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| ID | Type | Description | Link |
|---|---|---|---|
| R01NS086312-01 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| Infectious Disease Institute, Kampala, Uganda | OTHER |
| National Institute of Neurological Disorders and Stroke (NINDS) | NIH |
| Mbarara University of Science and Technology | OTHER |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Placebo | No Intervention | Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day) + placebo | |
| Sertraline 400mg | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Sertraline | Drug | Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Survival | 18-week survival. The comparison will be between sertraline 400mg group and placebo | 18 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Safety (Occurence of Adverse Events) | Safety and tolerability of adjunctive sertraline (grade 4-5) adverse reactions | 18 weeks |
| Count of Participants With Cerebrospinal Fluid Sterility | Number of participants with sterile cerebrospinal fluid at 2 weeks |
Not provided
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| David B Meya, MBCHB MMed | Infectious Disease Institute | Principal Investigator |
| Joshua Rhein, MD | University of Minnesota | Study Director |
| David R Boulware, MD MPH | University of Minnesota | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Infectious Disease Institute | Kampala | Uganda | ||||
| Mbarara University of Science and Technology |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 26971081 | Background | Rhein J, Morawski BM, Hullsiek KH, Nabeta HW, Kiggundu R, Tugume L, Musubire A, Akampurira A, Smith KD, Alhadab A, Williams DA, Abassi M, Bahr NC, Velamakanni SS, Fisher J, Nielsen K, Meya DB, Boulware DR; ASTRO-CM Study Team. Efficacy of adjunctive sertraline for the treatment of HIV-associated cryptococcal meningitis: an open-label dose-ranging study. Lancet Infect Dis. 2016 Jul;16(7):809-818. doi: 10.1016/S1473-3099(16)00074-8. Epub 2016 Mar 10. | |
| 22508310 |
| Label | URL |
|---|---|
| Infectious Disease Institute | View source |
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Open
Contact of the Principal Investigator
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| BG001 | Sertraline 400mg |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Survival | 18-week survival. The comparison will be between sertraline 400mg group and placebo | Posted | Count of Participants | Participants | 18 weeks |
|
18 weeks
Serious adverse events were collected on a condition-by-condition basis. Non-serious adverse event information was assessed in such a manner that the specific Adverse Event Terms cannot be separated.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Fever | General disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Non-serious Adverse Events | General disorders | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Joshua Rhein | University of Minnesota | 612-624-1966 | joshua.rhein@gmail.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Sep 1, 2015 | May 31, 2019 | Prot_SAP_000.pdf |
| ID | Term |
|---|---|
| D016919 | Meningitis, Cryptococcal |
| D016921 | Meningitis, Fungal |
| D008581 | Meningitis |
| ID | Term |
|---|---|
| D020314 | Central Nervous System Fungal Infections |
| D009181 | Mycoses |
| D001423 | Bacterial Infections and Mycoses |
| D007239 | Infections |
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| ID | Term |
|---|---|
| D020280 | Sertraline |
| ID | Term |
|---|---|
| D015057 | 1-Naphthylamine |
| D000588 | Amines |
| D009930 | Organic Chemicals |
| D009281 | Naphthalenes |
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| Medical Research Council |
| OTHER_GOV |
| Wellcome Trust | OTHER |
| Makerere University | OTHER |
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| 14 days |
| 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. | 14 weeks |
| 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. | 14 weeks |
| 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. | 14 days |
| 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 | 18 weeks |
| 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. | 18 weeks |
