Combination antifungal therapy for candida bloodstream infections

ISRCTN	ISRCTN56596656
DOI	https://doi.org/10.1186/ISRCTN56596656
Sponsor	Wits Health Consortium
Funder	Wellcome Trust

Submission date: 11/12/2025
Registration date: 19/12/2025
Last edited: 12/12/2025

Recruitment status: Not yet recruiting
Overall study status: Ongoing
Condition category: Infections and Infestations

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English summary of protocol

Background and study aims
The COMBAT Candida trial will investigate whether combination therapy with two drugs (micafungin and flucytosine) is better than micafungin alone for the treatment of patients with Candida Bloodstream Infections (BSI) at 5 hospitals in Johannesburg, South Africa. These drugs have been chosen because micafungin is internationally recommended as the first-line treatment of this infection, and the addition of flucytosine has been shown to improve fungal killing in laboratory experiments. Flucytosine is also used in combination therapy for another severe fungal infection, HIV-associated cryptococcal meningitis, where it has been shown to be safe and effective through randomised trials.

Who can participate?
Patients who have Candida BSI at the trial sites will be invited to participate.

What does the study involve?
If the participants do not have the capacity to make a decision about participation at the time of enrolment, informed consent will be obtained retrospectively from them at the earliest opportunity when they regain capacity and following provision of proxy consent. Proxy consent will be requested from their next of kin, a family member, or an independent clinician. If consent is provided, the participant will be randomly assigned to receive either micafungin alone (standard care) or micafungin plus flucytosine (the trial intervention) for two weeks after their blood is clear of Candida.

During the first phase of the trial, participants in the intervention arm will be further randomised to receive either a standard dose of flucytosine (100 mg/kg daily) or a half measure of this dose (50 mg/kg daily). The levels of flucytosine in the blood will then be measured and the lower dose will be selected to be used in the next phase of the trial providing that the first phase shows that sufficient levels are achieved with this dose to kill the Candida.

During the second phase of the trial, there will be two arms of the trial; micafungin alone (the internationally recommended treatment), or micafungin plus flucytosine at the selected dose. Success of each treatment arm of the trial will be measured by assessing survival of participants during the 30 days after enrolment into the study, how effectively the blood is cleared of Candida, whether the Candida infection persists on treatment or relapses following treatment, and whether antifungal resistance emerges in any Candida identified growing on the body (by using swabs of nose, mouth, hands, armpits, groins, and skin between the buttocks).

What are the possible benefits and risks of participating?
Benefits and risks not provided at registration.

Where is the study run from?
Wits Health Consortium, South Africa.

When is the study starting and how long is it expected to run for?
April 2026 t August 2030.

Who is funding the study?
Wellcome Trust, UK.

Who is the main contact?
Nelesh Govender, Nelesh.Govender@wits.ac.za

Contact information

Dr Lauriane Fomete
Scientific, Public

Wits Mycology Division
National Institute for Communicable Diseases
1 Modderfontein Road
Sandringham
Johannesburg
2131
South Africa

Phone	+27 63 914 1453
Email	lauriane.fomete@witshealth.co.za

Prof Nelesh Govender
Principal investigator

Wits Mycology Division
National Institute for Communicable Diseases
1 Modderfontein Road
Sandringham
Johannesburg
2131
South Africa

ORCID ID	0000-0001-7869-9462
Phone	+27 (0) 11 555 0353
Email	Nelesh.Govender@wits.ac.za

Dr Rae Wake
Principal investigator

Wits Mycology Division
National Institute for Communicable Diseases
1 Modderfontein Road
Sandringham
Johannesburg
2131
South Africa

