SGLT2 Inhibitor Adjunctive Therapy to Closed Loop Control in Type 1 Diabetes Mellitus (CiQ-SGLT2)

The primary purpose of this study is to evaluate the safety and efficacy of combining SGLT2 inhibitors with closed loop control (CLC).

Study Overview

• Status: Completed
• Conditions: Type 1 Diabetes
• Intervention / Treatment: Combination product: Empagliflozin + Control-IQ x 4 wks then Basal-IQ x 2 wks; Combination product: Empagliflozin + Basal-IQ x 2 wks then Control-IQ x 4 wks; Device: No Empagliflozin + Control-IQ x 4 wks then Basal-IQ x 2 wks; Device: No Empagliflozin + Basal-IQ x 2 wks then Control-IQ x 4 wks

Detailed Description

The first five participants will be enrolled in a Pilot Study to use the Basal-IQ with Empagliflozin 10 mg daily for approximately two weeks. These participants will participate in an estimated 36-48-hour hotel admission to initiate use of Closed Loop Control. The safety data from the Pilot Study will be presented to the Data Safety Monitoring Board (DSMB) for review.

Upon DSMB approval, approximately 40 participants will be randomized 1:1 in a crossover design. Participants will use empagliflozin 5 mg daily. This main study is a randomized control trial where approximately 50 participants, aged 18 to less than 65 y.o. at time of consent, will be in the trial for up to 10 weeks.

With empagliflozin:

• Control-IQ (CiQ) x 4 weeks (CiQ-EMPA) then Basal-IQ x 2 weeks (BiQ-EMPA)
• Basal-IQ x 2 weeks (BiQ-EMPA) then CiQ x 4 weeks (CiQ-EMPA)

Without empagliflozin:

• CiQ x 4 weeks (CiQ-NO EMPA) then Basal-IQ x 2 weeks (BiQ-NO EMPA)
• Basal-IQ x 2 weeks (BiQ-NO EMPA) then CiQ x 4 weeks (CiQ-NO EMPA)

• Study Type: Interventional
• Enrollment (Actual): 34
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Virginia
    • Charlottesville, Virginia, United States, 22903
      • University of Virginia, Center for Diabetes Technology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 61 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age ≥18.0 and ≤65 years old at time of consent
2. Clinical diagnosis, based on investigator assessment, of type 1 diabetes for at least one year
3. Currently using an insulin pump for at least six months
4. Currently using insulin for at least six months
5. Using insulin parameters such as carbohydrate ratio and correction factors consistently on their pump in order to dose insulin for meals or corrections
6. Access to internet and willingness to upload data during the study as needed
7. For females, not currently known to be pregnant or breastfeeding
8. If female and sexually active, must agree to use a form of contraception to prevent pregnancy while a participant in the study. A negative serum or urine pregnancy test will be required for all females of childbearing potential. Participants who become pregnant will be discontinued from the study. Also, participants who during the study develop and express the intention to become pregnant within the timespan of the study will be discontinued.
9. Willingness to suspend use of any personal CGM for the duration of the clinical trial once the study CGM is in use
10. Willingness to switch to lispro (Humalog) or aspart (Novolog) if not using already, and to use no other insulin besides lispro (Humalog) or aspart (Novolog) during the study
11. Total daily insulin dose (TDD) at least 10 U/day
12. Willingness not to start any new non-insulin glucose-lowering agent during the course of the trial (including metformin, GLP-1 agonists, pramlintide, DPP-4 inhibitors, biguanides, sulfonylureas and naturaceuticals)
13. Willingness to eat at least 100 grams of carbohydrates per day
14. An understanding and willingness to follow the protocol and signed informed consent
15. Pilot Participants: Agree to hotel/research house admission with other Pilot participants on a date selected by the study team.

