Adjunctive dexamethasone in HIV-infected adults with cryptococcal meningitis

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 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

https://portal.oucru.org/RS/04CN%20%20CryptoDe/Forms/AllItems.aspx

Type

Scientific

Contact name

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
-
jday@oucru.org

EudraCT/CTIS number

IRAS number

ClinicalTrials.gov number

Secondary identifying numbers

04CN

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(s)

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

Study setting(s)

Other

Study 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

Pharmaceutical study type(s)

Phase

Phase III

Drug/device/biological/vaccine name(s)

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 study start date

30/09/2012

Overall study end date

30/12/2015

Reason abandoned (if study stopped)

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(s)

Patient

Age group

Adult

Lower age limit

18 Years

Sex

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

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

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
England
United Kingdom
-
Heather.House@admin.ox.ac.uk

Sponsor type

University/education

Website

http://www.ox.ac.uk/

ROR

https://ror.org/052gg0110

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)

UK Medical Research Council, MRC

Funding Body Type

government organisation

Funding Body Subtype

National government

Location

United Kingdom

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

Individual participant data (IPD) Intention to share

No

IPD sharing plan

IPD sharing plan summary

Not provided at time of registration

Study outputs