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

January 11, 2023 updated by: Deanna Kelly, University of Maryland, Baltimore
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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

274

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Maryland
      • Catonsville, Maryland, United States, 21228
        • Maryland Psychiatric Research Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 64 years (ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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)*

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: NA
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Clozapine
Drug: Clozapine

What is the study measuring?

Primary Outcome Measures

Outcome Measure
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.
Time Frame: 24 week period baseline and endpoint
24 week period baseline and endpoint
Number of Episodes of Agranulocytosis (Count).
Time Frame: 6 months
6 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Maryland, Baltimore

Investigators

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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

July 1, 2015

Primary Completion (ACTUAL)

October 26, 2021

Study Completion (ACTUAL)

October 26, 2021

Study Registration Dates

First Submitted

February 26, 2015

First Submitted That Met QC Criteria

March 25, 2015

First Posted (ESTIMATE)

March 31, 2015

Study Record Updates

Last Update Posted (ACTUAL)

January 31, 2023

Last Update Submitted That Met QC Criteria

January 11, 2023

Last Verified

January 1, 2023

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • HP-00063484

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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