Type 2 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 2 diabetes that have already been treated with basal insulin.
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
* Type 2 diabetes mellitus according to the World Health Organization (WHO) criteria treated with basal insulin and up to 3 of the following oral antihyperglycemic medication (OAM): * dipeptidyl peptidase-4 (DPP-4) inhibitors * sodium-glucose cotransporter (SGLT-2) inhibitors * biguanides * alpha-glucosidase inhibitors * sulfonlyureas * HbA1c value of 6.5% to 10%, inclusive * Body mass index (BMI) between 20 and 45 kilograms per meter squared (kg/m2), inclusive
Exclusion criteria
* Type 1 diabetes mellitus or latent autoimmune diabetes * Any episodes of severe hypoglycemia and/or hypoglycemia unawareness within the 6 months prior to screening * Any of the following cardiovascular (CV) conditions: acute myocardial infarction, New York Heart Association Class III or IV heart failure, or cerebrovascular accident (stroke) * Acute or chronic hepatitis, or obvious clinical signs or symptoms of any other liver disease * Estimated glomerular filtration rate (eGFR) \<30 milliliters/minute/1.73 m2 * Active or untreated malignancy * Chronic (\>14 days) systemic glucocorticoid therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in HbA1c | Baseline, Week 32 | HbA1c is the glycosylated fraction of haemoglobin A. HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time. Change from baseline in HbA1c was analysed by mixed model repeated measures (MMRM) including fixed effects of treatment, stratification factors (country, BMI group \[\> 30 or ≤ 30\], sulfonylureas use at study entry), visit and treatment by visit interaction and baseline HbA1c as the covariate. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Fasting Glucose | Baseline, Week 32 | Change from baseline in fasting glucose was analysed by MMRM including fixed effects of treatment, stratification factors (country, BMI group \[\> 30 or ≤ 30\], sulfonylureas use at study entry, HbA1c strata \[\<8.5% or ≥8.5%\]), visit and treatment by visit interaction, and baseline fasting glucose as the covariate. |
| Change From Baseline in Insulin Dose (LY3209590) | Week 1, Week 32 | The baseline for both LY3209590 arms was the first regular weekly dose at Week 1. |
| Change From Baseline in Insulin Dose (Insulin Degludec) | Baseline, Week 32 | Change from Baseline in Insulin Dose for Insulin Degludec arm was reported. |
| Change From Baseline in HbA1c Compared to Insulin Degludec | Baseline, Week 32 | HbA1c is the glycosylated fraction of haemoglobin A. HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time. Change from baseline in HbA1c was analysed by MMRM including fixed effects of treatment, stratification factors (country, BMI group \[\> 30 or ≤ 30\], sulfonylureas use at study entry), visit and treatment by visit interaction, and baseline HbA1c as the covariate. |
| Change From Baseline in Body Weight | Baseline, Week 32 | Change from baseline in body weight was analysed by MMRM including fixed effects of treatment, visit and treatment by visit interaction, and baseline body weight as the covariate. |
| Pharmacokinetics (PK): Area Under the Concentration Time Curve (AUC) of LY3209590 | Week 32 | PK: AUC of LY3209590 was reported for LY3209590 Algorithm 1 and LY3209590 Algorithm 2 arms. AUC was calculated for individual participants using the participant's Week 32 LY3209590 dose amount and the participant's estimated clearance value. |
| Rate of Total Documented Symptomatic Hypoglycemia | Baseline through week 32 | The hypoglycemia events were defined by participant reported events with glucose ≤54 mg/dL (3.0 millimole per liter (mmol/L)). Relative Rate was calculated based on Group Mean. Group Mean was estimated by first taking the inverse link function on individual patient covariates, then averaging over all participants. |
Countries
Mexico, Puerto Rico, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| LY3209590 Algorithm 1 Participants received loading dose followed by weekly dose of LY3209590 based on the prior randomization basal insulin dose for a period of 32 weeks by subcutaneous (SC) injection. Dose titration was done to maintain fasting blood glucose of \<140 milligram mg.dL | 135 |
| LY3209590 Algorithm 2 Participants received loading dose followed by weekly dose of LY3209590 based on the prior randomization basal insulin dose for a period of 32 weeks by subcutaneous injection. Dose titration was done to maintain fasting blood glucose of \<120 mg/dL. | 132 |
| Insulin Degludec Participants received same dose of Degludec as the total basal insulin dose already administered prior to randomization. Dose was titrated to maintain fasting blood glucose of ≤100 mg/dL to achieve glycemic goal of HbA1C \<7%. | 132 |
