Type 1 Diabetes
Conditions
Brief summary
To test whether Mylan's insulin glargine once daily is non-inferior to Lantus® once daily (based on change in HbA1c from baseline to 24 weeks) when administered in combination with mealtime insulin lispro.
Detailed description
This trial is a multicenter, open-label, randomized, parallel-group trial in patients with Type 1 Diabetes Mellitus (T1DM) comparing the efficacy and safety of Mylan's insulin glargine with that of Lantus®.
Interventions
All patients will be shifted from their current mealtime insulin to insulin lispro at the start of the run-in period, and will continue on this for the complete trial. During the 6 week run-in period the doses of Lantus® and insulin lispro will be titrated (if required) to ensure diabetes control. After the run-in period, patients will be randomized to receive either Mylan's insulin glargine (in place of Lantus®), or to continue on Lantus®. During the period from 12 to 24 weeks dose titration will be kept to a minimum.
DRUGLantus®
All patients will be shifted from their current mealtime insulin to insulin lispro at the start of the run-in period; and will continue on this for the complete trial. During the 6week run-in period the doses of Lantus® and insulin lispro will be titrated (if required) to ensure diabetes control. After the run-in period, patients will be randomized to receive either Mylan's insulin glargine (in place of Lantus®), or to continue on Lantus®. During the period from 12 to 24 weeks dose titration will be kept to a minimum.
Sponsors
Mylan GmbH
Mylan Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Patients with an established diagnosis of T1DM per ADA 2014 criteria * Body mass index (BMI) of 18.5 to 35 kg/m2 at screening (both values inclusive). * Glycosylated hemoglobin (HbA1c) ≤9.5% at screening. * Hemoglobin ≥9.0 g/dL at screening.
Exclusion criteria
* History of hypersensitivity to any of the active or inactive ingredients of the insulin/insulin analogue preparations used in the trial, OR history of significant allergic drug reactions. * History of use of animal insulin within the last 3 years or use of biosimilar insulin glargine at any time prior. * History of use of a regular immunomodulator therapy in the 1 year prior to screening. * History of ≥2 episodes of severe hypoglycemia within the 6 months before screening or history of hypoglycemia unawareness (a sample questionnaire is provided in Appendix I), as judged by the investigator. * History of ≥1 episodes of diabetic ketoacidosis or emergency room visits for uncontrolled diabetes leading to hospitalization within the 6 months prior to screening. * Serological evidence of human immunodeficiency virus (HIV), hepatitis B (HbSAg) or hepatitis C (HCVAb) antibodies at screening. * History of drug or alcohol dependence or abuse during the 1 year prior to screening.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change in HbA1c From Baseline to 24 Weeks | 24 weeks |
Secondary
| Measure | Time frame |
|---|---|
| Change From Baseline in FPG Over Time | 24 and 52 weeks |
| Change From Baseline in 8-point SMBG Profile Over Time | 24 and 52 weeks |
| Change in Total Daily Insulin Dose Per Unit Body Weight From Baseline Over Time | 24 and 52 weeks |
| Rate of Hypoglycemic Events Per 30 Days Over Time | 24 and 52 weeks |
| Hypoglycemia Occurrence | 52 weeks |
| Summary of Actual and Change From Baseline in HbA1c | 24 and 52 weeks |
| Change in Total Insulin Antibody Percent Binding for Mylan's Insulin Glargine Assay Over Time | 24 and 52 weeks |
| Change in Total Insulin Antibody Percent Binding for Lantus Assay Over Time | 24 and 52 weeks |
| Change in Cross-reactive Insulin Antibody Percent Binding for Mylan's Insulin Glargine Assay Over Time | 24 and 52 weeks |
| Change in Cross-reactive Insulin Antibody Percent Binding for Lantus Assay Over Time | 24 and 52 weeks |
| Proportion of Patients With HbA1c < 7% | 24 and 52 weeks |
| Occurrence of Local and Systematic Reactions | 52 weeks |
Countries
Canada, Czechia, Estonia, Germany, Hungary, Latvia, Romania, Slovakia, South Africa, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Mylan's Insulin Glargine Receive Mylan's Insulin Glargine plus insulin lispro.
