Clozapine PoisoningPhase 2NCT05632094
The Efficacy of L-Carnitine in the Management of Acute Clozapine Intoxication
A Phase 2 study testing L-Carnitine in people with Clozapine Poisoning, run by Alexandria University.
Trial summary
Clozapine is a dibenzodiazepine that is used atypical antipsychotic drug. Clozapine-induced cytotoxicity could be attributed to increases in reactive oxygen species (ROS) that oxidize mitochondrial proteins and disrupt cellular respiration. Read more about this study
- Who is it for?
- Any age
- Conditions the study is for
- Clozapine Poisoning
- What is being tested?
- L-Carnitine
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 40 participants
- Where
- No sites listed yet
- Study dates
- Jun 2023to Dec 2024
- Phase
- Phase 2
- Are there results?
- None posted in the registry
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 Any age
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- The study will include patients with moderate and severe acute clozapine poisoning. The patient's condition will be assessed on admission using a Poisoning Severity Score.
Who cannot join
- When the diagnosis of acute clozapine poisoning is unconfirmed.
- Patients with significant comorbidities, especially advanced neurological and cardiac diseases.
- Patients that ingest other drugs other than clozapine.
- Patients who presented late to the poison center (>24 hr) following clozapine intake.
- Patients received treatment before hospital admission.
Trial locations and contacts
No sites are listed yet.
About this study
Clozapine is a dibenzodiazepine that is used atypical antipsychotic drug. Clozapine-induced cytotoxicity could be attributed to increases in reactive oxygen species (ROS) that oxidize mitochondrial proteins and disrupt cellular respiration.
L-Carnitine (4-N-trimethylammonium-3-hydroxybutyric acid) is an endogenous mitochondrial membrane compound that is essential for the normal functions of mitochondria. L-Carnitine is an effective ROS scavenger that prevents lipid peroxidation.
Read more
In an animal study, it was observed that clozapine decrease L-Carnitine level in plasma which results in metabolic disorders. Subsequently, the use of supplementation L-Carnitine was recommended to attenuate clozapine-induced side effects.
An in-vitro study investigated the cytotoxic effects of clozapine on human lymphocytes and the possible protective role of L-Carnitine, the results revealed that clozapine-induced cytotoxicity attributed to oxidative stress and mitochondrial dysfunction which significantly improved upon L-Carnitine administration.
In clinical toxicology, acute clozapine toxicity results in significant morbidities and mortalities in absence of a specific antidote. Therefore, it is essential to adopt pharmaceutical intervention based on the proposed mechanism of clozapine-induced cytotoxicity.
The objective of the current research is to assess the potential beneficial effects of L-Carnitine on the acute clozapine poisoning outcome.
The study will include patients with moderate and severe acute clozapine poisoning. The patient's condition will be assessed on admission using a Poisoning Severity Score.
Patients with acute clozapine poisoning will be assigned randomly into two groups; the Conventional group and the L-Carnitine group. Then, all patients will be closely followed up for vital signs, Glasgow Coma Scale, and Electrocardiogram. Clinical and laboratory reassessments will be performed. Lastly, the outcomes will be assessed and statistical analysis of the results will be performed.
Ethical approval was obtained from the Research Ethics Committee of the Faculty of Medicine, Alexandria University. This Ethics Committee is constituted and operates according to ICH GCP Guidelines and applicable local and institutional regulations and guidelines that govern the Ethics Committees operation. Written informed consent will be obtained from clozapine-intoxicated patients or their guardians (minors or those with disturbed mental status). Full details regarding the study's aim and procedures will be provided to all participants. A code number will be assigned to ensure confidentiality and anonymous analysis of data.
Read the detailed description
Study design:
Clinical controlled randomized clinical trial (phase II) will be conducted in Poison Center. The total required sample size is 40 patients, similar to the sample size calculated in the clinical trial that verified the efficacy of IV lipid emulsion in managing clozapine toxicity.
The diagnosis will be based on the history of intake of a large dose of clozapine along with the presence of the pill container. The diagnosis of acute clozapine toxicity will be supported by the clinical findings that include significant central nervous system depression, hypotension, tachycardia, and prolongation of QT interval.
All patients will be subject to the following:
- History taking: Sociodemographic data, the amount of ingested drug, time past since ingestion, pre-hospital management, current medical complaints, past medical and surgical history.
- Clinical assessment: Glasgow coma scale, vital signs, and general examination).
- Laboratory investigations that included: arterial blood gases (ABG), complete blood count, serum sodium and potassium levels, blood glucose level, liver functions (bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT)), renal functions (urea, creatinine, blood urea nitrogen (BUN)) and cardiac enzymes.
