Cryptococcal Optimal ART Timing Trial (COAT)

June 2, 2020 updated by: University of Minnesota

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

177

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • South Africa
      • Cape Town, South Africa
        • GF Jooste Hospital
  • Uganda
      • Kampala, Uganda
        • Infectious Disease Institute, Mulago Hospital, Makerere University
      • Mbarara, Uganda
        • Mbarara University of Science and Technology

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

14 years and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
26 weeks from study entry

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of Immune Reconstitution Inflammatory Syndrome
Time Frame: 46 weeks
Incidence of cryptococcal-related immune reconstitution inflammatory syndrome through 46 weeks after enrollment.
46 weeks
Incidence of Cryptococcal-relapse
Time Frame: 46 weeks
Incidence of culture positive cryptococcal meningitis relapse
46 weeks
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.
46 weeks
46-week Survival
Time Frame: 46 weeks
46-week survival by time-to-event analysis of all subjects enrolled
46 weeks
HIV-1 Viral Suppression
Time Frame: 26 weeks
HIV-1 virologic suppression to <400 copies/mL at 26-weeks after enrollment
26 weeks
Antiretroviral Therapy Tolerability
Time Frame: 26 weeks
Incidence of antiretroviral therapy interruption by >=3 consecutive days
26 weeks
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
46 weeks
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.
4 weeks

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
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).
26 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Minnesota

Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)
Makerere University
University of Cape Town
Mbarara University of Science and Technology

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

November 1, 2010

Primary Completion (Actual)

October 1, 2012

Study Completion (Actual)

March 1, 2013

Study Registration Dates

First Submitted

February 23, 2010

First Submitted That Met QC Criteria

February 23, 2010

First Posted (Estimate)

February 24, 2010

Study Record Updates

Last Update Posted (Actual)

June 9, 2020

Last Update Submitted That Met QC Criteria

June 2, 2020

Last Verified

June 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 0810M49622
  • U01AI089244 (U.S. NIH Grant/Contract)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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