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Trial record 24 of 39 for:    " February 17, 2010":" March 19, 2010"[FIRST-RECEIVED-DATE]AND HIV[CONDITION]

Cryptococcal Optimal ART Timing Trial (COAT)

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ClinicalTrials.gov Identifier: NCT01075152
Recruitment Status : Completed
First Posted : February 24, 2010
Results First Posted : August 20, 2014
Last Update Posted : August 26, 2015
Sponsor:
Collaborators:
Mbarara University of Science and Technology
Makerere University
National Institute of Allergy and Infectious Diseases (NIAID)
University of Cape Town
Information provided by (Responsible Party):
University of Minnesota - Clinical and Translational Science Institute

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Single (Outcomes Assessor);   Primary Purpose: Treatment
Conditions Cryptococcal Meningitis
HIV Infections
AIDS
Interventions Drug: efavirenz
Biological: nucleoside
Enrollment 177

Recruitment Details  
Pre-assignment Details  
Arm/Group Title Earlier HIV Therapy Deferred HIV Therapy
Hide 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 [1] 89 [1]
Completed 87 89
Not Completed 1 0
Reason Not Completed
Withdrawal by Subject             1             0
[1]
randomized
Arm/Group Title Earlier HIV Therapy Deferred HIV Therapy Total
Hide 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 Number of Baseline Participants 88 89 177
Hide Baseline Analysis Population Description
HIV-infected persons not previously receiving HIV therapy with first episode of cryptococcal meningitis diagnosed by CSF culture and/or CSF cryptococcal antigen testing.
Age, Continuous  
Median (Inter-Quartile Range)
Unit of measure:  Years
Number Analyzed 88 participants 89 participants 177 participants
35
(28 to 40)
36
(30 to 40)
35
(29 to 40)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 88 participants 89 participants 177 participants
Female
42
  47.7%
42
  47.2%
84
  47.5%
Male
46
  52.3%
47
  52.8%
93
  52.5%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 88 participants 89 participants 177 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
0
   0.0%
0
   0.0%
0
   0.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
88
 100.0%
89
 100.0%
177
 100.0%
White
0
   0.0%
0
   0.0%
0
   0.0%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 88 participants 89 participants 177 participants
Uganda 75 77 152
South Africa 13 12 25
CD4 Count, baseline  
Median (Inter-Quartile Range)
Unit of measure:  cells/mcL
Number Analyzed 88 participants 89 participants 177 participants
19
(9 to 69)
28
(11 to 76)
23
(10 to 73)
CSF Quantitative Culture, baseline  
Median (Inter-Quartile Range)
Unit of measure:  Log10 colony forming units/mL of CSF
Number Analyzed 88 participants 89 participants 177 participants
5.3
(4.2 to 5.7)
4.8
(3.8 to 5.5)
5.1
(4.0 to 5.6)
CSF Cryptococcal Antigen titer, 1:xxxx   [1] 
Median (Inter-Quartile Range)
Unit of measure:  Titers
Number Analyzed 88 participants 89 participants 177 participants
8000
(2000 to 16000)
4000
(1000 to 14400)
6400
(2000 to 16000)
[1]
Measure Description: as performed by serial dilutions with lateral flow assay (LFA)
HIV-1 Viral Load  
Median (Inter-Quartile Range)
Unit of measure:  Log10 copies/mL
Number Analyzed 88 participants 89 participants 177 participants
5.5
(5.2 to 5.8)
5.5
(5.3 to 5.8)
5.5
(5.2 to 5.8)
1.Primary Outcome
Title Mortality
Hide 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Earlier HIV Therapy Deferred HIV Therapy
Hide 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).
Overall Number of Participants Analyzed 88 89
Measure Type: Number
Unit of Measure: participants
40 27
Show Statistical Analysis 1 Hide 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
Comments [Not Specified]
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 [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.73
Confidence Interval (2-Sided) 95%
1.06 to 2.82
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
Hide Description Incidence of cryptococcal-related immune reconstitution inflammatory syndrome through 46 weeks after enrollment.
Time Frame 46 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
analysis is of persons who survived to initiate HIV therapy
Arm/Group Title Earlier HIV Therapy Deferred HIV Therapy
Hide 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)
Overall Number of Participants Analyzed 87 69
Measure Type: Number
Unit of Measure: participants
17 9
Show Statistical Analysis 1 Hide 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
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.32
Comments [Not Specified]
Method Gray's method of cumulative incidence
Comments [Not Specified]
3.Secondary Outcome
Title Incidence of Cryptococcal-relapse
Hide Description Incidence of culture positive cryptococcal meningitis relapse
Time Frame 46 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Earlier HIV Therapy Deferred HIV Therapy
Hide 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)
Overall Number of Participants Analyzed 88 89
Measure Type: Number
Unit of Measure: participants
2 8
Show Statistical Analysis 1 Hide 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
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.06
Comments [Not Specified]
Method Gray's method of cumulative incidence
Comments [Not Specified]
4.Secondary Outcome
Title Safety of ART Initiation
Hide 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Earlier HIV Therapy Deferred HIV Therapy
Hide 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)
Overall Number of Participants Analyzed 88 89
Measure Type: Number
Unit of Measure: participants
73 75
Show Statistical Analysis 1 Hide 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
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.98
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
5.Secondary Outcome
Title 46-week Survival
Hide Description 46-week survival by time-to-event analysis of all subjects enrolled
