InteractionPREDICTNCT04249674
Impact of CYP2D6 Genetic Polymorphisms on the Vulnerability to Drug-drug Interactions With Tramadol
An observational study of Interaction and Pain, run by University Hospital, Geneva at 1 site in Switzerland.
Trial summary
Despite its poor abundance in the liver, CYP2D6 is the second most important CYP in drug metabolism, metabolizing 20% of drugs. The high inter-individual variability in CYP2D6 expression is explained by genetic variations, but also by drug-drug interactions (DDIs). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Interaction, Pain
- What is being tested?
- Dextrometorphan and Genotyping by single nulcetoide polymorphism.
- How many people
- 172 participants
- Where
- 1 siteSwitzerland
- Study dates
- 4 Nov 2019to Dec 2022
- 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: Patients will be recruited through a pre-surgery anesthetic evaluation visit. During their scheduled visit with an anaesthesiologist, potential patients will be invited to participate to an information session where project aim and design, procedures involved, expected duration as well as possible risks will be explained in details. After sufficient time of reflection, volunteers willing to participate in the study will sign the consent form.
Who may be able to join
- Any male and female patients > 18 years scheduled for a surgery of less than 3 hours duration and planned to be treated with oral tramadol as a routine management of post-operative pain;
- Patients with physical conditions classified as ASA I to III, based on American Society of Anesthesiology classification;
- Patients treated chronically with a potent CYP2D6 inhibitor (for CYP2D6-inhibited arms only);
- Understanding of French language and able to give a written inform consent
Who cannot join
- Pregnant or breastfeeding woman
- Any pathologies, use of drugs or food that may affect CYP activity (for control arms only and based on the 'drug interactions and cytochromes P450' table published by The Service of clinical Pharmacology and Toxicology [3], HUG and on the investigator's knowledge)
- Liver transplantation history
- Sensitivity to dextromethorphan (CYP2D6 probe drug) or any contra-indication to dextrometorphan
- Medical history of cirrhosis (Child Pugh B and C) or/and hepatosteatosis.
- Glomerular filtration rate (GFR) < 30 ml/min/1.73m2
Trial locations and contacts
1 site in 1 country.
Switzerland1 site, 1 recruiting
- Recruiting
Geneva University Hospitals, HUG
Geneva
Caroline Samer, Dr, caroline.samer@hcuge.ch
Kenza Abouir, kenza.abouir@hcuge.ch
About this study
Official title: Impact of CYP2D6 Genetic Polymorphism on the Vulnerability to Drug-drug Interactions With Tramadol: a Gene-environment Interaction and Phenoconversion Study on Patients Undergoing a Steady Treatment With a Potent CYP2D6 Inhibitor.
Despite its poor abundance in the liver, CYP2D6 is the second most important CYP in drug metabolism, metabolizing 20% of drugs. The high inter-individual variability in CYP2D6 expression is explained by genetic variations, but also by drug-drug interactions (DDIs). Recent studies have pointed out the poor therapeutic predictable value of DDI. Indeed, the clinical outcomes of a DDI may involve several intrinsic factors affecting the vulnerability to and extent of DDI, such as genetic polymorphisms, comorbidities, age and sex.
In this regard, the present research project aims to investigate the effect of genetic polymorphism on DDIs involving CYP2D6 (gene-environment interaction) and its implications for tramadol efficacy and safety in a clinical setting. In a previous study, we demonstrated differences in both the rate of phenoconversion and the magnitude of DDI in healthy volunteers, that were either heterozygote normal metabolizers (NMs) carrying a non-functional CYP2D6 allele (activity score (AS) 1) and homozygous NM carrying two fully-functional CYP2D6 alleles (AS 2).
Read more
This prospective study will include patients scheduled for a general surgery of less than 3 hours and planned to be treated with oral tramadol as a routine post-operative pain management.
Patients taking part in the study may receive diagnosis, therapeutic or other interventions but the groups of individuals (controls vs inhibited) are predefined based on the routine treatment of the patients.
There will be no assigned specific interventions to the study participants and CYP2D6 phenotypes will be classified in five activity score groups (0.5, 1, 1.5, 2, >2) in the absence or presence of a potent CYP2D6 inhibitor received as part of routine medical care.
PK of tramadol and its active metabolite (M1), as well as its analgesic and PD effects and safety, will be compared between groups. Finally, the data generated will be used to build a physiologically-based PK (PBPK) model for tramadol in different sub-groups. The model will aim to predict the effect of CYP2D6 inhibition in virtual populations with different genetically-related CYP2D6 activities. This should allow prospective dose adjustment of tramadol (or appropriate drug selection) based on patients' genotype in the presence of a CYP2D6 inhibitor.
