The Efficacy of L-Carnitine in the Management of Acute Clozapine Intoxication

NCT05632094 | Unknown Phase 2 DMC

• 1 other identifier: 2302
• Study Type: interventional
• Target: 40
• Locations: 0 countries
• Sites: N/A

Brief 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. 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.

Conditions

Clozapine Poisoning

Keywords

Clozapine Toxicity; Clozapine Poisoning; Clozapine Intoxication; L-Carnitine; Antioxidant; Egypt

Outcome Measures

Primary Outcomes (3)

• Mortality

  Death

  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.

  up to 14 days

• Cardiotoxicity

  Changes in the rate of sinus rhythm and QT interval in Electrocardiogram

  up to 14 days

Secondary Outcomes (2)

• Intensive care unit admission

  up to 14 days

• Duration of hospital stay

  up to 14 days

Study Arms (2)

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

Dietary Supplement: L-Carnitine

Interventions

L-Carnitine DIETARY_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.

L-Carnitine Group

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Alexandria University: lead

Related Publications (5)

• 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

  BACKGROUND

• 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.

  PMID: 30465787 BACKGROUND

• Pourahmad 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

• 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.

  PMID: 32440337 BACKGROUND

• Elgazzar 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.

  PMID: 33401984 BACKGROUND

MeSH Terms

Interventions

Carnitine

Intervention Hierarchy (Ancestors)

Trimethyl Ammonium Compounds; Quaternary Ammonium Compounds; Amines; Organic Chemicals

Central Study Contacts

Zahraa K Sobh, MD

CONTACT

01020744739; zahraa.sobh@alexmed.edu.eg

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Forensic Medicine and Clinical Toxicology

Model Details: 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.

Study Record Dates

• First Submitted: November 10, 2022
• First Posted: November 30, 2022
• Study Start: June 1, 2023
• Primary Completion: June 1, 2024
• Study Completion: December 1, 2024
• Last Updated: December 2, 2022

Record last verified: 2022-11