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1. Remdesivir for the treatment of hospitalised patients with COVID-19: final results from the DisCoVeRy randomised, controlled, open-label trial

Author

Florence Ader, Maude Bouscambert-Duchamp, Maya Hites, Nathan Peiffer-Smadja, Julien Poissy, Drifa Belhadi, Alpha Diallo, Christelle Delmas, Juliette Saillard, Aline Dechanet, Claire Fougerou, Minh-Patrick Lê, Gilles Peytavin, Noémie Mercier, Priyanka Velou, Sarah Tubiana, Xavier Lescure, Emmanuel Faure, Saad Nseir, Jean-Christophe Richard, Florent Wallet, François Goehringer, Benjamin Lefèvre, Antoine Kimmoun, François Raffi, Benjamin Gaborit, Jean Reignier, Jean-Philippe Lanoix, Claire Andrejak, Yoann Zerbib, Firouzé Bani-Sadr, Bruno Mourvilliers, François Danion, Yvon Ruch, Raphaël Clere-Jehl, Vincent Le Moing, Kada Klouche, Karine Lacombe, Guillaume Martin-Blondel, Fanny Vardon-Bounes, André Cabié, Jean-Marie Turmel, Lionel Piroth, Mathieu Blot, Élisabeth Botelho-Nevers, Amandine Gagneux-Brunon, Guillaume Thiery, François Bénézit, Rostane Gaci, Joy Mootien, Sébastien Gallien, Denis Garot, Kevin Bouiller, Loïc Epelboin, Stéphane Jauréguiberry, Alexandre Gaymard, Gil Verschelden, Sandra Braz, Joao Miguel Ferreira Ribeiro, Michael Joannidis, Thérèse Staub, Antoine Altdorfer, Richard Greil, Alexander Egle, Jérémie Guedj, Marion Noret, Roberto Roncon-Albuquerque, Jose-Artur Paiva, Bruno Lina, Dominique Costagliola, Yazdan Yazdanpanah, Charles Burdet, France Mentré, Hospices Civils de Lyon (HCL), Université libre de Bruxelles (ULB), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), ANRS - Maladies infectieuses émergentes (ANRS - MIE), Institut National de la Santé et de la Recherche Médicale (INSERM), Pôle de Recherche Clinique [Paris] (PRC), Centre d'investigation Clinique [CHU Bichat] - Épidémiologie clinique (CIC 1425), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Croix-Rousse [CHU - HCL], Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Agents infectieux, résistance et chimiothérapie - UR UPJV 4294 (AGIR ), and Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie

Subjects
[SDV]Life Sciences [q-bio]
Abstract

BackgroundThe antiviral efficacy of remdesivir is still controversial. We aimed at evaluating its clinical effectiveness in hospitalised patients with COVID-19, with indication of oxygen and/or ventilator support. Following prior publication of preliminary results, here we present the final results after completion of data monitoring.MethodsIn this European multicentre, open-label, parallel-group, randomised, controlled trial (DisCoVeRy, NCT04315948; EudraCT2020-000936-23), participants were randomly allocated to receive usual standard of care (SoC) alone or in combination with remdesivir, lopinavir/ritonavir, lopinavir/ritonavir and IFN-β-1a, or hydroxychloroquine. Adult patients hospitalised with COVID-19 were eligible if they had clinical evidence of hypoxemic pneumonia, or required oxygen supplementation. Exclusion criteria included elevated liver enzyme, severe chronic kidney disease, any contra-indication to one of the studied treatments or their use in the 29 days before randomization, or use of ribavirin, as well as pregnancy or breast-feeding. Here, we report results for remdesivir + SoC versus SoC alone. Remdesivir was administered as 200 mg infusion on day 1, followed by once daily infusions of 100 mg up to 9 days, for a total duration of 10 days. It could be stopped after 5 days if the participant was discharged. Treatment assignation was performed via web-based block randomisation stratified on illness severity and administrative European region. The primary outcome was the clinical status at day 15 measured by the WHO 7-point ordinal scale, assessed in the intention-to-treat population.FindingsBetween March 22nd, 2020 and January 21st, 2021, 857 participants were randomised to one of the two arms in 5 European countries and 843 participants were included for the evaluation of remdesivir (control, n=423; remdesivir, n=420).At day 15, the distribution of the WHO ordinal scale was as follow in the remdesivir and control groups, respectively: Not hospitalized, no limitations on activities: 62/420 (14.8%) and 72/423 (17.0%); Not hospitalized, limitation on activities: 126/420 (30%) and 135/423 (31.9%); Hospitalized, not requiring supplemental oxygen: 56/420 (13.3%) and 31/423 (7.3%); Hospitalized, requiring supplemental oxygen: 75/420 (17.9%) and 65/423 (15.4%); Hospitalized, on non-invasive ventilation or high flow oxygen devices: 16/420 (3.8%) and 16/423 (3.8%); Hospitalized, on invasive mechanical ventilation or ECMO: 64/420 (15.2%) and 80/423 (18.9%); Death: 21/420 (5%) and 24/423 (5.7%). The difference between treatment groups was not statistically significant (OR for remdesivir, 1.02, 95% CI, 0.62 to 1.70, P=0.93). There was no significant difference in the occurrence of Serious Adverse Events between treatment groups (remdesivir, n=147/410, 35.9%, versus control, n=138/423, 32.6%, p=0.29).InterpretationRemdesivir use for the treatment of hospitalised patients with COVID-19 was not associated with clinical improvement at day 15.FundingEuropean Union Commission, French Ministry of Health, DIM One Health Île-de-France, REACTing, Fonds Erasme-COVID-ULB; Belgian Health Care Knowledge Centre (KCE), AGMT gGmbH, FEDER “European Regional Development Fund”, Portugal Ministry of Health, Portugal Agency for Clinical Research and Biomedical Innovation. Remdesivir was provided free of charge by Gilead.

