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
  Purpose

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 Intervention Phase
Cryptococcal Meningitis
HIV Infections
AIDS
Drug: efavirenz
Biological: nucleoside backbone
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Trial for the Optimal Timing of HIV Therapy After Cryptococcal Meningitis

Resource links provided by NLM:


Further study details as provided by University of Minnesota - Clinical and Translational Science Institute:

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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.


Other Outcome Measures:
  • 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).


Enrollment: 177
Study Start Date: November 2010
Study Completion Date: March 2013
Primary Completion Date: October 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
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
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.

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

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.

  Eligibility

Ages Eligible for Study:   14 Years and older
Genders Eligible for Study:   Both
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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: 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
University of Cape Town
Investigators
Principal Investigator: David R Boulware, MD, MPH University of Minnesota - Clinical and Translational Science Institute
  More Information

Additional Information:
Publications:

Responsible Party: David Boulware, Lois & Richard King Distinguished Associate Professor, University of Minnesota - Clinical and Translational Science Institute
ClinicalTrials.gov Identifier: NCT01075152     History of Changes
Other Study ID Numbers: DAIDS-ES ID 10795, U01AI089244
Study First Received: February 23, 2010
Results First Received: June 27, 2014
Last Updated: July 31, 2014
Health Authority: United States: Institutional Review Board
United States: Federal Government
Uganda: National Council for Science and Technology
South Africa: Human Research Ethics Committee

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

Additional relevant MeSH terms:
Cryptococcosis
Acquired Immunodeficiency Syndrome
HIV Infections
Meningitis
Meningitis, Cryptococcal
Central Nervous System Diseases
Central Nervous System Fungal Infections
Central Nervous System Infections
Immune System Diseases
Immunologic Deficiency Syndromes
Lentivirus Infections
Meningitis, Fungal
Mycoses
Nervous System Diseases
Retroviridae Infections
RNA Virus Infections
Sexually Transmitted Diseases
Sexually Transmitted Diseases, Viral
Slow Virus Diseases
Virus Diseases
Efavirenz
Lamivudine
Anti-HIV Agents
Anti-Infective Agents
Anti-Retroviral Agents
Antiviral Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors
Pharmacologic Actions

ClinicalTrials.gov processed this record on October 29, 2014