HealthyPhase 1NCT01409395
Drug-Drug Interaction Study With Metformin and Nizatidine
A Phase 1 study testing Metformin and nizatidine and Metformin in people with Healthy, run by University of California, San Francisco at 1 site in United States.
Trial summary
This study will address the following question: Does nizatidine affect the pharmacokinetics of metformin in healthy volunteers? Recent studies in the Giacomini laboratory have indicated that nizatidine may block metformin elimination from the kidney by inhibiting organic cation transporter efflux of metformin. Read more about this study
- Who is it for?
- Ages 18 to 45 yearsHealthy volunteers can take part
- Conditions the study is for
- Healthy
- What is being tested?
- Metformin and nizatidine and Metformin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 10 participants
- Where
- 1 siteUnited States
- Study dates
- Sep 2011to Mar 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 45 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Age 18-45 years
- Male or female
- If female, using appropriate contraception
- Healthy as judged by medical examination, medical history and normal biochemical and hematological measures
- Normal urinalysis and renal function
- Understand the nature and purpose of the study and provide informed consent
Who cannot join
- Pregnant or lactating woman (female subjects will have a urine pregnancy test at the screening visit)
- Abnormal bone marrow function (leukocyte, neutrophil, or platelet counts outside the normal range)
- History of hypersensitivity or allergic reaction to metformin or nizatidine
- Risk of congestive heart failure requiring pharmacologic treatment (medical history)
- History of renal or hepatic dysfunction (e.g., CLcr <60mL/min, ALT >80U/L, AST>60 U/L)
- Anemic (hemoglobin <12 g/dL)
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- Use of any medications (including over the counter products, herbal products, or mineral supplements) with the exception of a daily vitamin or oral contraceptives. In particular use of medications that are known to interfere with the pharmacokinetics of metformin and nizatidine such as cimetidine, cetirizine, ketoconazole, procainamide, St. John's Wort, and testosterone are prohibited.
- Laboratory parameters that are more than 2 standard deviations from the laboratory mean
- Subject carries a MATE2K gene variant that is predicted to effect MATE2K protein expression
Trial locations and contacts
1 site in 1 country.
About this study
Official title: The Pharmacokinetic Interaction Between Metformin and Nizatidine in Healthy Volunteers
This study will address the following question: Does nizatidine affect the pharmacokinetics of metformin in healthy volunteers? Recent studies in the Giacomini laboratory have indicated that nizatidine may block metformin elimination from the kidney by inhibiting organic cation transporter efflux of metformin. The investigators hypothesize that the co-administration of metformin and nizatidine will reduce the renal clearance (CLR) of metformin leading to increased plasma concentrations and potential risk for toxicities. Knowledge of the pharmacokinetic interaction profile of metformin with organic transporter inhibitors, such as nizatidine, is important to help develop safer more effective drug therapy with reduced side effects.
Read the detailed description
Screening Procedures:
Prior to enrollment, subjects will be asked to come to the Clinical and Translational Science (CTSI) Clinical Research Centre (CRC) at San Francisco General Hospital (SFGH). The study protocol and procedures will be explained in detail, all questions will be answered, and subjects will be provided a consent form to sign. The screening visit will be conducted within 14 days of the first inpatient visit i.e. first metformin alone or metformin with nizatidine dosing day.
Only after subjects have consented to participate in the study will the screening procedures commence. All subjects recruited in this study will have already consented to the pharmacogenomics in ethnically diverse populations (SOPHIE) study, a previously established cohort of healthy people living in San Francisco. A review of the subject's medical history and health questionnaire will be conducted to re-assess health status and confirm eligibility (see attached health questionnaire). Changes in medication or drug use history will be noted during the study.
During the screening visit, vital signs as well as blood and urine samples will be taken from all subjects for laboratory analysis. A single blood sample (10 mL) will be taken by venipuncture to measure a complete blood count (CBC), electrolytes, blood urea nitrogen (BUN), creatinine, and liver function tests (LFTs) to screen for anemia and renal or hepatic insufficiency (see Inclusion/Exclusion Criteria).
