Efficacy Assessment of Insulin Glargine Versus LiraglutidE After Oral Agents Failure

Diabetes Mellitus, Type 2 Clinical Trial

— EAGLE  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01117350
• Other study ID #: LANTU_C_03680
• Secondary ID: 2010-018437-21U1
• Status: Completed
• Phase: Phase 4
• First received: May 4, 2010
• Last updated: March 5, 2014
• Start date: July 2010
• Est. completion date: March 2013

Study information

• Verified date: March 2014
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Health authority: Czech Republic: State Institute for Drug ControlUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 978
• Est. completion date: March 2013
• Est. primary completion date: October 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 35 Years to 75 Years

Eligibility

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 a-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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 2

Intervention

Drug:
• Insulin glargine
100 Units/mL solution for injection in a pre-filled SoloStar pen
• Liraglutide
6 mg/mL solution for injection in a 3-mL pre-filled pen (18mg)
• Metformin
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.

Locations

Country	Name	City	State
Austria	Investigational Site Number 040-006	Salzburg
Austria	Investigational Site Number 040-007	Salzburg
Austria	Investigational Site Number 040-003	Stockerau
Austria	Investigational Site Number 040-001	Vienna
Austria	Investigational Site Number 040-002	Vienna
Austria	Investigational Site Number 040-004	Vienna
Austria	Investigational Site Number 040-005	Vienna
Brazil	Investigational Site Number 076-004	Belém
Brazil	Investigational Site Number 076-001	Fortaleza
Brazil	Investigational Site Number 076-006	Fortaleza
Brazil	Investigational Site Number 076-007	Fortaleza
Brazil	Investigational Site Number 076-005	Marília
Brazil	Investigational Site Number 076-002	São Paulo
Canada	Investigational Site Number 124-003	Mississauga
Canada	Investigational Site Number 124-001	Montreal
Canada	Investigational Site Number 124-006	Montreal
Canada	Investigational Site Number 124-004	Toronto
Canada	Investigational Site Number 124-008	Vancouver
Canada	Investigational Site Number 124-007	Victoria
Czech Republic	Investigational Site Number 203001	Hradec Kralove
Czech Republic	Investigational Site Number 203003	Krnov
Czech Republic	Investigational Site Number 203005	Kromeriz
Czech Republic	Investigational Site Number 203002	Olomouc
Czech Republic	Investigational Site Number 203006	Praha 5
Finland	Investigational Site Number 246003	Harjavalta
Finland	Investigational Site Number 246001	Kuopio
Finland	Investigational Site Number 246002	Oulu
Finland	Investigational Site Number 246004	Turku
France	Investigational Site Number 250-007	Annecy
France	Investigational Site Number 250-017	Bois Guillaume Cedex
France	Investigational Site Number 250-003	Boulogne Billancourt
France	Investigational Site Number 250-011	Brest
France	Investigational Site Number 250-008	Cahors Cedex 9
France	Investigational Site Number 250-012	Corbeil Essonnes
France	Investigational Site Number 250-009	La Rochelle Cedex 1
France	Investigational Site Number 250-004	Le Creusot
France	Investigational Site Number 250-006	Mantes La Jolie
France	Investigational Site Number 250-021	Nanterre
France	Investigational Site Number 250-020	Strasbourg
France	Investigational Site Number 250022	Strasbourg
France	Investigational Site Number 250-002	Toulouse
France	Investigational Site Number 250-016	Venissieux
Greece	Investigational Site Number 300003	Athens
Greece	Investigational Site Number 300004	Athens
Greece	Investigational Site Number 300001	Haidari, Athens
Ireland	Investigational Site Number 372001	Dublin 4
Israel	Investigational Site Number 376004	Hadera
Israel	Investigational Site Number 376002	Petah Tiqwa
Israel	Investigational Site Number 376003	Tel-Aviv
Mexico	Investigational Site Number 484004	Guadalajara
Mexico	Investigational Site Number 484001	Mexico
Mexico	Investigational Site Number 484002	Mexico
Mexico	Investigational Site Number 484003	Zapopan
Netherlands	Investigational Site Number 528001	Beek
Netherlands	Investigational Site Number 528006	Enschede
Netherlands	Investigational Site Number 528002	Hoogeveen
Netherlands	Investigational Site Number 528007	Nijverdal
Netherlands	Investigational Site Number 528003	Rotterdam
Netherlands	Investigational Site Number 528004	s-Hertogenbosch
Netherlands	Investigational Site Number 528005	Woerden
Russian Federation	Investigational Site Number 643-009	Kazan
Russian Federation	Investigational Site Number 643008	Kirov
Russian Federation	Investigational Site Number 643001	Moscow
Russian Federation	Investigational Site Number 643006	Samara
Russian Federation	Investigational Site Number 643007	Samara
Russian Federation	Investigational Site Number 643005	Saratov
Russian Federation	Investigational Site Number 643004	St-Petersburg
Russian Federation	Investigational Site Number 643003	St-Ptetersburg
