High-Dose Fluconazole for the Treatment of Cryptococcal Meningitis in HIV-Infected Individuals
- Conditions
- Cryptococcal MeningitisHIV Infections
- Interventions
- Registration Number
- NCT00885703
- Brief Summary
Cryptococcal meningitis (CM) is an infection of the membranes covering the brain and spinal cord, caused by the fungus Cryptococcus neoformans. CM most often affects people with compromised immune systems, like those with advanced HIV infection. This study explored the safety, tolerability, and therapeutic effect of a new treatment regimen with high-dose fluconazole for management of CM in HIV-infected patients.
- Detailed Description
CM is the most common central nervous system (CNS) complication of AIDS worldwide and accounts for up to a third of all deaths from AIDS in many developing countries. Current treatments for CM are lacking in both effectiveness and accessibility, particularly in limited-resources settings. Conventional therapies utilizing an amphotericin B deoxycholate (ampho B)-based regimen require maintaining intravenous access (IV) and monitoring and treating any associated complications. The price to acquire ampho B can also be prohibitive to successful treatment. Cumulatively, a treatment course with ampho B is neither cost effective nor administratively efficient, leaving patients either untreated or inadequately treated with low-dose regimens of fluconazole alone.
Fluconazole is widely available, inexpensive, can be given orally, has a demonstrated safety profile over a broad range of doses, and has proven activity against the fungus that causes CM, Cryptococcus neoformans. All of these factors make fluconazole a potential treatment option for a wide range of people. However, at its present recommended dosage, fluconazole is only expected to be successful in 34% to 42% of patients. This rate is lower than regimens combining fluconazole with other treatments including flucytosine or ampho B.
The purpose of this study was to evaluate whether high-dose fluconazole is safe and effective for the treatment of CM for up to 10 weeks. This study also collected information about treating CM with ampho B (either alone or with another drug, either flucytosine or fluconazole).
For this study, 168 HIV-infected people with CM participated for a duration of 24 weeks. This study proceeded with 2 stages and each stage consisted of up to 4 steps. Participants could take part in only one stage of the study. Stage 1 measured the maximum tolerated dose (MTD) of fluconazole in participants. Stage 2 consisted of dose validation and safety monitoring.
In Stage 1, participants were randomly assigned to receive either fluconazole only or an ampho B-based regimen (a regimen that is either ampho B alone or ampho B in combination with 5-fluorocytosine or fluconazole, according to the local standard of care).Three doses of fluconazole were tested, and the MTD was found to be 2000 mg/day. The two higher doses of fluconazole tested in Stage 1 (1600 mg/day and 2000 mg/day doses) were tested further in Stage 2 of the study.
Participants enrolled in Stage 2 were randomly assigned to receive treatment with either fluconazole only (at one of the 2 doses (1600 mg/day or 2000 mg/day) found to be safe in Stage 1) or an ampho B-based regimen.
After randomization in Step 1, participants in both Stage 1 and Stage 2 could be enrolled in up to three additional steps. In Step 2, participants who were randomly assigned to receive the ampho B-based regimen and who were intolerant to the regimen (experienced a treatment limiting toxicity \[TLT\]) received fluconazole (400-800mg daily). Participants who received study-provided fluconazole in Step 1 or in Step 2 could be enrolled in Step 3 if they had a negative cerebrospinal fluid (CSF) culture. Participants in Step 3 received fluconazole (400mg daily) until Week 10. At Week 10, all participants were enrolled in Step 4 and received a daily dose of fluconazole of 200mg until the end of the study (Week 24). Participants in both stages beginning treatment with ampho B received daily ampho B intravenously for up to 2 weeks.
Before entering the study, potential participants attended a screening visit where they had CSF collected via lumbar puncture. HIV testing was also conducted, along with clinical assessments, and a health and medical history questionnaire. Participants had blood collection, an electrocardiogram (ECG), and a pregnancy test (if applicable) at that visit. Once accepted into the study, participants again answered questions about their health and medication history; had a complete physical exam, blood collection, HIV testing, neurological exam, lumbar puncture, and ECG; and may have had a pregnancy test (if applicable).
Study visits occurred during Weeks 1 (at Days 1, 4, and 7), 2, 4, 6, 8, 10, and 24, and extra visits could occur for individualized reasons. Total study duration was 24 weeks. Plasma, urine, serum, and CSF samples were collected from all participants and stored for possible future use.
