AIDS-Related Opportunistic Infections, Cryptococcal Infections, Cryptococcosis
Conditions
Keywords
cryptococcal antigen, preemptive treatment, CRAG+, sertraline, fluconazole, randomized clinical trial, HIV
Brief summary
Cryptococcal meningitis or Crypto is a life threatening fungal infection around the brain that requires hospitalization for treatment for 14 days and then continued therapy. Crypto causes 15-20% of HIV/AIDS-related deaths worldwide. However, this infection can be detected before one develops symptoms and becomes ill. People can be screened for infection by a blood test to detect cryptococcal antigen, (called CrAg), which is part of the fungus, in blood. The World Health Organization and over 22 countries worldwide recommend CrAg screening of all persons with advanced AIDS entering or re-entering into HIV care. However, it is not known how best to treat people with cryptococcal antigen in their blood, who don't otherwise yet have symptoms of infection around their brain. If no treatment is given, almost all people will develop infection of the brain and/or die. International guidelines suggest using both HIV medicines and an anti-fungal medicine, called fluconazole, to treat this early infection. However, despite this treatment approximately 1 in 4 people may get sick and/or die. Researchers have recently discovered another medicine that may work against the Cryptococcus fungus. This medicine is called Sertraline, and it is actually a medicine that has been used for more than 25 years to treat depression (sadness). Sertraline is one of the most commonly used medicines worldwide. The purpose of this research clinical trial is to determine if standard fluconazole antifungal therapy plus a high dose of Sertraline, will be better than standard fluconazole therapy alone for treating early disseminated cryptococcal infection in persons who are asymptomatic and do not yet have infection of the brain (i.e. meningitis). This study seeks to test if Sertraline will improve survival through 6-months. Prior studies have shown that \>90% of those who survive 6-months will survive \>5 years.
Detailed description
This is a double-blind, randomized placebo-controlled clinical trial testing sertraline as an antifungal medicine in combination with fluconazole for treatment of HIV-infected persons with AIDS and asymptomatic cryptococcal antigenemia (CrAg+).
Interventions
DRUGSertraline
sertraline 400mg/day
DRUGPlacebo Oral Tablet
matched placebo tablet
DRUGFluconazole
Standard of Care Fluconazole per World Health Organization and Ugandan Guidelines (800mg/day x 2 weeks, 400mg/day x10 weeks, 200mg through 6 months).
Sponsors
Infectious Diseases Institute, Uganda
National Institute of Allergy and Infectious Diseases (NIAID)
Mbarara University of Science and Technology
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
* HIV-infected * Cryptococcal antigen (CrAg) positive in blood * Age \>=18 years * Written informed consent * Women of childbearing potential who are participating in sexual activity that could lead to pregnancy must agree to use one reliable method of contraception while receiving fluconazole \>=400mg/day
Exclusion criteria
* Prior history of cryptococcal meningitis * Suspected meningitis or mania * Suspected/known cirrhosis, jaundice, or alanine aminotransferase (ALT) \>5x upper limit of normal * Receiving an antidepressant medicine * Receiving antifungal therapy, \>1 week * Pregnant or Breastfeeding * Contraindication to sertraline or fluconazole * Current rifampin use or other prohibited medication * Electrocardiogram corrected QT interval (QTc) \>450ms
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 6 Month Meningitis-free Survival | 6 months | Cryptococcal meningitis free survival with retention-in-care through 6 months * Those who die of any cause are failures * Those developing symptomatic cryptococcal meningitis are failures * Those lost to follow up and unable to be tracked are considered failures |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 6-month Survival | 6 months | Survival through 6 months |
