Study of Insulin Lispro in Participants With Inadequately Controlled Type 2 Diabetes

Study Overview
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Brief Summary
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Evidence regarding optimal methods of insulin dose adjustment is lacking in the literature. The purpose of this study is to evaluate the efficacy and safety of two approaches to escalate prandial insulin therapy in participants with type 2 diabetes mellitus not achieving adequate glycemic control on basal insulin.

Detailed Description
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Participants who enter the study and are already taking insulin glargine with a screening HbA1c >7.0% will be randomized to one of two treatment arms. Both arms will add prandial insulin to existing basal insulin therapy.

Official Title
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Two Approaches to Escalate Lispro Therapy in Patients With Type 2 Diabetes Mellitus Not Achieving Adequate Glycemic Control on Basal Insulin Therapy and Oral Agents Alone (AUTONOMY)

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Insulin lispro
* Drug: Glargine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have type 2 diabetes Have been treated for at least 90 days with insulin glargine, neutral protamine Hagedorn (NPH), or detemir in combination with oral antihyperglycemic agents as monotherapy, dual, or triple therapy [sulfonylurea, meglitinide, metformin, pioglitazone, or dipeptidyl peptidase-4 (DPP-4) inhibitor] and in the opinion of the investigator requires further intensification of therapy Are treated with insulin glargine, NPH, or detemir at least 20 units per day (U/day) at enrollment Have an glycated hemoglobin (HbA1c) value greater than 7.0% and less than or equal to 12.0% according to the central laboratory at screening Capable of and willing to do the following: inject insulin with a prefilled pen, perform self blood glucose monitoring and record keeping as required by this protocol, as determined by the investigator Have given written informed consent to participate in this study in accordance with local regulations Exclusion Criteria: Prior rapid- or short-acting insulin therapy: participants receiving scheduled long-term short-acting or rapid-acting or premixed insulin therapy within the past 6 months will not be eligible to participate in the study. Participants who have previously received short- or rapid-acting insulin as part of short-term insulin therapy (during gestational diabetes, during an acute hospitalization or illness) or occasional use will be allowed to participate in this study. Occasional use (e.g., used to treat acute hyperglycemia) shall be defined as less than daily administration of not more than 1 dose per day of short- or rapid-acting insulin Concomitant medications: glucagon-like peptide-1 (GLP-1) receptor agonist, alpha-glucosidase inhibitor, or rosiglitazone use concurrently or within 3 months prior to entry into the study Severe hypoglycemia: have had more than one episode of severe hypoglycemia (defined as requiring assistance of a third party due to disabling hypoglycemia) within 6 months prior to entry into the study Excessive insulin resistance: received a total daily dose of insulin greater than 2.0 units per kilogram (U/kg) at the time of randomization Morbid obesity: defined as a body mass index greater than or equal to 45 kilograms per square meter (kg/m²) Malignancy: have active or untreated malignancy, or have been in remission from clinically significant malignancy (other than basal cell or squamous cell skin cancer) for less than 5 years Cardiovascular: have cardiac disease with functional status that is New York Heart Association Class III or IV (see New York Heart Association Cardiac Disease Classifications) or have Congestive Heart Failure (CHF) requiring pharmacologic treatment or, in the investigator's opinion, have severe dependent edema (i.e., edema of the feet or ankles) or have any condition associated with hypoperfusion, hypoxemia, dehydration, or sepsis Renal: have a history of renal transplantation or are currently receiving renal dialysis or have serum creatinine greater than or equal to 2 milligrams per deciliter (mg/dL) if not on metformin Hepatic: have obvious clinical signs or symptoms of liver disease, acute or chronic hepatitis, or alanine aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT) greater than 3 times the upper limit of the reference range as defined by the central laboratory Hematologic: have known hemoglobinopathy or chronic anemia or other known blood disorder Reproductive:(for women) are pregnant or intend to become pregnant during the course of the study; are sexually active women of childbearing potential not actively practicing birth control by a method determined by the investigator to be medically acceptable; or are breastfeeding Allergy: have known allergy to insulin lispro, insulin glargine, or excipients contained in these products Glucocorticoid therapy: receiving chronic (lasting longer than 2 weeks) systemic glucocorticoid therapy (excluding topical and inhaled preparations) or have received such therapy within 2 weeks immediately before screening Adherence to protocol: have any other condition (including known drug or alcohol abuse or psychiatric disorder) that precludes the participant from following and completing the protocol Prior participation: are currently enrolled in, or have participated in, an interventional medical, surgical, or pharmaceutical drug or device or off-label use study (an investigational study in which a medical or surgical treatment was given) within 30 days prior to entry into the study, or persons who have previously completed or withdrawn from this study (after having signed the informed consent document). Participants may be ineligible if they are concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study Non-approved drug: have been treated with a drug within the last 30 days that has not received regulatory approval at the time of study entry

