A clinical trial of dexamethasone to reduce mortality in cryptococcal meningitis

Lead Research Organisation: University of Oxford
Department Name: Tropical Medicine

Abstract

Cryptococcal meningitis is a brain infection due to a yeast called Cryptococcus neoformans. It is important because it is a major cause of death in people infected with HIV. There are over 600 000 deaths each year, and most of these occur in poorer countries in Africa and Asia. Even if patients receive treatment with antifungal drugs, the death rate remains high - about 55% of people with disease in Asia and 70% in Africa will die within 3 months of diagnosis. A combination of antifungal drugs is given to kill the yeast, but researchers have been unable to improve on the antifungal treatment combination that has been recommended for the past 10 years. This is despite extensive research. We believe that new approaches are needed to try and improve outcome in this disease. The features of infectious diseases are the result of not only the infectious agent, but also the way our bodies respond to them. When our bodies? immune systems fight infection, this causes inflammation which can sometimes make disease worse. When people have cryptococcal meningitis, there is inflammation and raised pressure in the brain. The inflammation can result in parts of the brain dying (a stroke). The raised pressure leads to the brain getting squeezed (compressed) against the inside of the skull. This can impair the blood supply and can directly damage the brain tissue itself. These processes can lead to death. Steroids are drugs that can reduce inflammation, and are frequently used to lower raised pressure in brain diseases. They have been found to be useful in other forms of meningitis, such as acute bacterial meningitis and tuberculous meningitis. These diseases share some features with cryptococcal meningitis. We want to test whether giving dexamethasone, a steroid, alongside antifungal therapy, can reduce the death rate in people with cryptococcal meningitis. Dexamethasone is cheap, safe, and widely available, and if successful is a treatment that would be affordable and practical for the majority of patients around the world with this disease. We want to do this study in Africa and Asia, because this is where most people with cryptococcal meningitis live.

Technical Summary

Cryptococcal meningitis is the leading cause of death in HIV patients in Asia and Africa with death rates between 55 and 70%. There are an estimated 625 000 deaths each year, most occurring in poorer countries and within 3 months of diagnosis. There has been no major advance in treatment since 1997 - no combination of antifungal drugs with greater sterilizing power than amphotericin and flucytosine has since been identified. In order to make a significant impact on mortality, alternative approaches need to be trialled. Adjuvant therapies are relatively untested in cryptococcal meningitis. Raised intracranial pressure, vasculitis with infarction and cerebral oedema are all complications of cryptococcal meningitis and are believed to contribute towards its high mortality. These pathologies are potentially modifiable with dexamethasone. Dexamethasone is a corticosteroid which is frequently used to treat intracranial pathology including vasculitides, raised pressure, and cerebral oedema. It is of proven benefit in reducing the death rate of tuberculous meningitis, a chronic meningitis that has some pathophysiological similarities to cryptococcal meningitis. Moreover, it has an excellent safety profile, is cheap and practicable. In addition, animal studies show that dexamethasone does not impair the action of antifungal drugs.
Therefore, we propose a multicentre double blind randomised controlled trial of dexamethasone in HIV infected patients with cryptococcal meningitis. The study will be based in countries in Africa (Uganda, South Africa, Malawi) and Southeast Asia (Thailand, Laos, Vietnam, Indonesia) where this disease is a significant health burden, and in centres with track records of successful completion of large clinical trials and the subsequent translation of findings into national and international policy. The multi-centre nature of the trial, recruiting in African and Asian countries, ensures that the results of the trial will have generalizability and impact. The primary endpoint will be survival until 10 weeks after randomization. The study will have 80% power to detect a reduction in the death rate of 30% (Hazard Ratio 0.7), and will require 880 patients (allowing for 10% loss to follow up). The study will also have 80% power to detect a 40% reduction in death rate in each continent. Patients will receive optimised antifungal therapy and be randomised to receive dexamethasone or identical placebo. Secondary endpoints include disability, survival to 6 months, adverse event rates, opportunistic infection rates and the rate of fungal clearance.

