Type 1 Diabetes Mellitus
Conditions
Brief summary
The main purpose of this study is to evaluate the efficacy of the study drug LY900014 compared to insulin lispro, both in combination with insulin glargine or insulin degludec, in adults with type 1 diabetes (T1D).
Interventions
DRUGLY900014
Administered SC
DRUGInsulin Lispro
Administered SC
DRUGInsulin Glargine
Administered SC
DRUGInsulin Degludec
Administered SC
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Have T1D for at least 1 year prior to screening and continuously using insulin for at least 1 year. * HbA1c of ≥7.0 and ≤9.5%. * Use insulin lispro, insulin aspart, or insulin glulisine as prandial insulin. * Use insulin glargine, insulin detemir, insulin degludec, or neutral protamine Hagedorn (NPH) insulin as basal insulin.
Exclusion criteria
* Have used other antihyperglycemic medications or therapies (inhaled, oral or injectable) within 90-days of screening. * Have had more than 1 severe hypoglycemic episode within 6 months of screening. * Have had more than 1 hospitalization related to hyperglycemia or diabetic ketoacidosis within 6 months of screening. * Have clinically significant gastrointestinal disease.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Hemoglobin A1c (HbA1c) Efficacy Estimand at Week 26 | Baseline, Week 26 | HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time. Least Squares (LS) mean was determined by mixed model repeated measures (MMRM) model with strata (pooled country, type of basal insulin, prandial insulin dosing plan, and HbA1c stratum) and treatment as fixed effects and baseline as a covariate. The efficacy estimand included participant data when baseline and at least one post-baseline measurement were available prior to permanent discontinuation of study drug. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in 1-hour Postprandial Glucose (PPG) Excursion During Mixed-Meal Tolerance Test (MMTT) Efficacy Estimand at Week 26 | Baseline, Week 26 | A standardized MMTT was used to characterize postprandial glucose control following administration of the study insulin. Serum glucose measured at 1-hour timepoint after the start of meal minus fasting serum glucose. 1-hour PPG excursion during MMTT uses the ANCOVA model with strata (pooled country, type of basal insulin, prandial insulin dosing plan, and HbA1c stratum) and treatment as fixed effects and baseline as a covariate. The efficacy estimand included participant data when baseline and at least one post-baseline measurement were available prior to permanent discontinuation of study drug. |
| Change From Baseline in 2-hour PPG Excursion During MMTT Efficacy Estimand at Week 26 | Baseline, Week 26 | A standardized MMTT was used to characterize postprandial glucose control following administration of the study insulin. Serum glucose measured at 2-hour timepoint after the start of meal minus fasting serum glucose. 2-hour PPG excursion during MMTT uses the ANCOVA model with strata (pooled country, type of basal insulin, prandial insulin dosing plan, and HbA1c stratum) and treatment as fixed effects and baseline as a covariate. The efficacy estimand included participant data when baseline and at least one post-baseline measurement were available prior to permanent discontinuation of study drug. |
| Rate of Severe Hypoglycemia at Week 26 | Baseline through Week 26 | Severe hypoglycemia is defined as an event requiring assistance of another person to administer carbohydrate, glucagon, or other resuscitative actions. During these episodes, the participant has an altered mental status and cannot assist in his or her own care, or may be semiconscious or unconscious, or experience coma with or without seizures, and may require parenteral therapy. Rate of severe hypoglycemia events per 100 years during a defined period was calculated by total number of severe hypoglycemia episodes within the period divided by the cumulative days on treatment from all participants within a treatment group \*36525. |
| Rate of Documented Symptomatic Hypoglycemia at Week 26 | Baseline through Week 26 | Documented symptomatic hypoglycemia is an event during which typical symptoms of hypoglycemia are accompanied by blood glucose (BG) of \<54 mg/dL \[3.0 millimole per liter (mmol/L)\]. The rate of documented symptomatic hypoglycemia was estimated by negative binomial model: number of episodes = treatment with log (treatment exposure in days/365.25) as an offset variable. |
| Change From Baseline in 1,5-Anhydroglucitol (1,5-AG) at Week 26 | Baseline, Week 26 | 1,5-anhydroglucitol (1,5-AG) is a marker of short-term glycemic control especially postprandial hyperglycemia. 1,5-AG accurately predicts rapid changes in glycemia and is tightly associated with glucose fluctuations and postprandial glucose. LS Mean was calculated using mixed model repeated measures (MMRM) including fixed class effects of treatment, strata (pooled country, type of basal insulin, HbA1c stratum and number of prandial doses at study entry), visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline value. The analysis included data collected prior to permanent discontinuation of study drug. |
