COAT: Cryptococcal Optimal ART Timing Trial

• Sponsor: University of Minnesota (Other)
• Overall Status: Completed
• CT.gov ID: NCT01075152
• Collaborator: Mbarara University of Science and Technology (Other), Makerere University (Other), National Institute of Allergy and Infectious Diseases (NIAID) (NIH), University of Cape Town (Other)
• Enrollment: 177
• Locations: 3
• Arms: 2
• Duration (Months): 28
• Patients Per Site: 59
• Patients Per Site Per Month: 2.1

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Cryptococcal Meningitis; HIV Infections; AIDS	Drug: efavirenz; Biological: nucleoside	Phase 4

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 Design

• Study Type: Interventional
• Actual Enrollment: 177 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Trial for the Optimal Timing of HIV Therapy After Cryptococcal Meningitis
• Study Start Date: Nov 1, 2010
• Actual Primary Completion Date: Oct 1, 2012
• Actual Study Completion Date: Mar 1, 2013

Arms and Interventions

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: zidovudine or stavudine lamivudine
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: zidovudine or stavudine lamivudine

Outcome Measures

Primary Outcome Measures

1. Mortality [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.

Secondary Outcome Measures

1. Incidence of Immune Reconstitution Inflammatory Syndrome [46 weeks]

   Incidence of cryptococcal-related immune reconstitution inflammatory syndrome through 46 weeks after enrollment.

2. Incidence of Cryptococcal-relapse [46 weeks]

   Incidence of culture positive cryptococcal meningitis relapse

3. Safety of ART Initiation [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.

4. 46-week Survival [46 weeks]

   46-week survival by time-to-event analysis of all subjects enrolled

5. HIV-1 Viral Suppression [26 weeks]

   HIV-1 virologic suppression to <400 copies/mL at 26-weeks after enrollment

6. Antiretroviral Therapy Tolerability [26 weeks]

   Incidence of antiretroviral therapy interruption by >=3 consecutive days

7. Karnofsky Functional Status [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

8. Microbiologic Clearance [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.

Other Outcome Measures

1. Percentage of Participants, Per CSF WBC Subgroup, Who Died by Week 26 [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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 14 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GF Jooste Hospital	Cape Town		South Africa
2	Infectious Disease Institute, Mulago Hospital, Makerere University	Kampala		Uganda
3	Mbarara University of Science and Technology	Mbarara		Uganda

Sponsors and Collaborators

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

Investigators

• Principal Investigator: David R Boulware, MD, MPH, University of Minnesota

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

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

Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

• Responsible Party: University of Minnesota
• ClinicalTrials.gov Identifier: NCT01075152
• Other Study ID Numbers: 0810M49622; U01AI089244
• First Posted: Feb 24, 2010
• Last Update Posted: Jun 9, 2020
• Last Verified: Jun 1, 2020

• Keywords provided by University of Minnesota: cryptococcal meningitis; cryptococcus; cryptococcosis; HIV; AIDS; strategy
• Additional relevant MeSH terms: Meningitis, Cryptococcal; Meningitis; Lamivudine; Zidovudine; Efavirenz; Stavudine

Study Results

Participant Flow

Arm/Group Title	Earlier HIV Therapy	Deferred HIV Therapy
Arm/Group Description	HIV therapy initiated at 7-13 days after cryptococcal diagnosis	HIV therapy initiated at 5 weeks after cryptococcal meningitis diagnosis (+/1 week)
Period Title: Overall Study
STARTED	88	89
COMPLETED	87	89
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Earlier HIV Therapy	Deferred HIV Therapy	Total
Arm/Group Description	HIV therapy initiated at 7-13 days after cryptococcal meningitis diagnosis.	HIV therapy initiated at 5 weeks after cryptococcal meningitis diagnosis (+/- 1 week)	Total of all reporting groups
Overall Participants	88	89	177
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	35	36	35
Sex: Female, Male (Count of Participants)
Female	42 47.7%	42 47.2%	84 47.5%
Male	46 52.3%	47 52.8%	93 52.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	88 100%	89 100%	177 100%
White	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Uganda	75 85.2%	77 86.5%	152 85.9%
South Africa	13 14.8%	12 13.5%	25 14.1%
CD4 Count, baseline (cells/mcL) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [cells/mcL]	19	28	23
CSF Quantitative Culture, baseline (log10 colony forming units/mL of CSF) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [log10 colony forming units/mL of CSF]	5.3	4.8	5.1
CSF Cryptococcal Antigen titer, 1:xxxx (titers) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [titers]	8000	4000	6400
HIV-1 Viral Load (log10 copies/mL) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [log10 copies/mL]	5.5	5.5	5.5

