Alcohol WithdrawalNCT05563350
Metabolism of Chlordiazepoxide in the Treatment of Alcohol Withdrawal Symptoms
An observational study of Alcohol Withdrawal, run by University Hospital Bispebjerg and Frederiksberg at 1 site in Denmark.
Trial summary
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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Alcohol Withdrawal
- What is being tested?
- Blood samples
- How many people
- 26 participants
- Where
- 1 siteDenmark
- Study dates
- 29 Jan 2022to 1 Jul 2023
- How long will I take part?
- 90 Days
- Phase
- Observational
- 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 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: 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.
Who may be able to join
- Age ≥18 years
- Treatment with minimum 200 mg chlordiazepoxide for alcohol withdrawal symptoms during hospital admission
- Acute admittance to ICU or HDU due to respiratory insufficiency, impaired consciousness or agitation.
Who cannot join
- Allergies to omeprazole/esomeprazole and midazolam
- Treatment with chlordiazepoxide within the first 12 h after inclusion (from blood samples at inclusion until blood samples 12 h after inclusion)
- Treatment with omeprazole/esomeprazole within 1 day prior to ICU/HDU admission and within the first 12 h after inclusion.
- Treatment with midazolam within 1 day prior to ICU/HDU admission
- Cardiac arrest prior to admission
- Pregnancy (a negative hcg (from urine or blood sample) has to be present before inclusion of women aged <50 years)
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Association Between Variations in CYP Pheno- and Genotypes and Plasma Concentration of Chlordiazepoxide in the Treatment of Alcohol Withdrawal Symptoms
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.
Read the detailed description
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.
Chlordiazepoxide 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.
The 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.
Blood 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.
Independent variables:
- Variations in genotypes of CYP3A4/3A5 and CYP2C19.
- Phenotypes of CYP3A4/3A5 and CYP2C19, analyzed as above /below the median value of enzyme activity.
Variations in genotypes of CYP3A4/3A5 and CYP2C19 will be analyzed from blood samples.
Phenotyping 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
By 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).
- Conditions
- Alcohol Withdrawal
- Being tested
- Blood samples
- Keywords
- ICU, Intensive care, CYP3A4, CYP2C19, Chlordiazepoxide
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Blood samplesDiagnostic test
Also called Midazolam and omeprazole as pharmacological probes
p-chlordiazepoxide and metabolites, p-omeprazole and metabolites, p-midazolam and metabolites, CYP3A4 and CYP2C19 genotyping
What is being measured
The primary outcome is the main question the study is designed to answer.
Plasma concentration of chlordiazepoxide and metabolites
p-chlordiazepoxide and metabolites.
Measured: At inclusion and 12 hours after inclusion
Secondary outcomes (4)
Half-life (T½) for chlordiazepoxide
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.
Measured: At inclusion and 12 hours after inclusion
Cumulative dose of chlordiazepoxide before admission to ICU/HDU
Chlordiazepoxide dose in mg
Measured: 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
ICU/HDU and hospital length of stay (LOS) within 90 days
ICU Length of stay and Hospital length of stay
Measured: 90 days after ICU admission and 90 days after hospital admission
Need for mechanical ventilation within 90 days
Duration of treatment with mechanical ventilation
Measured: 90 days after inclusion
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Oct 2022
- Study start29 Jan 2022
- Primary completion11 Jun 2023
- Study completion1 Jul 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Alcohol WithdrawalStudies 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
- Prospective
- Enrolment
- 26 participants (actual)
- Target duration
- 90 Days
Sponsor and investigators
- Lead sponsor
- University Hospital Bispebjerg and Frederiksberg
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Nanna Reiter, University Hospital Bispebjerg and Frederiksberg
- Investigators
- Nanna Reiter, MD, Principal investigator, Bispebjerg and Frederiksberg Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05563350
- Sponsor's protocol ID
- KLOPOXID2021
- Status last verified
- Sep 2022
- First submitted
- 1 Sep 2022
- Last updated
- 7 May 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 7 May 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Association Between Variations in CYP Pheno- and Genotypes and Plasma Concentration of Chlordiazepoxide in the Treatment of Alcohol Withdrawal Symptoms
- ClinicalTrials.gov ID
- NCT05563350
- Acronym / sponsor ID
- KLOPOXID2021
- Conditions
- Alcohol Withdrawal
- Keywords
- ICU, Intensive care, CYP3A4, CYP2C19, Chlordiazepoxide
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 26 participants (actual)
- Lead sponsor
- University Hospital Bispebjerg and FrederiksbergUniversity, hospital or other
- Study start
- 29 Jan 2022 (actual)
- Primary completion
- 11 Jun 2023 (actual)
- Study completion
- 1 Jul 2023 (actual)
- First posted
- 3 Oct 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.
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.
Detailed description
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.
Chlordiazepoxide 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.
The 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.
Blood 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.
Independent variables:
- Variations in genotypes of CYP3A4/3A5 and CYP2C19.
- Phenotypes of CYP3A4/3A5 and CYP2C19, analyzed as above /below the median value of enzyme activity.
Variations in genotypes of CYP3A4/3A5 and CYP2C19 will be analyzed from blood samples.
Phenotyping 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
By 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).
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Target follow-up
- 90 Days
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- 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.
Key inclusion criteria (3 listed)
- Age ≥18 years
- Treatment with minimum 200 mg chlordiazepoxide for alcohol withdrawal symptoms during hospital admission
- Acute admittance to ICU or HDU due to respiratory insufficiency, impaired consciousness or agitation.
Key exclusion criteria (6 listed)
- Allergies to omeprazole/esomeprazole and midazolam
- Treatment with chlordiazepoxide within the first 12 h after inclusion (from blood samples at inclusion until blood samples 12 h after inclusion)
- Treatment with omeprazole/esomeprazole within 1 day prior to ICU/HDU admission and within the first 12 h after inclusion.
- Treatment with midazolam within 1 day prior to ICU/HDU admission
- Cardiac arrest prior to 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 |
|---|---|---|
| Blood samplesAlso: Midazolam and omeprazole as pharmacological probesp-chlordiazepoxide and metabolites, p-omeprazole and metabolites, p-midazolam and metabolites, CYP3A4 and CYP2C19 genotyping | Diagnostic test | – |
Primary outcome
Plasma concentration of chlordiazepoxide and metabolites
Time frame: At inclusion and 12 hours after inclusion
p-chlordiazepoxide and metabolites.
4 secondary outcomes
Half-life (T½) for chlordiazepoxide
Time frame: At inclusion and 12 hours after inclusion
Cumulative dose of chlordiazepoxide before admission to ICU/HDU
Time frame: 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
ICU/HDU and hospital length of stay (LOS) within 90 days
Time frame: 90 days after ICU admission and 90 days after hospital admission
Need for mechanical ventilation within 90 days
Time frame: 90 days after inclusion
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 May 2024.
- Individual participant dataSharing planned: Undecided
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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.
Nanna Reiter, MD principal investigator
Bispebjerg and Frederiksberg Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Alcohol Withdrawal, run by University Hospital Bispebjerg and Frederiksberg at 1 site in Denmark.
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 3 inclusion and 6 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: finished, as of the sponsor's last update on 7 May 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Denmark. Whether a site is taking part right now should be confirmed with that site. See every site.
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?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Plasma concentration of chlordiazepoxide and metabolites (time frame: At inclusion and 12 hours after inclusion). 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 7 May 2024.