Cryptococcal MeningitisNCT00830856
Early Versus Delayed Antiretroviral Therapy (ART) in the Treatment of Cryptococcal Meningitis in Africa
A study testing Fluconazole, Fixed dose - Stavudine, lamivudine and Nevirapine and Fixed dose - Stavudine, Lamivudine, Nevirapine in people with Cryptococcal Meningitis and HIV Infections, run by University of Zimbabwe at 1 site in Zimbabwe.
Trial summary
Cryptococcal Meningitis continues to be one of the most devastating AIDS defining illness in sub-Saharan Africa. Despite the availability of azoles such as fluconazole for treatment, mortality remains high with some studies showing 100% mortality. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Cryptococcal Meningitis, HIV Infections
- What is being tested?
- Fluconazole, Fixed dose - Stavudine, lamivudine and Nevirapine and Fixed dose - Stavudine, Lamivudine, Nevirapine
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 54 participants
- Where
- 1 siteZimbabwe
- Study dates
- Oct 2006to Oct 2009
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- HIV infection documented by a positive HIV antibody test at enrollment;
- Adult men and women (age>18);
- Cryptococcal meningitis infection documented by a positive CSF CRAG or CSF identification of C. neoformans.
- Place of residence is located within a 50km radius of Harare.
Who cannot join
- Previous diagnosis (>1 week) of and treatment for cryptococcal meningitis
- Currently on ARVs, or have been intermittently on and off ART in the past.
- Concurrent use of medications that affect the metabolism of fluconazole e.g., antiseizure medications, oral hypoglycaemic agents.
- History of cardiac failure and or predisposition to arrhythmias will be excluded.
- They are pregnant or active lactation women
- History of active hepatitis or hepatic or renal dysfunction will be excluded.
Trial locations and contacts
1 site in 1 country.
Zimbabwe1 site
University of Zimbabwe, College of Health Sciences
Harare, Harare
About this study
Official title: Randomized Control Trial of Early vs Delayed ART in the Treatment of Cryptococcal Meningitis.
Cryptococcal Meningitis continues to be one of the most devastating AIDS defining illness in sub-Saharan Africa. Despite the availability of azoles such as fluconazole for treatment, mortality remains high with some studies showing 100% mortality. The investigators designed a study to determine if timing of the initiation of antiretroviral therapy (ART) in patients with cryptococcal meningitis and HIV would improve survival. The investigators hypothesis was that early initiation of ART result in improved mortality for patients with HIV and cryptococcal meningitis.
Read the detailed description
Cryptococcosis is an invasive fungal infection caused by an encapsulated yeast. Cryptococcosis in humans is almost always caused by Cryptococcus neoformans. The advent of the HIV epidemic has lead to a profound increase in the number of reported cases of cryptococcal meningoencephalitis throughout the world, particularly in sub-Saharan Africa. In Zimbabwe an analysis of the case reports at one of the major tertiary care hospitals showed an increase in the admission rate from meningitis between 1985-1995 from 78 to 523 cases per 100000 admissions with an increase in the number of those cases due to cryptococcosis from 5% to 46.2%.
Cryptococcosis typically develops at a CD4 count of less than 50 cells/ mm3, and is the initial AIDS defining illness in up to 50-60% of patients.
Prior to the introduction of amphotericin B, flucytosine and azoles, mortality from C neoformans meningoencephalitis was close to 100%. The introduction of amphotericin B led to a significant decrease in mortality with 60-70% of patients being successfully treated. The introduction of fluconazole prophylaxis in the 1990s lead to a significant decrease in the incidence of cryptococcosis. The use of antiretroviral therapy has also caused a significant decrease in the incidence of cryptococcal meningitis.
Due to the prohibitive cost of amphotericin B and flucytosine, in many developing countries such as Zimbabwe, the mainstay of the treatment of CM is fluconazole. The current standard treatment is with fluconazole 400mg/day for 8-10 weeks, may be too low to result in adequate CNS concentration of the drug to achieve adequate killing of C. neoformans. Clinically some physicians in Zimbabwe have noted that patients are not responding adequately to this regimen and have started to treat patients with higher doses of fluconazole. Previous studies have shown that higher doses of fluconazole can be used for the treatment of CM and are well tolerated. In our proposed study, patients will be treated with high dose oral fluconazole at 800mg/day for a total 10 week period.
The advent of the increased access to ART in sub-Saharan Africa provides an additional opportunity to improve morbidity and mortality in all AIDS patients. There are as yet no definitive studies to indicate if there is an advantage to immediate ART therapy in the setting of acute CM compared to deferring therapy after the first 10 weeks of intensive CM therapy. This study is designed to address this question and provide physicians in sub-Saharan Africa with evidence based guidelines for the appropriate management of HIV positive patients with acute presentation of CM.