| Change From Baseline in HbA1c at Week 52 | Baseline, Week 52 | HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time. Least Squares (LS) mean was determined by MMRM model with variables of baseline, pooled country, type of basal insulin during lead-in, prandial Insulin Dosing Plan, treatment (Type III sum of squares) as fixed factors. The analysis included data prior to permanent discontinuation of study drug. |
| Change From Baseline in Insulin Dose at Week 26 | Baseline, Week 26 | LS Mean was analyzed using mixed model repeated measures (MMRM) including fixed class effects of treatment, strata (pooled country, type of basal insulin, HbA1c stratum and number of prandial doses at study entry), visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline value. The analysis included data prior to permanent discontinuation of study drug. |
| Change From Baseline in Insulin Treatment Satisfaction Questionnaire (ITSQ) Regimen Inconvenience Domain Score at Week 26 | Baseline, Week 26 | ITSQ is a validated instrument containing 22 items that assess treatment satisfaction for participants with diabetes and on insulin. The questionnaire measures satisfaction from the following 5 domains: Inconvenience of Regimen, Lifestyle Flexibility, Glycemic Control, Hypoglycemic Control, and Insulin Delivery Device. Data presented are the transformed overall score on a scale of 0-100, where higher scores indicate better treatment satisfaction. LS Mean was calculated using the ANCOVA model with strata (pooled country, type of basal insulin, number of prandial doses at study entry, and HbA1c stratum), and treatment as fixed effects and baseline as covariate. The analysis included data prior to permanent discontinuation of study drug. The analysis included data prior to permanent discontinuation of study drug. |
| Change From Baseline in ITSQ Lifestyle Flexibility Domain Score at Week 26 | Baseline, Week 26 | ITSQ is a validated instrument containing 22 items that assess treatment satisfaction for participants with diabetes and on insulin. The questionnaire measures satisfaction from the following 5 domains: Inconvenience of Regimen, Lifestyle Flexibility, Glycemic Control, Hypoglycemic Control, and Insulin Delivery Device. Data presented are the transformed overall score on a scale of 0-100, where higher scores indicate better treatment satisfaction. LS Mean was calculated using the analysis of covariance (ANCOVA) with strata (pooled country, type of basal insulin, number of prandial doses at study entry, and HbA1c stratum), and treatment as fixed effects and baseline as covariate. The analysis included data prior to permanent discontinuation of study drug. The analysis included data prior to permanent discontinuation of study drug. |
| Percentage of Participants With HbA1c <7% | Week 26 | Hemoglobin A1c (HbA1c) is the glycosylated fraction of hemoglobin A. HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time. |
| Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 26 | Baseline, Week 26 | SMBG 10-point profiles were measured at fasting, 1-hour post morning meal, 2-hours post morning meal, pre midday meal, 1-hour post midday meal, 2-hours post midday meal, pre evening meal, 1-hour post evening meal, 2-hours post evening meal, and bedtime. LS Mean was analyzed using mixed model repeated measures (MMRM) including fixed class effects of treatment, strata (pooled country, type of basal insulin, HbA1c stratum and number of prandial doses at study entry), visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline value. The efficacy estimand included participant data when baseline and at least one post-baseline measurement prior to permanent discontinuation of study drug. |
Countries
Argentina, Australia, Austria, Brazil, Germany, Greece, India, Italy, Japan, Mexico, New Zealand, Poland, Puerto Rico, Romania, Russia, Slovakia, Spain, Sweden, Taiwan, United States
Participant flow
Recruitment details
The study consists of 2 double-blind arms (LY900014 and Insulin Lispro (Humalog)) and one Open-label treatment group (LY900014 Postmeal). Double-blind group: The study included 8-week lead-in period followed by a 52-week treatment period. Open-label treatment group: The treatment period ended after 26 weeks.
Pre-assignment details
The purpose of the Lead-in Period was to titrate basal insulin prior to randomization. Participants were then randomized to either LY900014 at mealtime, Insulin Lispro (Humalog) at mealtime, or LY900014 administered 20 minutes after the start of a meal (LY900014 Postmeal) in the treatment period (Period 2).