Procedures During Main Study:
An equal number of subjects will be randomized, by a computer program, into one of the two study arms described below, prior to their screening visit. After at least a 1-week washout period, subjects will be assigned to the other treatment arm. The duration of the study will consist of two 24-hour inpatient study visits (2 non-consecutive overnight stays), separated by at least 1-week wash out period.
Randomized Study Visit Day 1: Metformin alone Subjects will report to the CRC at approximately 7:30 AM, after an overnight fast of at least 10 hours (fasted from approximately 10:00 PM). Vital signs and a brief history will be taken upon arrival. If all inclusion/exclusion criteria are met, one intravenous (IV) catheter will be inserted into a forearm vein to facilitate blood sampling. An initial blood sample of 10 mL will be drawn (from the IV line) for the determination of plasma metformin, creatinine, and nizatidine concentrations prior to the administration of metformin (i.e. baseline measurement). Next, each subject will receive an oral dose of 850 mg of metformin with 8 oz of water. Blood samples (5 mL each) will then be drawn at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, and 24 hours post-dose for the determination of plasma metformin and nizatidine concentrations. An additional 5 mL of blood will be drawn at the 6-hour and 12-hour time points for the measurement of serum creatinine to allow the calculation of creatinine clearance (CLcr). Blood samples obtained by finger prick will be taken at 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5 and 4 hours after ingestion of metformin (total of 0.1 mL) to measure blood glucose levels. Additional biomarkers of metformin/nizatidine response and toxicities, such as plasma insulin, glucose and AMPK activation, may also be determined on the blood samples collected. Subjects will remain at the CRC and receive standardized meals starting 4 hours post metformin dosing. Subjects will be discharged and allowed to go home the following morning after the collection of the last (24 hour) blood and urine sample at approximately 8 AM. All blood samples will be centrifuged, and the plasma separated immediately and stored at -80oC until analysis.
Urine collection:Subjects will be asked to void their bladder prior to metformin administration (baseline urine sample) and to drink 8 oz of water every 4 hours to maintain urine flow and pH. Aliquots of urine will be collected for the following time frames: 0-2, 2-4, 4-8, 8-12, and 12-24 hours post metformin dosing. Additionally, aliquots from collections taken between 0-12 and 0-24 hours will be pooled for analysis of creatinine. Subjects will be advised to collect all urine produced during the inpatient visit. The volume and pH of each urine collection will be recorded and an aliquot (20 mL) from each collection period will be stored at -80°C for determination of urinary metformin, creatinine, nizatidine and nizatidine metabolite concentrations.
Randomized Study Visit Day 2:Co-administration of metformin with nizatidine Subjects will report to the CRC after an overnight fast as previously described. After the collection of the baseline blood and urine samples, subjects will receive an oral dose of 600 mg nizatidine and 850 mg of metformin with 8 oz of water. The study procedures described in "Randomized Study Visit Day 1" and "Urine collection" will be repeated.
Study Restrictions:
Concomitant Medications:
The study requires that healthy participants refrain from taking any medications (except for daily vitamins or oral contraceptives) for the duration of the study, in particular medication(s) that interfere with the pharmacokinetics of metformin or nizatidine (See Exclusion criteria 13.7).
Other Study Restrictions:
Subjects will be required to use adequate contraceptive means to avoid pregnancy throughout the study. Subjects must remain within the CRC throughout the two 24 hour inpatient visits unless accompanied by a CRC staff member. Subjects are to refrain from smoking and from ingesting caffeine, alcohol, orange and grapefruit juice containing products from the night before each inpatient study day until the study is complete, approximately 24 hours after dosing.
Clinical and Laboratory Determinations:
Analytical Methods:
Measurement of metformin, creatinine, nizatidine and nizatidine metabolites in plasma and urine will be preformed by High Performance Liquid Chromatography (HPLC) with tandem mass spectrometry (MS/MS), using assays previously described and validated20-22.
Hematology, Blood Chemistry and Urinalysis:
The following standard biochemistry, blood chemistry and urinalysis will be performed at the screening visit:
- Hematology, (Complete Blood Count with differential, CDP): WBC with differential, red blood cells (RBC), RBC indices (HGB, HCT, MCV, MCH, MCHC) and platelet count.
- Blood chemistry (Metabolic Comprehensive Panel, METC): sodium, potassium, chloride, carbon dioxide, creatinine, blood urea nitrogen, glucose, calcium, bilirubin (total), phosphate (total), AST, ALT, albumin and alkaline phosphatase
- Urinalysis: urine protein (dipstick) and blood (dipstick).
Other: Pregnancy test:
A urine test will be administered to females who have had their first menstrual period to make ensure that they are not pregnant. Pregnant females will be excluded from the study.
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Metformin and nizatidineDrug
Also called Metformin: Fortamet, Glucophage, Nizatidine: Axid
Subjects will be given a single oral dose of 850 mg of metformin and a single oral dose of 600 mg of nizatidine
MetforminDrug
Also called GLUCOPHAGE
Subjects will be given a single oral dose of 850 mg of metformin
| Study group | Role | What they receive |
|---|---|---|
| Metformin | Experimental | Subjects will be dosed with Metformin alone (850 mg) Receives: Drug: Metformin |
| Metformin and Nizatidine | Experimental | Subjects will be dosed with metformin in conjunction with nizatidine Receives: Drug: Metformin and nizatidine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Composite of Pharmacokinetics of co-administration of nizatidine & metformin in healthy volunteers.
Cmax and Tmax will be determined from AUC-time curve Glomerular filtration rate (GFR) will be approximated by measured creatinine clearance using the following equation:GFR calculation: GFR = CLcreatinine = (Urinary creatinine * V) / (Plasma creatinine)
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 posted4 Aug 2011 (estimated)
- Study startSep 2011
- Primary completionMar 2013
- Study completionMar 2013
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for HealthyStudies of the same condition, open and under way.
- More trials run by University of California, San FranciscoThe 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
- Single group
- Masking
- None (open label)
- Enrolment
- 10 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of California, San Francisco
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute of General Medical Sciences (NIGMS)
- Responsible party
- Sponsor
- Investigators
- Kathleen M Giacomini, Ph.D, Principal investigator, University of California, San Francisco
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01409395
- Sponsor's protocol ID
- 6968
- Other IDs
- R01GM036780
- Status last verified
- Apr 2014
- First submitted
- 29 Jul 2011
- Last updated
- 10 Apr 2014
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 10 Apr 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Pharmacokinetic Interaction Between Metformin and Nizatidine in Healthy Volunteers
- ClinicalTrials.gov ID
- NCT01409395
- Acronym / sponsor ID
- 6968
- Conditions
- Healthy
- Keywords
- Drug drug interaction
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 10 participants (actual)
- Lead sponsor
- University of California, San FranciscoUniversity, hospital or other
- Collaborators
- National Institute of General Medical Sciences (NIGMS)
- Study start
- Sep 2011
- Primary completion
- Mar 2013 (actual)
- Study completion
- Mar 2013 (actual)
- First posted
- 4 Aug 2011 (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 study will address the following question: Does nizatidine affect the pharmacokinetics of metformin in healthy volunteers? Recent studies in the Giacomini laboratory have indicated that nizatidine may block metformin elimination from the kidney by inhibiting organic cation transporter efflux of metformin. The investigators hypothesize that the co-administration of metformin and nizatidine will reduce the renal clearance (CLR) of metformin leading to increased plasma concentrations and potential risk for toxicities. Knowledge of the pharmacokinetic interaction profile of metformin with organic transporter inhibitors, such as nizatidine, is important to help develop safer more effective drug therapy with reduced side effects.
Detailed description
Screening Procedures:
Prior to enrollment, subjects will be asked to come to the Clinical and Translational Science (CTSI) Clinical Research Centre (CRC) at San Francisco General Hospital (SFGH). The study protocol and procedures will be explained in detail, all questions will be answered, and subjects will be provided a consent form to sign. The screening visit will be conducted within 14 days of the first inpatient visit i.e. first metformin alone or metformin with nizatidine dosing day.
Only after subjects have consented to participate in the study will the screening procedures commence. All subjects recruited in this study will have already consented to the pharmacogenomics in ethnically diverse populations (SOPHIE) study, a previously established cohort of healthy people living in San Francisco. A review of the subject's medical history and health questionnaire will be conducted to re-assess health status and confirm eligibility (see attached health questionnaire). Changes in medication or drug use history will be noted during the study.
During the screening visit, vital signs as well as blood and urine samples will be taken from all subjects for laboratory analysis. A single blood sample (10 mL) will be taken by venipuncture to measure a complete blood count (CBC), electrolytes, blood urea nitrogen (BUN), creatinine, and liver function tests (LFTs) to screen for anemia and renal or hepatic insufficiency (see Inclusion/Exclusion Criteria).
Procedures During Main Study:
An equal number of subjects will be randomized, by a computer program, into one of the two study arms described below, prior to their screening visit. After at least a 1-week washout period, subjects will be assigned to the other treatment arm. The duration of the study will consist of two 24-hour inpatient study visits (2 non-consecutive overnight stays), separated by at least 1-week wash out period.
Randomized Study Visit Day 1: Metformin alone Subjects will report to the CRC at approximately 7:30 AM, after an overnight fast of at least 10 hours (fasted from approximately 10:00 PM). Vital signs and a brief history will be taken upon arrival. If all inclusion/exclusion criteria are met, one intravenous (IV) catheter will be inserted into a forearm vein to facilitate blood sampling. An initial blood sample of 10 mL will be drawn (from the IV line) for the determination of plasma metformin, creatinine, and nizatidine concentrations prior to the administration of metformin (i.e. baseline measurement). Next, each subject will receive an oral dose of 850 mg of metformin with 8 oz of water. Blood samples (5 mL each) will then be drawn at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, and 24 hours post-dose for the determination of plasma metformin and nizatidine concentrations. An additional 5 mL of blood will be drawn at the 6-hour and 12-hour time points for the measurement of serum creatinine to allow the calculation of creatinine clearance (CLcr). Blood samples obtained by finger prick will be taken at 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5 and 4 hours after ingestion of metformin (total of 0.1 mL) to measure blood glucose levels. Additional biomarkers of metformin/nizatidine response and toxicities, such as plasma insulin, glucose and AMPK activation, may also be determined on the blood samples collected. Subjects will remain at the CRC and receive standardized meals starting 4 hours post metformin dosing. Subjects will be discharged and allowed to go home the following morning after the collection of the last (24 hour) blood and urine sample at approximately 8 AM. All blood samples will be centrifuged, and the plasma separated immediately and stored at -80oC until analysis.
Urine collection:Subjects will be asked to void their bladder prior to metformin administration (baseline urine sample) and to drink 8 oz of water every 4 hours to maintain urine flow and pH. Aliquots of urine will be collected for the following time frames: 0-2, 2-4, 4-8, 8-12, and 12-24 hours post metformin dosing. Additionally, aliquots from collections taken between 0-12 and 0-24 hours will be pooled for analysis of creatinine. Subjects will be advised to collect all urine produced during the inpatient visit. The volume and pH of each urine collection will be recorded and an aliquot (20 mL) from each collection period will be stored at -80°C for determination of urinary metformin, creatinine, nizatidine and nizatidine metabolite concentrations.
Randomized Study Visit Day 2:Co-administration of metformin with nizatidine Subjects will report to the CRC after an overnight fast as previously described. After the collection of the baseline blood and urine samples, subjects will receive an oral dose of 600 mg nizatidine and 850 mg of metformin with 8 oz of water. The study procedures described in "Randomized Study Visit Day 1" and "Urine collection" will be repeated.
