MetforminPhase 1NCT03335423

Inter- and Intra-individual Variations in Metformin Pharmacokinetics - The Importance of Genes and Drug Interactions

A Phase 1 study testing Oral metformin, Intravenous metformin and Oral codeine and oral metformin in people with Metformin and Organic Cation Transporter 1, run by University of Southern Denmark at 1 site in Denmark.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

The investigators aim to investigate the interindividual variation in metformin AUC in a large cohort of healthy volunteers after a single dose of metformin. Part 1 is driven by the hypothesis that metformin AUC and renal clearance exhibit significant interindividual variation. Read more about this study

Who is it for?: Ages 18 to 65 yearsHealthy volunteers can take part
Conditions the study is for: Metformin, Organic Cation Transporter 1, Codeine
What is being tested?: Oral metformin, Intravenous metformin and Oral codeine and oral metformin
Type of treatment: Pill or oral medicine, Injection or infusion
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 228 participants
Where: 1 siteDenmark
Study dates: 1 Mar 2018to 13 Jun 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 65 years
All sexes
Healthy volunteers accepted
Adult, Older adult

Inclusion Criteria Part 1 (and 2): Men and women. Apparent good general health. eGFR, creatinine, Hba1c, must be within the reference range or clinically insignificantly differ from this. Written consent must be given. Age 18-65. BMI 18,5 - 29,9kg/m².

Exclusion Criteria part 1 (and 2): Daily consumption of medicine (prescription, over the counter and herbal medicines, dietary supplements (oral contraceptives and regular vitamin pills are accepted)). Alcohol abuse. Hypersensitivity for metformin. For women: positive pregnancy test and not using safe contraceptives for 24 hours after intake of metformin and breastfeeding.

Inclusion Criteria Part 3:Apparent good general health. eGFR, creatinine, Hba1c, glucose, ALAT and bilirubin must be within the reference range or clinically insignificantly differ from this. Written consent must be given. Age 18-30 . BMI 18,5 - 29,9kg/m².

Exclusion Criteria part 3: Daily consumption of medicine (prescription, over the counter and herbal medicines, dietary supplements (regular vitamin pills are accepted)). Alcohol abuse. Hypersensitivity for metformin, codeine or morphine. Genetically proven CYP2D6 slow or ultra-fast metabolizers. Genetically proven loss-of-function allele in OCT1

Trial locations and contacts

1 site in 1 country.

Denmark1 site

The department of clinical pharmacy and pharmacology
Odense, 5000

Other trials in Denmark

About this study

The investigators aim to investigate the potential interaction between codeine and metformin in the intestine. The hypothesis underlying part 3 is that the increased risk of early discontinuation of metformin during co-administration with codeine is primarily due to local inhibition of OCT1 via codeine at the intestinal level.

Read the detailed description

Part 1: The investigators intend to investigate the inter-individual variation in metformin Area Under Plasma Concentration Curve (AUC) following a single dose of oral metformin based on the plasma concentration of metformin after 3 and 10 hours and urine collection for 24 hours . Part 2: The investigators intend to contribute with DNA and metformin AUC determinations from subjects from part 1 to a major international study that aime to highlight the Genome Wide Association (GWA) between the entire genome and variations in metformin pharmacokinetics (AUC) in a large group of healthy subjects and patients. Part 3: The investigators aim to investigate the potential interaction between codeine and metformin in the intestine.

The investigators secondary objective in part 3 is to investigate if the plasma concentration of morphine increases when codeine and metformin are given together due to competitive inhibition of the Organic cation transporter 1 (OCT1) transport protein (in the liver). Furthermore, the investigators will measure lactate after metformin ingestion as a proxy for metformin's effect on the intestinal mucosa, both after oral and intravenous metformin

Conditions: Metformin, Organic Cation Transporter 1, Codeine
Being tested: Oral metformin, Intravenous metformin, Oral codeine and oral metformin, Oral codeine and intravenous metformin

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Oral metforminDrug
The study was designed as a randomized, cross-over trial with a washout period of at least 1 week between the phases. Metformin was given both orally and through an intravenous route to be able to determine the absolute bioavailability of metformin. Metformin was given alone and together with codeine to investigate a potential interaction between the drugs. Lactate was measured as a proxy for metformin effect on the intestinal mucosa, both after oral and intravenous metformin
Intravenous metforminDrug
The study was designed as a randomized, cross-over trial with a washout period of at least 1 week between the phases. Metformin was given both orally and through an intravenous route to be able to determine the absolute bioavailability of metformin. Metformin was given alone and together with codeine to investigate a potential interaction between the drugs. Lactate was measured as a proxy for metformin effect on the intestinal mucosa, both after oral and intravenous metformin
Oral codeine and oral metforminDrug
The study was designed as a randomized, cross-over trial with a washout period of at least 1 week between the phases. Metformin was given both orally and through an intravenous route to be able to determine the absolute bioavailability of metformin. Metformin was given alone and together with codeine to investigate a potential interaction between the drugs. Lactate was measured as a proxy for metformin effect on the intestinal mucosa, both after oral and intravenous metformin
Oral codeine and intravenous metforminDrug
The study was designed as a randomized, cross-over trial with a washout period of at least 1 week between the phases. Metformin was given both orally and through an intravenous route to be able to determine the absolute bioavailability of metformin. Metformin was given alone and together with codeine to investigate a potential interaction between the drugs. Lactate was measured as a proxy for metformin effect on the intestinal mucosa, both after oral and intravenous metformin

