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 and is associated with up to 500,000 deaths each year in Africa alone. A large proportion of patients 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, because it is relatively expensive and needs to be given intravenously and has side effects, often starting in the second week, meaning monitoring is needed with frequent blood tests. The alternative oral tablet treatment, fluconazole, that is available and cheap and currently commonly used, is much less effective. Therefore, based on a number of earlier small trials by the study team, we wish to test 2 new treatments, (1) Short, 1-week amphotericin B, and (2) Combination tablet treatment with high dose fluconazole plus another drug called flucytosine, that are as fast and effective in killing the infection as 2 weeks of amphotericin B. We will compare these new treatments with 2 weeks amphotericin B, in a larger, randomised trial that will enable us to see whether they are as good in preventing deaths from the infection. After 2 weeks of the study treatments, all patients will receive the usual follow on therapy with fluconazole, and will be started on drugs for the underlying HIV infection, as currently recommended, and followed up for 10 weeks. 570 patients (190 given each alternative treatment) will be studied. This is the 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 there are many cases and where alternative, affordable and practical treatments are urgently needed. Each centre has the laboratories needed, and experience in doing such trials. Both test 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 than 2 weeks amphotericin B. However, if 2 weeks amphotericin B was found to be the best treatment, then the costs required for its use could be justified. The costs as well as the effectiveness of the treatments will be compared to help decide which treatment to recommend in the future.
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