Mylan's insulin glargine: All patients will be shifted from their current mealtime insulin to insulin lispro at the start of the run-in period, and will continue on this for the complete trial. During the 6 week run-in period the doses of Lantus® and insulin lispro will be titrated (if required) to ensure diabetes control. After the run-in period, patients will be randomized to receive either Mylan's insulin glargine (in place of Lantus®), or to continue on Lantus®. During the period from 12 to 24 weeks dose titration will be kept to a minimum. | 280 |
| Lantus® Receive Lantus® plus insulin lispro
Lantus®: All patients will be shifted from their current mealtime insulin to insulin lispro at the start of the run-in period; and will continue on this for the complete trial. During the 6week run-in period the doses of Lantus® and insulin lispro will be titrated (if required) to ensure diabetes control. After the run-in period, patients will be randomized to receive either Mylan's insulin glargine (in place of Lantus®), or to continue on Lantus®. During the period from 12 to 24 weeks dose titration will be kept to a minimum. | 278 |
| Total | 558 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 3 |
| Overall Study | Lost to Follow-up | 1 | 2 |
| Overall Study | Other | 0 | 2 |
| Overall Study | Protocol Violation | 7 | 9 |
| Overall Study | Withdrawal by Subject | 7 | 6 |
Baseline characteristics
| Characteristic | Mylan's Insulin Glargine | Lantus® | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 6 Participants | 11 Participants |
| Age, Categorical Between 18 and 65 years | 275 Participants | 272 Participants | 547 Participants |
| Age, Continuous | 42 years STANDARD_DEVIATION 12.03 | 42.2 years STANDARD_DEVIATION 11.97 | 42.1 years STANDARD_DEVIATION 11.99 |
| Baseline fasting C-peptide | 0.298 mmol/L STANDARD_DEVIATION 0.2291 | 0.291 mmol/L STANDARD_DEVIATION 0.2508 | 0.295 mmol/L STANDARD_DEVIATION 0.2395 |
| Baseline fasting plasma glucose | 167.4 mg/dL STANDARD_DEVIATION 68.43 | 163.9 mg/dL STANDARD_DEVIATION 61.61 | 165.6 mg/dL STANDARD_DEVIATION 65.09 |
| Baseline HbA1c | 7.37 percent STANDARD_DEVIATION 0.869 | 7.39 percent STANDARD_DEVIATION 0.843 | 7.38 percent STANDARD_DEVIATION 0.855 |
| Body Mass Index (BMI) | 26.435 kg/m2 STANDARD_DEVIATION 3.7058 | 26.636 kg/m2 STANDARD_DEVIATION 4.2022 | 26.535 kg/m2 STANDARD_DEVIATION 3.9586 |
| Dosing Time Evening | 242 Participants | 238 Participants | 480 Participants |
| Dosing Time Morning | 38 Participants | 40 Participants | 78 Participants |
| Duration of Diabetes | 18.685 years STANDARD_DEVIATION 11.7771 | 19.697 years STANDARD_DEVIATION 11.2868 | 19.206 years STANDARD_DEVIATION 11.5411 |
| Insulin History No | 0 Participants | 1 Participants | 1 Participants |
| Insulin History Yes | 280 Participants | 277 Participants | 557 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants | 2 Participants | 4 Participants |
| Race/Ethnicity, Customized Black | 2 Participants | 5 Participants | 7 Participants |
| Race/Ethnicity, Customized Caucasian | 263 Participants | 265 Participants | 528 Participants |
| Race/Ethnicity, Customized Hispanic | 6 Participants | 3 Participants | 9 Participants |
| Race/Ethnicity, Customized Other | 7 Participants | 3 Participants | 10 Participants |
| Region of Enrollment Europe | 145 Participants | 145 Participants | 290 Participants |
