Efficacy Assessment of Insulin Glargine Versus LiraglutidE After Oral Agents Failure

Study Overview
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Brief Summary
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Primary objective: To demonstrate the superiority of insulin glargine over liraglutide in terms of percentage of patients reaching a Glycosylated Haemoglobin (HbA1c) < 7% at the end of the comparative period (24 weeks) in Type 2 diabetic patients failing lifestyle management and oral agents Secondary objectives of the comparative period (24 weeks): >To assess the effect of insulin glargine in comparison with liraglutide on: HbA1c level Percentage of patients whose HbA1c has decreased but remains >= 7% at the end of the comparative period Percentage of patients whose HbA1c has increased at the end of the comparative period Fasting Plasma Glucose (FPG) 7-point Plasma Glucose (PG) profiles Hypoglycemia occurrence Body weight Adverse events Objectives of the extension period (24 weeks): >To assess the effect of insulin glargine in patients not adequately controlled with liraglutide on: HbA1c level FPG 7-point PG profiles Hypoglycemia occurrence Body weight Adverse events

Detailed Description
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Maximum estimated study duration per patient: either 27 weeks (patients randomized to insulin glargine arm) or 51 weeks (patients randomized to liraglutide arm) broken down as follow: A 2-week of screening period, A 24-week comparative period, A 24-week extension period (only for patients treated with liraglutide, not adequately controlled at the end of the comparative period), A 1-week follow-up period

Official Title
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A 24-week, Multicenter, International, Randomized (1:1), Parallel-group, Open-label, Comparative Study of Insulin Glargine Versus Liraglutide in Insulin-naïve Patients With Type 2 Diabetes Treated With Oral Agents and Not Adequately Controlled, Followed by a 24-week Extension Period With Insulin Glargine for Patients Not Adequately Controlled With Liraglutide

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Insulin glargine
* Drug: Liraglutide
* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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Inclusion criteria (comparative period): Patients With Type 2 Diabetes diagnosed for at least 1 year, Treated with lifestyle interventions and metformin at the maximum tolerated dosage (with a minimum daily dosage of 1g), either alone or in combination with an oral insulin secretagogue (sulfonylurea, glinide or DiPeptidyl Peptidase IV inhibitor), for more than 3 months, 7.5% < HbA1c <= 12%, Body Mass Index (BMI) between 25 and 40 kg/m2 inclusively, Ability and willingness to perform PG (Plasma Glucose) self monitoring using the sponsor-provided glucose meter and to complete the patient diary, Willingness and ability to comply with the study protocol, Signed informed consent obtained prior to any study procedure. Inclusion criteria (extension period): Patients treated with liraglutide (at the maximal tolerated dosage), having a mean FPG ≥ 250 mg/dL at visit 10 (Week 12) or visit 11 (Week 18), or a HbA1c≥ 7% at visit 12 (Week 24) Dosage of metformin compliant with the inclusion criteria of visit 1 (i.e. maximum tolerated dosage, with a minimum daily dosage of 1g), and maintained stable during the comparative period. Exclusion criteria: Previous treatment with Glucagon Like Peptide-1 analogues or insulin in the past year (except in case of temporary treatment for gestational diabetes, surgery, hospitalization...), Treatment with thiazolidinediones or α-Glucosidases inhibitors within 3 months prior to study entry, Diabetes other than Type 2 diabetes (e.g. secondary to pancreatic disorders, drug or chemical agents intake), Pregnant women (women of childbearing potential must have a negative pregnancy test at study entry and a medically approved contraceptive method), Lactating women, Hospitalized patients (except hospitalization for routine diabetes check-up), Active proliferative retinopathy, as defined by a photocoagulation or vitrectomy occurrence in the 6 months prior to study entry, or any other unstable (rapidly progressing) retinopathy that may require photocoagulation or surgical treatment during the study, documented by a retina examination within 2 years prior to study entry, Impaired renal function (creatinine clearance < 60 mL/mn), Impaired hepatic function (Alanine Aminotransferase, Aspartate Aminotransferase 2.5 times the upper limit of normal range), Personal or family history of medullary thyroid carcinoma, Multiple endocrine neoplasia syndrome type 2, Severe gastro-intestinal disease (including inflammatory bowel disease or diabetic gastroparesis), Congestive heart failure, History of acute pancreatitis, Treatment with corticosteroids with potential systemic action for more than 10 days within 3 months prior to study entry, Alcohol or drug abuse in the past 5 years, History of sensitivity to the study drugs or to drugs with a similar chemical structure. Night shift worker, Presence of any condition (medical, psychological, social or geographical), current or anticipated that would compromise the patients safety or limit the patient successful participation in the study, Participation in a clinical trial (drug or device) within 3 months prior to study entry, Refusal or inability to give informed consent to participate in the study, Patient is the Investigator or any sub-Investigator, research assistant, pharmacist, study coordinator, other staff or relative thereof directly involved in the conduct of the protocol. Additional exclusion criteria for the extension period: Treatment with oral antidiabetic drugs other than metformin and patient's usual sulfonylurea if any, or with insulin during the comparative period (except in case of an emergency, for a period of time less than 7 days), Treatment with corticosteroids with potential systemic action within the last 3 months of the comparative period. History of sensitivity to insulin glargine.

