Clinical trial NCT02404155: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Schizophrenia
Lead sponsor: University of Maryland, Baltimore
Sponsor class: OTHER
First posted: 2015-03-31
Enrollment: 274
Sex: ALL
Minimum age (years): 18
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


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)\*

Primary outcomes:
measure: Change in White Blood Cell (WBC) (mm3) and Absolute Neutrophil Counts (ANC) (mm3) in Persons According to Presence of the DARC Null Allele.
timeFrame: 24 week period baseline and endpoint
measure: Number of Episodes of Agranulocytosis (Count).
timeFrame: 6 months
Secondary outcomes:
Other outcomes:
Locations:
city: Catonsville
country: United States
facility: Maryland Psychiatric Research Center
state: Maryland
Study officials:
affiliation: Principal Investigator
name: Deanna L Kelly, Pharm.D, BCPP
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.