Exclusion Criteria:

1. Hemoglobin A1c >9%
2. History of diabetic ketoacidosis (DKA) in the 12 months prior to enrollment
3. Severe hypoglycemia resulting in seizure or loss of consciousness in the 12 months prior to enrollment
4. Pregnancy or intent to become pregnant during the trial
5. Currently breastfeeding or planning to breastfeed
6. Currently being treated for a seizure disorder
7. Planned surgery during study duration
8. History of cardiac arrhythmia (except for benign premature atrial contractions and benign premature ventricular contractions which are permitted)
9. Clinically significant electrocardiogram (ECG) abnormality at time of Screening, as interpreted by the study medical physician
10. Use of diuretics (e.g. Lasix, Thiazides)
11. History of chronic or recurrent genital infections
12. eGFR lab value below 60 mL/min/1.73 m2
13. Treatment with any non-insulin glucose-lowering agent (including metformin, GLP-1 agonists, pramlintide, DPP-4 inhibitors, SGLT-2 inhibitors, biguanides, sulfonylureas and naturaceuticals)

14. A known medical condition that in the judgment of the investigator might interfere with the completion of the protocol such as the following examples:

    1. Severe renal impairment, end-stage renal disease, or dialysis
    2. Inpatient psychiatric treatment in the past six months
    3. Presence of a known adrenal disorder
    4. Abnormal liver function test results (Transaminase>2 times the upper limit of normal); testing required for subjects taking medications known to affect liver function or with diseases known to affect liver function
    5. Uncontrolled thyroid disease
15. Severe renal impairment, end-stage renal disease, or dialysis
16. Use of an automated insulin delivery mechanism that is not downloadable by the subject or study team
17. Current enrollment in another clinical trial, unless approved by the investigator of both studies or if clinical trial is a non-interventional registry trial
18. Alcohol restricted to no more than 2 drinks per night in men and no more than 1 drink per night in women
19. Low carb diet (less than 100g per day)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Empagliflozin + Control-IQ x 4 wks then Basal-IQ x 2 wks; Control-IQ x 4 weeks (CiQ-EMPA) then Basal-IQ x 2 weeks (BiQ-EMPA)	Combination product: Empagliflozin + Control-IQ x 4 wks then Basal-IQ x 2 wks; Participants with be provided with Empagliflozin to take daily for approximately 10 weeks. Along with the study medication, participants will initially use the Tandem t:slim insulin pump with Control-IQ Technology for 4 weeks. Participants will then transition to using the Tandem t:slim insulin pump with Basal-IQ Technology for 2 weeks.
Experimental: Empagliflozin + Basal-IQ x 2 wks then CiQ x 4 wks; Basal-IQ x 2 weeks (BiQ-EMPA) then Control-IQ x 4 weeks (CiQ-EMPA)	Combination product: Empagliflozin + Basal-IQ x 2 wks then Control-IQ x 4 wks; Participants with be provided with Empagliflozin to take daily for approximately 10 weeks. Along with the study medication, participants will initially use the Tandem t:slim insulin pump with Basal-IQ Technology for 2 weeks. Participants will then transition to using the Tandem t:slim insulin pump with Control-IQ Technology for 4 weeks.
Active Comparator: No Empagliflozin + Control-IQ x 4 wks then Basal-IQ x 2 wks; Control-IQ x 4 weeks (CiQ-NO EMPA) then Basal-IQ x 2 weeks (BiQ-NO EMPA)	Device: No Empagliflozin + Control-IQ x 4 wks then Basal-IQ x 2 wks; Participants will initially use the Tandem t:slim insulin pump with Control-IQ Technology for 4 weeks. Participants will then transition to using the Tandem t:slim insulin pump with Basal-IQ Technology for 2 weeks. Empaglizflozin will not be provided to this group.
Active Comparator: No Empagliflozin + Basal-IQ x 2 wks then Control-IQ x 4 wks; Basal-IQ x 2 weeks (BiQ-NO EMPA) then Control-IQ x 4 weeks (CiQ-NO EMPA)	Device: No Empagliflozin + Basal-IQ x 2 wks then Control-IQ x 4 wks; Participants will initially use the Tandem t:slim insulin pump with Basal-IQ Technology for 2 weeks. Participants will then transition to using the Tandem t:slim insulin pump with Control-IQ Technology for 4 weeks. Empaglizflozin will not be provided to this group.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CGM-measured time in the target range 70-180mg/dl (TIR) during the day	CGM-measured time in the target range 70-180mg/dl (TIR) during the day	6 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time below 70 mg/dl	Time below 70 mg/dl	6 weeks
Time above 180 mg/dl	Time above 180 mg/dl	6 weeks
Time between 70-140 mg/dl 5 hours post prandial	Time between 70-140 mg/dl 5 hours post prandial	6 weeks
Glucose variability index HBGI	Glucose variability index HBGI	6 weeks
Glucose variability index LBGI	Glucose variability index LBGI	6 weeks
Glucose variability index ADRR	Glucose variability index ADRR	6 weeks
Safety evaluation of empagliflozin as adjuvant therapy added to a closed loop artificial pancreas system	Number of episodes of diabetic ketoacidosis (DKA)	6 weeks
Safety evaluation of empagliflozin as adjuvant therapy added to a closed loop artificial pancreas system	Number of episodes of severe hypoglycemia (glucose <50 mg/dl)	6 weeks
Episodes of diabetes ketoacidosis (DKA)	The number of DKA events in the experimental group as compared to the control group	6 weeks
Episodes of severe hypoglycemia (glucose <50 mg/dL)	The number of hypoglycemic events in the experimental group as compared to the control group	6 weeks
Genital infections	Number of genital infections (balanitis, urethritis, vulvar infections, Fournier's gangrene) that occur in the experimental group versus the control group	6 weeks
Urinary Tract Infections	Number of urinary tract infections that occur in the experimental group versus the control group	6 weeks
Total amount of insulin used	The number of amount of insulin used in the experimental group as compared to the control group	6 weeks
Number of hyperglycemic episodes as defined by contiguous CGM above 300 mg/dL	Number of hyperglycemic episodes, defined as contiguous CGM values above 300 mg/dL, that occur in the experimental group versus the control group	6 weeks

Collaborators and Investigators

• Sponsor: Ananda Basu, MD
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); DexCom, Inc.; Tandem Diabetes Care, Inc.
• Investigators: Principal Investigator: Ananda Basu, MD, University of Virginia; Study Chair: Ralf Nass, MD, University of Virginia

Publications and helpful links

General Publications

• Garcia-Tirado J, Farhy L, Nass R, Kollar L, Clancy-Oliveri M, Basu R, Kovatchev B, Basu A. Automated Insulin Delivery with SGLT2i Combination Therapy in Type 1 Diabetes. Diabetes Technol Ther. 2022 Jul;24(7):461-470. doi: 10.1089/dia.2021.0542. Epub 2022 Mar 14.

Study record dates

Study Major Dates

• Study Start (Actual): February 24, 2020
• Primary Completion (Actual): September 7, 2021
• Study Completion (Actual): September 7, 2021

Study Registration Dates

• First Submitted: November 4, 2019
• First Submitted That Met QC Criteria: December 13, 2019
• First Posted (Actual): December 17, 2019

Study Record Updates

• Last Update Posted (Actual): August 11, 2022
• Last Update Submitted That Met QC Criteria: August 9, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: Artificial Pancreas (AP); Continuous Glucose Monitor (CGM); Closed Loop Control; Sodium-glucose co-transporter 2 (SGLT2) inhibitor; Insulin Pumps; Low blood glucose index (LBGI); High blood glucose index (HBGI)
• 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; Empagliflozin
• Other Study ID Numbers: 190017; DP3DK106785 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: To be determined
• IPD Sharing Time Frame: After publication for one year
• IPD Sharing Supporting Information Type: Study Protocol

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: Yes