| Total | 399 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 1 |
| Overall Study | Death | 1 | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 2 | 3 |
| Overall Study | Non compliance with study drug | 1 | 1 | 0 |
| Overall Study | Physician Decision | 0 | 1 | 1 |
| Overall Study | Protocol Violation | 1 | 4 | 3 |
| Overall Study | Sponsor Decision | 1 | 0 | 0 |
| Overall Study | Unknown/Missing data | 3 | 2 | 1 |
| Overall Study | Withdrawal by Subject | 9 | 6 | 4 |
Baseline characteristics
| Characteristic | LY3209590 Algorithm 2 | Total | LY3209590 Algorithm 1 | Insulin Degludec |
|---|---|---|---|---|
| Age, Continuous | 59.6 years STANDARD_DEVIATION 11.3 | 60.2 years STANDARD_DEVIATION 10.4 | 60.2 years STANDARD_DEVIATION 9.9 | 60.8 years STANDARD_DEVIATION 10 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 78 Participants | 218 Participants | 67 Participants | 73 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 54 Participants | 181 Participants | 68 Participants | 59 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Haemoglobin A1c (HbA1c) | 8.03 HbA1C percentage (%) STANDARD_DEVIATION 0.89 | 8.12 HbA1C percentage (%) STANDARD_DEVIATION 0.88 | 8.20 HbA1C percentage (%) STANDARD_DEVIATION 0.87 | 8.13 HbA1C percentage (%) STANDARD_DEVIATION 0.88 |
| Race (NIH/OMB) American Indian or Alaska Native | 18 Participants | 53 Participants | 16 Participants | 19 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 15 Participants | 4 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants | 36 Participants | 16 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 3 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 3 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 97 Participants | 288 Participants | 97 Participants | 94 Participants |
| Region of Enrollment Mexico | 19 Participants | 61 Participants | 21 Participants | 21 Participants |
| Region of Enrollment Puerto Rico | 16 Participants | 49 Participants | 18 Participants | 15 Participants |
| Region of Enrollment United States | 97 Participants | 289 Participants | 96 Participants | 96 Participants |
| Sex: Female, Male Female | 70 Participants | 202 Participants | 67 Participants | 65 Participants |
| Sex: Female, Male Male | 62 Participants | 197 Participants | 68 Participants | 67 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 135 | 0 / 132 | 1 / 132 |
| other Total, other adverse events | 17 / 135 | 29 / 132 | 13 / 132 |
| serious Total, serious adverse events | 7 / 135 | 8 / 132 | 10 / 132 |
Outcome results
Primary
Change From Baseline in HbA1c
HbA1c is the glycosylated fraction of haemoglobin A. HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time. Change from baseline in HbA1c was analysed by mixed model repeated measures (MMRM) including fixed effects of treatment, stratification factors (country, BMI group \[\> 30 or ≤ 30\], sulfonylureas use at study entry), visit and treatment by visit interaction and baseline HbA1c as the covariate.
Time frame: Baseline, Week 32
Population: The data after using rescue medication or stopping study medication were censored. Participants with non-missing baseline value and at least one post baseline value of response were included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY3209590 Algorithm 1 | Change From Baseline in HbA1c | -0.58 HbA1C % | Standard Error 0.083 |
| LY3209590 Algorithm 2 | Change From Baseline in HbA1c | -0.57 HbA1C % | Standard Error 0.085 |
| Insulin Degludec | Change From Baseline in HbA1c | -0.66 HbA1C % | Standard Error 0.084 |
p-value: <0.001Mixed Models Analysis
p-value: <0.001Mixed Models Analysis
p-value: <0.001Mixed Models Analysis
Secondary
Change From Baseline in Body Weight
Change from baseline in body weight was analysed by MMRM including fixed effects of treatment, visit and treatment by visit interaction, and baseline body weight as the covariate.
Time frame: Baseline, Week 32
Population: All randomized participants who received at least one dose of study medication and with non-missing baseline value and at least one post baseline value of response were included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY3209590 Algorithm 1 | Change From Baseline in Body Weight | 1.0 Kilogram (kg) | Standard Error 0.33 |
| LY3209590 Algorithm 2 | Change From Baseline in Body Weight | 1.0 Kilogram (kg) | Standard Error 0.33 |
| Insulin Degludec | Change From Baseline in Body Weight | 2.0 Kilogram (kg) | Standard Error 0.33 |
Secondary
Change From Baseline in Fasting Glucose
Change from baseline in fasting glucose was analysed by MMRM including fixed effects of treatment, stratification factors (country, BMI group \[\> 30 or ≤ 30\], sulfonylureas use at study entry, HbA1c strata \[\<8.5% or ≥8.5%\]), visit and treatment by visit interaction, and baseline fasting glucose as the covariate.
