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Journal of Critical Care 60 (2020) 140–142 Contents lists available at ScienceDirect Journal of Critical Care journal homepage: www.journals.elsevier.com/journal-of-critical-care Meta-trial of awake prone positioning with nasal high flow therapy: Invitation to join a pandemic collaborative research effort Jie Li a, Ivan Pavlov b, John G. Laffey c,h, Oriol Roca d,i,j, Sara Mirza e, Yonatan Perez f, Bairbre McNicholas c,h, David Cosgrave c,h, David Vines a, Elsa Tavernier g,k, Stephan Ehrmann f,l,⁎ a Department of Cardiopulmonary Sciences, Division of Respiratory Care, Rush University Medical Center, Chicago, IL, United States of America b Department of Emergency Medicine, Hôpital de Verdun, Montréal, Québec, Canada c Anaesthesia and Intensive Care Medicine, School of Medicine, National University of Ireland Galway, Ireland d Servei de Medicina Intensiva, Hospital Universitari Vall d'Hebron, Institut de Recerca Vall d'Hebron, Barcelona, Spain e Division of Pulmonary and Critical care, Department of Internal Medicine, Rush University Medical Center, Chicago, IL, United States of America f CHRU Tours, Médecine Intensive Réanimation, CIC INSERM 1415, REVA and CRICS-TriggerSEP Research Networks, Tours, France g Universities of Tours and Nantes, INSERM 1246-SPHERE, Tours, France h Department of Anaesthesia, University Hospital Galway, Saolta Hospital Group, Ireland i Departament de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain j Ciber Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain k Clinical Investigation Center, INSERM 1415, CHRU Tours, Tours, France l INSERM, Centre d'étude des Pathologies Respiratoires, U1100, Université de Tours, Tours, France 1. Introduction 3. Pros/cons of national independent trials vs international trials The ongoing coronavirus disease pandemic (COVID-19) poses a Numerous such trials launched simultaneously across hospitals in great challenge to healthcare systems worldwide. Beyond challenges various countries address similar research questions. E.g. the search for direct patient care, optimal conduct of research under the specific terms of “COVID AND Prone” to retrieve studies evaluating patient conditions of the pandemic is a matter of concern and discussion. We prone positioning on clinicaltrials.gov yielded 6, 31 and 44 results on present the meta-trial concept as a scientifically, clinically, ethically the 5th of April, 5th of May and 5th of June respectively. This poses a and socially sound method to carry out optimal clinical research in the major risk of redundant work, poor research resource allocation and setting of a pandemic. We take the example of such a meta-trial, set incompletion of some trials – this happened all too often during previ- up to investigate prone positioning among awake patients undergoing ous epidemics [1-3]. Researchers may waste time writing protocols nasal high flow therapy and invite journal readers to join this collabora- from scratch while others already obtained funding or regulatory ap- tive research effort. provals. Although data generated by these numerous trials may ulti- mately be meta-analyzed, the time required for these numerous individual trials to publish and then compile data may be incompatible with the pressure of the epidemic. Several stakeholders called for a co- 2. COVID-19 constraints to clinical research ordinated research effort, which should ideally take place at the interna- tional level [1]. The pandemic has placed the research community under great However, setting up an international trial requires tremendous re- pressure with the urgent need for results, given the lack of knowl- sources and time to finalize a unique protocol translated in various edge concerning optimal management of patients suffering this languages, coordinate all regulatory and ethical approvals, and con- new disease. Public pressure is high due to the lack of specific effec- duct trials and data quality assessment in each country [4,5]. Such ef- tive therapy regarding this major threat to public health; the tradi- forts have been conducted successfully for observational studies with tional pace of clinical research being considered as not adapted by the support of international research networks and scientific societies most stakeholders. Worldwide funding agencies and regulatory bod- [6]. However, the hurdles to set up a large scale international inter- ies changed their procedures in order to speed up the research pro- ventional randomized controlled trial are incompatible with the re- cess. This effort has led to the launch of a high number of clinical sources of an academic sponsor and are thus often restricted to studies