Diabetes Mellitus, Type 2
Conditions
Keywords
Metabolic Diseases, Diabetes Mellitus, Type 2, Glargine, Diabetes Mellitus, Insulin LISPRO, Insulin
Brief summary
The study is a comparison of twice-daily insulin lispro low mixture versus once-daily basal insulin glargine and once-daily prandial insulin lispro, in participants with Type 2 Diabetes.
Interventions
DRUGInsulin Lispro Low Mixture (LM)
Participant-dependent dose, administered subcutaneously for 24 weeks
DRUGInsulin Glargine
Participant-dependent dose, administered subcutaneously for 24 weeks
DRUGPrandial Insulin Lispro
Participant-dependent dose, administered subcutaneously for 24 weeks
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 75 Years
Healthy volunteers
No
Inclusion criteria
* Present with type 2 diabetes mellitus * Have been taking metformin and/or pioglitazone * Have received treatment with basal insulin glargine, injected once a day, for greater than or equal to 90 days * Have glycosylated hemoglobin A1c (HbA1c) concentration between greater than or equal to 7.5% and less than or equal to 10.5 * Have a fasting plasma glucose concentration of less than or equal to 6.7 millimoles per liter \[mmol/L, less than or equal to 121 milligrams per deciliter (mg/dL)\], or greater than 6.7 mmol/L (greater than 121 mg/dL) if the investigator considers that further titration of basal insulin glargine is not possible for safety reasons * Not pregnant or breastfeeding
Exclusion criteria
* Have Type 1 Diabetes * Their stable dose of pioglitazone is greater than the maximum dose approved for use in combination with insulin in their country * Have a body mass index (BMI) greater than 45 kilograms per square meter (kg/m2). * Have a history of scheduled mealtime (prandial) insulin use within 12 weeks of the screening visit and the total duration of the prandial insulin treatment was greater than 2 weeks * Have had more than one episode of severe hypoglycaemia within 24 weeks prior to entry into the study * Have cardiac disease with a functional status that is Class III or IV * Have a history of renal or liver disease * Have had a blood transfusion or have a blood disorder
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in HbA1c From Baseline to 24 Weeks Endpoint (Per Protocol Population) | Baseline, 24 weeks | The change from baseline to 24 weeks in the percentage of glycosylated hemoglobin A1c (HbA1c) in plasma. The least squares (LS) mean was estimated from a mixed-effects model with repeated measures (MMRM) that included baseline HbA1c concentration as a covariate, treatment, country, week of visit, and treatment-by-week interaction as fixed effects, and participant and error as random effects. |
| Change in HbA1c From Baseline to 24 Weeks Endpoint (Intention-to-Treat Population) | Baseline, 24 weeks | The change from baseline to 24 weeks in the percentage of glycosylated hemoglobin A1c (HbA1c) in plasma. The least squares (LS) mean was estimated from a mixed-effects model with repeated measures (MMRM) that included baseline HbA1c concentration as a covariate, treatment, country, week of visit, and treatment-by-week interaction as fixed effects, and participant and error as random effects. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in the Fasting Plasma Glucose Concentration From Baseline to 12 Weeks and 24 Weeks | Baseline, 12 weeks, and 24 weeks | The least squares (LS) mean was estimated from a mixed-effects model with repeated measures (MMRM) that included baseline fasting plasma glucose value as a covariate, treatment, country, baseline HbA1c stratification level, week of visit, and treatment-by-week interaction as fixed effects, and participant and error as random effects. |
| 7-point Self-Monitored Blood Glucose (SMBG) Profiles at 12 Weeks and 24 Weeks | 12 weeks, 24 weeks | 7-point Self-monitored Blood Glucose (SMBG) Profiles are measures of blood glucose taken 7 times a day at the morning pre-meal, morning 2-hours post-meal, midday pre-meal, midday 2-hours post-meal, evening pre-meal, evening 2-hours post-meal, and 0300 hour \[3 am\]. Each participant took measures on 3 non-consecutive days and the average was calculated for each of the 7 time points. The mean of the 7-point averages was calculated for all the participants at baseline, Weeks 12 and 24. The least squares (LS) mean was estimated from mixed-effects model with repeated measures that included the baseline value of the variable as a covariate, treatment, country, baseline glycosylated hemoglobin A1c (HbA1c)stratification level, week of visit, and treatment-by-week interaction as fixed effects, and participant and error as random effects. |
| Glycemic Variability From the 7-point Self-Monitored Blood Glucose (SMBG) Profiles at 12 Weeks and 24 Weeks | 12 weeks, 24 weeks | The 7-point SMBG profile was calculated as the average blood glucose concentration across the 7 pre-specified time points in a day that was then averaged over 3 non-consecutive days in the 2 weeks prior to the 12 week visit and 24 week visit. Glycemic variability was calculated as the standard deviation of the 7-point SMBG profiles. Standard deviation was first calculated for each day and then averaged over 3 non-consecutive days for each visit. The least squares (LS) mean was estimated from mixed-effects model with repeated measures that included the baseline value of the variable as a covariate, treatment, country, baseline glycosylated hemoglobin A1c (HbA1c)stratification level, week of visit, and treatment-by-week interaction as fixed effects, and participant and error as random effects. |
