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):
University of Minnesota - Clinical and Translational Science Institute
ClinicalTrials.gov Identifier:
NCT01075152
First received: February 23, 2010
Last updated: March 4, 2013
Last verified: March 2013

February 23, 2010
March 4, 2013
November 2010
October 2012   (final data collection date for primary outcome measure)
Survival [ Time Frame: 26 weeks from study entry ] [ Designated as safety issue: Yes ]
Intention to treat analysis of 26 week survival of all subjects enrolled.
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: 26 weeks ] [ Designated as safety issue: Yes ]
    Incidence of cryptococcal-related immune reconstitution inflammatory syndrome through 26 weeks after enrollment.
  • Incidence of Cryptococcal-relapse [ Time Frame: 26 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
  • 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
  • Function status [ Time Frame: 46 weeks ] [ Designated as safety issue: No ]
    Function status via Karnofsky performance status score at 4, 26, 46 weeks.
  • Microbiologic Clearance [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
    Microbiologic clearance of cryptococcus as measured by serial quantitative cryptococcal cultures collected at screening, study entry, study day 7, any additional therapeutic lumbar punctures, and/or time of outpatient clinic registration (week 4).
Not Provided
Pre Specified Subgroups [ Time Frame: 46 weeks ] [ Designated as safety issue: No ]
  • Altered mental status, Glasgow Coma Scale <=14 versus 15
  • Antigen burden

    1. Initial Diagnostic CSF quantitative culture
    2. Study entry CSF quantitative cultures
    3. Study entry: CRAG titer >1:2048
    4. Completion of Amphotericin: CSF culture positive (Study Day 7)
    5. Completion of Amphotericin: CRAG titer >1:1024 (Study Day 7)
  • Low antigen burden (CSF culture negative, CSF CRAG positive at study entry)
  • CSF inflammation (CSF WBC, CSF protein) by quartiles
  • CRP at study entry by quartiles; by log2 transformation as continuous variable
  • CD4 < 50 cells/mcL at study entry vs. >50 cells/mcL
  • CD4 at entry by quartiles
  • HIV-1 viral load at entry
  • Renal function (calculated creatinine clearance) at study entry by quartiles
  • Receiving TB treatment at entry
  • ART regimen initially prescribed (documented pre-randomization).
  • Duration/dose of amphotericin 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
  • Other: Early HIV Therapy Initiation
    Treatment strategy of when to initiate first line HIV therapy
    Other Name: HIV
  • Other: Active Comparer Standard HIV Therapy Initiation
    Treatment strategy of when to initiate first line HIV therapy
    Other Name: HIV Drugs
  • Experimental: Early HIV Therapy
    HIV therapy initiated within 48 hours after study entry (at 7-11 days of cryptococcal treatment)
    Intervention: Other: Early HIV Therapy Initiation
  • Active Comparator: Standard HIV Therapy
    HIV therapy initiated at >=4 weeks after study entry (at 7-11 days of cryptococcal meningitis treatment), per the usual standard of care
    Intervention: Other: Active Comparer Standard HIV Therapy Initiation

*   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
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
March 2013

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