Safety Study of Fluconazole in Combination With Flucytosine for the Treatment of Early Cryptococcal Infection (SToP-Crypto)

• Survival at 2 weeks [ Time Frame: 2 weeks ] [ Designated as safety issue: Yes ]
• Survival at 24 weeks [ Time Frame: 24 weeks ] [ Designated as safety issue: Yes ]
• Number of individuals who develop cryptococcal meningitis [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]

  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 ] [ Designated as safety issue: No ]

  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 ] [ Designated as safety issue: No ]
• Proportion of individuals requiring treatment discontinuation [ Time Frame: 4 weeks ] [ Designated as safety issue: Yes ]
• Proportion of individuals requiring dose reduction [ Time Frame: 24 weeks ] [ Designated as safety issue: Yes ]
• Number of individuals with treatment related adverse events [ Time Frame: 24 weeks ] [ Designated as safety issue: Yes ]
• Number of individuals with treatment related serious adverse events [ Time Frame: 24 weeks ] [ Designated as safety issue: Yes ]
• Cryptococcal meningitis-free survival at 24 weeks [ Time Frame: 24 weeks ] [ Designated as safety issue: Yes ]

  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.

• Survival at 2 weeks [ Time Frame: 2 weeks ] [ Designated as safety issue: Yes ]
• Survival at 24 weeks [ Time Frame: 24 weeks ] [ Designated as safety issue: Yes ]
• Number of individuals who develop cryptococcal meningitis [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]

  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 ] [ Designated as safety issue: No ]

  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 ] [ Designated as safety issue: No ]
• Proportion of individuals requiring treatment discontinuation [ Time Frame: 4 weeks ] [ Designated as safety issue: Yes ]
• Proportion of individuals requiring dose reduction [ Time Frame: 24 weeks ] [ Designated as safety issue: Yes ]
• Number of individuals with treatment related adverse events [ Time Frame: 24 weeks ] [ Designated as safety issue: Yes ]
• Number of individuals with treatment related serious adverse events [ Time Frame: 24 weeks ] [ Designated as safety issue: Yes ]

The purpose of this study is to determine if treatment with two medicines in combination (fluconazole and flucytosine) is safe as compared with one medicine alone (fluconazole) for the treatment of an early infection with a fungus called cryptococcus.

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.

• 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:

  • Ancobon
  • Diflucan
• 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

• Experimental: 5FC plus fluconazole
  Combination therapy with oral fluconazole and flucytosine
  Intervention: Drug: Flucytosine and fluconazole
• Active Comparator: fluconazole alone
  Intervention: Drug: Fluconazole

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

• National Institute of Neurological Disorders and Stroke (NINDS)
• Kenya Medical Research Institute
• Valeant Pharmaceuticals International, Inc.
• University of Nairobi