AIDS, Cryptococcal Meningitis, HIV Infections
Conditions
Keywords
cryptococcal meningitis, cryptococcus, cryptococcosis, HIV, AIDS, strategy
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.
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.
Interventions
DRUGefavirenz
Treatment strategy of when to initiate first line HIV therapy after cryptococcal meningitis diagnosis.
BIOLOGICALnucleoside
Treatment strategy of when to initiate first line HIV therapy after cryptococcal meningitis diagnosis.
Sponsors
Mbarara University of Science and Technology
Makerere University
National Institute of Allergy and Infectious Diseases (NIAID)
University of Cape Town
University of Minnesota
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
14 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Immune Reconstitution Inflammatory Syndrome | 46 weeks | Incidence of cryptococcal-related immune reconstitution inflammatory syndrome through 46 weeks after enrollment. |
| Incidence of Cryptococcal-relapse | 46 weeks | Incidence of culture positive cryptococcal meningitis relapse |
| 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. |
| 46-week Survival | 46 weeks | 46-week survival by time-to-event analysis of all subjects enrolled |
| Antiretroviral Therapy Tolerability | 26 weeks | Incidence of antiretroviral therapy interruption by \>=3 consecutive days |
| 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 |
| 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. |
| HIV-1 Viral Suppression | 26 weeks | HIV-1 virologic suppression to \<400 copies/mL at 26-weeks after enrollment |
Other
| Measure | Time frame | Description |
|---|---|---|
| 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). |
Countries
South Africa, Uganda
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Earlier HIV Therapy HIV therapy initiated at 7-13 days after cryptococcal meningitis diagnosis. | 88 |
| Deferred HIV Therapy HIV therapy initiated at 5 weeks after cryptococcal meningitis diagnosis (+/- 1 week) | 89 |
| Total | 177 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Earlier HIV Therapy | Total | Deferred HIV Therapy |
|---|---|---|---|
| Age, Continuous | 35 years | 35 years | 36 years |
| CD4 Count, baseline | 19 cells/mcL | 23 cells/mcL | 28 cells/mcL |
| CSF Cryptococcal Antigen titer, 1:xxxx | 8000 titers | 6400 titers | 4000 titers |
| CSF Quantitative Culture, baseline | 5.3 log10 colony forming units/mL of CSF | 5.1 log10 colony forming units/mL of CSF | 4.8 log10 colony forming units/mL of CSF |
| HIV-1 Viral Load | 5.5 log10 copies/mL | 5.5 log10 copies/mL | 5.5 log10 copies/mL |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 88 Participants | 177 Participants | 89 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment South Africa | 13 participants | 25 participants | 12 participants |
| Region of Enrollment Uganda | 75 participants | 152 participants | 77 participants |
| Sex: Female, Male Female | 42 Participants | 84 Participants | 42 Participants |
| Sex: Female, Male Male | 46 Participants | 93 Participants | 47 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 73 / 88 | 75 / 89 |
| serious Total, serious adverse events | 49 / 88 | 53 / 89 |
Outcome results
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.
Time frame: 26 weeks from study entry
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Earlier HIV Therapy | Mortality | 40 participants |
| Deferred HIV Therapy | Mortality | 27 participants |
Comparison: 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.p-value: 0.0395% CI: [1.06, 2.82]Regression, Cox
Secondary
46-week Survival
46-week survival by time-to-event analysis of all subjects enrolled
Time frame: 46 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Earlier HIV Therapy | 46-week Survival | 41 participants |
| Deferred HIV Therapy | 46-week Survival | 29 participants |
Comparison: We compared the randomization arms for survival using time-to-event methods of Cox proportional hazards models.p-value: 0.0495% CI: [1.03, 2.68]Regression, Cox
Secondary
Antiretroviral Therapy Tolerability
Incidence of antiretroviral therapy interruption by \>=3 consecutive days
Time frame: 26 weeks
Population: Analysis is of persons who survived to initiate HIV therapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Earlier HIV Therapy | Antiretroviral Therapy Tolerability | 5 participants |
| Deferred HIV Therapy | Antiretroviral Therapy Tolerability | 1 participants |
Comparison: Categorical secondary endpoints were compared with Fisher's exact tests.p-value: 0.23Fisher Exact
Secondary
HIV-1 Viral Suppression
HIV-1 virologic suppression to \<400 copies/mL at 26-weeks after enrollment
Time frame: 26 weeks
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Earlier HIV Therapy | HIV-1 Viral Suppression | 43 participants |
| Deferred HIV Therapy | HIV-1 Viral Suppression | 49 participants |
Comparison: Categorical secondary endpoints were compared with Fisher's exact tests.p-value: 0.26Fisher Exact
Secondary
Incidence of Cryptococcal-relapse
Incidence of culture positive cryptococcal meningitis relapse
Time frame: 46 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Earlier HIV Therapy | Incidence of Cryptococcal-relapse | 2 participants |
| Deferred HIV Therapy | Incidence of Cryptococcal-relapse | 8 participants |
Comparison: 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).p-value: 0.06Gray's method of cumulative incidence
Secondary
Incidence of Immune Reconstitution Inflammatory Syndrome
Incidence of cryptococcal-related immune reconstitution inflammatory syndrome through 46 weeks after enrollment.
