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Clozapine (CLZ) is the most effective antipsychotic for treatment-refractory schizophrenia (SZ). Despite the overwhelming evidence of superior efficacy, CLZ is infrequently prescribed in the US, at a considerably lower rate than the estimated prevalence of treatment-resistant SZ, especially for African-Americans (AA). Recent evidence suggests that low Absolute Neutrophil Counts (ANC), either at baseline or during treatment are a significant barrier to CLZ use in AA patients in the US, where guidelines mandate CLZ discontinuation if ANC drops below 1500 cells/mm3. The investigators group has found that discontinuation of CLZ in AA patients is over twice that in European-American (EA) patients (N~400; 42% vs.19%, P=0.041) and initiation rates are 50% lower. In a Statewide study (N=1875), the investigators reported that discontinuation was more frequently due to neutropenia in the AA sample, though no AA had developed agranulocytosis (8 cases in EA). Benign Ethnic Neutropenia (BEN) in people of African ancestry, including AAs, identifies a group (50% of AA) with low ANCs but no increased risk of agranulocytosis or infection. Low baseline or in-treatment fluctuations requiring CLZ discontinuation under current prescribing guidelines are common in CLZ-treated persons with BEN. In the investigators recent pilot study of N=12 AA patients with BEN, treatment was safely and successfully continued with CLZ despite low baseline ANC (outside current guidelines). Recent evidence implicates a polymorphism in the Duffy Antigen Receptor Chemokine (DARC) gene in the pathophysiology of BEN. In homozygotes (FY-/-) for the DARC null allele, mean within-subject neutrophil counts are reduced, resulting in sporadic ANC <1500 cells/mm3 in 10-15% of people with the allele. In population studies, the FY-/- genotype is found in 0.01% of EAs, 99.3% of sub-Saharan Africans (SSA), and 68% of AAs. Further, a missense DARC mutation has been reported to interact with the DARC FY-/- in determining low WBC in AAs. Normal patterns of week-to-week fluctuation in ANC levels in individuals of African ancestry with BEN and the DARC null genotype are not known, and no published research has examined variation in ANC in African ancestry CLZ-treated SZ patients with BEN and the DARC null genotype (FY-/-). Such data are also lacking on individuals with BEN without the DARC null genotype. Conducting such research will generate genetic marker and safety data that could be used to expand access to CLZ for AA patients who otherwise are eligible to receive this superior treatment option.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Clozapine | Experimental |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Clozapine | Drug |
|
| Measure | Description | Time Frame |
|---|---|---|
| Change in White Blood Cell (WBC) (mm3) and Absolute Neutrophil Counts (ANC) (mm3) in Persons According to Presence of the DARC Null Allele. | 24 week period baseline and endpoint | |
| Number of Episodes of Agranulocytosis (Count). | 6 months |
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Inclusion Criteria
Exclusion Criteria
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| Name | Affiliation | Role |
|---|---|---|
| Deanna L Kelly, Pharm.D, BCPP | Principal Investigator | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Maryland Psychiatric Research Center | Catonsville | Maryland | 21228 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 35358857 | Derived | Cavaliere VS, Glassman M, DiPaula BA, Mackowick M, Wehring HJ, Liu F, Chen S, Park J, Love RC, Richardson CM, Vyas G, Kearns AM, Kelly DL. Anti-aggressive effects of clozapine in involuntarily committed black patients with severe mental illness. Schizophr Res. 2022 May;243:163-169. doi: 10.1016/j.schres.2022.03.006. Epub 2022 Mar 28. |
| Label | URL |
|---|---|
| Maryland Psychiatric Research Center | View source |
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| ID | Title | Description |
|---|---|---|
| FG000 | Clozapine | Clozapine |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Clozapine | Clozapine |
| 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 | Change in White Blood Cell (WBC) (mm3) and Absolute Neutrophil Counts (ANC) (mm3) in Persons According to Presence of the DARC Null Allele. | Genetic information was only able to be collected and analyzed on 249 of t he 274 overall participants. | Posted | Mean | Standard Deviation | cells/mm3 | 24 week period baseline and endpoint |
|
|
For each participants 6 months of enrollment
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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 | Clozapine | Clozapine | 0 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Prolapsed Rectum | Gastrointestinal disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Abdominal Pain | Gastrointestinal disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Deanna L. Kelly, Pharm.D., BCPP | Maryland Psychiatric Research Center | 410-402-6860 | dlkelly@som.umaryland.edu |
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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 | Aug 27, 2019 | Nov 1, 2022 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D012559 | Schizophrenia |
| ID | Term |
|---|---|
| D019967 | Schizophrenia Spectrum and Other Psychotic Disorders |
| D001523 | Mental Disorders |
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| ID | Term |
|---|---|
| D003024 | Clozapine |
| ID | Term |
|---|---|
| D003984 | Dibenzazepines |
| D006575 | Heterocyclic Compounds, 3-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
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| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
|
| Primary | Number of Episodes of Agranulocytosis (Count). | Posted | Number | Episodes | 6 months |
|
|
|
| 274 |
| 19 |
| 274 |
| 264 |
| 274 |
| Stroke | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Seizure | Nervous system disorders | Systematic Assessment |
|
| Pulmonary Emobolism | Cardiac disorders | Systematic Assessment |
|
| Myocarditis | Cardiac disorders | Systematic Assessment |
|
| Hospitalization for Clinical Worsening | General disorders | Systematic Assessment |
|
| Diverticulitis | Gastrointestinal disorders | Systematic Assessment |
|
| Severe Neutropenia | Blood and lymphatic system disorders | Systematic Assessment |
|
| Dehydration | General disorders | Systematic Assessment |
|
| Urinary Tract Infection | Infections and infestations | Systematic Assessment |
|
| Atypical Neuroleptic Malignant Syndrome/ Drug Fever | General disorders | Systematic Assessment |
|
| Infection/Cellulitis | Infections and infestations | Systematic Assessment |
|
| Pneumonia | General disorders | Systematic Assessment |
|
| Severe Constipation | Gastrointestinal disorders | Systematic Assessment |
|
| Diffuse Ileus | Gastrointestinal disorders | Systematic Assessment |
|
| Pleural Effusion | General disorders | Systematic Assessment |
|
| Unresponsiveness | General disorders | Systematic Assessment |
|
| Anorexia | General disorders | Systematic Assessment |
|
| Bruising | General disorders | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | Systematic Assessment |
|
| Diarrhea | Gastrointestinal disorders | Systematic Assessment |
|
| Dizziness | General disorders | Systematic Assessment |
|
| Dry Mouth | General disorders | Systematic Assessment |
|
| Enuresis | Gastrointestinal disorders | Systematic Assessment |
|
| Fever | General disorders | Systematic Assessment |
|
| Headache | General disorders | Systematic Assessment |
|
| Insomnia | General disorders | Systematic Assessment |
|
| Malaise | General disorders | Systematic Assessment |
|
| Mucosal | General disorders | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | Systematic Assessment |
|
| Rash | General disorders | Systematic Assessment |
|
| Restlessness | Nervous system disorders | Systematic Assessment |
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| Salivation | Endocrine disorders | Systematic Assessment |
|
| Sedation | General disorders | Systematic Assessment |
|
| Stiffness | Musculoskeletal and connective tissue disorders | Systematic Assessment |
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| Sore Throat | General disorders | Systematic Assessment |
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| Tremors | Nervous system disorders | Systematic Assessment |
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| Urticaria | General disorders | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | Systematic Assessment |
|
| Weight loss | Gastrointestinal disorders | Systematic Assessment |
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| Tinnitus | General disorders | Systematic Assessment |
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| Abnormal Ejaculation/Erectile Dysfunction | General disorders | Systematic Assessment |
|
| Chest Pain | Cardiac disorders | Systematic Assessment |
|
| Diabetes/Hyperglycemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Disorientation/Confusion | General disorders | Systematic Assessment |
|
| Edema | General disorders | Systematic Assessment |
|
| Myocarditis | Cardiac disorders | Systematic Assessment |
|
| Myoclonus | General disorders | Systematic Assessment |
|
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