A Canadian Critical Care Trials Group project in collaboration with the international forum for acute care trialists - Collaborative H1N1 Adjuvant Treatment pilot trial (CHAT): study protocol and design of a randomized controlled trial

Karen E A Burns, Clarence Chant, Orla Smith, Brian Cuthbertson, Robert Fowler, Deborah J Cook, Peter Kruger, Steve Webb, Jamal Alhashemi, Guillermo Dominguez-Cherit, Carlos Zala, Gordon D Rubenfeld, John C Marshall, Karen E A Burns, Clarence Chant, Orla Smith, Brian Cuthbertson, Robert Fowler, Deborah J Cook, Peter Kruger, Steve Webb, Jamal Alhashemi, Guillermo Dominguez-Cherit, Carlos Zala, Gordon D Rubenfeld, John C Marshall

Abstract

Background: Swine origin influenza A/H1N1 infection (H1N1) emerged in early 2009 and rapidly spread to humans. For most infected individuals, symptoms were mild and self-limited; however, a small number developed a more severe clinical syndrome characterized by profound respiratory failure with hospital mortality ranging from 10 to 30%. While supportive care and neuraminidase inhibitors are the main treatment for influenza, data from observational and interventional studies suggest that the course of influenza can be favorably influenced by agents not classically considered as influenza treatments. Multiple observational studies have suggested that HMGCoA reductase inhibitors (statins) can exert a class effect in attenuating inflammation. The Collaborative H1N1 Adjuvant Treatment (CHAT) Pilot Trial sought to investigate the feasibility of conducting a trial during a global pandemic in critically ill patients with H1N1 with the goal of informing the design of a larger trial powered to determine impact of statins on important outcomes.

Methods/design: A multi-national, pilot randomized controlled trial (RCT) of once daily enteral rosuvastatin versus matched placebo administered for 14 days for the treatment of critically ill patients with suspected, probable or confirmed H1N1 infection. We propose to randomize 80 critically ill adults with a moderate to high index of suspicion for H1N1 infection who require mechanical ventilation and have received antiviral therapy for ≤ 72 hours. Site investigators, research coordinators and clinical pharmacists will be blinded to treatment assignment. Only research pharmacy staff will be aware of treatment assignment. We propose several approaches to informed consent including a priori consent from the substitute decision maker (SDM), waived and deferred consent. The primary outcome of the CHAT trial is the proportion of eligible patients enrolled in the study. Secondary outcomes will evaluate adherence to medication administration regimens, the proportion of primary and secondary endpoints collected, the number of patients receiving open-label statins, consent withdrawals and the effect of approved consent models on recruitment rates.

Discussion: Several aspects of study design including the need to include central randomization, preserve allocation concealment, ensure study blinding compare to a matched placebo and the use novel consent models pose challenges to investigators conducting pandemic research. Moreover, study implementation requires that trial design be pragmatic and initiated in a short time period amidst uncertainty regarding the scope and duration of the pandemic.

Trial registration number: ISRCTN45190901.

Figures

Figure 1
Figure 1
Study Overview.

