Cryptococcal Meningitis
Conditions
Brief summary
Cryptococcal meningitis (CM) is a fungal infection that causes a severe syndrome of meningitis that is 100% fatal without antifungal therapy. Even with antifungal therapy, mortality rates remain high, especially in Africa where the ongoing HIV/AIDS pandemic leads to higher prevalence of cryptococcosis. Combination of amphotericin and flucytosine (5-FC) is the mainstay of therapy for the initial management of CM. Indeed, it has even been shown that effective delivery of these therapies in Africa can lower mortality rates by 90%. This is a prospective open-label trial to compare the efficacy and safety of lower doses of 5FC during induction therapy to historical controls with standard 5FC dosing. Participants in the trial will receive 60mg/kg/day of 5-FC in 3 divided doses for 10 days. Single-dose liposomal amphotericin (10mg/kg) is preferred, if available. Amphotericin B 0.7-1.0 mg/kg/day may be used if needed. Historical controls drawn from the AMBITION trial will be used as a comparison group, selected weighted by inclusion/exclusion criteria, baseline characteristics and therapies received. Induction therapy for control group participants followed the 2018 WHO cryptococcal guidelines with 7 days of 5-FC 100mg/kg/day and 7 days of IV Amphotericin deoxycholate followed by 1200mg fluconazole/day for 7 days. The intervention group received single- dose liposomal amphotericin plus 5-FC and fluconazole 1200 mg/day. All participants will receive fluconazole 1200mg/day during consolidation therapy from day 1 to 14 then 800mg/day from day 15 to 10 weeks, and 200mg/day after 10 weeks. All participants will receive lumbar punctures at diagnosis, day 3, day 5-7, day 10-14, and additionally as required for control of intracranial pressure and documentation of CSF sterilization. Controls from Ambition will be matched for the same LP windows. Therapeutic LPs conducted during the first week have a \ 70% relative survival benefit.
Interventions
DRUGAMBITION trial control
Induction therapy for control group participants followed the 2018 WHO cryptococcal guidelines with 7 days of 5-FC 100mg/kg/day and 7 days of IV Amphotericin deoxycholate followed by 1200mg fluconazole/day for 7 days.
DRUGFlucytosine
Participants in the trial will receive 60mg/kg/day of 5-FC in 3 divided doses for 10 days. Single-dose liposomal amphotericin (10mg/kg) is preferred, if available. Amphotericin B 0.7-1.0 mg/kg/day may be used if needed.
Sponsors
Infectious Diseases Institute, Makerere University
Mbarara University of Science and Technology
Meningitis Foundation
University of Minnesota
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Prospective, open-label trial to compare the efficacy and safety of lower doses of 5FC during induction therapy to historical controls with standard 5FC dosing. Historical controls drawn from the AMBITION trial will be used as a comparison group, selected weighted by inclusion/exclusion criteria, baseline characteristics and therapies received.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* CSF cryptococcal antigen (CrAg) positive meningitis * Ability and willingness to provide informed consent * Willing to receive protocol-specified lumbar punctures
Exclusion criteria
* Age \<18 years * Inability to take enteral (oral or nasogastric) medicine * Cannot or unlikely to attend regular clinic visits * Receiving chemotherapy or corticosteroids * Suspected Paradoxical immune reconstitution inflammatory syndrome (IRIS) * Pregnancy or breastfeeding * CrCl \< 20 mL/minute * Absolute neutrophil count \<500 x10 6 cells/L * Thrombocytopenia \< 50,000 x 10 6 cells/L * Patients with prior 5-flucytosine exposure \>3 days in the 12 months prior to enrollment * Any condition for which participation would not be in the best interest of the participant or that could limit protocol specified assessments.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Early Fungicidal Activity | 2 weeks | Rate of clearance of Cryptococcus from CSF. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| CSF Culture Sterility | 18 weeks | Cryptococcus is cleared or not from the cerebrospinal fluid |
| Mortality | 16 weeks | The proportion of participants who died after 16 weeks follow up |
Countries
Uganda
Participant flow
Recruitment details
Controls were data drawn from another trial, not enrolled in this trial directly.
Participants by arm
| Arm | Count |
|---|---|
| Control Historical controls drawn from the AMBITION trial will be used as a comparison group, selected weighted by inclusion/exclusion criteria, baseline characteristics and therapies received.
AMBITION trial control: Induction therapy for control group participants followed the 2018 WHO cryptococcal guidelines with 7 days of 5-FC 100mg/kg/day and 7 days of IV Amphotericin deoxycholate followed by 1200mg fluconazole/day for 7 days. | 171 |
| Low Dose Flucytosine HIV-infected persons in Uganda with cryptococcal meningitis
Flucytosine: Participants in the trial will receive 60mg/kg/day of 5-FC in 3 divided doses for 10 days. Single-dose liposomal amphotericin (10mg/kg) is preferred, if available. Amphotericin B 0.7-1.0 mg/kg/day may be used if needed. | 48 |
| Total | 219 |
Baseline characteristics
| Characteristic | Control | Low Dose Flucytosine | Total |
|---|---|---|---|
| Age, Continuous | 36 years | 40 years | 37 years |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Sex: Female, Male Female | 70 Participants | 26 Participants | 96 Participants |
| Sex: Female, Male Male | 101 Participants | 22 Participants | 123 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 50 / 171 | 11 / 48 |
| other Total, other adverse events | 87 / 171 | 25 / 48 |
| serious Total, serious adverse events | 132 / 171 | 31 / 48 |
Outcome results
Primary
Early Fungicidal Activity
Rate of clearance of Cryptococcus from CSF.
Time frame: 2 weeks
Population: The number analyzed are lower because not all enrolled had data for these outcomes.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Control | Early Fungicidal Activity | 0.39 log10 CFU/mL/day | Standard Deviation 0.27 |
| Low Dose Flucytosine | Early Fungicidal Activity | 0.28 log10 CFU/mL/day | Standard Deviation 0.28 |
Secondary
CSF Culture Sterility
Cryptococcus is cleared or not from the cerebrospinal fluid
Time frame: 18 weeks
Population: The number analyzed are lower because not all enrolled had data for these outcomes.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Control | CSF Culture Sterility | 60 Participants |
| Low Dose Flucytosine | CSF Culture Sterility | 25 Participants |
Secondary
Mortality
The proportion of participants who died after 16 weeks follow up
Time frame: 16 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Control | Mortality | 50 Participants |
| Low Dose Flucytosine | Mortality | 11 Participants |