Time frame: Baseline, Week 32
Population: The data after using rescue medication or stopping study medication were excluded. Participants with non-missing baseline value and at least one post baseline value of response were included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY3209590 Algorithm 1 | Change From Baseline in Fasting Glucose | -13.1 Milligram per deicliter (mg/dL) | Standard Error 4.01 |
| LY3209590 Algorithm 2 | Change From Baseline in Fasting Glucose | -18.6 Milligram per deicliter (mg/dL) | Standard Error 4.14 |
| Insulin Degludec | Change From Baseline in Fasting Glucose | -31.5 Milligram per deicliter (mg/dL) | Standard Error 4.03 |
Secondary
Change From Baseline in HbA1c Compared to Insulin Degludec
HbA1c is the glycosylated fraction of haemoglobin A. HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time. Change from baseline in HbA1c was analysed by MMRM including fixed effects of treatment, stratification factors (country, BMI group \[\> 30 or ≤ 30\], sulfonylureas use at study entry), visit and treatment by visit interaction, and baseline HbA1c as the covariate.
Time frame: Baseline, Week 32
Population: The data after using rescue medication or stopping study medication were excluded. Participants with non-missing baseline value and at least one post baseline value of response were included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY3209590 Algorithm 1 | Change From Baseline in HbA1c Compared to Insulin Degludec | -0.58 HbA1C % | Standard Error 0.083 |
| LY3209590 Algorithm 2 | Change From Baseline in HbA1c Compared to Insulin Degludec | -0.57 HbA1C % | Standard Error 0.085 |
| Insulin Degludec | Change From Baseline in HbA1c Compared to Insulin Degludec | -0.66 HbA1C % | Standard Error 0.084 |
90% CI: [-0.11, 0.28]Mixed Models Analysis
90% CI: [-0.1, 0.29]Mixed Models Analysis
Secondary
Change From Baseline in Insulin Dose (Insulin Degludec)
Change from Baseline in Insulin Dose for Insulin Degludec arm was reported.
Time frame: Baseline, Week 32
Population: Participants with non-missing value at the specified timepoint were included.The data after using rescue medication or stopping study medication were excluded.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LY3209590 Algorithm 1 | Change From Baseline in Insulin Dose (Insulin Degludec) | 16.40 International Units (IU) | Standard Deviation 26.06 |
Secondary
Change From Baseline in Insulin Dose (LY3209590)
The baseline for both LY3209590 arms was the first regular weekly dose at Week 1.
Time frame: Week 1, Week 32
Population: Participants with non-missing value at the specified timepoint were included.The data after using rescue medication or stopping study medication were excluded.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LY3209590 Algorithm 1 | Change From Baseline in Insulin Dose (LY3209590) | 0.12 Milligrams (mg) | Standard Deviation 4.86 |
| LY3209590 Algorithm 2 | Change From Baseline in Insulin Dose (LY3209590) | 0.60 Milligrams (mg) | Standard Deviation 3.75 |
Secondary
Pharmacokinetics (PK): Area Under the Concentration Time Curve (AUC) of LY3209590
PK: AUC of LY3209590 was reported for LY3209590 Algorithm 1 and LY3209590 Algorithm 2 arms. AUC was calculated for individual participants using the participant's Week 32 LY3209590 dose amount and the participant's estimated clearance value.
Time frame: Week 32
Population: All randomized participants who received at least one dose of LY3209590 and had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| LY3209590 Algorithm 1 | Pharmacokinetics (PK): Area Under the Concentration Time Curve (AUC) of LY3209590 | 5360 Nanomole * hour per Liter (nmol * hr/L) | Geometric Coefficient of Variation 67 |
| LY3209590 Algorithm 2 | Pharmacokinetics (PK): Area Under the Concentration Time Curve (AUC) of LY3209590 | 5430 Nanomole * hour per Liter (nmol * hr/L) | Geometric Coefficient of Variation 60 |
Secondary
Rate of Total Documented Symptomatic Hypoglycemia
The hypoglycemia events were defined by participant reported events with glucose ≤54 mg/dL (3.0 millimole per liter (mmol/L)). Relative Rate was calculated based on Group Mean. Group Mean was estimated by first taking the inverse link function on individual patient covariates, then averaging over all participants.
Time frame: Baseline through week 32
Population: All randomized study participants who received at least one dose of study medication and had evaluable hypoglycaemic data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LY3209590 Algorithm 1 | Rate of Total Documented Symptomatic Hypoglycemia | 0.73 Events per participant per year | Standard Error 0.119 |
| LY3209590 Algorithm 2 | Rate of Total Documented Symptomatic Hypoglycemia | 1.22 Events per participant per year | Standard Error 0.378 |
| Insulin Degludec | Rate of Total Documented Symptomatic Hypoglycemia | 1.56 Events per participant per year | Standard Error 0.375 |