References

    1. Cohen J, Enserink M. Swine flu. After delays, WHO agrees: the 2009 pandemic has begun. Science. 2009;324(5934):1496–1497. doi: 10.1126/science.324_1496.
    1. Thompson WW, Shay DK, Weintraub E. et al.Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA. 2003;289(2):179–186. doi: 10.1001/jama.289.2.179.
    1. Johnson NP, Mueller J. Updating the accounts: global mortality of the 1918-1920 "Spanish" influenza pandemic. Bull Hist Med. 2002;76(1):105–115. doi: 10.1353/bhm.2002.0022.
    1. Smith GJ, Bahl J, Vijaykrishna D. et al.Dating the emergence of pandemic influenza viruses. Proc Natl Acad Sci USA. 2009;106(28):11709–11712. doi: 10.1073/pnas.0904991106.
    1. Gambotto A, Barrett-Boyes SM, de Jong M, Neumann G, Kawaoka Y. Human infection with highly pathogenic H5N1 influenza virus. Lancet. 2008;371(9622):1464–1475. doi: 10.1016/S0140-6736(08)60627-3.
    1. Perez-Padilla R, Rosa-Zamboni D, Ponce de LS. et al.Pneumonia and respiratory failure from swine-origin influenza A (H1N1) in Mexico. N Engl J Med. 2009;361(7):680–689. doi: 10.1056/NEJMoa0904252.
    1. Kumar A, Zarychanski R, Pinto R. et al.Critically Ill Patients with Novel Swine Origin Influenza A/H1N1 in Canada. JAMA. 2009;302(17):1872–1879. doi: 10.1001/jama.2009.1496.
    1. The ANZIC Influenza Investigators. Critical Care Services and 2009 H1N1 Influenza in Australia and New Zealand. N Engl J Med. 2009. in press .
    1. Extracorporeal Membrane Oxygenation for 2009 Influenza A(H1N1) Acute Respiratory Distress Syndrome. JAMA. 2009;302(17):1888–95. doi: 10.1001/jama.2009.1535.
    1. Pandemic (H1N1) 2009 briefing note 1 Viruses resistant to oseltamivir (Tamiflu) identified. Wkly Epidemiol Rec. 2009;84(29):299–399.
    1. Oseltamivir-resistant 2009 pandemic influenza A (H1N1) virus infection in two summer campers receiving prophylaxis--North Carolina, 2009. MMWR Morb Mortal Wkly Rep. 2009;58(35):969–972.
    1. Fedson DS. Meeting the challenge of influenza pandemic preparedness in developing countries. Emerg Infect Dis. 2009;15(3):365–371. doi: 10.3201/eid1503.080857.
    1. Fedson DS. Confronting an influenza pandemic with inexpensive generic agents: can it be done? Lancet Infect Dis. 2008;8(9):571–576. doi: 10.1016/S1473-3099(08)70070-7.
    1. Ooi EE, Chew JS, Loh JP, Chua RC. In vitro inhibition of human influenza A virus replication by chloroquine. Virol J. 2006;3:39. doi: 10.1186/1743-422X-3-39.
    1. Palamara AT, Nencioni L, Aquilano K. et al.Inhibition of influenza A virus replication by resveratrol. J Infect Dis. 2005;191(10):1719–1729. doi: 10.1086/429694.
    1. Drago L, Nicola L, Ossola F, De VE. In vitro antiviral activity of resveratrol against respiratory viruses. J Chemother. 2008;20(3):393–394.
    1. Enserink M. Infectious disease. Old drugs losing effectiveness against flu; could statins fill gap? Science. 2005;309(5743):1976–1977. doi: 10.1126/science.309.5743.1976a.
    1. Liappis AP, Kan VL, Rochester CG, Simon GL. The effect of statins on mortality in patients with bacteremia. Clin Infect Dis. 2001;33(8):1352–1357. doi: 10.1086/323334.
    1. Thomsen RW, Riis A, Kornum JB, Christensen S, Johnsen SP, Sorensen HT. Preadmission use of statins and outcomes after hospitalization with pneumonia: population-based cohort study of 29,900 patients. Arch Intern Med. 2008;168(19):2081–2087. doi: 10.1001/archinte.168.19.2081.
    1. Hackam DG, Mamdani M, Li P, Redelmeier DA. Statins and sepsis in patients with cardiovascular disease: a population-based cohort analysis. Lancet. 2006;367(9508):413–418. doi: 10.1016/S0140-6736(06)68041-0.
    1. Chalmers JD, Singanayagam A, Murray MP, Hill AT. Prior statin use is associated with improved outcomes in community-acquired pneumonia. Am J Med. 2008;121(11):1002–1007. doi: 10.1016/j.amjmed.2008.06.030.
    1. Tleyjeh IM, Kashour T, Hakim FA. et al.Statins for the prevention and treatment of infections: a systematic review and meta-analysis. Arch Intern Med. 2009;169(18):1658–1667. doi: 10.1001/archinternmed.2009.286.