Publications

10 25 50
 
Guideline Title http://hivinsite.ucsf.edu/InSite?page=md-ward86-cryptococcosis
Description CryptoDex Trial results references in the HIV InSIte website run by UCSF
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical guidelines
Impact Updates the use of corticosteroids in HIV associated cryptococcal meningitis
URL http://hivinsite.ucsf.edu/InSite?page=md-ward86-cryptococcosis
 
Description CryptoDex trial cited in a review article on management of opportunistic brain infections: Nature Reviews Neurology 12, 662-674 (2016)
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical reviews
Impact The results of our trial will influence use of corticosteroids in cryptococcal meningitis and will prevent unnecessary deaths. there are between 300 000 and 600 000 cases of cryptical meningitis per year.
URL http://www.nature.com/nrneurol/journal/v12/n11/abs/nrneurol.2016.149.html
 
Description Intermediate Clinical Fellowship
Amount £1,420,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2013 
End 12/2016
 
Description International Engagement Award
Amount £30,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 07/2015 
End 07/2016
 
Title Early fungicidal activity as a surrogate marker for survival in cryptococcal meningitis 
Description We have combined our patient datasets with those from other clinical resarch groups (University of Minnesota, MORU Thailand, St Geaorge's Hospital UK) in order to model the declines in fungal counts in realtion to different antifungal therapies to determine whether these surrogate data can be used to predict clinical outcome from cryptococcal disease. 
Type Of Material Database/Collection of data 
Provided To Others? No  
Impact We are driving this analysis. We have combined our data with other groups. all grouls can access the data. 
 
Description B Cell studies in cryptococcal meningitis 
Organisation Albert Einstein College of Medicine
Country United States 
Sector Academic/University 
PI Contribution We design clinical studies to provide clinical samples in order to further understand the factors that confer increased susceptibility to infection with Cryptococcus neoformans in HIV infected an duninfected patients.
Collaborator Contribution Our collaborators have the laboratory expertise to investigate host susceptibility to cryptococcal disease, which complements our grousp focus on the pathogen itself.
Impact None as yet - studies are on-going
Start Year 2013
 
Description CryptoDex Study 
Organisation Cho Ray Hospital
Department Department of Tropical Medicine
Country Viet Nam 
Sector Academic/University 
PI Contribution I am the PI, designed the study, funding application, SOPs, CRFs, assembled the study team.
Collaborator Contribution Review of the study protocol and grant application, ethcial submissions and permissions, patient recruitment, day to day runnning of the trial
Impact Study is in early stages but ethical and other pemissions sort and expect to begin study recruitment end of 2012
Start Year 2011
 
Description CryptoDex Study 
Organisation Hospital for Tropical Diseases HCM
Country Viet Nam 
Sector Hospitals 
PI Contribution I am the PI, designed the study, funding application, SOPs, CRFs, assembled the study team.
Collaborator Contribution Review of the study protocol and grant application, ethcial submissions and permissions, patient recruitment, day to day runnning of the trial
Impact Study is in early stages but ethical and other pemissions sort and expect to begin study recruitment end of 2012
Start Year 2011
 
Description CryptoDex Study 
Organisation Liverpool School of Tropical Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution I am the PI, designed the study, funding application, SOPs, CRFs, assembled the study team.
Collaborator Contribution Review of the study protocol and grant application, ethcial submissions and permissions, patient recruitment, day to day runnning of the trial
Impact Study is in early stages but ethical and other pemissions sort and expect to begin study recruitment end of 2012
Start Year 2011
 
Description CryptoDex Study 
Organisation Medical Research Council (MRC)
Department Medical Research Council (MRC), MRC/UVRI Unit, Uganda
Country Uganda 
Sector Public 
PI Contribution I am the PI, designed the study, funding application, SOPs, CRFs, assembled the study team.
Collaborator Contribution Review of the study protocol and grant application, ethcial submissions and permissions, patient recruitment, day to day runnning of the trial
Impact Study is in early stages but ethical and other pemissions sort and expect to begin study recruitment end of 2012
Start Year 2011
 