| Daily Insulin Dose: Total, Basal, and Prandial at 12 Weeks and 24 Weeks | 12 weeks, 24 weeks | — |
| Change in Weight From Baseline to 12 Weeks and 24 Weeks | Baseline, 12 weeks, 24 weeks | The least squares (LS) mean was estimated from a mixed-effects model with repeated measures (MMRM) that included baseline weight as a covariate, treatment, country, baseline glycosylated hemoglobin A1c (HbA1c) stratification level, week of visit, and the treatment-by-week interaction as fixed effects, and participant and error as random effects. |
| Change in the HbA1c Concentration From Baseline to 12 Weeks Endpoint | Baseline, 12 weeks | The change from baseline to 12 weeks in the percentage of glycosylated hemoglobin A1c (HbA1c) in plasma. The least squares (LS) mean was estimated from a mixed-effects model with repeated measures (MMRM) that included baseline HbA1c concentration as a covariate, treatment, country, week of visit, and treatment-by-week interaction as fixed effects, and participant and error as random effects. |
| Insulin Treatment Satisfaction Questionnaire (ITSQ) Score at 24 Weeks | 24 weeks | ITSQ: validated instrument containing 22 items which are measured on a 7-point scale: 1 (no bother at all) to 7 (a tremendous bother) used to assess insulin treatment satisfaction. Items are divided into 5 domains: Inconvenience of Regimen (5 items: domain score range 5 to 35), Lifestyle Flexibility (3 items: domain score range 3 to 21), Glycemic Control (3 items: domain score range 3 to 21), Hypoglycemic Control (5 items: domain score range 5 to 35), Insulin Delivery Device (6 items: domain score range 6 to 42) lower scores reflect better outcome. ITSQ Total Overall Score ranged from 22 to 154. Raw domain scores transformed on 0-100 scale, where transformed domain score = 100×\[(7-raw domain score)/6\]. Higher scores indicate better treatment satisfaction. Least squares (LS) mean estimated from analysis of covariance (ANCOVA) model that included baseline score as covariate and treatment, glycosylated hemoglobin A1c (HbA1c) stratum, and country as fixed effects. |
| Perceptions About Medications-Diabetes 21 (PAM-D21) Questionnaire Score at 24 Weeks | 24 weeks | PAM-D21 is a validated questionnaire consisting of 21 items to assess a participant's perceptions about their diabetes treatment regimens and perceived emotional and physical side-effects. The PAM-D21 consists of 4 subscales: Convenience/Flexibility (items 1 to 3); Perceived Effectiveness (items 4 to 6); Emotional Effects (items 7 to 11); and Physical Effects (items 12 to 21). Item scores range from 1 (none of the time) to 4 (all of the time). Subscale scores were linearly transformed to a 0-100, with higher score corresponds to better perceptions about diabetes medications. The least squares (LS) mean was estimated from an analysis of covariance (ANCOVA) model that included baseline score as a covariate and treatment, glycosylated hemoglobin A1c (HbA1c) stratum, and country as fixed effects. |
| The Rate of Hypoglycemic Episodes | Baseline through 24 weeks | The hypoglycemia rate per 30 days was calculated as the number of episodes reported for the interval between visits and during the study divided by the number of days in the given interval and multiplied by 30. |
| The Number of Participants With Severe Hypoglycemic Episodes | Baseline through 24 weeks | The number of participants who had a severe hypoglycemic episode anytime during the study. Severe hypoglycemia was defined as any event in which the participant required the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. |
| The Number of Participants With a Hypoglycemic Episodes (Incidence) | Baseline through 24 weeks | A hypoglycemic episode was defined as an event associated with 1) reported signs and symptoms of hypoglycemia, and/or 2) a documented blood glucose (BG) concentration of \<= 70 milligrams per deciliter \[mg/dL, 3.9 millimoles per liter (mmol/L)\]. |
| Number of Participants Who Achieve a Target HbA1c Concentration of Less Than 7% or Less Than or Equal to 6.5% at 24 Weeks | 24 weeks | — |
Countries
Argentina, Brazil, China, Egypt, India, South Korea, Spain, Turkey (Türkiye)
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Insulin Lispro Low Mixture Two daily injections (breakfast and dinner) of insulin lispro mix 75/25. Participant-dependent doses, administered subcutaneously for 24 weeks. | 236 |
| Insulin Glargine+Insulin Lispro Once-daily injection (bedtime) basal insulin glargine and once-daily injection (before the meal with the highest average 2-hour postprandial blood glucose concentration) prandial insulin lispro. Participant-dependent doses, administered subcutaneously for 24 weeks. | 240 |
| Total | 476 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 |
| Overall Study | Entry Criteria Not Met | 6 | 4 |
| Overall Study | Lack of Efficacy | 2 | 0 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Physician Decision | 0 | 4 |
| Overall Study | Protocol Violation | 2 | 5 |
| Overall Study | Sponsor Decision | 1 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 7 |