Study groups in NCT03335423
Study group	Role	What they receive
Oral Metformin	Experimental	Oral metformin 1000mg will be given as a single dosis Receives: Drug: Oral metformin
Intravenous metformin	Experimental	Intravenous metformin 500mg will be injected as a single dosis Receives: Drug: Intravenous metformin
Oral codeine and oral metformin	Experimental	Codeine 25 mg will be given at 5 occasions with approximately 6 hours between each dosing. The fifth and last dose will be given together with 1000 mg oral metformin Receives: Drug: Oral codeine and oral metformin
Oral codeine and intravenous metformin	Experimental	Codeine 25 mg will be given at 5 occasions with approximately 6 hours between each dosing. The fifth and last dose will be given together with 500 mg metformin administrated as an injection. Receives: Drug: Oral codeine and intravenous metformin

What is being measured

The primary outcome is the main question the study is designed to answer.

Metformin AUC
Outcomes of part 1: Variation in metformin AUC in a large cohort of healthy volunteers after a single dose of metformin
Measured: blood samples will be collected after 3 and 10 hours for each subject (N=300) after oral metformin ingestion. Urine is collected for 24 hours.
Metformin AUC
Outcome of part 3; differences in AUC for metformin when given alone and together with codeine
Measured: Blood samples will be drawn in each of the 4 arms from ingestion of the drug/drugs and for 24 hours at suitable times. Urine is collected after ingestion of metformin for 24 hours.

Secondary outcomes (2)

Codeine AUC
secondary outcome of part 3: differences in codeine AUC when codeine is given alone and together with metformin
Measured: Blood samples are collected for 6 hours after ingestion of the first codeine pill. Blood samples are also collected and measured for codeine, morphing, M3G,M6G for 6 hours after both oral and intravenous metformin
Lactate AUC
Secondary outcome of part 3: differences in lactate AUC after metformin is given orally and intravenously
Measured: Blood samples for lactate will be drawn in each arm after metformin ingestion for 24 hours at suitable times

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

1 Mar 201813 Jun 2020

First posted7 Nov 2017
Study start1 Mar 2018
Primary completion13 Jun 2020
Study completion13 Jun 2020

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Other trials for MetforminStudies of the same condition, open and under way.
More trials run by University of Southern DenmarkThe 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: Basic science
Allocation: Randomised
Intervention model: Crossover
Model description: In part 1 a single group of healthy volunteers will ingest a single dosis of metformin and then have a blood sample drawn after 3 and 10 hours. In part 3, 18 healthy subjects will be randomized to ingest: a) oral metformin b) intravenous metformin c) 4 pills of codeine with the 5th taken together with oral metformin and d) 4 pills of codeine with the 5th taken together with intravenous metformin.
Masking: None (open label)
Enrolment: 228 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT03335423
Sponsor's protocol ID: 1779
Status last verified: Jan 2018
First submitted: 25 Oct 2017
Last updated: 25 Jun 2020
Results posted: No
FDA-regulated drug: No
FDA-regulated device: No

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

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All Metformin trials

Study at a glance

From the registry record, last updated by the sponsor on 25 Jun 2020. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Inter- and Intra-individual Variations in Metformin Pharmacokinetics - The Importance of Genes and Drug Interactions
ClinicalTrials.gov ID: NCT03335423
Acronym / sponsor ID: 1779
Conditions: Metformin, Organic Cation Transporter 1, Codeine
Phase: Phase 1
Study type: Interventional
Recruitment status: Completed
Enrolment: 228 participants (actual)
Lead sponsor: University of Southern DenmarkUniversity, hospital or other
Study start: 1 Mar 2018 (actual)
Primary completion: 13 Jun 2020 (actual)
Study completion: 13 Jun 2020 (actual)
First posted: 7 Nov 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.

