Efficacy Assessment of Insulin Glargine Versus LiraglutidE After Oral Agents Failure (EAGLE)

Sanofi

Status and phase: Completed; Phase 4

Conditions: Diabetes Mellitus, Type 2

Treatments: Drug: Liraglutide; Drug: Insulin glargine; Drug: Metformin

Study type: Interventional

Funder types: Industry

Identifiers

NCT01117350

LANTU_C_03680

U1111-1116-9684 (Other Identifier)

2010-018437-21 (EudraCT Number)

Details and patient eligibility

About

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

Full description

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

Enrollment: 978 patients

Sex: All

Ages: 35 to 75 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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978 participants in 2 patient groups

Insulin Glargine

Experimental group

Description:

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.

Treatment:

Drug: Insulin glargine

Drug: Metformin

Liraglutide

Active Comparator group

Description:

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.

Treatment:

Drug: Metformin

Drug: Liraglutide