Type 1 Diabetes
Conditions
Keywords
Insulin glargine, insulin degludec
Brief summary
This study evaluates direct switching vs use of a bridging dose from insulin glargine to insulin degludec in type 1 DM patients. Half of the participants will receive a bridging insulin glargine dose along with the 1st dose of degludec, while other half will receive a placebo and 1st dose of degludec.
Detailed description
Insulin degludec (IDeg), an ultra-long-acting basal insulin, is increasingly used to treat patients with type 1 diabetes (T1D). IDeg has a half-life of 25 hours and duration of action exceeding 42 hours in patients with T1D and as a result does not require as stringent a dosing schedule as other basal insulins. However, steady state concentration of IDeg is not reached until 2 to 3 doses are administered daily, and this may result in greater glycemic variability in the 24 to 72 hours following the initiation of therapy with IDeg. Our hypothesis is that among patients who transition from insulin glargine to IDeg, those who use a bridging dose of insulin glargine will not have a significant change, on average, in time spent in target glycemic range during the transition period, whereas, those transitioning directly to IDeg will have a significant change in this parameter. We further hypothesize that those using the bridging dose of insulin glargine will have less hypoglycemia, less hyperglycemia and need fewer correction boluses than the direct-conversion patients during the transition period. Though IDeg is being increasingly used in clinical practice, there are no guidelines on what is the best way to transition patients from other long-acting insulins, such as glargine, to IDeg. The package insert recommends 1:1 dose conversion from other basal insulins to IDeg, but this does not account for the time taken by IDeg to achieve steady state (typically 48-72 hours). There is no guidance on what to do in those 48-72 hours. Given the time taken for IDeg to achieve steady state, the period of transition from one insulin to another, can result in significant glycemic variation in the 24-72 hours after the first dose. We want to study how best to avoid or minimize this and the option of using a small dose of their original long-acting insulin has anecdotal evidence of success in our practice.
Interventions
DRUGInsulin Degludec
Insulin Degludec injection
DRUGInsulin Glargine
Insulin Glargine injection
DRUGPlacebo
9g/L sodium chloride (normal saline) subcutaneous injection manufactured to mimic insulin glargine injection
Sponsors
University of Washington
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
* Patients must meet ALL inclusion criteria to be included in the study. 1. Patient age is 18-75 years. 2. Diagnosis of T1D of at least 1-year duration. 3. Has the ability to provide informed consent before any trial-related activities. 4. Treated with insulin glargine as their basal insulin in the 3 months preceding screening visit. 5. Stable insulin regimen (defined as change of \<20% in the total daily dose of insulin and no change to the basal insulin agent) over the 3 months preceding the screening visit. 6. Patient willing to dose their basal insulin at bedtime. 7. Hemoglobin A1c \< 9% in the 3 months preceding screening visit. 8. Able to self-administer their insulin doses. 9. Able to do self-monitoring of blood glucose using a glucose meter and willing to do this at least 2 times daily for patients using a CGM that requires calibration prior to the study and 4 times daily for patients who were not using a CGM prior to the study. 10. Agreeable to the use of a continuous glucose monitor (CGM) for the duration required in the study. If already using a CGM prior to the study, then agreeable to wearing the blinded study CGM concurrently during the study period. 11. Will be reachable by phone and/or email to comply with study procedures. 12. Will be able to comply with study procedures, per investigator's opinion. 13. Patient agrees to not use correctional insulin unless BG ≥250 for the 48 hours before and after 1st dose of IDeg.
