Adaptive Platform Trial Research Articles

Platform adaptive trial of novel antivirals for early treatment of COVID-19 In the community (PANORAMIC): protocol for a randomised, controlled, open-label, adaptive platform trial of community novel antiviral treatment of COVID-19 in people at increased risk of more severe disease

IntroductionThere is an urgent need to determine the safety, effectiveness and cost-effectiveness of novel antiviral treatments for COVID-19 in vaccinated patients in the community at increased risk of morbidity and...

Drug repurposing for COVID-19: current evidence from randomized controlled adaptive platform trials and living systematic reviews.

The coronavirus disease 2019 (COVID-19) pandemic resulted in a race to develop effective treatments largely through drug repurposing via adaptive platform trials on a global scale. Drug repurposing trials have focused on potential antiviral therapies aimed at preventing viral replication, anti-inflammatory agents, antithrombotic agents and immune modulators through a number of adaptive platform trials. Living systematic reviews have also enabled evidence synthesis and network meta-analysis as clinical trial data emerge globally. Recent published literature. Corticosteroids and immunomodulators that antagonize the interleukin-6 (IL-6) receptor have been shown to play a critical role in modulating inflammation and improving clinical outcomes in hospitalized patients. Inhaled budesonide reduces the time to recovery in older patients with mild-to-moderate COVID-19 managed in the community. The clinical benefit of remdesivir remains controversial with conflicting evidence from different trials. Remdesivir led to a reduction in time to clinical recovery in the ACTT-1 trial. However, the World Health Organization SOLIDARITY and DISCOVERY trial did not find a significant benefit on 28-day mortality and clinical recovery. Other treatments currently being investigated include antidiabetic drug empagliflozin, antimalarial drug artesunate, tyrosine kinase inhibitor imatinib, immunomodulatory drug infliximab, antiviral drug favipiravir, antiparasitic drug ivermectin and antidepressant drug fluvoxamine. The timing of therapeutic interventions based on postulated mechanisms of action and the selection of clinically meaningful primary end points remain important considerations in the design and implementation of COVID-19 therapeutic trials.

CRI-CCTG-0003/IND.240: An immunotherapy platform study in platinum-resistant high grade serous ovarian cancer (IPROC).

TPS5617 Background: Identifying new treatments for patients with platinum-resistant high grade serous ovarian cancer (HGSC) is a priority. Although several biological features of HGSC suggest inherent immunogenicity, immunotherapy has had limited efficacy to date. IPROC is an adaptive platform trial designed to evaluate multiple immunotherapy combinations selected and informed by an expert panel. IPROC accommodates both biomarker-agnostic and biomarker-directed combinations. Protocol and sub study specific translational studies are conducted on archived diagnostic tissue and serial prospective blood and tumor sample collection. Methods: IPROC is an open-label, multi center, phase II platform trial. Eligibility includes HGSC histology; progression within 6 months of the last platinum regimen; <1 prior line of chemotherapy for platinum resistant disease (unlimited prior lines for platinum sensitive); prior treatment with immunotherapy allowed (provided not discontinued for toxicity), ECOG 0/1. Patients must be willing and able to undergo study procedures. The primary endpoint is ORR (RECIST1.1). Secondary endpoints include iRECIST ORR, RECIST/iRECIST progression free and overall survival and safety. Exploratory objectives include whole exome sequencing and immune profiling of tumor and blood samples to identify biomarkers and new immunotherapy strategies/combinations for future evaluation. Tumor biopsy occurs at baseline, cycle 2 and progression (voluntary) with blood and plasma collected at each cycle and on progression. All sub studies use Simon 2-stage design with 10 patients (pts) enrolled in each stage. At the end of stage 1, in the absence of response, a modified cohort based on biomarker selection may be created through protocol amendment. In each substudy a null hypothesis that the objective response rate (ORR) is ≤5% is tested against a one-sided alternative that the ORR is ≥ 25%. A combination would be accepted as active if ≥4/20 pts respond with α=0.02 and power of 0.76. As of January 19, 2023, 2 sub studies are open and 12 patients have accrued. Sub study A is evaluating the combination of durvalumab and BA3011, a conditionally active anti-AXL humanized monoclonal antibody (IgG1) conjugated to monomethyl auristatin E (MMAE) in AXL overexpressing HGSC. Sub study B is evaluating durvalumab plus BA3021, a CAB anti-receptor tyrosine kinase orphan receptor 2 (ROR2) humanized monoclonal antibody (IgG1) conjugated to MMAE in ROR2 overexpressing HGSC. Further sub studies are planned (NCT04918186). Clinical trial information: NCT04918186 .

Oral Fluvoxamine With Inhaled Budesonide for Treatment of Early-Onset COVID-19 : A Randomized Platform Trial.