Participants by arm
| Arm | Count |
|---|---|
| Insulin Lispro (Humalog) 100 U/mL Insulin lispro given subcutaneously (SC) 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets. | 442 |
| LY900014 100 U/mL LY900014 given SC 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets. | 451 |
| LY900014 Postmeal 100 U/mL LY900014 given SC 20 minutes after the start of each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Prandial insulin doses were individualized and titrated according to protocol-defined targets. | 329 |
| Insulin Lispro (Humalog)-MEE 100 U/mL Insulin lispro given subcutaneously (SC) 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets. | 31 |
| LY900014-MEE 100 U/mL LY900014 given SC 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets. | 21 |
| LY900014 Postmeal-MEE 100 U/mL LY900014 given SC 20 minutes after the start of each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Prandial insulin doses were individualized and titrated according to protocol-defined targets. | 22 |
| Total | 1,296 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Lead-in Period | Adverse Event | 3 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Lead-in Period | Lost to Follow-up | 12 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Lead-in Period | Physician Decision | 12 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Lead-in Period | Protocol Violation | 5 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Lead-in Period | Sponsor Decision | 11 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Lead-in Period | Treatment Interruption | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Lead-in Period | Withdrawal by Subject | 50 | 0 | 0 | 0 | 2 | 0 | 0 | 0 |
| Treatment Period | Adverse Event | 0 | 1 | 4 | 2 | 0 | 0 | 0 | 0 |
| Treatment Period | Death | 0 | 1 | 1 | 1 | 0 | 0 | 0 | 0 |
| Treatment Period | Lost to Follow-up | 0 | 5 | 3 | 2 | 0 | 2 | 1 | 0 |
| Treatment Period | Physician Decision | 0 | 1 | 2 | 0 | 0 | 0 | 0 | 0 |
| Treatment Period | Protocol Violation | 0 | 3 | 0 | 0 | 0 | 0 | 0 | 0 |
| Treatment Period | Sponsor Decision | 0 | 3 | 0 | 0 | 0 | 0 | 0 | 0 |
| Treatment Period | Withdrawal by Subject | 0 | 20 | 23 | 14 | 0 | 1 | 1 | 1 |
Baseline characteristics
| Characteristic | LY900014 | Insulin Lispro (Humalog) | Total | LY900014 Postmeal-MEE | LY900014-MEE | Insulin Lispro (Humalog)-MEE | LY900014 Postmeal |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 44.1 Years STANDARD_DEVIATION 13.7 | 44.5 Years STANDARD_DEVIATION 13.6 | 43.7 Years STANDARD_DEVIATION 14 | 31.5 Years STANDARD_DEVIATION 12.7 | 32.4 Years STANDARD_DEVIATION 12.4 | 32.1 Years STANDARD_DEVIATION 12.3 | 44.5 Years STANDARD_DEVIATION 14.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 35 Participants | 33 Participants | 132 Participants | 9 Participants | 8 Participants | 12 Participants | 35 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 399 Participants | 397 Participants | 1121 Participants | 12 Participants | 12 Participants | 18 Participants | 283 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 17 Participants | 12 Participants | 43 Participants | 1 Participants | 1 Participants | 1 Participants | 11 Participants |
| Hemoglobin A1c (HbA1c) | 7.34 Percentage of HbA1c STANDARD_DEVIATION 0.65 | 7.33 Percentage of HbA1c STANDARD_DEVIATION 0.67 | 7.35 Percentage of HbA1c STANDARD_DEVIATION 0.66 | 7.60 Percentage of HbA1c STANDARD_DEVIATION 0.62 | 7.28 Percentage of HbA1c STANDARD_DEVIATION 0.67 | 7.52 Percentage of HbA1c STANDARD_DEVIATION 0.99 | 7.36 Percentage of HbA1c STANDARD_DEVIATION 0.64 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 5 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 86 Participants | 78 Participants | 266 Participants | 10 Participants | 11 Participants | 18 Participants | 63 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 9 Participants | 21 Participants | 0 Participants | 0 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 10 Participants | 11 Participants | 27 Participants | 0 Participants | 1 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 346 Participants | 344 Participants | 976 Participants | 11 Participants | 9 Participants | 12 Participants | 254 Participants |
| Region of Enrollment Argentina | 14 participants | 11 participants | 39 participants | 0 participants | 0 participants | 0 participants | 14 participants |
| Region of Enrollment Australia | 10 participants | 9 participants | 26 participants | 0 participants | 0 participants | 0 participants | 7 participants |
| Region of Enrollment Austria | 6 participants | 9 participants | 22 participants | 0 participants | 0 participants | 0 participants | 7 participants |
| Region of Enrollment Germany | 25 participants | 26 participants | 72 participants | 0 participants | 0 participants | 0 participants | 21 participants |
| Region of Enrollment Greece | 28 participants | 26 participants | 75 participants | 0 participants | 0 participants | 0 participants | 21 participants |
| Region of Enrollment India | 10 participants | 10 participants | 52 participants | 6 participants | 8 participants | 10 participants | 8 participants |
| Region of Enrollment Italy | 7 participants | 9 participants | 20 participants | 0 participants | 0 participants | 0 participants | 4 participants |
| Region of Enrollment Japan | 62 participants | 59 participants | 167 participants | 0 participants | 0 participants | 0 participants | 46 participants |
| Region of Enrollment Mexico | 4 participants | 6 participants | 46 participants | 9 participants | 8 participants | 11 participants | 8 participants |
| Region of Enrollment New Zealand | 11 participants | 10 participants | 24 participants | 0 participants | 0 participants | 0 participants | 3 participants |
| Region of Enrollment Poland | 47 participants | 49 participants | 123 participants | 0 participants | 0 participants | 0 participants | 27 participants |
| Region of Enrollment Puerto Rico | 3 participants | 2 participants | 7 participants | 0 participants | 0 participants | 0 participants | 2 participants |
| Region of Enrollment Romania | 30 participants | 34 participants | 87 participants | 0 participants | 0 participants | 0 participants | 23 participants |
| Region of Enrollment Russia | 11 participants | 8 participants | 30 participants | 3 participants | 1 participants | 2 participants | 5 participants |
| Region of Enrollment Slovakia | 6 participants | 6 participants | 16 participants | 0 participants | 0 participants | 0 participants | 4 participants |
| Region of Enrollment Spain | 30 participants | 25 participants | 75 participants | 0 participants | 0 participants | 0 participants | 20 participants |
| Region of Enrollment Sweden | 2 participants | 5 participants | 10 participants | 0 participants | 0 participants | 0 participants | 3 participants |
| Region of Enrollment Taiwan | 11 participants | 9 participants | 44 participants | 4 participants | 4 participants | 8 participants | 8 participants |
| Region of Enrollment United States | 134 participants | 129 participants | 361 participants | 0 participants | 0 participants | 0 participants | 98 participants |
| Sex: Female, Male Female | 201 Participants | 186 Participants | 570 Participants | 13 Participants | 9 Participants | 14 Participants | 147 Participants |
| Sex: Female, Male Male | 250 Participants | 256 Participants | 726 Participants | 9 Participants | 12 Participants | 17 Participants | 182 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 1,316 | 1 / 442 | 1 / 451 | 1 / 329 | 0 / 76 | 0 / 31 | 0 / 21 | 0 / 22 |
| other Total, other adverse events | 131 / 1,316 | 147 / 442 | 163 / 451 | 104 / 329 | 5 / 76 | 13 / 31 | 3 / 21 | 4 / 22 |
| serious Total, serious adverse events | 48 / 1,316 | 67 / 442 | 54 / 451 | 30 / 329 | 0 / 76 | 9 / 31 | 3 / 21 | 2 / 22 |
Outcome results
Primary
Change From Baseline in Hemoglobin A1c (HbA1c) Efficacy Estimand at Week 26
HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time. Least Squares (LS) mean was determined by mixed model repeated measures (MMRM) model with strata (pooled country, type of basal insulin, prandial insulin dosing plan, and HbA1c stratum) and treatment as fixed effects and baseline as a covariate. The efficacy estimand included participant data when baseline and at least one post-baseline measurement were available prior to permanent discontinuation of study drug.
Time frame: Baseline, Week 26
Population: All randomized participants with baseline and at least one post-baseline HbA1c data. As pre-specified in the analysis plan, outcome measures will not be reported for the Maximum Extended Enrollment (MEE) arms/groups but only for the main global study arms/groups.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY900014 | Change From Baseline in Hemoglobin A1c (HbA1c) Efficacy Estimand at Week 26 | -0.13 Percentage of HbA1c | Standard Error 0.031 |
| LY900014 Postmeal | Change From Baseline in Hemoglobin A1c (HbA1c) Efficacy Estimand at Week 26 | 0.08 Percentage of HbA1c | Standard Error 0.035 |
| Insulin Lispro (Humalog) | Change From Baseline in Hemoglobin A1c (HbA1c) Efficacy Estimand at Week 26 | -0.05 Percentage of HbA1c | Standard Error 0.031 |
p-value: 0.0695% CI: [-0.16, 0]Mixed Models Analysis
p-value: 0.00395% CI: [0.04, 0.22]Mixed Models Analysis
Secondary
Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 26
SMBG 10-point profiles were measured at fasting, 1-hour post morning meal, 2-hours post morning meal, pre midday meal, 1-hour post midday meal, 2-hours post midday meal, pre evening meal, 1-hour post evening meal, 2-hours post evening meal, and bedtime. LS Mean was analyzed using mixed model repeated measures (MMRM) including fixed class effects of treatment, strata (pooled country, type of basal insulin, HbA1c stratum and number of prandial doses at study entry), visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline value. The efficacy estimand included participant data when baseline and at least one post-baseline measurement prior to permanent discontinuation of study drug.
Time frame: Baseline, Week 26
Population: All randomized participants with baseline and at least one post-baseline SMBG data. As pre-specified in the analysis plan, outcome measures will not be reported for the MEE arms/groups but only for the main global study arms/groups.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| LY900014 | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 26 | Morning Premeal | -1.1 mg/dL | Standard Error 2.82 |
| LY900014 | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 26 | Morning 1-hour Postmeal | -14.8 mg/dL | Standard Error 3.3 |
| LY900014 | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 26 | Morning 2-hour Postmeal | -10.1 mg/dL | Standard Error 3.21 |
| LY900014 | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 26 | Midday Premeal | 6.6 mg/dL | Standard Error 2.8 |
| LY900014 | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 26 | Midday 1-hour Postmeal | -2.2 mg/dL | Standard Error 3.36 |
| LY900014 | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 26 | Midday 2-hour Postmeal | -5.2 mg/dL | Standard Error 3.24 |
| LY900014 | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 26 | Evening Premeal | 5.2 mg/dL | Standard Error 3.21 |
| LY900014 | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 26 | Evening 1-hour Postmeal | -7.0 mg/dL | Standard Error 3.53 |
| LY900014 | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 26 | Evening 2-hour Postmeal | -8.2 mg/dL | Standard Error 3.43 |
| LY900014 | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 26 | Bedtime | -6.8 mg/dL | Standard Error 3.58 |
| LY900014 Postmeal | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 26 | Evening 2-hour Postmeal | -1.6 mg/dL | Standard Error 3.83 |
| LY900014 Postmeal | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 26 | Morning Premeal | 2.9 mg/dL | Standard Error 3.19 |
| LY900014 Postmeal | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 26 | Midday 2-hour Postmeal | 0.0 mg/dL | Standard Error 3.67 |
| LY900014 Postmeal | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 26 | Midday 1-hour Postmeal | 11.4 mg/dL | Standard Error 3.81 |
| LY900014 Postmeal | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 26 | Morning 1-hour Postmeal | 5.4 mg/dL | Standard Error 3.71 |
| LY900014 Postmeal | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 26 | Bedtime | -11.0 mg/dL | Standard Error 4.08 |
| LY900014 Postmeal | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 26 | Evening 1-hour Postmeal | 15.3 mg/dL | Standard Error 3.95 |
| LY900014 Postmeal | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 26 | Morning 2-hour Postmeal | -0.2 mg/dL | Standard Error 3.63 |
| LY900014 Postmeal | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 26 | Evening Premeal | 0.4 mg/dL | Standard Error 3.64 |
| LY900014 Postmeal | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 26 | Midday Premeal | 4.0 mg/dL | Standard Error 3.17 |
| Insulin Lispro (Humalog) | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 26 | Evening 1-hour Postmeal | -0.9 mg/dL | Standard Error 3.57 |
| Insulin Lispro (Humalog) | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 26 | Midday Premeal | 1.9 mg/dL | Standard Error 2.83 |
| Insulin Lispro (Humalog) | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 26 | Midday 1-hour Postmeal | 1.4 mg/dL | Standard Error 3.4 |
| Insulin Lispro (Humalog) | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 26 | Midday 2-hour Postmeal | -2.7 mg/dL | Standard Error 3.28 |
| Insulin Lispro (Humalog) | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 26 | Evening 2-hour Postmeal | -0.6 mg/dL | Standard Error 3.45 |
| Insulin Lispro (Humalog) | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 26 | Evening Premeal | -1.4 mg/dL | Standard Error 3.24 |
| Insulin Lispro (Humalog) | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 26 | Morning Premeal | -3.3 mg/dL | Standard Error 2.84 |
| Insulin Lispro (Humalog) | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 26 | Bedtime | -2.9 mg/dL | Standard Error 3.56 |
| Insulin Lispro (Humalog) | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 26 | Morning 1-hour Postmeal | -1.0 mg/dL | Standard Error 3.31 |
| Insulin Lispro (Humalog) | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 26 | Morning 2-hour Postmeal | 1.4 mg/dL | Standard Error 3.22 |
Secondary
Change From Baseline in 1,5-Anhydroglucitol (1,5-AG) at Week 26
1,5-anhydroglucitol (1,5-AG) is a marker of short-term glycemic control especially postprandial hyperglycemia. 1,5-AG accurately predicts rapid changes in glycemia and is tightly associated with glucose fluctuations and postprandial glucose. LS Mean was calculated using mixed model repeated measures (MMRM) including fixed class effects of treatment, strata (pooled country, type of basal insulin, HbA1c stratum and number of prandial doses at study entry), visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline value. The analysis included data collected prior to permanent discontinuation of study drug.