Description CryptoDex Study 
Organisation University of Indonesia
Department Department of Neurology
Country Indonesia 
Sector Academic/University 
PI Contribution I am the PI, designed the study, funding application, SOPs, CRFs, assembled the study team.
Collaborator Contribution Review of the study protocol and grant application, ethcial submissions and permissions, patient recruitment, day to day runnning of the trial
Impact Study is in early stages but ethical and other pemissions sort and expect to begin study recruitment end of 2012
Start Year 2011
 
Description CryptoDex Study 
Organisation Wellcome Trust
Department Mahidol University-Oxford Tropical Medicine Research Programme
Country Thailand 
Sector Academic/University 
PI Contribution I am the PI, designed the study, funding application, SOPs, CRFs, assembled the study team.
Collaborator Contribution Review of the study protocol and grant application, ethcial submissions and permissions, patient recruitment, day to day runnning of the trial
Impact Study is in early stages but ethical and other pemissions sort and expect to begin study recruitment end of 2012
Start Year 2011
 
Description CryptoDex Study 
Organisation Wellcome Trust
Department Mahidol University-Oxford Tropical Medicine Research Programme
Country Thailand 
Sector Academic/University 
PI Contribution I am the PI, designed the study, funding application, SOPs, CRFs, assembled the study team.
Collaborator Contribution Review of the study protocol and grant application, ethcial submissions and permissions, patient recruitment, day to day runnning of the trial
Impact Study is in early stages but ethical and other pemissions sort and expect to begin study recruitment end of 2012
Start Year 2011
 
Description CryptoDex Study 
Organisation Wellcome Trust
Department Malawi-Liverpool Wellcome Trust Clinical Research Programme
Country Malawi 
Sector Charity/Non Profit 
PI Contribution I am the PI, designed the study, funding application, SOPs, CRFs, assembled the study team.
Collaborator Contribution Review of the study protocol and grant application, ethcial submissions and permissions, patient recruitment, day to day runnning of the trial
Impact Study is in early stages but ethical and other pemissions sort and expect to begin study recruitment end of 2012
Start Year 2011
 
Description CryptoDex Study 
Organisation Wellcome Trust
Department Wellcome Trust-Mahosot Hospital-Oxford University Tropical Medicine Research Collaboration
Country Lao People's Democratic Republic 
Sector Academic/University 
PI Contribution I am the PI, designed the study, funding application, SOPs, CRFs, assembled the study team.
Collaborator Contribution Review of the study protocol and grant application, ethcial submissions and permissions, patient recruitment, day to day runnning of the trial
Impact Study is in early stages but ethical and other pemissions sort and expect to begin study recruitment end of 2012
Start Year 2011
 
Description Fungal counts as a surrogate marker in cryptococcal disease 
Organisation St George's Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution We drive this collaboration between the main clinical trial groups in cryptococcal meningitis collating the data and perfoming the modelling analyses to determine whether rates of decline of yeast count in cerebrospinal fluid can serve as a surrogate marker of antifungal treatment in cryptococcal disease.
Collaborator Contribution Provide data on fungal count and outcome form the patients in their studies.
Impact On-going
Start Year 2014
 
Description Fungal counts as a surrogate marker in cryptococcal disease 
Organisation University of Minnesota
Country United States 
Sector Academic/University 
PI Contribution We drive this collaboration between the main clinical trial groups in cryptococcal meningitis collating the data and perfoming the modelling analyses to determine whether rates of decline of yeast count in cerebrospinal fluid can serve as a surrogate marker of antifungal treatment in cryptococcal disease.
Collaborator Contribution Provide data on fungal count and outcome form the patients in their studies.
Impact On-going
Start Year 2014
 
Description PK/PD of antifungals 
Organisation University of Liverpool
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaboration to understand the PK and PD of antifungal drugs in cryptococcal meningitis. We arrange and run the clinical studies, and obtain the clinical specimens and measure the pharmacodynamic outcome.
Collaborator Contribution William Hope and UNiversity of liverpool provide measurement of drug levels and expertise in analysis of results and data modelling.
Impact On-going
Start Year 2013
 