Previous trials have demonstrated the effects of fluvoxamine alone and inhaled budesonide alone for prevention of disease progression among outpatients with COVID-19. To determine whether the combination of fluvoxamine and inhaled budesonide would increase treatment effects in a highly vaccinated population. Randomized, placebo-controlled, adaptive platform trial. (ClinicalTrials.gov: NCT04727424). 12 clinical sites in Brazil. Symptomatic adults with confirmed SARS-CoV-2 infection and a known risk factor for progression to severe disease. Patients were randomly assigned to either fluvoxamine (100 mg twice daily for 10 days) plus inhaled budesonide (800 mcg twice daily for 10 days) or matching placebos. The primary outcome was a composite of emergency setting retention for COVID-19 for more than 6 hours, hospitalization, and/or suspected complications due to clinical progression of COVID-19 within 28 days of randomization. Secondary outcomes included health care attendance (defined as hospitalization for any cause or emergency department visit lasting >6 hours), time to hospitalization, mortality, patient-reported outcomes, and adverse drug reactions. Randomization occurred from 15 January to 6 July 2022. A total of 738 participants were allocated to oral fluvoxamine plus inhaled budesonide, and 738 received placebo. The proportion of patients observed in an emergency setting for COVID-19 for more than 6 hours or hospitalized due to COVID-19 was lower in the treatment group than the placebo group (1.8% [95% credible interval {CrI}, 1.1% to 3.0%] vs. 3.7% [95% CrI, 2.5% to 5.3%]; relative risk, 0.50 [95% CrI, 0.25 to 0.92]), with a probability of superiority of 98.7%. No relative effects were found between groups for any of the secondary outcomes. More adverse events occurred in the intervention group than the placebo group, but no important differences between the groups were detected. Low event rate overall, consistent with contemporary trials in vaccinated populations. Treatment with oral fluvoxamine plus inhaled budesonide among high-risk outpatients with early COVID-19 reduced the incidence of severe disease requiring advanced care. Latona Foundation, FastGrants, and Rainwater Charitable Foundation.

Abstract CT062: GBM AGILE: A global, phase 2/3 adaptive platform trial to evaluate multiple regimens in newly diagnosed and recurrent glioblastoma

Abstract Background: GBM AGILE (Glioblastoma Adaptive, Global, Innovative Learning Environment) is a biomarker based, multi-arm, international, seamless Phase 2/3 Response Adaptive Randomization platform trial designed to rapidly identify experimental therapies that improve overall survival and confirm efficacious experimental therapies and associated biomarker signatures to support new drug approvals and registration. GBM AGILE is a collaboration between academic investigators, patient organizations and industry to support new drug applications for newly diagnosed and recurrent GBM. Methods: The primary objective of GBM AGILE is to identify therapies that improve the overall survival in patients with newly diagnosed or recurrent GBM. Operating under a Master Protocol, GBM AGILE allows multiple drugs from different pharmaceutical/biotech companies to be evaluated simultaneously and/or over time against a common control. New experimental therapies are added as new information about promising new drugs is identified while other therapies are removed as they complete their evaluation. Bayesian response adaptive randomization is used within subtypes of the disease to assign participants to investigational arms based on their performance. GBM AGILE has screened over 1300 patients and enrollment rates are 3 to 4 times greater than traditional GBM trials, with active sites averaging 0.75 to 1 patients/site/month. There are 41 active sites in the US, 4 active sites in Canada and 3 active sites in Europe with 12 more sites anticipated to open across 3 countries in Europe. Expansion to Australia is in progress. Stratification of the newly diagnosed patients is based on methylation status per the MGMT assay provided by a central CLIA lab. Maintaining reasonable timelines for MGMT read out to support eligibility and screening requires ongoing operational oversight. In order to continue to improve MGMT testing times, the percentage discordance between results from central testing and local lab testing is being evaluated to assess if local lab testing can be utilized for randomization within GBM AGILE. Exploratory analyses are ongoing to expand knowledge of GBM. For example, information from imaging and clinical assessments will be used to build a longitudinal model, which may inform randomization by providing earlier and continuous information regarding how a given experimental arm is performing. Citation Format: Ingo K. Mellinghoff, Brian Alexander, Donald Berry, Nicholas Blondin, Meredith Buxton, Webster Cavenee, Howard Colman, John de Groot, Macarena I. de la Fuente, Benjamin Ellingson, Gary Gordon, Emma M.V. Hyddmark, Mustafa Khasraw, Andrew Lassman, Eudocia Lee, Wenbin Li, Michael Lim, Tom Mikkelsen, Apoorva Nelli, James Perry, Erik Sulman, Kirk Tanner, Michael Weller, Patrick Y. Wen, Timothy Cloughesy. GBM AGILE: A global, phase 2/3 adaptive platform trial to evaluate multiple regimens in newly diagnosed and recurrent glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT062.

