Efficacy and Safety of Alogliptin Plus Metformin Compared to Glipizide Plus Metformin in Patients With Type 2 Diabetes Mellitus (ENDURE)

A Multicenter, Randomized, Double-Blind, Active-Controlled Study to Evaluate the Durability of the Efficacy and Safety of Alogliptin Compared to Glipizide When Used in Combination With Metformin in Subjects With Type 2 Diabetes

The purpose of this study is to determine the safety and effectiveness of adding alogliptin, once daily (QD), compared to glipizide with metformin in diabetic patients.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes Mellitus
• Intervention / Treatment: Drug: Alogliptin; Drug: Metformin; Drug: Glipizide

Detailed Description

For patients diagnosed with type 2 diabetes mellitus, metformin is the usual first-line therapy in addition to diet control and exercise. For those patients with inadequate glycemic control with metformin monotherapy or experiencing serious side effects of metformin, sulfonylurea is a popular choice as a second-line oral antidiabetic treatment.

Alogliptin is a dipeptidyl peptidase-4 inhibitor currently being developed by Takeda for use in patients with type 2 diabetes mellitus.

This study is designed to further explore the durability of efficacy and safety of alogliptin compared to glipizide in type 2 diabetes mellitus patients whose blood sugar level is inadequately controlled with metformin therapy.

The duration of this study will be approximately 2 years.

• Study Type: Interventional
• Enrollment (Actual): 2639
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Mar del Plata, Argentina
• Australia
  • Australian Capital Territory
    • Garran, Australian Capital Territory, Australia
  • New South Wales
    • Wollongong, New South Wales, Australia
  • Queensland
    • Herston, Queensland, Australia
  • Western Australia
    • Nedlands, Western Australia, Australia
• Austria
  • Graz, Austria
  • Salzburg, Austria
• Brazil
  • Fortaleza, Brazil
  • São Paulo, Brazil
  • Pernambuco
    • Recife, Pernambuco, Brazil
  • Planalto Central
    • Brasília - DF, Planalto Central, Brazil
  • São Paulo
    • Mogi das Cruzes, São Paulo, Brazil
• Canada
  • Newfoundland and Labrador
    • St. John's, Newfoundland and Labrador, Canada
  • Ontario
    • Brampton, Ontario, Canada
    • Collingwood, Ontario, Canada
    • Corunna, Ontario, Canada
    • Etobichoke, Ontario, Canada
    • Etobicoke, Ontario, Canada
    • Mississauga, Ontario, Canada
    • Smith Falls, Ontario, Canada
    • Smiths Falls, Ontario, Canada
    • Toronto, Ontario, Canada
  • Quebec
    • Granby, Quebec, Canada
    • Montreal, Quebec, Canada
• Chile
  • Santiago, Chile
  • Santiago
    • Providencia, Santiago, Chile
• Germany
  • Brandenburg
    • Potsdam, Brandenburg, Germany
  • Hesse
    • Kelkheim, Hesse, Germany
    • Offenbach, Hesse, Germany
  • North Rhine-Westphalia
    • Münster, North Rhine-Westphalia, Germany
  • Rhineland-Palatinate
    • Mainz, Rhineland-Palatinate, Germany
    • Neuwied, Rhineland-Palatinate, Germany
    • Rhaunen, Rhineland-Palatinate, Germany
• Guatemala
  • Guatemala City, Guatemala
• Hong Kong
  • Kowloon, Hong Kong
  • Kowloon
    • Wong Tai Sin, Kowloon, Hong Kong
  • Southern District
    • Pok Fu Lam, Southern District, Hong Kong
• Hungary
  • Budapest, Hungary
  • Baranya
    • Pécs, Baranya, Hungary
  • Borsod-Abaúj-Zemplén
    • Miskolc, Borsod-Abaúj-Zemplén, Hungary
  • Bács-Kiskun
    • Kalocsa, Bács-Kiskun, Hungary
  • Békés
    • Gyula, Békés, Hungary
  • Csongrád
    • Makó, Csongrád, Hungary
    • Szentes, Csongrád, Hungary
  • Szabolcs-Szatmár-Bereg
    • Nyíregyháza, Szabolcs-Szatmár-Bereg, Hungary
  • Zala
    • Zalaegerszeg, Zala, Hungary
• India
  • Andhra Pradesh
    • Hyderabad, Andhra Pradesh, India
  • Bihar
    • Patna, Bihar, India
  • Haryana
    • Karnal, Haryana, India
  • Karnataka
    • Bangalore, Karnataka, India
    • Belgaum, Karnataka, India
  • Madhya Pradesh
    • Bhopal, Madhya Pradesh, India
  • Maharashtra
    • Mumbai, Maharashtra, India
  • Tamil Nadu
    • Trichy, Tamil Nadu, India
• Israel
  • Jerusalem, Israel
  • Zefat, Israel
  • Center District
    • Kfar-Saba, Center District, Israel
  • Central District
    • Kfar Saba, Central District, Israel
    • Matan, Central District, Israel
    • Petach Tikva, Central District, Israel
  • Haifa District
    • Hadera, Haifa District, Israel
    • Haifa, Haifa District, Israel
  • Northern District
    • Nahariya, Northern District, Israel
    • Safed, Northern District, Israel
  • Southern District
    • Ashkelon, Southern District, Israel
    • Be'er Sheva, Southern District, Israel
  • Tel Aviv
    • Holon, Tel Aviv, Israel
    • Tel- Aviv, Tel Aviv, Israel
• Italy
  • Perugia, Italy
  • Pistoia, Italy
  • Milan
    • Milano, Milan, Italy
• Korea, