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Trial record 28 of 38 for:    " January 14, 2009":" February 13, 2009"[FIRST-RECEIVED-DATE]AND HIV[CONDITION] AND AIDS

Early Versus Delayed Antiretroviral Therapy (ART) in the Treatment of Cryptococcal Meningitis in Africa

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ClinicalTrials.gov Identifier: NCT00830856
Recruitment Status : Completed
First Posted : January 28, 2009
Last Update Posted : July 18, 2016
Sponsor:
Collaborator:
AIDS Care Research in Africa
Information provided by (Responsible Party):
Chiratidzo Ndhlovu, University of Zimbabwe

Tracking Information
First Submitted Date  ICMJE January 27, 2009
First Posted Date  ICMJE January 28, 2009
Last Update Posted Date July 18, 2016
Study Start Date  ICMJE October 2006
Actual Primary Completion Date October 2008   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 27, 2009)
Mortality [ Time Frame: 2 years ]
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT00830856 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Outcome Measures  ICMJE Not Provided
Original Other Outcome Measures  ICMJE Not Provided
 
Descriptive Information
Brief Title  ICMJE Early Versus Delayed Antiretroviral Therapy (ART) in the Treatment of Cryptococcal Meningitis in Africa
Official Title  ICMJE Randomized Control Trial of Early vs Delayed ART in the Treatment of Cryptococcal Meningitis.
Brief 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. 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 Type  ICMJE Interventional
Study Phase Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Care Provider)
Primary Purpose: Treatment
Condition  ICMJE
  • Cryptococcal Meningitis
  • HIV Infections
Intervention  ICMJE
  • Drug: Fluconazole
    Fluconazole 800mg po qday
  • Drug: Fixed dose - Stavudine, lamivudine and Nevirapine
    Initiation within 72 hours of diagnosis of Cryptococcal meningitis.
  • Drug: Fixed dose - Stavudine, Lamivudine, Nevirapine
    Delayed initiation of ART defined as 10 weeks after initiation of high dose fluconazole therapy.
Study Arms
  • Experimental: 1
    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.
    Interventions:
    • Drug: Fluconazole
    • Drug: Fixed dose - Stavudine, lamivudine and Nevirapine
  • Experimental: 2
    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.
    Interventions:
    • Drug: Fluconazole
    • Drug: Fixed dose - Stavudine, Lamivudine, Nevirapine
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 27, 2009)
54
Original Actual Enrollment  ICMJE Same as current
Actual Study Completion Date October 2009
Actual Primary Completion Date October 2008   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • 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.

Exclusion Criteria:

  • 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.
Sex/Gender
Sexes Eligible for Study: All
Ages 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Zimbabwe
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00830856
Other Study ID Numbers  ICMJE ZimCrypto03
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement Not Provided
Responsible Party Chiratidzo Ndhlovu, University of Zimbabwe
Study Sponsor  ICMJE University of Zimbabwe
Collaborators  ICMJE AIDS Care Research in Africa
Investigators  ICMJE
Principal Investigator: Chiratidzo E Ndhlovu, MBChB, FRCP University of Zimbabwe, Department of Medicine
Principal Investigator: Azure T Makadzange, MD, DPhil University of Zimbabwe, Department of Immunology
Study Chair: James Hakim, MBChB, FRCP University of Zimbabwe, Department of Medicine
PRS Account University of Zimbabwe
Verification Date July 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP