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Cryptococcal Optimal ART Timing Trial (COAT)

Primary Purpose

Cryptococcal Meningitis, HIV Infections, AIDS

Status
Completed
Phase
Phase 4
Locations
International
Study Type
Interventional
Intervention
efavirenz
nucleoside
Sponsored by
University of Minnesota
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cryptococcal Meningitis focused on measuring cryptococcal meningitis, cryptococcus, cryptococcosis, HIV, AIDS, strategy

Eligibility Criteria

14 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • GF Jooste Hospital
  • Infectious Disease Institute, Mulago Hospital, Makerere University
  • Mbarara University of Science and Technology

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Earlier HIV Therapy

Deferred HIV Therapy

Arm Description

HIV therapy initiated at 7-13 days of cryptococcal meningitis diagnosis. HIV therapy consisting of a nucleoside with lamivudine and efavirenz.

HIV therapy initiated at 5 weeks after cryptococcal meningitis diagnosis (+/- 1 week). HIV therapy consisting of a nucleoside with lamivudine and efavirenz.

Outcomes

Primary Outcome Measures

Mortality
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
Incidence of cryptococcal-related immune reconstitution inflammatory syndrome through 46 weeks after enrollment.
Incidence of Cryptococcal-relapse
Incidence of culture positive cryptococcal meningitis relapse
Safety of ART Initiation
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
46-week survival by time-to-event analysis of all subjects enrolled
HIV-1 Viral Suppression
HIV-1 virologic suppression to <400 copies/mL at 26-weeks after enrollment
Antiretroviral Therapy Tolerability
Incidence of antiretroviral therapy interruption by >=3 consecutive days
Karnofsky Functional Status
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
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.

Full Information

First Posted
February 23, 2010
Last Updated
June 2, 2020
Sponsor
University of Minnesota
Collaborators
Mbarara University of Science and Technology, Makerere University, National Institute of Allergy and Infectious Diseases (NIAID), University of Cape Town
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1. Study Identification

Unique Protocol Identification Number
NCT01075152
Brief Title
Cryptococcal Optimal ART Timing Trial
Acronym
COAT
Official Title
Trial for the Optimal Timing of HIV Therapy After Cryptococcal Meningitis
Study Type
Interventional

2. Study Status

Record Verification Date
June 2020
Overall Recruitment Status
Completed
Study Start Date
November 2010 (undefined)
Primary Completion Date
October 2012 (Actual)
Study Completion Date
March 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Minnesota
Collaborators
Mbarara University of Science and Technology, Makerere University, National Institute of Allergy and Infectious Diseases (NIAID), University of Cape Town

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cryptococcal Meningitis, HIV Infections, AIDS
Keywords
cryptococcal meningitis, cryptococcus, cryptococcosis, HIV, AIDS, strategy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
Outcomes Assessor
Allocation
Randomized
Enrollment
177 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Earlier HIV Therapy
Arm Type
Experimental
Arm Description
HIV therapy initiated at 7-13 days of cryptococcal meningitis diagnosis. HIV therapy consisting of a nucleoside with lamivudine and efavirenz.
Arm Title
Deferred HIV Therapy
Arm Type
Active Comparator
Arm Description
HIV therapy initiated at 5 weeks after cryptococcal meningitis diagnosis (+/- 1 week). HIV therapy consisting of a nucleoside with lamivudine and efavirenz.
Intervention Type
Drug
Intervention Name(s)
efavirenz
Other Intervention Name(s)
sustiva
Intervention Description
Treatment strategy of when to initiate first line HIV therapy after cryptococcal meningitis diagnosis.
Intervention Type
Biological
Intervention Name(s)
nucleoside
Other Intervention Name(s)
zidovudine or stavudine, lamivudine
Intervention Description
Treatment strategy of when to initiate first line HIV therapy after cryptococcal meningitis diagnosis.
Primary Outcome Measure Information:
Title
Mortality
Description
Intention to treat analysis of 26 week survival of all subjects enrolled. Reported below are the numbers of participants who died by Week 26.
Time Frame
26 weeks from study entry
Secondary Outcome Measure Information:
Title
Incidence of Immune Reconstitution Inflammatory Syndrome
Description
Incidence of cryptococcal-related immune reconstitution inflammatory syndrome through 46 weeks after enrollment.
Time Frame
46 weeks
Title
Incidence of Cryptococcal-relapse
Description
Incidence of culture positive cryptococcal meningitis relapse
Time Frame
46 weeks
Title
Safety of ART Initiation
Description
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.
Time Frame
46 weeks
Title
46-week Survival
Description
46-week survival by time-to-event analysis of all subjects enrolled
Time Frame
46 weeks
Title
HIV-1 Viral Suppression
Description
HIV-1 virologic suppression to <400 copies/mL at 26-weeks after enrollment
Time Frame
26 weeks
Title
Antiretroviral Therapy Tolerability
Description
Incidence of antiretroviral therapy interruption by >=3 consecutive days
Time Frame
26 weeks
Title
Karnofsky Functional Status
Description
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
Time Frame
46 weeks
Title
Microbiologic Clearance
Description
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.
Time Frame
4 weeks
Other Pre-specified Outcome Measures:
Title
Percentage of Participants, Per CSF WBC Subgroup, Who Died by Week 26
Description
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).
Time Frame
26 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
14 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
David R Boulware, MD, MPH
Organizational Affiliation
University of Minnesota
Official's Role
Principal Investigator
Facility Information:
Facility Name
GF Jooste Hospital
City
Cape Town
Country
South Africa
Facility Name
Infectious Disease Institute, Mulago Hospital, Makerere University
City
Kampala
Country
Uganda
Facility Name
Mbarara University of Science and Technology
City
Mbarara
Country
Uganda

