Effect of SGLT2i in Conjunction With the Artificial Pancreas on Improving the Glycemia in T1DM in the Outpatient Setting (CLASS17)

Effect of SGLT2 Inhibition on Improving the Glycemic Performance of the Single Hormone Artificial Pancreas Configuration in Type 1 Diabetes in the Outpatient Setting - A Randomized Placebo Controlled Cross-Over Multicentre Clinical Trial

The most advanced configurations of the Artificial Pancreas (AP) have not yet been demonstrated to sufficiently maximize time in target glycemia. One limitation is the challenge of postprandial glycemic control, which currently requires ongoing patient engagement for accurate and detailed bolus dose estimation for meals. Sodium Glucose Linked Transporter 2 Inhibition (SGLT2i) provides an additional mechanism to attenuate post-prandial glycemic excursion, and may represent a strategy that could further alleviate carbohydrate counting burden and improve the performance of AP configurations. This trial aims to compare - using a randomized, masked placebo-controlled, crossover, multicenter design - the efficacy of the SGLT2i empagliflozin 25 mg oral per day each in the setting of single-hormone automated AP and conventional insulin pump therapy on the proportion of time spent in target and in hypoglycemia each during a 4-week day-and-night period. The pilot trial aims to enroll 28 adult patients with type 1 diabetes (T1D) across 2 research sites (one in Toronto and one in Montreal) and includes a 2- week therapy optimization run-in period, 4-weeks for each of the two AP intervention arms, and a 1- week washout in between the pharmacological intervention sequences. Glucose levels will be measured by continuous glucose monitoring (G5, Dexcom Inc.). Insulin will be infused using a subcutaneous infusion pump (t-slim, Tandem Diabetes Care) and communication between pumps and the algorithm will be implemented using Android Smartphone devices and Bluetooth technology communication.

Study Overview

• Status: Completed
• Conditions: Type1 Diabetes Mellitus
• Intervention / Treatment: Drug: empagliflozin; Device: artificial pancreas

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5T 3L9
      • Sinai Health System
  • Quebec
    • Montréal, Quebec, Canada, H3A 2B4
      • McGill University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Signed and dated written informed consent by the date of Visit 1 in accordance with Good Clinical Practice (GCP) and local legislation.
2. Males and females ≥ 18 years of age.
3. Clinical diagnosis of T1D for at least one year. The diagnosis of T1D is based on the investigator's clinical judgment; C peptide level and antibody determinations are not planned.
4. Insulin pump therapy use for at least 3 months.
5. HbA1c ≤ 10%.
6. eGFR ≥ 60 mL/min/1.73 m² as calculated by the CKD-EPI formula.
7. Women of child-bearing potential must be ready and able to use highly effective methods of birth control that result in a low failure rate of less than 1% per year when used consistently and correctly.

Exclusion Criteria:

1. Clinically significant nephropathy, neuropathy or retinopathy as judged by the investigator.
2. Recent (< 6 months) acute macrovascular event e.g. acute coronary syndrome or cardiac surgery.
3. Renal insufficiency (characterized at eGFR below 60 mmol/l at the beginning of the trial)
4. History of pheochromocytoma or insulinoma
5. Beta-blockers at high dose (interference with glucose management).
6. Chronic acetaminophen treatment (can interfere with glucose sensor measurements).
7. Warfarin chronic treatment if INR monitoring cannot be evaluated (can increase the risk of bleeding).
8. Current use of other non-insulin adjunct anti-hyperglycemic drug or use within 30 days prior to screening.
9. Use of loop diuretics (e.g. furosemide, due to possible interference with study drug mechanism of action).
10. Ongoing or planned pregnancy or breastfeeding.
11. Severe hypoglycemic episode within one month prior to Visit 1.
12. Diabetic ketoacidosis in the last 3 months prior to Visit 1.
13. Current use of glucocorticoid medication except low stable dose and inhaled steroids (can interfere with glucose sensor measurements).
14. Known or suspected allergy to the trial products.
15. Other serious medical illness likely to interfere with study participation or with the ability to complete the trial by the judgment of the investigator.
16. Anticipating a significant change in exercise regimen between initiation of two intervention blocks (i.e. starting or stopping an organized sport).
17. Recent history of genital or urinary infection (<1 month prior to Visit 1) or history of recurrent urinary tract infections.
18. Difficulty in using the artificial pancreas system following training.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Empagliflozin arm; Participant will be treated by empagliflozin for 8 weeks. During these 8 weeks he will use artificial pancreas to deliver the insulin for 4 weeks and conventional pump therapy for remaining 4 weeks, in a random order. After finishing the entire arm intervention participant will undergo 7 day of washout and enters the placebo arm. Participant and research staff is blinded to arm assignment.	Drug: empagliflozin; Treatment with empagliflozin 25mg orally once a day; Device: artificial pancreas; Insulin delivery via a closed loop single-hormone artificial pancreas system.
Placebo Comparator: Placebo arm; Participant will take placebo for 8 weeks. During these 8 weeks he will use artificial pancreas to deliver the insulin for 4 weeks and conventional pump therapy for remaining 4 weeks, in a random order. After finishing the entire arm intervention participant will undergo 7 day of washout and enters the empagliflozin arm. Participant and research staff is blinded to arm assignment.	Device: artificial pancreas; Insulin delivery via a closed loop single-hormone artificial pancreas system.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of time spent in sensor glucose target range defined as between 3.9 and 7.8 mmol/L compared between 4- weeks AP on empagliflozin and 4-weeks AP with placebo	Percentage of time spent in sensor glucose target range defined as between 3.9 and 7.8 mmol/L compared between 4- weeks AP on empagliflozin and 4-weeks AP with placebo.	20 weeks
Percentage of time spent in sensor glucose target range defined as between 3.9 and 7.8 mmol/L compared between 4- weeks conventional pump therapy on empagliflozin and 4- weeks conventional pump therapy with placebo	Percentage of time spent in sensor glucose target range defined as between 3.9 and 7.8 mmol/L compared between 4- weeks conventional pump therapy on empagliflozin and 4- weeks conventional pump therapy with placebo.	20 weeks
Percentage of time spent in sensor glucose target range defined as between 3.9 and 7.8 mmol/L on 4- weeks automated AP on empagliflozin when compared to 4-weeks conventional pump therapy on empagliflozin	Percentage of time spent in sensor glucose target range defined as between 3.9 and 7.8 mmol/L on 4- weeks automated AP on empagliflozin when compared to 4-weeks conventional pump therapy on empagliflozin.	20 weeks
Percentage of time spent in sensor glucose target range defined as between 3.9 and 7.8 mmol/L on 4- weeks automated AP on empagliflozin when compared to 4-weeks conventional pump therapy with placebo	Percentage of time spent in sensor glucose target range defined as between 3.9 and 7.8 mmol/L on 4- weeks automated AP on empagliflozin when compared to 4-weeks conventional pump therapy with placebo.	20 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of time spent in sensor glucose target range defined as between 3.9 and 10.0 mmol/L compared between 4- weeks conventional pump therapy on empagliflozin and 4-weeks AP on empagliflozin	Percentage of time spent in sensor glucose target range defined as between 3.9 and 10.0 mmol/L compared between 4- weeks conventional pump therapy on empagliflozin and 4-weeks AP on empagliflozin	20 weeks
Percentage of time spent in sensor glucose target range defined as between 3.9 and 10.0 mmol/L compared between 4- weeks AP on empagliflozin and 4- weeks AP with placebo	Percentage of time spent in sensor glucose target range defined as between 3.9 and 10.0 mmol/L compared between 4- weeks AP on empagliflozin and 4- weeks AP with placebo.	20 weeks
Hypoglycemia: Percentage of time with glucose <3.9 mmol/L applied to each of the primary and secondary outcome comparator groups	Hypoglycemia: Percentage of time with glucose <3.9 mmol/L applied to each of the primary and secondary outcome comparator groups.	20 weeks
Percentage of time spent in hypoglycemia, euglycemia and hyperglycemia	Percentage of time spent in the different glucose sensor levels characterized by amount spent between 3.9 and 10.0 mmol/L, 3.9 and 7.8 mmol/L, above 10.0 mmol/L, above 13.9 mmol/L, above 16.7 mmol/l, below 3.9 mmol/L, below 3.3 mmol/L, below 2.8 mmol/L	20 weeks
Absolute number of hypoglycemia events I.	Number of hypoglycemic events (> 20 minutes) below 3.3 mmol/L based on sensor glucose levels	20 weeks
Absolute number of hypoglycemia events II.	Number of symptomatic hypoglycemic events < 3.9 mmol/l or below 3.3 mmol/l without symptoms	20 weeks
Absolute number of hypoglycemia events III.	Number of treated hypoglycemic events	20 weeks
Statistical characteristics of glucose profile I.	Area under the curve of hypoglycemic glucose values (below 3.9 mmol/L, 3.3 mmol/L and 2.8 mmol/L)	20 weeks
Statistical characteristics of glucose profile II.	Standard deviation of glucose levels	20 weeks
Amount of total insulin delivery during interventions	Total insulin delivery measured by mean of units per day	20 weeks
Change in HbA1c	Change in HbA1c from baseline to after the first intervention and from the end of the first intervention to the end of the treatment period.	20 weeks
Mean fasting capillary ketone levels	Mean fasting capillary ketone levels.	20 weeks
Number of episodes of diabetic ketoacidosis	Number of episodes of diabetic ketoacidosis	20 weeks
Number of technical adverse events	Number of events when algorithm crashes or needs to be overridden for safety reasons.	20 weeks

Collaborators and Investigators

• Sponsor: Samuel Lunenfeld Research Institute, Mount Sinai Hospital
• Collaborators: McGill University Health Centre/Research Institute of the McGill University Health Centre
• Investigators: Principal Investigator: Bruce Perkins, MD, Samuel Lunenfeld Research Institute

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2019
• Primary Completion (Actual): August 31, 2021
• Study Completion (Actual): August 31, 2021

Study Registration Dates

• First Submitted: April 13, 2019
• First Submitted That Met QC Criteria: June 6, 2019
• First Posted (Actual): June 7, 2019

Study Record Updates

• Last Update Posted (Actual): June 7, 2022
• Last Update Submitted That Met QC Criteria: June 3, 2022
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Keywords: Empagliflozin; insulin pump; Type 1 Diabetes Mellitus; Artificial Pancreas; SGLT2 inhibitor; closed loop
• 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; Gastrointestinal Agents; Sodium-Glucose Transporter 2 Inhibitors; Empagliflozin; Pancrelipase
• Other Study ID Numbers: CLASS 17

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: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No