- Conditions
- Interaction, Pain
- Being tested
- Dextrometorphan, Genotyping by single nulcetoide polymorphism.
- Keywords
- Cytochrome, Polymorphism, Genotyping, Phenotyping, Tramadol, CYP2D6 inhibitor, Phenoconversion, Environment
- Medical subject headings
- Pain
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DextrometorphanDiagnostic test
Administration of 4 ml=10 mg of Dextrometorphan (Bexine sirup)
Genotyping by single nulcetoide polymorphism.Genetic
Single nucleotide polymorphism determination
| Study group | Role | What they receive |
|---|---|---|
| Patient under a CYP2D6 inhibitor and under Tramadol | Not described Receives: Diagnostic Test: Dextrometorphan; Genetic: Genotyping by single nulcetoide polymorphism. | |
| Patient not under a CYP2D6 inhibitor but under Tramadol | Not described Receives: Diagnostic Test: Dextrometorphan; Genetic: Genotyping by single nulcetoide polymorphism. |
What is being measured
The primary outcome is the main question the study is designed to answer.
Assess the proportion of patients in each group who acquires a phenotype switch (phenoconversion) with or without CYP2D6 inhibitor.
Measured: 10 hours
Secondary outcomes (3)
Comparison of Tramadol , Dexrometorphan and their metabolites maximum plasma concentration (Cmax) according to patient belonging to the control or inhibited group.
Measured: 24 hours
Comparison of Tramadol, Dextrometorphan and their metabolites Area Under the curve (AUC) according to patient belonging to the control or to the inhibited group and to his CYP2D6 phenotype
Measured: 24 hours
Comparison of Tramadol, Dextrometorphan and their metabolites Clearance (CL) according to patient belonging to the control or to the inhibited group.
Measured: 24 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted31 Jan 2020
- Study start4 Nov 2019
- Primary completion1 Nov 2022 (estimated)
- Study completionDec 2022 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for InteractionStudies of the same condition, open and under way.
- More trials run by University Hospital, GenevaThe 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
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 172 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University Hospital, Geneva
- Sponsor type
- University, hospital or other
- Collaborators
- Youssef Daali, Jules Desmeules, Kenza Abouir, Eduardo Schiffer, Bernard Walder
- Responsible party
- Principal investigator, Caroline Samer, University Hospital, Geneva
- Investigators
- Youssef Daali, Pr., Study director, University Hospital, GenevaCaroline Samer, Doctor, Principal investigator, University Hospital, Geneva
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04249674
- Sponsor's protocol ID
- 2019-01418
- Other IDs
- 2019
- Acronym
- PREDICT
- Status last verified
- Jan 2022
- First submitted
- 4 Dec 2019
- Last updated
- 19 Jan 2022
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 19 Jan 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Impact of CYP2D6 Genetic Polymorphism on the Vulnerability to Drug-drug Interactions With Tramadol: a Gene-environment Interaction and Phenoconversion Study on Patients Undergoing a Steady Treatment With a Potent CYP2D6 Inhibitor.
- ClinicalTrials.gov ID
- NCT04249674
- Acronym / sponsor ID
- PREDICT / 2019-01418
- Conditions
- Interaction, Pain
- Keywords
- Cytochrome, Polymorphism, Genotyping, Phenotyping, Tramadol, CYP2D6 inhibitor, Phenoconversion, Environment
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 172 participants (estimated)
- Lead sponsor
- University Hospital, GenevaUniversity, hospital or other
- Collaborators
- Youssef Daali, Jules Desmeules, Kenza Abouir, Eduardo Schiffer, Bernard Walder
- Study start
- 4 Nov 2019 (actual)
- Primary completion
- 1 Nov 2022 (estimated)
- Study completion
- Dec 2022 (estimated)
- First posted
- 31 Jan 2020 (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.
Despite its poor abundance in the liver, CYP2D6 is the second most important CYP in drug metabolism, metabolizing 20% of drugs. The high inter-individual variability in CYP2D6 expression is explained by genetic variations, but also by drug-drug interactions (DDIs). Recent studies have pointed out the poor therapeutic predictable value of DDI. Indeed, the clinical outcomes of a DDI may involve several intrinsic factors affecting the vulnerability to and extent of DDI, such as genetic polymorphisms, comorbidities, age and sex.
In this regard, the present research project aims to investigate the effect of genetic polymorphism on DDIs involving CYP2D6 (gene-environment interaction) and its implications for tramadol efficacy and safety in a clinical setting. In a previous study, we demonstrated differences in both the rate of phenoconversion and the magnitude of DDI in healthy volunteers, that were either heterozygote normal metabolizers (NMs) carrying a non-functional CYP2D6 allele (activity score (AS) 1) and homozygous NM carrying two fully-functional CYP2D6 alleles (AS 2).
