Type 1 Diabetes Mellitus
Conditions
Brief summary
The reason for this study is to see if the study drug LY3209590 is safe and effective in participants with type 1 diabetes.
Interventions
DRUGLY3209590
Administered SC
DRUGInsulin Degludec
Administered SC
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants must have a diagnosis of type 1 diabetes mellitus for at least 1 year * Participants must have been using multiple daily injections without interruption for at least 3 months * Participants must have HbA1c values of 5.6% to 9.5%, inclusive * Participants must have a body mass index (BMI) of ≤35 kilograms per meter squared (kg/m²)
Exclusion criteria
* Have had more than 1 emergency room visit or hospitalization due to poor glucose control within 6 months prior to study screening * Have any episodes of severe hypoglycemia and/or hypoglycemia unawareness within the 6 months prior to screening * Have any of the following cardiovascular (CV) conditions: acute myocardial infarction, New York Heart Association Class III or IV heart failure, or cerebrovascular accident (stroke) * Have acute or chronic hepatitis, or obvious clinical signs or symptoms of any other liver disease * Have an estimated glomerular filtration rate (eGFR) \<30 milliliters/minute/1.73 m² * Have active or untreated cancer * Are receiving chronic (\>14 days) systemic glucocorticoid therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Hemoglobin A1c (HbA1c) | Baseline, Week 26 | HbA1c is the glycosylated fraction of haemoglobin A. It is measured to identify average blood glucose concentration over prolonged periods of time. Least squares (LS) mean change from baseline was analysed by mixed model repeated measures (MMRM) model with treatment, country, visit, and treatment by visit interaction as fixed effects and the baseline HbA1c as a covariate. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Fasting Serum Glucose | Baseline, Week 26 | LS mean change from baseline was analysed by mixed model repeated measures (MMRM) model with treatment, country, HbA1c stratum, visit, and treatment by visit interaction as fixed effects and the baseline fasting serum glucose as a covariate. |
| Change From Baseline in Bolus Insulin Dose | Baseline, Week 26 | Bolus insulin dose was the sum of doses for morning, midday, evening meals, snack and correction. LS mean change from baseline was analysed by MMRM model with treatment, country, HbA1c stratum, visit, and treatment by visit interaction as fixed effects and the baseline bolus insulin dose as a covariate. |
| Rate of Documented Hypoglycemia | Baseline through Week 26 | Documented hypoglycemia is defined as any time a participant reports a self-monitoring blood glucose \<54 mg/dL (3.0 millimole per liter (mmol/L)). Negative binomial model using baseline hypoglycaemia incidence, baseline HbA1c and treatment as independent variables was performed to estimate the event rate. Data presented is group mean. Group Mean is estimated by first taking the inverse link function on individual participant covariates, then averaging over all participants. |
| Pharmacokinetics (PK): Area Under the Concentration Time Curve (AUC) of LY3209590 | Week 26 | AUC of LY3209590 was calculated for individual participants using the participant's Week 26 LY3209590 dose amount and the estimated clearance value. |
Countries
Austria, Germany, Puerto Rico, Spain, United States
Participant flow
Recruitment details
The study was initially designed as 3 arms: LY3209590 Algorithm 1 (Paper), LY3209590 Algorithm 2 (Digital), and Insulin Degludec. However, it was amended to terminate the LY3209590 Algorithm 2 (Digital) arm during early enrollment phase due to technical issues with data entry. Thus, this arm was excluded from the outcome measure analyses, but safety data was analysed and reported.
