Effect of Canagliflozin in T1DM (Type 1 Diabetes Melitus) After Interruption of Continuous Subcutaneous Insulin Infusion

Study Overview
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Brief Summary
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This study will be an open-label, cross-over study as subjects will be studied under both study conditions - suspension of subcutaneous insulin infusion via pump during treatment with insulin alone (control) vs. suspension of subcutaneous insulin via pump during treatment with insulin and canagliflozin.

Detailed Description
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The study will consist of 4 visits: an enrollment/screening visit, a control visit with pump suspension prior to treatment with canagliflozin, a visit with pump suspension while on canagliflozin and an end of study visit. Each of the pump suspension visits will be approximately 20-hour overnight admissions to the Hospital Research Unit (HRU).

Official Title
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Effect of Canagliflozin in T1DM After Interruption of Continuous Subcutaneous Insulin Infusion

Conditions
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Type 1 Diabetes

Intervention / Treatment
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* Drug: canagliflozin
* Other: basal interruption without canagliflozin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-45 years Clinical diagnosis of T1D (type 1 diabetes) (formal antibody and/or genetic testing will not be required) Duration of T1D ≥ 1 year HbA1c ≤ 9 % Treated with continuous subcutaneous insulin infusion (with or without adjunctive treatment with a SGLT2 inhibitor) for at least 3 months Body weight > 40 kg Be in good general health without other acute or chronic illness that in the judgment of the investigator could interfere with the study or jeopardize subject safety Normal hematocrit Able to give consent Female subjects of reproductive potential must be abstinent or consistently using appropriate family planning methods. Exclusion Criteria: Insulin resistant (defined as requiring > 1.5 units/kg/day at time of study enrollment) Renal impairment, determined as eGFR < 60 ml/minute/1.73m2 History of unstable or rapidly progressing renal disease Conditions of congenital renal glucosuria Renal allograft Recurrent UTI (urinary tract infection) History of Vesico-ureteral-reflux disease Presence of any medical or psychiatric disorder that may interfere with subject safety or study conduct Use of metformin, thiazolidinedione or GLP1 agonist within 1 month prior to screening visit. For those subjects on canagliflozin or other SGLT2 inhibitors, an alternate study procedure may be utilized as described above Use of any medications (besides insulin or SGLT2 inhibitor) known to effect blood glucose levels, including oral or other systemic glucocorticoid therapy. Inhaled, intranasal, or rectal corticosteroid use is allowed as long as not given within 2 weeks of the closed loop admissions. Use of topical glucocorticoids is allowable as long as affected skin area does not overlap with study device sites History of hypoglycemic seizure within last 3 months History of diabetic ketoacidosis (DKA) requiring medical intervention (ie. emergency room visit and/or hospitalization) within 1 month prior to the screening visit Allergies or contraindication to the contents of canagliflozin tablets or insulin Volume depleted subjects. Subjects at risk for volume depletion due to co-existing conditions or concomitant medications, such as loop diuretics who cannot carefully monitor their volume status should be excluded from the study Female subjects who are pregnant, lactating, or unwilling to be tested for pregnancy Recurrent GU (genitourinary) infections Uncircumcised males secondary to increased risk of development of GU infections History of hypotension, defined as blood pressure (BP) <10th% for age and sex

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Basal interruption<br>Subjects will undergo basal interruption without canagliflozin during an overnight stay on the research unit | Other: basal interruption without canagliflozin<br>* basal interruption<br>|
| Experimental: Basal interruption with canagliflozin<br>Subjects will undergo basal interruption with canagliflozin during an overnight stay on the research unit | Drug: canagliflozin<br>* basal interruption with canagliflozin<br>* Other names: Invokana;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Differences in Plasma Glucose Levels Following the Interruption of Basal Subcutaneous Infusion of Insulin | The primary outcome measure for this study will be differences in plasma glucose levels following the interruption of basal subcutaneous infusion of insulin under the two study conditions; i.e., control study during treatment with insulin alone vs. experimental study during treatment with insulin plus canagliflozin or other SGLT2 inhibitor. | 20 hours | 
| Differences in BHB (Beta-hydroxybutyrate) Levels Following Interruption of Basal |  | 20 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Differences in Free Fatty Acid Levels Following Interruption of Basal Subcutaneous Insulin Infusion |  | 20 hours | 
| Differences in Glucagon Levels Following the Interruption of the Basal Subcutaneous Insulin Infusion |  | 20 hours |