Note on efficacy population versus safety population: After entering the study, participants had their CM diagnosis confirmed by testing of the CSF collected via lumbar puncture. Confirmation could take up to 2 weeks after study entry. Due to the mortality rate of CM, participants received treatment before CM diagnosis confirmation. Post-entry 12 participants either reported non-confirmatory baseline results making them ineligible. An additional 2 participants were found to be ineligible for the study but died prior to being found ineligible (one had non-confirmatory baseline results, one was on a disallowed medication) All participants (n=168) are included in the safety population. Participants who were ineligible after study entry were excluded from the efficacy population (n=16). The efficacy population had 154 participants. Outcomes will specify if the efficacy population is used instead of the safety population.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 168
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Stage 1, Fluconazole 1200mg Fluconazole Participants receive Fluconazole 1200mg induction dose in Stage 1 Stage 1, Fluconazole 1600mg Fluconazole Participants receive Fluconazole 1600mg induction dose in Stage 1 Stage 1, Fluconazole 2000mg Fluconazole Participants receive Fluconazole 2000mg induction dose in Stage 1 Stage 1, Ampho B Fluconazole Participants receive Amphotericin B followed by Fluconazole in Stage 1 Stage 1, Ampho B Amphotericin B Participants receive Amphotericin B followed by Fluconazole in Stage 1 Stage 2, Fluconazole 1600mg Fluconazole Participants receive Fluconazole 1600mg induction dose in Stage 2 Stage 2, Fluconazole 2000mg Fluconazole Participants receive Fluconazole 2000mg induction dose in Stage 2 Stage 2, Ampho B Fluconazole Participants receive Amphotericin B followed by Fluconazole in Stage 2 Stage 2, Ampho B Amphotericin B Participants receive Amphotericin B followed by Fluconazole in Stage 2
- Primary Outcome Measures
Name Time Method Kaplan Meier (KM) Proportion of Participant Mortality Measured from study entry through Week 24 Kaplan Meier Proportion of participants who died over study with 90% Confidence Intervals.
Number of Participants Who Discontinued Study-provided High Dose Fluconazole or Ampho B Measured from study entry through Week10 Discontinuation of study-provided high dose fluconazole at or by week 10 Discontinuation of study-provided ampho B at or by week 2
Discontinuation includes discontinuing for any reason, including progression of symptoms, death, etc.Categorized Quantitative Culture Results At entry, Week 2, and Week 10 Count of participants who were CM negative (had no cryptococcal growth), CM negative after switching treatment (switched from Fluconazole to Ampho B or vice versa and later became CM negative), CM positive, Died, Lost to follow-up. Note: CM positive means continued to have cryptococcal growth.
Change in Log10 Quantitative CSF Culture Results Entry and Week 2 Change in quantitative CSF (cerebrospinal fluid) cultures.
Note: No further CSF specimens are drawn following a negative culture. Thus, only week 2 CSF cultures are considered in this analysis.
- Secondary Outcome Measures
Name Time Method Results of Functional Status Evaluation Measured 6 weeks before enrollment, at study entry, at Week 10, and at Week 24 Functional assessment of work status and ability. Consists of 2 measures: 1) Does participants have full time work status 2) Does participant have functional ability to work.
The measure from 6 week before enrollment will be referred to as 'baseline'.Length of Hospitalization Measured from study entry through Week 10 Duration of first hospitalization in days starting at entry in safety population.
Results of the Neurological Examination Measured at study entry, Week 2, and Week 10 Results from Glasgow Coma Score, which provides assessment of impairment of conscious level in response to defined stimuli. Min score of 0 and max score of 15 (no mental impairment).
Number of Hospital Admissions Measured from study entry through Week 24 Count of number of times a participant was admitted to the hospital.
Number of Participants With Progression of Symptoms Measured from study entry through Week 24 Progression of symptoms is defined as:
* Died (including early deaths)
* Discontinued Fluconazole and started ampho B
* Had a positive cryptococcal culture at week 10
* Microbiological Failure (i.e., relapse of CM)
* Complication of CM (e.g., obstructive hydrocephalus or vascular complications such as venous or arterial thrombosis)
* CM IRIS causing increased inflammation after ART exposure
* New CNS Ol (e.g., toxoplasmosis, PML, CNS lymphoma)
* Possibly related to CM but mechanism indeterminate
* Other defined complication unrelated to CMNumber of Participants With CNS IRIS Measured from study entry through Week 24 Number of participants who were diagnosed with CNS immune reconstitution inflammatory syndrome (IRIS)
Number of Participants With Grade 3 and 4 Adverse Events Measured from study entry through Week 24 Occurrence of grade 3 (severe) and 4 (life-threatening) sign and symptoms events (as defined by FSTRF Appendix 29)
Occurrence of grade 3 (severe) and 4 (life-threatening) laboratory events (as defined by FSTRF Appendix 76)
See DAIDS AE Grading table V1.0
Trial Locations
- Locations (10)
Joint Clinical Research Centre (JCRC)/Kampala Clinical Research Site
🇺🇬Kampala, Uganda
Durban International Clinical Research Site CRS
🇿🇦Durban, KwaZulu-Natal, South Africa
University of Southern California CRS
🇺🇸Los Angeles, California, United States
Wits Helen Joseph Hospital CRS (Wits HJH CRS)
🇿🇦Johannesburg, Gauteng, South Africa
Kenya Medical Research Institute/Walter Reed Project Clinical Research Center (KEMRI/WRP) CRS
🇰🇪Kericho, Rift Valley, Kenya
Byramjee Jeejeebhoy Medical College (BJMC) CRS
🇮🇳Pune, Maharashtra, India
Moi University Clinical Research Center (MUCRC) CRS
🇰🇪Eldoret, Kenya
San Miguel CRS
🇵🇪Lima, Peru
Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS
🇹ðŸ‡Chiang Mai, Thailand
Parirenyatwa CRS
🇿🇼Harare, Zimbabwe