Participants by arm
| Arm | Count |
|---|---|
| LY3209590 Algorithm 1 (Paper) Algorithm 1 is a paper-based algorithm where dose adjustments were manually determined by the investigator based on fasting glucose and hypoglycemia data. LY3209590 was provided in a 20 mg vial of reconstitutable lyophilized powder. Participants received individualized LY3209590 loading dose based on the basal insulin dose prior randomization and baseline fasting glucose by SC injection on day 1 followed by weekly adjustments for the first 12 weeks, then every 4 weeks, of a 26-week treatment period, to achieve target fasting glucose of \<=100 mg/dL. | 124 |
| LY3209590 Algorithm 2 (Digital) Algorithm 2 is a computer-based algorithm to determine dose adjustments. LY3209590 was provided in a 20 mg vial of reconstitutable lyophilized powder. Participants received individualized LY3209590 loading dose based on the basal insulin dose prior randomization and baseline fasting glucose by SC injection on day 1 followed by weekly adjustments for the first 12 weeks, then every 4 weeks, of a 26-week treatment period, to achieve target fasting glucose of \<=100 mg/dL. | 16 |
| Insulin Degludec Insulin degludec was provided as 100 U/mL in a prefilled pen. Participants received individually adjusted doses once daily by SC injection with a starting dose same as basal insulin dose prior randomization, during the 26-week treatment period, to achieve target fasting blood glucose of \<=100 mg/dL. | 126 |
| Total | 266 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 |
| Overall Study | Investigational site terminated by sponsor | 3 | 0 | 2 |
| Overall Study | Lost to Follow-up | 1 | 0 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 1 |
| Overall Study | Pregnancy | 1 | 0 | 0 |
| Overall Study | Protocol Violation | 2 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 10 | 1 | 4 |
Baseline characteristics
| Characteristic | Total | Insulin Degludec | LY3209590 Algorithm 1 (Paper) | LY3209590 Algorithm 2 (Digital) |
|---|---|---|---|---|
| Age, Continuous | 46.4 years STANDARD_DEVIATION 14.5 | 47.4 years STANDARD_DEVIATION 13.7 | 44.4 years STANDARD_DEVIATION 14.8 | 53.4 years STANDARD_DEVIATION 16.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 38 Participants | 10 Participants | 23 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 227 Participants | 116 Participants | 100 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Haemoglobin A1c (HbA1c) | 7.49 Percentage of HbA1c STANDARD_DEVIATION 0.85 | 7.45 Percentage of HbA1c STANDARD_DEVIATION 0.87 | 7.52 Percentage of HbA1c STANDARD_DEVIATION 0.85 | 7.64 Percentage of HbA1c STANDARD_DEVIATION 0.7 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 4 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 253 Participants | 120 Participants | 119 Participants | 14 Participants |
| Region of Enrollment Austria | 12 Participants | 6 Participants | 6 Participants | 0 Participants |
| Region of Enrollment Germany | 34 Participants | 18 Participants | 16 Participants | 0 Participants |
| Region of Enrollment Puerto Rico | 11 Participants | 3 Participants | 7 Participants | 1 Participants |
| Region of Enrollment Spain | 30 Participants | 15 Participants | 15 Participants | 0 Participants |
| Region of Enrollment United States | 179 Participants | 84 Participants | 80 Participants | 15 Participants |
| Sex: Female, Male Female | 102 Participants | 48 Participants | 50 Participants | 4 Participants |
| Sex: Female, Male Male | 164 Participants | 78 Participants | 74 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 124 | 0 / 16 | 0 / 126 |
| other Total, other adverse events | 21 / 124 | 7 / 16 | 11 / 126 |
| serious Total, serious adverse events | 5 / 124 | 0 / 16 | 4 / 126 |
Outcome results
Primary
Change From Baseline in Hemoglobin A1c (HbA1c)
HbA1c is the glycosylated fraction of haemoglobin A. It is measured to identify average blood glucose concentration over prolonged periods of time. Least squares (LS) mean change from baseline was analysed by mixed model repeated measures (MMRM) model with treatment, country, visit, and treatment by visit interaction as fixed effects and the baseline HbA1c as a covariate.
