Cryptococcal Meningitis, Fungal Meningitis
Conditions
Keywords
cryptococcal meningitis, cryptococcus, meningitis, yeast, fungus
Brief summary
This is a phase III trial to determine whether adjunctive sertraline will lead to improved survival 18-week survival. There was an initial phase I/II unmasked dose finding pharmacokinetic study of CSF concentrations in 172 persons conducted from August 2013 to August 2014. See NCT03002012.
Detailed description
This is a phase III randomized trial to evaluate whether sertraline when added to standard amphotericin-based therapy for cryptococcal meningitis, will lead to improved survival . Cryptococcal meningitis diagnosis will be made via CSF cryptococcal antigen (CRAG) at time of lumbar puncture (LP) with confirmation by CSF culture. After informed consent, subjects that meet eligibility requirements will be able to enter study. A non-randomized phase I dose-escalation study will first be conducted to help optimize dosing for a larger randomized phase II study. Phase III Design: Subjects will be randomized to standard induction therapy with masked placebo or sertraline at 400mg/day. We will use a permutated block randomization in a 1:1 allocation (n=275 per arm). Total anticipated enrollment: 550 subjects.
Interventions
DRUGSertraline
Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.
Sponsors
Infectious Disease Institute, Kampala, Uganda
National Institute of Neurological Disorders and Stroke (NINDS)
Mbarara University of Science and Technology
Medical Research Council
Wellcome Trust
Makerere University
University of Minnesota
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Cryptococcal meningitis diagnosed by CSF cryptococcal antigen (CRAG) * HIV-1 infection * Ability and willingness of the participant or legal guardian/representative to provide informed consent * Willing to receive protocol-specified lumbar punctures
Exclusion criteria
* Age \< 18 years * Receipt of \>=3 doses of amphotericin therapy * Cannot or unlikely to attend regular clinic visits * History of known liver cirrhosis * Presence of jaundice * Pregnancy * Current breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Survival | 18 weeks | 18-week survival. The comparison will be between sertraline 400mg group and placebo |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Count of Participants With Cerebrospinal Fluid Sterility | 14 days | Number of participants with sterile cerebrospinal fluid at 2 weeks |
| Center for Epidemiologic Studies in Depression (CES-D) Scale | 14 weeks | Center for Epidemiologic Studies in Depression (CES-D) scale at 14 weeks. CES-D scores are based on a 20 item survey with total scores ranging from 0 to 60. Higher scores suggest a greater presence of depressive symptoms. A CES-D score of 16 or higher is interpreted to indicate a risk for depression. |
| Quantitative Neurocognitive Performance Score (QNPZ-8) | 14 weeks | Quantitative neurocognitive performance Z-score (QNPZ-8) at 14 weeks. The QNPZ-8 is a mean score of testing of 8 neurocognitive domains. Eqach domain is scaled based on a Z-score where the mean = 0 for the HIV-negative Ugandan population, accounting for age and educational status. Each +1 unit is one standard deviation better than the population norm. Each -1 unit is one standard deviation worse than the population norm. |
| Safety (Occurence of Adverse Events) | 18 weeks | Safety and tolerability of adjunctive sertraline (grade 4-5) adverse reactions |
| Number of Participants Experiencing IRIS OR Relapse | 18 weeks | Cumulative incidence of central nervous system (CNS) cryptococcal-related paradoxical immune reconstitution inflammatory syndrome (IRIS) or culture-positive relapse |
| Event Free Survival | 18 weeks | Event free survival of composite events of: death,central nervous system (CNS) cryptococcal-related paradoxical immune reconstitution inflammatory syndrome (IRIS) or culture-positive relapse. |
| Fungal Clearance as Determined by Early Fungicidal Activity of CDF | 14 days | To determine whether adjunctive sertraline will lead to a faster rate of fungal clearance from cerebrospinal fluid (CSF), as measured by early fungicidal activity (EFA) of clearance of the Cryptococcus colony forming units (cfu) per mL of CSF per day, compared to standard therapy alone. |
Countries
Uganda
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day).
Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks. | 231 |
| Sertraline 400mg Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day plus adjunctive sertraline therapy at 400mg/day for 2 weeks, then 200mg for 12 weeks, and then tapered over 3 weeks.
