Safety Study of Fluconazole in Combination With Flucytosine for the Treatment of Early Cryptococcal Infection (SToP-Crypto)
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ClinicalTrials.gov Identifier: NCT01562132 |
Recruitment Status :
Terminated
(Stopped in accordance with pre-specified stopping rules for poor recruitment.)
First Posted : March 23, 2012
Results First Posted : August 31, 2015
Last Update Posted : August 31, 2015
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Condition or disease | Intervention/treatment | Phase |
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Cryptococcal Infection Disseminated | Drug: Flucytosine and fluconazole Drug: Fluconazole | Phase 2 |
Currently there is wide variation in practice and little evidence to guide the treatment of early cryptococcal infection in HIV-infected individuals with advanced immunosuppression. However, epidemiologic studies suggest that this may be a promising novel approach to decrease the mortality due to cryptococcal meningitis (CM), the second leading cause of death among HIV-infected individuals in many resource-limited settings. Screening asymptomatic HIV-infected individuals with advanced immunosuppression for serum cryptococcal antigen (CrAg) clearly identifies a population at high risk of CM and death and is a feasible screening method for resource-limited settings. However, screening with serum CrAg alone without additional diagnostic studies identifies a heterogeneous clinical population with early cryptococcal infection, many of whom already have sub-clinical meningeal infection or fungemia. The mainstay of anti-cryptococcal therapy in resource-limited settings is oral fluconazole though preliminary evidence suggests this is not an effective treatment. Thus, there is a critical need for potent therapies that (1) can be safely administered in resource-limited settings and (2) are effective in a heterogeneous population of HIV-infected individuals with advanced immunosuppression and early cryptococcal infection who are initiating anti-retroviral therapy (ART).
This single center, open-label, randomized Phase IIb study is being conducted to assess the safety and estimate the efficacy of oral fluconazole in combination with flucytosine for the treatment of early cryptococcal infection. The study will be based at two sites supported by Family AIDS Care and Education Services (FACES) in Western Kenya. A consecutive sample of 100 HIV-infected adults with CD4 cell count ≤100 cells/µl and serum CrAg titer ≥1:2 who have no signs or symptoms of severe, systemic cryptococcal infection will be enrolled. At enrollment, specimens from participants will be cultured for evidence of Cryptococcus neoformans. Individuals who meet inclusion and exclusion criteria and consent to participate in the study will be randomized to combination therapy with oral fluconazole (1200mg/day) plus flucytosine (100mg/kg/day) or fluconazole alone for the fourteen days of therapy. Subsequently both groups will receive anti-retroviral therapy as well as fluconazole 800mg/day for 8 weeks followed by 200mg/day. The primary safety endpoint will be the incidence of treatment-related adverse events and serious adverse events. The primary efficacy endpoint will be survival at 12 weeks.
In addition, we will offer additional diagnostic testing and aim for 50% participation, approximately 25 individuals from each arm. We will perform a battery of diagnostic tests including chest radiography, fungal cultures in blood, sputum, urine, stool and cerebrospinal fluid (CSF), cryptococcal antigen testing in the CSF, and gram stain, Ziehls-Nielsen stain and India Ink staining of CSF sediment. Anti-fungal susceptibility testing via broth microdilution and polymerase chain reaction serotyping and mating type analysis will be performed on clinical isolates.
Study Type : | Interventional (Clinical Trial) |
Actual Enrollment : | 6 participants |
Allocation: | Randomized |
Intervention Model: | Parallel Assignment |
Masking: | None (Open Label) |
Primary Purpose: | Treatment |
Official Title: | An Open Label Randomized Controlled Phase IIb Trial to Determine the Safety of Oral Fluconazole in Combination With Flucytosine as Compared to Fluconazole Alone |
Study Start Date : | September 2013 |
Actual Primary Completion Date : | July 2014 |
Actual Study Completion Date : | July 2014 |

Arm | Intervention/treatment |
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Experimental: 5FC plus fluconazole
Combination therapy with oral fluconazole and flucytosine
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Drug: Flucytosine and fluconazole
Flucytosine 100mg/kg/day in 4 divided doses orally for 14 days given in combination with fluconazole 1200mg orally once daily for 14 days, followed by 800mg orally once daily for 8 weeks, followed by 200mg orally once daily
Other Names:
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Active Comparator: fluconazole alone
Fluconazole monotherapy
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Drug: Fluconazole
fluconazole 1200mg orally once daily for 14 days, followed by 800mg orally once daily for 8 weeks, followed by 200mg orally once daily
Other Name: Diflucan |
- Survival at 12 Weeks [ Time Frame: 12 weeks ]
- Survival at 2 Weeks [ Time Frame: 2 weeks ]
- Survival at 24 Weeks [ Time Frame: 24 weeks ]
- Number of Individuals Who Develop Cryptococcal Meningitis [ Time Frame: 24 weeks ]
Clinical meningitis AND at least one of the following: cryptococcal antigen in the cerebrospinal fluid (CSF), cryptococcal organisms on India Ink stain, or fungal culture of CSF.
Clinical meningitis will be defined as:
- fever>39.0°C, AND
- severe headache, AND
At least one of the following:
- meningismus,
- photophobia,
- new onset seizure,
- focal neurological deficit localizable to the central nervous system
- papilledema
- confusion, delirium, or decreased level of consciousness.
- Number of Individuals Who Develop Immune Reconstitution Inflammatory Syndrome Due to Cryptococcus [ Time Frame: 24 weeks ]
Individuals who develop clinical meningitis without evidence of fungal, bacterial, or parasitic (e.g. malaria) organisms in the cerebrospinal fluid. Clinical meningitis will be defined as:
- fever>39.0°C, AND
- severe headache, AND
- At least one of the following:
- meningismus,
- photophobia,
- new onset seizure,
- focal neurological deficit localizable to the central nervous system
- papilledema
- confusion, delirium, or decreased level of consciousness.
- Achieve Targeted Recruitment, Retention and Adherence Rates [ Time Frame: 24 weeks ]
- Proportion of Individuals Requiring Treatment Discontinuation [ Time Frame: 4 weeks ]
- Proportion of Individuals Requiring Dose Reduction [ Time Frame: 24 weeks ]
- Number of Individuals With Treatment Related Adverse Events [ Time Frame: 24 weeks ]
- Number of Individuals With Treatment Related Serious Adverse Events [ Time Frame: 24 weeks ]
- Cryptococcal Meningitis-free Survival at 24 Weeks [ Time Frame: 24 weeks ]
Clinical meningitis AND at least one of the following: cryptococcal antigen in the cerebrospinal fluid (CSF), cryptococcal organisms on India Ink stain, or fungal culture of CSF.
Clinical meningitis will be defined as:
- fever>39.0°C, AND
- severe headache, AND
At least one of the following:
- meningismus,
- photophobia,
- new onset seizure,
- focal neurological deficit localizable to the central nervous system
- papilledema
- confusion, delirium, or decreased level of consciousness.

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Able and willing to give informed consent
- Age > 18 years
- HIV infection as confirmed by HIV-antibody test as per Kenyan guidelines
- CD4+ T-cell count ≤100 cells/µl
- Serum CrAg titer≥1:2
- Able to travel to district hubs (Sindo District Hospital, Lumumba Health Centre) for regular study visits
Exclusion Criteria:
- clinical meningitis:
- clinical sepsis:
- hemiparesis, aphasia, visual field deficit or other finding on neurological examination localizable to the central nervous system
- a history of culture proven or suspected (cryptococcal antigen present) cryptococcal meningitis
- a history of stroke or other infection of the central nervous system
- a seizure within the last 2 months
- currently taking or ever taken antiretroviral therapy
- currently taking anti-tuberculous therapy
- currently or recently (<2 months) prescribed fluconazole, itraconazole, clotrimazole troches, amphotericin or other oral anti-fungal medications
- pregnant or breast-feeding
- alanine aminotransferase concentration more than 3 times the upper limit of normal
- neutrophil count <1000x103 cells/mL
- hemoglobin <8g/dL
- platelet count <100,000x 103 platelets/mL
- creatinine clearance ≤50 ml/min
- individuals with active heavy alcohol use or active recreational drug use

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01562132
Kenya | |
Family AIDS Care and Education Services | |
Kisumu, Nyanza, Kenya | |
Family AIDS Care and Education Services | |
Sindo, Nyanza, Kenya |
Principal Investigator: | Ana-Claire L Meyer, MD, MSHS | University of California, San Francisco | |
Principal Investigator: | Mark A Jacobson, MD | University of California, San Francisco | |
Principal Investigator: | Judith K Kwasa, MBChB MMed | University of Nairobi |
Responsible Party: | Ana-Claire Meyer, Principal Investigator, Yale University |
ClinicalTrials.gov Identifier: | NCT01562132 |
Other Study ID Numbers: |
R21NS077858-01 ( U.S. NIH Grant/Contract ) R21NS077858-01 ( U.S. NIH Grant/Contract ) |
First Posted: | March 23, 2012 Key Record Dates |
Results First Posted: | August 31, 2015 |
Last Update Posted: | August 31, 2015 |
Last Verified: | July 2015 |
cryptococcus HIV |
Infection Fluconazole Flucytosine Antifungal Agents Anti-Infective Agents 14-alpha Demethylase Inhibitors Cytochrome P-450 Enzyme Inhibitors Enzyme Inhibitors |
Molecular Mechanisms of Pharmacological Action Steroid Synthesis Inhibitors Hormone Antagonists Hormones, Hormone Substitutes, and Hormone Antagonists Physiological Effects of Drugs Cytochrome P-450 CYP2C9 Inhibitors Cytochrome P-450 CYP2C19 Inhibitors Antimetabolites |