Baseline characteristics
| Characteristic | Insulin Glargine+Insulin Lispro | Total | Insulin Lispro Low Mixture |
|---|---|---|---|
| Age, Continuous | 57.7 years STANDARD_DEVIATION 9.12 | 57.5 years STANDARD_DEVIATION 9.52 | 57.4 years STANDARD_DEVIATION 9.93 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 17 participants | 32 participants | 15 participants |
| Race/Ethnicity, Customized Asian | 80 participants | 160 participants | 80 participants |
| Race/Ethnicity, Customized Black or African American | 1 participants | 6 participants | 5 participants |
| Race/Ethnicity, Customized More than one race | 6 participants | 9 participants | 3 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized White | 136 participants | 269 participants | 133 participants |
| Region of Enrollment Argentina | 39 participants | 79 participants | 40 participants |
| Region of Enrollment Brazil | 23 participants | 43 participants | 20 participants |
| Region of Enrollment China | 13 participants | 28 participants | 15 participants |
| Region of Enrollment Egypt | 7 participants | 12 participants | 5 participants |
| Region of Enrollment India | 41 participants | 81 participants | 40 participants |
| Region of Enrollment Korea, Republic of | 26 participants | 51 participants | 25 participants |
| Region of Enrollment Mexico | 20 participants | 40 participants | 20 participants |
| Region of Enrollment Romania | 38 participants | 76 participants | 38 participants |
| Region of Enrollment Russian Federation | 3 participants | 5 participants | 2 participants |
| Region of Enrollment Spain | 23 participants | 46 participants | 23 participants |
| Region of Enrollment Turkey | 7 participants | 15 participants | 8 participants |
| Sex: Female, Male Female | 142 Participants | 262 Participants | 120 Participants |
| Sex: Female, Male Male | 98 Participants | 214 Participants | 116 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 109 / 236 | 93 / 240 |
| serious Total, serious adverse events | 11 / 236 | 8 / 240 |
Outcome results
Primary
Change in HbA1c From Baseline to 24 Weeks Endpoint (Intention-to-Treat Population)
The change from baseline to 24 weeks in the percentage of glycosylated hemoglobin A1c (HbA1c) in plasma. The least squares (LS) mean was estimated from a mixed-effects model with repeated measures (MMRM) that included baseline HbA1c concentration as a covariate, treatment, country, week of visit, and treatment-by-week interaction as fixed effects, and participant and error as random effects.
Time frame: Baseline, 24 weeks
Population: Intention-to-treat population (ITT): randomized participants who received at least 1 dose of study drug and had HbA1c data at 24 weeks. Participants were analyzed per their assigned treatment arm regardless of the treatment they actually received.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Insulin Lispro Low Mixture | Change in HbA1c From Baseline to 24 Weeks Endpoint (Intention-to-Treat Population) | -1.30 percentage of HbA1c |
| Insulin Glargine+Insulin Lispro | Change in HbA1c From Baseline to 24 Weeks Endpoint (Intention-to-Treat Population) | -1.08 percentage of HbA1c |
95% CI: [-0.39, -0.05]
Primary
Change in HbA1c From Baseline to 24 Weeks Endpoint (Per Protocol Population)
The change from baseline to 24 weeks in the percentage of glycosylated hemoglobin A1c (HbA1c) in plasma. The least squares (LS) mean was estimated from a mixed-effects model with repeated measures (MMRM) that included baseline HbA1c concentration as a covariate, treatment, country, week of visit, and treatment-by-week interaction as fixed effects, and participant and error as random effects.
Time frame: Baseline, 24 weeks
Population: Per protocol population: randomized participants with the exception of participants who did not complete Week 24 visit, received study drug different from their randomized study treatment, violated any of the inclusion, exclusion, or discontinuation criteria, or were significantly noncompliant.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Insulin Lispro Low Mixture | Change in HbA1c From Baseline to 24 Weeks Endpoint (Per Protocol Population) | -1.30 percentage of HbA1c |
| Insulin Glargine+Insulin Lispro | Change in HbA1c From Baseline to 24 Weeks Endpoint (Per Protocol Population) | -1.09 percentage of HbA1c |
95% CI: [-0.38, -0.04]
Secondary
7-point Self-Monitored Blood Glucose (SMBG) Profiles at 12 Weeks and 24 Weeks
7-point Self-monitored Blood Glucose (SMBG) Profiles are measures of blood glucose taken 7 times a day at the morning pre-meal, morning 2-hours post-meal, midday pre-meal, midday 2-hours post-meal, evening pre-meal, evening 2-hours post-meal, and 0300 hour \[3 am\]. Each participant took measures on 3 non-consecutive days and the average was calculated for each of the 7 time points. The mean of the 7-point averages was calculated for all the participants at baseline, Weeks 12 and 24. The least squares (LS) mean was estimated from mixed-effects model with repeated measures that included the baseline value of the variable as a covariate, treatment, country, baseline glycosylated hemoglobin A1c (HbA1c)stratification level, week of visit, and treatment-by-week interaction as fixed effects, and participant and error as random effects.