Time frame: 46 weeks
Population: analysis is of persons who survived to initiate HIV therapy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Earlier HIV Therapy | Incidence of Immune Reconstitution Inflammatory Syndrome | 17 participants |
| Deferred HIV Therapy | Incidence of Immune Reconstitution Inflammatory Syndrome | 9 participants |
Comparison: 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).p-value: 0.32Gray's method of cumulative incidence
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
Time frame: 46 weeks
Population: Analysis is of persons alive at the time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Earlier HIV Therapy | Karnofsky Functional Status | 4 weeks | 70 Scores on a scale | Standard Deviation 19 |
| Earlier HIV Therapy | Karnofsky Functional Status | 26 weeks | 93 Scores on a scale | Standard Deviation 7 |
| Earlier HIV Therapy | Karnofsky Functional Status | 46 weeks | 92 Scores on a scale | Standard Deviation 10 |
| Deferred HIV Therapy | Karnofsky Functional Status | 4 weeks | 70 Scores on a scale | Standard Deviation 19 |
| Deferred HIV Therapy | Karnofsky Functional Status | 26 weeks | 93 Scores on a scale | Standard Deviation 10 |
| Deferred HIV Therapy | Karnofsky Functional Status | 46 weeks | 95 Scores on a scale | Standard Deviation 8 |
Comparison: 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.p-value: 0.34repeated measure analysis
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.
Time frame: 4 weeks
Population: All participants with \>2 quantitative CSF cultures obtained
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Earlier HIV Therapy | Microbiologic Clearance | EFA by mixed effects model | -0.31 log10 CFU/mL/day |
| Earlier HIV Therapy | Microbiologic Clearance | EFA by linear regression | -0.39 log10 CFU/mL/day |
| Deferred HIV Therapy | Microbiologic Clearance | EFA by mixed effects model | -0.31 log10 CFU/mL/day |
| Deferred HIV Therapy | Microbiologic Clearance | EFA by linear regression | -0.35 log10 CFU/mL/day |
Comparison: 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.p-value: 0.44Regression, Linear
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.
Time frame: 46 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Earlier HIV Therapy | Safety of ART Initiation | 73 participants |
| Deferred HIV Therapy | Safety of ART Initiation | 75 participants |
Comparison: Categorical secondary endpoints were compared with Fisher's exact tests.p-value: 0.98Fisher Exact
Other Pre-specified
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).
Time frame: 26 weeks
Population: among persons with a measured CSF white cell count at randomization (Day 7-11 of amphotericin treatment)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Earlier HIV Therapy | Percentage of Participants, Per CSF WBC Subgroup, Who Died by Week 26 | CSF WBC <5 /mcl (n=33, 31) | 48.5 percentage of participants |
| Earlier HIV Therapy | Percentage of Participants, Per CSF WBC Subgroup, Who Died by Week 26 | CSF WBC >5/mcL (n=42, 40) | 40.5 percentage of participants |
| Deferred HIV Therapy | Percentage of Participants, Per CSF WBC Subgroup, Who Died by Week 26 | CSF WBC <5 /mcl (n=33, 31) | 16.1 percentage of participants |
| Deferred HIV Therapy | Percentage of Participants, Per CSF WBC Subgroup, Who Died by Week 26 | CSF WBC >5/mcL (n=42, 40) | 45 percentage of participants |
Comparison: Pre-specified subgroups formed by baseline characteristics were compared for 26 week survival with models including an interaction term between treatment arm and subgroup.p-value: 0.02Regression, Cox