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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
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
Sponsor:
Collaborators:
National Institute of Neurological Disorders and Stroke (NINDS)
Kenya Medical Research Institute
Bausch Health Americas, Inc.
University of Nairobi
Information provided by (Responsible Party):
Ana-Claire Meyer, Yale University

Tracking Information
First Submitted Date  ICMJE March 21, 2012
First Posted Date  ICMJE March 23, 2012
Results First Submitted Date  ICMJE July 31, 2015
Results First Posted Date  ICMJE August 31, 2015
Last Update Posted Date August 31, 2015
Study Start Date  ICMJE September 2013
Actual Primary Completion Date July 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 21, 2012)
Survival at 12 Weeks [ Time Frame: 12 weeks ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 10, 2012)
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: March 21, 2012)
  • 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 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety Study of Fluconazole in Combination With Flucytosine for the Treatment of Early Cryptococcal Infection
Official Title  ICMJE An Open Label Randomized Controlled Phase IIb Trial to Determine the Safety of Oral Fluconazole in Combination With Flucytosine as Compared to Fluconazole Alone
Brief Summary 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.
Detailed Description

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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Cryptococcal Infection Disseminated
Intervention  ICMJE
  • 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
Study Arms  ICMJE
  • Experimental: 5FC plus fluconazole
    Combination therapy with oral fluconazole and flucytosine
    Intervention: Drug: Flucytosine and fluconazole
  • Active Comparator: fluconazole alone
    Fluconazole monotherapy
    Intervention: Drug: Fluconazole
Publications * Not Provided

*   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 Terminated
Actual Enrollment  ICMJE
 (submitted: May 7, 2014)
6
Original Estimated Enrollment  ICMJE
 (submitted: March 21, 2012)
100
Actual Study Completion Date  ICMJE July 2014
Actual Primary Completion Date July 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Kenya
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01562132
Other Study ID Numbers  ICMJE R21NS077858-01( U.S. NIH Grant/Contract )
R21NS077858-01 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Ana-Claire Meyer, Yale University
Study Sponsor  ICMJE Yale University
Collaborators  ICMJE
  • National Institute of Neurological Disorders and Stroke (NINDS)
  • Kenya Medical Research Institute
  • Bausch Health Americas, Inc.
  • University of Nairobi
Investigators  ICMJE
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
PRS Account Yale University
Verification Date July 2015

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