Co-designing and pilot testing an infographic to support patients/families through the REMAP-CAP consent process: a mixed-methods study protocol

BackgroundInformed consent is critical to the ethical conduct of clinical research and requires understanding of a trial including its purpose, process, potential risks and benefits, and alternatives to participation. This can be challenging for complex trials, such as platform trials, and in high-stress environments, such as the intensive care unit (ICU). REMAP-CAP (randomized, embedded, multifactorial, adaptive platform trial for community-acquired pneumonia) is a platform trial which studies treatments for ICU patients with community-acquired pneumonia, including COVID-19. Patient/family partners (PFP) identified challenges during the REMAP-CAP consent process.MethodsThis is a patient-centred co-design study to refine and test an infographic to supplement current REMAP-CAP consent documents. Infographic prototypes were developed by patients, substitute decision-makers (SDMs), and researchers with lived experience in the ICU or with ICU research. We will apply a two-phase exploratory sequential, mixed-methods research design. In phase 1, we will conduct focus groups with ICU patients, SDMs, and research coordinators (RCs). We will use inductive content analysis to inform infographic refinement, to be pilot tested in phase 2. Phase 2 is a prospective study within a trial (SWAT) at ≤ 5 REMAP-CAP sites. We will collect self-reported data from patients/SDMs and RCs. The primary outcome is feasibility (eligible consent encounters, receipt of infographic, consent to follow-up, completion of follow-up surveys). Data will be integrated to understand if/how quantitative results build upon the qualitatively informed infographic.DiscussionPhase 1 results will be used to co-design an infographic, directly informed by the perspectives of patients, SDMs, and RCs involved in ICU research consent discussions. Results from phase 2 will determine the feasibility of infographic implementation in REMAP-CAP consent encounters. These feasibility data will inform a larger SWAT to evaluate our consent infographic. If successful, use of a co-designed infographic to support REMAP-CAP consent documents may improve the experience of consent for patients, SDMs, and RCs.Trial registrationThe Northern Ireland Hub for Trials Methodology Research SWAT Repository (SWAT no. 176)

Governance of adaptive platform trials

Adaptive Clinical Trials (ACT) differ from conventional clinical trials because they permit continual modifications to key components of trial design during the trial. ACTs have grown in prevalence in recent years, with Adaptive Platform Trials (APTs), in particular, having demonstrated their significant scientific, clinical, and public health utility in relation to the COVID-19 pandemic. There has been a steady increase in the number of regulations and guidelines aimed at guiding the conduct of clinical trials. However, despite the potential of APTs to expedite the testing of new interventions in emergency situations, there is a relative dearth of published literature on why and how such trials should be governed. This work attempts to address this knowledge gap.

Core protocol for the adaptive Platform Trial In COVID-19 Vaccine priming and BOOsting (PICOBOO)

BackgroundThe need for coronavirus 2019 (COVID-19) vaccination in different age groups and populations is a subject of great uncertainty and an ongoing global debate. Critical knowledge gaps regarding COVID-19 vaccination include the duration of protection offered by different priming and booster vaccination regimens in different populations, including homologous or heterologous schedules; how vaccination impacts key elements of the immune system; how this is modified by prior or subsequent exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and future variants; and how immune responses correlate with protection against infection and disease, including antibodies and effector and T cell central memory.MethodsThe Platform Trial In COVID-19 priming and BOOsting (PICOBOO) is a multi-site, multi-arm, Bayesian, adaptive, randomised controlled platform trial. PICOBOO will expeditiously generate and translate high-quality evidence of the immunogenicity, reactogenicity and cross-protection of different COVID-19 priming and booster vaccination strategies against SARS-CoV-2 and its variants/subvariants, specific to the Australian context. While the platform is designed to be vaccine agnostic, participants will be randomised to one of three vaccines at trial commencement, including Pfizer’s Comirnaty, Moderna’s Spikevax or Novavax’s Nuvaxovid COVID-19 vaccine. The protocol structure specifying PICOBOO is modular and hierarchical. Here, we describe the Core Protocol, which outlines the trial processes applicable to all study participants included in the platform trial.DiscussionPICOBOO is the first adaptive platform trial evaluating different COVID-19 priming and booster vaccination strategies in Australia, and one of the few established internationally, that is designed to generate high-quality evidence to inform immunisation practice and policy. The modular, hierarchical protocol structure is intended to standardise outcomes, endpoints, data collection and other study processes for nested substudies included in the trial platform and to minimise duplication. It is anticipated that this flexible trial structure will enable investigators to respond with agility to new research questions as they arise, such as the utility of new vaccines (such as bivalent, or SARS-CoV-2 variant-specific vaccines) as they become available for use.Trial registrationAustralian and New Zealand Clinical Trials Registry ACTRN12622000238774. Registered on 10 February 2022.

