Diabetes Mellitus, Type 2Phase 1NCT01357876
Effect of Metformin on Gut Peptides , Bile Acids and Lipid Profiles in Type 2 Diabetics
A Phase 1 study testing Metformin in people with Diabetes Mellitus, Type 2, run by GlaxoSmithKline at 1 site in United Kingdom.
Trial summary
Metformin is a biguanide that is marketed as an oral anti-diabetic drug. Metformin treatment in concert with diet and exercise is the consensus first-line treatment for type 2 diabetes mellitus (T2DM), and therefore it will likely be an adjunct therapy for all assets in development by GSK for the treatment of T2DM. Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Diabetes Mellitus, Type 2
- What is being tested?
- Metformin
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 8 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- 1 Oct 2010to 7 Jul 2011
- 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 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- T2DM men and women between 18 -70 years of age on stable dose of metformin
- Subjects taking stable regimens of aspirin, ACE inhibitors, beta-blockers, calcium channel blockers, thyroid replacement hormone, and HMG-CoA reductase inhibitors (statins) will be allowed if their dose regimen(s) remain constant throughout the study period
- HBA1C >6.5% <8.5%
- BMI from 22.5 up to 37.5 kg/m2, inclusive
- AST, ALT, alkaline phosphatase and bilirubin less than or equal to 3xULN
- Has a normal ECG as determined by unit physician.
- Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
Who cannot join
- medically unable or unwilling to discontinue current metformin therapy for as required by the protocol and remain off medication until the completion of Visit 3
- past or present disease (other than T2DM) as judged by the Investigator, which may affect the outcome of this study. These diseases include, but are not limited to, cardiovascular disease, malignancy, hepatic disease, renal disease, haematological disease, neurological disease and endocrine disease.
- subject is currently on bile acid sequestrant therapy.
- Gastrointestinal surgery or disease that would compromise the use of the EnteroTest
- fasting triglycerides >450mg/dL (>5.1 mmol/L)
- Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
Show all 14Show fewer
- A positive pre-study drug/alcohol screen.
- History of regular alcohol consumption within 6 months of the study defined as:
- -An average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 8 g of alcohol: a half-pint (~240 ml) of beer, 1 glass (125 ml) of wine or 1 (25 ml) measure of spirits.
- Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety.
- Pregnant females as determined by positive (serum or urine) hCG test at screening or prior to dosing.
- Lactating females.
- Unwillingness or inability to follow the procedures outlined in the protocol.
- 12.Subject is mentally or legally incapacitated or unable to provide informed consent
Trial locations and contacts
1 site in 1 country.
United Kingdom1 site
GSK Investigational Site
Cambridge, Cambridgeshire, CB2 2GG
About this study
Metformin is a biguanide that is marketed as an oral anti-diabetic drug. Metformin treatment in concert with diet and exercise is the consensus first-line treatment for type 2 diabetes mellitus (T2DM), and therefore it will likely be an adjunct therapy for all assets in development by GSK for the treatment of T2DM. Metformin has potent effects in lowering circulating glucose concentrations, and it is believed to have additional benefits in improving macrovascular outcomes, fatty liver disease and polycystic ovarian syndrome. Its use in a significant proportion of T2DM subjects is limited by contraindications of heart failure and renal insufficiency or gastrointestinal side effects. The mechanisms underlying its glucose-lowering effect and adverse event profile of metformin are not well understood. Whilst activation of AMP kinase may be important for therapeutic effect, changes in incretin secretion and bile acid excretion have been described, but not consistently linked to its therapeutic effect or AE profile. The aim of this study is to recruit T2DM patients on prescribed metformin monotherapy to further investigate how the glucose effects are related to the alterations in bile acid absorption, incretin and lipid profiles by studying these parameters on and off the drug. This will be done in combination with frequent capillary blood glucose monitoring to ensure patient safety. This study will facilitate the development of a pharmacodynamic model that can be used by clinical teams developing non-absorbable NCEs such as iBAT inhibitors.