| Mbarara |
| Uganda |
| Zhai B, Wu C, Wang L, Sachs MS, Lin X. The antidepressant sertraline provides a promising therapeutic option for neurotropic cryptococcal infections. Antimicrob Agents Chemother. 2012 Jul;56(7):3758-66. doi: 10.1128/AAC.00212-12. Epub 2012 Apr 16. |
| 26324276 | Background | Smith KD, Achan B, Hullsiek KH, McDonald TR, Okagaki LH, Alhadab AA, Akampurira A, Rhein JR, Meya DB, Boulware DR, Nielsen K; ASTRO-CM/COAT Team. Increased Antifungal Drug Resistance in Clinical Isolates of Cryptococcus neoformans in Uganda. Antimicrob Agents Chemother. 2015 Dec;59(12):7197-204. doi: 10.1128/AAC.01299-15. Epub 2015 Aug 31. |
| 31345462 | Result | Rhein J, Huppler Hullsiek K, Tugume L, Nuwagira E, Mpoza E, Evans EE, Kiggundu R, Pastick KA, Ssebambulidde K, Akampurira A, Williams DA, Bangdiwala AS, Abassi M, Musubire AK, Nicol MR, Muzoora C, Meya DB, Boulware DR; ASTRO-CM team. Adjunctive sertraline for HIV-associated cryptococcal meningitis: a randomised, placebo-controlled, double-blind phase 3 trial. Lancet Infect Dis. 2019 Aug;19(8):843-851. doi: 10.1016/S1473-3099(19)30127-6. |
| 39972326 | Derived | Sadiq A, Kwizera R, Kiiza TK, Ayebare P, Ahimbisibwe C, Ndyetukira JF, Boulware DR, Meya DB. Experiences, challenges, gaps, and strategies for counselling persons presenting with advanced HIV-associated meningitis in Uganda. AIDS Res Ther. 2025 Feb 19;22(1):21. doi: 10.1186/s12981-025-00705-z. |
| 38152404 | Derived | Okurut S, Boulware DR, Okafor E, Rhein J, Kajumbula H, Bagaya BS, Bwanga F, Olobo JO, Manabe YC, Meya DB, Janoff EN. Divergent neuroimmune signatures in the cerebrospinal fluid predict differential gender-specific survival among patients with HIV-associated cryptococcal meningitis. Front Immunol. 2023 Dec 13;14:1275443. doi: 10.3389/fimmu.2023.1275443. eCollection 2023. |
| 36303432 | Derived | Bahr NC, Skipper CP, Huppler-Hullsiek K, Ssebambulidde K, Morawski BM, Engen NW, Nuwagira E, Quinn CM, Ramachandran PS, Evans EE, Lofgren SM, Abassi M, Muzoora C, Wilson MR, Meya DB, Rhein J, Boulware DR. Recurrence of Symptoms Following Cryptococcal Meningitis: Characterizing a Diagnostic Conundrum With Multiple Etiologies. Clin Infect Dis. 2023 Mar 21;76(6):1080-1087. doi: 10.1093/cid/ciac853. |
| 33677986 | Derived | Lofgren SM, Nicol MR, Kandole TK, Castillo-Mancilla J, Anderson PL, Mpoza E, Tugume L, Bangdiwala AS, Ssebambulidde K, Hullsiek KH, Rhein J, Meya DB, Boulware DR. Short Communication: A Descriptive Analysis of Dried Blood Spot Adherence Testing Among Ugandans with HIV Presenting with Cryptococcal Meningitis. AIDS Res Hum Retroviruses. 2021 Jul;37(7):529-533. doi: 10.1089/AID.2020.0202. Epub 2021 Apr 12. |
| 32843994 | Derived | Kwizera R, Sadiq A, Ndyetukira JF, Nalintya E, Williams D, Rhein J, Boulware DR, Meya DB; COAT and ASTRO trial teams. Impact of community engagement and social support on the outcomes of HIV-related meningitis clinical trials in a resource-limited setting. Res Involv Engagem. 2020 Aug 20;6:49. doi: 10.1186/s40900-020-00228-z. eCollection 2020. |
| 31242860 | Derived | Ahimbisibwe C, Kwizera R, Ndyetukira JF, Kugonza F, Sadiq A, Hullsiek KH, Williams DA, Rhein J, Boulware DR, Meya DB. Management of amphotericin-induced phlebitis among HIV patients with cryptococcal meningitis in a resource-limited setting: a prospective cohort study. BMC Infect Dis. 2019 Jun 26;19(1):558. doi: 10.1186/s12879-019-4209-7. |
| 30345376 | Derived | Atherton RR, Ellis J, Cresswell FV, Rhein J, Boulware DR. Ophthalmic signs in Ugandan adults with HIV-associated cryptococcal meningitis: A nested analysis of the ASTRO-CM cohort. Wellcome Open Res. 2018 Oct 12;3:80. doi: 10.12688/wellcomeopenres.14666.2. eCollection 2018. |
| 30325463 | Derived | Tugume L, Rhein J, Hullsiek KH, Mpoza E, Kiggundu R, Ssebambulidde K, Schutz C, Taseera K, Williams DA, Abassi M, Muzoora C, Musubire AK, Meintjes G, Meya DB, Boulware DR; COAT and ASTRO-CM teams. HIV-Associated Cryptococcal Meningitis Occurring at Relatively Higher CD4 Counts. J Infect Dis. 2019 Feb 23;219(6):877-883. doi: 10.1093/infdis/jiy602. |
