Cardiovascular Side Effects of ClozapineCOTTONSNCT06749041
Nor)Clozapine Kinetics and Side Effects in Therapy Resistant Schizophrenia and the Optimal Sampling Time for Therapeutic Drug Monitoring
An observational study of Cardiovascular Side Effects of Clozapine and Neutropenia Due to Clozapine, run by GGZ Noord-Holland-Noord.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Cardiovascular Side Effects of Clozapine, Neutropenia Due to Clozapine, General Side Effects of Clozapine
- Type of treatment
- Pill or oral medicine
- How many people
- 60 participants
- Where
- No sites listed yet
- Study dates
- 23 Dec 2024to 1 Dec 2027
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
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.
Who may be able to join
- 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.
- Routine metabolic screening performed at moment of inclusion.
- 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.
Who cannot join
- 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).
Show all 9Show fewer
- 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.
Trial locations and contacts
No sites are listed yet. Contact the study team or a site near you to ask about taking part.
About this study
Official title: Clozapine OpTimal Timing for Optimal moNitoring and Side Effects
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.
Read the detailed description
Rationale:
Therapeutic drug monitoring (TDM) is essential for clozapine and can enhance therapeutic outcomes and minimize side effects. As of yet, research on (nor)clozapine concentrations and their association to metabolic side effects is limited and inconclusive. Unfortunately, not enough is known about individual risk factors for developing metabolic side effects to personalize clozapine treatment. It would be desirable to have another way to predict which clozapine users are at increased risk of developing severe side effects. Current guidelines are based on limited evidence, potentially resulting in inconsistent or suboptimal monitoring and management.
Objective:
The primary objective is to evaluate the correlation between (nor)clozapine kinetics and serum level HbA1c. Secondary objectives include validating 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 and assessing the correlation of other metabolic and multiple laboratory parameters and influence of demographic and clinical parameters on the pharmacokinetics and -dynamics of clozapine and norclozapine.
- 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
- Keywords
- cardiovascular side effects, neutropenia, general side effects of clozapine, constipation, symptoms of schizophrenia, optimal blood sampling time, clozapine and norclozapine plasma level concentrations
- Medical subject headings
- Neutropenia, Constipation
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| 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. |
What is being measured
The primary outcome is the main question the study is designed to answer.
Correlation between serum level HbA1c and (nor)clozapine concentrations and ratio.
Assessed using a PK-PD turn over model.
Measured: 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.
The predictive performance of the model by Beex et al. (2023) for our population will be assessed through calculations of the prediction error for each observation as well as the root mean square error to measure the overall prediction accuracy.
- Percentage difference in clozapine and norclozapine median concentrations predicted 10, 11, 13 and 14-hour post intake (based on clinical samples) compared to median concentrations at current reference sampling time of 12-hour post intake.
- Percentage difference in clozapine and norclozapine concentrations based on different sampling times across entire concentration-time profiles to identify optimal sampling time or window within current therapeutic window of 350-700 μg/L.
Measured: 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.
Percentage difference in clozapine and norclozapine median concentrations predicted 10, 11, 13 and 14-hour post intake (based on clinical samples) compared to median concentrations at current reference sampling time of 12-hour post intake.
Measured: 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.
Percentage difference in clozapine and norclozapine concentrations based on different sampling times across entire concentration-time profiles to identify optimal sampling time or window within current therapeutic window of 350-700 μg/L.
Measured: 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.
Effect of covariates on the pharmacokinetics of clozapine, the metabolite norclozapine (and clozapine/norclozapine ratio). Covariates to be studied include: age, estradiol, comedication (e.g. fluvoxamine), ethnicity, pharmacogenetics, smoking behaviour, inflammation markers, phenylalanine and tyrosine.
Measured: 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.
Correlation between other metabolic parameters (such as fasting glucose, insulin, HOMA-IR, triglycerides, HDL, LDL, total cholesterol, BMI, abdominal circumference, blood pressure and heart rate)..
Measured: For each patient two years of follow-up will be collected (until a maximum of 01-12-2027).
Correlation between absolute neutrophilic count (ANC) and total white cell count (WCC) and the (nor)clozapine concentrations and ratio.
Correlation between ANC and TWC and the (nor)clozapine concentrations and ratio will be assessed using a PK-PD turn over model.
Measured: For each patient two years of follow-up will be collected (until a maximum of 01-12-2027).
Correlation between general side effects of clozapine and the (nor)clozapine concentrations and ratio.
Correlation between Glasgow Antipsychotic Side-effect Scale (GASS-C) and the (nor)clozapine concentrations and ratio will be assessed using a PK-PD turn over model.
Measured: For each patient two years of follow-up will be collected (until a maximum of 01-12-2027).
Correlation between constipation and the (nor)clozapine concentrations and ratio.
Correlation between the Bristol Stool Form Scale (BSFS) and the (nor)clozapine concentrations and ratio will be assessed using a PK-PD turn over model.
Measured: For each patient two years of follow-up will be collected (until a maximum of 01-12-2027).
Correlation between symptoms of schizophrenia and the (nor)clozapine concentrations and ratio.