Exclusion criteria
* Patient must not have ANY of the
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Percent Time in Range | 48 hours prior to 48 hours after 1st dose of degludec insulin | Change in percent time spent in target glycemic range (TIR, glucose 70-180 mg/dL, both values included) in the 48 hours before and the 48 hours after the 1st dose of IDeg. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Nocturnal Percent Time in Range of 70-180 mg/dL Nocturnal Time in Range (N-TIR) | 4 days: Outcome Measure Time Frame 48 hours prior to 48 hours after 1st dose of degludec insulin | Change in nocturnal (defined as midnight to 0600 hours) time in range (glucose in 70-180 mg/dL range) in the 48 hours before and the 48 hours after the 1st dose of IDeg, as noted on study continuous glucose monitor (dexcom G6) |
| Percent Time Above 180 mg/dL (TAR-1) | 4 days | Change in time above range (glucose in 181-250 mg/dL range, TAR-1) in the 48 hours before and the 48 hours after the 1st dose of IDeg, as noted on study continuous glucose monitor (dexcom G6) |
| Time Above Range-2 (TAR-2) | 4 days | Change in time above range (glucose above 250 mg/dL range, TAR-2) in the 48 hours before and the 48 hours after the 1st dose of IDeg, as noted on study continuous glucose monitor (dexcom G6) |
| Coefficient of Variation (CV) of Percent-time-in-range | 48 hours prior to 48 hours after 1st dose of degludec insulin | Change in coefficient of variation of glucose (CV) in the 48 hours before and the 48 hours after the 1st dose of IDeg, as noted on study continuous glucose monitor (dexcom G6) |
| Time Below Range-2 (TBR-2) | 48 hours prior to 48 hours after 1st dose of degludec insulin | Change in time below range (glucose below 54 mg/dL range, TBR-2) in the 48 hours before and the 48 hours after the 1st dose of IDeg, as noted on study continuous glucose monitor (dexcom G6) |
| Correction Boluses | 48 hours prior to 48 hours after 1st dose of degludec insulin | Change in the number of daily correction boluses administered in the 48 hours before and 48 hours after the 1st dose of degludec insulin, as noted on insulin logs maintained by participants |
| Time Below Range-1 (TBR-1) | 48 hours prior to 48 hours after 1st dose of degludec insulin | Change in time below range (glucose 54-70 mg/dL range, TBR-1) in the 48 hours before and the 48 hours after the 1st dose of IDeg, as noted on study continuous glucose monitor (dexcom G6) |
Countries
United States
Participant flow
Recruitment details
59 participants were screened, 37 were randomized, 37 completed the study.
Pre-assignment details
12 participants did not meet study inclusion/exclusion criteria and were screen failures. 47 participants started study procedures but only 37 were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Insulin Glargine and Insulin Degludec Insulin glargine, 100 units per mL injected subcutaneously daily Insulin Degludec, 100 units per mL injected subcutaneously daily
Insulin Degludec: Insulin Degludec injection
Insulin Glargine: Insulin Glargine injection | 19 |
| Insulin Degludec and Placebo Insulin Degludec, 100 units per mL injected subcutaneously daily Placebo, 9g/L sodium chloride (normal saline) injected subcutaneously daily
Insulin Degludec: Insulin Degludec injection
Placebo: 9g/L sodium chloride (normal saline) subcutaneous injection manufactured to mimic insulin glargine injection | 18 |
| Total | 37 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 0 | 10 |
Baseline characteristics
| Characteristic | Insulin Glargine and Insulin Degludec | Insulin Degludec and Placebo | Total |
|---|---|---|---|
| Age, Continuous | 51 years STANDARD_DEVIATION 14 | 44 years STANDARD_DEVIATION 16 | 47 years STANDARD_DEVIATION 15 |
| Body mass index | 24.9 kilograms/meters squared STANDARD_DEVIATION 6 | 27.1 kilograms/meters squared STANDARD_DEVIATION 5 | 26 kilograms/meters squared STANDARD_DEVIATION 5.4 |
| Coefficient of Variation of Glucose | 31.1 percent of variation STANDARD_DEVIATION 6.7 | 31.4 percent of variation STANDARD_DEVIATION 8.3 | 31.2 percent of variation STANDARD_DEVIATION 7.4 |
| Correction Boluses | 0.9 Number of boluses STANDARD_DEVIATION 1.2 | 1.5 Number of boluses STANDARD_DEVIATION 1.2 | 1.2 Number of boluses STANDARD_DEVIATION 1.5 |