Published
2023

2. Accelerating clinical trial implementation in the context of the COVID-19 pandemic: challenges, lessons learned and recommendations from DisCoVeRy and the EU-SolidAct EU response group

Author

Alpha Diallo, Marius Trøseid, Victoria Charlotte Simensen, Anaïs Boston, Jacques Demotes, Inge Christoffer Olsen, Florence Chung, José Artur Paiva, Maya Hites, Florence Ader, Jose Ramon Arribas, Andreas Baratt-Due, Øyvind Melien, Evelina Tacconelli, Thèrèse Staub, Richard Greil, Sotirios Tsiodras, Matthias Briel, Hélène Esperou, France Mentré, Joe Eustace, Juliette Saillard, Christelle Delmas, Soizic LeMestre, Marina Dumousseaux, Dominique Costagliola, John-Arne Røttingen, Yazdan Yazdanpanah, Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Oslo University Hospital [Oslo], European Clinical Research Infrastructures Network [Dusseldorf] (ECRIN), Hospital de São João [Porto], Université libre de Bruxelles (ULB), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), La Paz University Hospital, Norwegian Institute of Public Health [Oslo] (NIPH), Università degli studi di Verona = University of Verona (UNIVR), Centre Hospitalier de Luxembourg [Luxembourg] (CHL), Paracelsus Medizinische Privatuniversität = Paracelsus Medical University (PMU), National and Kapodistrian University of Athens (NKUA), University Hospital Basel [Basel], Pôle de Recherche Clinique [Paris] (PRC), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University College Cork (UCC), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CIC - CHU Bichat, Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord

Subjects
Microbiology (medical), Medical education, Coronavirus disease 2019 (COVID-19), Adaptive Clinical Trials as Topic, EU-RESPOSE, Financial hurdles, Legal hurdles, Platform trials, Regulatory hurdles, MEDLINE, COVID-19, Context (language use), General Medicine, Clinical trial, Infectious Diseases, Political science, Pandemic, Commentary, Government Regulation, Humans, European Union, Pandemics, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Published
2022
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3. Management of pharmacovigilance during the COVID-19 pandemic crisis by the safety department of an academic sponsor: Lessons learnt and challenges from the EU DisCoVeRy clinical trial

Author

Mercier, Noémie, Belhadi, Drifa, Dechanet, Aline, Delmas, Christelle, Saillard, Juliette, Dumousseaux, Marina, Le Mestre, Soizic, Fougerou-Leurent, Claire, Ferrane, Assia, Burdet, Charles, Espérou, Hélène, Ader, Florence, Hites, Maya, Peiffer-Smadja, Nathan, Poissy, Julien, Andrejak, Claire, Paiva, José Artur, Tacconelli, Evelina, Staub, Thérèse, Greil, Richard, Costagliola, Dominique, Mentre, France, Yazdanpanah, Yazdan, Diallo, Alpha, ANRS France Recherche Nord & sud Sida-hiv hépatites, Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d'investigation Clinique [CHU Bichat] - Épidémiologie clinique (CIC 1425), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Santé Publique, Université de Médecine Carol Davila, Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Pôle de Recherche Clinique [Paris] (PRC), Hospices Civils de Lyon (HCL), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université libre de Bruxelles (ULB), Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), CHU Lille, CHU Amiens-Picardie, Agents infectieux, résistance et chimiothérapie - UR UPJV 4294 (AGIR ), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Hospital de São João [Porto], Universitätsklinikum Tübingen - University Hospital of Tübingen, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Centre Hospitalier de Luxembourg [Luxembourg] (CHL), and Paracelsus Medizinische Privatuniversität = Paracelsus Medical University (PMU)

Subjects
EU-RESPONSE, [SDV]Life Sciences [q-bio], pharmacovigilance, adverse event, COVID-19, pandemic crisis
Abstract

International audience; The current COVID-19 pandemic was an exceptional health situation, including for drug use. As there was no known effective drug for COVID-19 at the beginning of the pandemic, different drug candidates were proposed. In this article, we present the challenges for an academic Safety Department to manage the global safety of a European trial during the pandemic. The National Institute for Health and Medical Research (Inserm) conducted a European multicenter, open-label, randomized, controlled trial involving three repurposed and one-in development drugs (lopinavir/ritonavir, IFN-β1a, hydroxychloroquine, and remdesivir) in adults hospitalized with COVID-19. From 25 March 2020 to 29 May 2020, the Inserm Safety Department had to manage 585 Serious Adverse Events (SAEs) initial notification and 396 follow-up reports. The Inserm Safety Department's staff was mobilized to manage these SAEs and to report Expedited safety reports to the competent authorities within the legal timeframes. More than 500 queries were sent to the investigators due to a lack of or incoherent information on SAE forms. At the same time, the investigators were overwhelmed by the management of patients suffering from COVID-19 infection. These particular conditions of missing data and lack of accurate description of adverse events made evaluation of the SAEs very difficult, particularly the assessment of the causal role of each investigational medicinal product. In parallel, working difficulties were accentuated by the national lockdown, frequent IT tool dysfunctions, delayed implementation of monitoring and the absence of automatic alerts for SAE form modification. Although COVID-19 is a confounding factor per se, the delay in and quality of SAE form completion and the real-time medical analysis by the Inserm Safety Department were major issues in the quick identification of potential safety signals. To conduct a high-quality clinical trial and ensure patient safety, all stakeholders must take their roles and responsibilities.