Time frame: 12 weeks, 24 weeks
Population: Intention-to-treat population (ITT): randomized participants who received at least 1 dose of study drug and had SMBG data at the specified time points. Participants were analyzed per their assigned treatment arm regardless of the treatment they actually received.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Insulin Lispro Low Mixture | 7-point Self-Monitored Blood Glucose (SMBG) Profiles at 12 Weeks and 24 Weeks | pre-morning meal (Week 12) (n=223, 222) | 6.87 millimoles per liter (mmol/L) |
| Insulin Lispro Low Mixture | 7-point Self-Monitored Blood Glucose (SMBG) Profiles at 12 Weeks and 24 Weeks | 2 hour post-morning meal (Week 12) (n=220, 221) | 8.82 millimoles per liter (mmol/L) |
| Insulin Lispro Low Mixture | 7-point Self-Monitored Blood Glucose (SMBG) Profiles at 12 Weeks and 24 Weeks | pre-midday meal (Week 12) (n=220, 221) | 6.96 millimoles per liter (mmol/L) |
| Insulin Lispro Low Mixture | 7-point Self-Monitored Blood Glucose (SMBG) Profiles at 12 Weeks and 24 Weeks | 2 hours post-midday meal (Week 12) (n=220, 221) | 9.46 millimoles per liter (mmol/L) |
| Insulin Lispro Low Mixture | 7-point Self-Monitored Blood Glucose (SMBG) Profiles at 12 Weeks and 24 Weeks | pre-evening meal (Week 12) (n=221, 221) | 7.98 millimoles per liter (mmol/L) |
| Insulin Lispro Low Mixture | 7-point Self-Monitored Blood Glucose (SMBG) Profiles at 12 Weeks and 24 Weeks | 2 hours post-evening meal (Week 12) (n=217, 220) | 9.15 millimoles per liter (mmol/L) |
| Insulin Lispro Low Mixture | 7-point Self-Monitored Blood Glucose (SMBG) Profiles at 12 Weeks and 24 Weeks | 3 am - during the night (Week 12)(n=197, 201) | 8.21 millimoles per liter (mmol/L) |
| Insulin Lispro Low Mixture | 7-point Self-Monitored Blood Glucose (SMBG) Profiles at 12 Weeks and 24 Weeks | pre-morning meal (Week 24) (n=217, 216) | 6.60 millimoles per liter (mmol/L) |
| Insulin Lispro Low Mixture | 7-point Self-Monitored Blood Glucose (SMBG) Profiles at 12 Weeks and 24 Weeks | 2 hours post-morning meal (Week 24) (n=216, 215) | 8.52 millimoles per liter (mmol/L) |
| Insulin Lispro Low Mixture | 7-point Self-Monitored Blood Glucose (SMBG) Profiles at 12 Weeks and 24 Weeks | pre-midday meal (Week 24) (n=215, 216) | 6.82 millimoles per liter (mmol/L) |
| Insulin Lispro Low Mixture | 7-point Self-Monitored Blood Glucose (SMBG) Profiles at 12 Weeks and 24 Weeks | 2 hours post-midday meal (Week 24) (n=216, 216) | 9.08 millimoles per liter (mmol/L) |
| Insulin Lispro Low Mixture | 7-point Self-Monitored Blood Glucose (SMBG) Profiles at 12 Weeks and 24 Weeks | pre-evening meal (Week 24) (n=216, 216) | 7.70 millimoles per liter (mmol/L) |
| Insulin Lispro Low Mixture | 7-point Self-Monitored Blood Glucose (SMBG) Profiles at 12 Weeks and 24 Weeks | 2 hours post-evening meal (Week 24) (n=212, 216) | 9.11 millimoles per liter (mmol/L) |
| Insulin Lispro Low Mixture | 7-point Self-Monitored Blood Glucose (SMBG) Profiles at 12 Weeks and 24 Weeks | 3 am - during the night (Week 24)(n=198, 195) | 8.05 millimoles per liter (mmol/L) |
| Insulin Glargine+Insulin Lispro | 7-point Self-Monitored Blood Glucose (SMBG) Profiles at 12 Weeks and 24 Weeks | 2 hours post-midday meal (Week 24) (n=216, 216) | 8.99 millimoles per liter (mmol/L) |
| Insulin Glargine+Insulin Lispro | 7-point Self-Monitored Blood Glucose (SMBG) Profiles at 12 Weeks and 24 Weeks | pre-morning meal (Week 12) (n=223, 222) | 6.20 millimoles per liter (mmol/L) |
| Insulin Glargine+Insulin Lispro | 7-point Self-Monitored Blood Glucose (SMBG) Profiles at 12 Weeks and 24 Weeks | pre-morning meal (Week 24) (n=217, 216) | 6.26 millimoles per liter (mmol/L) |
| Insulin Glargine+Insulin Lispro | 7-point Self-Monitored Blood Glucose (SMBG) Profiles at 12 Weeks and 24 Weeks | 2 hour post-morning meal (Week 12) (n=220, 221) | 9.01 millimoles per liter (mmol/L) |
| Insulin Glargine+Insulin Lispro | 7-point Self-Monitored Blood Glucose (SMBG) Profiles at 12 Weeks and 24 Weeks | 2 hours post-evening meal (Week 24) (n=212, 216) | 8.95 millimoles per liter (mmol/L) |
