Cryptococcal Optimal ART Timing Trial

NCT01075152 | Completed Phase 4 Results DMC

• 2 other identifiers: 0810M49622U01AI089244
• Study Type: interventional
• Target: 177
• Locations: 2 countries
• Sites: 3

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.

Conditions

Cryptococcal Meningitis; HIV Infections; AIDS

Keywords

cryptococcal meningitis; cryptococcus; cryptococcosis; HIV; AIDS; strategy

Outcome Measures

Primary Outcomes (1)

• 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.

  26 weeks from study entry

Secondary Outcomes (8)

• Incidence of Immune Reconstitution Inflammatory Syndrome

  46 weeks

• Incidence of Cryptococcal-relapse

  46 weeks

• Safety of ART Initiation

  46 weeks

• 46-week Survival

  46 weeks

• HIV-1 Viral Suppression

  26 weeks

Other Outcomes (1)

• Percentage of Participants, Per CSF WBC Subgroup, Who Died by Week 26

  26 weeks

Study Arms (2)

Earlier HIV Therapy

EXPERIMENTAL

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

Drug: efavirenz; Biological: nucleoside

Deferred HIV Therapy

ACTIVE COMPARATOR

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

Drug: efavirenz; Biological: nucleoside

Interventions

efavirenz DRUG

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

Also known as: sustiva

Deferred HIV Therapy; Earlier HIV Therapy

nucleoside BIOLOGICAL

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

Also known as: zidovudine or stavudine, lamivudine

Deferred HIV Therapy; Earlier HIV Therapy

Eligibility Criteria

• Age: 14 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Minnesota: lead
• Mbarara University of Science and Technology: collaborator
• Makerere University: collaborator
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator
• University of Cape Town: collaborator

Study Sites (3)

GF Jooste Hospital

Cape Town, South Africa

Location

Infectious Disease Institute, Mulago Hospital, Makerere University

Kampala, Uganda

Location

Mbarara University of Science and Technology

Mbarara, Uganda

Location

Related Publications (21)

• 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.

  PMID: 24655747 BACKGROUND

• 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.

  PMID: 24399496 BACKGROUND

• 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.

  PMID: 24378231 BACKGROUND

• 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.

  PMID: 24065327 BACKGROUND

• 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.

  PMID: 23945372 BACKGROUND

• 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.

  PMID: 23466647 BACKGROUND

• 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.

  PMID: 23055838 BACKGROUND

• 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.

  PMID: 25057102 BACKGROUND

• 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.

  PMID: 25651842 BACKGROUND

• 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.

  PMID: 25838287 BACKGROUND

• 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.

  PMID: 25385864 BACKGROUND

• 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.

  PMID: 25734161 BACKGROUND

• 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.

  PMID: 25492918 BACKGROUND

• 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.

  PMID: 25734140 BACKGROUND

• 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.

  PMID: 25078453 BACKGROUND

• 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.

  PMID: 24963568 RESULT

• 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.

  PMID: 39972326 DERIVED

• 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.

  PMID: 32843994 DERIVED

• 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.

  PMID: 31504335 DERIVED

• 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.

  PMID: 31319498 DERIVED

• 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.

  PMID: 30325463 DERIVED

Related Links

• NIH NIAID FAQ on COAT Trial (Preliminary Results)

MeSH Terms

Conditions

Meningitis, Cryptococcal; HIV Infections; Acquired Immunodeficiency Syndrome; Cryptococcosis

Interventions

efavirenz; Nucleosides; Zidovudine; Stavudine; Lamivudine

Condition Hierarchy (Ancestors)

Meningitis, Fungal; Central Nervous System Fungal Infections; Mycoses; Bacterial Infections and Mycoses; Infections; Central Nervous System Infections; Central Nervous System Diseases; Nervous System Diseases; Meningitis; Neuroinflammatory Diseases; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Slow Virus Diseases

Intervention Hierarchy (Ancestors)

Glycosides; Carbohydrates; Nucleic Acids, Nucleotides, and Nucleosides; Thymidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Dideoxynucleosides; Deoxyribonucleosides; Zalcitabine; Deoxycytidine; Cytidine

Limitations and Caveats

The differences in mortality in the two arms were of sufficient magnitude that trial enrollment was stopped early by the Data and Safety Monitoring Board. Historically, trials stopped early routinely over-estimate the magnitude of benefit or harm.

Results Point of Contact

• Title: Dr. David R Boulware
• Organization: University of Minnesota

coat.trial@gmail.com

6126249996

Study Officials

• David R Boulware, MD, MPH

  University of Minnesota

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 23, 2010
• First Posted: February 24, 2010
• Study Start: November 1, 2010
• Primary Completion: October 1, 2012
• Study Completion: March 1, 2013
• Last Updated: June 9, 2020
• Results First Posted: August 20, 2014

Record last verified: 2020-06

Locations

UG (2); ZA (1)