Type 1 Diabetes
Conditions
Brief summary
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
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).
Interventions
DRUGcanagliflozin
basal interruption with canagliflozin
OTHERbasal interruption without canagliflozin
basal interruption
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Yale University
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
No
Inclusion criteria
1. Age 18-45 years 2. Clinical diagnosis of T1D (type 1 diabetes) (formal antibody and/or genetic testing will not be required) 3. Duration of T1D ≥ 1 year 4. HbA1c ≤ 9 % 5. Treated with continuous subcutaneous insulin infusion (with or without adjunctive treatment with a SGLT2 inhibitor) for at least 3 months 6. Body weight \> 40 kg 7. 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 8. Normal hematocrit 9. Able to give consent 10. Female subjects of reproductive potential must be abstinent or consistently using appropriate family planning methods.
Exclusion criteria
1. Insulin resistant (defined as requiring \> 1.5 units/kg/day at time of study enrollment) 2. Renal impairment, determined as eGFR \< 60 ml/minute/1.73m2 1. History of unstable or rapidly progressing renal disease 2. Conditions of congenital renal glucosuria 3. Renal allograft 4. Recurrent UTI (urinary tract infection) 5. History of Vesico-ureteral-reflux disease 3. Presence of any medical or psychiatric disorder that may interfere with subject safety or study conduct 4. 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 5. 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 6. History of hypoglycemic seizure within last 3 months 7. History of diabetic ketoacidosis (DKA) requiring medical intervention (ie. emergency room visit and/or hospitalization) within 1 month prior to the screening visit 8. Allergies or contraindication to the contents of canagliflozin tablets or insulin 9. 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 10. Female subjects who are pregnant, lactating, or unwilling to be tested for pregnancy 11. Recurrent GU (genitourinary) infections 12. Uncircumcised males secondary to increased risk of development of GU infections 13. History of hypotension, defined as blood pressure (BP) \<10th% for age and sex
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Differences in Plasma Glucose Levels Following the Interruption of Basal Subcutaneous Infusion of Insulin | 20 hours | 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. |
| Differences in BHB (Beta-hydroxybutyrate) Levels Following Interruption of Basal | 20 hours | — |
Secondary
| Measure | 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Basal Interruption With or Without Canagliflozin Subjects will undergo basal interruption with canagliflozin during an overnight stay on the research unit
canagliflozin: basal interruption with canagliflozin | 10 |
| Total | 10 |
Baseline characteristics
| Characteristic | Basal Interruption With or Without Canagliflozin |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 10 |
| other Total, other adverse events | 0 / 10 | 1 / 10 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 |
Outcome results
Primary
Differences in BHB (Beta-hydroxybutyrate) Levels Following Interruption of Basal
Time frame: 20 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Basal Interruption | Differences in BHB (Beta-hydroxybutyrate) Levels Following Interruption of Basal | 1.2 mmol/L | Standard Error 0.2 |
| Basal Interruption With Canagliflozin | Differences in BHB (Beta-hydroxybutyrate) Levels Following Interruption of Basal | 1.5 mmol/L | Standard Error 0.2 |
Primary
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.
Time frame: 20 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Basal Interruption | Differences in Plasma Glucose Levels Following the Interruption of Basal Subcutaneous Infusion of Insulin | 197 mg/dL | Standard Error 24 |
| Basal Interruption With Canagliflozin | Differences in Plasma Glucose Levels Following the Interruption of Basal Subcutaneous Infusion of Insulin | 99 mg/dL | Standard Error 13 |
Secondary
Differences in Free Fatty Acid Levels Following Interruption of Basal Subcutaneous Insulin Infusion
Time frame: 20 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Basal Interruption | Differences in Free Fatty Acid Levels Following Interruption of Basal Subcutaneous Insulin Infusion | 0.8 mmol/L | Standard Error 0.1 |
| Basal Interruption With Canagliflozin | Differences in Free Fatty Acid Levels Following Interruption of Basal Subcutaneous Insulin Infusion | 0.7 mmol/L | Standard Error 0.1 |
Secondary
Differences in Glucagon Levels Following the Interruption of the Basal Subcutaneous Insulin Infusion
Time frame: 20 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Basal Interruption | Differences in Glucagon Levels Following the Interruption of the Basal Subcutaneous Insulin Infusion | 14 pg/mL | Standard Error 5 |
| Basal Interruption With Canagliflozin | Differences in Glucagon Levels Following the Interruption of the Basal Subcutaneous Insulin Infusion | 36 pg/mL | Standard Error 15 |