Time frame: Baseline, Week 26
Population: All participants randomized to either LY3209590 Algorithm 1 (Paper) or Insulin degludec, received at least one dose of study drug and had baseline, post-baseline HbA1c data prior to treatment discontinuation.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY3209590 Algorithm 1 (Paper) | Change From Baseline in Hemoglobin A1c (HbA1c) | 0.04 Percentage of HbA1c | Standard Error 0.068 |
| Insulin Degludec | Change From Baseline in Hemoglobin A1c (HbA1c) | -0.13 Percentage of HbA1c | Standard Error 0.065 |
90% CI: [0.01, 0.32]
Secondary
Change From Baseline in Bolus Insulin Dose
Bolus insulin dose was the sum of doses for morning, midday, evening meals, snack and correction. LS mean change from baseline was analysed by MMRM model with treatment, country, HbA1c stratum, visit, and treatment by visit interaction as fixed effects and the baseline bolus insulin dose as a covariate.
Time frame: Baseline, Week 26
Population: All participants randomized to either LY3209590 Algorithm 1 (Paper) or Insulin degludec, received at least one dose of study drug and had baseline, post-baseline bolus insulin dose data prior to treatment discontinuation.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY3209590 Algorithm 1 (Paper) | Change From Baseline in Bolus Insulin Dose | 0.04 Units per kilogram per day (U/kg/day) | Standard Error 0.019 |
| Insulin Degludec | Change From Baseline in Bolus Insulin Dose | 0.05 Units per kilogram per day (U/kg/day) | Standard Error 0.018 |
Secondary
Change From Baseline in Fasting Serum Glucose
LS mean change from baseline was analysed by mixed model repeated measures (MMRM) model with treatment, country, HbA1c stratum, visit, and treatment by visit interaction as fixed effects and the baseline fasting serum glucose as a covariate.
Time frame: Baseline, Week 26
Population: All participants randomized to either LY3209590 Algorithm 1 (Paper) or Insulin degludec, received at least one dose of study drug and had baseline, post-baseline fasting serum glucose data prior to treatment discontinuation.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY3209590 Algorithm 1 (Paper) | Change From Baseline in Fasting Serum Glucose | -5.9 milligrams per deciliter (mg/dL) | Standard Error 5.65 |
| Insulin Degludec | Change From Baseline in Fasting Serum Glucose | -16.7 milligrams per deciliter (mg/dL) | Standard Error 5.21 |
Secondary
Pharmacokinetics (PK): Area Under the Concentration Time Curve (AUC) of LY3209590
AUC of LY3209590 was calculated for individual participants using the participant's Week 26 LY3209590 dose amount and the estimated clearance value.
Time frame: Week 26
Population: All participants randomized to LY3209590 Algorithm 1 (Paper), received at least one dose of study drug and had evaluable PK data at Week 26.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| LY3209590 Algorithm 1 (Paper) | Pharmacokinetics (PK): Area Under the Concentration Time Curve (AUC) of LY3209590 | 3520 Nanomole*hour per Liter (nmol*hr/L) | Geometric Coefficient of Variation 53 |
Secondary
Rate of Documented Hypoglycemia
Documented hypoglycemia is defined as any time a participant reports a self-monitoring blood glucose \<54 mg/dL (3.0 millimole per liter (mmol/L)). Negative binomial model using baseline hypoglycaemia incidence, baseline HbA1c and treatment as independent variables was performed to estimate the event rate. Data presented is group mean. Group Mean is estimated by first taking the inverse link function on individual participant covariates, then averaging over all participants.
Time frame: Baseline through Week 26
Population: All participants randomized to either LY3209590 Algorithm 1 (Paper) or Insulin degludec, received at least one dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LY3209590 Algorithm 1 (Paper) | Rate of Documented Hypoglycemia | 20.7 Events per participant per year | Standard Error 2.27 |
| Insulin Degludec | Rate of Documented Hypoglycemia | 18.4 Events per participant per year | Standard Error 2 |