This prospective study will include patients scheduled for a general surgery of less than 3 hours and planned to be treated with oral tramadol as a routine post-operative pain management.
Patients taking part in the study may receive diagnosis, therapeutic or other interventions but the groups of individuals (controls vs inhibited) are predefined based on the routine treatment of the patients.
There will be no assigned specific interventions to the study participants and CYP2D6 phenotypes will be classified in five activity score groups (0.5, 1, 1.5, 2, >2) in the absence or presence of a potent CYP2D6 inhibitor received as part of routine medical care.
PK of tramadol and its active metabolite (M1), as well as its analgesic and PD effects and safety, will be compared between groups. Finally, the data generated will be used to build a physiologically-based PK (PBPK) model for tramadol in different sub-groups. The model will aim to predict the effect of CYP2D6 inhibition in virtual populations with different genetically-related CYP2D6 activities. This should allow prospective dose adjustment of tramadol (or appropriate drug selection) based on patients' genotype in the presence of a CYP2D6 inhibitor.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Patient under a CYP2D6 inhibitor and under Tramadol | – | Diagnostic Test: Dextrometorphan, Genetic: Genotyping by single nulcetoide polymorphism. |
| Patient not under a CYP2D6 inhibitor but under Tramadol | – | Diagnostic Test: Dextrometorphan, Genetic: Genotyping by single nulcetoide polymorphism. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Patients will be recruited through a pre-surgery anesthetic evaluation visit. During their scheduled visit with an anaesthesiologist, potential patients will be invited to participate to an information session where project aim and design, procedures involved, expected duration as well as possible risks will be explained in details. After sufficient time of reflection, volunteers willing to participate in the study will sign the consent form.
Key inclusion criteria (4 listed)
- Any male and female patients > 18 years scheduled for a surgery of less than 3 hours duration and planned to be treated with oral tramadol as a routine management of post-operative pain;
- Patients with physical conditions classified as ASA I to III, based on American Society of Anesthesiology classification;
- Patients treated chronically with a potent CYP2D6 inhibitor (for CYP2D6-inhibited arms only);
- Understanding of French language and able to give a written inform consent
Key exclusion criteria (6 listed)
- Pregnant or breastfeeding woman
- Any pathologies, use of drugs or food that may affect CYP activity (for control arms only and based on the 'drug interactions and cytochromes P450' table published by The Service of clinical Pharmacology and Toxicology [3], HUG and on the investigator's knowledge)
- Liver transplantation history
- Sensitivity to dextromethorphan (CYP2D6 probe drug) or any contra-indication to dextrometorphan
- Medical history of cirrhosis (Child Pugh B and C) or/and hepatosteatosis.
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 |
|---|---|---|
| DextrometorphanAdministration of 4 ml=10 mg of Dextrometorphan (Bexine sirup) | Diagnostic test | Patient not under a CYP2D6 inhibitor but under Tramadol, Patient under a CYP2D6 inhibitor and under Tramadol |
| Genotyping by single nulcetoide polymorphism.Single nucleotide polymorphism determination | Genetic | Patient not under a CYP2D6 inhibitor but under Tramadol, Patient under a CYP2D6 inhibitor and under Tramadol |
Primary outcome
Assess the proportion of patients in each group who acquires a phenotype switch (phenoconversion) with or without CYP2D6 inhibitor.
Time frame: 10 hours
3 secondary outcomes
Comparison of Tramadol , Dexrometorphan and their metabolites maximum plasma concentration (Cmax) according to patient belonging to the control or inhibited group.
Time frame: 24 hours
Comparison of Tramadol, Dextrometorphan and their metabolites Area Under the curve (AUC) according to patient belonging to the control or to the inhibited group and to his CYP2D6 phenotype
Time frame: 24 hours
Comparison of Tramadol, Dextrometorphan and their metabolites Clearance (CL) according to patient belonging to the control or to the inhibited group.
Time frame: 24 hours
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Jan 2022.
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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.
Youssef Daali, Pr. study director
University Hospital, Geneva
Caroline Samer, Doctor principal investigator
University Hospital, Geneva
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 Interaction and Pain, run by University Hospital, Geneva at 1 site in Switzerland.
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 4 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: status not confirmed, as of the sponsor's last update on 19 Jan 2022. 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 Switzerland. 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?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Caroline Samer, Doctor (022 372 99 47, caroline.samer@hcuge.ch), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Assess the proportion of patients in each group who acquires a phenotype switch (phenoconversion) with or without CYP2D6 inhibitor. (time frame: 10 hours). 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 19 Jan 2022.