A Phase 2 interventional study of AMBITION trial control and Flucytosine in Cryptococcal Meningitis, sponsored by University of Minnesota. Completed at 2 sites in Uganda. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2025-08-27.
Sponsored by University of Minnesota · Phase 2, Interventional, and Treatment
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.
54 studies on the registry are indexed under Meningitis, Cryptococcal; 6 are open to participants now.
This study's enrollment of 48 is below the median of 143 across 35 interventional studies indexed under Meningitis, Cryptococcal.
Browse Meningitis, Cryptococcal studies →University of Minnesota is the lead sponsor of 1,216 studies on the registry; 197 are open to participants now.
Of its 136 completed or terminated interventional studies of FDA-regulated products, 95 (70%) have results posted.
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Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.
Studies differ in what they allow: check which steroid medicines, routes (tablets, injections, creams, inhalers, eye drops) and doses this study accepts.
How quickly the kidneys clear creatinine, a waste product, from the blood. A study may estimate it from a blood test with age, weight and sex (often by the Cockcroft–Gault formula), or measure it using blood and urine collected over a set time. Given in mL/min; higher is better.
The number of neutrophils, white blood cells that help fight infection, in a given amount of blood. Too few raises the risk of infection.
It is a count, not a percentage of the white cells. Limits are written in units that mean the same: ≥ 1.5 × 10⁹/L is ≥ 1,500 per mm³ (µL). Each lab has its own reference range.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Corticosteroids (steroids)
Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.
Studies differ in what they allow: check which steroid medicines, routes (tablets, injections, creams, inhalers, eye drops) and doses this study accepts.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Creatinine clearance (CrCl)
How quickly the kidneys clear creatinine, a waste product, from the blood. A study may estimate it from a blood test with age, weight and sex (often by the Cockcroft–Gault formula), or measure it using blood and urine collected over a set time. Given in mL/min; higher is better.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Absolute neutrophil count (ANC)
The number of neutrophils, white blood cells that help fight infection, in a given amount of blood. Too few raises the risk of infection.
It is a count, not a percentage of the white cells. Limits are written in units that mean the same: ≥ 1.5 × 10⁹/L is ≥ 1,500 per mm³ (µL). Each lab has its own reference range.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
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.
Drug: AMBITION trial control
HIV-infected persons in Uganda with cryptococcal meningitis
Drug: Flucytosine
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.
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.
Early Fungicidal Activity
Rate of clearance of Cryptococcus from CSF.
Time frame: 2 weeks
CSF Culture Sterility
Cryptococcus is cleared or not from the cerebrospinal fluid
Time frame: 18 weeks
Mortality
The proportion of participants who died after 16 weeks follow up
Time frame: 16 weeks
Controls were data drawn from another trial, not enrolled in this trial directly.
| Milestone | Control | Low Dose Flucytosine |
|---|---|---|
| Started | 171 | 48 |
| Completed | 171 | 47 |
| Not completed | 0 | 1 |
Rate of clearance of Cryptococcus from CSF.
| log10 CFU/mL/day | Control | Low Dose Flucytosine |
|---|---|---|
| Early Fungicidal Activity | 0.39 ± 0.27 | 0.28 ± 0.28 |
Cryptococcus is cleared or not from the cerebrospinal fluid
| Participants | Control | Low Dose Flucytosine |
|---|---|---|
| CSF Culture Sterility | 60 | 25 |
The proportion of participants who died after 16 weeks follow up
| Participants | Control | Low Dose Flucytosine |
|---|---|---|
| Mortality | 50 | 11 |
Collected over 16 weeks. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Control | 50/171 (29.2%) | 132/171 (77.2%) | 87/171 (50.9%) |
| Low Dose Flucytosine | 11/48 (22.9%) | 31/48 (64.6%) | 25/48 (52.1%) |
| Event | Control | Low Dose Flucytosine |
|---|---|---|
| Death, unknown causeInvestigations | 29/171 | 0/48 |
| ReadmissionSurgical and medical procedures | 25/171 | 0/48 |
| CM RelapseInfections and infestations | 2/171 | 6/48 |
| Prolonged HospitalizationSurgical and medical procedures | 15/171 | 0/48 |
| Acute Kidney InjuryRenal and urinary disorders | 2/171 | 4/48 |
| Paradoxical CM IRISInfections and infestations | 4/171 | 4/48 |
| AspirationRespiratory, thoracic and mediastinal disorders | 0/171 | 3/48 |
| Metabolic EncephalopathyMetabolism and nutrition disorders | 0/171 | 3/48 |
| OtherGeneral disorders | 0/171 | 3/48 |
| AnemiaBlood and lymphatic system disorders | 5/171 | 2/48 |
| Event | Control | Low Dose Flucytosine |
|---|---|---|
| Hemoglobin Grade 3 or WorseBlood and lymphatic system disorders | 17/171 | 7/48 |
| Neutropenia Grade 3 or worseBlood and lymphatic system disorders | 23/171 | 7/48 |
| Leukopenia Grade 3 or worseBlood and lymphatic system disorders | 16/171 | 5/48 |
| Elevated Liver Enzymes, Grade 3 or WorseHepatobiliary disorders | 5/171 | 3/48 |
| ThrombocytopeniaBlood and lymphatic system disorders | 9/171 | 0/48 |
| Potassium Grade 3 or worseMetabolism and nutrition disorders | 7/171 | 1/48 |
| Hyponatremia Grade 3 or worseMetabolism and nutrition disorders | 7/171 | 1/48 |
| Creatinine Grade 3 or WorseRenal and urinary disorders | 3/171 | 1/48 |
| Age, Continuous(years) | Control | Low Dose Flucytosine | Total |
|---|---|---|---|
| Mean | 36 (30 to 42) | 40 (31 to 46) | 37 (32 to 44) |
| Sex: Female, Male(Participants) | Control | Low Dose Flucytosine | Total |
|---|---|---|---|
| Female | 70 | 26 | 96 |
| Male | 101 | 22 | 123 |
| Race and Ethnicity Not Collected(Participants) | Control | Low Dose Flucytosine | Total |
|---|---|---|---|
| Count of participants | — | — | 0 |
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This study is completed, as verified in Aug 2025. You cannot join it, but the record below documents what was studied.
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Studies of the drug tested here: Flucytosine