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.
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.


METHODS
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.


BACKGROUND
International Standard Randomised Controlled Trial Number: ISRCTN59144167 26-July-2012.
Jeremy
J
Day
Darma
D
Imran
Ahmed Rizal
AR
Ganiem
Natriana
N
Tjahjani
Retno
R
Wahyuningsih
Robiatul
R
Adawiyah
David
D
Dance
Mayfong
M
Mayxay
Paul
P
Newton
Rattanaphone
R
Phetsouvanh
Sayaphet
S
Rattanavong
Adrienne K
AK
Chan
Robert
R
Heyderman
Joep J
JJ
van Oosterhout
Wirongrong
W
Chierakul
Nick
N
Day
Anatoli
A
Kamali
Freddie
F
Kibengo
Eugene
E
Ruzagira
Alastair
A
Gray
David G
DG
Lalloo
Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme Vietnam, Ho Chi Minh City, Vietnam. jbeardsley@oucru.org.
Justin
J
Beardsley
Tran Quang
TQ
Binh
Tran Thi Hong
TT
Chau
Nguyen Van Vinh
NV
Chau
Ngo Thi Kim
NT
Cuc
Jeremy
J
Farrar
Tran Tinh
TT
Hien
Nguyen
N
Van Kinh
Laura
L
Merson
Lan
L
Phuong
Loc Truong
LT
Tho
Pham Thanh
PT
Thuy
Guy
G
Thwaites
Heiman
H
Wertheim
Marcel
M
Wolbers
D017088:AIDS-Related Opportunistic Infections / Q000175:diagnosis / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D000893:Anti-Inflammatory Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000935:Antifungal Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001208:Asia; D002985:Clinical Protocols; D003907:Dexamethasone / Q000009:adverse effects / Q000627:therapeutic use*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D015658:HIV Infections / Q000150:complications* / Q000175:diagnosis / Q000401:mortality / Q000821:virology; D006801:Humans; D008295:Malawi; D016919:Meningitis, Cryptococcal / Q000175:diagnosis / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D012107:Research Design; D013997:Time Factors; D016896:Treatment Outcome; D014454:Uganda
D000893:Anti-Inflammatory Agents; D000935:Antifungal Agents; D003907:Dexamethasone