Study Restrictions:
Concomitant Medications:
The study requires that healthy participants refrain from taking any medications (except for daily vitamins or oral contraceptives) for the duration of the study, in particular medication(s) that interfere with the pharmacokinetics of metformin or nizatidine (See Exclusion criteria 13.7).
Other Study Restrictions:
Subjects will be required to use adequate contraceptive means to avoid pregnancy throughout the study. Subjects must remain within the CRC throughout the two 24 hour inpatient visits unless accompanied by a CRC staff member. Subjects are to refrain from smoking and from ingesting caffeine, alcohol, orange and grapefruit juice containing products from the night before each inpatient study day until the study is complete, approximately 24 hours after dosing.
Clinical and Laboratory Determinations:
Analytical Methods:
Measurement of metformin, creatinine, nizatidine and nizatidine metabolites in plasma and urine will be preformed by High Performance Liquid Chromatography (HPLC) with tandem mass spectrometry (MS/MS), using assays previously described and validated20-22.
Hematology, Blood Chemistry and Urinalysis:
The following standard biochemistry, blood chemistry and urinalysis will be performed at the screening visit:
- Hematology, (Complete Blood Count with differential, CDP): WBC with differential, red blood cells (RBC), RBC indices (HGB, HCT, MCV, MCH, MCHC) and platelet count.
- Blood chemistry (Metabolic Comprehensive Panel, METC): sodium, potassium, chloride, carbon dioxide, creatinine, blood urea nitrogen, glucose, calcium, bilirubin (total), phosphate (total), AST, ALT, albumin and alkaline phosphatase
- Urinalysis: urine protein (dipstick) and blood (dipstick).
Other: Pregnancy test:
A urine test will be administered to females who have had their first menstrual period to make ensure that they are not pregnant. Pregnant females will be excluded from the study.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Metformin | Experimental | Drug: MetforminSubjects will be dosed with Metformin alone (850 mg) |
| Metformin and Nizatidine | Experimental | Drug: Metformin and nizatidineSubjects will be dosed with metformin in conjunction with nizatidine |
Who may qualify
- Ages
- 18 to 45 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (6 listed)
- Age 18-45 years
- Male or female
- If female, using appropriate contraception
- Healthy as judged by medical examination, medical history and normal biochemical and hematological measures
- Normal urinalysis and renal function
Key exclusion criteria (9 listed)
- Pregnant or lactating woman (female subjects will have a urine pregnancy test at the screening visit)
- Abnormal bone marrow function (leukocyte, neutrophil, or platelet counts outside the normal range)
- History of hypersensitivity or allergic reaction to metformin or nizatidine
- Risk of congestive heart failure requiring pharmacologic treatment (medical history)
- History of renal or hepatic dysfunction (e.g., CLcr <60mL/min, ALT >80U/L, AST>60 U/L)
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 |
|---|---|---|
| Metformin and nizatidineAlso: Metformin: Fortamet, Glucophage, Nizatidine: AxidSubjects will be given a single oral dose of 850 mg of metformin and a single oral dose of 600 mg of nizatidine | Drug | Metformin and Nizatidine |
| MetforminAlso: GLUCOPHAGESubjects will be given a single oral dose of 850 mg of metformin | Drug | Metformin |
Primary outcome
Composite of Pharmacokinetics of co-administration of nizatidine & metformin in healthy volunteers.
Time frame: 24 hours
Cmax and Tmax will be determined from AUC-time curve Glomerular filtration rate (GFR) will be approximated by measured creatinine clearance using the following equation:GFR calculation: GFR = CLcreatinine = (Urinary creatinine * V) / (Plasma creatinine)
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 10 Apr 2014.
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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.
Kathleen M Giacomini, Ph.D principal investigator
University of California, San Francisco
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 Metformin and nizatidine and Metformin in people with Healthy, run by University of California, San Francisco at 1 site in United States.
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 10 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 United States. 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?
Composite of Pharmacokinetics of co-administration of nizatidine & metformin in healthy volunteers. (time frame: 24 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 10 Apr 2014.