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 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: 3 Day Algorithm<br>Basal insulin glargine plus mealtime bolus insulin lispro titrated based on blood glucose readings from the past three days. (Sites were assigned to Study A and Study B according to an allocation plan that was pre-specified before initiation of Study A and Study B) | Drug: Insulin lispro<br>* Administered subcutaneously, up to three times daily for 24 weeks<br>* Other names: LY275585;Drug: Glargine<br>* Administered subcutaneously, dosage determined by investigator once daily for 24 weeks<br>|
| Experimental: Daily Algorithm<br>Basal insulin glargine plus mealtime bolus insulin lispro titrated based on blood glucose readings from the previous day. (Sites were assigned to Study A and Study B according to an allocation plan that was pre-specified before initiation of Study A and Study B) | Drug: Insulin lispro<br>* Administered subcutaneously, up to three times daily for 24 weeks<br>* Other names: LY275585;Drug: Glargine<br>* Administered subcutaneously, dosage determined by investigator once daily for 24 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to 24 Week Endpoint in Glycated Hemoglobin (HbA1c) | The change from baseline to 24 weeks in the percentage of HbA1c in plasma. The Least Squares (LS) mean was estimated from a mixed-effects model with repeated measures (MMRM) that included the independent variables: fixed effects for treatment, country, sulfonylurea/meglitinide use, visit, treatment by visit interaction with baseline HbA1c as a covariate. | Baseline, 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Glycated Hemoglobin (HbA1c) Target Values | Percentage of participants who achieved HbA1c levels of ≤7.0% or ≤6.5%. | 24-week endpoint | 
| Percentage of Participants ≥65 Years of Age Achieving Glycated Hemoglobin (HbA1c) Target Concentration | Percentage of participants ≥65 years of age achieving HbA1c target concentration of ≤7.0% or ≤6.5%. | 24-week endpoint | 
| Change From Baseline to 24 Week Endpoint in Body Weight | Body weight was measured twice at each indicated visit and the average of the 2 measurements was used for analyses. Least Squares (LS) mean calculated using mixed model repeating measure (MMRM) analysis that included baseline, treatment, country, sulfonylurea/meglitinide use, baseline glycated hemoglobin (HbA1c) strata (≤8% and >8%), visit and treatment-by-visit interaction . | Baseline, 24-weeks | 
| Time to Reach Glycated Hemoglobin (HbA1c) Target Values | Percentage of participants is the number of participants who achieved HbA1c target values of ≤6.5% or ≤7.0% during the specified time period divided by the total number of participants who did not discontinue from the study but had not reached HbA1c target at the beginning of the specified post baseline time period (≤100 days and ≥101 days). Participants who did not experience an outcome before discontinuation or completion of the study were censored using the date of discontinuation. Participants who were lost to follow up the date of discontinuation were considered to be the date of last contact. | Baseline through 24 weeks | 
| Change From Baseline to 24 Week Endpoint in Fasting Glucose | Least Squares (LS) mean calculated using mixed model repeating measure (MMRM) analysis that included baseline, treatment, country, sulfonylurea/meglitinide use, baseline glycated hemoglobin (HbA1c) strata (≤8% and >8%), visit and treatment-by-visit interaction. | Baseline, 24 weeks | 
| Change From Baseline to 24 Week Endpoint in Fasting Glucose in Participants ≥65 Years of Age | Least Squares (LS) mean calculated using mixed model repeating measure (MMRM) analysis that included baseline, treatment, country, sulfonylurea/meglitinide use, baseline glycated hemoglobin (HbA1c) strata (≤8% and >8%), visit and treatment-by-visit interaction. | Baseline, 24 weeks | 