| Creatinine | 0.82 milligrams/deciliter STANDARD_DEVIATION 0.21 | 0.84 milligrams/deciliter STANDARD_DEVIATION 0.1 | 0.83 milligrams/deciliter STANDARD_DEVIATION 0.2 |
| Duration of Diabetes | 26 years STANDARD_DEVIATION 21 | 17 years STANDARD_DEVIATION 16 | 22 years STANDARD_DEVIATION 19 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants | 16 Participants | 35 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Hemoglobin A1c | 6.7 percent glycated hemoglobin STANDARD_DEVIATION 0.6 | 6.9 percent glycated hemoglobin STANDARD_DEVIATION 1 | 6.8 percent glycated hemoglobin STANDARD_DEVIATION 0.8 |
| Nocturnal time in range (N-TIR) | 60.3 percent of time measured STANDARD_DEVIATION 28.9 | 74.4 percent of time measured STANDARD_DEVIATION 25.5 | 67.2 percent of time measured STANDARD_DEVIATION 27.8 |
| Sex: Female, Male Female | 11 Participants | 2 Participants | 13 Participants |
| Sex: Female, Male Male | 8 Participants | 16 Participants | 24 Participants |
| Time above range-1 (TAR-1) | 26.8 percent of time measured STANDARD_DEVIATION 17.2 | 19.4 percent of time measured STANDARD_DEVIATION 13.7 | 23.2 percent of time measured STANDARD_DEVIATION 15.9 |
| Time above range-2 (TAR-2) | 5.5 percent of time measured STANDARD_DEVIATION 7.1 | 5.9 percent of time measured STANDARD_DEVIATION 8 | 5.7 percent of time measured STANDARD_DEVIATION 7.5 |
| Time below range-1 (TBR-1) | 2.1 percent of time measured STANDARD_DEVIATION 2.1 | 4.1 percent of time measured STANDARD_DEVIATION 5.7 | 3 percent of time measured STANDARD_DEVIATION 4.3 |
| Time below range-2 (TBR-2) | 0.3 percent of time measured STANDARD_DEVIATION 0.7 | 1.6 percent of time measured STANDARD_DEVIATION 5 | 0.9 percent of time measured STANDARD_DEVIATION 3.3 |
| Time in range (TIR) | 65.4 percent of time measured STANDARD_DEVIATION 21.6 | 69.4 percent of time measured STANDARD_DEVIATION 17.2 | 67.4 percent of time measured STANDARD_DEVIATION 19.4 |
| Total Daily Dose of Insulin | 0.6 Units/kilogram body weight/day STANDARD_DEVIATION 0.2 | 0.8 Units/kilogram body weight/day STANDARD_DEVIATION 0.4 | 0.7 Units/kilogram body weight/day STANDARD_DEVIATION 0.3 |
| Weight | 73.7 kilograms STANDARD_DEVIATION 19.2 | 87.7 kilograms STANDARD_DEVIATION 23.6 | 80 kilograms STANDARD_DEVIATION 22.2 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 18 | 0 / 59 |
| other Total, other adverse events | 0 / 19 | 0 / 18 | 0 / 59 |
| serious Total, serious adverse events | 0 / 19 | 0 / 18 | 0 / 59 |
Outcome results
Primary
Mean Change in Percent Time in Range
Change in percent time spent in target glycemic range (TIR, glucose 70-180 mg/dL, both values included) in the 48 hours before and the 48 hours after the 1st dose of IDeg.
Time frame: 48 hours prior to 48 hours after 1st dose of degludec insulin
Population: Change in percent time spent in target glycemic range (TIR, glucose 70-180 mg/dL, both values included) in the 48 hours before and the 48 hours after the 1st dose of IDeg, as noted on study continuous glucose monitor (dexcom G6)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glargine and Insulin Degludec | Mean Change in Percent Time in Range | 2 percentage of time in measured period | Standard Deviation 14.7 |
| Insulin Degludec and Placebo | Mean Change in Percent Time in Range | -6.1 percentage of time in measured period | Standard Deviation 17.6 |
Comparison: For our power calculations, we assumed the true change in TIR to be 0% for the bridging group and 15% for the direct-conversion group, and we assumed a common standard deviation of 15% (meaning the distributions of change in TIR are separated by 1 standard-deviation unit), and thereby obtained that 20 patients in each group would provide 87% power to observe a statistically significant (at the two-sided level of .05) difference in mean change of TIR.p-value: 0.14t-test, 2 sided
Secondary
Coefficient of Variation (CV) of Percent-time-in-range
Change in coefficient of variation of glucose (CV) in the 48 hours before and the 48 hours after the 1st dose of IDeg, as noted on study continuous glucose monitor (dexcom G6)
Time frame: 48 hours prior to 48 hours after 1st dose of degludec insulin
