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

Primary Purpose

Clozapine Poisoning

Status
Not yet recruiting
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
L-Carnitine
Sponsored by
Alexandria University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Clozapine Poisoning focused on measuring Clozapine Toxicity, Clozapine Poisoning, Clozapine Intoxication, L-Carnitine, Antioxidant, Egypt

Eligibility Criteria

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Inclusion Criteria: 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. Exclusion criteria: 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.

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    No Intervention

    Experimental

    Arm Label

    Conventional Group

    L-Carnitine Group

    Arm Description

    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).

    This group will comprise 20 patients who will receive conventional supportive care (same as group 1), in addition to IV L-carnitine

    Outcomes

    Primary Outcome Measures

    Mortality
    Death
    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.
    Cardiotoxicity
    Changes in the rate of sinus rhythm and QT interval in Electrocardiogram

    Secondary Outcome Measures

    Intensive care unit admission
    Number of patients who need intensive care unit admission
    Duration of hospital stay
    Hours passed since admission till discharge or death

    Full Information

    First Posted
    November 10, 2022
    Last Updated
    November 30, 2022
    Sponsor
    Alexandria University
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    1. Study Identification

    Unique Protocol Identification Number
    NCT05632094
    Brief Title
    The Efficacy of L-Carnitine in the Management of Acute Clozapine Intoxication
    Official Title
    The Efficacy of L-Carnitine in the Management of Acute Clozapine Intoxication
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    November 2022
    Overall Recruitment Status
    Not yet recruiting
    Study Start Date
    June 2023 (Anticipated)
    Primary Completion Date
    June 2024 (Anticipated)
    Study Completion Date
    December 2024 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Principal Investigator
    Name of the Sponsor
    Alexandria University

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    No
    Studies a U.S. FDA-regulated Device Product
    No
    Data Monitoring Committee
    Yes

    5. Study Description

    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.
    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).

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Clozapine Poisoning
    Keywords
    Clozapine Toxicity, Clozapine Poisoning, Clozapine Intoxication, L-Carnitine, Antioxidant, Egypt

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 2
    Interventional Study Model
    Parallel Assignment
    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)
    Allocation
    Randomized
    Enrollment
    40 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    Conventional Group
    Arm Type
    No Intervention
    Arm Description
    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).
    Arm Title
    L-Carnitine Group
    Arm Type
    Experimental
    Arm Description
    This group will comprise 20 patients who will receive conventional supportive care (same as group 1), in addition to IV L-carnitine
    Intervention Type
    Dietary Supplement
    Intervention Name(s)
    L-Carnitine
    Intervention Description
    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.
    Primary Outcome Measure Information:
    Title
    Mortality
    Description
    Death
    Time Frame
    up to 14 days
    Title
    Neurotoxicity
    Description
    Changes in Scores of Glasgow Coma Scale (GCS). GCS is scored between 3 and 15, with 3 being the worst and 15 the best.
    Time Frame
    up to 14 days
    Title
    Cardiotoxicity
    Description
    Changes in the rate of sinus rhythm and QT interval in Electrocardiogram
    Time Frame
    up to 14 days
    Secondary Outcome Measure Information:
    Title
    Intensive care unit admission
    Description
    Number of patients who need intensive care unit admission
    Time Frame
    up to 14 days
    Title
    Duration of hospital stay
    Description
    Hours passed since admission till discharge or death
    Time Frame
    up to 14 days

    10. Eligibility

    Sex
    All
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: 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. Exclusion criteria: 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.
    Central Contact Person:
    First Name & Middle Initial & Last Name or Official Title & Degree
    Zahraa K Sobh, MD
    Phone
    01020744739
    Ext
    +2
    Email
    zahraa.sobh@alexmed.edu.eg

    12. IPD Sharing Statement

    Plan to Share IPD
    Undecided
    IPD Sharing Plan Description
    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.
    Citations:
    Citation
    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
    Results Reference
    background
    PubMed Identifier
    30465787
    Citation
    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.
    Results Reference
    background
    Citation
    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
    Results Reference
    background
    PubMed Identifier
    32440337
    Citation
    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.
    Results Reference
    background
    PubMed Identifier
    33401984
    Citation
    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.
    Results Reference
    background

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

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