AMBITION-cm: AMBIsome Therapy Induction OptimizatioN - Intermittent high dose AmBisome® on a high dose fluconazole backbone for cryptococcal meningitis induction therapy in sub-Saharan Africa

• Register: ISRCTN
• Last refreshed on: 15 March 2021
• Main ID: ISRCTN10248064
• Date of registration: 22/01/2014
• Prospective Registration: Yes
• Primary sponsor: St George's University of London (UK)
• Public title: AMBITION-cm: AMBIsome Therapy Induction OptimizatioN - Intermittent high dose AmBisome® on a high dose fluconazole backbone for cryptococcal meningitis induction therapy in sub-Saharan Africa
• Scientific title: Intermittent high dose AmBisome® on a high dose fluconazole backbone for cryptococcal meningitis induction therapy in sub-Saharan Africa: An adaptive randomized controlled non-inferiority trial
• Date of first enrolment: 01/11/2014
• Target sample size: 1010
• Recruitment status: Completed
• URL: http://isrctn.com/ISRCTN10248064
• Study type: Interventional
• Study design: Adaptive open-label phase II/III randomised non-inferiority trial (Treatment)
• Phase: Phase II/III

Countries of recruitment

Botswana, South Africa, Tanzania, Zimbabwe

Contacts

• Name: Thomas Harrison

Key inclusion & exclusion criteria

Inclusion criteria:
1. Consecutive patients (male and female) 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 agree to participate in the study

Exclusion criteria:
1. Pregnancy or lactation
2. Previous serious reaction to study drugs
3. Already taking antifungals for >48 hours
4. Concomitant medication that is contraindicated with study drugs


Age minimum:
Age maximum:
Gender: Both

Health Condition(s) or Problem(s) studied

HIV-associated cryptococcal meningitis
Infections and Infestations
Human immunodeficiency virus [HIV] disease resulting in other conditions

Intervention(s)

Current interventions as of 24/10/2017:
A trial to compare alternative short course AmBisome® (amphotericin) regimens for the treatment of HIV-associated cryptococcal meningitis.

STEP 1 (EFA endpoint, phase II):
Patients will be randomised into one of four alternative treatment strategies for the initial treatment of HIV-associated cryptococcal meningitis.
1. AmBisome® 10 mg/kg day 1 (single dose)
2. AmBisome® 10 mg/kg day 1, AmBisome® 5 mg/kg day 3 (two doses)
3. AmBisome® 10 mg/kg day 1, AmBisome® 5 mg/kg days 3, and 7 (three doses)
4. AmBisome® 3 mg/kg/d for 14 days (standard dose, 'control arm')

STEP 2 (clinical endpoint, Phase III):

1. L-AmB 10 mg/kg day 1 (“single dose”) given with fluconazole 1200mg/day plus flucytosine 100mg/kg/d for 14-days.
2. Amphotericin B deoxycholate 1 mg/kg/d for 7-days given with flucytosine 100mg/kg/d (standard dose, “control arm”) followed by fluconazole 1200mg/day for 7-days.
All patients also receive fluconazole 1200 mg/d for first 2 weeks, then 800 mg/d until 10 weeks, and 200 mg/d thereafter. ART will be commenced 4-6 weeks after initiation of antifungal therapy.

Previous interventions:
A trial to compare alternative short course AmBisome® (amphotericin) regimens for the treatment of HIV-associated cryptococcal meningitis.

STEP 1 (EFA endpoint, phase II):
Patients will be randomised into one of four alternative treatment strategies for the initial treatment of HIV-associated cryptococcal meningitis.
1. AmBisome® 10 mg/kg day 1 (single dose)

Primary Outcome(s)

Current primary outcome measures as of 24/10/2017:
STEP 1: Early Fungicidal Activity (EFA) in the first 2 weeks of treatment
STEP 2: all-cause mortality within the first 10 weeks after randomization (non-inferiority)

Previous primary outcome measures:
STEP 1: Early Fungicidal Activity (EFA) in the first 2 weeks of treatment
STEP 2: All-cause mortality in the first 14 and 70 days after randomization

Secondary Outcome(s)

Current secondary outcome meaures as of 24/10/2017:
Step 1:
1. Pharmacokinetic (PK) parameters and Pharmacokinetic/Pharmacodynamic (PK/PD) associations of alternative schedules of intermittent high dose Ambisome.
2. Proportion of patients in each arm suffering clinical and laboratory-defined grade iii/iv adverse events; median % change from baseline in laboratory-defined parameters by treatment arm.
3. Health service costs by treatment arm.

Step2:
1. Early Fungicidal Activity
2. Proportions of patients developing clinical and laboratory-defined grade III/IV adverse events; median % change from baseline in laboratory defined parameters
3. PK parameters and PK/PD associations
4. Health service costs by treatment arm
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 / IRIS within the first 10 weeks
8. Disability at 10 weeks

Previous secondary outcome measures:
1. Pharmacokinetic (PK) parameters and Pharmacokinetic/Pharmacodynamic (PK/PD) associations of alternative schedules of intermittent high dose Ambisome.
2. Proportion of patients in each arm suffering clinical and laboratory-defined grade iii/iv adverse events; median % change from baseline in laboratory-defined parameters by treatment arm.
3. Health service costs by treatment arm.

Secondary ID(s)

13.0204 (Sponsor number)

Source(s) of Monetary Support

Gilead (UK) - Investigator Initiated Award (Step 1)

Ethics review

Status:
Approval date:
Contact:

1. UK: London School of Hygiene and Tropical Medicine Research Ethics Committee, approval granted 10/02/2014 2. Botswana: Princess Marina Hospital REC, Health Research Development Committee, Ministry of Health, approval granted 29/06/2014; Health Research Development Committee (HRDC), approval granted 29/07/2014 3. Tanzania: Bugando Medical Centre/Catholic University of Health and Allied Sciences (BMC/CUHAS) Research Ethics Committee,

Results

• Results available: Yes
• Date Completed: 30/11/2017