| Cumulative Incidence of Symptomatic Cryptococcal Meningoencephalitis | 6 months | Cumulative incidence of symptomatic cryptococcal meningoencephalitis through 6 months |
| Number of Clinical Adverse Events (Grade 3-5) | 6 months | Number of Clinical Adverse Events by Division of AIDS (DAIDS) Scale for Grade 3-5 events through 6 months |
| All-Cause Premature Study Drug/Placebo Discontinuation | 6 months | Number of participants whose study drug/placebo use was halted prematurely due to any cause through 6 months |
| Prevalence of Depression by Patient Health Questionnaire (PHQ-9) Over Time | 12 weeks | Prevalence of depression by Patient Health Questionnaire (PHQ-9) over 6 months as measured at baseline, 4 weeks, 8 weeks, and 12 weeks. The PHQ-9 is a 9-item instrument for screening, diagnosing, monitoring, and measuring the severity of depression. Items are rated on a scale from 0 (not at all) to 3 (nearly every day). Total score is a sum of 9 item scores (Range 0-27). Greater scores indicate greater depressive symptoms. PHQ-9 scores of: 0-4 Minimal/No depression; 5-9 Mild depression; 10-14 Moderate depression; 15-19 Moderate severe depression; 20-27 Severe depression. This endpoint reports the median (interquartile range) of the PHQ-9 scores over time. |
| Number of Laboratory Grade 3-5 Adverse Events | 6 months | Number of Laboratory Grade 3-5 Adverse Events through 6 months as per the Division of AIDS (DAIDS) grading scale |
Other
| Measure | Time frame | Description |
|---|---|---|
| Adherence to Study Drug | 12 weeks | Participants' percent adherence to study drug regiment by pharmacy medication counts, representing the percent of the total prescribed medication taken by participants. |
Countries
Uganda
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sertraline Fluconazole Standard of Care + Sertraline
Sertraline: sertraline 400mg/day
Fluconazole: Standard of Care Fluconazole per World Health Organization and Ugandan Guidelines (800mg/day x 2 weeks, 400mg/day x10 weeks, 200mg through 6 months). | 11 |
| Control Fluconazole Standard of Care + Placebo Oral Tablet
Placebo Oral Tablet: matched placebo tablet
Fluconazole: Standard of Care Fluconazole per World Health Organization and Ugandan Guidelines (800mg/day x 2 weeks, 400mg/day x10 weeks, 200mg through 6 months). | 11 |
| Total | 22 |
Baseline characteristics
| Characteristic | Sertraline | Control | Total |
|---|---|---|---|
| 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 | 11 Participants | 11 Participants | 22 Participants |
| Age, Continuous | 32 years | 35 years | 32 years |
| CD4 Cell Count | 38 cells/mm3 | 50 cells/mm3 | 42 cells/mm3 |
| On Antiretroviral Therapy (ART) at Radomization Not on ART | 5 Participants | 3 Participants | 8 Participants |
| On Antiretroviral Therapy (ART) at Radomization On ART | 6 Participants | 8 Participants | 14 Participants |
| 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 | 0 Participants | 0 Participants | 0 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 | 11 Participants | 11 Participants | 22 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Uganda | 11 participants | 11 participants | 22 participants |
| Sex: Female, Male Female | 6 Participants | 7 Participants | 13 Participants |
| Sex: Female, Male Male | 5 Participants | 4 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 1 / 11 |
| other Total, other adverse events | 4 / 11 | 1 / 11 |
| serious Total, serious adverse events | 4 / 11 | 3 / 11 |
Outcome results
Primary
6 Month Meningitis-free Survival
Cryptococcal meningitis free survival with retention-in-care through 6 months * Those who die of any cause are failures * Those developing symptomatic cryptococcal meningitis are failures * Those lost to follow up and unable to be tracked are considered failures
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sertraline | 6 Month Meningitis-free Survival | 11 Participants |
| Control | 6 Month Meningitis-free Survival | 9 Participants |
Secondary
6-month Survival
Survival through 6 months
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sertraline | 6-month Survival | 11 Participants |
| Control | 6-month Survival | 10 Participants |
Secondary
All-Cause Premature Study Drug/Placebo Discontinuation
