Diabetes Mellitus, Type 2Phase 2LEGEND-ANCT02830048
Low dosE GlibENclamide in Diabetes Part A
A Phase 2 study testing Glibenclamide in people with Diabetes Mellitus, Type 2, run by University of Oxford at 1 site in United Kingdom.
Trial summary
Diabetes is a chronic condition that affects 1 in 16 people in the UK, and leads to difficulty controlling blood sugar levels. This is due to an imbalance between two main hormones: insulin, which lowers blood sugar, and glucagon, which causes it to rise. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Diabetes Mellitus, Type 2
- What is being tested?
- Glibenclamide
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 16 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- Jul 2016to 9 Mar 2017
- Phase
- Phase 2
- 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 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Diagnosis of T2DM.
- Age 18 years or over.
- Diet controlled or on metformin only for diabetic control.
- Body mass index 40 kg/m2 or less.
- HbA1c 6.0% to 9.5% (42mmol/mol to 80mmol/mol) inclusive.
Who cannot join
- Taking anti-diabetic therapies other than metformin
- Pregnancy or women of childbearing age without adequate contraception
- Women who are breastfeeding
- Major psychiatric disease including diagnosed eating disorders, history of drug or alcohol abuse
- Known sight-threatening retinopathy
- Renal impairment (eGFR < 60 ml/min; CKD Stage 3)
Show all 17Show fewer
- Abnormal liver function tests (> 1.5 x upper limit of normal range)
- Known ischaemic heart disease or heart failure
- Known history of a stroke
- Known history of porphyria
- Concomitant use of miconazole or other oral antifungal medication.
- Known or suspected allergy to trial product or related products
- Oral steroid treatment 30 days prior to the start or at any time during the trial period.
- Known malignancy or any other condition or circumstance which, in the opinion of the investigator, would affect the patient's ability to participate in the protocol.
- Ketoacidosis
- Felt to be unsuitable to participate in the trial in the opinion of the Chief Investigator.
- Receipt of any investigational trial drug within 3 month prior to participation in the current trial.
Trial locations and contacts
1 site in 1 country.
United Kingdom1 site
Clinical Research Unit, OCDEM, Churchill Hospital
Oxford, Oxfordshire, OX3 7LE
About this study
Official title: Low-dose Glibenclamide in Type 2 Diabetes Mellitus - Part A
Diabetes is a chronic condition that affects 1 in 16 people in the UK, and leads to difficulty controlling blood sugar levels. This is due to an imbalance between two main hormones: insulin, which lowers blood sugar, and glucagon, which causes it to rise. Most current anti-diabetic medications work to improve insulin levels, however research is now shifting to better understand how glucagon levels play a key role in this disease.
Glibenclamide is a type of anti-diabetic medication (sulfonylurea) which is commonly used to increase the amount of insulin released by the pancreatic beta-cells. Studies in mice and human cells from donors with type 2 diabetes have shown that sulfonylureas can also improve glucagon levels when used in very small doses by working on different cells in the pancreas (alpha-cells).
Read more
The aim of this study is to find out whether low doses of glibenclamide can improve glucagon levels in patients with type 2 diabetes, and whether in the future this could be used to better control high blood sugar levels, without the risk of causing low blood sugar.
Participants with type 2 diabetes who are diet-controlled or on metformin will be given a liquid containing a low dose of glibenclamide. They will need to attend the OCDEM Clinical Research Unit at the Churchill Hospital, Oxford, for early morning blood tests every 3-4 days over a period of 3 weeks. A continuous glucose monitor will also be fitted during this time.
This study is funded by the NIHR OxBRC.
Read the detailed description
This investigator-initiated clinical trial is a single-centre, open-label, non-randomised, dose-finding study. The am is to investigate whether treatment with low-dose glibenclamide can lead to a decrease in fasting glucagon levels in patients with type 2 diabetes, and whether this has an impact on overall blood glucose control.
It will be conducted in the Clinical Research Unit (CRU) of the Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM) at the Churchill Hospital, Oxford. The aim is to find the dose of glibenclamide that causes a reduction in fasting glucagon levels in patients with T2DM.
Participants will self-administer increasing doses of an oral glibenclamide suspension from 0.3-6mg every 3 or 4 days, over a period of 21 days. They will attend the CRU for fasting pre-dose blood tests for insulin, glucagon, C- peptide and glucose prior to each dose change.
Additionally, participants will have the option of having a continuous glucose monitoring (CGM) sensor attached for the duration of the study, which will be checked and changed at each visit to CRU. This will measure the impact of treatment on overall blood glucose control.
No human trials have used doses of glibenclamide under 5mg previously in the measurement of insulin and glucagon secretion. Our sample size calculations are based on experimental data from isolated human islets from T2DM donors, which were performed in Professor Patrik Rorsman's lab. These suggest that 15 participants (allowing for a 15% dropout) would give the study 80% power to detect a 57% reduction in baseline glucagon levels with an alpha error of 5%.
