Biomarker and Safety Study of Clozapine in Patients With Benign Ethnic Neutropenia (BEN) (BEN)

• ClinicalTrials.gov Identifier: NCT02404155
• Recruitment Status: Completed
• First Posted: March 31, 2015
• Results First Posted: January 31, 2023
• Last Update Posted: January 31, 2023
• Sponsor: University of Maryland, Baltimore
• Information provided by (Responsible Party): Deanna Kelly, University of Maryland, Baltimore

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Schizophrenia	Drug: Clozapine	Not Applicable

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 274 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Biomarker and Safety Study of Clozapine in Patients With Benign Ethnic Neutropenia (BEN)
• Actual Study Start Date: July 2015
• Actual Primary Completion Date: October 26, 2021
• Actual Study Completion Date: October 26, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Clozapine	Drug: Clozapine

Outcome Measures

Primary Outcome Measures :

1. Change in White Blood Cell (WBC) (mm3) and Absolute Neutrophil Counts (ANC) (mm3) in Persons According to Presence of the DARC Null Allele. [ Time Frame: 24 week period baseline and endpoint ]
2. Number of Episodes of Agranulocytosis (Count). [ Time Frame: 6 months ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 64 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria

• Eligible and recommended for clozapine treatment (e.g. treatment resistant schizophrenia, schizoaffective disorder, bipolar disorder, other psychotic disorder, delusional disorder, hostility, other documented rationale)
• Male or Female
• African Ancestry (African, African-American or African-Caribbean). This population will make up the majority of the study. However, there are cases of BEN in individuals of Middle Eastern, Caucasian, and other ethnicity. The investigators will accept these patients as they may have unknown African ancestry and genotyping will be important.
• Age: 18 to 64 years.
• History of a low absolute neutrophil count (ANC<2500 cells/mm3 in past 24 months)
• Documented ability to sign informed consent. This is a score of ≥10/12 on ESC.
• Effective birth control if of child bearing potential

Exclusion Criteria

• DSM-IV diagnosis of Mental Retardation
• Pregnancy or lactation
• History of myeloproliferative disorder
• Uncontrolled seizure disorder
• History of paralytic ileus
• History of clozapine-induced ANC < 700 mm3
• Systemic Lupus Erythematosus, Multiple Sclerosis, Hashimoto's Thyroiditis, Sjogren's Syndrome, Grave's Disease*
• Medical condition whose pathology or treatment would likely alter the presentation or treatment of schizophrenia or significantly increase the risks associated with the proposed protocol.
• Medical condition affecting patient's ability to mount an immune response
• Current bacterial or viral infection*
• Sickle cell anemia
• Positive for bacteria in urine culture*
• Temperature > 37.5 º Celsius, 99.5 º Fahrenheit*
• Current treated or untreated cancer*
• Documented nutritional deficiencies (such as Beriberi, Pellagra, Rickets, Scurvy, Keshan Disease)*

Contacts and Locations

Locations

United States, Maryland

Maryland Psychiatric Research Center

Catonsville, Maryland, United States, 21228

Sponsors and Collaborators

University of Maryland, Baltimore

Investigators

• Principal Investigator: Deanna L Kelly, Pharm.D, BCPP; Principal Investigator

  Study Documents (Full-Text)

Documents provided by Deanna Kelly, University of Maryland, Baltimore:

Study Protocol and Statistical Analysis Plan  [PDF] August 27, 2019

More Information

Additional Information:

Maryland Psychiatric Research Center 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Deanna Kelly, Principal Investigator, University of Maryland, Baltimore
• ClinicalTrials.gov Identifier: NCT02404155
• Other Study ID Numbers: HP-00063484
• First Posted: March 31, 2015
• Results First Posted: January 31, 2023
• Last Update Posted: January 31, 2023
• Last Verified: January 2023

Additional relevant MeSH terms:

Neutropenia; Schizophrenia; Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders; Agranulocytosis; Leukopenia; Cytopenia; Hematologic Diseases; Leukocyte Disorders; Clozapine; Serotonin Antagonists; Serotonin Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Physiological Effects of Drugs; Antipsychotic Agents; Tranquilizing Agents; Central Nervous System Depressants; Psychotropic Drugs; GABA Antagonists; GABA Agents