Published
2023
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4. The economic, medical and psychosocial consequences of whole genome sequencing for the genetic diagnosis of patients with intellectual disability: The DEFIDIAG study protocol

Author

Catherine Lejeune, Charley Robert-Viard, Nicolas Meunier-Beillard, Myriam Alice Borel, Léna Gourvès, Stéphanie Staraci, Anne-Laure Soilly, Francis Guillemin, Valerie Seror, Hamza Achit, Marion Bouctot, Marie-Laure Asensio, Anne-Sophie Briffaut, Christelle Delmas, Ange-Line Bruel, Alexia Benoit, Alban Simon, Bénédicte Gerard, Hamza Hadj Abdallah, Stanislas Lyonnet, Laurence Faivre, Christel Thauvin-Robinet, Sylvie Odent, Delphine Heron, Damien Sanlaville, Thierry Frebourg, Jean Muller, Yannis Duffourd, Anne Boland, Jean-François Deleuze, Hélène Espérou, Christine Binquet, Hélène Dollfus, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe EPICAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Délégation à la recherche clinique et à l'innovation [CHU Dijon] (DRCI), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Vecteurs - Infections tropicales et méditerranéennes (VITROME), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées (IRBA), Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Centre d'investigation clinique - Epidémiologie clinique [Nancy] (CIC-EC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Pôle de Recherche Clinique [Paris] (PRC), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Bourgogne Franche-Comté [COMUE] (UBFC), FHU TRANSLAD (CHU de Dijon), Equipe GAD (LNC - U1231), Institut de génétique médicale, Les Hôpitaux Universitaires de Strasbourg (HUS), Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Centre de référence Maladies Rares CLAD-Ouest [Rennes], Hospices Civils de Lyon (HCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, CHU Rouen, Normandie Université (NU), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), TheDEFIDIAG study is funded by grants from the French Ministry of Health in the framewok of the national French initiative for genomic medicine. Institut national de la santé et de la recherche médicale (Inserm) is the sponsor of the DEFDIAG study., COMBE, Isabelle, and Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA)

Subjects
[SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, micro-costing, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, genome sequencing, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, intellectual disability, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Genetics, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Molecular Medicine, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, cost-effectiveness, Genetics (clinical), [SDV.MP.PAR] Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, qualitative stud
Abstract

Introduction: Like other countries, France has invested in a national medical genomics program. Among the four pilot research studies, the DEFIDIAG project focuses on the use of whole genome sequencing (WGS) for patients with intellectual disability (ID), a neurodevelopmental condition affecting 1–3% of the general population but due to a plethora of genes. However, the access to genomic analyses has many potential individual and societal issues in addition to the technical challenges. In order to help decision-makers optimally introduce genomic testing in France, there is a need to identify the socio-economic obstacles and leverages associated with the implementation of WGS.Methods and Analysis: This humanities and social sciences analysis is part of the DEFIDIAG study. The main goal of DEFIDIAG is to compare the percentage of causal genetic diagnoses obtained by trio WGS (including the patient and both parents) (WGST) to the percentage obtained using the minimal reference strategy currently used in France (Fragile-X testing, chromosomal microarray analysis, and gene panel strategy including 44 ID genes) for patients with ID having their first clinical genetics consultation. Additionally, four complementary studies will be conducted. First, a cost-effectiveness analysis will be undertaken in a subsample of 196 patients consulting for the first time for a genetic evaluation; in a blinded fashion, WGST and solo (index case, only) genomic analysis (WGSS) will be compared to the reference strategy. In addition, quantitative studies will be conducted: the first will estimate the cost of the diagnostic odyssey that could potentially be avoidable with first-line WGST in all patients previously investigated in the DEFIDIAG study; the second will estimate changes in follow-up of the patients in the year after the return of the WGST analysis compared to the period before inclusion. Finally, through semi-directive interviews, we will explore the expectations of 60 parents regarding genomic analyses.Discussion: Humanities and social sciences studies can be used to demonstrate the efficiency of WGS and assess the value that families associate with sequencing. These studies are thus expected to clarify trade-offs and to help optimize the implementation of genomic sequencing in France.Ethics Statement: The protocol was approved by the Ethics Committee Sud Méditerranée I (June 2019)—identification number: 2018-A00680-55 and the French data privacy commission (CNIL, authorization 919361).Clinical Trial Registration: (ClinicalTrials.gov), identifier (NCT04154891).

Published
2022
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5. Crise sanitaire : quelles opportunités pour la recherche clinique sur le médicament ?