Details of the study visits are as follows:
CRU visit 1 (1 hour):
- Informed consent will be obtained by a member of the clinical trial team.
- Inclusion and exclusion criteria checked.
- Concomitant medication checked.
- Demographics documented in case report form (CRF): date of birth, gender, weight, height.
- Observations documented in CRF: resting heart rate and blood pressure.
- Blood sample for HbA1c and safety blood tests (full blood count, renal function tests, electrolytes and liver function tests).
- Pregnancy test in women of childbearing age (18-49 years old).
- Participant informed to fast on next CRU visit.
CRU visit 2 (1 hour):
- Observations documented in CRF: resting heart rate and blood pressure
- Fasting blood sample for insulin, glucagon, C-peptide and glucose.
- CGM sensor inserted.
- Participants issued with oral glibenclamide suspension (0.6mg/ml) and dosing syringe. Educated on self-administration and given dosing schedule.
CRU visit 3 (30 minutes):
- Observations documented in CRF: resting heart rate and blood pressure
- Fasting blood sample for insulin, glucagon, C-peptide and glucose.
- CGM sensor changed and data downloaded.
CRU visit 4 - 8 (30 minutes):
- Observations documented in CRF: resting heart rate and blood pressure
- Fasting pre-dose blood sample for insulin, glucagon, C-peptide and glucose.
- CGM sensor changed and data downloaded.
- Adverse event recording.
- Check compliance. (visit 7 only: Participants issues with 6mg/ml oral glibenclamide suspension)
CRU visit 9 (30 minutes):
- Observations documented in CRF: resting heart rate and blood pressure
- Fasting pre-dose blood sample for insulin, glucagon, C-peptide and glucose.
- CGM sensor removed and data downloaded. CGM system returned to CRU.
- Adverse event recording.
- Check compliance.
- Unused oral glibenclamide suspension returned \& document drug accountability.
- Participants informed about end of study.
Telephone follow-up (15min):
Documentation of any adverse events occurred following the discontinuation of the trial medication.
Home visits:
For those participants not using the CGM and who are unable to attend the CRU for fasting blood tests, early morning home visits will be arranged. These will be conducted by a member of the research team and will replace CRU visits 3-9.
- Conditions
- Diabetes Mellitus, Type 2
- Being tested
- Glibenclamide
- Keywords
- diabetes, glibenclamide, glucagon
- Medical subject headings
- Diabetes Mellitus, Type 2, Diabetes Mellitus
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
GlibenclamideDrug
Also called GlibenTek
| Study group | Role | What they receive |
|---|---|---|
| Glibenclamide dose titration | Experimental | Increasing doses of glibenclamide oral suspension from 0.3mg/day to 6mg/day. Receives: Drug: Glibenclamide |
What is being measured
The primary outcome is the main question the study is designed to answer.
Decrease in fasting plasma glucagon concentration
Concentration of plasma glucagon using fasting blood samples prior to each dose change.
Measured: After 3-4 days of treatment at each dose increment
Secondary outcomes (3)
Overall improvement in glycaemic control throughout the day
Change in the percentage of Continuous Glucose Monitoring (CGM) readings under 4 mmol/L, between 4-10 mmol/L and above 10 mmol/L before starting glibenclamide and prior to each change in dose.
Measured: After 3-4 days of treatment at each dose increment
Effect on fasting glucose, insulin and C-peptide levels
Concentration of glucose, insulin and C-peptide using fasting blood samples prior to each dose change.
Measured: After 3-4 days of treatment at each dose increment
Pre-dose plasma concentration of glibenclamide
Concentration of plasma glibenclamide using fasting blood samples prior to each dose change.
Measured: After 3-4 days of treatment at each dose increment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Jul 2016 (estimated)
- Study startJul 2016
- Primary completion9 Mar 2017
- Study completion9 Mar 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Diabetes Mellitus, Type 2Studies of the same condition, open and under way.
- More trials run by University of OxfordThe 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 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 16 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Oxford
- Sponsor type
- University, hospital or other
- Collaborators
- Oxford University Hospitals NHS Trust
- Responsible party
- Sponsor
- Investigators
- Ioannis Spiliotis, MD, Principal investigator, University of Oxford
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02830048
- Sponsor's protocol ID
- 19062015
- Other IDs
- 2015-002837-23, 2015
- Acronym
- LEGEND-A
- Status last verified
- May 2017
- First submitted
- 8 Jul 2016
- Last updated
- 31 May 2017
- Results posted
- No
- Data monitoring committee
- Yes
- Individual data sharing
- Yes: The anonymised data (i.e. with studyID only) generated from this study will be deposited in the Oxford Research Archive (http://ora.ox.ac.uk/). This will provide a link between the results presented in publications and the underlying data. At the end of the retention period (currently 5 years), the data will be deleted from the archive.
