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Cryptococcal Optimal ART Timing Trial (COAT)

This study has been completed.
Sponsor:
Collaborators:
Mbarara University of Science and Technology
Makerere University
University of Cape Town
Information provided by (Responsible Party):
David Boulware, University of Minnesota - Clinical and Translational Science Institute
ClinicalTrials.gov Identifier:
NCT01075152
First received: February 23, 2010
Last updated: July 31, 2014
Last verified: July 2014

February 23, 2010
July 31, 2014
November 2010
October 2012   (final data collection date for primary outcome measure)
Mortality [ Time Frame: 26 weeks from study entry ] [ Designated as safety issue: Yes ]
Intention to treat analysis of 26 week survival of all subjects enrolled. Reported below are the numbers of participants who died by Week 26.
Survival [ Time Frame: 26 weeks from study entry ] [ Designated as safety issue: Yes ]
Complete list of historical versions of study NCT01075152 on ClinicalTrials.gov Archive Site
  • Incidence of Immune Reconstitution Inflammatory Syndrome [ Time Frame: 46 weeks ] [ Designated as safety issue: Yes ]
    Incidence of cryptococcal-related immune reconstitution inflammatory syndrome through 46 weeks after enrollment.
  • Incidence of Cryptococcal-relapse [ Time Frame: 46 weeks ] [ Designated as safety issue: Yes ]
    Incidence of culture positive cryptococcal meningitis relapse
  • Safety of ART Initiation [ Time Frame: 46 weeks ] [ Designated as safety issue: Yes ]
    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-week Survival [ Time Frame: 46 weeks ] [ Designated as safety issue: Yes ]
    46-week survival by time-to-event analysis of all subjects enrolled
  • HIV-1 Viral Suppression [ Time Frame: 26 weeks ] [ Designated as safety issue: Yes ]
    HIV-1 virologic suppression to <400 copies/mL at 26-weeks after enrollment
  • Antiretroviral Therapy Tolerability [ Time Frame: 26 weeks ] [ Designated as safety issue: Yes ]
    Incidence of antiretroviral therapy interruption by >=3 consecutive days
  • Karnofsky Functional Status [ Time Frame: 46 weeks ] [ Designated as safety issue: No ]

    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

  • Microbiologic Clearance [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
    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.
Not Provided
Percentage of Participants, Per CSF WBC Subgroup, Who Died by Week 26 [ Time Frame: 26 weeks ] [ Designated as safety issue: No ]
Percentage of Participants who died by week 26 based on CSF white blood cell (WBC) count at study entry (time of randomization at a median of 8 days of anti-fungal therapy).
Not Provided
 
Cryptococcal Optimal ART Timing Trial
Trial for the Optimal Timing of HIV Therapy After Cryptococcal Meningitis

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.

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.

Interventional
Phase 4
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Outcomes Assessor)
Primary Purpose: Treatment
  • Cryptococcal Meningitis
  • HIV Infections
  • AIDS
  • Drug: efavirenz
    Treatment strategy of when to initiate first line HIV therapy after cryptococcal meningitis diagnosis.
    Other Name: sustiva
  • Biological: nucleoside backbone
    Treatment strategy of when to initiate first line HIV therapy after cryptococcal meningitis diagnosis.
    Other Names:
    • zidovudine or stavudine
    • lamivudine
  • Experimental: Earlier HIV Therapy
    HIV therapy initiated at 7-13 days of cryptococcal meningitis diagnosis. HIV therapy consistent of a nucleoside with lamivudine and efavirenz.
    Interventions:
    • Drug: efavirenz
    • Biological: nucleoside backbone
  • Active Comparator: Deferred HIV Therapy

    HIV therapy initiated at 5 weeks after cryptococcal meningitis diagnosis (+/- 1 week).

    HIV therapy consistent of a nucleoside with lamivudine and efavirenz.

    Interventions:
    • Drug: efavirenz
    • Biological: nucleoside backbone

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
177
March 2013
October 2012   (final data collection date for primary outcome measure)

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
Both
14 Years and older
No
Contact information is only displayed when the study is recruiting subjects
South Africa,   Uganda
 
NCT01075152
DAIDS-ES ID 10795, U01AI089244
Yes
David Boulware, University of Minnesota - Clinical and Translational Science Institute
University of Minnesota - Clinical and Translational Science Institute
  • Mbarara University of Science and Technology
  • Makerere University
  • National Institute of Allergy and Infectious Diseases (NIAID)
  • University of Cape Town
Principal Investigator: David R Boulware, MD, MPH University of Minnesota - Clinical and Translational Science Institute
University of Minnesota - Clinical and Translational Science Institute
July 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP