Cryptococcal Optimal ART Timing Trial

NCT ID: NCT01075152

Last Updated: 2020-06-09

Study Results

Results available

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE4

Total Enrollment

177 participants

Study Classification

INTERVENTIONAL

Study Start Date

2010-11-30

Study Completion Date

2013-03-31

Brief Summary

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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

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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.

Conditions

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Cryptococcal Meningitis HIV Infections AIDS

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

SINGLE

Outcome Assessors

Study Groups

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Earlier HIV Therapy

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

Group Type EXPERIMENTAL

efavirenz

Intervention Type DRUG

Treatment strategy of when to initiate first line HIV therapy after cryptococcal meningitis diagnosis.

nucleoside

Intervention Type BIOLOGICAL

Treatment strategy of when to initiate first line HIV therapy after cryptococcal meningitis diagnosis.

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.

Group Type ACTIVE_COMPARATOR

efavirenz

Intervention Type DRUG

Treatment strategy of when to initiate first line HIV therapy after cryptococcal meningitis diagnosis.

nucleoside

Intervention Type BIOLOGICAL

Treatment strategy of when to initiate first line HIV therapy after cryptococcal meningitis diagnosis.

Interventions

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efavirenz

Treatment strategy of when to initiate first line HIV therapy after cryptococcal meningitis diagnosis.

Intervention Type DRUG

nucleoside

Treatment strategy of when to initiate first line HIV therapy after cryptococcal meningitis diagnosis.

Intervention Type BIOLOGICAL

Other Intervention Names

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sustiva zidovudine or stavudine lamivudine

Eligibility Criteria

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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
Minimum Eligible Age

14 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Mbarara University of Science and Technology

OTHER

Sponsor Role collaborator

Makerere University

OTHER

Sponsor Role collaborator

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role collaborator

University of Cape Town

OTHER

Sponsor Role collaborator

University of Minnesota

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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David R Boulware, MD, MPH

Role: PRINCIPAL_INVESTIGATOR

University of Minnesota

Locations

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GF Jooste Hospital

Cape Town, , South Africa

Site Status

Infectious Disease Institute, Mulago Hospital, Makerere University

Kampala, , Uganda

Site Status

Mbarara University of Science and Technology

Mbarara, , Uganda

Site Status

Countries

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South Africa Uganda

References

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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.

Reference Type BACKGROUND
PMID: 24655747 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 24399496 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 24378231 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 24065327 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 23945372 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 23466647 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 23055838 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 25057102 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 25651842 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 25838287 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 25385864 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 25734161 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 25492918 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 25734140 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 25078453 (View on PubMed)

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.

Reference Type RESULT
PMID: 24963568 (View on PubMed)

Sadiq A, Kwizera R, Kiiza TK, Ayebare P, Ahimbisibwe C, Ndyetukira JF, Boulware DR, Meya DB. Experiences, challenges, gaps, and strategies for counselling persons presenting with advanced HIV-associated meningitis in Uganda. AIDS Res Ther. 2025 Feb 19;22(1):21. doi: 10.1186/s12981-025-00705-z.

Reference Type DERIVED
PMID: 39972326 (View on PubMed)

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.

Reference Type DERIVED
PMID: 32843994 (View on PubMed)

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.

Reference Type DERIVED
PMID: 31504335 (View on PubMed)

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.

Reference Type DERIVED
PMID: 31319498 (View on PubMed)

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.

Reference Type DERIVED
PMID: 30325463 (View on PubMed)

Related Links

Access external resources that provide additional context or updates about the study.

http://www.niaid.nih.gov/news/QA/Pages/COATqa.aspx

NIH NIAID FAQ on COAT Trial (Preliminary Results)

http://dx.doi.org/10.1056/NEJMoa1312884

N Engl J Med 2014 - Final Results

Other Identifiers

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U01AI089244

Identifier Type: NIH

Identifier Source: secondary_id

View Link

0810M49622

Identifier Type: -

Identifier Source: org_study_id

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