Towards achieving transnational research partnership equity: lessons from implementing adaptive platform trials in low- and middle-income countries

Background: Use of adaptive clinical trials, particularly adaptive platform trials, has grown exponentially in response to the coronavirus disease (COVID-19) pandemic. Implementation of these trials in low- and middle-income countries (LMICs) has been fostered through the formation or modification of transnational research partnerships, typically between research groups from LMICs and high-income countries (HICs). While these partnerships are important to promote collaboration and overcome the structural and economic disadvantages faced by LMIC health researchers, it is critical to focus attention on the multiple dimensions of partnership equity. Methods: Based on informal literature reviews and meetings with leaders of one of the multinational COVID-19 adaptive platform trials, we describe what can be learned about research partnership equity from these experiences. Results: We organize these considerations into eight thematic categories: 1) epistemic structures, 2) funding, 3) ethics oversight, 4) regulatory oversight, 5) leadership, 6) post-trial access to interventions, data, and specimens, 7) knowledge translation, and 8) research capacity strengthening and maintenance. Within each category we review the normative claims that support its relevance to research partnership equity followed by discussion of how adaptive platform trials highlight new dimensions, considerations, or challenges. Conclusion: These observations provide insight into procedural and substantive equity-building measures within transnational global health research partnerships more broadly.

Report of the first seven agents in the I-SPY COVID trial: a phase 2, open label, adaptive platform randomised controlled trial

An urgent need exists to rapidly screen potential therapeutics for severe COVID-19 or other emerging pathogens associated with high morbidity and mortality. Using an adaptive platform design created to rapidly evaluate investigational agents, hospitalised patients with severe COVID-19 requiring ≥6L/min oxygen were randomised to either a backbone regimen of dexamethasone and remdesivir alone (controls) or backbone plus one open-label investigational agent. Patients were enrolled to the arms described between July 30, 2020 and June 11, 2021 in 20 medical centres in the United States. The platform contained up to four potentially available investigational agents and controls available for randomisation during a single time-period. The two primary endpoints were time-to-recovery (<6L/min oxygen for two consecutive days) and mortality. Data were evaluated biweekly in comparison to pre-specified criteria for graduation (i.e., likely efficacy), futility, and safety, with an adaptive sample size of 40-125 individuals per agent and a Bayesian analytical approach. Criteria were designed to achieve rapid screening of agents and to identify large benefit signals. Concurrently enrolled controls were used for all analyses. https://clinicaltrials.gov/ct2/show/NCT04488081. The first 7 agents evaluated were cenicriviroc (CCR2/5 antagonist; n=92), icatibant (bradykinin antagonist; n=96), apremilast (PDE4 inhibitor; n=67), celecoxib/famotidine (COX2/histamine blockade; n=30), IC14 (anti-CD14; n=67), dornase alfa (inhaled DNase; n=39) and razuprotafib (Tie2 agonist; n=22). Razuprotafib was dropped from the trial due to feasibility issues. In the modified intention-to-treat analyses, no agent met pre-specified efficacy/graduation endpoints with posterior probabilities for the hazard ratios [HRs] for recovery ≤1.5 between 0.99 and 1.00. The data monitoring committee stopped Celecoxib/Famotidine for potential harm (median posterior HR for recovery 0.5, 95% credible interval [CrI] 0.28-0.90; median posterior HR for death 1.67, 95% CrI 0.79-3.58). None of the first 7 agents to enter the trial met the prespecified criteria for a large efficacy signal. Celecoxib/Famotidine was stopped early for potential harm. Adaptive platform trials may provide a useful approach to rapidly screen multiple agents during a pandemic. Quantum Leap Healthcare Collaborative is the trial sponsor. Funding for this trial has come from: the COVID R&D Consortium, Allergan, Amgen Inc., Takeda Pharmaceutical Company, Implicit Bioscience, Johnson & Johnson, Pfizer Inc., Roche/Genentech, Apotex Inc., FAST Grant from Emergent Venture George Mason University, The DoD Defense Threat Reduction Agency (DTRA), The Department of Health and Human ServicesBiomedical Advanced Research and Development Authority (BARDA), and The Grove Foundation. Effort sponsored by the U.S. Government under Other Transaction number W15QKN-16-9-1002 between the MCDC, and the Government.

