Ignite Creation Date:
2025-12-24 @ 4:49 PM
Ignite Modification Date:
2026-01-01 @ 4:55 PM
Study NCT ID:
NCT05563350
Status:
COMPLETED
Last Update Posted:
2024-05-07
First Post:
2022-09-01
Is NOT Gene Therapy:
True
Has Adverse Events:
False
Brief Title:
Metabolism of Chlordiazepoxide in the Treatment of Alcohol Withdrawal Symptoms
Sponsor:
Organization:
Raw JSON
{'hasResults': False, 'derivedSection': {'miscInfoModule': {'versionHolder': '2025-12-24'}, 'interventionBrowseModule': {'meshes': [{'id': 'D001800', 'term': 'Blood Specimen Collection'}], 'ancestors': [{'id': 'D013048', 'term': 'Specimen Handling'}, {'id': 'D019411', 'term': 'Clinical Laboratory Techniques'}, {'id': 'D019937', 'term': 'Diagnostic Techniques and Procedures'}, {'id': 'D003933', 'term': 'Diagnosis'}, {'id': 'D011677', 'term': 'Punctures'}, {'id': 'D013514', 'term': 'Surgical Procedures, Operative'}, {'id': 'D008919', 'term': 'Investigative Techniques'}]}}, 'protocolSection': {'designModule': {'bioSpec': {'retention': 'NONE_RETAINED', 'description': 'Blood samples'}, 'studyType': 'OBSERVATIONAL', 'designInfo': {'timePerspective': 'PROSPECTIVE', 'observationalModel': 'COHORT'}, 'enrollmentInfo': {'type': 'ACTUAL', 'count': 26}, 'targetDuration': '90 Days', 'patientRegistry': True}, 'statusModule': {'overallStatus': 'COMPLETED', 'startDateStruct': {'date': '2022-01-29', 'type': 'ACTUAL'}, 'expandedAccessInfo': {'hasExpandedAccess': False}, 'statusVerifiedDate': '2022-09', 'completionDateStruct': {'date': '2023-07-01', 'type': 'ACTUAL'}, 'lastUpdateSubmitDate': '2024-05-06', 'studyFirstSubmitDate': '2022-09-01', 'studyFirstSubmitQcDate': '2022-09-28', 'lastUpdatePostDateStruct': {'date': '2024-05-07', 'type': 'ACTUAL'}, 'studyFirstPostDateStruct': {'date': '2022-10-03', 'type': 'ACTUAL'}, 'primaryCompletionDateStruct': {'date': '2023-06-11', 'type': 'ACTUAL'}}, 'outcomesModule': {'primaryOutcomes': [{'measure': 'Plasma concentration of chlordiazepoxide and metabolites', 'timeFrame': 'At inclusion and 12 hours after inclusion', 'description': 'p-chlordiazepoxide and metabolites.'}], 'secondaryOutcomes': [{'measure': 'Half-life (T½) for chlordiazepoxide', 'timeFrame': 'At inclusion and 12 hours after inclusion', 'description': 'Half-life (T½) for chlordiazepoxide will be estimated from the area under the concentration time curve (AUC) from concentrations of chlordiazepoxide at inclusion and 12 hours after inclusion.'}, {'measure': 'Cumulative dose of chlordiazepoxide before admission to ICU/HDU', 'timeFrame': 'From date of hospital admittance until the date of inclusion in the study no later than 12 hours after admission on either ICU or HDU', 'description': 'Chlordiazepoxide dose in mg'}, {'measure': 'ICU/HDU and hospital length of stay (LOS) within 90 days', 'timeFrame': '90 days after ICU admission and 90 days after hospital admission', 'description': 'ICU Length of stay and Hospital length of stay'}, {'measure': 'Need for mechanical ventilation within 90 days', 'timeFrame': '90 days after inclusion', 'description': 'Duration of treatment with mechanical ventilation'}]}, 'oversightModule': {'isUsExport': False, 'oversightHasDmc': True, 'isFdaRegulatedDrug': True, 'isFdaRegulatedDevice': False}, 'conditionsModule': {'keywords': ['ICU', 'Intensive care', 'CYP3A4', 'CYP2C19', 'Chlordiazepoxide'], 'conditions': ['Alcohol Withdrawal']}, 'descriptionModule': {'briefSummary': 'The aim of this study is to elucidate if CYP-phenotypes, variations in CYP-genotypes and dose of chlordiazepoxide is correlated to chlordiazepoxide plasma concentrations in patients admitted to Intensive Care or High Dependency Units due to either respiratory insufficiency and/or agitation while treated for alcohol withdrawal symptoms.', 'detailedDescription': "Pharmacological treatment caries a risk of overdosing and adverse events. Chlordiazepoxide, among other sedative drugs, has been associated with an increased risk of death. Chlordiazepoxide treatment for alcohol withdrawal symptoms will render some patients in need of ventilatory support and ICU admission. Other patients will not obtain the desired effect from the treatment and will be in a state of agitation despite having received high doses of chlordiazepoxide. This individual variation in effect is not predictable and may be explained by variations in the capacity of drug metabolism.\n\nChlordiazepoxide is extensively metabolized in the liver by hepatic microsomal enzymes and exhibits capacity limited, protein binding sensitive, hepatic clearance. Metabolism is primarily by cytochrome P450 (CYP), especially CYP3A4 and CYP2C19 systems. Evaluation of CYP phenotypes by drug probe phenotyping is extensively used. Midazolam possesses several characteristics that makes it useable as a pharmacological probe for CYP3A activity despite having already received other benzodiazepines. It is metabolized to a primary metabolite exclusively by CYP3A4/3A5.Omeprazole can likewise be used as a pharmacological probe for CYP2C19.