Number of participants whose study drug/placebo use was halted prematurely due to any cause through 6 months
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sertraline | All-Cause Premature Study Drug/Placebo Discontinuation | 1 Participants |
| Control | All-Cause Premature Study Drug/Placebo Discontinuation | 0 Participants |
Secondary
Cumulative Incidence of Symptomatic Cryptococcal Meningoencephalitis
Cumulative incidence of symptomatic cryptococcal meningoencephalitis through 6 months
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sertraline | Cumulative Incidence of Symptomatic Cryptococcal Meningoencephalitis | 0 meningitis events |
| Control | Cumulative Incidence of Symptomatic Cryptococcal Meningoencephalitis | 1 meningitis events |
Secondary
Number of Clinical Adverse Events (Grade 3-5)
Number of Clinical Adverse Events by Division of AIDS (DAIDS) Scale for Grade 3-5 events through 6 months
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sertraline | Number of Clinical Adverse Events (Grade 3-5) | 4 number of grade 3-5 adverse events |
| Control | Number of Clinical Adverse Events (Grade 3-5) | 2 number of grade 3-5 adverse events |
Secondary
Number of Laboratory Grade 3-5 Adverse Events
Number of Laboratory Grade 3-5 Adverse Events through 6 months as per the Division of AIDS (DAIDS) grading scale
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sertraline | Number of Laboratory Grade 3-5 Adverse Events | 4 number of grade 3-5 adverse events |
| Control | Number of Laboratory Grade 3-5 Adverse Events | 1 number of grade 3-5 adverse events |
Secondary
Prevalence of Depression by Patient Health Questionnaire (PHQ-9) Over Time
Prevalence of depression by Patient Health Questionnaire (PHQ-9) over 6 months as measured at baseline, 4 weeks, 8 weeks, and 12 weeks. The PHQ-9 is a 9-item instrument for screening, diagnosing, monitoring, and measuring the severity of depression. Items are rated on a scale from 0 (not at all) to 3 (nearly every day). Total score is a sum of 9 item scores (Range 0-27). Greater scores indicate greater depressive symptoms. PHQ-9 scores of: 0-4 Minimal/No depression; 5-9 Mild depression; 10-14 Moderate depression; 15-19 Moderate severe depression; 20-27 Severe depression. This endpoint reports the median (interquartile range) of the PHQ-9 scores over time.
Time frame: 12 weeks
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Sertraline | Prevalence of Depression by Patient Health Questionnaire (PHQ-9) Over Time | Week 4 | 5 score on a scale |
| Sertraline | Prevalence of Depression by Patient Health Questionnaire (PHQ-9) Over Time | Week 8 | 6 score on a scale |
| Sertraline | Prevalence of Depression by Patient Health Questionnaire (PHQ-9) Over Time | Week 12 | 2 score on a scale |
| Control | Prevalence of Depression by Patient Health Questionnaire (PHQ-9) Over Time | Week 4 | 5 score on a scale |
| Control | Prevalence of Depression by Patient Health Questionnaire (PHQ-9) Over Time | Week 8 | 3 score on a scale |
| Control | Prevalence of Depression by Patient Health Questionnaire (PHQ-9) Over Time | Week 12 | 2 score on a scale |
Other Pre-specified
Adherence to Study Drug
Participants' percent adherence to study drug regiment by pharmacy medication counts, representing the percent of the total prescribed medication taken by participants.
Time frame: 12 weeks
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Sertraline | Adherence to Study Drug | Week 2 | 100 Percent of total prescribed medication t |
| Sertraline | Adherence to Study Drug | Week 4 | 100 Percent of total prescribed medication t |
| Sertraline | Adherence to Study Drug | Week 8 | 97 Percent of total prescribed medication t |
| Sertraline | Adherence to Study Drug | Week 12 | 89 Percent of total prescribed medication t |
| Control | Adherence to Study Drug | Week 12 | 100 Percent of total prescribed medication t |
| Control | Adherence to Study Drug | Week 2 | 100 Percent of total prescribed medication t |
| Control | Adherence to Study Drug | Week 8 | 100 Percent of total prescribed medication t |
| Control | Adherence to Study Drug | Week 4 | 100 Percent of total prescribed medication t |