- Electrocardiogram.
- Calculation of Poisoning Severity Score (PSS) that classifies poisoning severity as none (0), minor (1), moderate (2), severe (3), and fatal (4).
- Conditions
- Clozapine Poisoning
- Being tested
- L-Carnitine
- Keywords
- Clozapine Toxicity, Clozapine Poisoning, Clozapine Intoxication, L-Carnitine, Antioxidant, Egypt
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
L-CarnitineDietary supplement
The clozapine-intoxicated patients will receive conventional supportive care in addition to IV L-carnitine with a loading dose of 100 mg/kg IV over 30-60 min (maximum 6 g) and the maintenance dose was 50 mg/kg IV every 8 h.
| Study group | Role | What they receive |
|---|---|---|
| Conventional Group | No intervention | This group will comprise 20 patients who will receive conventional supportive care for the treatment of acute clozapine toxicity that include the following: * Airway: maintaining clear patent airways. * Breathing: oxygen inhalation, respiratory support whenever required (mechanical ventilation). * Circulation: intravenous fluids, and symptomatic treatment according to ECG abnormalities. * Decontamination: administration of activated charcoal (1 gm/kg). |
| L-Carnitine Group | Experimental | This group will comprise 20 patients who will receive conventional supportive care (same as group 1), in addition to IV L-carnitine Receives: Dietary Supplement: L-Carnitine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Mortality
Death
Measured: up to 14 days
Neurotoxicity
Changes in Scores of Glasgow Coma Scale (GCS). GCS is scored between 3 and 15, with 3 being the worst and 15 the best.
Measured: up to 14 days
Cardiotoxicity
Changes in the rate of sinus rhythm and QT interval in Electrocardiogram
Measured: up to 14 days
Secondary outcomes (2)
Intensive care unit admission
Number of patients who need intensive care unit admission
Measured: up to 14 days
Duration of hospital stay
Hours passed since admission till discharge or death
Measured: up to 14 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Nov 2022
- Study startJun 2023 (estimated)
- Primary completionJun 2024 (estimated)
- Study completionDec 2024 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Clozapine PoisoningStudies of the same condition, open and under way.
- More trials run by Alexandria UniversityThe sponsor's other registered studies.
- 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
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Clinical controlled randomized clinical trial (phase II) will be conducted in Poison Center. The total required sample size is 40 patients who suffer from acute clozapine intoxication.
- Masking
- None (open label)
- Enrolment
- 40 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Alexandria University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, zahraa khalifa sobh, Alexandria University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05632094
- Sponsor's protocol ID
- 2302
- Status last verified
- Nov 2022
- First submitted
- 10 Nov 2022
- Last updated
- 2 Dec 2022
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided: The confidentiality of the personal data of participants will be maintained. I intended to publish the current study in an international academic journal. Then, the published data could be accessed and used for any purpose.
Publications
Abbas MF, Abbas AH. Clozapine-induced myocarditis in rats: role of L-carnitine in protection. The Egypt J. Forensic Sci. Appli. Toxicol. 2016; 16(1): 141-157. doi: 10.21608/ejfsat.2016.39958
Wang W, Bai M, Jiang T, Li C, Li P, Zhou H, Wang Z, Li L, Jiang H. Clozapine-induced reduction of l-carnitine reabsorption via inhibition/down-regulation of renal carnitine/organic cation transporter 2 contributes to liver lipid metabolic disorder in mice. Toxicol Appl Pharmacol. 2019 Jan 15;363:47-56. doi: 10.1016/j.taap.2018.11.007. Epub 2018 Nov 19.
PubMed 30465787Pourahmad J, Salimi A, Imani F, Jamali Z, Ahvar N. The clozapine-induced toxicity via induction of oxidative stress and mitochondrial dysfunction in human blood lymphocytes and protecting role of L-Carnitine. Int. pharm. acta. 2020;3(1), 3e9:1-9. https://doi.org/10.22037/ipa.v3i1.32179
Sherif NA, El-Banna AS, ElBourini MM, Khalil NO. Efficacy of L-carnitine and propranolol in the management of acute theophylline toxicity. Toxicol Res (Camb). 2020 Mar 11;9(1):45-54. doi: 10.1093/toxres/tfaa002. eCollection 2020 Feb.
PubMed 32440337Elgazzar FM, Elgohary MS, Basiouny SM, Lashin HI. Intravenous lipid emulsion as an adjuvant therapy of acute clozapine poisoning. Hum Exp Toxicol. 2021 Jul;40(7):1053-1063. doi: 10.1177/0960327120983873. Epub 2021 Jan 5.