Phone	+27 (0)115550323
Email	rwake@sgul.ac.uk

Study information

Primary study design	Interventional
Allocation	Randomized controlled trial
Masking	Open (masking not used)
Control	Active
Assignment	Parallel
Purpose	Treatment
Scientific title	Combination antifungal therapy with micafungin plus flucytosine vs. micafungin alone for adults with candida bloodstream infections: an open-label phase III randomised controlled trial
Study acronym	COMBAT Candida
Study objectives	Primary Objective To determine whether combination treatment of micafungin plus flucytosine for 2 weeks following blood sterility is superior to standard treatment of micafungin monotherapy in improving clinical, mycological and resistance outcomes. Secondary Objectives To determine the following: 1. All-cause mortality at day 30 and 90; 2. Time to all-cause mortality within 30 and 90 days; 3. Proportion of participants who have a breakthrough of Candida BSI during treatment; 4. Proportion of participants who have a relapse of Candida BSI at day 14, EOT +5 days, day 30 and EOT +30days; 5. Time to blood culture sterility; 6. Time to micafungin resistance in colonising or invasive Candida spp; 7. Proportion of participants who have any micafungin resistance detected in any colonising or invasive Candida spp up until day 14, EOT+5 days, day 30; 8. Duration of ICU admission and hospitalisation; 9. Rate of change in fungal biomarkers (serum beta-D-glucan (BDG), blood Candida qPCR) up until day 30; 10. Proportion who develop grade 3 cytopaenias, other grade 4 adverse events and other serious adverse events (SAEs) up until EOT +5 days.
Ethics approval(s)	Not yet submitted
Health condition(s) or problem(s) studied	Candida spp. Bloodstream Infections
Intervention	A randomisation sequence was generated using a computer algorithm with permuted blocks stratified by site only. Step 1 – Dose-selection Micafungin 100 mg/d IV plus flucytosine 50 mg/kg PO/NG (split QDS) Micafungin 100 mg/d IV plus flucytosine 100 mg/kg PO/NG (split QDS) Micafungin 100 mg/d IV – INTERNATIONAL FIRST-LINE STANDARD Step 2 – Optimal dose Micafungin 100 mg/d IV plus flucytosine either 50 mg/kg or 100 mg/kg PO/NG (split QDS) - INTERVENTION Micafungin 100 mg/d IV – INTERNATIONAL FIRST-LINE STANDARD For each arm: - Oral switch to fluconazole 800 mg (or fluconazole plus flucytosine if in a combination arm) can be made if clinical improvement, bloodstream clearance of Candida and fluconazole susceptibility is confirmed after 7 days of treatment. - Antifungals to be continued for 2 weeks following blood culture sterility (a single blood culture negative for Candida is referred to as sterility throughout) The intervention will be given for 14 days following the first blood culture which is negative for Candida spp taken during treatment (initial +/- any breakthrough Candida BSI). During Step 1 (dose-selection phase), plasma will be taken at 12 time points during the first week: 0.25, 0.5, 1, 2, 6, 24, 48, 72, 96, 120, 148, 168 hours, for the analysis of flucytosine and micafungin PK in participants of the intervention arms.  During both steps, blood will be drawn at baseline to check full blood count and differential (FBC), serum creatinine and alanine transaminase (ALT) and aspartate aminotransferase (AST) levels, then every 3-4 days for FBC and ALT/AST up until EOT +5 days. Blood cultures will be taken at baseline (0h), 12h (+/-6h), 24h (+/-6h), 36h (+/- 6h), 48h (+/-6h) after treatment is started and 12 hourly as per this schedule until blood cultures are negative for >48 hours (usually takes 1-2 days), and then every 3-4 days until 5 days after end of treatment (EOT), to check for breakthrough (or relapse) of infection. Composite superficial swabs will be taken from commonly colonised body sites (i.e. nares/ oral, hands/ axillae/ groins and perianal skin) twice weekly until discharge from hospital, and during a study visit at day 30 after start of treatment for Candida culture and resistance testing. Participants will be followed at least every 3 days during treatment until EOT + 5days to record any grade 3 cytopenias, other grade 4 AEs and SAEs, and at 30 days and 90 days (by phone call, or visit if discharged from hospital) to determine hospitalisation and survival status. A further pre-dose plasma level of micafungin and flucytosine will be taken along with safety bloods on day 1 and day 7.
Intervention type	Drug
Phase	Phase III
Drug / device / biological / vaccine name(s)	Micafungin, Flucytosine
Primary outcome measure(s)	STEP 1 – Dose-selection: population pharmacokinetic modelling of flucytosine plasma concentrations to assess for achievement of target drug exposure of flucytosine in plasma measured using PK blood sampling at day 1 and day 7 STEP 2 – Primary efficacy outcome (hierarchical composite at 30 days): 1) time to death (all-cause mortality, measured in ordinal blocks of 5 days); 2) breakthrough Candida BSI during treatment (binary – whether or not any blood cultures taken subsequent to blood culture sterility for ≥48 hours, become positive with Candida spp); 3) Candida BSI relapse within 30 days after end of treatment (binary - whether or not a blood culture taken following the end of treatment is positive with the same Candida spp as grown from the initial blood culture, measured until EOT +30); 4) time-to-blood culture-sterility (measured in ordinal blocks of 12 hour periods from first blood culture positive, to first blood culture negative, when blood cultures remain negative during twice daily testing); 5) time to emergence of micafungin resistance (MIC > EUCAST breakpoint) in any commensal Candida species (measured as an ordinal variable using twice weekly swabbing episode) measured using Win Ratio (Hierarchical Composite) at day 30
Key secondary outcome measure(s)	All-cause mortality measured using number of deaths (site records) at day 30 and day 90 Time to all-cause mortality measured using time-to-event at day 30 and day 90 Candida BSI breakthrough during treatment measured using proportion of patients with a positive blood culture indicating a new Candida bloodstream infection at scheduled timepoints until EOT+5 Relapse of Candida BSI after treatment measured using proportion of participants with a positive blood culture from the same Candida spp at day 14, EOT +5, day 30 and EOT +30 Time to blood culture sterility measured using time to negative blood culture with no subsequent positive within 48 hours. at scheduled timepoints until EOT +5 Time to micafungin resistance in colonising or invasive Candida spp measured using time to detection of micafungin resistance (MIC above EUCAST breakpoint) in a colonising or invasive Candida spp at every 3/4 days until day 30 Proportion of participants who have micafungin resistance detected measured using resitance (MIC above EUCAST breakpoint) detected in any colonising or invasive Candida spp at day 14, EOT+5 & day 30 Duration of ICU admission and hospitalisation measured using time spent in ICU/hospital from site records at up until day 90 Rate of change in fungal biomarkers measured using serum beta-D-glucan & blood Candida qPCR at until day 30 SAEs measured using proportion with grade 3 cytopaenias, other grade 4 adverse events and other serious adverse events at up until EOT +5
Completion date	31/08/2030