Time frame: Baseline, Week 26
Population: All randomized participants with baseline and at least one post-baseline 1,5-AG data. As pre-specified in the analysis plan, outcome measures will not be reported for the MEE arms/groups but only for the main global study arms/groups.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY900014 | Change From Baseline in 1,5-Anhydroglucitol (1,5-AG) at Week 26 | 0.19 milligram per liter (mg/L) | Standard Error 0.108 |
| LY900014 Postmeal | Change From Baseline in 1,5-Anhydroglucitol (1,5-AG) at Week 26 | -0.38 milligram per liter (mg/L) | Standard Error 0.124 |
| Insulin Lispro (Humalog) | Change From Baseline in 1,5-Anhydroglucitol (1,5-AG) at Week 26 | -0.22 milligram per liter (mg/L) | Standard Error 0.109 |
Secondary
Change From Baseline in 1-hour Postprandial Glucose (PPG) Excursion During Mixed-Meal Tolerance Test (MMTT) Efficacy Estimand at Week 26
A standardized MMTT was used to characterize postprandial glucose control following administration of the study insulin. Serum glucose measured at 1-hour timepoint after the start of meal minus fasting serum glucose. 1-hour PPG excursion during MMTT uses the ANCOVA model with strata (pooled country, type of basal insulin, prandial insulin dosing plan, and HbA1c stratum) and treatment as fixed effects and baseline as a covariate. The efficacy estimand included participant data when baseline and at least one post-baseline measurement were available prior to permanent discontinuation of study drug.
Time frame: Baseline, Week 26
Population: All randomized participants with baseline and at least one post-baseline 1-hour PPG excursion data. As pre-specified in the analysis plan, outcome measures will not be reported for the MEE arms/groups but only for the main global study arms/groups.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY900014 | Change From Baseline in 1-hour Postprandial Glucose (PPG) Excursion During Mixed-Meal Tolerance Test (MMTT) Efficacy Estimand at Week 26 | -28.6 milligrams per deciliter (mg/dL) | Standard Error 3.33 |
| LY900014 Postmeal | Change From Baseline in 1-hour Postprandial Glucose (PPG) Excursion During Mixed-Meal Tolerance Test (MMTT) Efficacy Estimand at Week 26 | 12.5 milligrams per deciliter (mg/dL) | Standard Error 3.74 |
| Insulin Lispro (Humalog) | Change From Baseline in 1-hour Postprandial Glucose (PPG) Excursion During Mixed-Meal Tolerance Test (MMTT) Efficacy Estimand at Week 26 | -0.7 milligrams per deciliter (mg/dL) | Standard Error 3.34 |
p-value: <0.00195% CI: [-35.3, -20.6]ANCOVA
p-value: 0.00295% CI: [5, 21.4]ANCOVA
Secondary
Change From Baseline in 2-hour PPG Excursion During MMTT Efficacy Estimand at Week 26
A standardized MMTT was used to characterize postprandial glucose control following administration of the study insulin. Serum glucose measured at 2-hour timepoint after the start of meal minus fasting serum glucose. 2-hour PPG excursion during MMTT uses the ANCOVA model with strata (pooled country, type of basal insulin, prandial insulin dosing plan, and HbA1c stratum) and treatment as fixed effects and baseline as a covariate. The efficacy estimand included participant data when baseline and at least one post-baseline measurement were available prior to permanent discontinuation of study drug.
Time frame: Baseline, Week 26
Population: All randomized participants with baseline and at least one post-baseline 2-hour PPG excursion data. As pre-specified in the analysis plan, outcome measures will not be reported for the MEE arms/groups but only for the main global study arms/groups.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY900014 | Change From Baseline in 2-hour PPG Excursion During MMTT Efficacy Estimand at Week 26 | -34.7 mg/dL | Standard Error 4.5 |
| LY900014 Postmeal | Change From Baseline in 2-hour PPG Excursion During MMTT Efficacy Estimand at Week 26 | -10.2 mg/dL | Standard Error 5.04 |
| Insulin Lispro (Humalog) | Change From Baseline in 2-hour PPG Excursion During MMTT Efficacy Estimand at Week 26 | -3.5 mg/dL | Standard Error 4.51 |
p-value: <0.00195% CI: [-41.1, -21.2]ANCOVA
p-value: 0.23595% CI: [-17.6, 4.3]ANCOVA
Secondary
Change From Baseline in HbA1c at Week 52
HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time. Least Squares (LS) mean was determined by MMRM model with variables of baseline, pooled country, type of basal insulin during lead-in, prandial Insulin Dosing Plan, treatment (Type III sum of squares) as fixed factors. The analysis included data prior to permanent discontinuation of study drug.
