Drug-drug InteractionPhase 1NCT04621253
Inhibition Metamizole 2020
A Phase 1 study testing Novalgin in people with Drug-drug Interaction, run by University Hospital, Basel, Switzerland at 1 site in Switzerland.
Trial summary
This clinical phase I trial had 3 arms: inhibition by fluconazole, inhibition by ciprofloxacin and placebo. Subjects were treated for 3 days prior to the study day. The intervention was a single dose of 1 gram metamizole. Read more about this study
- Who is it for?
- Ages 18 to 45 years, men onlyHealthy volunteers can take part
- Conditions the study is for
- Drug-drug Interaction
- What is being tested?
- Novalgin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 12 participants
- Where
- 1 siteSwitzerland
- Study dates
- 29 Apr 2020to 2 Oct 2020
- 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 45 years
- Men only
- Healthy volunteers accepted
- Adult
Who may be able to join
- Body mass index between 18 and 28 kg/m2 (inclusive) and bodyweight at least 50 kg at screening
- Systolic blood pressure: 100-140 mmHg, diastolic blood pressure: 60-90 mmHg and heart rate: 45-90 bpm (inclusive), measured on the leading arm*, in the supine position at screening
- No clinically significant findings on the physical examination on the physical examination at screening
- Signed informed consent prior to any study-mandated procedure
- Haematology and clinical chemistry results not deviating from the normal range to clinically relevant extent at screening
- Ability to communicate well with the investigator to understand and comply with the requirements of the study
Who cannot join
- Smoking > 5 cigarettes per day
- History or clinical evidence of alcoholism or drug abuse within the 3- year period prior to screening
- Loss of ≥ 250 ml of blood within 3 months prior to screening
- Treatment with an investigational drug within 30 days prior to screening
- Previous treatment with any prescribed or over the counter medication (including herbal medicines such as St John's Wort) within 2 weeks prior to the intended start of the study
- Legal incapacity or limited legal capacity at screening
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- Positive results from urine drug screen at screening
- History or clinical evidence of any disease
- Known hypersensitivity to Metamizole (Novalgin®), ciprofloxacin (Ciproxin®), fluconazole (Diflucan®) or any other excipients in the drug formulation
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Interaction of Cytochrome P450 Inhibition With Metamizole Metabolism in Healthy Subjects
This clinical phase I trial had 3 arms: inhibition by fluconazole, inhibition by ciprofloxacin and placebo. Subjects were treated for 3 days prior to the study day. The intervention was a single dose of 1 gram metamizole. We took blood samples at set time points and analysed the concentration of the main metabolites of metamizole at each time point in plasma.
Read the detailed description
While the clinical pharmacokinetics of metamizole have been described in detail before, the enzymes responsible for the metabolism have not been identified yet (except for the acetylation of 4-aminoantipyrine). Former investigations delivered mixed results and the question of the participation of the hepatic cytochrome p450 enzymes could not been answered.
Thus, a double-blind randomized cross over clinical phase I study with healthy, male, caucasian volunteers was conducted. After giving consent for participation and enrolment, the subjects were treated for 3 days with either one inhibitor (either ciprofloxacin, CYP1A2 inhibitor, or fluconazole, strong CYP2C9 and moderate CYP2C19 and CYP3A4 inhibitor) or placebo. The doses were 750 mg ciprofloxacin twice daily for 3 days and in the morning of the study day or 400 mg fluconazole loading dose with consecutive 200 mg fluconazole once daily. For the study day, the subject were invited to the study center and a venous access was placed on the non-dominant arm. The last dose of either inhibitor or placebo was taken 1h prior to a single dose of 1000 mg metamizole. Blood samples were drawn at t: 0h, 0.25h, 0.5h, 0.75h, 1h, 2h, 3h, 4h, 6h, 8h, 12h and 24h. The blood samples were centrifuged, the plasma was isolated and frozen at -20°C. All subjects received both inhibitors and placebo treatment, attending to a total of 3 study days. Furthermore, the genotype for CYP1A2, CYP2B6, CYP2C9, CYP2C19 and CYP2D6 was assessed.
