HIV EPIDEMIOLOGY AND PREVENTION / A Randomized Phase III Trial of Adjunctive Dexamethasone in HIV infected Adults with Cryptococcal Meningitis

Lead Research Organisation: MRC/UVRI Uganda Research Unit on AIDS

Abstract

The significance of this trial is the high death rate associated with Cryptococcal Meningitis (CM) among AIDS patients in many developing countries. CM is caused by a fungus. Management of CM even in cases where recommended antifungal medications have been used has remained challenging. There has been little improvement in management of CM, and matters have not been helped by lack of any new antifungal medications since the 1970s, before advent of the AIDS epidemic.
This trial aims to determine whether adjuvant therapy with dexamethasone in addition to standard antifungal therapy will reduce the mortality rate from cryptococcal meningitis in patients with HIV. The trial patients will be randomised to receive either dexamethasone or placebo in addition to optimal antifungal therapy.

Technical Summary

The problem being addressed by this multicentre trial is the high mortality rate associated with Cryptococcal Meningitis (CM) among AIDS patients. Management of CM even in cases where recommended antifungal medications have been used has remained challenging. There has been little improvement in management of CM, and matters have not been helped by lack of any new antifungal medications since the 1970s, before advent of the AIDS epidemic. The few trials that analysed use of adjunctive dexamethasone for treatment of CM had many limitations. There is therefore still a need to investigate dexamethasone further in a Randomised Controlled Trial. This study therefore aims to determine whether adjuvant therapy with dexamethasone in addition to standard antifungal therapy will reduce mortality rate from CM in AIDS patients.
Dexamethasone is a cheap, readily available, practicable intervention which will be easy to scale out if found to be beneficial and its side effect profile is also relatively well known. The study is currently being conducted in 2 African countries (Uganda and Malawi) and four South East Asian countries (Laos, Indonesia, Vietnam and Thailand).
The study is a randomized, double blind, placebo-controlled phase III trial of adjunctive Dexamethasone in HIV infected adults with CM. This trial aims to determine whether adjuvant therapy with dexamethasone in addition to standard antifungal therapy will reduce mortality rate from CM in patients with HIV. In this double blind trial, patients are randomised to receive either dexamethasone or placebo for 6 weeks in addition to optimal antifungal therapy.
The primary aim is to investigate the effect of dexamethasone adjunctive therapy on 10-week survival in adult HIV infected patients with cryptococcal meningitis.
The secondary aims are; to determine the effect of adjuvant treatment with dexamethasone on survival at 6 months, disability at 10 weeks and 6 months, the rate of sterilisation of cerebrospinal fluid (CSF), the frequency of grades 3, 4 and serious adverse events, the incidence of Immune Reconstitution Inflammatory Syndrome (IRIS), the incidence of other opportunistic infections, re-treatment for cryptococcal meningitis, and the presence of visual deficit at 10 weeks. In addition, the effect of steroids on survival by continent will be assessed.

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