Triple Therapy in T1DM

Study Overview
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Brief Summary
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To assess whether the addition of dapagliflozin to semaglutide and insulin (triple therapy) improves glycemic control in patients with type 1 diabetes compared with semaglutide and insulin (dual therapy) and insulin only (standard) treatment.

Detailed Description
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This will be a 52 week study for type 1 diabetics looking into the effect of semaglutide and dapagliflozin on HbA1c and glycemic control.

Official Title
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Triple Therapy for Type 1 Diabetes With Insulin, Semaglutide, and Dapagliflozin

Conditions
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Type 1 Diabetes Mellitus

Intervention / Treatment
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* Drug: Insulin
* Drug: Semaglutide
* Drug: Dapagliflozin
* Drug: Placebo to Dapagliflozin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 1 Diabetes for at least 1 year on staple use of continuous subcutaneous insulin infusion (CSII) or multiple daily (four or more) injections (MDI) of insulin for last 3 months. C-peptide <0.23 nM Minimum dose of insulin in Units/kg at entry: 0.5 U/kg for MDI and 0.4 U/kg for CSII Regularly measuring blood sugars four or more times daily. HbA1c of >7.5%. Well versed in CHO counting* Age 18-70 years. BMI ≥25 kg/m2. Exclusion Criteria: Type 1 diabetes for less than 12 months, type 2 diabetes, chronic pancreatitis, MODY Previous use of any agent other than insulin for treatment of diabetes in the last 3 months. History of diabetic ketoacidosis (DKA) requiring medical intervention (e.g., emergency room visit and/or hospitalization) within 3 month prior to the screening visit Frequent episodes of severe hypoglycemia as defined by more than one episode requiring medical assistance, emergency care (paramedics or emergency room care), and/or glucagon therapy administered by a third-party individual within 1 month prior to the screening visit Symptoms of poorly controlled diabetes that would preclude participation in this trial Subjects on a commercial weight loss program with ongoing weight loss, or on an intensive exercise program History of bariatric surgery or lap-band procedure within 12 months prior to screening History of Addison's disease or chronic adrenal insufficiency History of diabetes insipidus Hepatic disease or cirrhosis with Aspartate Aminotransferase (AST) > 3X Upper limit of normal (ULN) and/or Alanine aminotransferase (ALT) > 3X ULN Serum Total Bilirubin > 2X ULN unless exclusively caused by Gilbert's Syndrome Hemoglobin < 11.0 g/dL (110 g/L) for men; hemoglobin < 10.0 g/dL (100 g/L) for women. Coronary event or procedure (myocardial infarction, unstable angina, coronary artery bypass, surgery or coronary angioplasty) in the previous 3 months or patients with congestive heart failure. ESRD on hemodialysis; and or e-GFR < 60 ml/min/1.73m2 HIV or Hepatitis B/C positive status Any other life-threatening, noncardiac disease History of pancreatitis Women who are pregnant or women of childbearing potential who are not using adequate contraception or who are breast feeding Inability to give informed consent History of gastroparesis History of medullary thyroid carcinoma or MEN 2 syndrome History of serious hypersensitivity reaction to these agents Painful gallstones Alcoholism Hypertriglyceridemia (>500 mg/dl) Recurrent genital mycotic infection. Hypovolemic patients or with chronic renal insufficiency. Patients with any malignancy except treated in situ malignancy and basal cell carcinoma of the skin Unexplained hematuria Patients with a history of diabetic retinopathy Use of an investigational agent or therapeutic regimen within 30 days of study Participation in any other concurrent interventional clinical trial