| Insulin Glargine+Insulin Lispro | 7-point Self-Monitored Blood Glucose (SMBG) Profiles at 12 Weeks and 24 Weeks | pre-midday meal (Week 12) (n=220, 221) | 7.44 millimoles per liter (mmol/L) |
| Insulin Glargine+Insulin Lispro | 7-point Self-Monitored Blood Glucose (SMBG) Profiles at 12 Weeks and 24 Weeks | 2 hours post-morning meal (Week 24) (n=216, 215) | 8.86 millimoles per liter (mmol/L) |
| Insulin Glargine+Insulin Lispro | 7-point Self-Monitored Blood Glucose (SMBG) Profiles at 12 Weeks and 24 Weeks | 2 hours post-midday meal (Week 12) (n=220, 221) | 9.14 millimoles per liter (mmol/L) |
| Insulin Glargine+Insulin Lispro | 7-point Self-Monitored Blood Glucose (SMBG) Profiles at 12 Weeks and 24 Weeks | pre-evening meal (Week 24) (n=216, 216) | 7.95 millimoles per liter (mmol/L) |
| Insulin Glargine+Insulin Lispro | 7-point Self-Monitored Blood Glucose (SMBG) Profiles at 12 Weeks and 24 Weeks | pre-evening meal (Week 12) (n=221, 221) | 8.25 millimoles per liter (mmol/L) |
| Insulin Glargine+Insulin Lispro | 7-point Self-Monitored Blood Glucose (SMBG) Profiles at 12 Weeks and 24 Weeks | pre-midday meal (Week 24) (n=215, 216) | 7.44 millimoles per liter (mmol/L) |
| Insulin Glargine+Insulin Lispro | 7-point Self-Monitored Blood Glucose (SMBG) Profiles at 12 Weeks and 24 Weeks | 2 hours post-evening meal (Week 12) (n=217, 220) | 9.10 millimoles per liter (mmol/L) |
| Insulin Glargine+Insulin Lispro | 7-point Self-Monitored Blood Glucose (SMBG) Profiles at 12 Weeks and 24 Weeks | 3 am - during the night (Week 24)(n=198, 195) | 8.26 millimoles per liter (mmol/L) |
| Insulin Glargine+Insulin Lispro | 7-point Self-Monitored Blood Glucose (SMBG) Profiles at 12 Weeks and 24 Weeks | 3 am - during the night (Week 12)(n=197, 201) | 8.52 millimoles per liter (mmol/L) |
Secondary
Change in the Fasting Plasma Glucose Concentration From Baseline to 12 Weeks and 24 Weeks
The least squares (LS) mean was estimated from a mixed-effects model with repeated measures (MMRM) that included baseline fasting plasma glucose value as a covariate, treatment, country, baseline HbA1c stratification level, week of visit, and treatment-by-week interaction as fixed effects, and participant and error as random effects.
Time frame: Baseline, 12 weeks, and 24 weeks
Population: Intention-to-treat population (ITT): randomized participants who received at least 1 dose of study drug and had fasting plasma glucose concentration data at the specified time points. Participants were analyzed per their assigned treatment arm regardless of the treatment they actually received.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Insulin Lispro Low Mixture | Change in the Fasting Plasma Glucose Concentration From Baseline to 12 Weeks and 24 Weeks | Change at 24 Weeks (n=219, 217) | 0.89 millimoles per liter (mmol/L) |
| Insulin Lispro Low Mixture | Change in the Fasting Plasma Glucose Concentration From Baseline to 12 Weeks and 24 Weeks | Change at 12 Weeks (n= 222, 222) | 1.04 millimoles per liter (mmol/L) |
| Insulin Glargine+Insulin Lispro | Change in the Fasting Plasma Glucose Concentration From Baseline to 12 Weeks and 24 Weeks | Change at 12 Weeks (n= 222, 222) | 0.64 millimoles per liter (mmol/L) |
| Insulin Glargine+Insulin Lispro | Change in the Fasting Plasma Glucose Concentration From Baseline to 12 Weeks and 24 Weeks | Change at 24 Weeks (n=219, 217) | 0.75 millimoles per liter (mmol/L) |
p-value: 0.0827Mixed Models Analysis
p-value: 0.5353Mixed Models Analysis
Secondary
Change in the HbA1c Concentration From Baseline to 12 Weeks Endpoint
The change from baseline to 12 weeks in the percentage of glycosylated hemoglobin A1c (HbA1c) in plasma. The least squares (LS) mean was estimated from a mixed-effects model with repeated measures (MMRM) that included baseline HbA1c concentration as a covariate, treatment, country, week of visit, and treatment-by-week interaction as fixed effects, and participant and error as random effects.