Author

Dominique Deplanque, Stanislas Cviklinski, Marc Bardou, Florence Ader, Hervé Blanchard, Philippe Barthélémy, Isabelle David, Eric D’Ortenzio, Hélène Espérou, Odile Launay, Milan Lazarevic, Philippe Lechat, Françoise Lethiec, Yves Levy, David Pérol, Virginie Rage, Matthieu Roustit, Gabriel Thabut, CHU Lille, Centre d'Investigation Clinique - Innovation Technologique de Lille - CIC 1403 - CIC 9301 (CIC Lille), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire Roche SAS [Boulogne Billancourt], Ministère des Solidarités et de la Santé [Paris, France], Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL), Pfizer France, Pfizer, AstraZeneca [Courbevoie], SANOFI Recherche, Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Pôle de Recherche Clinique [Paris] (PRC), Institut National de la Santé et de la Recherche Médicale (INSERM), CIC Cochin Pasteur (CIC 1417), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu-Groupe hospitalier Broca-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hôpital Cochin [AP-HP], Direction de la Recherche Clinique et de l'Innovation [AP-HP] (DRCI), Agence Générale des Equipements et Produits de Santé [Paris] (AGEPS), Janssen-Cilag [Issy-les-Moulineaux], Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre Léon Bérard [Lyon], Centre européen d'études et de recherche droit et santé (CEERDS), Dynamiques du droit (DD), Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), CHU Grenoble, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Centre d'Investigation Clinique [Grenoble] (CIC Grenoble), and CHU Grenoble-Hôpital Michallon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)

Subjects
Recherche clinique, HEADING: Ateliers de Giens 2021/Recherche clinique et évaluation des produits de santé, Réglementation, Partage des données, COVID-19, Pharmacology (medical), [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Médicament
Abstract

International audience; La pandémie de coronavirus disease-19 (COVID-19) a conduit au déploiement d’un effort de recherche académique et industriel sans précédent dont on peut regretter le caractère parfois redondant ainsi que le manque de pilotage tant national qu’international. Pourtant, force est de constater qu’à l’occasion de cette crise, les procédures réglementaires ont été adaptées de même que certains freins dans l’organisation de la recherche clinique ont pu être en partie levés pour contribuer au déploiement d’essais au plus près des patients et faciliter les modalités de suivi et de contrôle. La digitalisation de certains processus et la décentralisation de certaines activités ont pu être mises en œuvre sous couvert d’une mobilisation des autorités et de l’ensemble des acteurs institutionnels, académiques ou industriels. Si outre-manche, l’optimisation des ressources, au travers d’un essai de plateforme unique, a permis de montrer ou d’infirmer l’efficacité de nombreux traitements, en France la crise sanitaire a mis en lumière la fragilité de l’organisation de la recherche clinique, notamment un déficit de coordination et de financement, des difficultés dans la mise en œuvre des études ou encore une certaine frilosité concernant le partage des données. Cependant, la crise a aussi révélé les capacités d’adaptation des différents acteurs et permis l’amélioration de plusieurs processus utiles au déploiement de l’innovation thérapeutique. Gageons que les leçons tirées à l’occasion de cette crise permettront une meilleure efficacité en cas de nouvelle pandémie et surtout que les progrès obtenus continueront de s’appliquer à l’ensemble des activités de recherche clinique futures.

Published
2022
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6. Health crisis: What opportunities for clinical drug research?

Author

Dominique Deplanque, Stanislas Cviklinski, Marc Bardou, Florence Ader, Hervé Blanchard, Philippe Barthélémy, Isabelle David, Eric D’Ortenzio, Hélène Espérou, Odile Launay, Milan Lazarevic, Philippe Lechat, Françoise Lethiec, Yves Levy, David Pérol, Virginie Rage, Matthieu Roustit, Gabriel Thabut, Centre d'Investigation Clinique - Innovation Technologique de Lille - CIC 1403 - CIC 9301 (CIC Lille), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Lille, Laboratoire Roche SAS [Boulogne Billancourt], Ministère des Solidarités et de la Santé [Paris, France], Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL), Pfizer France, Pfizer, AstraZeneca [Courbevoie], Sanofi Aventis R&D [Chilly-Mazarin], ANRS - Maladies infectieuses émergentes (ANRS - MIE), Institut National de la Santé et de la Recherche Médicale (INSERM), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Pôle de Recherche Clinique [Paris] (PRC), CIC Cochin Pasteur (CIC 1417), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu-Groupe hospitalier Broca-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hôpital Cochin [AP-HP], Direction de la Recherche Clinique et de l'Innovation [AP-HP] (DRCI), Agence Générale des Equipements et Produits de Santé [Paris] (AGEPS), Janssen-Cilag [Issy-les-Moulineaux], Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Vaccine Research Institute [Créteil, France] (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre Léon Bérard [Lyon], Université de Montpellier (UM), Centre d'Investigation Clinique [Grenoble] (CIC Grenoble), CHU Grenoble-Hôpital Michallon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), CHU Grenoble, and Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble

Subjects
Clinical Trials as Topic, Biomedical Research, [SDV]Life Sciences [q-bio], COVID-19, Article, United Kingdom, Clinical research, COVID-19 Drug Treatment, Pharmaceutical Preparations, Humans, Pharmacology (medical), Data sharing, France, Drug, Pandemics, Regulation
Abstract

International audience; The COVID-19 pandemic led to the deployment of an unprecedented academic and industrial research effort, the sometimes redundant nature of which is regrettable, as is the lack of both national and international management. However, it must be noted that during this crisis, regulatory procedures were adapted and certain obstacles in the organisation of clinical research were partly removed to contribute to the deployment of trials as close as possible to patients and to facilitate monitoring and control procedures. The digitisation of certain processes and the decentralisation of certain activities were implemented under the cover of a mobilisation of the authorities and all institutional, academic and industrial players. While in the UK, the optimisation of resources through a single platform trial has made it possible to demonstrate or invalidate the efficacy of many treatments, in France the health crisis has highlighted the fragility of the organisation of clinical research, in particular a lack of coordination and funding, difficulties in implementing studies and a certain reluctance to share data. However, the crisis has also revealed the adaptability of the various stakeholders and has led to the improvement of several processes useful for the deployment of therapeutic innovation. Let us hope that the lessons learned during this crisis will allow for greater efficiency in the event of a new pandemic and, above all, that the progress made will continue to apply to all future clinical research activities.

