Drug BiotransformationPhase 1NCT01845194
Repeated Dose Study for the Investigation of Heritability of and Genetic Influences on Drug Pharmacokinetics
A Phase 1 study testing Codeine, Midazolam and Pravastatin in people with Drug Biotransformation and Membrane Transport, run by Institut fuer anwendungsorientierte Forschung und klinische Studien GmbH at 1 site in Germany.
Trial summary
This human pharmacokinetic study investigates, whether processes of drug metabolism and transport are determined by genetic or hereditary factors. Therefore, approved drugs are applied to twins and metabolism and transport processes are investigated. Read more about this study
- Who is it for?
- Ages 18 to 65 yearsHealthy volunteers can take part
- Conditions the study is for
- Drug Biotransformation, Membrane Transport
- What is being tested?
- Codeine, Midazolam and Pravastatin
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 117 participants
- Where
- 1 siteGermany
- Study dates
- Dec 2009to Oct 2013
- Phase
- Phase 1
- 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 to 65 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Written informed consent obtained prior to study entry including informed consent for genetic research
- Both genders (male and female)
- Healthy adults aged ≥18 to < 65 years
- Body weight of subjects of both genders not less than 50 kg and not more than 120 kg. BMI not less than 18 kg/m² and not greater than 33 kg/m²
- Willingness to meet the study instructions and to co-operate with the study personal
- No clinically relevant pathological findings in any of the investigations at the Screening visit. Minor deviations of laboratory values from the normal range may be accepted, if judged by the investigator to have no clinical relevance
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- Female subjects will only be included if they have negative serum pregnancy test during screening and the willingness not to become pregnant during the entire study period by practicing reliable methods of contraception as specified in the respective protocol section.
- Dizygotic twins will only be included if both siblings are of the same gender, either male or female and triplets, quadruplets or other multiplets if at least two siblings are of the same gender
- Smokers will only be included if both siblings are smoking to a similar extend (+/- 10 cigarettes per day)
Who cannot join
- Involvement in the planning and conduct of the study (applies to staff directly employed at the study site / department)
- Participation in a clinical study during the last 30 days or use of any other investigational or non-registered drug or vaccine during the study period or within 30 days preceding the first dose of study drugs
- Blood, plasma or thrombozyte donation during the last 30 days prior to application of the test drugs
- Age < 18 years or > 65 years
- Known pregnancy or lactation period
- Any relevant pathological findings in any of the investigations at the screening visit including significant abnormalities as result of the medical-screening-laboratory-analysis, especially of the liver and kidney related parameters.
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- Any disease affecting liver or kidney or impairment of the liver or kidney-function
- Any cardiac disease in which use of beta-blockers or caffeine might be contraindicated.
- Bronchogenic asthma requiring constant drug treatment (stages 2 to 4 asthma)
- Known Raynaud's syndrome
- Any major acute disease or fever (Temp. > 37.5 C)
- Any major gastrointestinal disease and any gastrointestinal disorder that is expected to significantly interfere with the pharmacokinetics of the study drug
- Gastrointestinal surgery which may interfere with the pharmacokinetics of the study drug (except appendectomy or herniotomy)
- Taking any medication within 7 days before or during the trial with the following exceptions: Single doses of mild analgesics (e.g. aspirin, paracetamol, ibuprofen) may have been taken except for the time from 6 hours prior to taking the test drug until 24 hours after taking the test drug. Oral contraceptive drug used will be documented but will not be an exclusion criterion. Other medication might be allowed on single case basis if considered necessary for the subject's safety and well-being.