Sertraline: Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks. | 229 |
| Total | 460 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 106 | 120 |
Baseline characteristics
| Characteristic | Sertraline 400mg | Total | Placebo |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 229 Participants | 460 Participants | 231 Participants |
| Age, Continuous | 35 years | 35 years | 35 years |
| 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 | 229 Participants | 460 Participants | 231 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 Uganda | 229 participants | 460 participants | 231 participants |
| Sex: Female, Male Female | 97 Participants | 184 Participants | 87 Participants |
| Sex: Female, Male Male | 132 Participants | 276 Participants | 144 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 106 / 231 | 120 / 229 |
| other Total, other adverse events | 65 / 231 | 66 / 229 |
| serious Total, serious adverse events | 121 / 231 | 141 / 229 |
Outcome results
Primary
Survival
18-week survival. The comparison will be between sertraline 400mg group and placebo
Time frame: 18 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Survival | 125 Participants |
| Sertraline 400mg | Survival | 109 Participants |
Secondary
Center for Epidemiologic Studies in Depression (CES-D) Scale
Center for Epidemiologic Studies in Depression (CES-D) scale at 14 weeks. CES-D scores are based on a 20 item survey with total scores ranging from 0 to 60. Higher scores suggest a greater presence of depressive symptoms. A CES-D score of 16 or higher is interpreted to indicate a risk for depression.
Time frame: 14 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Center for Epidemiologic Studies in Depression (CES-D) Scale | 16.6 score on a scale |
| Sertraline 400mg | Center for Epidemiologic Studies in Depression (CES-D) Scale | 13.2 score on a scale |
Secondary
Count of Participants With Cerebrospinal Fluid Sterility
Number of participants with sterile cerebrospinal fluid at 2 weeks
Time frame: 14 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Count of Participants With Cerebrospinal Fluid Sterility | 90 Participants |
| Sertraline 400mg | Count of Participants With Cerebrospinal Fluid Sterility | 101 Participants |
Secondary
Event Free Survival
Event free survival of composite events of: death,central nervous system (CNS) cryptococcal-related paradoxical immune reconstitution inflammatory syndrome (IRIS) or culture-positive relapse.
Time frame: 18 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Event Free Survival | 116 Participants |
| Sertraline 400mg | Event Free Survival | 103 Participants |
Secondary
Fungal Clearance as Determined by Early Fungicidal Activity of CDF
To determine whether adjunctive sertraline will lead to a faster rate of fungal clearance from cerebrospinal fluid (CSF), as measured by early fungicidal activity (EFA) of clearance of the Cryptococcus colony forming units (cfu) per mL of CSF per day, compared to standard therapy alone.
Time frame: 14 days
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Placebo | Fungal Clearance as Determined by Early Fungicidal Activity of CDF | General Linear Regression | 0.47 -log10 CFU/ml/day |
| Placebo | Fungal Clearance as Determined by Early Fungicidal Activity of CDF | Mixed-Effects Regression | 0.33 -log10 CFU/ml/day |
| Sertraline 400mg | Fungal Clearance as Determined by Early Fungicidal Activity of CDF | General Linear Regression | .43 -log10 CFU/ml/day |
| Sertraline 400mg | Fungal Clearance as Determined by Early Fungicidal Activity of CDF | Mixed-Effects Regression | .33 -log10 CFU/ml/day |
Secondary
Number of Participants Experiencing IRIS OR Relapse
Cumulative incidence of central nervous system (CNS) cryptococcal-related paradoxical immune reconstitution inflammatory syndrome (IRIS) or culture-positive relapse
Time frame: 18 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants Experiencing IRIS OR Relapse | 9 Participants |
| Sertraline 400mg | Number of Participants Experiencing IRIS OR Relapse | 5 Participants |
Secondary
Quantitative Neurocognitive Performance Score (QNPZ-8)
Quantitative neurocognitive performance Z-score (QNPZ-8) at 14 weeks. The QNPZ-8 is a mean score of testing of 8 neurocognitive domains. Eqach domain is scaled based on a Z-score where the mean = 0 for the HIV-negative Ugandan population, accounting for age and educational status. Each +1 unit is one standard deviation better than the population norm. Each -1 unit is one standard deviation worse than the population norm.
Time frame: 14 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Quantitative Neurocognitive Performance Score (QNPZ-8) | -1.4 score |
| Sertraline 400mg | Quantitative Neurocognitive Performance Score (QNPZ-8) | -1.3 score |
Secondary
Safety (Occurence of Adverse Events)
Safety and tolerability of adjunctive sertraline (grade 4-5) adverse reactions
Time frame: 18 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Safety (Occurence of Adverse Events) | 121 events |
| Sertraline 400mg | Safety (Occurence of Adverse Events) | 141 events |