| 30256903 | Derived | Ssebambulidde K, Bangdiwala AS, Kwizera R, Kandole TK, Tugume L, Kiggundu R, Mpoza E, Nuwagira E, Williams DA, Lofgren SM, Abassi M, Musubire AK, Cresswell FV, Rhein J, Muzoora C, Hullsiek KH, Boulware DR, Meya DB; Adjunctive Sertraline for Treatment of HIV-associated Cryptococcal Meningitis Team. Symptomatic Cryptococcal Antigenemia Presenting as Early Cryptococcal Meningitis With Negative Cerebral Spinal Fluid Analysis. Clin Infect Dis. 2019 May 30;68(12):2094-2098. doi: 10.1093/cid/ciy817. |
| Accordia Global Health Foundation | View source |
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. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Median | Inter-Quartile Range | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
|
|
| Secondary | Safety (Occurence of Adverse Events) | Safety and tolerability of adjunctive sertraline (grade 4-5) adverse reactions | Posted | Number | events | 18 weeks |
|
|
|
| Secondary | Count of Participants With Cerebrospinal Fluid Sterility | Number of participants with sterile cerebrospinal fluid at 2 weeks | Posted | Count of Participants | Participants | 14 days |
|
|
|
| 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. | Posted | Mean | 95% Confidence Interval | score on a scale | 14 weeks |
|
|
|
| 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. | Posted | Mean | 95% Confidence Interval | score | 14 weeks |
|
|
|
| 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. | Posted | Mean | 95% Confidence Interval | -log10 CFU/ml/day | 14 days |
|
|
|
| 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 | Posted | Count of Participants | Participants | 18 weeks |
|
|
|
| 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. | Posted | Count of Participants | Participants | 18 weeks |
|
|
|
| 106 |
| 231 |
| 121 |
| 231 |
| 65 |
| 231 |
| EG001 | 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. | 120 | 229 | 141 | 229 | 66 | 229 |
| Infection | Infections and infestations | Non-systematic Assessment |
|
| Hypotension | General disorders | Non-systematic Assessment |
|
| Thrombosis | Blood and lymphatic system disorders | Non-systematic Assessment |
|
| Diarrhea | Gastrointestinal disorders | Non-systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | Non-systematic Assessment |
|
| Altered Mental Status | Psychiatric disorders | Non-systematic Assessment |
|
| Headache | General disorders | Non-systematic Assessment |
|
| Seizure | Nervous system disorders | Non-systematic Assessment |
|
| Respiratory Distress | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Elevated Creatinine | Blood and lymphatic system disorders | Non-systematic Assessment |
|
| Hypokalemia | Blood and lymphatic system disorders | Non-systematic Assessment |
|
| Hyperkalemia | Blood and lymphatic system disorders | Non-systematic Assessment |
|
| Hyponatremia | Blood and lymphatic system disorders | Non-systematic Assessment |
|
| Hypernatremia | Blood and lymphatic system disorders | Non-systematic Assessment |
|
| Hypomagnesemia | Blood and lymphatic system disorders | Non-systematic Assessment |
|
| Acidosis | Blood and lymphatic system disorders | Non-systematic Assessment |
|
| Anemia | Blood and lymphatic system disorders | Non-systematic Assessment |
|
| Leukopenia | Blood and lymphatic system disorders | Non-systematic Assessment |
|
| Neutropenia | Blood and lymphatic system disorders | Non-systematic Assessment |
|
| Thrombocytopenia | Blood and lymphatic system disorders | Non-systematic Assessment |
|
| Lymphopenia | Blood and lymphatic system disorders | Non-systematic Assessment |
|
| Elevated ALT | Blood and lymphatic system disorders | Non-systematic Assessment |
|
| Elevated AST | Blood and lymphatic system disorders | Non-systematic Assessment |
|
| Elevated Bilirubin | Blood and lymphatic system disorders | Non-systematic Assessment |
|
| Anorexia | General disorders | Non-systematic Assessment |
|
Not provided
Not provided
| D003453 | Cryptococcosis |
| D002494 | Central Nervous System Infections |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D000090862 | Neuroinflammatory Diseases |
| D011084 |
| Polycyclic Aromatic Hydrocarbons |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D011083 | Polycyclic Compounds |