High dose AMBISOME on a fluconazole backbone for cryptococcal meningitis induction therapy in sub-Saharan Africa

• Register: ISRCTN
• Last refreshed on: 5 December 2022
• Main ID: ISRCTN72509687
• Date of registration: 13/07/2017
• Prospective Registration: Yes
• Primary sponsor: London School of Hygiene and Tropical Medicine
• Public title: High dose AMBISOME on a fluconazole backbone for cryptococcal meningitis induction therapy in sub-Saharan Africa
• Scientific title: High dose AMBISOME on a fluconazole backbone for cryptococcal meningitis induction therapy in sub-Saharan Africa: a Phase 3 randomised controlled non-Inferiority trial
• Date of first enrolment: 01/09/2017
• Target sample size: 850
• Recruitment status: Completed
• URL: https://www.isrctn.com/ISRCTN72509687
• Study type: Interventional
• Study design: Randomised controlled trial (Treatment)
• Phase: Phase III

Countries of recruitment

Botswana, Malawi, South Africa, Uganda, Zimbabwe

Contacts

• Name: Joe Jarvis

Key inclusion & exclusion criteria

Inclusion criteria:
1. Consecutive patients aged > 18 years with a first episode of cryptococcal meningitis (CSF India ink or CrAg test)
2. Known to be HIV positive or willing to undertake an HIV test
3. Willing to participate in the study or, if unable to consent, has a next of kin who agrees to the patient participating in the study

Exclusion criteria:
1. Pregnancy (confirmed by urinary or serum pregnancy test) or lactation
2. Previous serious reaction to study drugs
3. Already taking antifungal treatment at cryptococcal meningitis treatment doses (amphotericin B =0.7mg/kg or fluconazole =800mg/day) for >48 hours
4. Concomitant medication that is contraindicated with study drugs
5. HIV negative


Age minimum:
Age maximum:
Gender: Both

Health Condition(s) or Problem(s) studied

Cryptococcal meningitis in HIV patients
Infections and Infestations
Cerebral cryptococcosis

Intervention(s)

Current interventions as of 01/08/2018:
850 patients will be enrolled and randomised 1:1 into two arms:
1. L-AmB 10 mg/kg day 1 (single dose)
2. Amphotericin-B 1mg/kg/d for 7 days (standard dose “control arm”)
The intake will take place over a 3-year period, and follow-up will occur for 16 weeks after the start of treatment.

Previous interventions:
850 patients will be enrolled and randomised 1:1 into two arms:
1. L-AmB 10 mg/kg day 1 (single dose)
2. Amphotericin-B 1mg/kg/d for 14 days (standard dose “control arm”)
The intake will take place over a 3-year period, and follow-up will occur for 16 weeks after the start of treatment.

Randomisation
Patients will be randomised individually and randomisation codes will be generated using SAS PROC PLAN via permuted-block randomisation method stratified by site. Block sizes will vary at 4 and 6. Randomisation lists will be created for each site by an independent statistician and each list will be housed on the electronic database system (EDC) for that particular site, and will be inaccessible to trial staff except to randomise the next eligible participant. Randomised allocation for each trial participant will be provided to trial staff by extracting the next available randomisation allocation, obtained from the randomisation list for that site housed on the database. Internally the EDC selects against an electronic randomization list prepared in advance by the Statistician. The EDC guarantees to make the selection in the natural order of the list filtering by study site only. Once a selection is made, the randomization record is tagged

Primary Outcome(s)

All-cause mortality within the first 10 weeks after randomisation (non-inferiority)

Secondary Outcome(s)

1. Early fungicidal activity, derived from serial lumbar punctures on days 1, 7 and 14
2. Clinical and laboratory-defined grade III/IV adverse events; median % change from baseline in laboratory defined parameters as and when AEs occur
3. Pharmacokinetic parameters and pharmacokinetic/pharmcodynamic associations of single high-dose L-AmB at 3, 6, 8 and 24 hours post L-AmB dose
4. Health service costs within the first 10 weeks
5. All-cause mortality within the first 2 and 4 weeks
6. All-cause mortality within the first 10 weeks (superiority)
7. Rates of cryptococcal relapse/immune reconstitution inflammatory syndrome within the first 10 weeks
8. Disability, measured using a simple two-question assessment and modified Rankin Score at 10 weeks

Secondary ID(s)

Ambition P3

Source(s) of Monetary Support

European and Developing Countries Clinical Trials Partnership, Wellcome Trust, Medical Research Council, Department for International Development Joint Global Health Trials (JGHT)

Ethics review

Status:
Approval date:
Contact:

LSHTM Interventional Committee Review Board, 09/06/2017, ref: 14322

Results

• Results available: Yes
• Date Completed: 30/06/2021