV RNA level at W42 (median: 4.63 log10 cp/ml; IQR 4.00-5.09) without any difference between arms. No patient resumed c-ART for CD4 cell count drop. Globally, the vaccine strategy was safe. However, a secondary HIV transmission during ATI was observed. These data show that the prime-boost combination of DNA and LIPO-5 vaccines elicited broad and polyfunctional T cells. The contrast between the quality of immune responses and the lack of potent viral control underscores the need of combined immunomodulatory strategies. IMPORTANCE In this placebo-controlled phase II randomized clinical trial, we evaluated the safety and immunogenicity of a therapeutic prime-boost vaccine strategy using a recombinant DNA vaccine (GTU®-MultiHIV B clade) followed by a boost vaccination by a lipopeptide vaccine (HIV-LIPO-5) in HIV-infected patients while on combined antiretroviral therapy. We show that this prime-boost strategy is well tolerated, consistently with previous studies in HIV-1 infected individuals and healthy volunteers who received each vaccine component individually. Compared to placebo group, vaccines elicited strong and polyfunctional HIV-specific CD4+ and CD8+ T cell responses. However, these immune responses presenting some qualitative defects were not able to control viremia following antiretroviral treatment interruption as no difference in HIV viral rebound was observed in vaccine and placebo groups. Several lessons were learned from these results pointing out the urgent need to combine the vaccine strategies with other immune-based interventions.

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“…With time, the control arm can also be updated with evidence-based proven therapies. Examples of such trial designs are seen in STAMPEDE, evaluating the use of adjuvant treatments in men with advanced prostate cancer, and EHVA T01 evaluating various HIV vaccines in the management of HIV-positive patients (22,23).…”

Section: Trial Designmentioning

confidence: 99%

Comparative Healthcare Research Outcomes of Novel Surgery in prostate cancer (IP4-CHRONOS): A prospective, multi-centre therapeutic phase II parallel Randomised Control Trial

Reddy

Shah

Dudderidge

et al. 2020

Contemporary Clinical Trials

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Introduction: Focal therapy (FT) targets individual areas of cancer within the prostate, to confer oncological control with minimal side-effects. Early evidence demonstrates encouraging shortmedium-term outcomes. With no randomised controlled trials (RCT) comparing FT to radical therapies, Comparative Healthcare Research Outcomes of Novel Surgery in prostate cancer (CHRONOS) will compare the cancer control of these two treatment strategies.Patients and Methods: CHRONOS is a parallel phase II RCT for patients with clinically significant nonmetastatic prostate cancer. CHRONOS-A will randomise patients to either radical treatment or FT.CHRONOS-B is a multi-arm, multistage RCT comparing focal therapy alone to FT with neoadjuvant agents that might improve the current focal therapy outcomes. An internal pilot will determine the feasibility of randomisation and compliance to allocation, whilst the proposed definitive study will recruit and randomise 1190 patients into CHRONOS-A and 1260 patients into CHRONOS-B.Results: Primary outcome in CHRONOS-A is progression-free survival (the transition to salvage local or systemic therapy, development of metastases or prostate-cancer-related mortality) and in CHRONOS-B is failure-free survival (includes the above definition and recurrence of clinically significant prostate cancer after initial FT). Secondary outcomes include adverse events, health economics and continence, erectile and bowel function measured using validated questionnaires. CHRONOS is powered to assess non-inferiority of FT compared to radical therapy in CHRONOS-A, and superiority of neoadjuvant agents with FT in CHRONOS-B.Discussion: CHRONOS will assess the oncological outcomes after FT compared to radical therapy and determine whether neoadjuvant treatments might improve cancer control following one FT session.

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Multi-arm, multi-stage randomised controlled trials for evaluating therapeutic HIV cure interventions

Cited by 7 publications

References 31 publications

Uptake of the multi-arm multi-stage (MAMS) adaptive platform approach: a trial-registry review of late-phase randomised clinical trials

Uptake of the multi-arm multi-stage (MAMS) adaptive platform approach: a trial-registry review of late-phase randomised clinical trials

A Randomized Placebo-Controlled Efficacy Study of a Prime Boost Therapeutic Vaccination Strategy in HIV-1-Infected Individuals: VRI02 ANRS 149 LIGHT Phase II Trial

Comparative Healthcare Research Outcomes of Novel Surgery in prostate cancer (IP4-CHRONOS): A prospective, multi-centre therapeutic phase II parallel Randomised Control Trial

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