Published
2021
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7. Molecular profiling of advanced soft-tissue sarcomas: the MULTISARC randomized trial

Author

Italiano, Antoine, Dinart, Derek, Soubeyran, Isabelle, Bellera, Carine, Espérou, Hélène, Delmas, Christelle, Mercier, Noémie, Albert, Sabrina, Poignie, Ludivine, Boland, Anne, Bourdon, Aurélien, Geneste, Damien, Cavaille, Quentin, Laizet, Yec’han, Khalifa, Emmanuel, Auzanneau, Céline, Squiban, Barbara, Truffaux, Nathalène, Olaso, Robert, Gerber, Zuzana, Wallet, Cédrick, Bénard, Antoine, Blay, Jean-Yves, Laurent-Puig, Pierre, Deleuze, Jean-François, Lucchesi, Carlo, Mathoulin-Pelissier, Simone, Institut Bergonié [Bordeaux], UNICANCER, Actions for OnCogenesis understanding and Target Identification in ONcology (ACTION), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bordeaux Segalen - Bordeaux 2-Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC Bordeaux, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Pôle de Recherche Clinique [Paris] (PRC), Institut National de la Santé et de la Recherche Médicale (INSERM), Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), CHU Bordeaux [Bordeaux], Centre Léon Bérard [Lyon], Université Sorbonne Paris Cité (USPC), Université Paris Descartes - Paris 5 (UPD5), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Malbec, Odile, and UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Adult, Umbrella, Biomarker-driven, Time Factors, Cost-Benefit Analysis, [SDV]Life Sciences [q-bio], High-Throughput Nucleotide Sequencing, Sarcoma, Soft Tissue Neoplasms, Soft-tissue sarcomas, [SDV] Life Sciences [q-bio], Study Protocol, Sample Size, Next generation sequencing, Exome Sequencing, Feasibility Studies, Humans, France, Prospective Studies
Abstract

Background Soft-tissue sarcomas (STS) represent a heterogeneous group of rare tumors including more than 70 different histological subtypes. High throughput molecular analysis (next generation sequencing exome [NGS]) is a unique opportunity to identify driver mutations that can change the usual one-size-fits-all treatment paradigm to a patient-driven therapeutic strategy. The primary objective of the MULTISARC trial is to assess whether NGS can be conducted for a large proportion of metastatic STS participants within a reasonable time, and, secondarily to determine whether a NGS-guided therapeutic strategy improves participant’s outcome. Methods This is a randomized, multicentre, phase II/III trial inspired by the design of umbrella and biomarker-driven trials. The setting plans up to 17 investigational centres across France and the recruitment of 960 participants. Participants aged at least 18 years, with unresectable locally advanced and/or metastatic STS confirmed by the French sarcoma pathological reference network, are randomized according to 1:1 allocation ratio between the experimental arm “NGS” and the standard “No NGS”. NGS will be considered feasible if (i) NGS results are available and interpretable, and (ii) a report of exome sequencing including a clinical recommendation from a multidisciplinary tumor board is provided to investigators within 7 weeks from reception of the samples on the biopathological platform. A feasibility rate of more than 70% is expected (null hypothesis: 70% versus alternative hypothesis: 80%). In terms of care, participants randomized in “No NGS” arm and who fail treatment will be able to switch to the NGS arm at the request of the investigator. Discussion The MULTISARC trial is a prospective study designed to provide high-level evidence to support the implementation of NGS in routine clinical practice for advanced STS participants, on a large scale. Trial registration clinicaltrial.gov NCT03784014. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-08878-2.

Published
2021
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8. Partnership for Research on Ebola VACcination (PREVAC): protocol of a randomized, double-blind, placebo-controlled phase 2 clinical trial evaluating three vaccine strategies against Ebola in healthy volunteers in four West African countries

Author

Moses Badio, Edouard Lhomme, Mark Kieh, Abdoul Habib Beavogui, Stephen B Kennedy, Seydou Doumbia, Bailah Leigh, Samba O Sow, Alpha Diallo, Daniela Fusco, Matthew Kirchoff, Monique Termote, Renaud Vatrinet, Deborah Wentworth, Helène Esperou, H Clifford Lane, Jerome Pierson, Deborah Watson-Jones, Céline Roy, Eric D'Ortenzio, Brian Greenwood, Genevieve Chêne, Laura Richert, James D Neaton, Yazdan Yazdanpanah, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), REACTing, Institut National de la Santé et de la Recherche Médicale (INSERM), Pôle de Recherche Clinique [Paris] (PRC), Services de Maladies Infectieuses et Tropicales [CHU Bichat], AP-HP - Hôpital Bichat - Claude Bernard [Paris], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Study Protocol, Clinical trials, Ebola, Protocol, Randomized controlled trials, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.IMM.VAC]Life Sciences [q-bio]/Immunology/Vaccinology, Vaccine, 3. Good health
Abstract