Ages Eligible for Study
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Minimum Age: 35 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 Glargine<br>Insulin glargine administered once a day, in the morning or in the evening, at the most convenient time. The time of injection, once chosen was to remain unchanged during the whole duration of the study. The starting dose was 0.2 Unit per kilogram of body weight or 10 Units. Patients were empowered to adjust their insulin doses, under strict investigator's supervision. Insulin titration (by 2 or 4 Units) was done every 3 days according to the median value of Fasting Plasma Glucose (FPG) of the last 3 days. The goal was to achieve 70 < FPG ≤ 100 mg/dL (3.9 < FPG ≤ 5.5 mmol/L). Minor deviations from the titration scheme could be allowed, based on Investigator's judgment and patient's situation. | Drug: Insulin glargine<br>* 100 Units/mL solution for injection in a pre-filled SoloStar pen<br>* Other names: Lantus®;Drug: Metformin<br>* Metformin was a background treatment, mandatory for each patient randomized in the study (at the minimum dose of 1g/day). It was not supplied by the sponsor.<br>|
| Active Comparator: Liraglutide<br>Liraglutide administered once a day, in the morning or in the evening, at the most convenient time. The time of injection , once chosen was to remain unchanged during the whole duration of the study. The dose was 0.6 mg/day during the first week, 1.2 mg/day during the second week and 1.8 mg/day until week 24. The dose might be decreased to 1.2 mg for safety reasons (e.g. gastro-intestinal tolerability), based on Investigator's judgment. | Drug: Liraglutide<br>* 6 mg/mL solution for injection in a 3-mL pre-filled pen (18mg)<br>* Other names: Victoza®;Drug: Metformin<br>* Metformin was a background treatment, mandatory for each patient randomized in the study (at the minimum dose of 1g/day). It was not supplied by the sponsor.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients Whose Glycosylated Haemoglobin (HbA1c) <7% at the End of the Comparative Period | The value at the end of the comparative period was defined as the last available HbA1c value measured during the comparative period plus 14 days after the last dose of Investigational Product (i.e. last-observation-carried-forward [LOCF] value). | week 12, week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients Whose Glycosylated Haemoglobin (HbA1c) Has Decreased But Remains ≥7% at the End of the Comparative Period | Percentage of patients with: * HbA1c value at end of the comparative period (LOCF) lower than HbA1c baseline value AND * HbA1c value at end of the comparative period (LOCF) ≥7% | baseline (week -2), week 12, week 24 | 
| Percentage of Patients Whose Glycosylated Haemoglobin (HbA1c) Has Increased at the End of the Comparative Period | Percentage of patients with HbA1c value at end of the comparative period (LOCF) higher than HbA1c baseline value | baseline (week -2), week 12, week 24 | 
| Glycosylated Haemoglobin (HbA1c): Change From Baseline to the End of Comparative Period | Change in HbA1C from baseline to the last observation carried forward (LOCF) measured during the comparative period = LOCF value - baseline value | baseline (week -2), week 12, week 24 | 
| Glycosylated Haemoglobin (HbA1c): Change From Beginning to the End of the Extension Period | Change in HbA1C from beginning of the extension period (week 24) to the last observation carried forward (LOCF) measured during the extension period = LOCF value - week 24 value | week 24, week 36, week 48 | 
| Percentage of Patients Whose Glycosylated Haemoglobin (HbA1c) <7% at the End of the Extension Period | Value at the end of the extension period defined as last available HbA1c value measured during the extension period (i.e. last observation carried forward (LOCF) value) | week 36, week 48 | 
| Self-Monitored Fasting Plasma Glucose (SMFPG) Measurements: Change From Baseline to the End of the Comparative Period | SMFPG = mean value of Self-Monitored Fasting Plasma Glucose measurements over 3 consecutive days in the week before each visit Value at the end of the comparative period defined as last available value during the comparative period (i.e. last-observation-carried-forward [LOCF] value) Change = LOCF value - baseline value | baseline (week 0), week 6, week 12, week 18, week 24 | 
