Dapagliflozin As Additional Treatment To Liraglutide And Insulin In Patients With Type 1 Diabetes

This investigation will be single center, prospective, randomized, double blinded placebo
controlled study conducted in type 1 diabetics. The study will be conducted at Diabetes -
Endocrinology Center of WNY, affiliated to the State University of New York at Buffalo.

Visit 1: Screening Day (day -21):- Each patient will have completed the following procedures
prior to participating in the study.

1. Medical History;

2. Physical Exam;

3. Informed consent.

4. Baseline lab draws to measure CBC, comprehensive metabolic panel, Hba1c, Fructosamine
and lipid profile. All labs will be drawn in the fasting state in the morning before
10am.

Visit 2: Randomization Visit (day -14): After the screening visit, subjects who meet the
inclusion and exclusion criteria will participate in the study period. Randomization will be
done by a ratio of 2:1(drug: placebo) using Microsoft Excel randomization function.
Liraglutide will be obtained from Novo Nordisk pharmaceuticals. Dapagliflozin/placebo will
be obtained from Astra Zeneca pharmaceuticals. All subjects will be instructed by the study
staff in the dosing and administration of the study medication. Subjects will be seen by a
registered dietitian who will review their carbohydrate counting and make an assessment of
their carbohydrate intake. A CGM sensor will be inserted and the patient will be asked to
keep it for 2 weeks. Detailed instruction on changing the sensor weekly will be provided and
insulin titration will be done to control blood sugar between 70-180 mg/dl. A urine
container to collect urine for 24 hours to measure 24-hour urinary glucose will be provided
(urine to be collected one day before the next visit).

All subjects will be advised to monitor their capillary blood glucose by finger stick before
each meal and at bedtime and to wear their CGM constantly for the first two weeks and the
last two weeks of the study The subjects will be asked to keep a diary of their food intake
to measure their carbohydrate intake. For the entire duration of the study, the patients
will maintain a diary to record any hypoglycemia and other untoward side effects like
nausea, changes in appetite and other experiences. Patients will be instructed to call the
Diabetes Center or an endocrinology fellow directly in case of any problem or untoward side
effects. They will be specifically asked to call if they have hypoglycemia (blood sugar <70
mg/dl) or hyperglycemia (blood sugar >250 mg/dl) on more than one occasion.

Visit 3 Study Intervention: day 0:- Subjects will come fasting for this visit. Urine will be
collected. CGM and it's related supplies will be collected back. Records of blood glucose
concentrations monitored by finger stick and CGM for the previous 14 days will be obtained
to assess their glycemic control while on liraglutide and insulin treatment. They will
undergo a meal challenge test (described below). Fructosamine assay will be done on this
day. Two questionnaires namely DSQOLS (Diabetes Specific Quality of Life Scale) and PAID
(problem areas in Diabetes survey) will be completed. Dapagliflozin or placebo at 5 mg will
be started the day after their meal challenge test. Careful adjustments will be made to
insulin doses at the discretion of the investigators on the basis of the glucose data
obtained from the patients. The target blood glucose will be 70-180 mg/dl at all times of
the day and night without increasing the incidence of blood glucose < 70mg/dl. Patients will
return to the center after 7 days. Subjects will be asked to make a follow-up appointment
with their primary care physician or their endocrinologist a week after the completion of
the study i.e. Visit 12(Day 84) to maintain continuity of care and to ensure smooth
transition.

Visit 4: Study Intervention day 7:- Insulin dose will be adjusted based on fingerstick blood
glucose. Patients will be assessed for any untoward adverse effects with the use of study
drug. The dose of dapagliflozin (or placebo) will be increased to 10 mg daily based on
investigator's discretion and blood glucose readings.

Visits 5-10: Study Interventions days 14, 21, 35, 49, and 63,70:- Records of blood glucose
concentrations of the last 7 days for visit 5 and 6 and for the last 14 days for all other
visits will be collected. Insulin dose will be adjusted at the discretion of the study
investigator to optimize blood sugar control as per the targets mentioned above on day 0
visit. Any adverse effects with study drug will be assessed. The dose of dapagliflozin (or
placebo) will be increased to 10 mg daily based on investigator's discretion if they are
still on the starting dose (i.e. 5 mg of dapagliflozin) at the time of visit 5, 6 and 7
only. No further increase in dose of these medications will be made after visit 6. CGM will
be fitted on day 70 and will stay on for 2 weeks till day 84.

Visit 11 (Day 77):

CGM will be fitted on this day and will stay on for 2 weeks till day 84. A urine container
to collect urine for 24 hours to measure 24-hour urinary glucose will be provided. They will
bring the urine specimen with them on Day 84. Subjects will be allowed to conduct this
intervention anytime between Day 77 and Day 82 if they choose so.

Visit 12: Study Intervention (day 84). Subjects will come fasting for this visit. Records of
blood glucose concentrations monitored by finger stick or CGM for the previous 7 days will
be obtained to assess their glycemic control. They will undergo meal challenge test
(described below). Two questionnaires namely DSQOLS and PAID will be completed. CGM and
related supplies and 24 hour urinary specimen will be collected back. After this visit,
subjects will be discharged from the study. Labs will be drawn to measure CBC, comprehensive
metabolic panel, Hba1c, Fructosamine and lipid profile. Careful insulin adjustments will be
made at the discretion of the investigator depending upon if they choose to continue with
liraglutide and or dapagliflozin to optimize blood sugars.

Meal challenge test:- In order to assess the changes induced by dapagliflozin compared to
placebo, a meal challenge will be carried before and at the end of the study (day 0 and day
84). (910 Calorie High fat High carbohydrate meal as in several of our previous papers).
Dapagliflozin final dose will be administered only on day 84 (45 min prior to the meal).
Sequential blood samples will be obtained at 0, 15, 30, 45, 60, 90, 120, 150, 180, 210, 240
and 300 min. Samples at 15, 30, 45, 90, 150 and 210 min will be 5 ml while those at 0, 60,
120, 180, 240 and 300 min will be 30 ml (total volume=210 ml). Blood will be collected from
an indwelling intravenous canula in a superficial forearm vein.

Inclusion Criteria:

- Patients with type 1 diabetes mellitus: Fasting c-peptide < 0.1nmol/l on insulin
therapy for more than 12 months with or without history of diabetic ketoacidosis and
treatment with liraglutide at maximal tolerated doses for at least 6 months prior to
start of the study.

- Willing to use a continuous glucose monitoring device (CGM) and regularly measuring
their blood sugars four times daily

- HbA1c of less than or equal to 11%.

- Well versed with carbohydrate counting

- Age 18-75 years

Exclusion Criteria:

- Type 1 diabetes for less than 12 months.

- Coronary event or procedure (myocardial infarction, unstable angina, coronary artery
bypass, surgery or coronary angioplasty) in the previous four weeks

- Hepatic disease (transaminase > 3 times normal) or cirrhosis

- ESRD on hemodialysis; and or e-GFR less than 30 ml/min/1.73m2

- HIV or Hepatitis C positive status

- Participation in any other concurrent clinical trial

- Any other life-threatening, non-cardiac disease

- Use of an investigational agent or therapeutic regimen within 30 days of study

- History of pancreatitis

- Pregnancy

- Inability to give informed consent

- History of gastroparesis

- History of medullary thyroid carcinoma or MEN 2 syndrome

- Family history of MEN 2, Family history of medullary thyroid cancer, or familial
medullary thyroid cancer

- Women of childbearing potential who are not using adequate contraception

- Women who are pregnant

- History of serious hypersensitivity reaction to these agents.