Trial Outcomes & Findings for Cryptococcal Optimal ART Timing Trial (NCT NCT01075152)

NCT ID: NCT01075152

Last Updated: 2020-06-09

Results Overview

Intention to treat analysis of 26 week survival of all subjects enrolled. Reported below are the numbers of participants who died by Week 26.

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 177 participants
• Primary outcome timeframe: 26 weeks from study entry
• Results posted on: 2020-06-09

Participant Flow

Participant milestones

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

Reasons for withdrawal

Measure	Earlier HIV Therapy HIV therapy initiated at 7-13 days after cryptococcal diagnosis	Deferred HIV Therapy HIV therapy initiated at 5 weeks after cryptococcal meningitis diagnosis (+/1 week)
Overall Study Withdrawal by Subject	1	0

Baseline Characteristics

Cryptococcal Optimal ART Timing Trial

Baseline characteristics by cohort

Measure	Earlier HIV Therapy n=88 Participants HIV therapy initiated at 7-13 days after cryptococcal meningitis diagnosis.	Deferred HIV Therapy n=89 Participants HIV therapy initiated at 5 weeks after cryptococcal meningitis diagnosis (+/- 1 week)	Total n=177 Participants Total of all reporting groups
Age, Continuous	35 years n=5 Participants	36 years n=7 Participants	35 years n=5 Participants
Sex: Female, Male Female	42 Participants n=5 Participants	42 Participants n=7 Participants	84 Participants n=5 Participants
Sex: Female, Male Male	46 Participants n=5 Participants	47 Participants n=7 Participants	93 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	88 Participants n=5 Participants	89 Participants n=7 Participants	177 Participants n=5 Participants
Race (NIH/OMB) White	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment Uganda	75 participants n=5 Participants	77 participants n=7 Participants	152 participants n=5 Participants
Region of Enrollment South Africa	13 participants n=5 Participants	12 participants n=7 Participants	25 participants n=5 Participants
CD4 Count, baseline	19 cells/mcL n=5 Participants	28 cells/mcL n=7 Participants	23 cells/mcL n=5 Participants
CSF Quantitative Culture, baseline	5.3 log10 colony forming units/mL of CSF n=5 Participants	4.8 log10 colony forming units/mL of CSF n=7 Participants	5.1 log10 colony forming units/mL of CSF n=5 Participants
CSF Cryptococcal Antigen titer, 1:xxxx	8000 titers n=5 Participants	4000 titers n=7 Participants	6400 titers n=5 Participants
HIV-1 Viral Load	5.5 log10 copies/mL n=5 Participants	5.5 log10 copies/mL n=7 Participants	5.5 log10 copies/mL n=5 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Measure	Earlier HIV Therapy n=88 Participants HIV therapy initiated at 7-13 days after cryptococcal meningitis diagnosis	Deferred HIV Therapy n=89 Participants HIV therapy initiated at 5 weeks after cryptococcal meningitis (+/- 1 week).
Mortality	40 participants	27 participants

SECONDARY outcome

Timeframe: 46 weeks

Population: analysis is of persons who survived to initiate HIV therapy

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

Outcome measures

Measure	Earlier HIV Therapy n=87 Participants HIV therapy initiated at 7-13 days after cryptococcal meningitis diagnosis	Deferred HIV Therapy n=69 Participants HIV therapy initiated at 5 weeks after cryptococcal meningitis (+/- 1 week).
Incidence of Immune Reconstitution Inflammatory Syndrome	17 participants	9 participants

SECONDARY outcome

Timeframe: 46 weeks

Incidence of culture positive cryptococcal meningitis relapse

Outcome measures

Measure	Earlier HIV Therapy n=88 Participants HIV therapy initiated at 7-13 days after cryptococcal meningitis diagnosis	Deferred HIV Therapy n=89 Participants HIV therapy initiated at 5 weeks after cryptococcal meningitis (+/- 1 week).
Incidence of Cryptococcal-relapse	2 participants	8 participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Earlier HIV Therapy n=88 Participants HIV therapy initiated at 7-13 days after cryptococcal meningitis diagnosis	Deferred HIV Therapy n=89 Participants HIV therapy initiated at 5 weeks after cryptococcal meningitis (+/- 1 week).
Safety of ART Initiation	73 participants	75 participants

SECONDARY outcome

Timeframe: 46 weeks

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

Outcome measures

Measure	Earlier HIV Therapy n=88 Participants HIV therapy initiated at 7-13 days after cryptococcal meningitis diagnosis	Deferred HIV Therapy n=89 Participants HIV therapy initiated at 5 weeks after cryptococcal meningitis (+/- 1 week).
46-week Survival	41 participants	29 participants

SECONDARY outcome

Timeframe: 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.

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

Outcome measures

Measure	Earlier HIV Therapy n=47 Participants HIV therapy initiated at 7-13 days after cryptococcal meningitis diagnosis	Deferred HIV Therapy n=59 Participants HIV therapy initiated at 5 weeks after cryptococcal meningitis (+/- 1 week).
HIV-1 Viral Suppression	43 participants	49 participants

SECONDARY outcome

Timeframe: 26 weeks

Population: Analysis is of persons who survived to initiate HIV therapy.

Incidence of antiretroviral therapy interruption by >=3 consecutive days

Outcome measures

Measure	Earlier HIV Therapy n=87 Participants HIV therapy initiated at 7-13 days after cryptococcal meningitis diagnosis	Deferred HIV Therapy n=69 Participants HIV therapy initiated at 5 weeks after cryptococcal meningitis (+/- 1 week).
Antiretroviral Therapy Tolerability	5 participants	1 participants

SECONDARY outcome

Timeframe: 46 weeks

Population: Analysis is of persons alive at the time point.