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This will be a two-center, randomized, open-label then double-blind, parallel group, placebo and standard of care controlled prospective study in type 1 diabetes.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Control<br>Standard of care insulin will be used as an active comparator arm for 1/3 of patients (38 patients) for the entire duration of the study. | Drug: Insulin<br>* Standard of care insulin for pump or injection and serves as a control<br>|
| Experimental: Dual Therapy<br>Once a week injection of Semaglutide (a GLP-1 receptor agonist) in addition to standard of care insulin for the first six months in 2/3 of patients (76 patients). Semaglutide is a clear, colorless solution that contains 2 mg of semaglutide in a 1.5 mL (1.34 mg/mL) pre-filled, disposable, single-patient-use pen injector. Semaglutide will be started at the 0.25 mg dose for the first two weeks, then increased to 0.5 mg at week 2, and then yet again increased to 1.0 mg at week 4. | Drug: Insulin<br>* Standard of care insulin for pump or injection and serves as a control<br>Drug: Semaglutide<br>* Injectable weekly GLP-1RA given as open label experimental drug<br>* Other names: Ozempic;|
| Experimental: Triple therapy<br>Once a day oral pill (green, plain, diamond shaped film coated 5 mg tablet) of Dapagliflozin (an SGLT-2 inhibitor) added to once a week injection of semaglutide and standard of care insulin in the second 6 months of 1/2 of the dual therapy arm (1/3 of total patients (38 patients)). Dapagliflozin will be started at 5 mg for one week, and then increased to 10 mg for the remainder of the study | Drug: Insulin<br>* Standard of care insulin for pump or injection and serves as a control<br>Drug: Semaglutide<br>* Injectable weekly GLP-1RA given as open label experimental drug<br>* Other names: Ozempic;Drug: Dapagliflozin<br>* Oral daily SGLT2 Inhibitor given as experimental drug<br>* Other names: Farxigo;|
| Placebo Comparator: Triple therapy control<br>Once a day oral pill (green, plain, diamond shaped film coated 5 mg tablet) of the Placebo form of Dapagliflozin added to once a week injection of semaglutide and standard of care insulin in the second 6 months of 1/2 of the dual therapy arm (1/3 of total patients (38 patients)). | Drug: Insulin<br>* Standard of care insulin for pump or injection and serves as a control<br>Drug: Semaglutide<br>* Injectable weekly GLP-1RA given as open label experimental drug<br>* Other names: Ozempic;Drug: Placebo to Dapagliflozin<br>* Placebo to Dapagliflozin given as a control to the experimental drug<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in HbA1c | Change in HbA1c at 6 months following dapagliflozin or placebo therapy in addition to combined semaglutide and insulin treatment. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in HbA1c | Change in HbA1c from baseline at 12 months in triple therapy group compared to insulin only group. | 12 months | 
| Change in HbA1c | Change in HbA1c from baseline at 6 months in dual therapy group compared to insulin only group. | 6 months | 
| Assessment of hyperglycemia level 1 | Change in percent Time hyperglycemia Level 1(180-250mg/dl) as assessed by CGM | 12 months | 
| Assessment of hyperglycemia level 2 | Change in percent Time in hyperglycemia Level 2 ( >250mg/dl) as assessed by CGM | 12 months | 
| Assessment of hypoglycemia | Change in percent Time in hypoglycemia Level 1 (54-70mg/dl) as assessed by CGM | 12 months | 
| Assessment of percent time glucose in range | Change in percent Time in Range (70- 180 mg/dl) as assessed by CGM | 12 months | 
| Fructosamine indices | Assessment of fructosamine | 12 months | 
| Weekly fasting glucose indices | Assessment of change of weekly fasting glucose | 12 months | 
| Insulin requirement indices | Assessment of the change in insulin requirement | 12 months | 
| body weight assessment | Change in body weight as assessed by DSQOLS questionnaire at 6 months. | 6 months | 
| body weight assessment | Change in quality of life as assessed by DSQOLS questionnaire at 6 months. | 6 months | 
| body weight assessment | Change in body weight as assessed by DSQOLS questionnaire at 12 months. | 12 months | 
| body weight assessment | Change in quality of life as assessed by DSQOLS questionnaire at 12 months. | 12 months | 
| body weight assessment | Change in body weight as assessed by PAID questionnaire at 6 months. | 6 months | 
| body weight assessment | Change in quality of life as assessed by PAID questionnaire at 6 months. | 6 months | 
| body weight assessment | Change in body weight as assessed by PAID questionnaire at 12 months. | 12 months | 
| body weight assessment | Change in quality of life as assessed by PAID questionnaire at 12 months. | 12 months | 
| Blood pressure assessment | Anti-hypertensive effects including change in systolic BP. | 12 months | 
| Blood pressure assessment | Anti-hypertensive effects including change in diastolic BP | 12 months | 
| Blood pressure assessment | Anti-hypertensive effects including change in numbers of BP medications required. | 12 months | 
| Severe hypoglycemia assessment | Differences in rates of hypoglycemic events Level 2 (<54mg/dl) characterized by altered mental and/or physical status requiring assistance) in standard therapy arm. | 12 months | 
| Severe hypoglycemia assessment | Differences in rates of hypoglycemic events Level 2 (<54mg/dl) characterized by altered mental and/or physical status requiring assistance) in investigative arms. | 12 months | 
| Severe hyperglycemia assessment | Differences in rates of Level 3 hyperglycemia (A severe event characterized by altered mental and/or physical status requiring assistance) between in investigative arms. | 12 months | 
| Severe hyperglycemia assessment | Differences in rates of Level 3 hyperglycemia (A severe event characterized by altered mental and/or physical status requiring assistance) in standard therapy arm. | 12 months | 
| Diabetic ketoacidosis assessment | Differences in rates of diabetic ketoacidosis defined as elevated serum ketones (greater than the upper limit of the normal range) in investigative arms. | 12 months | 
| Diabetic ketoacidosis assessment | Differences in rates of diabetic ketoacidosis defined as elevated urine ketones (greater than the upper limit of the normal range) in investigative arms. | 12 months | 
| Diabetic ketoacidosis assessment | Differences in rates of diabetic ketoacidosis defined as elevated serum bicarbonate <15 mmol/L in investigative arms. | 12 months | 
| Diabetic ketoacidosis assessment | Differences in rates of diabetic ketoacidosis defined as Blood pH <7.3 in investigative arms. | 12 months | 
| Diabetic ketoacidosis assessment | Differences in rates of diabetic ketoacidosis defined as elevated serum ketones (greater than the upper limit of the normal range) in standard therapy arm. | 12 months | 
| Diabetic ketoacidosis assessment | Differences in rates of diabetic ketoacidosis defined as elevated urine ketones (greater than the upper limit of the normal range) in standard therapy arm. | 12 months | 
| Diabetic ketoacidosis assessment | Differences in rates of diabetic ketoacidosis defined as elevated serum bicarbonate <15 mmol/L in standard therapy arm. | 12 months | 
| Diabetic ketoacidosis assessment | Differences in rates of diabetic ketoacidosis defined as elevated Blood pH <7.3 in standard therapy arm. | 12 months |