SGLT2 Inhibitor Adjunctive Therapy to Closed Loop Control in Type 1 Diabetes Mellitus

Phase 1

Completed

• Conditions: Type 1 Diabetes
• Interventions: Combination Product: 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; 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

• Registration Number: NCT04201496
• Lead Sponsor: Ananda Basu, MD

Brief Summary

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

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 Timeline

• Study First Submitted: 2019-11-04
• Study First Submitted QC: 2019-12-13
• Study First Posted: 2019-12-17
• Study Start: 2020-02-24
• Primary Completion: 2021-09-07
• Study Completion: 2021-09-07
• Status Verified: 2022-08
• Last Update Submitted: 2022-08-09
• Last Update Posted: 2022-08-11

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 34

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Empagliflozin + Control-IQ x 4 wks then Basal-IQ x 2 wks	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)
No Empagliflozin + Basal-IQ x 2 wks then Control-IQ x 4 wks	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)
Empagliflozin + Basal-IQ x 2 wks then CiQ x 4 wks	Empagliflozin + Basal-IQ x 2 wks then Control-IQ x 4 wks	Basal-IQ x 2 weeks (BiQ-EMPA) then Control-IQ x 4 weeks (CiQ-EMPA)
No Empagliflozin + Control-IQ x 4 wks then Basal-IQ x 2 wks	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)

Primary Outcome Measures

Name	Time	Method
CGM-measured time in the target range 70-180mg/dl (TIR) during the day	6 weeks	CGM-measured time in the target range 70-180mg/dl (TIR) during the day

Secondary Outcome Measures

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

Trial Locations

Locations (1)

University of Virginia, Center for Diabetes Technology; 🇺🇸 Charlottesville, Virginia, United States