Description Pathogenicity of C. neoformans 
Organisation Duke University
Department Department of Medical Mycology
Country United States 
Sector Academic/University 
PI Contribution In collaboration with Duke university we are investigating the relative pathogenicity of different types of C. neoformans. This work is funded through my Wellcome Trust Intermediate Fellowship.
Collaborator Contribution DUke will provide animal models and help with next generations equencing technology and data interpretation.
Impact None as yet, but a PhD student will visit their lab for 6 months early 2014
Start Year 2013
 
Description Population genetics of C. neoformans 
Organisation The Wellcome Trust Sanger Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution We have amassed a library of 800 strains of Cryptococcus neoformans. These are being sequenced in collbaortion with the Sanger Institute. Data will be analysed by my PhD student
Collaborator Contribution The Sanger Institute will carry out the sequencing work and provide advice and bioinformatic analysis and advice
Impact On-going work
Start Year 2015
 
Title CryptoDex Study 
Description A randomised placebo controlled trial of adjunctive treatment wit dexamethasone in HIV associated cryptococcal meningitis. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2012
Development Status Under active development_distribution
Clinical Trial? Yes
UKCRN/ISCTN Identifier ISRCTN59144167
Impact This is an on-going clinical trial that beagn recruiting patients across 6 countries in February 2013. The estimated date for follo-wup completion is 2015/16. This is the first ever RCT of adjunctive treatment in cryptococcal meningitis and will be the largest ever RCT in cryptococcal disease. 
URL http://www.controlled-trials.com/ISRCTN59144167/
 
Title Pharmacokinetics and dynamics of WHO recommended antifungal tehrapy in cryptococcal meningitis in Vietnam and Uganda 
Description In collaboration with Liverpoool University we are defining the pharmacodynamic and kinetice realtionships of amphotericin b and fluconaozle in blood and cerebrospinal fluid uisng novel modelling techniques 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2015
Development Status Under active development/distribution
Impact We hope this study will lead to more rational use of antifungal therapy in cryptococcal menignitis, define the hetrogeneity in treatment respo9nse in a real world situatiion, and so help us to continue to improve outcomes. 
 
Description 'Ask the scientists' magazine page 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Devised, set up and coordinate the 'Ask the scientist' page in a national Vietnamese childrens magazine. Has a weekly readership of > 50 000. Children send science questions in to us and we publish these alng side answers from a panel of Vietnamese and interational scientists with broad skills and interests that we ahve assembled.

Very popular - hundreds of questions received
Year(s) Of Engagement Activity 2014,2015
 
Description 'Beyond the Hospital' - determine the community experiences and resources that benefit survivors of brain infections in order to develop a discharge pack to aid discharge and recovery in the community 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact This is on-going. we are consulting with survivors of neruological infections to understand how they have coped with disability in an environment where there is a paucity of resources to enable folk to cope with diability. we are engagingwith health care workers to understand the perceptions of the difficulties fo such patients. we will develop a resource detailing facilitues, NGOs etc avaialble in teh community to be shread by health care workers with patients on discharge in order ot lead to more successful rehabilittaion and improve communciation between health care workers and patients.

On-going project. we hope to influence discharge planning at govenrment hospitals and patient recovery.
Year(s) Of Engagement Activity 2014,2015
 
Description Contributed 2 articles to a local children's magazine on science - venomous snakes and the world of fungi. 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact The magazine has a circulation of approximatley 50 000 children per week.

Has stimulated children to contact us with questions about science
Year(s) Of Engagement Activity 2013,2014
 
Description Public Lecture - Clinical Trials - exploitation or essential health care? 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Gave a talk at a local arts cafe which we have developed a PE collaboration. Spoke for 45 miniutes on why we need trials, how they work, how patients are kept safe. Used data from CryptoDex to illustrate points.
Year(s) Of Engagement Activity 2017
URL https://www.facebook.com/events/671239416597540/