Comparison of the Efficacy and Safety of Two Insulin Intensification Strategies

Study Overview
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Brief Summary
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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.

Official Title
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Comparison of Twice-Daily Insulin Lispro Low Mixture Versus Once-Daily Basal Insulin Glargine and Once-Daily Prandial Insulin Lispro as Insulin Intensification Strategies in Patients With Type 2 Diabetes Who Have Inadequate Glycemic Control on Basal Insulin Glargine and Metformin and/or Pioglitazone

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Insulin Lispro Low Mixture (LM)
* Drug: Insulin Glargine
* Drug: Prandial Insulin Lispro


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Insulin lispro low mixture (LM)<br>Two daily injections (breakfast and dinner) of insulin lispro mix 75/25 | Drug: Insulin Lispro Low Mixture (LM)<br>* Participant-dependent dose, administered subcutaneously for 24 weeks<br>* Other names: Humalog Mix75/25 (75% insulin lispro protamine suspension and 25% insulin lispro injection);|
| Active Comparator: Insulin glargine+insulin lispro<br>Once-daily (bedtime) basal insulin glargine and once-daily (before the main meal with the highest average 2-hour postprandial blood glucose concentration) prandial insulin lispro | Drug: Insulin Glargine<br>* Participant-dependent dose, administered subcutaneously for 24 weeks<br>Drug: Prandial Insulin Lispro<br>* Participant-dependent dose, administered subcutaneously for 24 weeks<br>* Other names: LY275585;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline, 24 weeks | 
| 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. | Baseline, 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline, 12 weeks | 
| 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 | 
| 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. | Baseline, 12 weeks, and 24 weeks | 
| 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. | 12 weeks, 24 weeks | 
| 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. | 12 weeks, 24 weeks | 
| 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 | 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. | Baseline, 12 weeks, 24 weeks | 
| 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)]. | Baseline through 24 weeks | 
| 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. | 24 weeks | 
| 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. | 24 weeks | 
| 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. | Baseline through 24 weeks | 
| 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. | Baseline through 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metabolic Diseases, Diabetes Mellitus, Type 2, Glargine, Diabetes Mellitus, Insulin LISPRO, Insulin