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Earlier HIV Therapy	Deferred HIV Therapy
Arm/Group Description	HIV therapy initiated at 7-13 days after cryptococcal meningitis diagnosis	HIV therapy initiated at 5 weeks after cryptococcal meningitis (+/- 1 week).
Measure Participants	88	89
Number [participants]	40 45.5%	27 30.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Earlier HIV Therapy, Deferred HIV Therapy
	Comments	We compared the randomization arms for the primary endpoint of survival using time-to-event methods of Cox proportional hazards models by the intention-to-treat principle, based on two-sided type-I error with alpha=0.05. The trial was statistically powered to detect a 25% relative survival benefit (15% absolute benefit) with 90% power and overall two-sided alpha=0.05 with an intended sample size of 500 participants. The trial was halted early by the Data and Safety Monitoring Board.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.03
	Comments	A Lan-DeMets spending function analog of the O'Brien-Fleming boundaries was proposed to control the type-I error resulting from multiple interim analyses.
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.73
	Confidence Interval	(2-Sided) 95%; 1.06 to 2.82
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard Ratio describes the risk of earlier HIV therapy in comparison to deferred HIV therapy initiation as the reference group.

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

analysis is of persons who survived to initiate HIV therapy

Arm/Group Title	Earlier HIV Therapy	Deferred HIV Therapy
Arm/Group Description	HIV therapy initiated at 7-13 days after cryptococcal meningitis diagnosis	HIV therapy initiated at 5 weeks after cryptococcal meningitis (+/- 1 week)
Measure Participants	87	69
Number [participants]	17 19.3%	9 10.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Earlier HIV Therapy, Deferred HIV Therapy
	Comments	To account for the competing risk of death, the cumulative incidence function compared the randomized groups for endpoints of IRIS, relapse, and adverse events (Gray's method).
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.32
	Comments
	Method	Gray's method of cumulative incidence
	Comments

3. Secondary Outcome

Title	Incidence of Cryptococcal-relapse
Description	Incidence of culture positive cryptococcal meningitis relapse
Time Frame	46 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Earlier HIV Therapy	Deferred HIV Therapy
Arm/Group Description	HIV therapy initiated at 7-13 days after cryptococcal meningitis diagnosis	HIV therapy initiated at 5 weeks after cryptococcal meningitis (+/- 1 week)
Measure Participants	88	89
Number [participants]	2 2.3%	8 9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Earlier HIV Therapy, Deferred HIV Therapy
	Comments	To account for the competing risk of death, the cumulative incidence function compared the randomized groups for endpoints of IRIS, relapse, and adverse events (Gray's method).
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.06
	Comments
	Method	Gray's method of cumulative incidence
	Comments

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Earlier HIV Therapy	Deferred HIV Therapy
Arm/Group Description	HIV therapy initiated at 7-13 days after cryptococcal meningitis diagnosis	HIV therapy initiated at 5 weeks after cryptococcal meningitis (+/- 1 week)
Measure Participants	88	89
Number [participants]	73 83%	75 84.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Earlier HIV Therapy, Deferred HIV Therapy
	Comments	Categorical secondary endpoints were compared with Fisher's exact tests.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.98
	Comments
	Method	Fisher Exact
	Comments

5. Secondary Outcome

Title	46-week Survival
Description	46-week survival by time-to-event analysis of all subjects enrolled
Time Frame	46 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Earlier HIV Therapy	Deferred HIV Therapy
Arm/Group Description	HIV therapy initiated at 7-13 days after cryptococcal meningitis diagnosis	HIV therapy initiated at 5 weeks after cryptococcal meningitis (+/- 1 week)
Measure Participants	88	89
Number [participants]	41 46.6%	29 32.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Earlier HIV Therapy, Deferred HIV Therapy
	Comments	We compared the randomization arms for survival using time-to-event methods of Cox proportional hazards models.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.04
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.66
	Confidence Interval	(2-Sided) 95%; 1.03 to 2.68
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	HIV-1 Viral Suppression
Description	HIV-1 virologic suppression to <400 copies/mL at 26-weeks after enrollment
Time Frame	26 weeks

Outcome Measure Data

Analysis Population Description

Among persons alive at 26 weeks. 1 participant in the early ART arm had consent withdrawn by their family on day 2 after study entry. 3 participants in the deferred ART arm missing their 26 week viral load sampling.

Arm/Group Title	Earlier HIV Therapy	Deferred HIV Therapy
Arm/Group Description	HIV therapy initiated at 7-13 days after cryptococcal meningitis diagnosis	HIV therapy initiated at 5 weeks after cryptococcal meningitis (+/- 1 week)
Measure Participants	47	59
Number [participants]	43 48.9%	49 55.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Earlier HIV Therapy, Deferred HIV Therapy
	Comments	Categorical secondary endpoints were compared with Fisher's exact tests.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.26
	Comments
	Method	Fisher Exact
	Comments

7. Secondary Outcome

Title	Antiretroviral Therapy Tolerability
Description	Incidence of antiretroviral therapy interruption by >=3 consecutive days
Time Frame	26 weeks

Outcome Measure Data

Analysis Population Description

Analysis is of persons who survived to initiate HIV therapy.