| Region of Enrollment North America | 126 Participants | 126 Participants | 252 Participants |
| Region of Enrollment South Africa | 9 Participants | 7 Participants | 16 Participants |
| Sex: Female, Male Female | 116 Participants | 106 Participants | 222 Participants |
| Sex: Female, Male Male | 164 Participants | 172 Participants | 336 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 280 | 1 / 278 |
| other Total, other adverse events | 225 / 225 | 239 / 239 |
| serious Total, serious adverse events | 18 / 280 | 22 / 278 |
Outcome results
Primary
Change in HbA1c From Baseline to 24 Weeks
Time frame: 24 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Mylan's Insulin Glargine | Change in HbA1c From Baseline to 24 Weeks | 0.14 percent | Standard Error 0.054 |
| Lantus® | Change in HbA1c From Baseline to 24 Weeks | 0.11 percent | Standard Error 0.054 |
Secondary
Change From Baseline in 8-point SMBG Profile Over Time
Time frame: 24 and 52 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Mylan's Insulin Glargine | Change From Baseline in 8-point SMBG Profile Over Time | week 24 | 0.038 mmol/L | Standard Deviation 2.3751 |
| Mylan's Insulin Glargine | Change From Baseline in 8-point SMBG Profile Over Time | week 52 | -0.082 mmol/L | Standard Deviation 1.5032 |
| Lantus® | Change From Baseline in 8-point SMBG Profile Over Time | week 24 | -0.095 mmol/L | Standard Deviation 1.5012 |
| Lantus® | Change From Baseline in 8-point SMBG Profile Over Time | week 52 | -0.082 mmol/L | Standard Deviation 1.5267 |
Secondary
Change From Baseline in FPG Over Time
Time frame: 24 and 52 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Mylan's Insulin Glargine | Change From Baseline in FPG Over Time | week 24 | -0.81 mmol/L | Standard Deviation 4.485 |
| Mylan's Insulin Glargine | Change From Baseline in FPG Over Time | week 52 | 0.23 mmol/L | Standard Deviation 4.281 |
| Lantus® | Change From Baseline in FPG Over Time | week 24 | 0.09 mmol/L | Standard Deviation 4.507 |
| Lantus® | Change From Baseline in FPG Over Time | week 52 | 0.43 mmol/L | Standard Deviation 4.455 |
Secondary
Change in Cross-reactive Insulin Antibody Percent Binding for Lantus Assay Over Time
Time frame: 24 and 52 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Mylan's Insulin Glargine | Change in Cross-reactive Insulin Antibody Percent Binding for Lantus Assay Over Time | week 24 | -0.265 %SB | Standard Deviation 7.2543 |
| Mylan's Insulin Glargine | Change in Cross-reactive Insulin Antibody Percent Binding for Lantus Assay Over Time | week 52 | -1.060 %SB | Standard Deviation 8.4414 |
| Lantus® | Change in Cross-reactive Insulin Antibody Percent Binding for Lantus Assay Over Time | week 24 | 0.055 %SB | Standard Deviation 7.3985 |
| Lantus® | Change in Cross-reactive Insulin Antibody Percent Binding for Lantus Assay Over Time | week 52 | -1.367 %SB | Standard Deviation 8.6848 |
Secondary
Change in Cross-reactive Insulin Antibody Percent Binding for Mylan's Insulin Glargine Assay Over Time
Time frame: 24 and 52 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Mylan's Insulin Glargine | Change in Cross-reactive Insulin Antibody Percent Binding for Mylan's Insulin Glargine Assay Over Time | week 24 | -0.363 %SB | Standard Deviation 7.1081 |
| Mylan's Insulin Glargine | Change in Cross-reactive Insulin Antibody Percent Binding for Mylan's Insulin Glargine Assay Over Time | week 52 | -1.132 %SB | Standard Deviation 8.3911 |
