Cryptococcal Optimal ART Timing Trial

HIV Infections Clinical Trial

— COAT  

Official title:

Trial for the Optimal Timing of HIV Therapy After Cryptococcal Meningitis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01075152
• Other study ID #: 0810M49622
• Secondary ID: U01AI089244
• Status: Completed
• Phase: Phase 4
• Start date: November 2010
• Est. completion date: March 2013

Study information

• Verified date: June 2020
• Source: University of Minnesota
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 177
• Est. completion date: March 2013
• Est. primary completion date: October 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 14 Years and older

Eligibility

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

Related Conditions & MeSH terms

• AIDS
• Cryptococcal Meningitis
• HIV Infections
• Meningitis
• Meningitis, Cryptococcal

Intervention

Drug:
• efavirenz
Treatment strategy of when to initiate first line HIV therapy after cryptococcal meningitis diagnosis.

Biological:
• nucleoside
Treatment strategy of when to initiate first line HIV therapy after cryptococcal meningitis diagnosis.

Locations

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

Sponsors (5)

Lead Sponsor	Collaborator
University of Minnesota	Makerere University, Mbarara University of Science and Technology, National Institute of Allergy and Infectious Diseases (NIAID), University of Cape Town

Countries where clinical trial is conducted

South Africa,  Uganda, 

References & Publications (16)

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. — View 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 T — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View Citation

* Note: There are 16 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Percentage of Participants, Per CSF WBC Subgroup, Who Died by Week 26	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
Primary	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	Incidence of Immune Reconstitution Inflammatory Syndrome	Incidence of cryptococcal-related immune reconstitution inflammatory syndrome through 46 weeks after enrollment.	46 weeks
Secondary	Incidence of Cryptococcal-relapse	Incidence of culture positive cryptococcal meningitis relapse	46 weeks
Secondary	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 weeks
Secondary	46-week Survival	46-week survival by time-to-event analysis of all subjects enrolled	46 weeks
Secondary	HIV-1 Viral Suppression	HIV-1 virologic suppression to <400 copies/mL at 26-weeks after enrollment	26 weeks
Secondary	Antiretroviral Therapy Tolerability	Incidence of antiretroviral therapy interruption by >=3 consecutive days	26 weeks
Secondary	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	46 weeks
Secondary	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.	4 weeks

External Links

•   N Engl J Med 2014 - Final Results
•   NIH NIAID FAQ on COAT Trial (Preliminary Results)