Arm/Group Title	Earlier HIV Therapy	Deferred HIV Therapy
Arm/Group Description	HIV therapy initiated at 7-13 days after cryptococcal meningitis diagnosis]	HIV therapy initiated at 5 weeks after cryptococcal meningitis (+/- 1 week)
Measure Participants	87	69
Number [participants]	5 5.7%	1 1.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Earlier HIV Therapy, Deferred HIV Therapy
	Comments	Categorical secondary endpoints were compared with Fisher's exact tests.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.23
	Comments
	Method	Fisher Exact
	Comments

8. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Analysis is of persons alive at the time point.

Arm/Group Title	Earlier HIV Therapy	Deferred HIV Therapy
Arm/Group Description	HIV therapy initiated at 7-13 days after cryptococcal meningitis diagnosis	HIV therapy initiated at 5 weeks after cryptococcal meningitis (+/- 1 week)
Measure Participants	88	89
4 weeks	70 (19)	70 (19)
26 weeks	93 (7)	93 (10)
46 weeks	92 (10)	95 (8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Earlier HIV Therapy, Deferred HIV Therapy
	Comments	The overall change from baseline in Karnofsky performance status scores was compared between groups via a repeated measure analysis, unstructured covariance matrix, adjusted for baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.34
	Comments
	Method	repeated measure analysis
	Comments

9. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

All participants with >2 quantitative CSF cultures obtained

Arm/Group Title	Earlier HIV Therapy	Deferred HIV Therapy
Arm/Group Description	HIV therapy initiated at 7-13 days after cryptococcal meningitis diagnosis	HIV therapy initiated at 5 weeks after cryptococcal meningitis (+/- 1 week)
Measure Participants	83	83
EFA by mixed effects model	-0.31	-0.31
EFA by linear regression	-0.39	-0.35

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Earlier HIV Therapy, Deferred HIV Therapy
	Comments	To describe early fungicidal activity, a linear mixed effects regression model fit with a random intercept and slope estimated the rate of clearance of log10 colony forming units (CFU) of Cryptococcus, per mL of CSF per day, for all participants with >2 cultures obtained.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.44
	Comments
	Method	Regression, Linear
	Comments	a linear mixed effects regression model fit with a random intercept and slope estimated the rate of clearance

10. Other Pre-specified Outcome

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

Outcome Measure Data

Analysis Population Description

among persons with a measured CSF white cell count at randomization (Day 7-11 of amphotericin treatment)

Arm/Group Title	Earlier HIV Therapy	Deferred HIV Therapy
Arm/Group Description	HIV therapy initiated at 7-13 days after cryptococcal meningitis diagnosis	HIV therapy initiated at 5 weeks after cryptococcal meningitis (+/- 1 week)
Measure Participants	75	71
CSF WBC <5 /mcl (n=33, 31)	48.5 55.1%	16.1 18.1%
CSF WBC >5/mcL (n=42, 40)	40.5 46%	45 50.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Earlier HIV Therapy, Deferred HIV Therapy
	Comments	Pre-specified subgroups formed by baseline characteristics were compared for 26 week survival with models including an interaction term between treatment arm and subgroup.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.02
	Comments	This is the interaction p-value for CSF white cell count at randomization (implying there is a statistical difference in the outcome by arm based on this parameter).
	Method	Regression, Cox
	Comments

Adverse Events

Time Frame	46 weeks
Adverse Event Reporting Description	Grade 3,4,5 adverse events were protocol specified secondary endpoint and were collected.
Arm/Group Title	Earlier HIV Therapy		Deferred HIV Therapy
Arm/Group Description	HIV therapy initiated at 7-13 days after cryptococcal meningitis diagnosis		HIV therapy initiated at 5 weeks after cryptococcal meningitis (+/- 1 week)
All Cause Mortality
	Earlier HIV Therapy		Deferred HIV Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Earlier HIV Therapy		Deferred HIV Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	49/88 (55.7%)		53/89 (59.6%)
Nervous system disorders
Grade 5 AEs	11/88 (12.5%)	14	5/89 (5.6%)	10
Grade 4 Serious AEs	38/88 (43.2%)	59	42/89 (47.2%)	57
Grade 3 Serious AEs	40/88 (45.5%)	48	38/89 (42.7%)	47
Other (Not Including Serious) Adverse Events
	Earlier HIV Therapy		Deferred HIV Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	73/88 (83%)		75/89 (84.3%)
Blood and lymphatic system disorders
Hematology	41/88 (46.6%)	99	47/89 (52.8%)	128
Infections and infestations
Infection	10/88 (11.4%)	13	18/89 (20.2%)	26
Metabolism and nutrition disorders
Chemistries	32/88 (36.4%)	65	25/89 (28.1%)	53

Limitations/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.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.