Plasma samples will be analyzed and the concentrations of the main metabolites of metamizole and the inhibitors will be measured. Pharmacokinetic parameters such as maximal concentration, half life, time to reach maximal concentration and the area under the curve will be assessed and compared.
- Conditions
- Drug-drug Interaction
- Being tested
- Novalgin
- Keywords
- Metamizole, Inhibition, Cytochrome P450
- Medical subject headings
- Inhibition, Psychological
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
NovalginDrug
Single dose of 1000 mg metamizole, 1h after the last inhibitor or placebo intake
| Study group | Role | What they receive |
|---|---|---|
| Ciprofloxacin | Active comparator | Day 1: 750 mg ciprofloxacin capsule in the morning and evening Day 2: 750 mg ciprofloxacin capsule in the morning and evening Day 3: 750 mg ciprofloxacin capsule in the morning and evening Day 4: Study day, 750 mg ciprofloxacin 1h prior to 1000 mg metamizole. Receives: Drug: Novalgin |
| Fluconazole | Active comparator | Day 1: 400 mg fluconazole in the morning, placebo capsule in the evening Day 2: 200 mg fluconazole in the morning, placebo capsule in the evening Day 3: 200 mg fluconazole in the morning, placebo capsule in the evening Day 4: Study day, 200 mg fluconazole 1h prior to 1000 mg metamizole. Receives: Drug: Novalgin |
| Placebo | Placebo comparator | Day 1: placebo capsule in the morning and evening Day 2: placebo capsule in the morning and evening Day 3: placebo capsule in the morning and evening Day 4: Study day, placebo capsule 1h prior to 1000 mg metamizole. Receives: Drug: Novalgin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Assessment of the area under the plasma concentration vs time (AUC)
Assessment of the change in AUC of the main metabolites of metamizole (4-methylaminoantipyrine, 4-aminoantipyrine, 4-acetylaminoantipyrine and 4-formylaminoantipyrine) in the 3 arms
Measured: Study day (24 hours)
Assessment of peak plasma concentration (Cmax)
Assessment of the change of Cmax of the main metabolites of metamizole (4-methylaminoantipyrine, 4-aminoantipyrine, 4-acetylaminoantipyrine and 4-formylaminoantipyrine) in the 3 arms
Measured: Study day (24 hours)
Assessment of the time to reach peak plasma concentration (tmax)
Assessment of the change in tmax of the main metabolites of metamizole (4-methylaminoantipyrine, 4-aminoantipyrine, 4-acetylaminoantipyrine and 4-formylaminoantipyrine) in the 3 arms
Measured: Study day (24 hours)
Assessment of the half-life (t1/2)
Assessment of the change in t1/2 of the main metabolites of metamizole (4-methylaminoantipyrine, 4-aminoantipyrine, 4-acetylaminoantipyrine and 4-formylaminoantipyrine) in the 3 arms
Measured: Study day (24 hours)
Secondary outcomes (1)
Compliance to the Pretreatment with Ciprofloxacin and Fluconazole
Assessment of the area under the plasma concentration vs time of ciprofloxacin and fluconazole on the study day
Measured: Study day (24 hours)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Nov 2020
- Study start29 Apr 2020
- Primary completion2 Oct 2020
- Study completion2 Oct 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Drug-drug InteractionStudies of the same condition, open and under way.
- More trials run by University Hospital, Basel, SwitzerlandThe 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
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- Randomized cross-over treatment with 3 different sequences
- Masking
- Single blind
- Who is masked
- Investigator
- Enrolment
- 12 participants (actual)
Sponsor and investigators
- Lead sponsor
- University Hospital, Basel, Switzerland
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04621253
- Sponsor's protocol ID
- 2019-01404
- Other IDs
- 2019
- Status last verified
- Nov 2020
- First submitted
- 26 Oct 2020
- Last updated
- 9 Nov 2020
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Bachmann F, Duthaler U, Rudin D, Krahenbuhl S, Haschke M. N-demethylation of N-methyl-4-aminoantipyrine, the main metabolite of metamizole. Eur J Pharm Sci. 2018 Jul 30;120:172-180. doi: 10.1016/j.ejps.2018.05.003. Epub 2018 May 8.
