CryptoDex: A randomised, double-blind, placebo-controlled phase III trial of adjunctive dexamethasone in HIV-infected adults with cryptococcal meningitis: study protocol for a randomised control trial

Publication Date: 
Friday, December 5, 2014
Jeremy Day, Darma Imran, Ahmed Rizal Ganiem, Natriana Tjahjani, Retno Wahyuningsih, Robiatul Adawiyah, David Dance, Mayfong Mayxay, Paul Newton, Rattanaphone Phetsouvanh, Sayaphet Rattanavong, Adrienne K Chan, Robert Heyderman, Joep J van Oosterhout, Wirongrong Chieraku, Nick Day, Anatoli Kamali, Freddie Kibengo, Eugene Ruzagira, Alastair Gray, David G Lalloo, Justin Beardsley, Tran Quang Binh, Tran Thi Hong Chau, Nguyen Van Vinh Chau, Ngo Thi Kim Cuc, Jeremy Farrar, Tran Tinh Hien, Nguyen Van Kinh, Laura Merson, Lan Phuong, Loc Truong Tho, Pham Thanh Thuy, Guy Thwaites, Heiman Wertheim and Marcel Wolbers

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

Trials Journal
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