Single Dose Liposomal Amphotericin for Asymptomatic Cryptococcal Antigenemia

Study Overview
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Brief Summary
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This will be a randomized controlled trial of asymptomatic (Cryptococcal Antigen test)CrAg positive persons in Uganda. Patients will be randomized to receive preemptive treatment with 1 dose of liposomal amphotericin (10mg/kg) in addition to standard of care fluconazole therapy. How the enhanced antifungal therapy prevents progression to meningitis in the first 24-weeks and overall survival in those who receive the intervention compared with participants receiving fluconazole per World Health Organisation (WHO) and national standard of care therapy will be evaluated.

Official Title
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Evaluation of CrAg Screening With Enhanced Antifungal Therapy for Asymptomatic CrAg+ Persons

Conditions
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Cryptococcal Meningitis

Intervention / Treatment
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* Drug: Single dose liposomal Amphotericin and Fluconazole
* Drug: Fluconazole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV-1 infection Age > or equal to15 years Ability and willingness to give informed consent. Plasma/Serum cryptococcal antigen (CRAG)+ with a titer 1:160 or greater Exclusion Criteria: Cannot or unlikely to attend regular clinic visits History of cryptococcal infection Symptomatic meningitis (confirmed by CSF CRAG+) >14 days of fluconazole therapy Pregnancy (confirmed by urinary or serum pregnancy test) Current breastfeeding Known allergy to amphotericin

Ages Eligible for Study
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Minimum Age: 15 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single dose liposomal Amphotericin and fluconazole<br>Experimental: Single dose Ambisome 10mg/kg and Fluconazole 800mg for two weeks ,400mg for 8 weeks and 200mg upto 6 months. (standard of care therapy) | Drug: Single dose liposomal Amphotericin and Fluconazole<br>* Intravenous Single dose of 10mg/kg of Ambisome and fluconazole as per WHO guidelines for six months.<br>* Other names: AMBISOME and fluconazole;|
| Active Comparator: fluconazole (standard of care)<br>Standard of care pre-emptive treatment fluconazole 800mg for two weeks ,400mg for 8 weeks and 200mg upto 6 months | Drug: Fluconazole<br>* Fluconazole 800mg for 2 weeks,400mg for 8 weeks and 200mg up to six months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients that develop meningitis in the AMBISOME arm compared to the fluconazole arm. | Comparison will be made between those randomized to single dose liposomal amphotericin + standard of care (fluconazole) vs. standard of care (fluconazole) alone | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of grade 3 to 5 clinical adverse events or serious adverse events | Symptoms causing inability to perform social and functional activities and potentially life threatening symptoms requiring intervention or hospitalization. | within two weeks of enrollment | 
| Number of grade 3 to 5 laboratory adverse events by NIAID DAIDS toxicity scale | Abnormal laboratory findings that meet the DAIDS categorization of grade 3 and 4. | within two weeks of enrollment | 
| Cost-effectiveness of single dose liposomal amphotericin + fluconazole compared to fluconazole preemptive therapy alone, and compared to no preemptive therapy. | what will be the added cost required to treat patients with AMBISOME when assessed in light of the outcomes. | 24 weeks | 
| Number of patients that will survive in the 24-week period. | How many patients will be alive at 24 weeks when the two arms are compared. | 24 weeks |