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CryptoDex: a randomised, double-blind, placebo-controlled phase III trial of adjunctive dexamethasone in HIV-infected
Jeremy Day, Darma Imran, Ahmed Rizal Ganiem
1Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme Vietnam, Ho Chi Minh City, Vietnam. jbeardsley@oucru.org.
Background:
Cryptococcal meningitis (CM) is a severe AIDS-defining illness with 90-day case mortality as high as 70% in sub-Saharan Africa, despite treatment. It is the leading cause of death in HIV patients in Asia and Africa.No major advance has been made in the treatment of CM since the 1970s. The mainstays of induction therapy are amphotericin B and flucytosine, but these are often poorly available where the disease burden is highest. Adjunctive treatments, such as dexamethasone, have had dramatic effects on mortality in other neurologic infections, but are untested in CM. Given the high death rates in patients receiving current optimal treatment, and the lack of new agents on the horizon, adjuvant treatments, which offer the potential to reduce mortality in CM, should be tested.The principal research question posed by this study is as follows: does adding dexamethasone to standard antifungal therapy for CM reduce mortality? Dexamethasone is a cheap, readily available, and practicable intervention.
Method:
A double-blind placebo-controlled trial with parallel arms in which patients are randomised to receive either dexamethasone or placebo, in addition to local standard of care. The study recruits patients in both Asia and Africa to ensure the relevance of its results to the populations in which the disease burden is highest. The 10-week mortality risk in the control group is expected to be between 30% and 50%, depending on location, and the target hazard ratio of 0.7 corresponds to absolute risk reductions in mortality from 30% to 22%, or from 50% to 38%. Assuming an overall 10-week mortality of at least 30% in our study population, recruitment of 824 patients will be sufficient to observe the expected number of deaths. Allowing for some loss to follow-up, the total sample size for this study is 880 patients. To generate robust evidence across both continents, we aim to recruit roughly similar numbers of patients from each continent. The primary end point is 10-week mortality. Ethical approval has been obtained from Oxford University's Tropical Research Ethics Committee (OxTREC), and as locally mandated at each site.
Trial Registration:
International Standard Randomised Controlled Trial Number: ISRCTN59144167 26-July-2012.
Insights
Adding dexamethasone to standard antifungal therapy for cryptococcal meningitis (CM) may reduce mortality. This study investigates the efficacy of dexamethasone as an adjunctive treatment for CM in HIV patients in Asia and Africa.
Area of Science:
- Infectious Diseases
- Neurology
- HIV/AIDS Research
Background:
- Cryptococcal meningitis (CM) is a severe AIDS-defining illness with high mortality rates, particularly in sub-Saharan Africa, Asia, and among HIV patients.
- Current treatments for CM have seen no major advances since the 1970s, with essential drugs like amphotericin B and flucytosine often unavailable in high-burden regions.
- Adjunctive therapies like dexamethasone, proven effective in other neurological infections, remain untested in CM despite high death rates.
Purpose of the Study:
- To determine if adding dexamethasone to standard antifungal therapy for cryptococcal meningitis (CM) can reduce patient mortality.
- To evaluate the efficacy and safety of dexamethasone as an adjuvant treatment for CM in resource-limited settings.
Main Methods:
- A double-blind, placebo-controlled, randomized trial involving 880 patients across Asia and Africa.
- Patients received either dexamethasone or a placebo, in addition to local standard antifungal care for CM.
- The primary endpoint is 10-week mortality, with expected mortality rates between 30-50% in the control group.
Main Results:
- The study aims to detect a hazard ratio of 0.7, indicating a significant reduction in mortality with dexamethasone.
- Expected absolute risk reductions range from 8% to 12%, depending on location.
- Recruitment of 880 patients is planned to ensure sufficient statistical power to observe the expected number of deaths.
Conclusions:
- Dexamethasone is a cheap, readily available, and potentially impactful intervention for reducing CM mortality.
- The findings will provide crucial evidence on the utility of dexamethasone in managing CM, especially in regions with high disease burden.
- This research addresses a critical unmet need in CM treatment, offering hope for improved patient outcomes.
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