A phase III randomised controlled trial of oral fluconazole plus flucytosine versus amphotericin B-based therapy for o

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Cryptococcal meningitis is one of the commonest causes of death in patients with AIDS andis associated with up to 500,000 deaths each year in Africa alone. A large proportion ofpatients die from the infection, in part because the current recommended treatment,amphotericin B for 2 weeks, is difficult to give in hospitals in the developing world, becauseit is relatively expensive and needs to be given intravenously and has side effects, oftenstarting in the second week, meaning monitoring is needed with frequent blood tests. Thealternative oral tablet treatment, fluconazole, that is available and cheap and currentlycommonly used, is much less effective.Therefore, based on a number of earlier small trials by the study team, we wish to test 2new treatments, (1) Short, 1-week amphotericin B, and (2) Combination tablet treatmentwith high dose fluconazole plus another drug called flucytosine, that are as fast and effectivein killing the infection as 2 weeks of amphotericin B. We will compare these new treatmentswith 2 weeks amphotericin B, in a larger, randomised trial that will enable us to see whetherthey are as good in preventing deaths from the infection. After 2 weeks of the studytreatments, all patients will receive the usual follow on therapy with fluconazole, and will bestarted on drugs for the underlying HIV infection, as currently recommended, and followedup for 10 weeks. 570 patients (190 given each alternative treatment) will be studied. This isthe minimum number needed to reliably compare the results of the treatments.The project has been developed with doctors in 3 centres in Malawi and Zambia where thereare many cases and where alternative, affordable and practical treatments are urgentlyneeded. Each centre has the laboratories needed, and experience in doing such trials. Bothtest treatments have been shown to be much more rapidly effective than fluconazole alone,and would have less side effects and be much more easily given in developing countries than2 weeks amphotericin B. However, if 2 weeks amphotericin B was found to be the besttreatment, then the costs required for its use could be justified. The costs as well as theeffectiveness of the treatments will be compared to help decide which treatment torecommend in the future.