Cryptococcal Infection Disseminated
Conditions
Keywords
cryptococcus, HIV
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.
Interventions
DRUGFlucytosine 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
DRUGFluconazole
fluconazole 1200mg orally once daily for 14 days, followed by 800mg orally once daily for 8 weeks, followed by 200mg orally once daily
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
Kenya Medical Research Institute
Bausch Health Americas, Inc.
University of Nairobi
Yale University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Number of Participants Alive at 12 Weeks | 12 weeks |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Survival at 24 Weeks | 24 weeks | — |
| 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. |
| 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. |
| Achieve Targeted Recruitment, Retention and Adherence Rates | 24 weeks | — |
| Number of Participants Alive at 2 Weeks | 2 weeks | — |
| Proportion of Individuals Requiring Dose Reduction | 24 weeks | — |
| Number of Individuals With Treatment Related Adverse Events | 24 weeks | — |
| Number of Individuals With Treatment Related Serious Adverse Events | 24 weeks | — |
| 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. |
| Proportion of Individuals Requiring Treatment Discontinuation | 4 weeks | — |
Countries
Kenya
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 5FC Plus Fluconazole 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 | 3 |
| Fluconazole Alone 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 | 3 |
| Total | 6 |
Baseline characteristics
| Characteristic | 5FC Plus Fluconazole | Fluconazole Alone | Total |
|---|---|---|---|
| Age, Continuous | 36 years | 31 years | 33.5 years |
| CD4+ T-cell Count | 22 cells/microliter | 13 cells/microliter | 17 cells/microliter |
| Region of Enrollment Kenya | 3 participants | 3 participants | 6 participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 2 / 3 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 |
Outcome results
Primary
Number of Participants Alive at 12 Weeks
Time frame: 12 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 5FC Plus Fluconazole | Number of Participants Alive at 12 Weeks | 2 participants |
| Fluconazole Alone | Number of Participants Alive at 12 Weeks | 2 participants |
Secondary
Achieve Targeted Recruitment, Retention and Adherence Rates
Time frame: 24 weeks
Secondary
Cryptococcal Meningitis-free Survival at 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.
Time frame: 24 weeks
Secondary
Number of Individuals Who Develop Cryptococcal Meningitis
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
Secondary
Number of Individuals Who Develop Immune Reconstitution Inflammatory Syndrome Due to Cryptococcus
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
Secondary
Number of Individuals With Treatment Related Adverse Events
Time frame: 24 weeks
Secondary
Number of Individuals With Treatment Related Serious Adverse Events
Time frame: 24 weeks
Secondary
Number of Participants Alive at 2 Weeks
Time frame: 2 weeks
Secondary
Proportion of Individuals Requiring Dose Reduction
Time frame: 24 weeks
Secondary
Proportion of Individuals Requiring Treatment Discontinuation
Time frame: 4 weeks
Secondary
Survival at 24 Weeks
Time frame: 24 weeks