Time frame: Baseline, 12 weeks
Population: Intention-to-treat population (ITT): randomized participants who received at least 1 dose of study drug and had HbA1c data at the 12 weeks. Participants were analyzed per their assigned treatment arm regardless of the treatment they actually received.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Insulin Lispro Low Mixture | Change in the HbA1c Concentration From Baseline to 12 Weeks Endpoint | -1.12 percentage of HbA1c |
| Insulin Glargine+Insulin Lispro | Change in the HbA1c Concentration From Baseline to 12 Weeks Endpoint | -1.01 percentage of HbA1c |
p-value: 0.1858Mixed Models Analysis
Secondary
Change in Weight From Baseline to 12 Weeks and 24 Weeks
The least squares (LS) mean was estimated from a mixed-effects model with repeated measures (MMRM) that included baseline weight as a covariate, treatment, country, baseline glycosylated hemoglobin A1c (HbA1c) stratification level, week of visit, and the treatment-by-week interaction as fixed effects, and participant and error as random effects.
Time frame: Baseline, 12 weeks, 24 weeks
Population: Safety population: randomized participants who took at least 1 dose of study drug and had evaluable body weight data at the specified time points.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Insulin Lispro Low Mixture | Change in Weight From Baseline to 12 Weeks and 24 Weeks | Change at 24 weeks (n=219, 217) | 1.13 kilograms (kg) |
| Insulin Lispro Low Mixture | Change in Weight From Baseline to 12 Weeks and 24 Weeks | Change at 12 weeks (n=224, 225) | 0.54 kilograms (kg) |
| Insulin Glargine+Insulin Lispro | Change in Weight From Baseline to 12 Weeks and 24 Weeks | Change at 12 weeks (n=224, 225) | 0.34 kilograms (kg) |
| Insulin Glargine+Insulin Lispro | Change in Weight From Baseline to 12 Weeks and 24 Weeks | Change at 24 weeks (n=219, 217) | 0.50 kilograms (kg) |
p-value: 0.2833Mixed Models Analysis
p-value: 0.0176Mixed Models Analysis
Secondary
Daily Insulin Dose: Total, Basal, and Prandial at 12 Weeks and 24 Weeks
Time frame: 12 weeks, 24 weeks
Population: Intention-to-treat population (ITT): randomized participants who received at least 1 dose of study drug and had dosing data at the specified time points. Participants were analyzed per their assigned treatment arm regardless of the treatment they actually received.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin Lispro Low Mixture | Daily Insulin Dose: Total, Basal, and Prandial at 12 Weeks and 24 Weeks | Total Insulin Dose at 12 Weeks (n=224, 224) | 51.2 international units (IU) | Standard Deviation 23.6 |
| Insulin Lispro Low Mixture | Daily Insulin Dose: Total, Basal, and Prandial at 12 Weeks and 24 Weeks | Total Insulin Dose at 24 Weeks LOCF (n=236, 240) | 53.1 international units (IU) | Standard Deviation 24.6 |
| Insulin Lispro Low Mixture | Daily Insulin Dose: Total, Basal, and Prandial at 12 Weeks and 24 Weeks | Basal Insulin Dose at 12 Weeks (n=224, 224) | 38.4 international units (IU) | Standard Deviation 17.7 |
| Insulin Lispro Low Mixture | Daily Insulin Dose: Total, Basal, and Prandial at 12 Weeks and 24 Weeks | Basal Insulin Dose at 24 Weeks LOCF (n=236, 240) | 39.8 international units (IU) | Standard Deviation 18.45 |
| Insulin Lispro Low Mixture | Daily Insulin Dose: Total, Basal, and Prandial at 12 Weeks and 24 Weeks | Prandial Insulin Dose at 12 Weeks (n=224, 224) | 12.8 international units (IU) | Standard Deviation 5.9 |
| Insulin Lispro Low Mixture | Daily Insulin Dose: Total, Basal, and Prandial at 12 Weeks and 24 Weeks | Prandial Insulin Dose at 24 Weeks LOCF(n=236, 240) | 13.3 international units (IU) | Standard Deviation 6.15 |
| Insulin Glargine+Insulin Lispro | Daily Insulin Dose: Total, Basal, and Prandial at 12 Weeks and 24 Weeks | Prandial Insulin Dose at 12 Weeks (n=224, 224) | 12.1 international units (IU) | Standard Deviation 5.1 |
| Insulin Glargine+Insulin Lispro | Daily Insulin Dose: Total, Basal, and Prandial at 12 Weeks and 24 Weeks | Total Insulin Dose at 12 Weeks (n=224, 224) | 49.2 international units (IU) | Standard Deviation 20.89 |
| Insulin Glargine+Insulin Lispro | Daily Insulin Dose: Total, Basal, and Prandial at 12 Weeks and 24 Weeks | Basal Insulin Dose at 24 Weeks LOCF (n=236, 240) | 37.4 international units (IU) | Standard Deviation 18.76 |
| Insulin Glargine+Insulin Lispro | Daily Insulin Dose: Total, Basal, and Prandial at 12 Weeks and 24 Weeks | Total Insulin Dose at 24 Weeks LOCF (n=236, 240) | 50.8 international units (IU) | Standard Deviation 21.96 |
| Insulin Glargine+Insulin Lispro | Daily Insulin Dose: Total, Basal, and Prandial at 12 Weeks and 24 Weeks | Prandial Insulin Dose at 24 Weeks LOCF(n=236, 240) | 13.5 international units (IU) | Standard Deviation 6.46 |
| Insulin Glargine+Insulin Lispro | Daily Insulin Dose: Total, Basal, and Prandial at 12 Weeks and 24 Weeks | Basal Insulin Dose at 12 Weeks (n=224, 224) | 37.1 international units (IU) | Standard Deviation 18.34 |
Secondary
Glycemic Variability From the 7-point Self-Monitored Blood Glucose (SMBG) Profiles at 12 Weeks and 24 Weeks
The 7-point SMBG profile was calculated as the average blood glucose concentration across the 7 pre-specified time points in a day that was then averaged over 3 non-consecutive days in the 2 weeks prior to the 12 week visit and 24 week visit. Glycemic variability was calculated as the standard deviation of the 7-point SMBG profiles. Standard deviation was first calculated for each day and then averaged over 3 non-consecutive days for each visit. The least squares (LS) mean was estimated from mixed-effects model with repeated measures that included the baseline value of the variable as a covariate, treatment, country, baseline glycosylated hemoglobin A1c (HbA1c)stratification level, week of visit, and treatment-by-week interaction as fixed effects, and participant and error as random effects.