Read the detailed description
As metformin has become first-line therapy for T2DM patients in many countries, it is important to ensure early-on in development that novel anti-diabetic NCEs work well as add-ons to this drug. Furthermore, the broad spectrum of effects of metformin that may be related to its glucose-lowering action offers the opportunity to use this drug as an investigative tool to explore the relationship between the various pharmacodynamic endpoints. In this situation, reliable PD endpoints are essential because systemic PK measurements are not available to track how a NCE target is being activated or inhibited. Therefore, a clearer understanding of metformin's mechanism of action as it relates to glycaemic control, lipid metabolism, bile acid excretion and gastrointestinal adverse effects will enable the EnteroEndocrine (EE) project teams to design more efficient studies for the evaluation of non-absorbable NCEs targeted to receptors that are accessible from the gut lumen, including the ileal bile acid transport inhibitor.
Because of the complexity of metformin kinetics within the gut, it is proposed to follow the rise and fall of fasting blood glucose during metformin washout and re-introduction, respectively, to determine the two appropriate timepoints for more detailed investigation.
As a result, subjects will be studied on 4 occasions:
- Whilst on their usual stable dose of metformin (baseline state),
- 7 days after stopping metformin to replicate the washout paradigm frequently used in early phase T2DM studies in GSK
- When fasting capillary glucose has increased by 25% from the pre-metformin washout level or two weeks from the start of the wash-out period.
- After metformin is re-introduced, when fasting capillary glucose has returned to the pre-metformin washout level (baseline state established at screening )
This study will entail the withdrawal and re-introduction of metformin under closely supervised conditions. The withdrawal of metformin will be for a maximum period up to three weeks and the glucose increases projected are not expected to result in significant long-term risk for the subjects.
If subjects do not already test blood glucose at home, a glucometer, instructions on its use, and testing strips will be provided to them for capillary blood glucose (CBG) monitoring during withdrawal and reinstatement of metformin. They will be instructed to test their blood glucose twice a day, fasting before breakfast and before dinner, and at any time they are concerned that blood glucose may have risen excessively. A written diary card will be kept by each subject for recording CBG values, beginning approximately 7 days before discontinuation of metformin after baseline assessments are completed during visit 1.
Fasting CBG values >15mM or < 3.5mM must be reported to the site at once. If fasting CBG are >15mM or < 3.5 mM on any two consecutive days during the wash-out period, the subject will be discontinued and the usual dose of metformin will be reinstated, if appropriate
Subjects are required to call the study centre while not in the unit or to alert site staff while in the clinical unit:
- When they have CBG values that are >15mM
- When they have CBG values that are <3.5mM
- When they have any concerns relating to their CBG levels
- When they have rapid, unexplained changes in their blood glucose levels
Study staff will attempt to contact the subjects daily to check on the CBG values and to record any adverse events whilst the subject is at home.
Subjects will be encouraged to keep their usual lifestyle in term of diet and exercise for all duration of the study.
The Entero-Test device is simple, safe device for the collection of duodenal bile. It is well tolerated, although some subjects may feel slight nausea on removal. Some blood may be seen on the string when removed. This occurs if the string "nicks" the oesophagus on removal, this is very minor trauma that heals rapidly and is not a cause for concern.
Primary enpoints-During metformin wash out and when treatment reinstated, pharmacodynamic endpoints will include the following as data permit:
- 24h profiles of blood glucose and insulin
- Faecal and serum bile acid profiles
- Enteroendocrine peptide profiling including but not limited to tGLP-1, tGIP, and tPYY
- Serum lipid analysis including but not limited to fasting HDL and LDL cholesterol, fasting and prandial TGs, ApoA1, ApoB and ApoE
Secondary Endpoints- • Relative bile acid composition as determined by EnteroTest bile string sampling of duodenal bile.