PubMed 33401984
Study at a glance
From the registry record, last updated by the sponsor on 2 Dec 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Efficacy of L-Carnitine in the Management of Acute Clozapine Intoxication
- ClinicalTrials.gov ID
- NCT05632094
- Acronym / sponsor ID
- 2302
- Conditions
- Clozapine Poisoning
- Keywords
- Clozapine Toxicity, Clozapine Poisoning, Clozapine Intoxication, L-Carnitine, Antioxidant, Egypt
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 40 participants (estimated)
- Lead sponsor
- Alexandria UniversityUniversity, hospital or other
- Study start
- Jun 2023 (estimated)
- Primary completion
- Jun 2024 (estimated)
- Study completion
- Dec 2024 (estimated)
- First posted
- 30 Nov 2022 (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.
Clozapine is a dibenzodiazepine that is used atypical antipsychotic drug. Clozapine-induced cytotoxicity could be attributed to increases in reactive oxygen species (ROS) that oxidize mitochondrial proteins and disrupt cellular respiration.
L-Carnitine (4-N-trimethylammonium-3-hydroxybutyric acid) is an endogenous mitochondrial membrane compound that is essential for the normal functions of mitochondria. L-Carnitine is an effective ROS scavenger that prevents lipid peroxidation.
In an animal study, it was observed that clozapine decrease L-Carnitine level in plasma which results in metabolic disorders. Subsequently, the use of supplementation L-Carnitine was recommended to attenuate clozapine-induced side effects.
An in-vitro study investigated the cytotoxic effects of clozapine on human lymphocytes and the possible protective role of L-Carnitine, the results revealed that clozapine-induced cytotoxicity attributed to oxidative stress and mitochondrial dysfunction which significantly improved upon L-Carnitine administration.
In clinical toxicology, acute clozapine toxicity results in significant morbidities and mortalities in absence of a specific antidote. Therefore, it is essential to adopt pharmaceutical intervention based on the proposed mechanism of clozapine-induced cytotoxicity.
The objective of the current research is to assess the potential beneficial effects of L-Carnitine on the acute clozapine poisoning outcome.
The study will include patients with moderate and severe acute clozapine poisoning. The patient's condition will be assessed on admission using a Poisoning Severity Score.
Patients with acute clozapine poisoning will be assigned randomly into two groups; the Conventional group and the L-Carnitine group. Then, all patients will be closely followed up for vital signs, Glasgow Coma Scale, and Electrocardiogram. Clinical and laboratory reassessments will be performed. Lastly, the outcomes will be assessed and statistical analysis of the results will be performed.
Ethical approval was obtained from the Research Ethics Committee of the Faculty of Medicine, Alexandria University. This Ethics Committee is constituted and operates according to ICH GCP Guidelines and applicable local and institutional regulations and guidelines that govern the Ethics Committees operation. Written informed consent will be obtained from clozapine-intoxicated patients or their guardians (minors or those with disturbed mental status). Full details regarding the study's aim and procedures will be provided to all participants. A code number will be assigned to ensure confidentiality and anonymous analysis of data.
Detailed description
Study design:
Clinical controlled randomized clinical trial (phase II) will be conducted in Poison Center. The total required sample size is 40 patients, similar to the sample size calculated in the clinical trial that verified the efficacy of IV lipid emulsion in managing clozapine toxicity.
The diagnosis will be based on the history of intake of a large dose of clozapine along with the presence of the pill container. The diagnosis of acute clozapine toxicity will be supported by the clinical findings that include significant central nervous system depression, hypotension, tachycardia, and prolongation of QT interval.
All patients will be subject to the following:
- History taking: Sociodemographic data, the amount of ingested drug, time past since ingestion, pre-hospital management, current medical complaints, past medical and surgical history.
- Clinical assessment: Glasgow coma scale, vital signs, and general examination).
- Laboratory investigations that included: arterial blood gases (ABG), complete blood count, serum sodium and potassium levels, blood glucose level, liver functions (bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT)), renal functions (urea, creatinine, blood urea nitrogen (BUN)) and cardiac enzymes.
- Electrocardiogram.
- Calculation of Poisoning Severity Score (PSS) that classifies poisoning severity as none (0), minor (1), moderate (2), severe (3), and fatal (4).
