Cryptococcal MeningitisPhase 2NCT06414512
Optimizing the Dose of Flucytosine for the Treatment of Cryptococcal Meningitis
A Phase 2 study testing Flucytosine in people with Cryptococcal Meningitis, run by University of Minnesota at 2 sites in Uganda.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Cryptococcal Meningitis
- What is being tested?
- Flucytosine
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 48 participants
- Where
- 2 sitesUganda
- Study dates
- 9 Apr 2024to 2 Oct 2024
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- CSF cryptococcal antigen (CrAg) positive meningitis
- Ability and willingness to provide informed consent
- Willing to receive protocol-specified lumbar punctures
Who cannot join
- 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
Show all 11Show fewer
- 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.
Trial locations and contacts
2 sites in 1 country.
Uganda2 sites
Infectious Disease Institute, Mulago Hospital Complex
Kampala, 22418
Mbarara University of Science and Technology
Mbarara, 1410
About this study
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.
- Conditions
- Cryptococcal Meningitis
- Being tested
- AMBITION trial control, Flucytosine
- Medical subject headings
- Meningitis, Cryptococcal
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AMBITION trial controlDrug
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.
FlucytosineDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| control | Active comparator | 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. Receives: Drug: AMBITION trial control |
| Low Dose Flucytosine | Experimental | HIV-infected persons in Uganda with cryptococcal meningitis Receives: Drug: Flucytosine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Early Fungicidal Activity
Rate of clearance of Cryptococcus from CSF.
Measured: 2 weeks
Secondary outcomes (2)
CSF Culture Sterility
Cryptococcus is cleared or not from the cerebrospinal fluid
Measured: 18 weeks
Mortality
The proportion of participants who died after 16 weeks follow up
Measured: 16 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 May 2024
- Study start9 Apr 2024
- Primary completion2 Oct 2024
- Study completion2 Oct 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Cryptococcal MeningitisStudies of the same condition, open and under way.
- More trials run by University of MinnesotaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- 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.
- Masking
- None (open label)
- Enrolment
- 48 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Minnesota
- Sponsor type
- University, hospital or other
- Collaborators
- Infectious Diseases Institute, Makerere University, Mbarara University of Science and Technology, Meningitis Foundation
- Responsible party
- Sponsor
- Investigators
- David B Meya, Principal investigator, University of MinnesotaDavid R Boulware, Principal investigator, University of Minnesota
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06414512
- Sponsor's protocol ID
- STUDY00017800
- Other IDs
- R01NS0863121
- Status last verified
- Aug 2025
- First submitted
- 7 May 2024
- Last updated
- 27 Aug 2025
- Results posted
- Yes, on ClinicalTrials.gov
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Rutakingirwa MK, Skipper CP, Dai B, Wele A, Namombwe S, Mugabi T, Ndyetukira JF, Sadiq A, Kabahubya M, Chemusto L, Ahimbisibwe C, Nabbale S, Kandole TK, Muyise RCB, Kagimu E, Luggya T, Mulungi J, Jjunju S, Nicol MR, Stott KE, Kwizera R, Meya DB, Boulware DR, McHale TC; FLOOR trial team. Evaluating the Use of Lower Dose Flucytosine for the Treatment of Cryptococcal Meningitis: A Clinical Trial. Clin Infect Dis. 2026 Feb 9;82(1):67-74. doi: 10.1093/cid/ciaf432.
PubMed 40795226
Study at a glance
From the registry record, last updated by the sponsor on 27 Aug 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Optimizing the Dose of Flucytosine for the Treatment of Cryptococcal Meningitis
- ClinicalTrials.gov ID
- NCT06414512
- Acronym / sponsor ID
- STUDY00017800
- Conditions
- Cryptococcal Meningitis
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 48 participants (actual)
- Lead sponsor
- University of MinnesotaUniversity, hospital or other
- Collaborators
- Infectious Diseases Institute, Makerere University, Mbarara University of Science and Technology, Meningitis Foundation
- Study start
- 9 Apr 2024 (actual)
- Primary completion
- 2 Oct 2024 (actual)
- Study completion
- 2 Oct 2024 (actual)
- First posted
- 16 May 2024 (actual)
- Results
- Posted 27 Aug 2025
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- 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.
| Arm | Type | Receives |
|---|---|---|
| control | Active comparator | Drug: AMBITION trial controlHistorical controls drawn from the AMBITION trial will be used as a comparison group, selected weighted by inclusion/exclusion criteria, baseline characteristics and therapies received. |
| Low Dose Flucytosine | Experimental | Drug: FlucytosineHIV-infected persons in Uganda with cryptococcal meningitis |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- CSF cryptococcal antigen (CrAg) positive meningitis
- Ability and willingness to provide informed consent
- Willing to receive protocol-specified lumbar punctures
Key exclusion criteria (11 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AMBITION trial controlInduction 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. | Drug | control |
| FlucytosineParticipants 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. | Drug | Low Dose Flucytosine |
Primary outcome
Early Fungicidal Activity
Time frame: 2 weeks
Rate of clearance of Cryptococcus from CSF.
2 secondary outcomes
CSF Culture Sterility
Time frame: 18 weeks
Mortality
Time frame: 16 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Aug 2025.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 40795226Rutakingirwa MK, Skipper CP, Dai B, Wele A, Namombwe S, Mugabi T, Ndyetukira JF, Sadiq A, Kabahubya M, Chemusto L, Ahimbisibwe C, Nabbale S, Kandole TK, Muyise RCB, Kagimu E, Luggya T, Mulungi J, Jjunju S, Nicol MR, Stott KE, Kwizera R, Meya DB, Boulware DR, McHale TC; FLOOR trial team. Evaluating the Use of Lower Dose Flucytosine for the Treatment of Cryptococcal Meningitis: A Clinical Trial. Clin Infect Dis. 2026 Feb 9;82(1):67-74. doi: 10.1093/cid/ciaf432.
Related trials for Cryptococcal Meningitis
RecruitingObservational study
Fungal Infection Susceptibility
Cryptococcal Infection, Cryptococcal Pneumonia
RecruitingObservational study
Etiology, Pathogenesis, and Natural History of Idiopathic CD4+ Lymphocytopenia
Idiopathic CD4+ Lymphocytopenia, Cryptococcal Meningitis
Not yet recruitingPhase 3
Optimizing Care for Cryptococcal Antigenemia: Evaluation of Short Course Fluconazole and ART Timing Among CrAg+ Persons With Low Titers
Cryptococcal Antigenemia, HIV-1-infection
RecruitingPhase 2/3
Platform Trial For Cryptococcal Meningitis (PLATFORM-CM)
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Single Dose Liposomal Amphotericin for Asymptomatic Cryptococcal Antigenemia
Cryptococcal Meningitis
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
David B Meya principal investigator
University of Minnesota
David R Boulware principal investigator
University of Minnesota
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Flucytosine in people with Cryptococcal Meningitis, run by University of Minnesota at 2 sites in Uganda.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 27 Aug 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Uganda. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 27 Aug 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Early Fungicidal Activity (time frame: 2 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06414512, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Aug 2025.