- Sparse metformin PK profiles will be determined from plasma samples
- Conditions
- Diabetes Mellitus, Type 2
- Being tested
- Metformin
- Medical subject headings
- Diabetes Mellitus, Type 2
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MetforminOther
withdrawral
| Study group | Role | What they receive |
|---|---|---|
| Type two diabetics | Other | Type two diabetics Receives: Other: Metformin |
What is being measured
The primary outcome is the main question the study is designed to answer.
To investigate the relationship between the glucose lowering action of metformin and Faecal and serum bile acid concentrations
Measured: We will track this measure over a 5 week period. This may change as a patient's response to withdrawl and resumption of metformin varies
To investigate the relationship between the glucose lowering action of metformin and enteroendocrine peptide profiles including, but not limited to, incretins and PYY
Measured: We will track this measure over a 5 week period. This may change as a patient's response to withdrawl and resumption of metformin varies
To investigate the relationship between the glucose lowering action of metformin and lipid metabolism including, but not limited to, fasting lipids and prandial TGs
Measured: We will track this measure over a 5 week period. This may change as a patient's response to withdrawl and resumption of metformin varies
Secondary outcomes (2)
• To provide a relative estimate of the composition of bile acids in bile sampled using the EnteroTest string
Measured: We will track this measure over a 5 week period. This may change as a patient's response to withdrawl and resumption of metformin varies
To measure sparse metformin profiles on the days when the PD endpoints are measured
Measured: We will track this measure over a 5 week period. This may change as a patient's response to withdrawl and resumption of metformin varies
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 May 2011 (estimated)
- Study start1 Oct 2010
- Primary completion7 Jul 2011
- Study completion7 Jul 2011
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 Diabetes Mellitus, Type 2Studies of the same condition, open and under way.
- More trials run by GlaxoSmithKlineThe 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
- Single group
- Masking
- None (open label)
- Enrolment
- 8 participants (actual)
Sponsor and investigators
- Lead sponsor
- GlaxoSmithKline
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- GSK Clinical Trials, Study director, GlaxoSmithKline
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01357876
- Sponsor's protocol ID
- 114453
- Status last verified
- Jun 2017
- First submitted
- 4 Nov 2010
- Last updated
- 22 Jun 2017
- Results posted
- No
- Data monitoring committee
- No
Publications
Napolitano A, Miller S, Nicholls AW, Baker D, Van Horn S, Thomas E, Rajpal D, Spivak A, Brown JR, Nunez DJ. Novel gut-based pharmacology of metformin in patients with type 2 diabetes mellitus. PLoS One. 2014 Jul 2;9(7):e100778. doi: 10.1371/journal.pone.0100778. eCollection 2014.
PubMed 24988476
Study at a glance
From the registry record, last updated by the sponsor on 22 Jun 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effect of Metformin on Gut Peptides , Bile Acids and Lipid Profiles in Type 2 Diabetics
- ClinicalTrials.gov ID
- NCT01357876
- Acronym / sponsor ID
- 114453
- Conditions
- Diabetes Mellitus, Type 2
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 8 participants (actual)
- Lead sponsor
- GlaxoSmithKlineIndustry (pharma, biotech, devices)
- Study start
- 1 Oct 2010 (actual)
- Primary completion
- 7 Jul 2011 (actual)
- Study completion
- 7 Jul 2011 (actual)
- First posted
- 23 May 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.
Metformin is a biguanide that is marketed as an oral anti-diabetic drug. Metformin treatment in concert with diet and exercise is the consensus first-line treatment for type 2 diabetes mellitus (T2DM), and therefore it will likely be an adjunct therapy for all assets in development by GSK for the treatment of T2DM. Metformin has potent effects in lowering circulating glucose concentrations, and it is believed to have additional benefits in improving macrovascular outcomes, fatty liver disease and polycystic ovarian syndrome. Its use in a significant proportion of T2DM subjects is limited by contraindications of heart failure and renal insufficiency or gastrointestinal side effects. The mechanisms underlying its glucose-lowering effect and adverse event profile of metformin are not well understood. Whilst activation of AMP kinase may be important for therapeutic effect, changes in incretin secretion and bile acid excretion have been described, but not consistently linked to its therapeutic effect or AE profile. The aim of this study is to recruit T2DM patients on prescribed metformin monotherapy to further investigate how the glucose effects are related to the alterations in bile acid absorption, incretin and lipid profiles by studying these parameters on and off the drug. This will be done in combination with frequent capillary blood glucose monitoring to ensure patient safety. This study will facilitate the development of a pharmacodynamic model that can be used by clinical teams developing non-absorbable NCEs such as iBAT inhibitors.