Early Treatment with Pegylated Interferon Lambda for Covid-19

BackgroundThe efficacy of a single dose of pegylated interferon lambda in preventing clinical events among outpatients with acute symptomatic coronavirus disease 2019 (Covid-19) is unclear.MethodsWe conducted a randomized, controlled, adaptive platform trial involving predominantly vaccinated adults with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in Brazil and Canada. Outpatients who presented with an acute clinical condition consistent with Covid-19 within 7 days after the onset of symptoms received either pegylated interferon lambda (single subcutaneous injection, 180 μg) or placebo (single injection or oral). The primary composite outcome was hospitalization (or transfer to a tertiary hospital) or an emergency department visit (observation for >6 hours) due to Covid-19 within 28 days after randomization.ResultsA total of 933 patients were assigned to receive pegylated interferon lambda (2 were subsequently excluded owing to protocol deviations) and 1018 were assigned to receive placebo. Overall, 83% of the patients had been vaccinated, and during the trial, multiple SARS-CoV-2 variants had emerged. A total of 25 of 931 patients (2.7%) in the interferon group had a primary-outcome event, as compared with 57 of 1018 (5.6%) in the placebo group, a difference of 51% (relative risk, 0.49; 95% Bayesian credible interval, 0.30 to 0.76; posterior probability of superiority to placebo, >99.9%). Results were generally consistent in analyses of secondary outcomes, including time to hospitalization for Covid-19 (hazard ratio, 0.57; 95% Bayesian credible interval, 0.33 to 0.95) and Covid-19–related hospitalization or death (hazard ratio, 0.59; 95% Bayesian credible interval, 0.35 to 0.97). The effects were consistent across dominant variants and independent of vaccination status. Among patients with a high viral load at baseline, those who received pegylated interferon lambda had lower viral loads by day 7 than those who received placebo. The incidence of adverse events was similar in the two groups.ConclusionsAmong predominantly vaccinated outpatients with Covid-19, the incidence of hospitalization or an emergency department visit (observation for >6 hours) was significantly lower among those who received a single dose of pegylated interferon lambda than among those who received placebo. (Funded by FastGrants and others; TOGETHER ClinicalTrials.gov number, NCT04727424.)

Systematic, comprehensive, evidence-based approach to identify neuroprotective interventions for motor neuron disease: using systematic reviews to inform expert consensus

ObjectivesMotor neuron disease (MND) is an incurable progressive neurodegenerative disease with limited treatment options. There is a pressing need for innovation in identifying therapies to take to clinical trial. Here,...

Consumer perspectives on simplified, layered consent for a low risk, but complex pragmatic trial

BackgroundFor decades, the research community has called for participant information sheets/consent forms (PICFs) to be improved. Recommendations include simplifying content, reducing length, presenting information in layers and using multimedia. However, there are relatively few studies that have evaluated health consumers’ (patients/carers) perspectives on the type and organisation of information, and the level of detail to be included in a PICF to optimise an informed decision to enter a trial.We aimed to elicit consumers’ views on a layered approach to consent that provides the key information for decision-making in a short PICF (layer 1) with additional optional information that is accessed separately (layer 2). We also elicited consumers’ views on the optimal content and layout of the layered consent materials for a large and complex Bayesian adaptive platform trial (the SNAP trial).MethodsWe conducted a qualitative multicentre study (4 focus groups and 2 semi-structured interviews) involving adolescent and adult survivors of Staphylococcus aureus bloodstream infection (22) and their carers (2). Interview transcripts were examined using inductive thematic analysis.ResultsConsumers supported a layered approach to consent. The primary theme that emerged was the value of agency; the ability to exert some control over the amount of information read before the consent form is signed. Three other themes emerged; the need to prioritise participants’ information needs; the importance of health literacy; the importance of information about a trial’s benefits (over its risks) for decision-making and the interplay between the two.ConclusionsOur findings suggest that consumers may challenge the one-size-fits-all approach currently applied to the development of PICFs in countries like Australia. Consumers supported a layered approach to consent that offers choice in the amount of information to be read before deciding whether to enter a trial. A 3-page PICF was considered sufficient for decision-making for the SNAP trial, provided that further information was available and accessible.