Slovakia	Investigational Site Number 703002	Bratislava
Slovakia	Investigational Site Number 703004	Kosice
Slovakia	Investigational Site Number 703001	Nitra
Slovakia	Investigational Site Number 703005	Nove Mesto nad Vahom
Slovakia	Investigational Site Number 703003	Zilina
Spain	Investigational Site Number 724007	Bilbao
Spain	Investigational Site Number 724006	Cádiz
Spain	Investigational Site Number 724001	Las Palmas de Gran Canaria
Spain	Investigational Site Number 724005	LLeida
Spain	Investigational Site Number 724008	Madrid
Spain	Investigational Site Number 724003	Málaga
Spain	Investigational Site Number 724009	Sabadell
Spain	Investigational Site Number 721002	Valencia
Spain	Investigational Site Number 724004	Valencia
Spain	Investigational Site Number 724010	Vigo
Sweden	Investigational Site Number 752-03	Ängelholm
Sweden	Investigational Site Number 752-002	Göteborg
Sweden	Investigational Site Number 752-005	Karlskoga
Sweden	Investigational Site Number 752-006	Motala
Sweden	Investigational Site Number 752-007	Örebro
Sweden	Investigational Site Number 752-001	Stockholm
Turkey	Investigational Site Number 792-001	Antalya
Turkey	Investigational Site Number 792-002	Istanbul
United States	Investigational Site Number 840009	Arlington Heights	Illinois
United States	Investigational Site Number 840015	Atco	New Jersey
United States	Investigational Site Number 840023	Birmingham	Alabama
United States	Investigational Site Number 840008	Blackwood	New Jersey
United States	Investigational Site Number 840006	Bryan	Ohio
United States	Investigational Site Number 840016	Carnegie	Pennsylvania
United States	Investigational Site Number 840035	Cincinnati	Ohio
United States	Investigational Site Number 840001	Dallas	Texas
United States	Investigational Site Number 840007	Dallas	Texas
United States	Investigational Site Number 840028	Denver	Colorado
United States	Investigational Site Number 840038	Eagan	Minnesota
United States	Investigational Site Number 840049	Fargo	North Dakota
United States	Investigational Site Number 840002	Goodyear	Arizona
United States	Investigational Site Number 840034	Grand Junction	Colorado
United States	Investigational Site Number 840005	Hickory	North Carolina
United States	Investigational Site Number 840013	Houston	Texas
United States	Investigational Site Number 840050	Indianapolis	Indiana
United States	Investigational Site Number 840031	Kansas City	Kansas
United States	Investigational Site Number 840017	La Jolla	California
United States	Investigational Site Number 840036	La Mesa	California
United States	Investigational Site Number 840022	Lawrenceville	Georgia
United States	Investigational Site Number 840037	Loma Linda	California
United States	Investigational Site Number 840045	Long Beach	California
United States	Investigational Site Number 840026	Longmont	Colorado
United States	Investigational Site Number 840027	Mineola	New York
United States	Investigational Site Number 840030	Minneapolis	Minnesota
United States	Investigational Site Number 840048	Mission Hills	California
United States	Investigational Site Number 840033	Mission Viejo	California
United States	Investigational Site Number 840004	Paducah	Kentucky
United States	Investigational Site Number 840019	Palm Springs	California
United States	Investigational Site Number 840047	Phoenix	Arizona
United States	Investigational Site Number 840024	Rapid City	South Dakota
United States	Investigational Site Number 840014	Renton	Washington
United States	Investigational Site Number 840010	Rockville	Maryland
United States	Investigational Site Number 840029	Roswell	Georgia
United States	Investigational Site Number 840039	San Diego	California
United States	Investigational Site Number 840042	San Diego	California
United States	Investigational Site Number 840046	Spokane	Washington
United States	Investigational Site Number 840051	Springfield	Illinois
United States	Investigational Site Number 840012	St Louis	Missouri
United States	Investigational Site Number 840044	St. Louis	Missouri
United States	Investigational Site Number 840011	Staten Island	New York
United States	Investigational Site Number 840043	Tustin	California
United States	Investigational Site Number 840020	Uniontown	Pennsylvania
United States	Investigational Site Number 840052	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Sanofi

Countries where clinical trial is conducted

United States,  Austria,  Brazil,  Canada,  Czech Republic,  Finland,  France,  Greece,  Ireland,  Israel,  Mexico,  Netherlands,  Russian Federation,  Slovakia,  Spain,  Sweden,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	Daily Dose of Insulin Glargine		week 1, week 2, week 6, week 12, week 24	No
Secondary	Daily Dose of Liraglutide		week 1, week 2, week 6, week 12, week 24	No
Secondary	Daily Dose of Insulin Glargine Administered During the Extension Period		week 30, week 36, week 48	No
Secondary	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)	Yes
Secondary	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)	Yes