Detailed description
As metformin has become first-line therapy for T2DM patients in many countries, it is important to ensure early-on in development that novel anti-diabetic NCEs work well as add-ons to this drug. Furthermore, the broad spectrum of effects of metformin that may be related to its glucose-lowering action offers the opportunity to use this drug as an investigative tool to explore the relationship between the various pharmacodynamic endpoints. In this situation, reliable PD endpoints are essential because systemic PK measurements are not available to track how a NCE target is being activated or inhibited. Therefore, a clearer understanding of metformin's mechanism of action as it relates to glycaemic control, lipid metabolism, bile acid excretion and gastrointestinal adverse effects will enable the EnteroEndocrine (EE) project teams to design more efficient studies for the evaluation of non-absorbable NCEs targeted to receptors that are accessible from the gut lumen, including the ileal bile acid transport inhibitor.
Because of the complexity of metformin kinetics within the gut, it is proposed to follow the rise and fall of fasting blood glucose during metformin washout and re-introduction, respectively, to determine the two appropriate timepoints for more detailed investigation.
As a result, subjects will be studied on 4 occasions:
- Whilst on their usual stable dose of metformin (baseline state),
- 7 days after stopping metformin to replicate the washout paradigm frequently used in early phase T2DM studies in GSK
- When fasting capillary glucose has increased by 25% from the pre-metformin washout level or two weeks from the start of the wash-out period.
- After metformin is re-introduced, when fasting capillary glucose has returned to the pre-metformin washout level (baseline state established at screening )
This study will entail the withdrawal and re-introduction of metformin under closely supervised conditions. The withdrawal of metformin will be for a maximum period up to three weeks and the glucose increases projected are not expected to result in significant long-term risk for the subjects.
If subjects do not already test blood glucose at home, a glucometer, instructions on its use, and testing strips will be provided to them for capillary blood glucose (CBG) monitoring during withdrawal and reinstatement of metformin. They will be instructed to test their blood glucose twice a day, fasting before breakfast and before dinner, and at any time they are concerned that blood glucose may have risen excessively. A written diary card will be kept by each subject for recording CBG values, beginning approximately 7 days before discontinuation of metformin after baseline assessments are completed during visit 1.
Fasting CBG values >15mM or < 3.5mM must be reported to the site at once. If fasting CBG are >15mM or < 3.5 mM on any two consecutive days during the wash-out period, the subject will be discontinued and the usual dose of metformin will be reinstated, if appropriate
Subjects are required to call the study centre while not in the unit or to alert site staff while in the clinical unit:
- When they have CBG values that are >15mM
- When they have CBG values that are <3.5mM
- When they have any concerns relating to their CBG levels
- When they have rapid, unexplained changes in their blood glucose levels
Study staff will attempt to contact the subjects daily to check on the CBG values and to record any adverse events whilst the subject is at home.
Subjects will be encouraged to keep their usual lifestyle in term of diet and exercise for all duration of the study.
The Entero-Test device is simple, safe device for the collection of duodenal bile. It is well tolerated, although some subjects may feel slight nausea on removal. Some blood may be seen on the string when removed. This occurs if the string "nicks" the oesophagus on removal, this is very minor trauma that heals rapidly and is not a cause for concern.