Long-term (180-Day) Outcomes in Critically Ill Patients With COVID-19 in the REMAP-CAP Randomized Clinical Trial

The longer-term effects of therapies for the treatment of critically ill patients with COVID-19 are unknown. To determine the effect of multiple interventions for critically ill adults with COVID-19 on longer-term outcomes. Prespecified secondary analysis of an ongoing adaptive platform trial (REMAP-CAP) testing interventions within multiple therapeutic domains in which 4869 critically ill adult patients with COVID-19 were enrolled between March 9, 2020, and June 22, 2021, from 197 sites in 14 countries. The final 180-day follow-up was completed on March 2, 2022. Patients were randomized to receive 1 or more interventions within 6 treatment domains: immune modulators (n = 2274), convalescent plasma (n = 2011), antiplatelet therapy (n = 1557), anticoagulation (n = 1033), antivirals (n = 726), and corticosteroids (n = 401). The main outcome was survival through day 180, analyzed using a bayesian piecewise exponential model. A hazard ratio (HR) less than 1 represented improved survival (superiority), while an HR greater than 1 represented worsened survival (harm); futility was represented by a relative improvement less than 20% in outcome, shown by an HR greater than 0.83. Among 4869 randomized patients (mean age, 59.3 years; 1537 [32.1%] women), 4107 (84.3%) had known vital status and 2590 (63.1%) were alive at day 180. IL-6 receptor antagonists had a greater than 99.9% probability of improving 6-month survival (adjusted HR, 0.74 [95% credible interval {CrI}, 0.61-0.90]) and antiplatelet agents had a 95% probability of improving 6-month survival (adjusted HR, 0.85 [95% CrI, 0.71-1.03]) compared with the control, while the probability of trial-defined statistical futility (HR >0.83) was high for therapeutic anticoagulation (99.9%; HR, 1.13 [95% CrI, 0.93-1.42]), convalescent plasma (99.2%; HR, 0.99 [95% CrI, 0.86-1.14]), and lopinavir-ritonavir (96.6%; HR, 1.06 [95% CrI, 0.82-1.38]) and the probabilities of harm from hydroxychloroquine (96.9%; HR, 1.51 [95% CrI, 0.98-2.29]) and the combination of lopinavir-ritonavir and hydroxychloroquine (96.8%; HR, 1.61 [95% CrI, 0.97-2.67]) were high. The corticosteroid domain was stopped early prior to reaching a predefined statistical trigger; there was a 57.1% to 61.6% probability of improving 6-month survival across varying hydrocortisone dosing strategies. Among critically ill patients with COVID-19 randomized to receive 1 or more therapeutic interventions, treatment with an IL-6 receptor antagonist had a greater than 99.9% probability of improved 180-day mortality compared with patients randomized to the control, and treatment with an antiplatelet had a 95.0% probability of improved 180-day mortality compared with patients randomized to the control. Overall, when considered with previously reported short-term results, the findings indicate that initial in-hospital treatment effects were consistent for most therapies through 6 months.

ASCOT ADAPT study of COVID-19 therapeutics in hospitalised patients: an international multicentre adaptive platform trial

BackgroundSARS-CoV-2 infection is associated with a significant risk of hospitalisation, death, and prolonged impact on quality of life. Evaluation of new treatment options and optimising therapeutic management of people hospitalised with SARS-CoV-2 infection remains essential, but rapid changes in pandemic conditions and potential therapies have limited the utility of traditional approaches to randomised controlled trials.MethodsASCOT ADAPT is an international, investigator-initiated, adaptive platform, randomised controlled trial of therapeutics for non-critically ill patients hospitalised with COVID-19. The study design is open label and pragmatic. Potential participants are hospitalised adults with PCR confirmed, symptomatic, SARS-CoV-2 infection, within 14 days of symptom onset. Domains include antiviral, antibody and anticoagulant interventions, with a composite primary outcome of 28-day mortality or progression to intensive-care level respiratory or haemodynamic support. Initial interventions include intravenous nafamostat and variable dose anticoagulation. A range of secondary endpoints, and substudies for specific domains and interventions are outlined.DiscussionThis paper presents the trial protocol and management structure, including international governance, remote site monitoring and biobanking activities and provides commentary on ethical and pragmatic considerations in establishing the ASCOT ADAPT trial under pandemic conditions.Trial registrationAustralian and New Zealand Clinical Trials Registry (ACTRN12620000445976) and ClinicalTrials.gov (NCT04483960).