| Lantus® | Change in Cross-reactive Insulin Antibody Percent Binding for Mylan's Insulin Glargine Assay Over Time | week 24 | 0.27 %SB | Standard Deviation 7.1204 |
| Lantus® | Change in Cross-reactive Insulin Antibody Percent Binding for Mylan's Insulin Glargine Assay Over Time | week 52 | -1.21 %SB | Standard Deviation 8.4096 |
Secondary
Change in Total Daily Insulin Dose Per Unit Body Weight From Baseline Over Time
Time frame: 24 and 52 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Mylan's Insulin Glargine | Change in Total Daily Insulin Dose Per Unit Body Weight From Baseline Over Time | week 24 | 0.0203 U/Kg | Standard Deviation 0.09962 |
| Mylan's Insulin Glargine | Change in Total Daily Insulin Dose Per Unit Body Weight From Baseline Over Time | week 52 | 0.0278 U/Kg | Standard Deviation 0.1044 |
| Lantus® | Change in Total Daily Insulin Dose Per Unit Body Weight From Baseline Over Time | week 24 | 0.0127 U/Kg | Standard Deviation 0.10871 |
| Lantus® | Change in Total Daily Insulin Dose Per Unit Body Weight From Baseline Over Time | week 52 | 0.0138 U/Kg | Standard Deviation 0.11372 |
Secondary
Change in Total Insulin Antibody Percent Binding for Lantus Assay Over Time
Time frame: 24 and 52 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Mylan's Insulin Glargine | Change in Total Insulin Antibody Percent Binding for Lantus Assay Over Time | week 24 | -0.215 %SB | Standard Deviation 7.3298 |
| Mylan's Insulin Glargine | Change in Total Insulin Antibody Percent Binding for Lantus Assay Over Time | week 52 | -0.896 %SB | Standard Deviation 8.561 |
| Lantus® | Change in Total Insulin Antibody Percent Binding for Lantus Assay Over Time | week 24 | 0.157 %SB | Standard Deviation 7.411 |
| Lantus® | Change in Total Insulin Antibody Percent Binding for Lantus Assay Over Time | week 52 | -1.233 %SB | Standard Deviation 8.623 |
Secondary
Change in Total Insulin Antibody Percent Binding for Mylan's Insulin Glargine Assay Over Time
Time frame: 24 and 52 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Mylan's Insulin Glargine | Change in Total Insulin Antibody Percent Binding for Mylan's Insulin Glargine Assay Over Time | week 24 | -0.3063 %SB | Standard Deviation 7.22075 |
| Mylan's Insulin Glargine | Change in Total Insulin Antibody Percent Binding for Mylan's Insulin Glargine Assay Over Time | week 52 | -0.9591 %SB | Standard Deviation 8.51754 |
| Lantus® | Change in Total Insulin Antibody Percent Binding for Mylan's Insulin Glargine Assay Over Time | week 24 | 0.3592 %SB | Standard Deviation 7.16624 |
| Lantus® | Change in Total Insulin Antibody Percent Binding for Mylan's Insulin Glargine Assay Over Time | week 52 | -1.0634 %SB | Standard Deviation 8.42794 |
Secondary
Hypoglycemia Occurrence
Time frame: 52 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Mylan's Insulin Glargine | Hypoglycemia Occurrence | Any hypoglycemic event | 273 Number of patients |
| Mylan's Insulin Glargine | Hypoglycemia Occurrence | Unknown | 77 Number of patients |
| Mylan's Insulin Glargine | Hypoglycemia Occurrence | Severe hypoglycemia | 11 Number of patients |
| Mylan's Insulin Glargine | Hypoglycemia Occurrence | Documented symptomatic hypoglycemia | 249 Number of patients |
| Mylan's Insulin Glargine | Hypoglycemia Occurrence | Asymptomatic hypoglycemia | 246 Number of patients |