Introduction The Ebola virus disease (EVD) outbreak in 2014–2016 in West Africa was the largest on record and provided an opportunity for large clinical trials and accelerated efforts to develop an effective and safe preventative vaccine. Multiple questions regarding the safety, immunogenicity, and efficacy of EVD vaccines remain unanswered. To address these gaps in the evidence base, the Partnership for Research on Ebola Vaccines (PREVAC) trial was designed. This paper describes the design, methods, and baseline results of the PREVAC trial and discusses challenges that led to different protocol amendments. Methods This is a randomized, double-blind, placebo-controlled phase 2 clinical trial of three vaccine strategies against the Ebola virus in healthy volunteers 1 year of age and above. The three vaccine strategies being studied are the rVSVΔG-ZEBOV-GP vaccine, with and without a booster dose at 56 days, and the Ad26.ZEBOV,MVA-FN-Filo vaccine regimen with Ad26.ZEBOV given as the first dose and the MVA-FN-Filo vaccination given 56 days later. There have been 4 versions of the protocol with those enrolled in Version 4.0 comprising the primary analysis cohort. The primary endpoint is based on the antibody titer against the Ebola virus surface glycoprotein measured 12 months following the final injection. Results From April 2017 to December 2018, a total of 5002 volunteers were screened and 4789 enrolled. Participants were enrolled at 6 sites in four countries (Guinea, Liberia, Sierra Leone, and Mali). Of the 4789 participants, 2560 (53%) were adults and 2229 (47%) were children. Those

Published
2021
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9. Long-lasting severe immune dysfunction in Ebola virus disease survivors

Author

Wiedemann, Aurélie, Foucat, Emile, Hocini, Hakim, Lefebvre, Cécile, Hejblum, Boris P., Durand, Mélany, Krüger, Miriam, Keita, Alpha Kabinet, Ayouba, Ahidjo, Mély, Stéphane, Fernandez, José-Carlos, Touré, Abdoulaye, Fourati, Slim, Lévy-Marchal, Claire, Raoul, Hervé, Delaporte, Eric, Koivogui, Lamine, Thiébaut, Rodolphe, Lacabaratz, Christine, Lévy, Yves, Vaccine Research Institute (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Statistics In System biology and Translational Medicine (SISTM), Inria Bordeaux - Sud-Ouest, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)- Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Santé publique, Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques er émergentes (TransVIHMI), Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Gamal Abdel Nasser de Conakry, Laboratoire P4 - Jean Mérieux, Centre Européen de Virologie/Immunologie-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de Santé Publique [Conakry, Guinée] (INSP), Ministère de la Santé [Conakry, Guinea], CHU Henri Mondor, Pôle de Recherche Clinique [Paris] (PRC), Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Bordeaux [Bordeaux], This work was supported by INSERM and by the Investissements d’Avenir program, Vaccine Research Institute (VRI), managed by the ANR under reference ANR-10-LABX-77-01., PostEboGui Study Group, ANR-10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), Bodescot, Myriam, Laboratoires d'excellence - Initiative for the creation of a Vaccine Research Institute - - VRI2010 - ANR-10-LABX-0077 - LABX - VALID, Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Inria Bordeaux - Sud-Ouest, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Université Montpellier 1 (UM1)-Institut de Recherche pour le Développement (IRD)-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Universtié Yaoundé 1 [Cameroun]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), ANR-10-LABX-0077/10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Université de Bordeaux (UB), Laboratoire P4 Jean Mérieux-Inserm [Lyon] (Unité de service 3), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Européen de Recherche en Virologie et Immunologie [Lyon] (Tour Inserm CERVI), Groupe Henri Mondor-Albert Chenevier, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Universtié Yaoundé 1 [Cameroun]-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Institut national de la santé publique (INSP), Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques et émergentes (TransVIHMI), and CHU Henri Mondor [Créteil]

Subjects
Adult, Genetic Markers, Male, [SDV.IMM] Life Sciences [q-bio]/Immunology, T-Lymphocytes, Immunology, Antibodies, Viral, Lymphocyte Activation, Antiviral Agents, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Article, Young Adult, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Humans, Survivors, Immunological disorders, Inflammation, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, B-Lymphocytes, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Hemorrhagic Fever, Ebola, Ebolavirus, SISTM, Immune System Diseases, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Immunoglobulin G, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Infection, Transcriptome
Abstract

Long-term follow up studies from Ebola virus disease (EVD) survivors (EBOV_S) are lacking. Here, we evaluate immune and gene expression profiles in 35 Guinean EBOV_S from the last West African outbreak, a median of 23 months (IQR [18–25]) after discharge from treatment center. Compared with healthy donors, EBOV_S exhibit increases of blood markers of inflammation, intestinal tissue damage, T cell and B cell activation and a depletion of circulating dendritic cells. All survivors have EBOV-specific IgG antibodies and robust and polyfunctional EBOV-specific memory T-cell responses. Deep sequencing of the genes expressed in blood reveals an enrichment in ‘inflammation’ and ‘antiviral’ pathways. Integrated analyses identify specific immune markers associated with the persistence of clinical symptoms. This study identifies a set of biological and genetic markers that could be used to define a signature of “chronic Ebola virus disease (CEVD)”., Patients who have recovered from Ebola virus can have ongoing health problems. Here, the authors show that 35 Guinean survivors of the last West African Ebola epidemic have a chronic disease with high inflammatory cytokine expression and other markers of immune activation as well as evidence of intestinal tissue damage nearly two years after their release from hospital.