Anticoagulation Strategies in Non–Critically Ill Patients with Covid-19

BackgroundOptimal thromboprophylaxis for hospitalized patients with coronavirus disease 2019 (Covid-19) is uncertain.MethodsIn an open-label, adaptive platform trial, we randomly assigned hospitalized adults with Covid-19 to low-dose low-molecular-weight heparin thromboprophylaxis or intermediate-dose or low-dose plus aspirin. In response to external evidence, the aspirin intervention was discontinued and a therapeutic-dose arm added. The primary end point was death or the requirement for new organ support by day 28, analyzed with a Bayesian logistic model. Enrolment was closed as a result of operational constraints.ResultsBetween February 2021 and March 2022, 1574 patients were randomly assigned. Among 1526 participants included in the analysis (India, n=1273; Australia and New Zealand, n=138; and Nepal, n=115), the primary outcome occurred in 35 (5.9%) of 596 in low-dose, 25 (4.2%) of 601 in intermediate-dose, 20 (7.2%) of 279 in low-dose plus aspirin, and 7 (14%) of 50 in therapeutic-dose anticoagulation. Compared with low-dose thromboprophylaxis, the median adjusted odds ratio for the primary outcome for intermediate-dose was 0.74 (95% credible interval [CrI], 0.43 to 1.27; posterior probability of effectiveness [adjusted odds ratio<1; Pr], 86%), for low-dose plus aspirin 0.88 (95% CrI, 0.47 to 1.64; Pr, 65%), and for therapeutic-dose anticoagulation 2.22 (95% CrI, 0.77 to 6.20; Pr, 7%). Overall thrombotic and bleeding rates were 0.8% and 0.4%, respectively. There were 10 serious adverse reactions related to anticoagulation strategy, of which nine were grade 1 or 2 across study interventions and one grade 4 episode of retroperitoneal hematoma in a patient receiving intermediate-dose anticoagulation.ConclusionsIn hospitalized non–critically ill adults with Covid-19, compared with low-dose, there was an 86% posterior probability that intermediate-dose, 65% posterior probability that low-dose plus aspirin, and a 7% posterior probability that therapeutic-dose anticoagulation reduced the odds of death or requirement for organ support. No treatment strategy met prespecified stopping criteria before trial closure, precluding definitive conclusions. (Funded by Australian National Health and Medical Research Council or Medical Research Future Fund Investigator and Practitioner Grants and others; ClinicalTrials.gov number, NCT04483960.)

CTNI-38. UPDATE ON GBM AGILE: A GLOBAL, PHASE 2/3 ADAPTIVE PLATFORM TRIAL TO EVALUATE MULTIPLE REGIMENS IN NEWLY DIAGNOSED AND RECURRENT GLIOBLASTOMA

Abstract BACKGROUND GBM AGILE (Glioblastoma Adaptive, Global, Innovative Learning Environment) is a biomarker based, multi-arm, international, seamless Phase 2/3 response adaptive randomization platform trial designed to rapidly identify experimental therapies that improve overall survival and confirm efficacious experimental therapies and associated biomarker signatures to support new drug approvals and registration. GBM AGILE is a collaboration between academic investigators, patient organizations and industry to support new drug applications for newly diagnosed and recurrent GBM. METHODS The primary objective of GBM AGILE is to identify therapies that effectively improve the overall survival in patients with ND or recurrent GBM. Bayesian response adaptive randomization is used within subtypes of the disease to assign participants to investigational arms based on their performance. Operating under a Master Protocol, GBM AGILE allows multiple drugs from different pharmaceutical/biotech companies to be evaluated simultaneously and/or over time against a common control. New experimental therapies are added as information about promising new drugs is identified while therapies are removed as they complete their evaluation. The master protocol/ trial infrastructure includes efficiencies through an adaptive trial design, shared control arm and operational processes to serve the goal of helping patients receive optimal care in a fast and efficient manner. GBM AGILE has screened over 1200 patients and enrollment rates are 3 to 4 times greater than traditional GBM trials, with active sites averaging 0.75 to 1 patients/sites/month. There are 41 active sites in the US, 4 active sites in Canada and 3 active sites in Europe with more sites anticipated to open across 5 countries in Europe. Expansion to China and Australia are under progress. Through the use of improved and flexible processes, GBM AGILE serves as a global trial that supports the efficient and rapid incorporation and evaluation of new experimental therapies for patients with GBM.Clinical trial information: NCT03970447.

Association of Residual Ductal Carcinoma In Situ With Breast Cancer Recurrence in the Neoadjuvant I-SPY2 Trial

Pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) in breast cancer strongly correlates with overall survival and has become the standard end point in neoadjuvant trials. However, there is controversy regarding whether the definition of pCR should exclude or permit the presence of residual ductal carcinoma in situ (DCIS). To examine the association of residual DCIS in surgical specimens after neoadjuvant chemotherapy for breast cancer with survival end points to inform standards for the assessment of pathologic complete response. The study team analyzed the association of residual DCIS after NAC with 3-year event-free survival (EFS), distant recurrence-free survival (DRFS), and local-regional recurrence (LRR) in the I-SPY2 trial, an adaptive neoadjuvant platform trial for patients with breast cancer at high risk of recurrence. This is a retrospective analysis of clinical specimens and data from the ongoing I-SPY2 adaptive platform trial of novel therapeutics on a background of standard of care for early breast cancer. I-SPY2 participants are adult women diagnosed with stage II/III breast cancer at high risk of recurrence. Participants were randomized to receive taxane and anthracycline-based neoadjuvant therapy with or without 1 of 10 investigational agents, followed by definitive surgery. The presence of DCIS and EFS, DRFS, and LRR. The study team identified 933 I-SPY2 participants (aged 24 to 77 years) with complete pathology and follow-up data. Median follow-up time was 3.9 years; 337 participants (36%) had no residual invasive disease (residual cancer burden 0, or pCR). Of the 337 participants with pCR, 70 (21%) had residual DCIS, which varied significantly by tumor-receptor subtype; residual DCIS was present in 8.5% of triple negative tumors, 15.6% of hormone-receptor positive tumors, and 36.6% of ERBB2-positive tumors. Among those participants with pCR, there was no significant difference in EFS, DRFS, or LRR based on presence or absence of residual DCIS. The analysis supports the definition of pCR as the absence of invasive disease after NAC regardless of the presence or absence of DCIS. ClinicalTrials.gov Identifier NCT01042379.