Time frame: 12 weeks, 24 weeks
Population: Intention-to-treat population (ITT): randomized participants who received at least 1 dose of study drug and had SMBG glycemic variability data at the specified time points. Participants were analyzed per their assigned treatment arm regardless of the treatment they actually received.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Insulin Lispro Low Mixture | Glycemic Variability From the 7-point Self-Monitored Blood Glucose (SMBG) Profiles at 12 Weeks and 24 Weeks | SMBG glycemic variability, 12 weeks (n=220, 221) | 2.12 millimoles/liter (mmol/L) |
| Insulin Lispro Low Mixture | Glycemic Variability From the 7-point Self-Monitored Blood Glucose (SMBG) Profiles at 12 Weeks and 24 Weeks | SMBG glycemic variability, 24 weeks (n=216, 216) | 2.03 millimoles/liter (mmol/L) |
| Insulin Glargine+Insulin Lispro | Glycemic Variability From the 7-point Self-Monitored Blood Glucose (SMBG) Profiles at 12 Weeks and 24 Weeks | SMBG glycemic variability, 12 weeks (n=220, 221) | 2.13 millimoles/liter (mmol/L) |
| Insulin Glargine+Insulin Lispro | Glycemic Variability From the 7-point Self-Monitored Blood Glucose (SMBG) Profiles at 12 Weeks and 24 Weeks | SMBG glycemic variability, 24 weeks (n=216, 216) | 1.99 millimoles/liter (mmol/L) |
Secondary
Insulin Treatment Satisfaction Questionnaire (ITSQ) Score at 24 Weeks
ITSQ: validated instrument containing 22 items which are measured on a 7-point scale: 1 (no bother at all) to 7 (a tremendous bother) used to assess insulin treatment satisfaction. Items are divided into 5 domains: Inconvenience of Regimen (5 items: domain score range 5 to 35), Lifestyle Flexibility (3 items: domain score range 3 to 21), Glycemic Control (3 items: domain score range 3 to 21), Hypoglycemic Control (5 items: domain score range 5 to 35), Insulin Delivery Device (6 items: domain score range 6 to 42) lower scores reflect better outcome. ITSQ Total Overall Score ranged from 22 to 154. Raw domain scores transformed on 0-100 scale, where transformed domain score = 100×\[(7-raw domain score)/6\]. Higher scores indicate better treatment satisfaction. Least squares (LS) mean estimated from analysis of covariance (ANCOVA) model that included baseline score as covariate and treatment, glycosylated hemoglobin A1c (HbA1c) stratum, and country as fixed effects.
Time frame: 24 weeks
Population: Randomized participants who received at least 1 dose of study drug and had ITSQ scores at 24 weeks. Last observation carried forward (LOCF).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Insulin Lispro Low Mixture | Insulin Treatment Satisfaction Questionnaire (ITSQ) Score at 24 Weeks | 80.91 units on a scale |
| Insulin Glargine+Insulin Lispro | Insulin Treatment Satisfaction Questionnaire (ITSQ) Score at 24 Weeks | 81.84 units on a scale |
Secondary
Number of Participants Who Achieve a Target HbA1c Concentration of Less Than 7% or Less Than or Equal to 6.5% at 24 Weeks
Time frame: 24 weeks
Population: Intention-to-treat population (ITT): randomized participants who received at least 1 dose of study drug and had HbA1c data at 24 weeks. Participants were analyzed per their assigned treatment arm regardless of the treatment they actually received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Insulin Lispro Low Mixture | Number of Participants Who Achieve a Target HbA1c Concentration of Less Than 7% or Less Than or Equal to 6.5% at 24 Weeks | HbA1c <7% | 76 participants |
| Insulin Lispro Low Mixture | Number of Participants Who Achieve a Target HbA1c Concentration of Less Than 7% or Less Than or Equal to 6.5% at 24 Weeks | HbA1c <=6.5% | 36 participants |
| Insulin Glargine+Insulin Lispro | Number of Participants Who Achieve a Target HbA1c Concentration of Less Than 7% or Less Than or Equal to 6.5% at 24 Weeks | HbA1c <7% | 66 participants |
| Insulin Glargine+Insulin Lispro | Number of Participants Who Achieve a Target HbA1c Concentration of Less Than 7% or Less Than or Equal to 6.5% at 24 Weeks | HbA1c <=6.5% | 31 participants |
p-value: 0.3588Fisher Exact
p-value: 0.5958Fisher Exact
Secondary
Perceptions About Medications-Diabetes 21 (PAM-D21) Questionnaire Score at 24 Weeks
PAM-D21 is a validated questionnaire consisting of 21 items to assess a participant's perceptions about their diabetes treatment regimens and perceived emotional and physical side-effects. The PAM-D21 consists of 4 subscales: Convenience/Flexibility (items 1 to 3); Perceived Effectiveness (items 4 to 6); Emotional Effects (items 7 to 11); and Physical Effects (items 12 to 21). Item scores range from 1 (none of the time) to 4 (all of the time). Subscale scores were linearly transformed to a 0-100, with higher score corresponds to better perceptions about diabetes medications. The least squares (LS) mean was estimated from an analysis of covariance (ANCOVA) model that included baseline score as a covariate and treatment, glycosylated hemoglobin A1c (HbA1c) stratum, and country as fixed effects.