Time Frame 46 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Earlier HIV Therapy Deferred HIV Therapy
Hide 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)
Overall Number of Participants Analyzed 88 89
Measure Type: Number
Unit of Measure: participants
41 29
Show Statistical Analysis 1 Hide 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
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.04
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.66
Confidence Interval (2-Sided) 95%
1.03 to 2.68
Estimation Comments [Not Specified]
6.Secondary Outcome
Title HIV-1 Viral Suppression
Hide Description HIV-1 virologic suppression to <400 copies/mL at 26-weeks after enrollment
Time Frame 26 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide 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
Hide 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)
Overall Number of Participants Analyzed 47 59
Measure Type: Number
Unit of Measure: participants
43 49
Show Statistical Analysis 1 Hide 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
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.26
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
7.Secondary Outcome
Title Antiretroviral Therapy Tolerability
Hide Description Incidence of antiretroviral therapy interruption by >=3 consecutive days
Time Frame 26 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Analysis is of persons who survived to initiate HIV therapy.
Arm/Group Title Earlier HIV Therapy Deferred HIV Therapy
Hide 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)
Overall Number of Participants Analyzed 87 69
Measure Type: Number
Unit of Measure: participants
5 1
Show Statistical Analysis 1 Hide 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
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.23
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
8.Secondary Outcome
Title Karnofsky Functional Status
Hide 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Analysis is of persons alive at the time point.
Arm/Group Title Earlier HIV Therapy Deferred HIV Therapy
Hide 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)
Overall Number of Participants Analyzed 88 89
Mean (Standard Deviation)
Unit of Measure: Scores on a scale
4 weeks 70  (19) 70  (19)
26 weeks 93  (7) 93  (10)
46 weeks 92  (10) 95  (8)
Show Statistical Analysis 1 Hide 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
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.34
Comments [Not Specified]
Method repeated measure analysis
Comments [Not Specified]
9.Secondary Outcome
Title Microbiologic Clearance
Hide 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All participants with >2 quantitative CSF cultures obtained
Arm/Group Title Earlier HIV Therapy Deferred HIV Therapy
Hide 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)
Overall Number of Participants Analyzed 83 83
Mean (95% Confidence Interval)
Unit of Measure: log10 CFU/mL/day
EFA by mixed effects model
-0.31
(-0.34 to -0.28)
-0.31
(-0.34 to -0.28)
EFA by linear regression
-0.39
(-0.45 to -0.32)
-0.35
(-0.39 to -0.31)
Show Statistical Analysis 1 Hide 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
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.44
Comments [Not Specified]
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
Hide 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
Show Outcome Measure DataHide Outcome Measure Data
Hide 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
Hide 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)
Overall Number of Participants Analyzed 75 71
Measure Type: Number
Unit of Measure: percentage of participants
CSF WBC <5 /mcl (n=33, 31) 48.5 16.1
CSF WBC >5/mcL (n=42, 40) 40.5 45
Show Statistical Analysis 1 Hide 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
Comments [Not Specified]
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 [Not Specified]
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
Hide 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 (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Earlier HIV Therapy Deferred HIV Therapy
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   49/88 (55.68%)      53/89 (59.55%)    
Nervous system disorders     
Grade 5 AEs * 1 [1]  11/88 (12.50%)  14 5/89 (5.62%)  10
Grade 4 Serious AEs * 1 [2]  38/88 (43.18%)  59 42/89 (47.19%)  57
Grade 3 Serious AEs * 1 [3]  40/88 (45.45%)  48 38/89 (42.70%)  47
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, DAIDS Toxicity Table
[1]
Death (The number of AEs is greater than the number of persons as multiple AEs could occur simultaneously in the same participant).
[2]
Initial Grade 4 serious AEs
[3]
Grade 3-5 serious AEs
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Earlier HIV Therapy Deferred HIV Therapy
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   73/88 (82.95%)      75/89 (84.27%)    
Blood and lymphatic system disorders     
Hematology  1  41/88 (46.59%)  99 47/89 (52.81%)  128
Infections and infestations     
Infection  1  10/88 (11.36%)  13 18/89 (20.22%)  26
Metabolism and nutrition disorders     
Chemistries  1  32/88 (36.36%)  65 25/89 (28.09%)  53
Indicates events were collected by systematic assessment
1
Term from vocabulary, DAIDS Toxicity Table
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.
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Name/Title: Dr. David R Boulware
Organization: University of Minnesota
Phone: 6126249996
Other Publications:
Responsible Party: University of Minnesota - Clinical and Translational Science Institute
ClinicalTrials.gov Identifier: NCT01075152     History of Changes
Other Study ID Numbers: DAIDS-ES ID 10795
U01AI089244 ( U.S. NIH Grant/Contract )
First Submitted: February 23, 2010
First Posted: February 24, 2010
Results First Submitted: June 27, 2014
Results First Posted: August 20, 2014
Last Update Posted: August 26, 2015