Cytochrome P450 CYP3A Enzyme DeficiencyPhase 4PiSANCT03204578
Physiological Study of the Human CYP3A Activity (PiSA)
A Phase 4 study testing AB (Midazolam OD formulation/Dormicum) and BA (Dormicum/Midazolam OD formulation) in people with Cytochrome P450 CYP3A Enzyme Deficiency, run by University Hospital, Basel, Switzerland at 1 site in Switzerland.
Trial summary
Investigator-initiated physiological study to characterize the function of a major drug metabolizing enzyme using a microdosed phenotyping probe to avoid unwanted, concentration-dependent effects. Read more about this study
- Who is it for?
- Ages 18 to 50 yearsHealthy volunteers can take part
- Conditions the study is for
- Cytochrome P450 CYP3A Enzyme Deficiency
- What is being tested?
- AB (Midazolam OD formulation/Dormicum) and BA (Dormicum/Midazolam OD formulation)
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 12 participants
- Where
- 1 siteSwitzerland
- Study dates
- 18 Aug 2017to 25 Sep 2017
- Phase
- Phase 4
- 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 50 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Healthy male or female subjects, age of 18 to 50 years, body mass index (BMI) of 18.0 to 29.9 kg/m2
Who cannot join
- Any intake of a substance known to induce or inhibit drug metabolising enzymes or transport system enzymes within a period of less than 10 times the respective elimination half-life or 3 weeks (whatever is longer).
- Any participation in a clinical trial within the last four weeks before inclusion.
- History or clinical evidence of any disease or medical condition, which may interfere with the pharmacokinetics of midazolam or which may increase the risk for toxicity or adverse events.
- Allergies (except for mild forms of hay fever) or history of hypersensitivity reactions.
Trial locations and contacts
1 site in 1 country.
Switzerland1 site
University Hospital Basel,
Basel, Canton of Basel-City, 4031
About this study
Investigator-initiated physiological study to characterize the function of a major drug metabolizing enzyme using a microdosed phenotyping probe to avoid unwanted, concentration-dependent effects.
Read the detailed description
Disposition of a drug depends on absorption, distribution, metabolism, and elimination (ADME). Quantifying the ADME capacity of a patient may help to individualize target exposure by choosing the corresponding dose required for this individual. The large group of drugs eliminated by members of the CYP3A isozyme subfamily accounts for about 50% of all marketed drugs. Co-medication can modulate CYP3A activity 400-fold either by inducing isozyme expression or inhibiting expressed enzyme. Therefore, due to the variability of CYP3A activity, dose requirements of CYP3A substrates vary considerably between individual patients and may even rapidly vary within a patient. There is clinical interest in using CYP3A activity as a biomarker to predict optimal CYP3A drug dosing, improve therapeutic efficacy, and minimize adverse drug effects.
Determination of CYP3A activity is usually done with oral midazolam doses of 2-7.5 mg (phenotyping). Because therapeutic doses have pharmacological effects and can cause sedation, especially if CYP3A is inhibited, a microdosing approach for CYP phenotyping was developed to avoid any pharmacological activity. Oral midazolam pharmacokinetics are linear over a 30,000-fold range and 300 ng doses can reliably predict drug interactions with strong CYP3A inhibitors like ketoconazole.
The primary objective of this trial is to determine CYP3A activity using microdosed midazolam delivered from an oral disintegrating formulation in comparison to an oral midazolam solution. The oral disintegrating formulation is an innovative application form that would facilitate administration of the phenotyping probe in special patient populations.
- Conditions
- Cytochrome P450 CYP3A Enzyme Deficiency
- Being tested
- AB (Midazolam OD formulation/Dormicum), BA (Dormicum/Midazolam OD formulation)
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AB (Midazolam OD formulation/Dormicum)Drug
Also called oral disintegrating (OD) formulation containing midazolam
Oral disintegrating formulation (Midazolam OD Formulation). The Midazolam OD Formulation was developed by Kyukyu Pharmaceutical Co., Ltd
BA (Dormicum/Midazolam OD formulation)Drug
Also called oral disintegrating (OD) formulation containing midazolam
Oral disintegrating film (Midazolam OD Formulation). The Midazolam OD Formulation was developed by Kyukyu Pharmaceutical Co., Ltd
| Study group | Role | What they receive |
|---|---|---|
| AB (Midazolam OD/Dormicum) | Experimental | Subjects with sequence AB will first receive the Intervention OD formulation (Period A, 30 µg Midazolam) and at the second visit the oral solution (Period B, 30 µg Dormicum ). Receives: Drug: AB (Midazolam OD formulation/Dormicum) |
| BA (Dormicum/midazolam OD) | Experimental | Subjects with sequence BA will first receive the Intervention oral solution (Period B, 30 µg Dormicum) and at the second visit the OD disintegrating formulation (Period A, 30 µg Midazolam). Receives: Drug: BA (Dormicum/Midazolam OD formulation) |
What is being measured
The primary outcome is the main question the study is designed to answer.
AUC0-12 of midazolam in plasma
Midazolam OD Formulation was developed by Kyukyu Pharmaceutical Co., Ltd. and is provided free of charge in support of the present study.
Measured: 0,1,2,3,4,5,6,7,8,9,10,11,12 hours
Secondary outcomes (1)
Cmax of midazolam in plasma
Midazolam OD Formulation was developed by Kyukyu Pharmaceutical Co., Ltd. and is provided free of charge in support of the present study.
Measured: 0,1,2,3,4,5,6,7,8,9,10,11,12 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Jul 2017
- Study start18 Aug 2017
- Primary completion25 Sep 2017
- Study completion25 Sep 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Cytochrome P450 CYP3A Enzyme DeficiencyStudies 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 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- Open-label, randomised, single-dose crossover design
- Masking
- None (open label)
- Enrolment
- 12 participants (actual)
Sponsor and investigators
- Lead sponsor
- University Hospital, Basel, Switzerland
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Stephan Krähenbühl, Principal investigator, University Hospital, Basel, Switzerland
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03204578
- Sponsor's protocol ID
- 2017-00545
- Other IDs
- me16Haschke, 2017
- Acronym
- PiSA
- Status last verified
- Apr 2018
- First submitted
- 22 Jun 2017
- Last updated
- 18 Apr 2018
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Kiene K, Hayasi N, Burhenne J, Uchitomi R, Sunderhauf C, Schmid Y, Haschke M, Haefeli WE, Krahenbuhl S, Mikus G, Inada H, Huwyler J. Microdosed midazolam for the determination of cytochrome P450 3A activity: Development and clinical evaluation of a buccal film. Eur J Pharm Sci. 2019 Jul 1;135:77-82. doi: 10.1016/j.ejps.2019.05.010. Epub 2019 May 16.
PubMed 31102650
Study at a glance
From the registry record, last updated by the sponsor on 18 Apr 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Physiological Study of the Human CYP3A Activity (PiSA)
- ClinicalTrials.gov ID
- NCT03204578
- Acronym / sponsor ID
- PiSA / 2017-00545
- Conditions
- Cytochrome P450 CYP3A Enzyme Deficiency
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 12 participants (actual)
- Lead sponsor
- University Hospital, Basel, SwitzerlandUniversity, hospital or other
- Study start
- 18 Aug 2017 (actual)
- Primary completion
- 25 Sep 2017 (actual)
- Study completion
- 25 Sep 2017 (actual)
- First posted
- 2 Jul 2017 (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.
Investigator-initiated physiological study to characterize the function of a major drug metabolizing enzyme using a microdosed phenotyping probe to avoid unwanted, concentration-dependent effects.
Detailed description
Disposition of a drug depends on absorption, distribution, metabolism, and elimination (ADME). Quantifying the ADME capacity of a patient may help to individualize target exposure by choosing the corresponding dose required for this individual. The large group of drugs eliminated by members of the CYP3A isozyme subfamily accounts for about 50% of all marketed drugs. Co-medication can modulate CYP3A activity 400-fold either by inducing isozyme expression or inhibiting expressed enzyme. Therefore, due to the variability of CYP3A activity, dose requirements of CYP3A substrates vary considerably between individual patients and may even rapidly vary within a patient. There is clinical interest in using CYP3A activity as a biomarker to predict optimal CYP3A drug dosing, improve therapeutic efficacy, and minimize adverse drug effects.
Determination of CYP3A activity is usually done with oral midazolam doses of 2-7.5 mg (phenotyping). Because therapeutic doses have pharmacological effects and can cause sedation, especially if CYP3A is inhibited, a microdosing approach for CYP phenotyping was developed to avoid any pharmacological activity. Oral midazolam pharmacokinetics are linear over a 30,000-fold range and 300 ng doses can reliably predict drug interactions with strong CYP3A inhibitors like ketoconazole.
The primary objective of this trial is to determine CYP3A activity using microdosed midazolam delivered from an oral disintegrating formulation in comparison to an oral midazolam solution. The oral disintegrating formulation is an innovative application form that would facilitate administration of the phenotyping probe in special patient populations.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- Open-label, randomised, single-dose crossover design
| Arm | Type | Receives |
|---|---|---|
| AB (Midazolam OD/Dormicum) | Experimental | Drug: AB (Midazolam OD formulation/Dormicum)Subjects with sequence AB will first receive the Intervention OD formulation (Period A, 30 µg Midazolam) and at the second visit the oral solution (Period B, 30 µg Dormicum ). |
| BA (Dormicum/midazolam OD) | Experimental | Drug: BA (Dormicum/Midazolam OD formulation)Subjects with sequence BA will first receive the Intervention oral solution (Period B, 30 µg Dormicum) and at the second visit the OD disintegrating formulation (Period A, 30 µg Midazolam). |
Who may qualify
- Ages
- 18 to 50 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (1 listed)
- Healthy male or female subjects, age of 18 to 50 years, body mass index (BMI) of 18.0 to 29.9 kg/m2
Key exclusion criteria (4 listed)
- Any intake of a substance known to induce or inhibit drug metabolising enzymes or transport system enzymes within a period of less than 10 times the respective elimination half-life or 3 weeks (whatever is longer).
- Any participation in a clinical trial within the last four weeks before inclusion.
- History or clinical evidence of any disease or medical condition, which may interfere with the pharmacokinetics of midazolam or which may increase the risk for toxicity or adverse events.
- Allergies (except for mild forms of hay fever) or history of hypersensitivity reactions.
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 |
|---|---|---|
| AB (Midazolam OD formulation/Dormicum)Also: oral disintegrating (OD) formulation containing midazolamOral disintegrating formulation (Midazolam OD Formulation). The Midazolam OD Formulation was developed by Kyukyu Pharmaceutical Co., Ltd | Drug | AB (Midazolam OD/Dormicum) |
| BA (Dormicum/Midazolam OD formulation)Also: oral disintegrating (OD) formulation containing midazolamOral disintegrating film (Midazolam OD Formulation). The Midazolam OD Formulation was developed by Kyukyu Pharmaceutical Co., Ltd | Drug | BA (Dormicum/midazolam OD) |
Primary outcome
AUC0-12 of midazolam in plasma
Time frame: 0,1,2,3,4,5,6,7,8,9,10,11,12 hours
Midazolam OD Formulation was developed by Kyukyu Pharmaceutical Co., Ltd. and is provided free of charge in support of the present study.
1 secondary outcome
Cmax of midazolam in plasma
Time frame: 0,1,2,3,4,5,6,7,8,9,10,11,12 hours
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 18 Apr 2018.
- Derived from this study: PubMed 31102650Kiene K, Hayasi N, Burhenne J, Uchitomi R, Sunderhauf C, Schmid Y, Haschke M, Haefeli WE, Krahenbuhl S, Mikus G, Inada H, Huwyler J. Microdosed midazolam for the determination of cytochrome P450 3A activity: Development and clinical evaluation of a buccal film. Eur J Pharm Sci. 2019 Jul 1;135:77-82. doi: 10.1016/j.ejps.2019.05.010. Epub 2019 May 16.
- Individual participant dataSharing planned: No
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.
Stephan Krähenbühl principal investigator
University Hospital, Basel, Switzerland
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing AB (Midazolam OD formulation/Dormicum) and BA (Dormicum/Midazolam OD formulation) in people with Cytochrome P450 CYP3A Enzyme Deficiency, run by University Hospital, Basel, Switzerland 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 1 inclusion and 4 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 18 Apr 2018. 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.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
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?
AUC0-12 of midazolam in plasma (time frame: 0,1,2,3,4,5,6,7,8,9,10,11,12 hours). 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 NCT03204578, which also lists 1 linked publication.
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 18 Apr 2018.