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- Clinical controlled randomized clinical trial (phase II) will be conducted in Poison Center. The total required sample size is 40 patients who suffer from acute clozapine intoxication.
| Arm | Type | Receives |
|---|---|---|
| Conventional Group | No intervention | –This group will comprise 20 patients who will receive conventional supportive care for the treatment of acute clozapine toxicity that include the following: * Airway: maintaining clear patent airways. * Breathing: oxygen inhalation, respiratory support whenever required (mechanical ventilation). * Circulation: intravenous fluids, and symptomatic treatment according to ECG abnormalities. * Decontamination: administration of activated charcoal (1 gm/kg). |
| L-Carnitine Group | Experimental | Dietary Supplement: L-CarnitineThis group will comprise 20 patients who will receive conventional supportive care (same as group 1), in addition to IV L-carnitine |
Who may qualify
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (1 listed)
- The study will include patients with moderate and severe acute clozapine poisoning. The patient's condition will be assessed on admission using a Poisoning Severity Score.
Key exclusion criteria (5 listed)
- When the diagnosis of acute clozapine poisoning is unconfirmed.
- Patients with significant comorbidities, especially advanced neurological and cardiac diseases.
- Patients that ingest other drugs other than clozapine.
- Patients who presented late to the poison center (>24 hr) following clozapine intake.
- Patients received treatment before hospital admission.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| L-CarnitineThe clozapine-intoxicated patients will receive conventional supportive care in addition to IV L-carnitine with a loading dose of 100 mg/kg IV over 30-60 min (maximum 6 g) and the maintenance dose was 50 mg/kg IV every 8 h. | Dietary supplement | L-Carnitine Group |
Primary outcome
Mortality
Time frame: up to 14 days
Death
Neurotoxicity
Time frame: up to 14 days
Changes in Scores of Glasgow Coma Scale (GCS). GCS is scored between 3 and 15, with 3 being the worst and 15 the best.
Cardiotoxicity
Time frame: up to 14 days
Changes in the rate of sinus rhythm and QT interval in Electrocardiogram
2 secondary outcomes
Intensive care unit admission
Time frame: up to 14 days
Duration of hospital stay
Time frame: up to 14 days
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Dec 2022.
- BackgroundAbbas MF, Abbas AH. Clozapine-induced myocarditis in rats: role of L-carnitine in protection. The Egypt J. Forensic Sci. Appli. Toxicol. 2016; 16(1): 141-157. doi: 10.21608/ejfsat.2016.39958
- Background: PubMed 30465787Wang W, Bai M, Jiang T, Li C, Li P, Zhou H, Wang Z, Li L, Jiang H. Clozapine-induced reduction of l-carnitine reabsorption via inhibition/down-regulation of renal carnitine/organic cation transporter 2 contributes to liver lipid metabolic disorder in mice. Toxicol Appl Pharmacol. 2019 Jan 15;363:47-56. doi: 10.1016/j.taap.2018.11.007. Epub 2018 Nov 19.
- BackgroundPourahmad J, Salimi A, Imani F, Jamali Z, Ahvar N. The clozapine-induced toxicity via induction of oxidative stress and mitochondrial dysfunction in human blood lymphocytes and protecting role of L-Carnitine. Int. pharm. acta. 2020;3(1), 3e9:1-9. https://doi.org/10.22037/ipa.v3i1.32179
- Background: PubMed 32440337Sherif NA, El-Banna AS, ElBourini MM, Khalil NO. Efficacy of L-carnitine and propranolol in the management of acute theophylline toxicity. Toxicol Res (Camb). 2020 Mar 11;9(1):45-54. doi: 10.1093/toxres/tfaa002. eCollection 2020 Feb.
- Background: PubMed 33401984Elgazzar FM, Elgohary MS, Basiouny SM, Lashin HI. Intravenous lipid emulsion as an adjuvant therapy of acute clozapine poisoning. Hum Exp Toxicol. 2021 Jul;40(7):1053-1063. doi: 10.1177/0960327120983873. Epub 2021 Jan 5.
- Individual participant dataSharing planned: Undecided. The confidentiality of the personal data of participants will be maintained. I intended to publish the current study in an international academic journal. Then, the published data could be accessed and used for any purpose.
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. This study is not recruiting at the moment.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing L-Carnitine in people with Clozapine Poisoning, run by Alexandria University.
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 1 inclusion and 5 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: status not confirmed, as of the sponsor's last update on 2 Dec 2022. 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.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Zahraa K Sobh, MD (01020744739 ext. +2, zahraa.sobh@alexmed.edu.eg), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Mortality (time frame: up to 14 days). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05632094, which also lists 5 linked publications.
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 2 Dec 2022.