| Mylan's Insulin Glargine | Hypoglycemia Occurrence | Probable symptomatic hypoglycemia | 37 Number of patients |
| Mylan's Insulin Glargine | Hypoglycemia Occurrence | Relative hypoglycemia | 35 Number of patients |
| Mylan's Insulin Glargine | Hypoglycemia Occurrence | Other hypoglycemia | 19 Number of patients |
| Lantus® | Hypoglycemia Occurrence | Documented symptomatic hypoglycemia | 249 Number of patients |
| Lantus® | Hypoglycemia Occurrence | Other hypoglycemia | 19 Number of patients |
| Lantus® | Hypoglycemia Occurrence | Probable symptomatic hypoglycemia | 36 Number of patients |
| Lantus® | Hypoglycemia Occurrence | Unknown | 71 Number of patients |
| Lantus® | Hypoglycemia Occurrence | Any hypoglycemic event | 269 Number of patients |
| Lantus® | Hypoglycemia Occurrence | Asymptomatic hypoglycemia | 243 Number of patients |
| Lantus® | Hypoglycemia Occurrence | Severe hypoglycemia | 13 Number of patients |
| Lantus® | Hypoglycemia Occurrence | Relative hypoglycemia | 44 Number of patients |
Secondary
Occurrence of Local and Systematic Reactions
Time frame: 52 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Mylan's Insulin Glargine | Occurrence of Local and Systematic Reactions | Local | 3 Number of patients |
| Mylan's Insulin Glargine | Occurrence of Local and Systematic Reactions | Systemic | 2 Number of patients |
| Lantus® | Occurrence of Local and Systematic Reactions | Local | 4 Number of patients |
| Lantus® | Occurrence of Local and Systematic Reactions | Systemic | 2 Number of patients |
Secondary
Proportion of Patients With HbA1c < 7%
Time frame: 24 and 52 weeks
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Mylan's Insulin Glargine | Proportion of Patients With HbA1c < 7% | week 24 | 73 Participants |
| Mylan's Insulin Glargine | Proportion of Patients With HbA1c < 7% | week 52 | 65 Participants |
| Lantus® | Proportion of Patients With HbA1c < 7% | week 24 | 84 Participants |
| Lantus® | Proportion of Patients With HbA1c < 7% | week 52 | 61 Participants |
Secondary
Rate of Hypoglycemic Events Per 30 Days Over Time
Time frame: 24 and 52 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Mylan's Insulin Glargine | Rate of Hypoglycemic Events Per 30 Days Over Time | week 24 | -5.162 Episodes/30 Days | Standard Deviation 9.0724 |
| Mylan's Insulin Glargine | Rate of Hypoglycemic Events Per 30 Days Over Time | week 52 | -6.241 Episodes/30 Days | Standard Deviation 9.214 |
| Lantus® | Rate of Hypoglycemic Events Per 30 Days Over Time | week 24 | -4.93 Episodes/30 Days | Standard Deviation 8.3815 |
| Lantus® | Rate of Hypoglycemic Events Per 30 Days Over Time | week 52 | -5.765 Episodes/30 Days | Standard Deviation 8.3658 |
Secondary
Summary of Actual and Change From Baseline in HbA1c
Time frame: 24 and 52 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Mylan's Insulin Glargine | Summary of Actual and Change From Baseline in HbA1c | week 24 | 0.12 percent | Standard Deviation 0.599 |
| Mylan's Insulin Glargine | Summary of Actual and Change From Baseline in HbA1c | week 52 | 0.2 percent | Standard Deviation 0.633 |
| Lantus® | Summary of Actual and Change From Baseline in HbA1c | week 24 | 0.09 percent | Standard Deviation 0.526 |
| Lantus® | Summary of Actual and Change From Baseline in HbA1c | week 52 | 0.25 percent | Standard Deviation 0.595 |