Time frame: Baseline, Week 52
Population: All randomized participants with baseline and at least one postbaseline observation for HbA1c. As pre-specified in the analysis plan, outcome measures will not be reported for the MEE arms/groups but only for the main global study arms/groups. Only double blind arms analysed for this outcome because open label group ended at week 26.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY900014 | Change From Baseline in HbA1c at Week 52 | 0.13 Percentage of HbA1c | Standard Error 0.036 |
| LY900014 Postmeal | Change From Baseline in HbA1c at Week 52 | 0.20 Percentage of HbA1c | Standard Error 0.037 |
p-value: 0.18495% CI: [-0.16, 0.03]Mixed Models Analysis
Secondary
Change From Baseline in Insulin Dose at Week 26
LS Mean was analyzed using mixed model repeated measures (MMRM) including fixed class effects of treatment, strata (pooled country, type of basal insulin, HbA1c stratum and number of prandial doses at study entry), visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline value. The analysis included data prior to permanent discontinuation of study drug.
Time frame: Baseline, Week 26
Population: All randomized participants with baseline and at least one post-baseline basal insulin dose data. As pre-specified in the analysis plan, outcome measures will not be reported for the MEE arms/groups but only for the main global study arms/groups.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| LY900014 | Change From Baseline in Insulin Dose at Week 26 | Daily Prandial Insulin Dose | 1.5 Units (U)/day | Standard Error 0.59 |
| LY900014 | Change From Baseline in Insulin Dose at Week 26 | Daily Basal Insulin Dose | 1.0 Units (U)/day | Standard Error 0.28 |
| LY900014 | Change From Baseline in Insulin Dose at Week 26 | Total Daily Insulin Dose | 2.9 Units (U)/day | Standard Error 0.72 |
| LY900014 Postmeal | Change From Baseline in Insulin Dose at Week 26 | Daily Basal Insulin Dose | 1.2 Units (U)/day | Standard Error 0.33 |
| LY900014 Postmeal | Change From Baseline in Insulin Dose at Week 26 | Total Daily Insulin Dose | 2.2 Units (U)/day | Standard Error 0.83 |
| LY900014 Postmeal | Change From Baseline in Insulin Dose at Week 26 | Daily Prandial Insulin Dose | 1.0 Units (U)/day | Standard Error 0.68 |
| Insulin Lispro (Humalog) | Change From Baseline in Insulin Dose at Week 26 | Total Daily Insulin Dose | 2.0 Units (U)/day | Standard Error 0.73 |
| Insulin Lispro (Humalog) | Change From Baseline in Insulin Dose at Week 26 | Daily Prandial Insulin Dose | 0.9 Units (U)/day | Standard Error 0.6 |
| Insulin Lispro (Humalog) | Change From Baseline in Insulin Dose at Week 26 | Daily Basal Insulin Dose | 0.9 Units (U)/day | Standard Error 0.29 |
Secondary
Change From Baseline in Insulin Treatment Satisfaction Questionnaire (ITSQ) Regimen Inconvenience Domain Score at Week 26
ITSQ is a validated instrument containing 22 items that assess treatment satisfaction for participants with diabetes and on insulin. The questionnaire measures satisfaction from the following 5 domains: Inconvenience of Regimen, Lifestyle Flexibility, Glycemic Control, Hypoglycemic Control, and Insulin Delivery Device. Data presented are the transformed overall score on a scale of 0-100, where higher scores indicate better treatment satisfaction. LS Mean was calculated using the ANCOVA model with strata (pooled country, type of basal insulin, number of prandial doses at study entry, and HbA1c stratum), and treatment as fixed effects and baseline as covariate. The analysis included data prior to permanent discontinuation of study drug. The analysis included data prior to permanent discontinuation of study drug.
Time frame: Baseline, Week 26
Population: All randomized participants with baseline and post-baseline data. Missing endpoints were imputed by applying the Last Observation Carried Forward (LOCF) method to post-baseline data. As pre-specified in the analysis plan, outcome measures will not be reported for the MEE arms/groups but only for the main global study arms/groups.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY900014 | Change From Baseline in Insulin Treatment Satisfaction Questionnaire (ITSQ) Regimen Inconvenience Domain Score at Week 26 | 1.4 Units on a scale | Standard Error 0.92 |
| LY900014 Postmeal | Change From Baseline in Insulin Treatment Satisfaction Questionnaire (ITSQ) Regimen Inconvenience Domain Score at Week 26 | 1.5 Units on a scale | Standard Error 1.01 |
| Insulin Lispro (Humalog) | Change From Baseline in Insulin Treatment Satisfaction Questionnaire (ITSQ) Regimen Inconvenience Domain Score at Week 26 | 0.7 Units on a scale | Standard Error 0.91 |
Secondary
Change From Baseline in ITSQ Lifestyle Flexibility Domain Score at Week 26
ITSQ is a validated instrument containing 22 items that assess treatment satisfaction for participants with diabetes and on insulin. The questionnaire measures satisfaction from the following 5 domains: Inconvenience of Regimen, Lifestyle Flexibility, Glycemic Control, Hypoglycemic Control, and Insulin Delivery Device. Data presented are the transformed overall score on a scale of 0-100, where higher scores indicate better treatment satisfaction. LS Mean was calculated using the analysis of covariance (ANCOVA) with strata (pooled country, type of basal insulin, number of prandial doses at study entry, and HbA1c stratum), and treatment as fixed effects and baseline as covariate. The analysis included data prior to permanent discontinuation of study drug. The analysis included data prior to permanent discontinuation of study drug.