Publications
Spiliotis II, Chalk R, Gough S, Rorsman P. Reducing hyperglucagonaemia in type 2 diabetes using low-dose glibenclamide: Results of the LEGEND-A pilot study. Diabetes Obes Metab. 2022 Aug;24(8):1671-1675. doi: 10.1111/dom.14740. Epub 2022 May 18. No abstract available.
PubMed 35491519
Study at a glance
From the registry record, last updated by the sponsor on 31 May 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Low-dose Glibenclamide in Type 2 Diabetes Mellitus - Part A
- ClinicalTrials.gov ID
- NCT02830048
- Acronym / sponsor ID
- LEGEND-A / 19062015
- Conditions
- Diabetes Mellitus, Type 2
- Keywords
- diabetes, glibenclamide, glucagon
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 16 participants (actual)
- Lead sponsor
- University of OxfordUniversity, hospital or other
- Collaborators
- Oxford University Hospitals NHS Trust
- Study start
- Jul 2016
- Primary completion
- 9 Mar 2017 (actual)
- Study completion
- 9 Mar 2017 (actual)
- First posted
- 12 Jul 2016 (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.
Diabetes is a chronic condition that affects 1 in 16 people in the UK, and leads to difficulty controlling blood sugar levels. This is due to an imbalance between two main hormones: insulin, which lowers blood sugar, and glucagon, which causes it to rise. Most current anti-diabetic medications work to improve insulin levels, however research is now shifting to better understand how glucagon levels play a key role in this disease.
Glibenclamide is a type of anti-diabetic medication (sulfonylurea) which is commonly used to increase the amount of insulin released by the pancreatic beta-cells. Studies in mice and human cells from donors with type 2 diabetes have shown that sulfonylureas can also improve glucagon levels when used in very small doses by working on different cells in the pancreas (alpha-cells).
The aim of this study is to find out whether low doses of glibenclamide can improve glucagon levels in patients with type 2 diabetes, and whether in the future this could be used to better control high blood sugar levels, without the risk of causing low blood sugar.
Participants with type 2 diabetes who are diet-controlled or on metformin will be given a liquid containing a low dose of glibenclamide. They will need to attend the OCDEM Clinical Research Unit at the Churchill Hospital, Oxford, for early morning blood tests every 3-4 days over a period of 3 weeks. A continuous glucose monitor will also be fitted during this time.
This study is funded by the NIHR OxBRC.
Detailed description
This investigator-initiated clinical trial is a single-centre, open-label, non-randomised, dose-finding study. The am is to investigate whether treatment with low-dose glibenclamide can lead to a decrease in fasting glucagon levels in patients with type 2 diabetes, and whether this has an impact on overall blood glucose control.
It will be conducted in the Clinical Research Unit (CRU) of the Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM) at the Churchill Hospital, Oxford. The aim is to find the dose of glibenclamide that causes a reduction in fasting glucagon levels in patients with T2DM.
Participants will self-administer increasing doses of an oral glibenclamide suspension from 0.3-6mg every 3 or 4 days, over a period of 21 days. They will attend the CRU for fasting pre-dose blood tests for insulin, glucagon, C- peptide and glucose prior to each dose change.
Additionally, participants will have the option of having a continuous glucose monitoring (CGM) sensor attached for the duration of the study, which will be checked and changed at each visit to CRU. This will measure the impact of treatment on overall blood glucose control.
No human trials have used doses of glibenclamide under 5mg previously in the measurement of insulin and glucagon secretion. Our sample size calculations are based on experimental data from isolated human islets from T2DM donors, which were performed in Professor Patrik Rorsman's lab. These suggest that 15 participants (allowing for a 15% dropout) would give the study 80% power to detect a 57% reduction in baseline glucagon levels with an alpha error of 5%.
Details of the study visits are as follows:
CRU visit 1 (1 hour):
- Informed consent will be obtained by a member of the clinical trial team.
- Inclusion and exclusion criteria checked.
- Concomitant medication checked.
- Demographics documented in case report form (CRF): date of birth, gender, weight, height.
- Observations documented in CRF: resting heart rate and blood pressure.
- Blood sample for HbA1c and safety blood tests (full blood count, renal function tests, electrolytes and liver function tests).
- Pregnancy test in women of childbearing age (18-49 years old).
- Participant informed to fast on next CRU visit.
CRU visit 2 (1 hour):
- Observations documented in CRF: resting heart rate and blood pressure
- Fasting blood sample for insulin, glucagon, C-peptide and glucose.
- CGM sensor inserted.
- Participants issued with oral glibenclamide suspension (0.6mg/ml) and dosing syringe. Educated on self-administration and given dosing schedule.