- Conditions
- Cryptococcal Meningitis, HIV Infections
- Being tested
- Fluconazole, Fixed dose - Stavudine, lamivudine and Nevirapine, Fixed dose - Stavudine, Lamivudine, Nevirapine
- Keywords
- Cryptococcal Meningitis, HIV, Fluconazole, Antiretroviral therapy, Africa, treatment naive
- Medical subject headings
- Meningitis, Cryptococcal, HIV Infections
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
FluconazoleDrug
Fluconazole 800mg po qday
Fixed dose - Stavudine, lamivudine and NevirapineDrug
Initiation within 72 hours of diagnosis of Cryptococcal meningitis.
Fixed dose - Stavudine, Lamivudine, NevirapineDrug
Delayed initiation of ART defined as 10 weeks after initiation of high dose fluconazole therapy.
| Study group | Role | What they receive |
|---|---|---|
| 1 | Experimental | Early initiation of antiretroviral therapy. Patients in this treatment group were started on Fluconazole 800mg by mouth every day for Cryptococcal Meningitis, and within 72hrs of diagnosis were started on First line antiretroviral therapy per Zimbabwe treatment guidelines which is Stavudine, Lamivudine and Nevirapine. Receives: Drug: Fluconazole; Drug: Fixed dose - Stavudine, lamivudine and Nevirapine |
| 2 | Experimental | Delayed initiation of antiretroviral therapy. Patients in this treatment group were started on Fluconazole 800mg by mouth every day for Cryptococcal Meningitis, and after completion of high dose fluconazole for 10 weeks, the patients in this group were started on First line antiretroviral therapy per Zimbabwe treatment guidelines which is Stavudine, Lamivudine and Nevirapine. Receives: Drug: Fluconazole; Drug: Fixed dose - Stavudine, Lamivudine, Nevirapine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Mortality
Measured: 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Jan 2009 (estimated)
- Study startOct 2006
- Primary completionOct 2008
- Study completionOct 2009
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Cryptococcal MeningitisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind
- Who is masked
- Care provider
- Enrolment
- 54 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Zimbabwe
- Sponsor type
- University, hospital or other
- Collaborators
- AIDS Care Research in Africa
- Responsible party
- Principal investigator, Chiratidzo Ndhlovu, University of Zimbabwe
- Investigators
- Chiratidzo E Ndhlovu, MBChB, FRCP, Principal investigator, University of Zimbabwe, Department of MedicineAzure T Makadzange, MD, DPhil, Principal investigator, University of Zimbabwe, Department of ImmunologyJames Hakim, MBChB, FRCP, Study chair, University of Zimbabwe, Department of Medicine
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00830856
- Sponsor's protocol ID
- ZimCrypto03
- Status last verified
- Jul 2016
- First submitted
- 27 Jan 2009
- Last updated
- 18 Jul 2016
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Makadzange AT, Ndhlovu CE, Takarinda K, Reid M, Kurangwa M, Gona P, Hakim JG. Early versus delayed initiation of antiretroviral therapy for concurrent HIV infection and cryptococcal meningitis in sub-saharan Africa. Clin Infect Dis. 2010 Jun 1;50(11):1532-8. doi: 10.1086/652652.
PubMed 20415574
Study at a glance
From the registry record, last updated by the sponsor on 18 Jul 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Randomized Control Trial of Early vs Delayed ART in the Treatment of Cryptococcal Meningitis.
- ClinicalTrials.gov ID
- NCT00830856
- Acronym / sponsor ID
- ZimCrypto03
- Conditions
- Cryptococcal Meningitis, HIV Infections
- Keywords
- Cryptococcal Meningitis, HIV, Fluconazole, Antiretroviral therapy, Africa, treatment naive
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 54 participants (actual)
- Lead sponsor
- University of ZimbabweUniversity, hospital or other
- Collaborators
- AIDS Care Research in Africa
- Study start
- Oct 2006
- Primary completion
- Oct 2008 (actual)
- Study completion
- Oct 2009 (actual)
- First posted
- 28 Jan 2009 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Cryptococcal Meningitis continues to be one of the most devastating AIDS defining illness in sub-Saharan Africa. Despite the availability of azoles such as fluconazole for treatment, mortality remains high with some studies showing 100% mortality. The investigators designed a study to determine if timing of the initiation of antiretroviral therapy (ART) in patients with cryptococcal meningitis and HIV would improve survival. The investigators hypothesis was that early initiation of ART result in improved mortality for patients with HIV and cryptococcal meningitis.
Detailed description
Cryptococcosis is an invasive fungal infection caused by an encapsulated yeast. Cryptococcosis in humans is almost always caused by Cryptococcus neoformans. The advent of the HIV epidemic has lead to a profound increase in the number of reported cases of cryptococcal meningoencephalitis throughout the world, particularly in sub-Saharan Africa. In Zimbabwe an analysis of the case reports at one of the major tertiary care hospitals showed an increase in the admission rate from meningitis between 1985-1995 from 78 to 523 cases per 100000 admissions with an increase in the number of those cases due to cryptococcosis from 5% to 46.2%.