\n\nThe drug of investigation is chlordiazepoxide, which has been given before study inclusion. After inclusion and during the study period (12 hours), it is not allowed to administer chlordiazepoxide to the patient. In case of abstinence, the recommended therapy is diazepam or propofol.\n\nBlood samples will be collected and plasma concentrations of chlordiazepoxide and metabolites will be analyzed and compared with the amount of chlordiazepoxide administered at inclusion and 12 hours after inclusion.\n\nIndependent variables:\n\n* Variations in genotypes of CYP3A4/3A5 and CYP2C19.\n* Phenotypes of CYP3A4/3A5 and CYP2C19, analyzed as above /below the median value of enzyme activity.\n\nVariations in genotypes of CYP3A4/3A5 and CYP2C19 will be analyzed from blood samples.\n\nPhenotyping of CYP3A4/3A5 and CYP2C19 will be performed with midazolam and omeprazole as pharmacological probes respectively. 2 mg of midazolam and 10 mg of omeprazole will be administered intravenously as bolus within 12 hours after inclusion. Blood samples 2 h after dosing (t=2 h dosing) will be collected and analyzed for plasma concentrations of omeprazole, hydroxyomeprazole, midazolam and 1-hydroxymidazolam. The ratio between omeprazole and hydroxyomeprazole will be used to classify the CYP2C19 phenotype as the ratio between midazolam and 1-hydroxymidazolam will be used in the classification of CYP3A4/3A5\n\nBy measuring concentration of chlordiazepoxide and the ability to metabolize chlordiazepoxide in ICU- or HDU-patients with respiratory insufficiency, impaired consciousness or agitation after treatment for alcohol withdrawal symptoms, we will investigate if there is a correlation between the patient's phenotypes of the CYP3A4/3A5 and CYP2C19 systems (independent variable) and the concentration of chlordiazepoxide (primary outcome)."}, 'eligibilityModule': {'sex': 'ALL', 'stdAges': ['ADULT', 'OLDER_ADULT'], 'minimumAge': '18 Years', 'samplingMethod': 'NON_PROBABILITY_SAMPLE', 'studyPopulation': '26 consecutive patients will be included no later than 12 h after ICU or HDU admission after treatment with moderate or large doses (minimum dose 200 mg independently of body weight) of chlordiazepoxide for alcohol withdrawal symptoms.', 'healthyVolunteers': False, 'eligibilityCriteria': 'Inclusion Criteria:\n\n* Age ≥18 years\n* Treatment with minimum 200 mg chlordiazepoxide for alcohol withdrawal symptoms during hospital admission\n* Acute admittance to ICU or HDU due to respiratory insufficiency, impaired consciousness or agitation.\n* Inclusion possible within 12 h of ICU/HDU admission.\n\nExclusion Criteria:\n\n* Allergies to omeprazole/esomeprazole and midazolam\n* Treatment with chlordiazepoxide within the first 12 h after inclusion (from blood samples at inclusion until blood samples 12 h after inclusion)\n* Treatment with omeprazole/esomeprazole within 1 day prior to ICU/HDU admission and within the first 12 h after inclusion.\n* Treatment with midazolam within 1 day prior to ICU/HDU admission\n* Cardiac arrest prior to admission\n* Pregnancy (a negative hcg (from urine or blood sample) has to be present before inclusion of women aged \\<50 years)'}, 'identificationModule': {'nctId': 'NCT05563350', 'briefTitle': 'Metabolism of Chlordiazepoxide in the Treatment of Alcohol Withdrawal Symptoms', 'organization': {'class': 'OTHER', 'fullName': 'University Hospital Bispebjerg and Frederiksberg'}, 'officialTitle': 'Association Between Variations in CYP Pheno- and Genotypes and Plasma Concentration of Chlordiazepoxide in the Treatment of Alcohol Withdrawal Symptoms', 'orgStudyIdInfo': {'id': 'KLOPOXID2021'}}, 'armsInterventionsModule': {'interventions': [{'name': 'Blood samples', 'type': 'DIAGNOSTIC_TEST', 'otherNames': ['Midazolam and omeprazole as pharmacological probes'], 'description': 'p-chlordiazepoxide and metabolites, p-omeprazole and metabolites, p-midazolam and metabolites, CYP3A4 and CYP2C19 genotyping'}]}, 'contactsLocationsModule': {'locations': [{'zip': '2400', 'city': 'Copenhagen', 'country': 'Denmark', 'facility': 'Bispebjerg and Frederiksberg Hospital', 'geoPoint': {'lat': 55.67594, 'lon': 12.56553}}], 'overallOfficials': [{'name': 'Nanna Reiter, MD', 'role': 'PRINCIPAL_INVESTIGATOR', 'affiliation': 'Bispebjerg and Frederiksberg Hospital'}]}, 'ipdSharingStatementModule': {'ipdSharing': 'UNDECIDED'}, 'sponsorCollaboratorsModule': {'leadSponsor': {'name': 'University Hospital Bispebjerg and Frederiksberg', 'class': 'OTHER'}, 'responsibleParty': {'type': 'PRINCIPAL_INVESTIGATOR', 'investigatorTitle': 'Principal investigator', 'investigatorFullName': 'Nanna Reiter', 'investigatorAffiliation': 'University Hospital Bispebjerg and Frederiksberg'}}}}