Cryptococcal Optimal ART Timing Trial

Phase 4

Completed

Conditions: AIDS
Cryptococcal Meningitis
HIV Infections

Interventions: Drug: efavirenz
Biological: nucleoside

Registration Number: NCT01075152

Lead Sponsor: University of Minnesota

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 177

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Deferred HIV Therapy	nucleoside	HIV therapy initiated at 5 weeks after cryptococcal meningitis diagnosis (+/- 1 week). HIV therapy consisting of a nucleoside with lamivudine and efavirenz.
Earlier HIV Therapy	nucleoside	HIV therapy initiated at 7-13 days of cryptococcal meningitis diagnosis. HIV therapy consisting of a nucleoside with lamivudine and efavirenz.
Earlier HIV Therapy	efavirenz	HIV therapy initiated at 7-13 days of cryptococcal meningitis diagnosis. HIV therapy consisting of a nucleoside with lamivudine and efavirenz.
Deferred HIV Therapy	efavirenz	HIV therapy initiated at 5 weeks after cryptococcal meningitis diagnosis (+/- 1 week). HIV therapy consisting of a nucleoside with lamivudine and efavirenz.

Primary Outcome Measures

Name	Time	Method
Mortality	26 weeks from study entry	Intention to treat analysis of 26 week survival of all subjects enrolled. Reported below are the numbers of participants who died by Week 26.

Secondary Outcome Measures

Name	Time	Method
Safety of ART Initiation	46 weeks	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.
Karnofsky Functional Status	46 weeks	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
Incidence of Immune Reconstitution Inflammatory Syndrome	46 weeks	Incidence of cryptococcal-related immune reconstitution inflammatory syndrome through 46 weeks after enrollment.
HIV-1 Viral Suppression	26 weeks	HIV-1 virologic suppression to \<400 copies/mL at 26-weeks after enrollment
Antiretroviral Therapy Tolerability	26 weeks	Incidence of antiretroviral therapy interruption by \>=3 consecutive days
46-week Survival	46 weeks	46-week survival by time-to-event analysis of all subjects enrolled
Incidence of Cryptococcal-relapse	46 weeks	Incidence of culture positive cryptococcal meningitis relapse
Microbiologic Clearance	4 weeks	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.

Trial Locations

Locations (3): Mbarara University of Science and Technology
🇺🇬
Mbarara, Uganda
Infectious Disease Institute, Mulago Hospital, Makerere University
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Kampala, Uganda
GF Jooste Hospital
🇿🇦
Cape Town, South Africa