Nor)Clozapine Kinetics and Side Effects in Therapy Resistant Schizophrenia and the Optimal Sampling Time for Therapeutic Drug Monitoring

NCT06749041 | Not Yet Recruiting

• 1 other identifier: COTTONS-v2-22/11/2024
• Study Type: observational
• Target: 60
• Locations: 0 countries
• Sites: N/A

Brief Summary

The goal of this observational study is to better understand how clozapine treatment can be tailored as regards minimizing side effects and optimizing efficacy and monitoring. Firstly, how clozapine is broken down into norclozapine in the liver and how both clozapine and norclozapine affect side effects are examined. In order to investigate this metabolization process in the liver inflammation levels in the blood are assessed, which inhibit the conversion of clozapine into norclozapine. In addition, various factors related to physical health are assessed, such as blood sugar, cholesterol, weight, waist circumference, blood pressure and heart rate. The role of hormones is investigated, such as cortisol, a stress hormone that affects metabolism and stress levels. Amino acids are examined, which are building blocks of proteins, and specific parts of DNA that influence clozapine metabolism. In addition, investigation follows whether 12 hours after ingestion is a well-chosen time at which the amount of clozapine is measured in the blood in case of ingestion once a day and twice a day. Finally, specific side effects of clozapine are assessed - with special attention to stool - and the severity of the psychiatric symptoms in patients with therapy resistant schizophrenia spectrum disorders.

Conditions

Cardiovascular Side Effects of Clozapine; Neutropenia Due to Clozapine; General Side Effects of Clozapine; Constipation Due to Clozapine; Symptoms of Schizophrenia; Optimal Blood Sampling Time for Clozapine in Patients Who Receive Clozapine Once and Twice Daily; Clozapine and Norclozapine Plasma Level Concentrations

Keywords

cardiovascular side effects; neutropenia; general side effects of clozapine; constipation; symptoms of schizophrenia; optimal blood sampling time; clozapine and norclozapine plasma level concentrations

Outcome Measures

Primary Outcomes (1)

• Correlation between serum level HbA1c and (nor)clozapine concentrations and ratio.

  Assessed using a PK-PD turn over model.

  For each patient two years of follow-up will be collected (until a maximum of 01-12-2027).

Secondary Outcomes (10)

• Validation of an existing population pharmacokinetic model, assessing the validity of the current 12-hour post-intake sampling practice, determining the optimal sampling window for once-daily clozapine TDM.

  For the secondary endpoint pertaining to the sample times retrospective data will be collected from 01-02-2024 up to 01-02-2025.

• The validity of the current 12-hour post-intake sampling practice.

  For the secondary endpoint pertaining to the sample times retrospective data will be collected from 01-02-2024 up to 01-02-2025.

• The optimal sampling window for once-daily clozapine therapeutic drug monitoring.

  For the secondary endpoint pertaining to the sample times retrospective data will be collected from 01-02-2024 up to 01-02-2025.

• The influence of demographic and clinical parameters on the pharmacokinetics and -dynamics of clozapine and norclozapine.

  For each patient two years of follow-up will be collected (until a maximum of 01-12-2027).

• The correlation of other metabolic and multiple laboratory parameters on the pharmacokinetics and -dynamics of clozapine and norclozapine.

  For each patient two years of follow-up will be collected (until a maximum of 01-12-2027).

Study Arms (1)

Adult patients with treatment resistant schizophrenia spectrum disorders receiving clozapine.

Adult patients (age between 18 and 70) with treatment resistant schizophrenia of schizoaffective disorder, treated with oral, once or twice-daily clozapine.

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

The population includes adult patients (age between 18 and 70) with treatment resistant schizophrenia of schizoaffective disorder, treated with oral, once or twice-daily clozapine. Data will be collected from mental healthcare organization GGZ-NHN. All the patients have been treated with clozapine as part of standard care, as well as sampled routinely as part of standard care.

You may qualify if:

• Standard treatment of a stable, oral dose of clozapine for at least one week (at steady state).
• Age between 18-70 years.
• Registered time of intake as well as sampling time and dosage.
• Registered smoking status (yes/no).
• At least two samples in the elimination phase of clozapine with both clozapine and norclozapine measured.
• Measurement of the white cell count at least every three months or more often.
• Subjects should be able to understand the study information and procedures and give informed consent or when incapacitated subjects are not reliably able to give informed consent their legal representatives should give informed consent under the condition that these subjects are willing to participate.

You may not qualify if:

• Pregnancy.
• Malignancy or treatment with immunosuppressive medication.
• Samples where cessation, start or dose change of interacting co-medication (such as valproic acid, gemfibrozil, fluvoxamine, omeprazole and cyclic oral contraceptives \[21 on, 7 days off\]) or changes in use of tobacco containing products occurred within seven days prior to blood sampling (21, 28, 34, 35).
• Acute inflammation, infection or samples shortly after intoxication. In case this information is unknown, it may be derived by large unexpected change in levels compared to previous or target levels.
• Not sampled at Starlet (blood collection site) or sampled by dried blood spot
• Unknown status of smoking (including vaping).
• Unknown time of intake of clozapine.
• Unknown time of blood sampling.
• If informed consent is not obtained by the patient or by a legal representative in a mentally incapacitated patient, i.e. a legally incompetent adult.

Sponsors & Collaborators

• GGZ Noord-Holland-Noord: lead

Biospecimen

Retention: SAMPLES WITH DNA

Clozapine and norclozapine concentrations, fasting glucose, serum level HbA1c, insulin, HOMA-IR, triglycerides, HDL, LDL, total cholesterol, the absolute neutrophil count (ANC), inflammation markers, phenylalanine and tyrosine, the genes CYP2C19 and CYP3A4 and genes related to metabolic markers.

MeSH Terms

Conditions

Neutropenia; Constipation

Condition Hierarchy (Ancestors)

Agranulocytosis; Leukopenia; Cytopenia; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukocyte Disorders; Signs and Symptoms, Digestive; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Officials

• Paul Bank, PharmD, PhD

  North West Clinics

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Selene Veerman, MD, PhD

CONTACT

+31623993164; s.veerman@ggz-nhn.nl

Jan Bogers, MD

CONTACT

+31613731329; j.bogers@rivierduinen.nl

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: OTHER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 19, 2024
• First Posted: December 27, 2024
• Study Start: December 23, 2024
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2027
• Last Updated: December 30, 2024

Record last verified: 2024-12