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

Outcome measures

Measure	Earlier HIV Therapy n=88 Participants HIV therapy initiated at 7-13 days after cryptococcal meningitis diagnosis	Deferred HIV Therapy n=89 Participants HIV therapy initiated at 5 weeks after cryptococcal meningitis (+/- 1 week).
Karnofsky Functional Status 4 weeks	70 Scores on a scale Standard Deviation 19	70 Scores on a scale Standard Deviation 19
Karnofsky Functional Status 26 weeks	93 Scores on a scale Standard Deviation 7	93 Scores on a scale Standard Deviation 10
Karnofsky Functional Status 46 weeks	92 Scores on a scale Standard Deviation 10	95 Scores on a scale Standard Deviation 8

SECONDARY outcome

Timeframe: 4 weeks

Population: All participants with \>2 quantitative CSF cultures obtained

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.

Outcome measures

Measure	Earlier HIV Therapy n=83 Participants HIV therapy initiated at 7-13 days after cryptococcal meningitis diagnosis	Deferred HIV Therapy n=83 Participants HIV therapy initiated at 5 weeks after cryptococcal meningitis (+/- 1 week).
Microbiologic Clearance EFA by mixed effects model	-0.31 log10 CFU/mL/day Interval -0.34 to -0.28	-0.31 log10 CFU/mL/day Interval -0.34 to -0.28
Microbiologic Clearance EFA by linear regression	-0.39 log10 CFU/mL/day Interval -0.45 to -0.32	-0.35 log10 CFU/mL/day Interval -0.39 to -0.31

OTHER_PRE_SPECIFIED outcome

Timeframe: 26 weeks

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

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).

Outcome measures

Measure	Earlier HIV Therapy n=75 Participants HIV therapy initiated at 7-13 days after cryptococcal meningitis diagnosis	Deferred HIV Therapy n=71 Participants HIV therapy initiated at 5 weeks after cryptococcal meningitis (+/- 1 week).
Percentage of Participants, Per CSF WBC Subgroup, Who Died by Week 26 CSF WBC <5 /mcl (n=33, 31)	48.5 percentage of participants	16.1 percentage of participants
Percentage of Participants, Per CSF WBC Subgroup, Who Died by Week 26 CSF WBC >5/mcL (n=42, 40)	40.5 percentage of participants	45 percentage of participants

Adverse Events

Earlier HIV Therapy

Serious events: 49 serious events

Other events: 73 other events

Deaths: 0 deaths

Deferred HIV Therapy

Serious events: 53 serious events

Other events: 75 other events

Deaths: 0 deaths

Serious adverse events

Measure	Earlier HIV Therapy n=88 participants at risk HIV therapy initiated at 7-13 days after cryptococcal meningitis diagnosis	Deferred HIV Therapy n=89 participants at risk HIV therapy initiated at 5 weeks after cryptococcal meningitis (+/- 1 week)
Nervous system disorders Grade 5 AEs	12.5% 11/88 • Number of events 14 • 46 weeks Grade 3,4,5 adverse events were protocol specified secondary endpoint and were collected.	5.6% 5/89 • Number of events 10 • 46 weeks Grade 3,4,5 adverse events were protocol specified secondary endpoint and were collected.
Nervous system disorders Grade 4 Serious AEs	43.2% 38/88 • Number of events 59 • 46 weeks Grade 3,4,5 adverse events were protocol specified secondary endpoint and were collected.	47.2% 42/89 • Number of events 57 • 46 weeks Grade 3,4,5 adverse events were protocol specified secondary endpoint and were collected.
Nervous system disorders Grade 3 Serious AEs	45.5% 40/88 • Number of events 48 • 46 weeks Grade 3,4,5 adverse events were protocol specified secondary endpoint and were collected.	42.7% 38/89 • Number of events 47 • 46 weeks Grade 3,4,5 adverse events were protocol specified secondary endpoint and were collected.

Other adverse events

Measure	Earlier HIV Therapy n=88 participants at risk HIV therapy initiated at 7-13 days after cryptococcal meningitis diagnosis	Deferred HIV Therapy n=89 participants at risk HIV therapy initiated at 5 weeks after cryptococcal meningitis (+/- 1 week)
Blood and lymphatic system disorders Hematology	46.6% 41/88 • Number of events 99 • 46 weeks Grade 3,4,5 adverse events were protocol specified secondary endpoint and were collected.	52.8% 47/89 • Number of events 128 • 46 weeks Grade 3,4,5 adverse events were protocol specified secondary endpoint and were collected.
Metabolism and nutrition disorders Chemistries	36.4% 32/88 • Number of events 65 • 46 weeks Grade 3,4,5 adverse events were protocol specified secondary endpoint and were collected.	28.1% 25/89 • Number of events 53 • 46 weeks Grade 3,4,5 adverse events were protocol specified secondary endpoint and were collected.
Infections and infestations Infection	11.4% 10/88 • Number of events 13 • 46 weeks Grade 3,4,5 adverse events were protocol specified secondary endpoint and were collected.	20.2% 18/89 • Number of events 26 • 46 weeks Grade 3,4,5 adverse events were protocol specified secondary endpoint and were collected.

Additional Information

Dr. David R Boulware

University of Minnesota

Phone: 6126249996

Email: coat.trial@gmail.com

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place