Designing and conducting a randomized trial for pandemic critical illness: the 2009 H1N1 influenza pandemic

• Published in: Intensive care medicine Vol. 38; no. 1; pp. 29 - 39
• Main Authors: Annane, Djillali, Antona, Marion, Lehmann, Blandine, Kedzia, Cecile, Chevret, Sylvie
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 2012; Springer; Springer Nature B.V
• Subjects: Adrenal Cortex Hormones - therapeutic use; Analysis; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Anesthesiology; Biological and medical sciences; Clinical trial. Drug monitoring; Clinical trials; Corticoids; Corticosteroids; Critical Care Medicine; Critical Illness; Double-Blind Method; Drug approval; Drugs; Emergency Medicine; Ethical aspects; Ethics; Ethics, Research; Female; General pharmacology; Hospital patients; Hospitals; Humans; Hydrocortisone; Independent regulatory commissions; Infection; Influenza; Influenza A Virus, H1N1 Subtype; Influenza, Human - drug therapy; Influenza, Human - epidemiology; Influenza, Human - virology; Intensive; Intensive care medicine; Male; Medical sciences; Medicine; Medicine & Public Health; Pain Medicine; Pandemics; Pediatrics; Personnel; Pharmacists; Pharmacology. Drug treatments; Pneumology/Respiratory System; Pneumonia; Prospective Studies; Research Design; Severity of Illness Index; Special Article; Swine influenza; Ventilation; Waves; France; United Kingdom; Design; Ethics; Critical illness; Clinical trial; Pandemic crisis; H1N1; Intensive care; Respiratory disease; H1N1 influenza; Crisis; Infection; Viral disease; Resuscitation
• ISSN: 0342-4642; 1432-1238
• DOI: 10.1007/s00134-011-2409-8

Purpose To analyze the hurdles in implementing a randomized trial of corticosteroids for severe 2009 H1N1 influenza infections. Methods This was an investigator-led, multicenter, randomized, placebo-controlled, double-blind trial of corticosteroids in ICU patients with 2009 H1N1 influenza pneumonia requiring mechanical ventilation. The feasibility of and hurdles in designing and initiating a phase III trial in a short-lived pandemic crisis were analyzed. The regulatory agency and ethics committee approved the study’s scientific, financial, and ethical aspects within 4 weeks. Hydrocortisone and placebo were prepared centrally and shipped to participating hospitals within 6 weeks. The inclusion period started on November 9, 2009. Results From August 1, 2009 to March 8, 2010, only 205/224 ICU patients with H1N1 infections required mechanical ventilation. The peak of the wave was missed by 2–3 weeks and only 26 patients were randomized. The two main reasons for non-inclusion were patients’ admission before the beginning of the trial and ICU personnel overwhelmed by clinical duties. Parallel rather than sequential regulatory and ethics approval, and preparation and masking of study drugs by local pharmacists would have allowed the study to start 1 month earlier and before the peak of the “flu” wave. A dedicated research team in each participating center would have increased the ratio of screened to randomized patients. Conclusion This report highlights the main hurdles in implementing a randomized trial for a pandemic critical illness and proposes solutions for future trials.