Plain English Summary
Background and study aims
Cryptococcal meningitis (CM) causes around 625,000 deaths every year, most of which occur within 3 months of diagnosis. It is the leading cause of death in HIV patients in Asia and Africa. The incidence in these regions is the highest in the world - in Africa, it is estimated there are more deaths due to CM than due to tuberculosis. There has been no major advance in the treatment of CM since the 1970s. The main drugs used to treat CM (amphotericin B and flucytosine) are over 50 years old, and they are often poorly available where the disease burden is highest. While effective antifungal therapy is key, adjunctive treatments, which have been seen to have dramatic effects on death rates in other nervous system infections, are untested in CM. Given the high death rates in patients receiving the best current treatment and the lack of new drugs on the horizon, adjuvant treatments offer the greatest potential to reduce death rates in CM. Dexamethasone is a cheap, readily available and practical treatment. This study aims to find out whether adding dexamethasone to standard antifungal therapy reduces death rates in CM.
Who can participate?
Patients who are more than 18 years of age, HIV-positive and have CM can participate in the study.
What does the study involve?
Eligible participants will randomly be allocated to one of two groups: the dexamethasone group or the dummy drug (placebo) group. The dexamethasone dose will depend on the participants body weight and the dose will be reduced each week. All patients will also receive antifungal treatment consisting of 2 weeks of amphotericin B combined with high-dose fluconazole, followed by fluconazole alone for 8 weeks (10 weeks in total). Patients will be in hospital for at least 2 weeks and then followed-up until week 10 and if possible to 6 months.
What are the possible benefits and risks of participating?
It is unknown if the participants in the dexamethasone group will benefit from the treatment. The additional monitoring and follow-up of patients by dedicated study staff may be of benefit to patients treated in resource-limited settings. The study results will help us to understand how to best treat CM and it may help others with this disease in the future. This study will use a drug that has been studied thoroughly and its toxicities are well known. Blood and cerebral spinal fluid will be taken for research tests. These volumes have very little risk of affecting the participant's health. This procedure carries a small risk of bruising and infection. Dexamethasone may be suppress growth in children and fetuses. Therefore, children and pregnant women have been excluded from this study.
Where is the study run from?
Vietnam, Indonesia, Thailand, Laos, Uganda and Malawi
When is the study starting and how long is it expected to run for?
It started in September 2012 and it should run for about three years
Who is funding the study?
The Department for International Development, the Wellcome Trust and the Medical Research Council in the UK
Who is the main contact?
Dr Jeremy Day
jday@oucru.org
Trial website
https://portal.oucru.org/RS/04CN%20%20CryptoDe/Forms/AllItems.aspx
Contact information
Type
Scientific
Primary contact
Dr Jeremy Day
ORCID ID
Contact details
Centre for Tropical Medicine
Oxford University Clinical Research Unit (Vietnam)
764 Vo Van Kiet
Ward 1
District 5
Ho Chi Minh
084
Viet Nam
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jday@oucru.org
Additional identifiers
EudraCT number
ClinicalTrials.gov number
Protocol/serial number
04CN
Study information
Scientific title
A randomized, double-blind, placebo-controlled phase III trial of adjunctive dexamethasone in HIV-infected adults with cryptococcal meningitis (CRYPTODEX)
Acronym
CRYPTODEX
Study hypothesis
Dexamethasone used as adjunctive therapy may improve the 10-week survival in adult HIV-infected patients with cryptococcal meningitis.
Ethics approval
Oxford Tropical Research Ethics Committee, 13/06/2012, ref: 25-12
Study design
Randomized double-blind placebo-controlled trial with two parallel arms
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Other
Trial type
Treatment
Patient information sheet
Not available in web format, please use the contact details below to request a patient information sheet
Condition
Cryptococcus meningitis/HIV
Intervention
Eligible participants will randomly be allocated to either dexamethasone or placebo group.
Dexamethasone will be given in a reducing dose according to body weight.
This dose is identical to the dose used in patients with Grade 1 tuberculous meningitis and has been shown to have a low rate of side effects. Dexamethasone/placebo will be administered intravenously while the antifungal treatment is intravenous, and orally once antifungal treatment is administered orally. Treatment will be weight-dosed to the nearest half milligram. With the exception of the first dose, which should be given with the first dose of anti-fungal therapy, dexamethasone should be given in the morning.
