Cryptococcal Infection DisseminatedPhase 2SToP-CryptoNCT01562132
Safety Study of Fluconazole in Combination With Flucytosine for the Treatment of Early Cryptococcal Infection
A Phase 2 study testing Flucytosine and fluconazole and Fluconazole in people with Cryptococcal Infection Disseminated, run by Yale University at 2 sites in Kenya.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Cryptococcal Infection Disseminated
- What is being tested?
- Flucytosine and fluconazole and Fluconazole
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 6 participants
- Where
- 2 sitesKenya
- Study dates
- Sep 2013to Jul 2014
- 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
- 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
Who cannot join
- 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
Show all 16Show fewer
- 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
Trial locations and contacts
2 sites in 1 country.
Kenya2 sites
Family AIDS Care and Education Services
Kisumu, Nyanza
Family AIDS Care and Education Services
Sindo, Nyanza
About this study
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
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.
Read the 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.
- Conditions
- Cryptococcal Infection Disseminated
- Being tested
- Flucytosine and fluconazole, Fluconazole
- Keywords
- cryptococcus, HIV
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Flucytosine and fluconazoleDrug
Also called Ancobon, Diflucan
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
FluconazoleDrug
Also called Diflucan
fluconazole 1200mg orally once daily for 14 days, followed by 800mg orally once daily for 8 weeks, followed by 200mg orally once daily
| Study group | Role | What they receive |
|---|---|---|
| 5FC plus fluconazole | Experimental | Combination therapy with oral fluconazole and flucytosine Receives: Drug: Flucytosine and fluconazole |
| fluconazole alone | Active comparator | Fluconazole monotherapy Receives: Drug: Fluconazole |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Participants Alive at 12 Weeks
Measured: 12 weeks
Secondary outcomes (10)
Number of Participants Alive at 2 Weeks
Measured: 2 weeks
Survival at 24 Weeks
Measured: 24 weeks
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.
Measured: 24 weeks
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.
Measured: 24 weeks
Achieve Targeted Recruitment, Retention and Adherence Rates
Measured: 24 weeks
Proportion of Individuals Requiring Treatment Discontinuation
Measured: 4 weeks
Proportion of Individuals Requiring Dose Reduction
Measured: 24 weeks
Number of Individuals With Treatment Related Adverse Events
Measured: 24 weeks
Number of Individuals With Treatment Related Serious Adverse Events
Measured: 24 weeks
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.
Measured: 24 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Mar 2012 (estimated)
- Study startSep 2013
- Primary completionJul 2014
- Study completionJul 2014
Why it stopped: Stopped in accordance with pre-specified stopping rules for poor recruitment.
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.
- Other trials for Cryptococcal Infection DisseminatedStudies of the same condition, open and under way.
- More trials run by Yale UniversityThe 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
- Masking
- None (open label)
- Enrolment
- 6 participants (actual)
Sponsor and investigators
- Lead sponsor
- Yale University
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute of Neurological Disorders and Stroke (NINDS), Kenya Medical Research Institute, Bausch Health Americas, Inc., University of Nairobi
- Responsible party
- Sponsor
- Investigators
- Ana-Claire L Meyer, MD, MSHS, Principal investigator, University of California, San FranciscoMark A Jacobson, MD, Principal investigator, University of California, San FranciscoJudith K Kwasa, MBChB MMed, Principal investigator, University of Nairobi
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01562132
- Sponsor's protocol ID
- 1307012426
- Other IDs
- R21NS077858-01
- Acronym
- SToP-Crypto
- Status last verified
- Sep 2021
- First submitted
- 21 Mar 2012
- Last updated
- 29 Sep 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 29 Sep 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT01562132
- Acronym / sponsor ID
- SToP-Crypto / 1307012426
- Conditions
- Cryptococcal Infection Disseminated
- Keywords
- cryptococcus, HIV
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Stopped in accordance with pre-specified stopping rules for poor recruitment.
- Enrolment
- 6 participants (actual)
- Lead sponsor
- Yale UniversityUniversity, hospital or other
- Collaborators
- National Institute of Neurological Disorders and Stroke (NINDS), Kenya Medical Research Institute, Bausch Health Americas, Inc., University of Nairobi
- Study start
- Sep 2013
- Primary completion
- Jul 2014 (actual)
- Study completion
- Jul 2014 (actual)
- First posted
- 23 Mar 2012 (estimated)
- Results
- Posted 31 Aug 2015
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| 5FC plus fluconazole | Experimental | Drug: Flucytosine and fluconazoleCombination therapy with oral fluconazole and flucytosine |
| fluconazole alone | Active comparator | Drug: FluconazoleFluconazole monotherapy |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 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
Key exclusion criteria (16 listed)
- 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
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 |
|---|---|---|
| Flucytosine and fluconazoleAlso: Ancobon, DiflucanFlucytosine 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 | Drug | 5FC plus fluconazole |
| FluconazoleAlso: Diflucanfluconazole 1200mg orally once daily for 14 days, followed by 800mg orally once daily for 8 weeks, followed by 200mg orally once daily | Drug | fluconazole alone |
Primary outcome
Number of Participants Alive at 12 Weeks
Time frame: 12 weeks
10 secondary outcomes
Number of Participants Alive at 2 Weeks
Time frame: 2 weeks
Survival at 24 Weeks
Time frame: 24 weeks
Number of Individuals Who Develop Cryptococcal Meningitis
Time frame: 24 weeks
Number of Individuals Who Develop Immune Reconstitution Inflammatory Syndrome Due to Cryptococcus
Time frame: 24 weeks
Achieve Targeted Recruitment, Retention and Adherence Rates
Time frame: 24 weeks
Proportion of Individuals Requiring Treatment Discontinuation
Time frame: 4 weeks
Proportion of Individuals Requiring Dose Reduction
Time frame: 24 weeks
Number of Individuals With Treatment Related Adverse Events
Time frame: 24 weeks
Number of Individuals With Treatment Related Serious Adverse Events
Time frame: 24 weeks
Cryptococcal Meningitis-free Survival at 24 Weeks
Time frame: 24 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Sep 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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.
Ana-Claire L Meyer, MD, MSHS principal investigator
University of California, San Francisco
Mark A Jacobson, MD principal investigator
University of California, San Francisco
Judith K Kwasa, MBChB MMed principal investigator
University of Nairobi
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 and fluconazole and Fluconazole in people with Cryptococcal Infection Disseminated, run by Yale University at 2 sites in Kenya.
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 6 inclusion and 16 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: stopped early, as of the sponsor's last update on 29 Sep 2021. 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 Kenya. 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 31 Aug 2015). 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?
Number of Participants Alive at 12 Weeks (time frame: 12 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 29 Sep 2021.