12. IPD Sharing Statement

Citations:
PubMed Identifier
24655747
Citation
Rajasingham R, Williams D, Meya DB, Meintjes G, Boulware DR, Scriven J. Nosocomial drug-resistant bacteremia in 2 cohorts with cryptococcal meningitis, Africa. Emerg Infect Dis. 2014 Apr;20(4):722-4. doi: 10.3201/eid2004.131277. No abstract available.
Results Reference
background
PubMed Identifier
24399496
Citation
Carlson RD, Rolfes MA, Birkenkamp KE, Nakasujja N, Rajasingham R, Meya DB, Boulware DR. Predictors of neurocognitive outcomes on antiretroviral therapy after cryptococcal meningitis: a prospective cohort study. Metab Brain Dis. 2014 Jun;29(2):269-279. doi: 10.1007/s11011-013-9476-1. Epub 2014 Jan 9.
Results Reference
background
PubMed Identifier
24378231
Citation
Boulware DR, Rolfes MA, Rajasingham R, von Hohenberg M, Qin Z, Taseera K, Schutz C, Kwizera R, Butler EK, Meintjes G, Muzoora C, Bischof JC, Meya DB. Multisite validation of cryptococcal antigen lateral flow assay and quantification by laser thermal contrast. Emerg Infect Dis. 2014 Jan;20(1):45-53. doi: 10.3201/eid2001.130906.
Results Reference
background
PubMed Identifier
24065327
Citation
Kabanda T, Siedner MJ, Klausner JD, Muzoora C, Boulware DR. Point-of-care diagnosis and prognostication of cryptococcal meningitis with the cryptococcal antigen lateral flow assay on cerebrospinal fluid. Clin Infect Dis. 2014 Jan;58(1):113-6. doi: 10.1093/cid/cit641. Epub 2013 Sep 24.
Results Reference
background
PubMed Identifier
23945372
Citation
Robertson EJ, Najjuka G, Rolfes MA, Akampurira A, Jain N, Anantharanjit J, von Hohenberg M, Tassieri M, Carlsson A, Meya DB, Harrison TS, Fries BC, Boulware DR, Bicanic T. Cryptococcus neoformans ex vivo capsule size is associated with intracranial pressure and host immune response in HIV-associated cryptococcal meningitis. J Infect Dis. 2014 Jan 1;209(1):74-82. doi: 10.1093/infdis/jit435. Epub 2013 Aug 14.
Results Reference
background
PubMed Identifier
23466647
Citation
Durski KN, Kuntz KM, Yasukawa K, Virnig BA, Meya DB, Boulware DR. Cost-effective diagnostic checklists for meningitis in resource-limited settings. J Acquir Immune Defic Syndr. 2013 Jul 1;63(3):e101-8. doi: 10.1097/QAI.0b013e31828e1e56.
Results Reference
background
PubMed Identifier
23055838
Citation
Rajasingham R, Rolfes MA, Birkenkamp KE, Meya DB, Boulware DR. Cryptococcal meningitis treatment strategies in resource-limited settings: a cost-effectiveness analysis. PLoS Med. 2012;9(9):e1001316. doi: 10.1371/journal.pmed.1001316. Epub 2012 Sep 25.
Results Reference
background
PubMed Identifier
25057102
Citation
Rolfes MA, Hullsiek KH, Rhein J, Nabeta HW, Taseera K, Schutz C, Musubire A, Rajasingham R, Williams DA, Thienemann F, Muzoora C, Meintjes G, Meya DB, Boulware DR. The effect of therapeutic lumbar punctures on acute mortality from cryptococcal meningitis. Clin Infect Dis. 2014 Dec 1;59(11):1607-14. doi: 10.1093/cid/ciu596. Epub 2014 Jul 23. Erratum In: Clin Infect Dis. 2015 May 1;60(9):1449.
Results Reference
background
PubMed Identifier
25651842
Citation
Scriven JE, Rhein J, Hullsiek KH, von Hohenberg M, Linder G, Rolfes MA, Williams DA, Taseera K, Meya DB, Meintjes G, Boulware DR; COAT Team. Early ART After Cryptococcal Meningitis Is Associated With Cerebrospinal Fluid Pleocytosis and Macrophage Activation in a Multisite Randomized Trial. J Infect Dis. 2015 Sep 1;212(5):769-78. doi: 10.1093/infdis/jiv067. Epub 2015 Feb 4.
Results Reference
background
PubMed Identifier
25838287
Citation
Williams DA, Kiiza T, Kwizera R, Kiggundu R, Velamakanni S, Meya DB, Rhein J, Boulware DR. Evaluation of fingerstick cryptococcal antigen lateral flow assay in HIV-infected persons: a diagnostic accuracy study. Clin Infect Dis. 2015 Aug 1;61(3):464-7. doi: 10.1093/cid/civ263. Epub 2015 Apr 1.
Results Reference
background
PubMed Identifier
25385864
Citation
Rajasingham R, Rhein J, Klammer K, Musubire A, Nabeta H, Akampurira A, Mossel EC, Williams DA, Boxrud DJ, Crabtree MB, Miller BR, Rolfes MA, Tengsupakul S, Andama AO, Meya DB, Boulware DR. Epidemiology of meningitis in an HIV-infected Ugandan cohort. Am J Trop Med Hyg. 2015 Feb;92(2):274-9. doi: 10.4269/ajtmh.14-0452. Epub 2014 Nov 10.