CRU visit 3 (30 minutes):
- Observations documented in CRF: resting heart rate and blood pressure
- Fasting blood sample for insulin, glucagon, C-peptide and glucose.
- CGM sensor changed and data downloaded.
CRU visit 4 - 8 (30 minutes):
- Observations documented in CRF: resting heart rate and blood pressure
- Fasting pre-dose blood sample for insulin, glucagon, C-peptide and glucose.
- CGM sensor changed and data downloaded.
- Adverse event recording.
- Check compliance. (visit 7 only: Participants issues with 6mg/ml oral glibenclamide suspension)
CRU visit 9 (30 minutes):
- Observations documented in CRF: resting heart rate and blood pressure
- Fasting pre-dose blood sample for insulin, glucagon, C-peptide and glucose.
- CGM sensor removed and data downloaded. CGM system returned to CRU.
- Adverse event recording.
- Check compliance.
- Unused oral glibenclamide suspension returned \& document drug accountability.
- Participants informed about end of study.
Telephone follow-up (15min):
Documentation of any adverse events occurred following the discontinuation of the trial medication.
Home visits:
For those participants not using the CGM and who are unable to attend the CRU for fasting blood tests, early morning home visits will be arranged. These will be conducted by a member of the research team and will replace CRU visits 3-9.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Glibenclamide dose titration | Experimental | Drug: GlibenclamideIncreasing doses of glibenclamide oral suspension from 0.3mg/day to 6mg/day. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- Diagnosis of T2DM.
- Age 18 years or over.
- Diet controlled or on metformin only for diabetic control.
- Body mass index 40 kg/m2 or less.
- HbA1c 6.0% to 9.5% (42mmol/mol to 80mmol/mol) inclusive.
Key exclusion criteria (17 listed)
- Taking anti-diabetic therapies other than metformin
- Pregnancy or women of childbearing age without adequate contraception
- Women who are breastfeeding
- Major psychiatric disease including diagnosed eating disorders, history of drug or alcohol abuse
- Known sight-threatening retinopathy
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 |
|---|---|---|
| GlibenclamideAlso: GlibenTek | Drug | Glibenclamide dose titration |
Primary outcome
Decrease in fasting plasma glucagon concentration
Time frame: After 3-4 days of treatment at each dose increment
Concentration of plasma glucagon using fasting blood samples prior to each dose change.
3 secondary outcomes
Overall improvement in glycaemic control throughout the day
Time frame: After 3-4 days of treatment at each dose increment
Effect on fasting glucose, insulin and C-peptide levels
Time frame: After 3-4 days of treatment at each dose increment
Pre-dose plasma concentration of glibenclamide
Time frame: After 3-4 days of treatment at each dose increment
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 31 May 2017.
- Derived from this study: PubMed 35491519Spiliotis II, Chalk R, Gough S, Rorsman P. Reducing hyperglucagonaemia in type 2 diabetes using low-dose glibenclamide: Results of the LEGEND-A pilot study. Diabetes Obes Metab. 2022 Aug;24(8):1671-1675. doi: 10.1111/dom.14740. Epub 2022 May 18. No abstract available.
- Individual participant dataSharing planned: Yes. The anonymised data (i.e. with studyID only) generated from this study will be deposited in the Oxford Research Archive (http://ora.ox.ac.uk/). This will provide a link between the results presented in publications and the underlying data. At the end of the retention period (currently 5 years), the data will be deleted from the archive.
Related trials for Diabetes Mellitus, Type 2
Not yet recruiting
SWitching to Appropriate Prescription in Cardiovascular-Kidney-Metabolic Syndrome
Cardiovascular-kidney-metabolic Syndrome, Diabete Type 2
Active, not recruiting
Pilot of Continuous Glucose Monitor-Augmented Food Is Medicine
Nutrition, Type 2 Diabetes
Recruiting
Whole Food for Families: A Pilot RCT of a Dietary Guidelines-Based Intervention to Prevent Type 2 Diabetes
PreDiabetes, Diet, Healthy
Not yet recruiting
Safety and Efficacy of the Fully Closed Loop iLet Bionic Pancreas in Adults With Type 1 and Type 2 Diabetes
Diabetes (Insulin-requiring, Type 1 or Type 2)
Recruiting
6-Weeks of Blood Flow Restriction Training on Immune Cell Function and Bioenergetics
Type 2 Diabetes
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.
Ioannis Spiliotis, MD principal investigator
University of Oxford
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Glibenclamide in people with Diabetes Mellitus, Type 2, run by University of Oxford 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 5 inclusion and 17 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 31 May 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 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
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?
Decrease in fasting plasma glucagon concentration (time frame: After 3-4 days of treatment at each dose increment). 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 NCT02830048, 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 31 May 2017.