Published
2020
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10. Partnership for Research on Ebola VACcination (PREVAC): protocol of a randomized, double-blind, placebo-controlled phase 2 clinical trial evaluating three vaccine strategies against Ebola in healthy volunteers in four West African countries

Author

Badio, Moses, Lhomme, Edouard, Kieh, Mark, Beavogui, Abdoul Habib, Kennedy, Stephen B., Doumbia, Seydou, Leigh, Bailah, Sow, Samba O., Diallo, Alpha, Fusco, Daniela, Kirchoff, Matthew, Termote, Monique, Vatrinet, Renaud, Wentworth, Deborah, Esperou, Helène, Lane, H. Clifford, Pierson, Jerome, Watson-Jones, Deborah, Roy, Céline, D’Ortenzio, Eric, Greenwood, Brian, Chêne, Genevieve, Richert, Laura, Neaton, James D., Yazdanpanah, Yazdan, Abdoulaye, Coulibaly, Aboulhab, Jamilia, Akoo, Pauline, Akpa, Esther, Akpata, Robert, Albert, Sara, Ale, Boni Maxime, C. Andrews, Benetta, Anoma, Stephane, Assiandi, Saw-San, Augier, Augustin, Awuondo, Ken, Bagayoko, Aminata, Bakare, Nyasha, Balde, Abby, Bangura, Lamin Molecule, Barrington, Kesha, Barte de Saint Fare, Eric, Baseler, Beth, Bauder, Ali, Bauduin, Claire, Bawo, Luke, Habib Beavogui, Abdoul, Belson, Michael, Bererd, Marion, Beyslow, Teedoh, Binachon, Blandine, Blie, Julie, Bockstal, Viki, Boire, Youba, Boison, Patricia, Bolay, Fatorma, Boly, Aliou, Gael Borg, Anne, Bowers, Donna, Browne, Sarah, Cagniard, Barbara, Cahill, Kelly, Abdoulaye Camara, Aissata, Camara, Keira, Camara, Modet, Campion, Cécilia, Cash, Jennifer, Pin Chai, Siew, Chambelin, Francois, Chieck, Keita, Chêne, Geneviève, Ciancia, Séverine, Ndiaga Cisse, Papa, Clide, Elfrida, Colin, Céline, Coller, Beth-Ann, Siaka Conde, Djélikan, Cone, Katherine, Connor, Laurie, Connor, Nicholas, Boye Cooper, Joseph, Couffin-Cardiergues, Sandrine, Coulibaly, Fatoumata, Coulibaly, Mariam, Dabakuyo-Yonli, Sandrine, Dabitao, Djeneba, Damerval, Thierry, Davis, Bionca, Fadlu Deen, Gibrilla, Dekeyster, Eline, Delfraissy, Jean-François, Delmas, Christelle, Dembele, Rokia, Diakite, Mahamadou, Saliou Diallo, Mamadou, Diarra, Ayouba, Diawara, Oualy, Dighero-kemp, Bonnie, Diop, Samba, Diouf, Waly, Doepel, Laurie, Moise Doumbia, Moussa, Douoguih, Macaya, DuChêne, Alain, Duvenhage, Michael, Eckes, Risa Eckes, Egan, Avril, Enria, Luisa, Espérou, Hélène, Etienne, Cécile, Eyler, Allison, Faye, Sylvain, Fernandez, José, Fleck, Suzanne, Fofana, Vemy, Franklin, Kokulo, Gaddah, Auguste, Gaignet, Marylène, Gallagher, Katherine, Garcia Gozalbes, Julia, Grandits, Greg, Gray, Maima, Greijer, Astrid, Grue, Louis, Grund, Birgit, Guindo, Oumar, Gupta, Swati, Haidara, Fadima, Hamze, Benjamin, Hancox, Emma, Hart, Gavin, Hébert, Jean-Christophe, Heijnen, Esther, Hensley, Patricia, Hensley, Lisa, Higgs, Elisabeth, Hilton, Trudi, Holley, Preston, Hoover, Marie, Howard, Natasha, Hughes, Melissa, Ilo, Dicko, Imes, Jen, Irvine, Skip, Ishola, David, Jacob, Will, Jato, Yvonne, Johnson, Melvin, Jusu, Morrison, Sidiki Kaba, Aboubacar, Kante, Myriam, Katoudi, Judith, Keita, Sakoba, Kennedy, Stephen, Jide Keshinro, Babajide, Khon, Brian, Kiawu, Hassan, Kirchoff, Matt, Kodio, Mamoudou, Koivogui, Lamine, Kombi, Tania, Kopka, Stacy, Kowuors, Dickens, Lacabaratz, Christine, Lacarra, Boris, Lambert, Laurie, Lane, Cliff, Lee, Shona, Lees, Shelley, Lefevre, Annabelle, Lemarcis, Frederic, Lévy, Yves, Levy-Marchal, Claire, Lewally, Jemilla, Leyssen, Maarten, Liu, Ken, Lowe, Brett, Lysander, Julia, Madelaine, Claire, Mahamadou, Ibrah, Manno, Daniela, Marchand, Johnathan, Marynissen, Siegfried, Massaquoi, Moses B.F., Masson, Laure, Matard, Charly, Matthew, Onorato, McCullough, John, Mercier, Noemie, Michavila, Pauline, Miller, Tracey, Miranda, Alejandra, Mohamed, Soumaya, Mooney, Tom, Morsch, Hans, Muamba, Dally, Lukoo Ndamenyaa, Rita, Neaton, James, Neboua, Désiré, Nelson, Micki, Newell, Kevin, Nguyen, Vinh-kim, Nielsen, Leslie, Niouma, Millimouno, Offergeld, Kim, Onorato, Matthew, Onwuchekwa, Uma, Orsega, Susan, Ortega-Perez, Inmaculada, Osborne, Cynthia, Otieno, Tuda, Patel, Sushma, Peiffer-Smadj, Nathan, Phillips, Robert, Piot, Peter, Piziali, Micheal, Pong, Stephany, Proffitt, Calvin, Quach, Alexandre, Ramers-verhoeven, Corina, Randunu, Nadeeka, Rivière, Priscille, Robinson, Cynthia, Van Roey, Griet, Falk Russell, Amy, Samai, Sibiry Samake, Mohamed, Sangare, Ballan, Sanogo, Ibrahim, Sadio Sarro, Yeya, Sarro, Sadio, Saville, Mélanie, Sawadogo, Serge, Schvartz, Maxime, Schwimmer, Christine, Secka, Fatou, Seraphin, Jacques, Shelley, Denise, Siddiqui, Sophia, Simon, Jakub, Simpson, Shelly, Muyisa Sivahera, Billy, Skip, Irvine, Slater, Karen, Smolskis, Mary, Smout, Elizabeth, Snowden, Emily, Soutthiphong, Anne-Aygline, Sow, Samba, Sow, Ydrissa, Splinter, Daniel, Spreng, Simone, Stapleton, Helen, Stoop, Jeroen, Sweeney, Mary, Tamba, Sienneh, Tapia, Mili, Tegli, Jemee, Thiebaut, Rodolphe, Thompson, Greg, Tierney, John, Touré, Abdoulaye, Traina, Stacey, Traore, Awa, Traore, Moussa, Tyee, Tijili, Vallée, David, Van Der Donck, Katrien V, Verbruggen, Nadia, Vincent, Corine, Vogel, Susan, Wallet, Cedrick, Wesseh, Cecelia, Whitworth, Jimmy, Wiedemann, Aurelie, Willems, Wouter, Williams, Julian, Wilson, Barthalomew, Wissedi, Njoh, Wolf, Jayanthi, Woods, Ian, Wurie, Alie, Yamadjako, Delphine, Yaradouno, Marcel, Zeggani, Zara, Statistics In System biology and Translational Medicine (SISTM), Inria Bordeaux - Sud-Ouest, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)- Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), PREVAIL, Centre National de Formation et de Recherche en Santé Rurale [Maférinyah, Guinée] (CNFRSR), Malaria Research and Training Center [Bamako, Mali], Université de Bamako, University of Sierra Leone (USL), Institut National de Santé Publique [Bamako] = National Institute of Research on Public Health (INSP), ANRS - Maladies infectieuses émergentes (ANRS - MIE), Institut National de la Santé et de la Recherche Médicale (INSERM), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Minnesota [Twin Cities] (UMN), University of Minnesota System, Pôle de Recherche Clinique [Paris] (PRC), National Institute of Allergy and Infectious Diseases [Bethesda] (NIAID-NIH), National Institutes of Health [Bethesda] (NIH), and London School of Hygiene and Tropical Medicine (LSHTM)

