Low dosE GlibENclamide in Diabetes Part A

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.

Inclusion criteria

• 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.

Exclusion criteria

• 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)
• 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.