- History of alcohol and/or drug addiction and/or any abusive use of medicaments and/or positive drug screen
- Any other findings that could compromise the safety of the participant or the quality of the study-results
- History of severe hypersensitivity reactions and anaphylaxis
- If hypersensitivity or allergic reactions to one of the IMPs is known so enrolment is possible but application of the concerned IMP must not be allowed in all siblings (e.g. allergy to sulphonamide prohibits specifically the application of torsemide)
- Clinically significant diseases as judged by the investigator
- Body temperature > 37.5°C prior to drug application
- Known infection with HIV, Hepatitis B (HBsAg) or Hepatitis C
- Inability or unwillingness to avoid any intake of alcohol from 48h prior to until 72hours after IMP application
- Pregnancy (positive pregnancy test during screening and/or treatment)
- Lactation or unreliable contraception in female subjects with child-bearing potential
- Inability or unwillingness to provide informed consent and to abide by the requirements of the study
Trial locations and contacts
1 site in 1 country.
Germany1 site
Dept. of Clinical Pharmacology, Georg-August-University of Goettingen
Göttingen, 37075
About this study
Official title: Open Label Repeated Dose Study for the Evaluation of Heritability of and Genetic Influences on Drug Pharmacokinetics (TWINS II)
This human pharmacokinetic study investigates, whether processes of drug metabolism and transport are determined by genetic or hereditary factors. Therefore, approved drugs are applied to twins and metabolism and transport processes are investigated.
- Conditions
- Drug Biotransformation, Membrane Transport
- Being tested
- Codeine, Midazolam, Pravastatin, Torsemide, Talinolol
- Keywords
- pharmacokinetic, heritability, drug membrane transport, drug biotransformation
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
CodeineDrug
Treatment period 2:
5 mg Codeine once
MidazolamDrug
Treatment period 1:
0.2 mg Midazolam 3x
Treatment period 2:
1 mg Midazolam once
PravastatinDrug
Treatment period 2:
5 mg Pravastatin once
TorsemideDrug
Treatment period 1:
2.5 mg Torsemide 3x
Treatment period 2:
0.25 mg Torsemide once
TalinololDrug
Treatment period 1:
50 mg Talinolol 3x
Treatment period 2:
2.5 mg Talinolol once
CaffeineDrug
Treatment period 1:
50 mg Caffeine 3x
MetoprololDrug
Treatment period 1:
5 mg Metoprolol 3x
| Study group | Role | What they receive |
|---|---|---|
| Drug application | Experimental | Two treatment periods:
Treatment period 1:
three sequential oral and i.v. doses of 5 mg Metoprolol, 50 mg Talinolol, 2.5 mg Torsemide, 0.2 mg Midazolam and 50 mg Caffeine. At least 1 week of wash out between drug application
Treatment period 2:
combined application of a single oral dose of 2.5 mg Talinolol, 0.25 mg Torsemide, 5 mg Pravastatin, 1 mg Midazolam and 5 mg Codeine.
Treatment period 2 may take place after or before treatment period 1 with a time interval of at least 1 week Receives: Drug: Codeine; Drug: Midazolam; Drug: Pravastatin; Drug: Torsemide; Drug: Talinolol; Drug: Caffeine; Drug: Metoprolol |
What is being measured
The primary outcome is the main question the study is designed to answer.
plasma drug concentrations
Up to 8 (± 60 min.) hour after each application of combined drugs (treatment period 1 and treatment period 2) blood and urine collection is continuously performed and drug concentrations as specified in the sections "study arms" and "interventions" are measured. This is repeated once 24 hours after each drug application.
Measured: up to 24 h after drug application
Secondary outcomes (3)
PK and metabolic ratios
PK and metabolic ratios (MR, ratio between parent compound and metabolite) of the test substrates as specified in the sections "study arms" and "interventions" are measured.
Measured: up to 24 h after drug application
variants in known genetic traits
New variants in known genetic traits are investigated and new genetic traits are identified.
Measured: up to 24 h after drug application
design applicability
To evaluate the applicability of the repeated measure design for other, non drug-related genetic traits, such as blood coagulation pathways.
Measured: 54 months after study start
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 May 2013 (estimated)
- Study startDec 2009
- Primary completionOct 2013
- Study completionOct 2013
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Drug BiotransformationStudies 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
- Interventional
- Phase
- Phase 1
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 117 participants (actual)
Sponsor and investigators
- Lead sponsor
- Institut fuer anwendungsorientierte Forschung und klinische Studien GmbH
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Jürgen Brockmöller, Prof., Study chair, Dept. of Clinical Pharmacology, Georg-August-University of Goettingen, Robert-Koch-Str. 40, 37075 Goettingen, Germany
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01845194
- Sponsor's protocol ID
- TWINS-II-v1.9
- Status last verified
- Apr 2014
- First submitted
- 25 Apr 2013
- Last updated
- 21 Apr 2014
- Results posted
- No
- Data monitoring committee
- No
Publications
Matthaei J, Bonat WH, Kerb R, Tzvetkov MV, Strube J, Brunke S, Sachse-Seeboth C, Sehrt D, Hofmann U, von Bornemann Hjelmborg J, Schwab M, Brockmoller J. Inherited and Acquired Determinants of Hepatic CYP3A Activity in Humans. Front Genet. 2020 Aug 21;11:944. doi: 10.3389/fgene.2020.00944. eCollection 2020.
PubMed 32973880Matthaei J, Tzvetkov MV, Gal V, Sachse-Seeboth C, Sehrt D, Hjelmborg JB, Hofmann U, Schwab M, Kerb R, Brockmoller J. Low heritability in pharmacokinetics of talinolol: a pharmacogenetic twin study on the heritability of the pharmacokinetics of talinolol, a putative probe drug of MDR1 and other membrane transporters. Genome Med. 2016 Nov 8;8(1):119. doi: 10.1186/s13073-016-0372-2.
PubMed 27825374Matthaei J, Brockmoller J, Tzvetkov MV, Sehrt D, Sachse-Seeboth C, Hjelmborg JB, Moller S, Halekoh U, Hofmann U, Schwab M, Kerb R. Heritability of metoprolol and torsemide pharmacokinetics. Clin Pharmacol Ther. 2015 Dec;98(6):611-21. doi: 10.1002/cpt.258. Epub 2015 Oct 19.
PubMed 26344676
Study at a glance
From the registry record, last updated by the sponsor on 21 Apr 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Open Label Repeated Dose Study for the Evaluation of Heritability of and Genetic Influences on Drug Pharmacokinetics (TWINS II)
- ClinicalTrials.gov ID
- NCT01845194
- Acronym / sponsor ID
- TWINS-II-v1.9
- Conditions
- Drug Biotransformation, Membrane Transport
- Keywords
- pharmacokinetic, heritability, drug membrane transport, drug biotransformation
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 117 participants (actual)
- Lead sponsor
- Institut fuer anwendungsorientierte Forschung und klinische Studien GmbHUniversity, hospital or other
- Study start
- Dec 2009
- Primary completion
- Oct 2013 (actual)
- Study completion
- Oct 2013 (actual)
- First posted
- 3 May 2013 (estimated)
- 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.
This human pharmacokinetic study investigates, whether processes of drug metabolism and transport are determined by genetic or hereditary factors. Therefore, approved drugs are applied to twins and metabolism and transport processes are investigated.
Study design
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Drug application | Experimental | Drug: Codeine, Drug: Midazolam, Drug: Pravastatin, Drug: Torsemide, Drug: Talinolol, Drug: Caffeine, Drug: MetoprololTwo treatment periods: Treatment period 1: three sequential oral and i.v. doses of 5 mg Metoprolol, 50 mg Talinolol, 2.5 mg Torsemide, 0.2 mg Midazolam and 50 mg Caffeine. At least 1 week of wash out between drug application Treatment period 2: combined application of a single oral dose of 2.5 mg Talinolol, 0.25 mg Torsemide, 5 mg Pravastatin, 1 mg Midazolam and 5 mg Codeine. Treatment period 2 may take place after or before treatment period 1 with a time interval of at least 1 week |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- Written informed consent obtained prior to study entry including informed consent for genetic research
- Both genders (male and female)
- Healthy adults aged ≥18 to < 65 years
- Body weight of subjects of both genders not less than 50 kg and not more than 120 kg. BMI not less than 18 kg/m² and not greater than 33 kg/m²
- Willingness to meet the study instructions and to co-operate with the study personal
Key exclusion criteria (25 listed)
- Involvement in the planning and conduct of the study (applies to staff directly employed at the study site / department)
- Participation in a clinical study during the last 30 days or use of any other investigational or non-registered drug or vaccine during the study period or within 30 days preceding the first dose of study drugs
- Blood, plasma or thrombozyte donation during the last 30 days prior to application of the test drugs
- Age < 18 years or > 65 years
- Known pregnancy or lactation period
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 |
|---|---|---|
| CodeineTreatment period 2: 5 mg Codeine once | Drug | Drug application |
| MidazolamTreatment period 1: 0.2 mg Midazolam 3x Treatment period 2: 1 mg Midazolam once | Drug | Drug application |
| PravastatinTreatment period 2: 5 mg Pravastatin once | Drug | Drug application |
| TorsemideTreatment period 1: 2.5 mg Torsemide 3x Treatment period 2: 0.25 mg Torsemide once | Drug | Drug application |
| TalinololTreatment period 1: 50 mg Talinolol 3x Treatment period 2: 2.5 mg Talinolol once | Drug | Drug application |
| CaffeineTreatment period 1: 50 mg Caffeine 3x | Drug | Drug application |
| MetoprololTreatment period 1: 5 mg Metoprolol 3x | Drug | Drug application |
Primary outcome
plasma drug concentrations
Time frame: up to 24 h after drug application
Up to 8 (± 60 min.) hour after each application of combined drugs (treatment period 1 and treatment period 2) blood and urine collection is continuously performed and drug concentrations as specified in the sections "study arms" and "interventions" are measured. This is repeated once 24 hours after each drug application.
3 secondary outcomes
PK and metabolic ratios
Time frame: up to 24 h after drug application
variants in known genetic traits
Time frame: up to 24 h after drug application
design applicability
Time frame: 54 months after study start
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 21 Apr 2014.
- Derived from this study: PubMed 32973880Matthaei J, Bonat WH, Kerb R, Tzvetkov MV, Strube J, Brunke S, Sachse-Seeboth C, Sehrt D, Hofmann U, von Bornemann Hjelmborg J, Schwab M, Brockmoller J. Inherited and Acquired Determinants of Hepatic CYP3A Activity in Humans. Front Genet. 2020 Aug 21;11:944. doi: 10.3389/fgene.2020.00944. eCollection 2020.
- Derived from this study: PubMed 27825374Matthaei J, Tzvetkov MV, Gal V, Sachse-Seeboth C, Sehrt D, Hjelmborg JB, Hofmann U, Schwab M, Kerb R, Brockmoller J. Low heritability in pharmacokinetics of talinolol: a pharmacogenetic twin study on the heritability of the pharmacokinetics of talinolol, a putative probe drug of MDR1 and other membrane transporters. Genome Med. 2016 Nov 8;8(1):119. doi: 10.1186/s13073-016-0372-2.
- Derived from this study: PubMed 26344676Matthaei J, Brockmoller J, Tzvetkov MV, Sehrt D, Sachse-Seeboth C, Hjelmborg JB, Moller S, Halekoh U, Hofmann U, Schwab M, Kerb R. Heritability of metoprolol and torsemide pharmacokinetics. Clin Pharmacol Ther. 2015 Dec;98(6):611-21. doi: 10.1002/cpt.258. Epub 2015 Oct 19.
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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.
Jürgen Brockmöller, Prof. study chair
Dept. of Clinical Pharmacology, Georg-August-University of Goettingen, Robert-Koch-Str. 40, 37075 Goettingen, Germany
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Codeine, Midazolam and Pravastatin in people with Drug Biotransformation and Membrane Transport, run by Institut fuer anwendungsorientierte Forschung und klinische Studien GmbH at 1 site in Germany.
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 9 inclusion and 25 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 21 Apr 2014. 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 Germany. 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.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
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 drug concentrations (time frame: up to 24 h after drug application). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01845194, which also lists 3 linked publications.
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 21 Apr 2014.