Primary enpoints-During metformin wash out and when treatment reinstated, pharmacodynamic endpoints will include the following as data permit:
- 24h profiles of blood glucose and insulin
- Faecal and serum bile acid profiles
- Enteroendocrine peptide profiling including but not limited to tGLP-1, tGIP, and tPYY
- Serum lipid analysis including but not limited to fasting HDL and LDL cholesterol, fasting and prandial TGs, ApoA1, ApoB and ApoE
Secondary Endpoints- • Relative bile acid composition as determined by EnteroTest bile string sampling of duodenal bile.
- Sparse metformin PK profiles will be determined from plasma samples
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Type two diabetics | Other | Other: MetforminType two diabetics |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- T2DM men and women between 18 -70 years of age on stable dose of metformin
- Subjects taking stable regimens of aspirin, ACE inhibitors, beta-blockers, calcium channel blockers, thyroid replacement hormone, and HMG-CoA reductase inhibitors (statins) will be allowed if their dose regimen(s) remain constant throughout the study period
- HBA1C >6.5% <8.5%
- BMI from 22.5 up to 37.5 kg/m2, inclusive
- AST, ALT, alkaline phosphatase and bilirubin less than or equal to 3xULN
Key exclusion criteria (14 listed)
- medically unable or unwilling to discontinue current metformin therapy for as required by the protocol and remain off medication until the completion of Visit 3
- past or present disease (other than T2DM) as judged by the Investigator, which may affect the outcome of this study. These diseases include, but are not limited to, cardiovascular disease, malignancy, hepatic disease, renal disease, haematological disease, neurological disease and endocrine disease.
- subject is currently on bile acid sequestrant therapy.
- Gastrointestinal surgery or disease that would compromise the use of the EnteroTest
- fasting triglycerides >450mg/dL (>5.1 mmol/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 |
|---|---|---|
| Metforminwithdrawral | Other | Type two diabetics |
Primary outcome
To investigate the relationship between the glucose lowering action of metformin and Faecal and serum bile acid concentrations
Time frame: We will track this measure over a 5 week period. This may change as a patient's response to withdrawl and resumption of metformin varies
To investigate the relationship between the glucose lowering action of metformin and enteroendocrine peptide profiles including, but not limited to, incretins and PYY
Time frame: We will track this measure over a 5 week period. This may change as a patient's response to withdrawl and resumption of metformin varies
To investigate the relationship between the glucose lowering action of metformin and lipid metabolism including, but not limited to, fasting lipids and prandial TGs
Time frame: We will track this measure over a 5 week period. This may change as a patient's response to withdrawl and resumption of metformin varies
2 secondary outcomes
• To provide a relative estimate of the composition of bile acids in bile sampled using the EnteroTest string
Time frame: We will track this measure over a 5 week period. This may change as a patient's response to withdrawl and resumption of metformin varies
To measure sparse metformin profiles on the days when the PD endpoints are measured
Time frame: We will track this measure over a 5 week period. This may change as a patient's response to withdrawl and resumption of metformin varies
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 22 Jun 2017.
- Derived from this study: PubMed 24988476Napolitano A, Miller S, Nicholls AW, Baker D, Van Horn S, Thomas E, Rajpal D, Spivak A, Brown JR, Nunez DJ. Novel gut-based pharmacology of metformin in patients with type 2 diabetes mellitus. PLoS One. 2014 Jul 2;9(7):e100778. doi: 10.1371/journal.pone.0100778. eCollection 2014.
- Results for study 114453 can be found on the GSK Clinical Study Register.Link provided by the sponsor.
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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.
GSK Clinical Trials study director
GlaxoSmithKline
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 in people with Diabetes Mellitus, Type 2, run by GlaxoSmithKline at 1 site in United Kingdom.
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 7 inclusion and 14 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 22 Jun 2017. 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 Kingdom. 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?
To investigate the relationship between the glucose lowering action of metformin and Faecal and serum bile acid concentrations (time frame: We will track this measure over a 5 week period. This may change as a patient's response to withdrawl and resumption of metformin varies). The study lists 3 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 NCT01357876, 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 22 Jun 2017.