Results Reference
background
PubMed Identifier
25734161
Citation
Nabeta HW, Bahr NC, Rhein J, Fossland N, Kiragga AN, Meya DB, Dunlop SJ, Boulware DR. Accuracy of noninvasive intraocular pressure or optic nerve sheath diameter measurements for predicting elevated intracranial pressure in cryptococcal meningitis. Open Forum Infect Dis. 2014 Oct 11;1(3):ofu093. doi: 10.1093/ofid/ofu093. eCollection 2014 Dec.
Results Reference
background
PubMed Identifier
25492918
Citation
Meya DB, Okurut S, Zziwa G, Rolfes MA, Kelsey M, Cose S, Joloba M, Naluyima P, Palmer BE, Kambugu A, Mayanja-Kizza H, Bohjanen PR, Eller MA, Wahl SM, Boulware DR, Manabe YC, Janoff EN. Cellular immune activation in cerebrospinal fluid from ugandans with cryptococcal meningitis and immune reconstitution inflammatory syndrome. J Infect Dis. 2015 May 15;211(10):1597-606. doi: 10.1093/infdis/jiu664. Epub 2014 Dec 9.
Results Reference
background
PubMed Identifier
25734140
Citation
Bahr NC, Rolfes MA, Musubire A, Nabeta H, Williams DA, Rhein J, Kambugu A, Meya DB, Boulware DR. Standardized electrolyte supplementation and fluid management improves survival during amphotericin therapy for cryptococcal meningitis in resource-limited settings. Open Forum Infect Dis. 2014 Aug 25;1(2):ofu070. doi: 10.1093/ofid/ofu070. eCollection 2014 Sep.
Results Reference
background
PubMed Identifier
25078453
Citation
Kwizera R, Nguna J, Kiragga A, Nakavuma J, Rajasingham R, Boulware DR, Meya DB. Performance of cryptococcal antigen lateral flow assay using saliva in Ugandans with CD4 <100. PLoS One. 2014 Jul 31;9(7):e103156. doi: 10.1371/journal.pone.0103156. eCollection 2014.
Results Reference
background
PubMed Identifier
24963568
Citation
Boulware DR, Meya DB, Muzoora C, Rolfes MA, Huppler Hullsiek K, Musubire A, Taseera K, Nabeta HW, Schutz C, Williams DA, Rajasingham R, Rhein J, Thienemann F, Lo MW, Nielsen K, Bergemann TL, Kambugu A, Manabe YC, Janoff EN, Bohjanen PR, Meintjes G; COAT Trial Team. Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis. N Engl J Med. 2014 Jun 26;370(26):2487-98. doi: 10.1056/NEJMoa1312884.
Results Reference
result
PubMed Identifier
32843994
Citation
Kwizera R, Sadiq A, Ndyetukira JF, Nalintya E, Williams D, Rhein J, Boulware DR, Meya DB; COAT and ASTRO trial teams. Impact of community engagement and social support on the outcomes of HIV-related meningitis clinical trials in a resource-limited setting. Res Involv Engagem. 2020 Aug 20;6:49. doi: 10.1186/s40900-020-00228-z. eCollection 2020.
Results Reference
derived
PubMed Identifier
31504335
Citation
Skipper C, Schleiss MR, Bangdiwala AS, Hernandez-Alvarado N, Taseera K, Nabeta HW, Musubire AK, Lofgren SM, Wiesner DL, Rhein J, Rajasingham R, Schutz C, Meintjes G, Muzoora C, Meya DB, Boulware DR. Cytomegalovirus Viremia Associated With Increased Mortality in Cryptococcal Meningitis in Sub-Saharan Africa. Clin Infect Dis. 2020 Jul 27;71(3):525-531. doi: 10.1093/cid/ciz864.
Results Reference
derived
PubMed Identifier
31319498
Citation
Bayiyana A, Okurut S, Nabatanzi R, Zziwa G, Boulware DR, Lutwama F, Meya D. Longitudinal Changes in Cd4+, Cd8+ T Cell Phenotype and Activation Marker Expression Following Antiretroviral Therapy Initiation among Patients with Cryptococcal Meningitis. J Fungi (Basel). 2019 Jul 17;5(3):63. doi: 10.3390/jof5030063.
Results Reference
derived
PubMed Identifier
30325463
Citation
Tugume L, Rhein J, Hullsiek KH, Mpoza E, Kiggundu R, Ssebambulidde K, Schutz C, Taseera K, Williams DA, Abassi M, Muzoora C, Musubire AK, Meintjes G, Meya DB, Boulware DR; COAT and ASTRO-CM teams. HIV-Associated Cryptococcal Meningitis Occurring at Relatively Higher CD4 Counts. J Infect Dis. 2019 Feb 23;219(6):877-883. doi: 10.1093/infdis/jiy602.
Results Reference
derived
Links:
URL
http://www.niaid.nih.gov/news/QA/Pages/COATqa.aspx
Description
NIH NIAID FAQ on COAT Trial (Preliminary Results)

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Cryptococcal Optimal ART Timing Trial

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