Correlation between the Positive and Negative Syndrome Scale (PANSS-6) and the (nor)clozapine concentrations and ratio will be assessed using a PK-PD turn over model.
Measured: For each patient two years of follow-up will be collected (until a maximum of 01-12-2027).
The effect of cortisol concentration and genetics on the correlation of (nor)clozapine concentrations and/or ratio on the metabolic markers.
The influence of cortisol concentration and genetics on (nor)clozapine concentrations and/or ratio on the metabolic markers.
Measured: For each patient two years of follow-up will be collected (until a maximum of 01-12-2027).
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Dec 2024
- Study start23 Dec 2024 (estimated)
- Primary completion1 Dec 2027 (estimated)
- Study completion1 Dec 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Cardiovascular Side Effects of ClozapineStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Other
- Enrolment
- 60 participants (estimated)
Sponsor and investigators
- Lead sponsor
- GGZ Noord-Holland-Noord
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Paul Bank, PharmD, PhD, Principal investigator, North West Clinics
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06749041
- Sponsor's protocol ID
- COTTONS-v2-22/11/2024
- Acronym
- COTTONS
- Status last verified
- Dec 2024
- First submitted
- 19 Dec 2024
- Last updated
- 30 Dec 2024
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 30 Dec 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Clozapine OpTimal Timing for Optimal moNitoring and Side Effects
- ClinicalTrials.gov ID
- NCT06749041
- Acronym / sponsor ID
- COTTONS / COTTONS-v2-22/11/2024
- 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
- Keywords
- cardiovascular side effects, neutropenia, general side effects of clozapine, constipation, symptoms of schizophrenia, optimal blood sampling time, clozapine and norclozapine plasma level concentrations
- Study type
- Observational
- Recruitment status
- Not yet recruiting
- Enrolment
- 60 participants (estimated)
- Lead sponsor
- GGZ Noord-Holland-NoordUniversity, hospital or other
- Study start
- 23 Dec 2024 (estimated)
- Primary completion
- 1 Dec 2027 (estimated)
- Study completion
- 1 Dec 2027 (estimated)
- First posted
- 27 Dec 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
Rationale:
Therapeutic drug monitoring (TDM) is essential for clozapine and can enhance therapeutic outcomes and minimize side effects. As of yet, research on (nor)clozapine concentrations and their association to metabolic side effects is limited and inconclusive. Unfortunately, not enough is known about individual risk factors for developing metabolic side effects to personalize clozapine treatment. It would be desirable to have another way to predict which clozapine users are at increased risk of developing severe side effects. Current guidelines are based on limited evidence, potentially resulting in inconsistent or suboptimal monitoring and management.
Objective:
The primary objective is to evaluate the correlation between (nor)clozapine kinetics and serum level HbA1c. Secondary objectives include validating 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 and assessing the correlation of other metabolic and multiple laboratory parameters and influence of demographic and clinical parameters on the pharmacokinetics and -dynamics of clozapine and norclozapine.
Study design
- Observational model
- Cohort
- Time perspective
- Other
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| 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. |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- 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.
Key inclusion criteria (8 listed)
- 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.
Key exclusion criteria (9 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Correlation between serum level HbA1c and (nor)clozapine concentrations and ratio.
Time frame: For each patient two years of follow-up will be collected (until a maximum of 01-12-2027).
Assessed using a PK-PD turn over model.
10 secondary outcomes
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: For each patient two years of follow-up will be collected (until a maximum of 01-12-2027).
Correlation between absolute neutrophilic count (ANC) and total white cell count (WCC) and the (nor)clozapine concentrations and ratio.
Time frame: For each patient two years of follow-up will be collected (until a maximum of 01-12-2027).
Correlation between general side effects of clozapine and the (nor)clozapine concentrations and ratio.
Time frame: For each patient two years of follow-up will be collected (until a maximum of 01-12-2027).
Correlation between constipation and the (nor)clozapine concentrations and ratio.
Time frame: For each patient two years of follow-up will be collected (until a maximum of 01-12-2027).
Correlation between symptoms of schizophrenia and the (nor)clozapine concentrations and ratio.
Time frame: For each patient two years of follow-up will be collected (until a maximum of 01-12-2027).
The effect of cortisol concentration and genetics on the correlation of (nor)clozapine concentrations and/or ratio on the metabolic markers.
Time frame: For each patient two years of follow-up will be collected (until a maximum of 01-12-2027).
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Dec 2024.
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Paul Bank, PharmD, PhD principal investigator
North West Clinics
Questions about this trial
What is this clinical trial studying?
An observational study of Cardiovascular Side Effects of Clozapine and Neutropenia Due to Clozapine, run by GGZ Noord-Holland-Noord.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: opening soon, as of the sponsor's last update on 30 Dec 2024. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Selene Veerman, MD, PhD (+31623993164, s.veerman@ggz-nhn.nl), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Correlation between serum level HbA1c and (nor)clozapine concentrations and ratio. (time frame: For each patient two years of follow-up will be collected (until a maximum of 01-12-2027).). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Dec 2024.