Optimizing a Bayesian hierarchical adaptive platform trial design for stroke patients

BackgroundPlatform trials are well-known for their ability to investigate multiple arms on heterogeneous patient populations and their flexibility to add/drop treatment arms due to efficacy/lack of efficacy. Because of their complexity, it is important to develop highly optimized, transparent, and rigorous designs that are cost-efficient, offer high statistical power, maximize patient benefit, and are robust to changes over time.MethodsTo address these needs, we present a Bayesian platform trial design based on a beta-binomial model for binary outcomes that uses three key strategies: (1) hierarchical modeling of subgroups within treatment arms that allows for borrowing of information across subgroups, (2) utilization of response-adaptive randomization (RAR) schemes that seek a tradeoff between statistical power and patient benefit, and (3) adjustment for potential drift over time. Motivated by a proposed clinical trial that aims to find the appropriate treatment for different subgroup populations of ischemic stroke patients, extensive simulation studies were performed to validate the approach, compare different allocation rules, and study the model operating characteristics.Results and conclusionsOur proposed approach achieved high statistical power and good patient benefit and was also robust against population drift over time. Our design provided a good balance between the strengths of both the traditional RAR scheme and fixed 1:1 allocation and may be a promising choice for dichotomous outcomes trials investigating multiple subgroups.

P11.65.B GBM AGILE: A global, phase 2/3 adaptive platform trial to evaluate multiple treatment regimens in newly diagnosed and recurrent glioblastoma

Abstract Background GBM AGILE (Glioblastoma Adaptive, Global, Innovative Learning Environment) is a biomarker based, multi-arm, international, seamless Phase 2/3 Response Adaptive Randomization platform trial designed to rapidly identify experimental therapies that improve overall survival and confirm efficacious experimental therapies and associated biomarker signatures to support new drug approvals and registration. It is a collaboration between academic investigators, patient organizations and industry, under the sponsorship of the non-profit organization, Global Coalition for Adaptive Research, to support new drug applications for newly diagnosed and recurrent GBM. Material and Methods The primary objective of GBM AGILE is to identify therapies that effectively improve overall survival in patients with newly diagnosed or recurrent GBM. Bayesian response adaptive randomization is used within subtypes of the disease to assign participants to investigational arms based on their performance. Operating under a master protocol, GBM AGILE allows multiple drugs from different pharmaceutical companies to be evaluated simultaneously and/or over time against a common control arm. Based on performance, a drug may graduate and move to a Stage 2 (Phase 3) within the trial, and the totality of the data can be used for a new drug application and registration process. New experimental therapies are added as information about promising new drugs is identified while other therapies are removed as they complete their evaluation. The master protocol/ trial infrastructure includes efficiencies through an adaptive trial design, shared control arm and operational processes such as risk-based monitoring and enhanced remote activities. With its adaptable structure, GBM AGILE has continued trial activation, inclusion of new investigational therapies, and enrollment globally through the challenges of a global pandemic.GBM AGILE provides an efficient mechanism to screen and develop robust information regarding the efficacy of proposed novel therapeutics and associated biomarkers for GBM and to quickly move therapies and biomarkers into clinic. GBM AGILE received initial approval from the United States FDA in April 2019, and in Europe through the Voluntary Harmonization Procedure (VHP) in April, 2021. As of 2022, AGILE has screened over 1000 patients studying multiple investigational treatments. Enrollment rates are 3 to 4 times greater than traditional GBM trials, with active sites averaging 0.75 to 1 patients/site/month. Currently, there are 41 sites activated in the US, 4 in Canada and 2 in Switzerland and an estimated 24 sites yet to open in Germany, France, Switzerland, Italy and Austria. In addition to the continued expansion in Europe, effort is undergoing to extend the trial to China and Australia as well. Clinical trial information: NCT03970447