| Self-Monitored Fasting Plasma Glucose (SMFPG) Measurements: Change From Beginning to the End of the Extension Period | SMFPG = mean value of Self-Monitored Fasting Plasma Glucose measurements over 3 consecutive days in the week before each visit Value at the end of the extension period defined as last available value during the extension period (i.e. last-observation-carried-forward [LOCF] value) Change = LOCF value - week 24 value | week 24, week 30, week 36, week 48 | 
| Self-Monitored 7-point Plasma Glucose (PG) Profile: Change From Baseline to the End of the Comparative Period | Self-monitored 7-point plasma glucose profiles (before and 2 hours after the start of breakfast, lunch and dinner, and at bedtime) recorded on 3 consecutive days in the week before each visit Value at the end of the comparative period defined as last available value during the comparative period (i.e. last-observation-carried-forward [LOCF] value) Change = LOCF value - baseline value | baseline (week 0), week 12, week 24 | 
| Self-Monitored 7-point Plasma Glucose (PG) Profile: Change From Beginning to the End of the Extension Period | Self-monitored 7-point plasma glucose profiles (before and 2 hours after the start of breakfast, lunch and dinner, and at bedtime) recorded on 3 consecutive days in the week before each visit Value at the end of the extension period defined as last available value during the extension period (i.e. last-observation-carried-forward [LOCF] value) Change = LOCF value - week 24 value | week 24, week 36, week 48 | 
| Body Weight: Change From Baseline to the End of the Comparative Period | Change = Last weight value measured during the comparative period (LOCF value) - weight value at baseline | baseline (week 0), week 2, week 6, week 12, week 18, week 24 | 
| Body Weight: Change From Beginning to End of the Extension Period | Change = Last weight value measured during the extension period (LOCF value) - weight value at beginning of the Extension Period (Week 24) | week 24, week 30, week 36, week 48 | 
| Daily Dose of Insulin Glargine |  | week 1, week 2, week 6, week 12, week 24 | 
| Daily Dose of Liraglutide |  | week 1, week 2, week 6, week 12, week 24 | 
| Daily Dose of Insulin Glargine Administered During the Extension Period |  | week 30, week 36, week 48 | 
| Hypoglycemia Occurence: Number of Patients With at Least One Episode of Symptomatic / Severe Symptomatic Hypoglycemia During the Comparative Period | Symptomatic hypoglycemia was defined as an event with clinical symptoms that were considered to result from hypoglycemia. Severe symptomatic hypoglycemia was defined as an event with clinical symptoms that were considered to result from hypoglycemia, requiring the assistance of another person for active administration of carbohydrate, glucagon or other countermeasure because the patient could not treat him/herself due to acute neurological impairment directly resulting from the hypoglycemia (assistance by another person when the patient could have treated him/herself was not considered as requiring assistance)and one of the following criteria: The event was associated with a measured PG level < 36 mg/dL (2 mmol/L), Or, in absence of PG value, the event was associated with neurological recovery attributable to the restoration of PG to normal, after oral carbohydrate, intravenous glucose or glucagon administration. | all across the comparative period (from week 0 to week 24) | 
| Hypoglycemia Occurence: Number of Patients With at Least One Episode of Symptomatic / Severe Symptomatic Hypoglycemia During the Extension Period | Symptomatic hypoglycemia was defined as an event with clinical symptoms that were considered to result from hypoglycemia. Severe symptomatic hypoglycemia was defined as an event with clinical symptoms that were considered to result from hypoglycemia, requiring the assistance of another person for active administration of carbohydrate, glucagon or other countermeasure because the patient could not treat him/herself due to acute neurological impairment directly resulting from the hypoglycemia (assistance by another person when the patient could have treated him/herself was not considered as requiring assistance)and one of the following criteria: The event was associated with a measured PG level < 36 mg/dL (2 mmol/L), Or, in absence of PG value, the event was associated with neurological recovery attributable to the restoration of PG to normal, after oral carbohydrate, intravenous glucose or glucagon administration. | all across the extension period (from week 24 to week 48) |