Triple Therapy in T1DM

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

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.

Study Overview

• Status: Recruiting
• Conditions: Type 1 Diabetes Mellitus
• Intervention / Treatment: Drug: Insulin; Drug: Semaglutide; Drug: Dapagliflozin; Drug: Placebo to Dapagliflozin

Detailed Description

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

• Study Type: Interventional
• Enrollment (Estimated): 114
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Husam Ghanim, PhD; Phone Number: 716-881-8924; Email: ghanim@buffalo.edu
• Study Contact Backup: Name: Paresh Dandona, MD; Phone Number: 716-535-1850; Email: dandona@buffalo.edu

Study Locations

• United States
  • New York
    • Williamsville, New York, United States, 14221
      • Recruiting
      • Diabetes and Endocrinology Research Center of WNY
      • Contact: Jeanne Hejna, LPN; Phone Number: 716-535-1850; Email: jeannehe@buffalo.edu
      • Contact: Husam A Ghanim, PhD; Phone Number: 716-535-1852; Email: ghanim@buffalo.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 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.
2. C-peptide <0.23 nM
3. Minimum dose of insulin in Units/kg at entry: 0.5 U/kg for MDI and 0.4 U/kg for CSII
4. Regularly measuring blood sugars four or more times daily.
5. HbA1c of >7.5%.
6. Well versed in CHO counting*
7. Age 18-70 years.
8. BMI ≥25 kg/m2.

Exclusion Criteria:

1. Type 1 diabetes for less than 12 months, type 2 diabetes, chronic pancreatitis, MODY
2. Previous use of any agent other than insulin for treatment of diabetes in the last 3 months.
3. History of diabetic ketoacidosis (DKA) requiring medical intervention (e.g., emergency room visit and/or hospitalization) within 3 month prior to the screening visit
4. 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
5. Symptoms of poorly controlled diabetes that would preclude participation in this trial
6. Subjects on a commercial weight loss program with ongoing weight loss, or on an intensive exercise program
7. History of bariatric surgery or lap-band procedure within 12 months prior to screening
8. History of Addison's disease or chronic adrenal insufficiency
9. History of diabetes insipidus
10. Hepatic disease or cirrhosis with Aspartate Aminotransferase (AST) > 3X Upper limit of normal (ULN) and/or Alanine aminotransferase (ALT) > 3X ULN
11. Serum Total Bilirubin > 2X ULN unless exclusively caused by Gilbert's Syndrome
12. Hemoglobin < 11.0 g/dL (110 g/L) for men; hemoglobin < 10.0 g/dL (100 g/L) for women.
13. 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.
14. ESRD on hemodialysis; and or e-GFR < 60 ml/min/1.73m2
15. HIV or Hepatitis B/C positive status
16. Any other life-threatening, noncardiac disease
17. History of pancreatitis
18. Women who are pregnant or women of childbearing potential who are not using adequate contraception or who are breast feeding
19. Inability to give informed consent
20. History of gastroparesis
21. History of medullary thyroid carcinoma or MEN 2 syndrome
22. History of serious hypersensitivity reaction to these agents
23. Painful gallstones
24. Alcoholism
25. Hypertriglyceridemia (>500 mg/dl)
26. Recurrent genital mycotic infection.
27. Hypovolemic patients or with chronic renal insufficiency.
28. Patients with any malignancy except treated in situ malignancy and basal cell carcinoma of the skin
29. Unexplained hematuria
30. Patients with a history of diabetic retinopathy
31. Use of an investigational agent or therapeutic regimen within 30 days of study
32. Participation in any other concurrent interventional clinical trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Control; 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; Standard of care insulin for pump or injection and serves as a control
Experimental: Dual Therapy; 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; Standard of care insulin for pump or injection and serves as a control; Drug: Semaglutide; Injectable weekly GLP-1RA given as open label experimental drug; Other Names: Ozempic
Experimental: Triple therapy; 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; Standard of care insulin for pump or injection and serves as a control; Drug: Semaglutide; Injectable weekly GLP-1RA given as open label experimental drug; Other Names: Ozempic; Drug: Dapagliflozin; Oral daily SGLT2 Inhibitor given as experimental drug; Other Names: Farxigo
Placebo Comparator: Triple therapy control; 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; Standard of care insulin for pump or injection and serves as a control; Drug: Semaglutide; Injectable weekly GLP-1RA given as open label experimental drug; Other Names: Ozempic; Drug: Placebo to Dapagliflozin; Placebo to Dapagliflozin given as a control to the experimental drug

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in HbA1c following dapagliflozin	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
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
Diabetic ketoacidosis assessment	Differences in rates of diabetic ketoacidosis defined as Blood pH <7.3 in investigative arms.	12 months
Change in HbA1c with triple therapy	Change in HbA1c from baseline at 12 months in triple therapy group compared to insulin only group.	12 months
Change in HbA1c with semaglutide	Change in HbA1c from baseline at 6 months in dual therapy group (insulin and semaglutide) compared to insulin only group.	6 months
body weight assessment following dapagliflozin	Change in body weight at 6 months between dapagliflozin and placebo groups.	6 months
body weight assessment following semaglutide	Change in body weight at 6 months following starting semaglutide compared to standard of care (SOC) group.	6 months
body weight assessment following triple therapy	Change in body weight as assessed at 12 months on dapagliflozin and semaglutide compared to SOC therapy.	12 months
Systolic Blood pressure assessment after triple therapy	Anti-hypertensive effects including change in systolic BP on dapagliflozin and semaglutide compared to SOC therapy.	12 months
Diastolic Blood pressure assessment	Anti-hypertensive effects including change in diastolic BP on dapagliflozin and semaglutide compared to SOC therapy.	12 months
Blood pressure medication use	Anti-hypertensive effects including change in numbers of BP medications required in patients dapagliflozin and semaglutide compared to SOC therapy.	12 months
Level 2 hypoglycemia assessment	Differences in rates of hypoglycemic events Level 2 (<54mg/dl) between triple therapy and in standard therapy arm.	12 months
Severe (level 3) hypoglycemia assessment	Differences in rates of hypoglycemic events Level 3 (<54mg/dl) characterized by altered mental and/or physical status requiring assistance) between triple therapy and in standard therapy arm.	12 months
Level 1 hyperglycemia assessment	Differences in rates of Level 1 hyperglycemia (glucose levels >180mg/dl and <250mg dl) between triple therapy and in standard therapy arm.	12 months
Level 2 hyperglycemia assessment	Differences in rates of Level 2 hyperglycemia (glucose levels <250mg dl) between triple therapy and in standard therapy arm.	12 months
serum ketones 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
Urinary ketones 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

Collaborators and Investigators

• Sponsor: State University of New York at Buffalo
• Collaborators: Juvenile Diabetes Research Foundation; University of Glasgow
• Investigators: Study Director: Husam Ghanim, PhD, State University of NY at Buffalo

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2019
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): March 1, 2025

Study Registration Dates

• First Submitted: March 26, 2019
• First Submitted That Met QC Criteria: March 29, 2019
• First Posted (Actual): April 2, 2019

Study Record Updates

• Last Update Posted (Actual): January 3, 2024
• Last Update Submitted That Met QC Criteria: December 28, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Dapagliflozin
• Other Study ID Numbers: STUDY00002775; 1987 (Diabetes and Endocrinology Research Foundation)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No