PubMed 29746911Levy M, Zylber-Katz E, Rosenkranz B. Clinical pharmacokinetics of dipyrone and its metabolites. Clin Pharmacokinet. 1995 Mar;28(3):216-34. doi: 10.2165/00003088-199528030-00004.
PubMed 7758252
Study at a glance
From the registry record, last updated by the sponsor on 9 Nov 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Interaction of Cytochrome P450 Inhibition With Metamizole Metabolism in Healthy Subjects
- ClinicalTrials.gov ID
- NCT04621253
- Acronym / sponsor ID
- 2019-01404
- Conditions
- Drug-drug Interaction
- Keywords
- Metamizole, Inhibition, Cytochrome P450
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 12 participants (actual)
- Lead sponsor
- University Hospital, Basel, SwitzerlandUniversity, hospital or other
- Study start
- 29 Apr 2020 (actual)
- Primary completion
- 2 Oct 2020 (actual)
- Study completion
- 2 Oct 2020 (actual)
- First posted
- 9 Nov 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.
This clinical phase I trial had 3 arms: inhibition by fluconazole, inhibition by ciprofloxacin and placebo. Subjects were treated for 3 days prior to the study day. The intervention was a single dose of 1 gram metamizole. We took blood samples at set time points and analysed the concentration of the main metabolites of metamizole at each time point in plasma.
Detailed description
While the clinical pharmacokinetics of metamizole have been described in detail before, the enzymes responsible for the metabolism have not been identified yet (except for the acetylation of 4-aminoantipyrine). Former investigations delivered mixed results and the question of the participation of the hepatic cytochrome p450 enzymes could not been answered.
Thus, a double-blind randomized cross over clinical phase I study with healthy, male, caucasian volunteers was conducted. After giving consent for participation and enrolment, the subjects were treated for 3 days with either one inhibitor (either ciprofloxacin, CYP1A2 inhibitor, or fluconazole, strong CYP2C9 and moderate CYP2C19 and CYP3A4 inhibitor) or placebo. The doses were 750 mg ciprofloxacin twice daily for 3 days and in the morning of the study day or 400 mg fluconazole loading dose with consecutive 200 mg fluconazole once daily. For the study day, the subject were invited to the study center and a venous access was placed on the non-dominant arm. The last dose of either inhibitor or placebo was taken 1h prior to a single dose of 1000 mg metamizole. Blood samples were drawn at t: 0h, 0.25h, 0.5h, 0.75h, 1h, 2h, 3h, 4h, 6h, 8h, 12h and 24h. The blood samples were centrifuged, the plasma was isolated and frozen at -20°C. All subjects received both inhibitors and placebo treatment, attending to a total of 3 study days. Furthermore, the genotype for CYP1A2, CYP2B6, CYP2C9, CYP2C19 and CYP2D6 was assessed.