Time frame: 24 weeks
Population: Randomized participants who received at least 1 dose of study drug and had PAM-D21 scores at 24 weeks.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Insulin Lispro Low Mixture | Perceptions About Medications-Diabetes 21 (PAM-D21) Questionnaire Score at 24 Weeks | Convenience/Flexibility (n= 231, 230) | 83.90 units on a scale |
| Insulin Lispro Low Mixture | Perceptions About Medications-Diabetes 21 (PAM-D21) Questionnaire Score at 24 Weeks | Perceived Effectiveness (n=231, 230) | 76.78 units on a scale |
| Insulin Lispro Low Mixture | Perceptions About Medications-Diabetes 21 (PAM-D21) Questionnaire Score at 24 Weeks | Emotional Effects (n=231, 230) | 81.84 units on a scale |
| Insulin Lispro Low Mixture | Perceptions About Medications-Diabetes 21 (PAM-D21) Questionnaire Score at 24 Weeks | Physical Effects (n=231, 228) | 87.89 units on a scale |
| Insulin Glargine+Insulin Lispro | Perceptions About Medications-Diabetes 21 (PAM-D21) Questionnaire Score at 24 Weeks | Physical Effects (n=231, 228) | 89.04 units on a scale |
| Insulin Glargine+Insulin Lispro | Perceptions About Medications-Diabetes 21 (PAM-D21) Questionnaire Score at 24 Weeks | Convenience/Flexibility (n= 231, 230) | 84.13 units on a scale |
| Insulin Glargine+Insulin Lispro | Perceptions About Medications-Diabetes 21 (PAM-D21) Questionnaire Score at 24 Weeks | Emotional Effects (n=231, 230) | 81.86 units on a scale |
| Insulin Glargine+Insulin Lispro | Perceptions About Medications-Diabetes 21 (PAM-D21) Questionnaire Score at 24 Weeks | Perceived Effectiveness (n=231, 230) | 78.76 units on a scale |
Secondary
The Number of Participants With a Hypoglycemic Episodes (Incidence)
A hypoglycemic episode was defined as an event associated with 1) reported signs and symptoms of hypoglycemia, and/or 2) a documented blood glucose (BG) concentration of \<= 70 milligrams per deciliter \[mg/dL, 3.9 millimoles per liter (mmol/L)\].
Time frame: Baseline through 24 weeks
Population: Safety population: randomized participants who took at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Lispro Low Mixture | The Number of Participants With a Hypoglycemic Episodes (Incidence) | 144 participants |
| Insulin Glargine+Insulin Lispro | The Number of Participants With a Hypoglycemic Episodes (Incidence) | 150 participants |
Secondary
The Number of Participants With Severe Hypoglycemic Episodes
The number of participants who had a severe hypoglycemic episode anytime during the study. Severe hypoglycemia was defined as any event in which the participant required the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions.
Time frame: Baseline through 24 weeks
Population: Safety population: randomized participants who took at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Lispro Low Mixture | The Number of Participants With Severe Hypoglycemic Episodes | 2 participants |
| Insulin Glargine+Insulin Lispro | The Number of Participants With Severe Hypoglycemic Episodes | 0 participants |
Secondary
The Rate of Hypoglycemic Episodes
The hypoglycemia rate per 30 days was calculated as the number of episodes reported for the interval between visits and during the study divided by the number of days in the given interval and multiplied by 30.
Time frame: Baseline through 24 weeks
Population: Safety population: randomized participants who took at least 1 dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Lispro Low Mixture | The Rate of Hypoglycemic Episodes | 1.07 hypoglycemic episodes per 30 day period | Standard Deviation 1.181 |
| Insulin Glargine+Insulin Lispro | The Rate of Hypoglycemic Episodes | 1.36 hypoglycemic episodes per 30 day period | Standard Deviation 2.172 |