Detailed description

Study design

Primary purpose: Basic science
Allocation: Randomised
Intervention model: Crossover
Masking: None (open label)
Number of arms: 4
Model description: In part 1 a single group of healthy volunteers will ingest a single dosis of metformin and then have a blood sample drawn after 3 and 10 hours. In part 3, 18 healthy subjects will be randomized to ingest: a) oral metformin b) intravenous metformin c) 4 pills of codeine with the 5th taken together with oral metformin and d) 4 pills of codeine with the 5th taken together with intravenous metformin.

Arm	Type	Receives
Oral Metformin	Experimental	Drug: Oral metforminOral metformin 1000mg will be given as a single dosis
Intravenous metformin	Experimental	Drug: Intravenous metforminIntravenous metformin 500mg will be injected as a single dosis
Oral codeine and oral metformin	Experimental	Drug: Oral codeine and oral metforminCodeine 25 mg will be given at 5 occasions with approximately 6 hours between each dosing. The fifth and last dose will be given together with 1000 mg oral metformin
Oral codeine and intravenous metformin	Experimental	Drug: Oral codeine and intravenous metforminCodeine 25 mg will be given at 5 occasions with approximately 6 hours between each dosing. The fifth and last dose will be given together with 500 mg metformin administrated as an injection.

Who may qualify

Ages: 18 to 65 years
Sex: All
Healthy volunteers: Accepted
Age groups: Adult, Older adult

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
Oral metforminThe study was designed as a randomized, cross-over trial with a washout period of at least 1 week between the phases. Metformin was given both orally and through an intravenous route to be able to determine the absolute bioavailability of metformin. Metformin was given alone and together with codeine to investigate a potential interaction between the drugs. Lactate was measured as a proxy for metformin effect on the intestinal mucosa, both after oral and intravenous metformin	Drug	Oral Metformin
Intravenous metforminThe study was designed as a randomized, cross-over trial with a washout period of at least 1 week between the phases. Metformin was given both orally and through an intravenous route to be able to determine the absolute bioavailability of metformin. Metformin was given alone and together with codeine to investigate a potential interaction between the drugs. Lactate was measured as a proxy for metformin effect on the intestinal mucosa, both after oral and intravenous metformin	Drug	Intravenous metformin
Oral codeine and oral metforminThe study was designed as a randomized, cross-over trial with a washout period of at least 1 week between the phases. Metformin was given both orally and through an intravenous route to be able to determine the absolute bioavailability of metformin. Metformin was given alone and together with codeine to investigate a potential interaction between the drugs. Lactate was measured as a proxy for metformin effect on the intestinal mucosa, both after oral and intravenous metformin	Drug	Oral codeine and oral metformin
Oral codeine and intravenous metforminThe study was designed as a randomized, cross-over trial with a washout period of at least 1 week between the phases. Metformin was given both orally and through an intravenous route to be able to determine the absolute bioavailability of metformin. Metformin was given alone and together with codeine to investigate a potential interaction between the drugs. Lactate was measured as a proxy for metformin effect on the intestinal mucosa, both after oral and intravenous metformin	Drug	Oral codeine and intravenous metformin

Primary outcome

Metformin AUC
Time frame: blood samples will be collected after 3 and 10 hours for each subject (N=300) after oral metformin ingestion. Urine is collected for 24 hours.
Outcomes of part 1: Variation in metformin AUC in a large cohort of healthy volunteers after a single dose of metformin
Metformin AUC
Time frame: Blood samples will be drawn in each of the 4 arms from ingestion of the drug/drugs and for 24 hours at suitable times. Urine is collected after ingestion of metformin for 24 hours.
Outcome of part 3; differences in AUC for metformin when given alone and together with codeine

2 secondary outcomes

Codeine AUC
Time frame: Blood samples are collected for 6 hours after ingestion of the first codeine pill. Blood samples are also collected and measured for codeine, morphing, M3G,M6G for 6 hours after both oral and intravenous metformin
Lactate AUC
Time frame: Blood samples for lactate will be drawn in each arm after metformin ingestion for 24 hours at suitable times

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 25 Jun 2020.

Related trials for Metformin

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Active, not recruitingPhase 2
Effectiveness Study of a Lifestyle Intervention Versus Metformin in Mothers With Recent Gestational Diabetes
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RecruitingPhase 3
Maridebart Cafraglutide Versus Semaglutide in Participants With Type 2 Diabetes
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RecruitingPhase 3
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Not yet recruitingPhase 1
Investigating Senolytic Properties in Pulmonary Rehabilitation and Metformin in COPD Exacerbations
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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.

Kim Brøsen, professor, chief physcian study chair

University of Southern Denmark

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

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 25 Jun 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 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.

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?

Metformin AUC (time frame: blood samples will be collected after 3 and 10 hours for each subject (N=300) after oral metformin ingestion. Urine is collected for 24 hours.). The study lists 2 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 NCT03335423.

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 25 Jun 2020.