Time frame: Baseline, Week 26
Population: All randomized participants with baseline and post-baseline data. Missing endpoints were imputed by applying the LOCF method to the post-baseline data. As pre-specified in the analysis plan, outcome measures will not be reported for the MEE arms/groups but only for the main global study arms/groups.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY900014 | Change From Baseline in ITSQ Lifestyle Flexibility Domain Score at Week 26 | 2.1 Units on a scale | Standard Error 1.09 |
| LY900014 Postmeal | Change From Baseline in ITSQ Lifestyle Flexibility Domain Score at Week 26 | 3.7 Units on a scale | Standard Error 1.19 |
| Insulin Lispro (Humalog) | Change From Baseline in ITSQ Lifestyle Flexibility Domain Score at Week 26 | 1.3 Units on a scale | Standard Error 1.07 |
Secondary
Percentage of Participants With HbA1c <7%
Hemoglobin A1c (HbA1c) is the glycosylated fraction of hemoglobin A. HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time.
Time frame: Week 26
Population: All randomized participants with baseline and at least one post-baseline HbA1c \<7% data. As pre-specified in the analysis plan, outcome measures will not be reported for the MEE arms/groups but only for the main global study arms/groups.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LY900014 | Percentage of Participants With HbA1c <7% | 36.00 Percentage of participants |
| LY900014 Postmeal | Percentage of Participants With HbA1c <7% | 24.84 Percentage of participants |
| Insulin Lispro (Humalog) | Percentage of Participants With HbA1c <7% | 33.94 Percentage of participants |
Secondary
Rate of Documented Symptomatic Hypoglycemia at Week 26
Documented symptomatic hypoglycemia is an event during which typical symptoms of hypoglycemia are accompanied by blood glucose (BG) of \<54 mg/dL \[3.0 millimole per liter (mmol/L)\]. The rate of documented symptomatic hypoglycemia was estimated by negative binomial model: number of episodes = treatment with log (treatment exposure in days/365.25) as an offset variable.
Time frame: Baseline through Week 26
Population: All randomized participants with evaluable hypoglycemic data. As pre-specified in the analysis plan, outcome measures will not be reported for the MEE arms/groups but only for the main global study arms/groups.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY900014 | Rate of Documented Symptomatic Hypoglycemia at Week 26 | 6.71 Events per participant per year | Standard Error 0.479 |
| LY900014 Postmeal | Rate of Documented Symptomatic Hypoglycemia at Week 26 | 7.75 Events per participant per year | Standard Error 0.582 |
| Insulin Lispro (Humalog) | Rate of Documented Symptomatic Hypoglycemia at Week 26 | 7.35 Events per participant per year | Standard Error 0.697 |
Secondary
Rate of Severe Hypoglycemia at Week 26
Severe hypoglycemia is defined as an event requiring assistance of another person to administer carbohydrate, glucagon, or other resuscitative actions. During these episodes, the participant has an altered mental status and cannot assist in his or her own care, or may be semiconscious or unconscious, or experience coma with or without seizures, and may require parenteral therapy. Rate of severe hypoglycemia events per 100 years during a defined period was calculated by total number of severe hypoglycemia episodes within the period divided by the cumulative days on treatment from all participants within a treatment group \*36525.
Time frame: Baseline through Week 26
Population: All randomized participants with evaluable hypoglycemic data. As pre-specified in the analysis plan, outcome measures will not be reported for the MEE arms/groups but only for the main global study arms/groups.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LY900014 | Rate of Severe Hypoglycemia at Week 26 | 16.50 Events per 100 participant years |
| LY900014 Postmeal | Rate of Severe Hypoglycemia at Week 26 | 13.70 Events per 100 participant years |
| Insulin Lispro (Humalog) | Rate of Severe Hypoglycemia at Week 26 | 18.34 Events per 100 participant years |