Intervention type
Drug
Phase
Phase III
Drug names
Dexamethasone
Primary outcome measure
Overall survival until 10 weeks after randomisation
Secondary outcome measures
1. Survival until 6 months after randomization
2. Disability at 10 weeks and 6 months
3. Rate of CSF sterilisation during the first 2 weeks
4. Adverse events
5. Rate of IRIS until 10 weeks
6. Time to new AIDS-defining illnesses or death until 10 weeks
7. Visual deficit at 10 weeks
8. Time to new neurological event or death until 10 weeks
9. Longitudinal measurements of intracranial pressure during the first 2 weeks
10. Antifungal treatment intensification or re-treatment for cryptococcal meningitis in the 6 months post randomisation
Overall trial start date
30/09/2012
Overall trial end date
30/12/2015
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
1. Age >18 years
2. HIV antibody positive
3. Cryptococcal meningitis defined as a syndrome consistent with CM and one or more of:
3.1. Positive CSF India ink (budding encapsulated yeasts)
3.2. C. neoformans cultured from CSF or blood
3.3. Positive cryptococcal antigen Lateral Flow Antigen Test (LFA) in CSF
4. Informed consent to participate given by patient or acceptable representative
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
880
Participant exclusion criteria
Current exclusion criteria as of 23/09/2014:
1. Pregnancy
2. Active gastrointestinal bleeding (defined as vomiting blood or malaena stool in the previous week)
3. Currently receiving treatment for cryptococcal meningitis and having received > 1 week of anti-cryptococcal meningitis therapy
4. Known allergy to dexamethasone
5. Current steroid use defined as:
5.1. Currently receiving the equivalent of prednisolone 40 mg/day or more
5.2. Currently receiving steroid therapy (any dose) for more than 3 weeks (except topical steroids which are permitted)
6. Concurrent condition for which corticosteroids are indicated because of proven benefit (such as severe Pneumocystis pneumonia [pO2<70 mmHg] or tuberculous meningitis)
7. Renal failure (defined as creatinine >3*ULN, despite adequate hydration)
Previous exclusion criteria:
1. Pregnancy
2. Active gastrointestinal bleeding (defined as vomiting blood or malaena stool in the previous week)
3. Currently receiving treatment for cryptococcal meningitis and having received > 1 week of anti-cryptococcal meningitis therapy
4. Known allergy to dexamethasone
5. Current steroid use defined as:
5.1. Currently receiving the equivalent of prednisolone 40 mg/day or more
5.2. Currently receiving steroid therapy (any dose) for more than 3 weeks (except topical steroids which are permitted)
6. Renal failure (defined as creatinine >3*ULN, despite adequate hydration)
Recruitment start date
19/02/2013
Recruitment end date
29/08/2014
Locations
Countries of recruitment
Indonesia, Laos, Malawi, Thailand, Uganda, Viet Nam
Trial participating centre
Oxford University Clinical Research Unit
Ho Chi Minh
084
Viet Nam
Sponsor information
Organisation
University of Oxford (UK)
Sponsor details
c/o Ms Heather House
Head of Clinical Trials and Research Governance
Joint Research Office
Churchill Hospital
Old Road
Headington
Oxford
OX3 7LJ
United Kingdom
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Heather.House@admin.ox.ac.uk
Sponsor type
University/education
Website
Funders
Funder type
Charity
Funder name
Department for International Development
Alternative name(s)
Department for International Development, UK, DFID
Funding Body Type
government organisation
Funding Body Subtype
National government
Location
United Kingdom
Funder name
Wellcome Trust
Alternative name(s)
Funding Body Type
private sector organisation
Funding Body Subtype
International organizations
Location
United Kingdom
Funder name
Medical Research Council (UK), ref: G1100684/1
Alternative name(s)
MRC
Funding Body Type
government organisation
Funding Body Subtype
National government
Location
United Kingdom
Results and Publications
Publication and dissemination plan
Not provided at time of registration
Intention to publish date
Participant level data
Not provided at time of registration
Basic results (scientific)
Publication list
2014 protocol in: http://www.ncbi.nlm.nih.gov/pubmed/25391338
2016 results in: http://www.ncbi.nlm.nih.gov/pubmed/26863355
Publication citations
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Protocol
Day J, Imran D, Ganiem AR, Tjahjani N, Wahyuningsih R, Adawiyah R, Dance D, Mayxay M, Newton P, Phetsouvanh R, Rattanavong S, Chan AK, Heyderman R, van Oosterhout JJ, Chierakul W, Day N, Kamali A, Kibengo F, Ruzagira E, Gray A, Lalloo DG, Beardsley J, Binh TQ, Chau TT, Chau NV, Cuc NT, Farrar J, Hien TT, Van Kinh N, Merson L, Phuong L, Tho LT, Thuy PT, Thwaites G, Wertheim H, Wolbers M, 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., Trials, 2014, 15, 1, 441, doi: 10.1186/1745-6215-15-441.
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Results
Beardsley J, Wolbers M, Kibengo FM, Ggayi AB, Kamali A, Cuc NT, Binh TQ, Chau NV, Farrar J, Merson L, Phuong L, Thwaites G, Van Kinh N, Thuy PT, Chierakul W, Siriboon S, Thiansukhon E, Onsanit S, Supphamongkholchaikul W, Chan AK, Heyderman R, Mwinjiwa E, van Oosterhout JJ, Imran D, Basri H, Mayxay M, Dance D, Phimmasone P, Rattanavong S, Lalloo DG, Day JN; CryptoDex Investigators, Adjunctive Dexamethasone in HIV-Associated Cryptococcal Meningitis, N Engl J Med, 2016 , 374, 6, 542-554.