Population: Change in coefficient of variation of glucose (CV) in the 48 hours before and the 48 hours after the 1st dose of IDeg, as noted on study continuous glucose monitor (dexcom G6)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glargine and Insulin Degludec | Coefficient of Variation (CV) of Percent-time-in-range | 3 percent of variation | Standard Deviation 6.9 |
| Insulin Degludec and Placebo | Coefficient of Variation (CV) of Percent-time-in-range | -1.1 percent of variation | Standard Deviation 8.5 |
p-value: 0.11t-test, 2 sided
Secondary
Correction Boluses
Change in the number of daily correction boluses administered in the 48 hours before and 48 hours after the 1st dose of degludec insulin, as noted on insulin logs maintained by participants
Time frame: 48 hours prior to 48 hours after 1st dose of degludec insulin
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glargine and Insulin Degludec | Correction Boluses | 0 boluses in 48 hours measured | Standard Deviation 1 |
| Insulin Degludec and Placebo | Correction Boluses | 0 boluses in 48 hours measured | Standard Deviation 1.6 |
p-value: >0.99t-test, 2 sided
Secondary
Nocturnal Percent Time in Range of 70-180 mg/dL Nocturnal Time in Range (N-TIR)
Change in nocturnal (defined as midnight to 0600 hours) time in range (glucose in 70-180 mg/dL range) in the 48 hours before and the 48 hours after the 1st dose of IDeg, as noted on study continuous glucose monitor (dexcom G6)
Time frame: 4 days: Outcome Measure Time Frame 48 hours prior to 48 hours after 1st dose of degludec insulin
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glargine and Insulin Degludec | Nocturnal Percent Time in Range of 70-180 mg/dL Nocturnal Time in Range (N-TIR) | 5.1 percentage of time in measured period | Standard Deviation 34.6 |
| Insulin Degludec and Placebo | Nocturnal Percent Time in Range of 70-180 mg/dL Nocturnal Time in Range (N-TIR) | -7 percentage of time in measured period | Standard Deviation 34.2 |
p-value: 0.29t-test, 2 sided
Secondary
Percent Time Above 180 mg/dL (TAR-1)
Change in time above range (glucose in 181-250 mg/dL range, TAR-1) in the 48 hours before and the 48 hours after the 1st dose of IDeg, as noted on study continuous glucose monitor (dexcom G6)
Time frame: 4 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glargine and Insulin Degludec | Percent Time Above 180 mg/dL (TAR-1) | 5.4 percentage of time in measured period | Standard Deviation 15.4 |
| Insulin Degludec and Placebo | Percent Time Above 180 mg/dL (TAR-1) | 6.5 percentage of time in measured period | Standard Deviation 12.4 |
p-value: 0.015t-test, 2 sided
Secondary
Time Above Range-2 (TAR-2)
Change in time above range (glucose above 250 mg/dL range, TAR-2) in the 48 hours before and the 48 hours after the 1st dose of IDeg, as noted on study continuous glucose monitor (dexcom G6)
Time frame: 4 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glargine and Insulin Degludec | Time Above Range-2 (TAR-2) | 2.2 percentage of time in measured period | Standard Deviation 6.8 |
| Insulin Degludec and Placebo | Time Above Range-2 (TAR-2) | 1.9 percentage of time in measured period | Standard Deviation 6.2 |
p-value: 0.88t-test, 2 sided
Secondary
Time Below Range-1 (TBR-1)
Change in time below range (glucose 54-70 mg/dL range, TBR-1) in the 48 hours before and the 48 hours after the 1st dose of IDeg, as noted on study continuous glucose monitor (dexcom G6)
Time frame: 48 hours prior to 48 hours after 1st dose of degludec insulin
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glargine and Insulin Degludec | Time Below Range-1 (TBR-1) | 1.1 percentage of time in measured period | Standard Deviation 3.5 |
| Insulin Degludec and Placebo | Time Below Range-1 (TBR-1) | -1.5 percentage of time in measured period | Standard Deviation 3.4 |
p-value: 0.031t-test, 2 sided
Secondary
Time Below Range-2 (TBR-2)
Change in time below range (glucose below 54 mg/dL range, TBR-2) in the 48 hours before and the 48 hours after the 1st dose of IDeg, as noted on study continuous glucose monitor (dexcom G6)
Time frame: 48 hours prior to 48 hours after 1st dose of degludec insulin
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glargine and Insulin Degludec | Time Below Range-2 (TBR-2) | 0.3 percentage of time in measured period | Standard Deviation 0.7 |
| Insulin Degludec and Placebo | Time Below Range-2 (TBR-2) | -0.8 percentage of time in measured period | Standard Deviation 4.2 |
p-value: 0.27t-test, 2 sided