Adjunctive dexamethasone in HIV-infected adults with cryptococcal meningitis

ISRCTN ISRCTN59144167
DOI https://doi.org/10.1186/ISRCTN59144167
Secondary identifying numbers 04CN
Submission date
13/07/2012
Registration date
26/07/2012
Last edited
26/02/2016
Recruitment status
No longer recruiting
Overall study status
Completed
Condition category
Infections and Infestations
Prospectively registered
Protocol
Statistical analysis plan
Results
Individual participant data

Plain English summary of protocol

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 participant’s 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

Study website

Contact information

Dr Jeremy Day
Scientific

Centre for Tropical Medicine
Oxford University Clinical Research Unit (Vietnam)
764 Vo Van Kiet
Ward 1, District 5
Ho Chi Minh
084
Viet Nam

Email jday@oucru.org

Study information

Study designRandomized double-blind placebo-controlled trial with two parallel arms
Primary study designInterventional
Secondary study designRandomised controlled trial
Study setting(s)Other
Study typeTreatment
Participant information sheet Not available in web format, please use the contact details below to request a patient information sheet
Scientific titleA randomized, double-blind, placebo-controlled phase III trial of adjunctive dexamethasone in HIV-infected adults with cryptococcal meningitis (CRYPTODEX)
Study acronymCRYPTODEX
Study objectivesDexamethasone used as adjunctive therapy may improve the 10-week survival in adult HIV-infected patients with cryptococcal meningitis.
Ethics approval(s)Oxford Tropical Research Ethics Committee, 13/06/2012, ref: 25-12
Health condition(s) or problem(s) studiedCryptococcus meningitis/HIV
InterventionEligible 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 typeDrug
Pharmaceutical study type(s)
PhasePhase III
Drug / device / biological / vaccine name(s)Dexamethasone
Primary outcome measureOverall survival until 10 weeks after randomisation
Secondary outcome measures1. 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 study start date30/09/2012
Completion date30/12/2015

Eligibility

Participant type(s)Patient
Age groupAdult
Lower age limit18 Years
SexBoth
Target number of participants880
Key inclusion criteria1. 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
Key exclusion criteriaCurrent 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)
Date of first enrolment19/02/2013
Date of final enrolment29/08/2014

Locations

Countries of recruitment

  • Indonesia
  • Lao People's Democratic Republic
  • Malawi
  • Thailand
  • Uganda
  • Viet Nam

Study participating centre

Oxford University Clinical Research Unit
Ho Chi Minh
084
Viet Nam

Sponsor information

University of Oxford (UK)
University/education

c/o Ms Heather House
Head of Clinical Trials and Research Governance
Joint Research Office
Churchill Hospital
Old Road
Headington
Oxford
OX3 7LJ
England
United Kingdom

Email Heather.House@admin.ox.ac.uk
Website http://www.ox.ac.uk/
ROR logo "ROR" https://ror.org/052gg0110

Funders

Funder type

Charity

Department for International Development
Government organisation / National government
Alternative name(s)
Department for International Development, UK, DFID
Location
United Kingdom
Wellcome Trust
Private sector organisation / International organizations
Location
United Kingdom
Medical Research Council (UK), ref: G1100684/1
Government organisation / National government
Alternative name(s)
Medical Research Council (United Kingdom), UK Medical Research Council, MRC
Location
United Kingdom

Results and Publications

Intention to publish date
Individual participant data (IPD) Intention to shareNo
IPD sharing plan summaryNot provided at time of registration
Publication and dissemination planNot provided at time of registration
IPD sharing plan

Study outputs

Output type Details Date created Date added Peer reviewed? Patient-facing?
Protocol article protocol 12/11/2014 Yes No
Results article results 11/02/2016 Yes No

Editorial Notes

26/02/2016: Publication reference added.