Eligibility

Participant type(s)
Age group	Mixed
Lower age limit	18 Years
Upper age limit	100 Years
Sex	All
Target sample size at registration	470
Key inclusion criteria	1. Age ≥18 years 2. Evidence of microscopy-confirmed yeast bloodstream infection 3. ≥1 systemic signs of infection during a 24 hour period before and after blood culture draw
Key exclusion criteria	1. Complicated invasive candidiasis (e.g. septic arthritis in a prosthetic joint, osteomyelitis, endocarditis or myocarditis, endopthalmitis, chorioretinitis or any central nervous system involvement) 2. Pregnancy or breastfeeding 3. Receipt of a systemic antifungal, at treatment-dose, to which the Candida spp causing bloodstream infection is susceptible (> 3 doses of a once daily or >5 doses of a twice daily drug within 4 days of randomisation). This will be a late exclusion criteria once antifungal susceptibility testing results are available. 4. Micafungin or flucytosine resistant Candida spp (by EUCAST breakpoint) in initial bloodstream isolate (late exclusion criteria) 5. A known hypersensitivity to trial drugs 6. Co-administration of cytarabine 7. Known complete dihydropyrimidine dehydrogenase deficiency 8. Alanine transferase or aspartate aminotransferase level >10-fold upper limit of normal, or history of chronic cirrhosis (Child-Pugh score >9) 9. Neutrophil count <500 x10^6/L or platelet count <50,000 x 10^6/L 10. Previous participation in this trial or in another trial for the same indication 11. The principal investigator (PI) is of the opinion that the individual is not suitable for participation in the study due to any other medical factors 12. For Step 1 only, an estimated Glomerular Filtration Rate (eGFR) of <50mL/min/1.73 m^2, haemoglobin <8g/dL, or participants without adequate intravenous access for regular blood draws during the first 24 hours of treatment. Late Exclusion Criteria: 1. Yeast growing in blood culture is confirmed not to be a Candida spp (may take up to 3 days to identify the organism) 2. Evidence of Candida eye infection (retinopathy or endophthalmitis) on baseline fundoscopic examination (up to day 5 of treatment), or any other complication diagnosed after enrolment but up to day 5. 3. Participant enrolled but later found to be ineligible by any other trial inclusion and exclusion criteria.
Date of first enrolment	01/05/2026
Date of final enrolment	01/05/2030

Locations

Countries of recruitment

South Africa

Study participating centres

Charlotte Maxeke Johannesburg Academic Hospital (CMJAH)

Johannesburg
2193
South Africa

Chris Hani Baragwanath Academic Hospital (CHBAH)

Johannesburg
1864
South Africa

Helen Joseph Hospital (HJH)

Johannesburg
2092
South Africa

Netcare Milpark Hospital (NM)

Johannesburg
2193
South Africa

Wits Donald Gordon Medical Centre (WDGMC)

Johannesburg
2193
South Africa

Results and Publications

Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Data sharing statement to be made available at a later date
IPD sharing plan

Editorial Notes

12/12/2025: Study’s existence confirmed by the Wellcome Trust.