Cryptococcosis typically develops at a CD4 count of less than 50 cells/ mm3, and is the initial AIDS defining illness in up to 50-60% of patients.
Prior to the introduction of amphotericin B, flucytosine and azoles, mortality from C neoformans meningoencephalitis was close to 100%. The introduction of amphotericin B led to a significant decrease in mortality with 60-70% of patients being successfully treated. The introduction of fluconazole prophylaxis in the 1990s lead to a significant decrease in the incidence of cryptococcosis. The use of antiretroviral therapy has also caused a significant decrease in the incidence of cryptococcal meningitis.
Due to the prohibitive cost of amphotericin B and flucytosine, in many developing countries such as Zimbabwe, the mainstay of the treatment of CM is fluconazole. The current standard treatment is with fluconazole 400mg/day for 8-10 weeks, may be too low to result in adequate CNS concentration of the drug to achieve adequate killing of C. neoformans. Clinically some physicians in Zimbabwe have noted that patients are not responding adequately to this regimen and have started to treat patients with higher doses of fluconazole. Previous studies have shown that higher doses of fluconazole can be used for the treatment of CM and are well tolerated. In our proposed study, patients will be treated with high dose oral fluconazole at 800mg/day for a total 10 week period.
The advent of the increased access to ART in sub-Saharan Africa provides an additional opportunity to improve morbidity and mortality in all AIDS patients. There are as yet no definitive studies to indicate if there is an advantage to immediate ART therapy in the setting of acute CM compared to deferring therapy after the first 10 weeks of intensive CM therapy. This study is designed to address this question and provide physicians in sub-Saharan Africa with evidence based guidelines for the appropriate management of HIV positive patients with acute presentation of CM.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (care provider)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| 1 | Experimental | Drug: Fluconazole, Drug: Fixed dose - Stavudine, lamivudine and NevirapineEarly initiation of antiretroviral therapy. Patients in this treatment group were started on Fluconazole 800mg by mouth every day for Cryptococcal Meningitis, and within 72hrs of diagnosis were started on First line antiretroviral therapy per Zimbabwe treatment guidelines which is Stavudine, Lamivudine and Nevirapine. |
| 2 | Experimental | Drug: Fluconazole, Drug: Fixed dose - Stavudine, Lamivudine, NevirapineDelayed initiation of antiretroviral therapy. Patients in this treatment group were started on Fluconazole 800mg by mouth every day for Cryptococcal Meningitis, and after completion of high dose fluconazole for 10 weeks, the patients in this group were started on First line antiretroviral therapy per Zimbabwe treatment guidelines which is Stavudine, Lamivudine and Nevirapine. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- HIV infection documented by a positive HIV antibody test at enrollment;
- Adult men and women (age>18);
- Cryptococcal meningitis infection documented by a positive CSF CRAG or CSF identification of C. neoformans.
- Place of residence is located within a 50km radius of Harare.
Key exclusion criteria (6 listed)
- Previous diagnosis (>1 week) of and treatment for cryptococcal meningitis
- Currently on ARVs, or have been intermittently on and off ART in the past.
- Concurrent use of medications that affect the metabolism of fluconazole e.g., antiseizure medications, oral hypoglycaemic agents.
- History of cardiac failure and or predisposition to arrhythmias will be excluded.
- They are pregnant or active lactation women
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| FluconazoleFluconazole 800mg po qday | Drug | 1, 2 |
| Fixed dose - Stavudine, lamivudine and NevirapineInitiation within 72 hours of diagnosis of Cryptococcal meningitis. | Drug | 1 |
| Fixed dose - Stavudine, Lamivudine, NevirapineDelayed initiation of ART defined as 10 weeks after initiation of high dose fluconazole therapy. | Drug | 2 |
Primary outcome
Mortality
Time frame: 2 years
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Jul 2016.
- Derived from this study: PubMed 20415574Makadzange AT, Ndhlovu CE, Takarinda K, Reid M, Kurangwa M, Gona P, Hakim JG. Early versus delayed initiation of antiretroviral therapy for concurrent HIV infection and cryptococcal meningitis in sub-saharan Africa. Clin Infect Dis. 2010 Jun 1;50(11):1532-8. doi: 10.1086/652652.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Chiratidzo E Ndhlovu, MBChB, FRCP principal investigator
University of Zimbabwe, Department of Medicine
Azure T Makadzange, MD, DPhil principal investigator
University of Zimbabwe, Department of Immunology
James Hakim, MBChB, FRCP study chair
University of Zimbabwe, Department of Medicine
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Fluconazole, Fixed dose - Stavudine, lamivudine and Nevirapine and Fixed dose - Stavudine, Lamivudine, Nevirapine in people with Cryptococcal Meningitis and HIV Infections, run by University of Zimbabwe at 1 site in Zimbabwe.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 18 Jul 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Zimbabwe. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Mortality (time frame: 2 years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00830856, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Jul 2016.