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[SDV]Life Sciences [q-bio]
Abstract

International audience; Abstract Introduction The Ebola virus disease (EVD) outbreak in 2014–2016 in West Africa was the largest on record and provided an opportunity for large clinical trials and accelerated efforts to develop an effective and safe preventative vaccine. Multiple questions regarding the safety, immunogenicity, and efficacy of EVD vaccines remain unanswered. To address these gaps in the evidence base, the Partnership for Research on Ebola Vaccines (PREVAC) trial was designed. This paper describes the design, methods, and baseline results of the PREVAC trial and discusses challenges that led to different protocol amendments. Methods This is a randomized, double-blind, placebo-controlled phase 2 clinical trial of three vaccine strategies against the Ebola virus in healthy volunteers 1 year of age and above. The three vaccine strategies being studied are the rVSVΔG-ZEBOV-GP vaccine, with and without a booster dose at 56 days, and the Ad26.ZEBOV,MVA-FN-Filo vaccine regimen with Ad26.ZEBOV given as the first dose and the MVA-FN-Filo vaccination given 56 days later. There have been 4 versions of the protocol with those enrolled in Version 4.0 comprising the primary analysis cohort. The primary endpoint is based on the antibody titer against the Ebola virus surface glycoprotein measured 12 months following the final injection. Results From April 2017 to December 2018, a total of 5002 volunteers were screened and 4789 enrolled. Participants were enrolled at 6 sites in four countries (Guinea, Liberia, Sierra Leone, and Mali). Of the 4789 participants, 2560 (53%) were adults and 2229 (47%) were children. Those

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