    1. Kopterides P, Falagas ME. Statins for sepsis: a critical and updated review. Clin Microbiol Infect. 2009;15(4):325–334. doi: 10.1111/j.1469-0691.2009.02750.x.
    1. Falagas ME, Makris GC, Matthaiou DK, Rafailidis PI. Statins for infection and sepsis: a systematic review of the clinical evidence. J Antimicrob Chemother. 2008;61(4):774–785. doi: 10.1093/jac/dkn019.
    1. Ponce J, de la Ossa NP, Hurtado O. et al.Simvastatin reduces the association of NMDA receptors to lipid rafts: a cholesterol-mediated effect in neuroprotection. Stroke. 2008;39(4):1269–1275. doi: 10.1161/STROKEAHA.107.498923.
    1. Ghittoni R, Patrussi L, Pirozzi K. et al.Simvastatin inhibits T-cell activation by selectively impairing the function of Ras superfamily GTPases. FASEB J. 2005;19(6):605–607.
    1. Yasuda H, Yuen PS, Hu X, Zhou H, Star RA. Simvastatin improves sepsis-induced mortality and acute kidney injury via renal vascular effects. Kidney Int. 2006;69(9):1535–1542. doi: 10.1038/sj.ki.5000300.
    1. Shyamsundar M, McKeown ST, O'Kane CM. et al.Simvastatin decreases lipopolysaccharide-induced pulmonary inflammation in healthy volunteers. Am J Respir Crit Care Med. 2009;179(12):1107–1114. doi: 10.1164/rccm.200810-1584OC.
    1. Liu Z, Guo Z, Wang G. et al.Evaluation of the efficacy and safety of a statin/caffeine combination against H5N1, H3N2 and H1N1 virus infection in BALB/c mice. Eur J Pharm Sci. 2009;38(3):215–223. doi: 10.1016/j.ejps.2009.07.004.
    1. Frost FJ, Petersen H, Tollestrup K, Skipper B. Influenza and COPD mortality protection as pleiotropic, dose-dependent effects of statins. Chest. 2007;131(4):1006–1012. doi: 10.1378/chest.06-1997.
    1. Vandermeer M, Thomas A, Kamimoto L, Role of statins in preventing death among patients hospitalized with lab-confirmed influenza infections. Infectious Diseases Society of America 2009 Meeting; October 30, 2009; Philadelphia, PA. p. Abstract 706.
    1. Schmidt H, Hennen R, Keller A. et al.Association of statin therapy and increased survival in patients with multiple organ dysfunction syndrome. Intensive Care Med. 2006;32(8):1248–1251. doi: 10.1007/s00134-006-0246-y.
    1. Kor DJ, Iscimen R, Yilmaz M, Brown MJ, Brown DR, Gajic O. Statin administration did not influence the progression of lung injury or associated organ failures in a cohort of patients with acute lung injury. Intensive Care Med. 2009;35(6):1039–1046. doi: 10.1007/s00134-009-1421-8.
    1. McTaggart F, Buckett L, Davidson R. et al.Preclinical and clinical pharmacology of rosuvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Am J Cardiol. 2001;87(suppl):28B–32B. doi: 10.1016/S0002-9149(01)01454-0.
    1. Crestor Product Monograph. AstraZeneca Inc., Mississauga, Ontario Canada; 2010. Last Revised: April 28, 2010. Last accessed October 26, 2010.
    1. Cook DJ, Blythe D, Rischbieth A. et al.Enrollment of intensive care unit patients into clinical studies: a trinational survey of researchers' experiences, beliefs, and practices. Crit Care Med. 2008;36(7):2100–2105. doi: 10.1097/CCM.0b013e31817c00b0.
    1. Scripture CD, Pieper JA. Clinical pharmacokinetics of fluvastatin. Clin Pharmacokinet. 2001;40(4):263–281. doi: 10.2165/00003088-200140040-00003.
    1. Ercole A, Taylor BL, Rhodes A, Menon DK. Modelling the impact of an influenza A/H1N1 pandemic on critical care demand from early pathogenicity data: the case for sentinel reporting. Anaesthesia. 2009;64(9):937–941. doi: 10.1111/j.1365-2044.2009.06070.x.
    1. Cook D, Burns K, Finfer S, Clinical research ethics for critically ill patients during the H1N1 pandemic. Crit Care Med. 2009. in press .
    1. Levy MM, Baylor MS, Bernard GR. et al.Clinical issues and research in respiratory failure from severe acute respiratory syndrome. Am J Respir Crit Care Med. 2005;171(5):518–526. doi: 10.1164/rccm.200405-621WS.

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