| Change From Baseline to 24 Week Endpoint in 1,5-anhydroglucitol (1,5-AG) | Least Squares (LS) mean calculated using mixed model repeating measure (MMRM) analysis that included baseline treatment, country, sulfonylurea/meglitinide use, baseline glycated hemoglobin (HbA1c) strata (≤8% and >8%), visit and treatment-by-visit interaction. | Baseline, 24 weeks | 
| Change From Baseline to 24 Weeks in 7-Point Self-Monitored Blood Glucose (SMBG) Profile | 7-Point Self-Monitored Blood Glucose profiles are measures of blood glucose concentration taken 7 time a day at the morning pre-meal, morning 2-hours (HR) postprandial (PP), midday pre-meal, midday 2-hours post-meal, evening pre-meal, bedtime and 0300 hour (3 am). Each participant took measures over any 3 days and the average was calculated for each of the 7 time points. Least Squares (LS) mean calculated using mixed model repeating measure (MMRM) analysis that included baseline, treatment, country, sulfonylurea/meglitinide use, baseline glycated hemoglobin (HbA1c) strata (≤8% and >8%), visit and treatment-by-visit interaction. | Baseline, 24 weeks | 
| Daily Dose of Insulin: Total, Basal and Prandial (Bolus) | Total insulin was the sum of basal insulin (glargine) that was required to manage normal daily blood fluctuations and prandial insulin that was taken at meal time. Least Squares (LS) mean calculated using mixed model repeating measure (MMRM) analysis that included baseline, treatment, country, sulfonylurea/meglitinide use, baseline glycated hemoglobin (HbA1c) strata (≤8% and >8%), visit and treatment-by-visit interaction. | 24 weeks | 
| Daily Dose of Insulin Per Kilogram of Body Weight: Total, Basal and Prandial (Bolus) | Total insulin was the sum of basal insulin (glargine) that was required to manage normal daily blood fluctuations and prandial insulin that was taken at meal time. Total, basal and prandial amounts were then divided by the participant's body weight in kilograms (kg). Least Squares (LS) mean calculated using mixed model repeating measure (MMRM) analysis that included baseline, treatment, country, sulfonylurea/meglitinide use, baseline glycated hemoglobin (HbA1c) strata (≤8% and >8%), visit and treatment-by-visit interaction. | 24 weeks | 
| The Number of Participants With a Hypoglycemic Episode (Incidence) | A hypoglycemic episode was defined as any time a participant felt they were experiencing a sign or symptom that was associated with hypoglycemia, or had a blood glucose level of ≤70 milligram per deciliter [mg/dL, ≤3.9 millimoles per liter (mmol/L)] even if it was not associated with signs, symptoms or treatment (consistent with current American Diabetes Association 2005 guidelines). | Randomization through 24 weeks overall | 
| The Number of Participants ≥65 Years of Age With Hypoglycemic Episodes (Incidence) | A hypoglycemic episode in participants ≥ 65 years of age was defined as any time a participant felt they were experiencing a sign or symptom that was associated with hypoglycemia, or had a blood glucose level of ≤70 milligram per deciliter [mg/dL, ≤3.9 millimoles per liter (mmol/L)] even if it was not associated with signs, symptoms or treatment (consistent with current American Diabetes Association 2005 guidelines). | Randomization through 24 weeks overall | 
| The Rate of Hypoglycemic Episodes | The hypoglycemia rate per 30 days was calculated as the number of hypoglycemic episodes reported divided by the number of days at risk times 30. | Randomization through 24 weeks overall | 
| Percentage of Participants With Severe Hypoglycemic Episodes | Severe hypoglycemia is defined as an event requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. These episodes may be associated with sufficient neuroglycopenia to induce seizure or coma. Plasma glucose measurements may not be available during such an event, but neurological recovery attributable to the restoration of plasma glucose to normal is considered sufficient evidence that the event was induced by low plasma glucose. | Randomization up to 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 2 Diabetes, Insulin, Algorithms, Blood glucose levels