Outcome Assessments in Clinical Trials of Cryptococcal Meningitis: Considerations on Use of Early Fungicidal Activity as a Potential Surrogate Endpoint for All-Cause Mortality
Tóm tắt
Cryptococcal meningitis (CM) is a common disease in resource-challenged settings, with a high mortality within weeks of disease onset. Mortality remains high with current treatments, so more effective interventions are needed to decrease mortality. There has been interest in using the outcome assessment of quantification of fungus from cerebrospinal fluid as a replacement (surrogate) endpoint for all-cause mortality (ACM) as a means of decreasing sample size in randomized clinical trials in CM. To evaluate a biomarker as a potential surrogate endpoint to replace ACM requires several steps. This paper discusses the issues of determining whether the context of a disease is one where a potential surrogate endpoint is rational, the types of outcome assessments that might qualify as potential surrogates, and the process for evaluation of the evidence that a chosen biomarker is a valid replacement for ACM in the given context of use. We then apply those principles to the context of randomized clinical trials of CM.
Tài liệu tham khảo
Park BJ, Wannemuehler KA, Marston BJ, Govender N, Pappas PG, Chiller TM. Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS. AIDS. 2009;23(4):525–30.
Harrison TS. The burden of HIV-associated cryptococcal disease. AIDS. 2009;23(4):531–2.
Kambugu A, Meya DB, Rhein J, O'Brien M, Janoff EN, Ronald AR, et al. Outcomes of cryptococcal meningitis in Uganda before and after the availability of highly active antiretroviral therapy. Clin Infect Dis. 2008;46(11):1694–701.
Day JN, Chau TT, Lalloo DG. Combination antifungal therapy for cryptococcal meningitis. N Engl J Med. 2013;368(26):2522–3.
Kirch W, Schafii C. Misdiagnosis at a university hospital in 4 medical eras. Medicine (Baltimore). 1996;75(1):29–40.
Altman DG, Bland JM. How to randomise. BMJ. 1999;319(7211):703–4.
Fleming TR, DeMets DL. Surrogate end points in clinical trials: are we being misled? Ann Intern Med. 1996;125(7):605–13.
Fleming TR, Powers JH. Biomarkers and surrogate endpoints in clinical trials. Stat Med. 2012;31(25):2973–84. Explanation of the issues associated with the choice of biomarkers as surrogate endpoints, the pros and cons of the use of surrogates, and examples of successful and failed biomarkers as surrogate endpoints in randomized trials.
Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001;69(3):89–95.
Walton MK, Powers JH, Hobart J, Patrick DL, Marquis P, Vamvakas S, et al. Clinical outcome assessments: conceptual foundations. Value in Health. 2013;in press.
US Food and Drug Administration. Code of federal regulations. Subpart H – accelerated approval of new drugs for serious and life-threatening illnesses. Silver Spring: US FDA; 1992.
Avorn J. Approval of a tuberculosis drug based on a paradoxical surrogate measure. JAMA. 2013;309(13):1349–50.
Institute of Medicine. Evaluation of biomarkers and surrogate endpoints in chronic disease. Washington, DC: National Academies Press; 2010. Long but thorough discussion about the development process for potential surrogate endpoints.
Hartz A, He T, Wallace R, Powers J. Comparing hormone therapy effects in two RCTs and two large observational studies that used similar methods for comprehensive data collection and outcome assessment. BMJ Open. 2013;3(7). Example of lack of ability to control for unmeasured confounders in observational studies despite controlling for over 800 baseline variables.
Yusuf S, Wittes J, Probstfield J, Tyroler HA. Analysis and interpretation of treatment effects in subgroups of patients in randomized clinical trials. JAMA. 1991;266(1):93–8.
Day JN, Chau TT, Wolbers M, Mai PP, Dung NT, Mai NH, et al. Combination antifungal therapy for cryptococcal meningitis. N Engl J Med. 2013;368(14):1291–302. Clinical trial using all-cause mortality as an endpoint in cryptococcal meningitis.
Bicanic T, Meintjes G, Wood R, Hayes M, Rebe K, Bekker LG, et al. Fungal burden, early fungicidal activity, and outcome in cryptococcal meningitis in antiretroviral-naive or antiretroviral-experienced patients treated with amphotericin B or fluconazole. Clin Infect Dis. 2007;45(1):76–80.
Bicanic T, Muzoora C, Brouwer AE, Meintjes G, Longley N, Taseera K, et al. Independent association between rate of clearance of infection and clinical outcome of HIV-associated cryptococcal meningitis: analysis of a combined cohort of 262 patients. Clin Infect Dis. 2009;49(5):702–9.
Jarvis JN, Meintjes G, Rebe K, Williams GN, Bicanic T, Williams A, et al. Adjunctive interferon-gamma immunotherapy for the treatment of HIV-associated cryptococcal meningitis: a randomized controlled trial. AIDS. 2012;26(9):1105–13.
Bennett JE, Dismukes WE, Duma RJ, Medoff G, Sande MA, Gallis H, et al. A comparison of amphotericin B alone and combined with flucytosine in the treatment of cryptoccal meningitis. N Engl J Med. 1979;301(3):126–31.
van der Horst CM, Saag MS, Cloud GA, Hamill RJ, Graybill JR, Sobel JD, et al. Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. National Institute of Allergy and Infectious Diseases Mycoses Study Group and AIDS Clinical Trials Group. N Engl J Med. 1997;337(1):15–21.
Brouwer AE, Rajanuwong A, Chierakul W, Griffin GE, Larsen RA, White NJ, et al. Combination antifungal therapies for HIV-associated cryptococcal meningitis: a randomised trial. Lancet. 2004;363(9423):1764–7.
Montezuma-Rusca M, Powers JH, Williamson P, Sullivan B, DerSimonian R. Evaluation of fungal clearance as a surrogate endpoint for mortality in the treatment of cryptococal meninigitis. PROSPERO registry of systematic reviews: University of York; 2014.
Yao ZW, Lu X, Shen C, Lin DF. Comparison of flucytosine and fluconazole combined with amphotericin B for the treatment of HIV-associated cryptococcal meningitis: a systematic review and meta-analysis. Eur J Clin Microbiol Infect Dis. 2014;33(8):1339–40.
Proschan MA, Waclawiw MA. Practical guidelines for multiplicity adjustment in clinical trials. Control Clin Trials. 2000;21(6):527–39.