Cryptococcal Optimal ART Timing Trial

Study Overview
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Brief Summary
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The Cryptococcal Optimal ART Timing (COAT) trial seeks to determine after cryptococcal meningitis (CM) whether early initiation of antiretroviral therapy (ART) prior to hospital discharge results in superior survival compared to standard initiation of ART started as an outpatient.

Detailed Description
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After 7-11 days of amphotericin B therapy, subjects will be randomized in a 1:1 allocation to: Early initiation of ART (Experimental Group) = ART initiated within 48 hours after study entry, OR Standard initiation of ART (Control Group) = ART at >=4 weeks after study entry HIV therapy will be with efavirenz plus nucleoside backbone per national guidelines for first line therapy.

Official Title
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Trial for the Optimal Timing of HIV Therapy After Cryptococcal Meningitis

Conditions
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Cryptococcal Meningitis, HIV Infections, AIDS

Intervention / Treatment
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* Drug: efavirenz
* Biological: nucleoside


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV-infection, documented by ELISA Antiretroviral medication naïve (excluding mother-to-child transmission therapy) Age >14 years Cryptococcal meningitis diagnosed by either culture or CSF cryptococcal antigen (CRAG) Ability and willingness of the participant or legal guardian/representative to give informed consent. Receiving amphotericin-based anti-fungal therapy Exclusion Criteria: Study entry prior to receipt of <7 days or >11 days of amphotericin therapy History of prior, known cryptococcal meningitis Inability to take enteral medication Receiving chemotherapy or other immunosuppressant medications Cannot or unlikely to attend regular clinic visits Contraindication to immediate or delayed HIV therapy based on serious co-morbidities or co-infections, or laboratory values Pregnancy or Breastfeeding Female participants of childbearing potential who are participating in sexual activity that could lead to pregnancy must agree to use two reliable methods of contraception

Ages Eligible for Study
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Minimum Age: 14 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Earlier HIV Therapy<br>HIV therapy initiated at 7-13 days of cryptococcal meningitis diagnosis. HIV therapy consisting of a nucleoside with lamivudine and efavirenz. | Drug: efavirenz<br>* Treatment strategy of when to initiate first line HIV therapy after cryptococcal meningitis diagnosis.<br>* Other names: sustiva;Biological: nucleoside<br>* Treatment strategy of when to initiate first line HIV therapy after cryptococcal meningitis diagnosis.<br>* Other names: lamivudine;|
| Active Comparator: Deferred HIV Therapy<br>HIV therapy initiated at 5 weeks after cryptococcal meningitis diagnosis (+/- 1 week). HIV therapy consisting of a nucleoside with lamivudine and efavirenz. | Drug: efavirenz<br>* Treatment strategy of when to initiate first line HIV therapy after cryptococcal meningitis diagnosis.<br>* Other names: sustiva;Biological: nucleoside<br>* Treatment strategy of when to initiate first line HIV therapy after cryptococcal meningitis diagnosis.<br>* Other names: lamivudine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality | Intention to treat analysis of 26 week survival of all subjects enrolled. Reported below are the numbers of participants who died by Week 26. | 26 weeks from study entry | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Immune Reconstitution Inflammatory Syndrome | Incidence of cryptococcal-related immune reconstitution inflammatory syndrome through 46 weeks after enrollment. | 46 weeks | 
| Incidence of Cryptococcal-relapse | Incidence of culture positive cryptococcal meningitis relapse | 46 weeks | 
| Safety of ART Initiation | Incidence of Adverse Events (Grade 3,4,5) through 46-weeks, as defined by the National Institute of Allergy and Infectious Diseases, Division of AIDS toxicity classification scale, version 2009. | 46 weeks | 
| 46-week Survival | 46-week survival by time-to-event analysis of all subjects enrolled | 46 weeks | 
| HIV-1 Viral Suppression | HIV-1 virologic suppression to <400 copies/mL at 26-weeks after enrollment | 26 weeks | 
| Antiretroviral Therapy Tolerability | Incidence of antiretroviral therapy interruption by >=3 consecutive days | 26 weeks | 
| Karnofsky Functional Status | Functional status via Karnofsky performance status score at 4, 26, 46 weeks. Karnofsky Scale: 100 - Normal; no complaints; no evidence of disease. 90 - Able to carry on normal activity; minor signs or symptoms of disease. 80 - Normal activity with effort; some signs or symptoms of disease. 70 - Cares for self; unable to carry on normal activity or to do active work. 60 - Requires occasional assistance, but is able to care for most of his personal needs. 50 - Requires considerable assistance and frequent medical care. 40 - Disabled; requires special care and assistance. 30 - Severely disabled; hospital admission is indicated although death not imminent. 20 - Very sick; hospital admission necessary; active supportive treatment necessary. 10 - Moribund; fatal processes progressing rapidly. 0 - Dead | 46 weeks | 
| Microbiologic Clearance | Microbiologic clearance of cryptococcus as measured by serial quantitative cryptococcal cultures collected at diagnosis through 14 days of amphotericin therapy. The early fungicidal activity (EFA) of the rate of clearance is expressed as log10 colony forming units (CFU) of Cryptococcus neoformans per mL of CSF per day. | 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cryptococcal meningitis, cryptococcus, cryptococcosis, HIV, AIDS, strategy