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

Tracking Information

• First Submitted Date: February 26, 2015
• First Posted Date: March 31, 2015
• Results First Submitted Date: November 2, 2022
• Results First Posted Date: January 31, 2023
• Last Update Posted Date: January 31, 2023
• Actual Study Start Date: July 2015
• Actual Primary Completion Date: October 26, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 11, 2023)

• 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 ]
• Number of Episodes of Agranulocytosis (Count). [ Time Frame: 6 months ]

Original Primary Outcome Measures (submitted: March 25, 2015)

• 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: 12 week period, with measurements weekly ]
• Number of episodes of agranulocytosis (count) or serious infection (count). [ Time Frame: 6 months ]

• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Biomarker and Safety Study of Clozapine in Patients With Benign Ethnic Neutropenia (BEN)
• Official Title: Biomarker and Safety Study of Clozapine in Patients With Benign Ethnic Neutropenia (BEN)
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Schizophrenia
• Intervention: Drug: Clozapine

Study Arms

Experimental: Clozapine

Intervention: Drug: Clozapine

• Publications *: 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 26, 2021): 274
• Original Estimated Enrollment (submitted: March 25, 2015): 250
• Actual Study Completion Date: October 26, 2021
• Actual Primary Completion Date: October 26, 2021 (Final data collection date for primary outcome measure)

Eligibility 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)*

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 64 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02404155
• Other Study ID Numbers: HP-00063484
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Deanna Kelly, University of Maryland, Baltimore
• Original Responsible Party: DKelly, University of Maryland, Principal Investigator
• Current Study Sponsor: University of Maryland, Baltimore
• Original Study Sponsor: University of Maryland
• Collaborators: Not Provided

Investigators

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

• PRS Account: University of Maryland, Baltimore
• Verification Date: January 2023