within a short period of time to an unprecedented extent. pharmaceutical companies. When evaluating non-pharmacological As of 2020 June 15th, 2138 COVID-19 trials were registered in interventions such as prone positioning, which has been proven to clinicaltrials.gov. reduce mortality in mechanically ventilated patients with ARDS [7], the lack of foreseeable return on investment precludes such ⁎ Corresponding author at: Médecine Intensive Réanimation, CHRU de Tours, 2, Bd Tonnellé, 37044 Tours cedex 9, France. funding. E-mail address: stephanehrmann@gmail.com (S. Ehrmann). https://doi.org/10.1016/j.jcrc.2020.07.020 0883-9441/© 2020 Elsevier Inc. All rights reserved. J. Li et al. / Journal of Critical Care 60 (2020) 140–142 141 Table 1 Comparison of the meta-trial concept to alternative designs. Individual trials followed by a International single trial Meta-trial: prospective international retrospective meta-analysis meta-analysis Eligibility criteria for participants Heterogenous between trials Uniform within the trial Similar between trials (may have some heterogeneity within clinical relevance) Baseline data Heterogenous between trials Uniform within the trial Common set of variables in data sharing agreement Intervention details and how they were Heterogenous between trials Uniform within the trial Uniform between trials: agreement between administered individual investigators to deliver same intervention Pre-specified primary and secondary outcome Heterogenous between trials Uniform within the trial Uniform between trials (investigators agree on a measures common set of outcomes) Samples size and Interim analysis Heterogenous between trials, interim One sample size calculation for Meta-trial design transcends original sample size analyses impossible at the meta-level the trial, interim analyses calculation, interim analyses possible at the possible meta-level Randomization- sequence generation, Heterogenous between trials Centralized randomization May differ for each site but fundamental stratification, allocation sequence, randomization principles adhered to concealment and blinding Statistical methods Heterogenous original analyses, Uniform within the trial, Uniform within the trials, meta-analysis on meta-analysis on effect sizes to compute a adjustments possible individual participant data, adjustments possible summary effect Analysis populations: intention to treat, Per Heterogenous between studies Uniform within the trial Uniform between the trials (agreement on protocol, subgroups uniform analysis population) Data quality and safety monitoring Each trialist is responsible for his or her Centralized data monitoring Each trialist is responsible for his or her trial trial Funding Multiple funding Centralized funding Multiple funding Set-up time Short Long Short Time to completion Long Short Short Protocols Multiple original protocols One Multiple original protocols followed by a meta-trial protocol Ethics Each trialist is responsible for his or her Centralized submission Each trialist is responsible for his or her trial trial process 4. The meta-trial as a pragmatic solution for efficient pandemic clin- To the best of our knowledge, the meta-trial concept has never been ical research experienced in real life across several countries, and feasibility uncer- tainties do exist. The present project may serve as a guidance for future In order to combine the benefits of international research with the research projects set up in a pandemic context. fast setup of national trials, we propose to coordinate multiple national investigator-initiated trials in the form of a prospective meta-analysis. 5. How to join This so-called “meta-trial” consists of aggregating data from various na- tional trials during the data collection [8]. To study prone positioning in The meta-trial is a living project in the sense that other groups can awake patients with COVID-19 pneumonia, two such trials were regis- join as long as they adhere to the general principle and abide by ethical tered on clincaltrials.gov (one in the USA, the other in France) in mid- regulations in their country. Protocols and clinical record files are made march 2020, and the investigators got in contact with 3 other groups available upon request by the core investigator group of the meta-trial. planning trials with very similar inclusion and outcome criteria in Readers are invited to contact authors for any additional information Canada, Ireland and Spain, who all joined the meta-trial project. Each and to join the project (Awake.Prone.Meta.Trial@gmail.com). trial could be set up within a few weeks given the accelerated proce- dures in place during the COVID-19 outbreak. Planned sample sizes