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Cryptococcal Optimal ART Timing Trial (COAT)

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ClinicalTrials.gov Identifier: NCT01075152
Recruitment Status : Completed
First Posted : February 24, 2010
Results First Posted : August 20, 2014
Last Update Posted : August 26, 2015
Sponsor:
Collaborators:
Mbarara University of Science and Technology
Makerere University
National Institute of Allergy and Infectious Diseases (NIAID)
University of Cape Town
Information provided by (Responsible Party):
University of Minnesota - Clinical and Translational Science Institute

Study Description
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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.

Condition or disease Intervention/treatment Phase
Cryptococcal Meningitis HIV Infections AIDS Drug: efavirenz Biological: nucleoside Phase 4

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.


Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 177 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Trial for the Optimal Timing of HIV Therapy After Cryptococcal Meningitis
Study Start Date : November 2010
Actual Primary Completion Date : October 2012
Actual Study Completion Date : March 2013

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS Meningitis
Drug Information available for: Efavirenz

Arms and Interventions
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Arm Intervention/treatment
Experimental: Earlier HIV Therapy
HIV therapy initiated at 7-13 days of cryptococcal meningitis diagnosis. HIV therapy consisting of a nucleoside with lamivudine and efavirenz.
 Drug: efavirenz
Treatment strategy of when to initiate first line HIV therapy after cryptococcal meningitis diagnosis.
Other Name: sustiva

Biological: nucleoside
Treatment strategy of when to initiate first line HIV therapy after cryptococcal meningitis diagnosis.
Other Names:
  • zidovudine or stavudine
  • lamivudine
Active Comparator: Deferred HIV Therapy

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

HIV therapy consisting of a nucleoside with lamivudine and efavirenz.

 Drug: efavirenz
Treatment strategy of when to initiate first line HIV therapy after cryptococcal meningitis diagnosis.
Other Name: sustiva

Biological: nucleoside
Treatment strategy of when to initiate first line HIV therapy after cryptococcal meningitis diagnosis.
Other Names:
  • zidovudine or stavudine
  • lamivudine


Outcome Measures
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Primary Outcome Measures :
  1. Mortality [ Time Frame: 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 :
  1. Incidence of Immune Reconstitution Inflammatory Syndrome [ Time Frame: 46 weeks ]
    Incidence of cryptococcal-related immune reconstitution inflammatory syndrome through 46 weeks after enrollment.

  2. Incidence of Cryptococcal-relapse [ Time Frame: 46 weeks ]
    Incidence of culture positive cryptococcal meningitis relapse

  3. Safety of ART Initiation [ Time Frame: 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.

  4. 46-week Survival [ Time Frame: 46 weeks ]
    46-week survival by time-to-event analysis of all subjects enrolled

  5. HIV-1 Viral Suppression [ Time Frame: 26 weeks ]
    HIV-1 virologic suppression to <400 copies/mL at 26-weeks after enrollment

  6. Antiretroviral Therapy Tolerability [ Time Frame: 26 weeks ]
    Incidence of antiretroviral therapy interruption by >=3 consecutive days

  7. Karnofsky Functional Status [ Time Frame: 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


  8. Microbiologic Clearance [ Time Frame: 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.


Other Outcome Measures:
  1. Percentage of Participants, Per CSF WBC Subgroup, Who Died by Week 26 [ Time Frame: 26 weeks ]
    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).


Eligibility Criteria
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Ages Eligible for Study:   14 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01075152


Locations
South Africa
GF Jooste Hospital
Cape Town, South Africa
Uganda
Infectious Disease Institute, Mulago Hospital, Makerere University
Kampala, Uganda
Mbarara University of Science and Technology
Mbarara, Uganda
Sponsors and Collaborators
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
Investigators
Principal Investigator: David R Boulware, MD, MPH University of Minnesota - Clinical and Translational Science Institute
More Information
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Additional Information:
N Engl J Med 2014 - Final Results  This link exits the ClinicalTrials.gov site

Publications of Results:

Other Publications:

Responsible Party: University of Minnesota - Clinical and Translational Science Institute
ClinicalTrials.gov Identifier: NCT01075152     History of Changes
Other Study ID Numbers: DAIDS-ES ID 10795
U01AI089244 ( U.S. NIH Grant/Contract )
First Posted: February 24, 2010    Key Record Dates
Results First Posted: August 20, 2014
Last Update Posted: August 26, 2015
Last Verified: August 2015

Keywords provided by University of Minnesota - Clinical and Translational Science Institute:
cryptococcal meningitis
cryptococcus
cryptococcosis
 HIV
AIDS
strategy

Additional relevant MeSH terms:
HIV Infections
Meningitis
Meningitis, Cryptococcal
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Central Nervous System Diseases
Nervous System Diseases
Meningitis, Fungal
Central Nervous System Fungal Infections
 Mycoses
Cryptococcosis
Central Nervous System Infections
Lamivudine
Efavirenz
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Anti-HIV Agents
Cytochrome P-450 CYP2C9 Inhibitors
Cytochrome P-450 Enzyme Inhibitors