Plasma samples will be analyzed and the concentrations of the main metabolites of metamizole and the inhibitors will be measured. Pharmacokinetic parameters such as maximal concentration, half life, time to reach maximal concentration and the area under the curve will be assessed and compared.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Single blind (investigator)
- Number of arms
- 3
- Model description
- Randomized cross-over treatment with 3 different sequences
| Arm | Type | Receives |
|---|---|---|
| Ciprofloxacin | Active comparator | Drug: NovalginDay 1: 750 mg ciprofloxacin capsule in the morning and evening Day 2: 750 mg ciprofloxacin capsule in the morning and evening Day 3: 750 mg ciprofloxacin capsule in the morning and evening Day 4: Study day, 750 mg ciprofloxacin 1h prior to 1000 mg metamizole. |
| Fluconazole | Active comparator | Drug: NovalginDay 1: 400 mg fluconazole in the morning, placebo capsule in the evening Day 2: 200 mg fluconazole in the morning, placebo capsule in the evening Day 3: 200 mg fluconazole in the morning, placebo capsule in the evening Day 4: Study day, 200 mg fluconazole 1h prior to 1000 mg metamizole. |
| Placebo | Placebo comparator | Drug: NovalginDay 1: placebo capsule in the morning and evening Day 2: placebo capsule in the morning and evening Day 3: placebo capsule in the morning and evening Day 4: Study day, placebo capsule 1h prior to 1000 mg metamizole. |
Who may qualify
- Ages
- 18 to 45 years
- Sex
- Male only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (6 listed)
- Body mass index between 18 and 28 kg/m2 (inclusive) and bodyweight at least 50 kg at screening
- Systolic blood pressure: 100-140 mmHg, diastolic blood pressure: 60-90 mmHg and heart rate: 45-90 bpm (inclusive), measured on the leading arm*, in the supine position at screening
- No clinically significant findings on the physical examination on the physical examination at screening
- Signed informed consent prior to any study-mandated procedure
- Haematology and clinical chemistry results not deviating from the normal range to clinically relevant extent at screening
Key exclusion criteria (9 listed)
- Smoking > 5 cigarettes per day
- History or clinical evidence of alcoholism or drug abuse within the 3- year period prior to screening
- Loss of ≥ 250 ml of blood within 3 months prior to screening
- Treatment with an investigational drug within 30 days prior to screening
- Previous treatment with any prescribed or over the counter medication (including herbal medicines such as St John's Wort) within 2 weeks prior to the intended start of the study
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 |
|---|---|---|
| NovalginSingle dose of 1000 mg metamizole, 1h after the last inhibitor or placebo intake | Drug | Ciprofloxacin, Fluconazole, Placebo |
Primary outcome
Assessment of the area under the plasma concentration vs time (AUC)
Time frame: Study day (24 hours)
Assessment of the change in AUC of the main metabolites of metamizole (4-methylaminoantipyrine, 4-aminoantipyrine, 4-acetylaminoantipyrine and 4-formylaminoantipyrine) in the 3 arms
Assessment of peak plasma concentration (Cmax)
Time frame: Study day (24 hours)
Assessment of the change of Cmax of the main metabolites of metamizole (4-methylaminoantipyrine, 4-aminoantipyrine, 4-acetylaminoantipyrine and 4-formylaminoantipyrine) in the 3 arms
Assessment of the time to reach peak plasma concentration (tmax)
Time frame: Study day (24 hours)
Assessment of the change in tmax of the main metabolites of metamizole (4-methylaminoantipyrine, 4-aminoantipyrine, 4-acetylaminoantipyrine and 4-formylaminoantipyrine) in the 3 arms
Assessment of the half-life (t1/2)
Time frame: Study day (24 hours)
Assessment of the change in t1/2 of the main metabolites of metamizole (4-methylaminoantipyrine, 4-aminoantipyrine, 4-acetylaminoantipyrine and 4-formylaminoantipyrine) in the 3 arms
1 secondary outcome
Compliance to the Pretreatment with Ciprofloxacin and Fluconazole
Time frame: Study day (24 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 9 Nov 2020.
- Results publication: PubMed 29746911Bachmann F, Duthaler U, Rudin D, Krahenbuhl S, Haschke M. N-demethylation of N-methyl-4-aminoantipyrine, the main metabolite of metamizole. Eur J Pharm Sci. 2018 Jul 30;120:172-180. doi: 10.1016/j.ejps.2018.05.003. Epub 2018 May 8.
- Results publication: PubMed 7758252Levy M, Zylber-Katz E, Rosenkranz B. Clinical pharmacokinetics of dipyrone and its metabolites. Clin Pharmacokinet. 1995 Mar;28(3):216-34. doi: 10.2165/00003088-199528030-00004.
- Individual participant dataSharing planned: No
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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.
The record lists no contact. Use the official record to reach the sponsor.
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 Novalgin in people with Drug-drug Interaction, 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 6 inclusion and 9 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 9 Nov 2020. 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. Some participants in this study may receive a placebo. 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?
Assessment of the area under the plasma concentration vs time (AUC) (time frame: Study day (24 hours)). The study lists 4 primary outcomes in all. 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 NCT04621253, which also lists 2 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 9 Nov 2020.