of individual trials ranged from 198 to 346 patients with the total planned Authors contributions inclusion of 1386 patients across 5 countries. Investigators and method- ologists of all groups organized several web meetings to harmonize in- ET, JL and SE initially designed the project, SE drafted the manu- clusion criteria and primary and secondary outcomes of the meta-trial. script, all authors contributed significantly to study design and concept, Given the planned sample sizes, an interim analysis plan was developed all authors reviewed the manuscript for important intellectual content. at the meta-trial level analyzing aggregated data every 200 patients. A memorandum of understanding and data sharing agreement were Financial disclosure drafted (available upon request). The meta-trial concept enables researchers to combine the agility of This work was supported by OpenAI. (3180 18th St, San Francisco, smaller national trials into a much larger international project in a short CA 94110, United States), Fisher & Paykel (15 Maurice Paykel Place, period of time (Table 1). Meta-trial interim analysis enables to detect a East Tamaki, Auckland 2013 New Zealand), Rice Foundation (8600 positive or negative response to the scientific question as soon as an ad- Gross Point Rd, Skokie, IL 60077, United States) and the French Min- equate sample size is reached across several countries, thus potentially istry of Health (Appel d'offre PHRC inter-régional GIRCI grand-ouest). speeding up the research process dramatically [9,10]. Adherence to methodological standards of individual trials represents a guarantee of a high level of overall final quality. Furthermore, by estimating the treat- Declaration of Competing Interest ment effect across the various trials upfront, the meta-trial may provide stronger evidence in favor of external validity and replicability of the in- JL discloses research support from Fisher & Paykel Healthcare for an- dividual trials. other research project. IP has been a speaker for Fisher & Pakyel 142 J. Li et al. / Journal of Critical Care 60 (2020) 140–142 Healthcare within the last 3 years. All compensation was paid to the [3] Ivie RMJ, Vail EA, Wunsch H, Goldklang MP, Fowler R, Moitra VK. Patient eligibility for randomized controlled trials in critical care medicine: an international two- charitable foundation at the hospital where he works, and he did not center observational study. Crit Care Med 2017;45:216–24. personally receive any compensation. OR provides consultancy to Ham- [4] Rishu AH, Marinoff N, Julien L, Dumitrascu M, Marten N, Eggertson S, et al. Time re- ilton Medical but he did not receieved any personal fee. All compensa- quired to initiate outbreak and pandemic observational research. J Crit Care 2017; 40:7–10. tions were received by the Institute of Research of his Institution. He [5] Burns KEA, Rizvi L, Tan W, Marshall JC, Pope K. Participation of ICUs in critical care received speaker fees by Air Liquide. SE received unrestricted research pandemic research: a province wide, cross-sectional survey. Crit Care Med 2013; grants, travel fee reimbursements and speaker fees from Fisher & Paykel 41:1009–16. [6] Bellani G, Laffey JG, Pham T, Fan E, Brochard L, Esteban A, et al. Epidemiology, pat- Healthcare, consulting fees from La Diffusion Technique Française, con- terns of care, and mortality for patients with acute respiratory distress syndrome sulting fees and unrestricted research grants from Aerogen Ltd., and an in intensive care units in 50 countries. JAMA 2016;315:788–800. unrestricted research grant from Hamilton medical. Other authors have [7] Munshi L, Del Sorbo L, Adhikari NKJ, Hodgson CL, Wunsch H, Meade MO, et al. Prone position for acute respiratory distress syndrome. A systematic review and meta- no conflict of interest to declare. analysis. Ann Am Thorac Soc 2017;14:S280–8. [8] Tavernier E, Trinquart L, Giraudeau B. Finding alternatives to the dogma of power References based sample size calculation: is a fixed sample size prospective meta-experiment a potential alternative? Plos One 2016;11:e0158604. [1] Phua J, Weng L, Ling L, Egi M, Lim CM, Divatia JV, et al. Intensive care management of [9] Simonsen L, Higgs E, Taylor RJ. Clinical research networks are key to accurate and coronarvirus disease 2019 (COVID-19): challenges and recommendations. Lancet timely assessment of pandemic clinical severity. Lancet Glob Health 2018;6:e956–7. Respir Med 2020;8:506–17. [10] Memoli MJ. Pandemic research in the ICU: always be prepared. Crit Care Med 2013; [2] Baden LR, Rubin EJ, Morrissey S, Farrar JJ, Drazen JM. We can do better — improving 41:1147–8. outcomes in the midst of an emergency. N Engl J Med 2017;377:1482–4.