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

Sponsor
Yale University (Other)
Overall Status
Terminated
CT.gov ID
NCT01562132
Collaborator
National Institute of Neurological Disorders and Stroke (NINDS) (NIH), Kenya Medical Research Institute (Other), Bausch Health Americas, Inc. (Industry), University of Nairobi (Other)
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Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
Phase 2

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 Design

Study Type:
Interventional
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 :
Sep 1, 2013
Actual Primary Completion Date :
Jul 1, 2014
Actual Study Completion Date :
Jul 1, 2014

Arms and Interventions

Arm Intervention/Treatment
Experimental: 5FC plus fluconazole

Combination therapy with oral fluconazole and flucytosine

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
  • Active Comparator: fluconazole alone

    Fluconazole monotherapy

    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 Names:
  • Diflucan
  • Outcome Measures

    Primary Outcome Measures

    1. Number of Participants Alive at 12 Weeks [12 weeks]

    Secondary Outcome Measures

    1. Number of Participants Alive at 2 Weeks [2 weeks]

    2. Survival at 24 Weeks [24 weeks]

    3. Number of Individuals Who Develop Cryptococcal Meningitis [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.

    4. Number of Individuals Who Develop Immune Reconstitution Inflammatory Syndrome Due to Cryptococcus [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.

    5. Achieve Targeted Recruitment, Retention and Adherence Rates [24 weeks]

    6. Proportion of Individuals Requiring Treatment Discontinuation [4 weeks]

    7. Proportion of Individuals Requiring Dose Reduction [24 weeks]

    8. Number of Individuals With Treatment Related Adverse Events [24 weeks]

    9. Number of Individuals With Treatment Related Serious Adverse Events [24 weeks]

    10. Cryptococcal Meningitis-free Survival at 24 Weeks [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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Family AIDS Care and Education Services Kisumu Nyanza Kenya
    2 Family AIDS Care and Education Services Sindo Nyanza Kenya

    Sponsors and Collaborators

    • Yale University
    • National Institute of Neurological Disorders and Stroke (NINDS)
    • Kenya Medical Research Institute
    • Bausch Health Americas, Inc.
    • University of Nairobi

    Investigators

    • 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

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Yale University
    ClinicalTrials.gov Identifier:
    NCT01562132
    Other Study ID Numbers:
    • 1307012426
    • R21NS077858-01
    First Posted:
    Mar 23, 2012
    Last Update Posted:
    Sep 29, 2021
    Last Verified:
    Sep 1, 2021
    Studies a U.S. FDA-regulated Drug Product:
    No
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Yale University
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title 5FC Plus Fluconazole Fluconazole Alone
    Arm/Group Description Combination therapy with oral fluconazole and flucytosine 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 Fluconazole monotherapy Fluconazole: fluconazole 1200mg orally once daily for 14 days, followed by 800mg orally once daily for 8 weeks, followed by 200mg orally once daily
    Period Title: Overall Study
    STARTED 3 3
    COMPLETED 3 3
    NOT COMPLETED 0 0

    Baseline Characteristics

    Arm/Group Title 5FC Plus Fluconazole Fluconazole Alone Total
    Arm/Group Description Combination therapy with oral fluconazole and flucytosine 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 Fluconazole monotherapy Fluconazole: fluconazole 1200mg orally once daily for 14 days, followed by 800mg orally once daily for 8 weeks, followed by 200mg orally once daily Total of all reporting groups
    Overall Participants 3 3 6
    Age (years) [Median (Full Range) ]
    Median (Full Range) [years]
    36
    31
    33.5
    Sex: Female, Male (Count of Participants)
    Female
    1
    33.3%
    1
    33.3%
    2
    33.3%
    Male
    2
    66.7%
    2
    66.7%
    4
    66.7%
    Region of Enrollment (participants) [Number]
    Kenya
    3
    100%
    3
    100%
    6
    100%
    CD4+ T-cell Count (cells/microliter) [Median (Full Range) ]
    Median (Full Range) [cells/microliter]
    22
    13
    17

    Outcome Measures

    1. Primary Outcome
    Title Number of Participants Alive at 12 Weeks
    Description
    Time Frame 12 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title 5FC Plus Fluconazole Fluconazole Alone
    Arm/Group Description Combination therapy with oral fluconazole and flucytosine 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 Fluconazole monotherapy Fluconazole: fluconazole 1200mg orally once daily for 14 days, followed by 800mg orally once daily for 8 weeks, followed by 200mg orally once daily
    Measure Participants 3 3
    Number [participants]
    2
    66.7%
    2
    66.7%
    2. Secondary Outcome
    Title Number of Participants Alive at 2 Weeks
    Description
    Time Frame 2 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    3. Secondary Outcome
    Title Survival at 24 Weeks
    Description
    Time Frame 24 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    4. Secondary Outcome
    Title Number of Individuals Who Develop Cryptococcal Meningitis
    Description 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.
    Time Frame 24 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    5. Secondary Outcome
    Title Number of Individuals Who Develop Immune Reconstitution Inflammatory Syndrome Due to Cryptococcus
    Description 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.
    Time Frame 24 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    6. Secondary Outcome
    Title Achieve Targeted Recruitment, Retention and Adherence Rates
    Description
    Time Frame 24 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    7. Secondary Outcome
    Title Proportion of Individuals Requiring Treatment Discontinuation
    Description
    Time Frame 4 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    8. Secondary Outcome
    Title Proportion of Individuals Requiring Dose Reduction
    Description
    Time Frame 24 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    9. Secondary Outcome
    Title Number of Individuals With Treatment Related Adverse Events
    Description
    Time Frame 24 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    10. Secondary Outcome
    Title Number of Individuals With Treatment Related Serious Adverse Events
    Description
    Time Frame 24 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    11. Secondary Outcome
    Title Cryptococcal Meningitis-free Survival at 24 Weeks
    Description 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.
    Time Frame 24 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description

    Adverse Events

    Time Frame
    Adverse Event Reporting Description
    Arm/Group Title 5FC Plus Fluconazole Fluconazole Alone
    Arm/Group Description Combination therapy with oral fluconazole and flucytosine 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 Fluconazole monotherapy Fluconazole: fluconazole 1200mg orally once daily for 14 days, followed by 800mg orally once daily for 8 weeks, followed by 200mg orally once daily
    All Cause Mortality
    5FC Plus Fluconazole Fluconazole Alone
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN)
    Serious Adverse Events
    5FC Plus Fluconazole Fluconazole Alone
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/3 (0%) 0/3 (0%)
    Other (Not Including Serious) Adverse Events
    5FC Plus Fluconazole Fluconazole Alone
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 3/3 (100%) 2/3 (66.7%)
    Blood and lymphatic system disorders
    Neutropenia 2/3 (66.7%) 2 1/3 (33.3%) 1
    Gastrointestinal disorders
    Nausea 0/3 (0%) 0 1/3 (33.3%) 1
    Vomiting 0/3 (0%) 0 1/3 (33.3%) 1
    General disorders
    Unintentional Weight Loss 1/3 (33.3%) 1 0/3 (0%) 0

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

    Results Point of Contact

    Name/Title Dr. Ana-Claire Meyer
    Organization Yale University
    Phone 203-737-8372
    Email ana-claire.meyer@yale.edu
    Responsible Party:
    Yale University
    ClinicalTrials.gov Identifier:
    NCT01562132
    Other Study ID Numbers:
    • 1307012426
    • R21NS077858-01
    First Posted:
    Mar 23, 2012
    Last Update Posted:
    Sep 29, 2021
    Last Verified:
    Sep 1, 2021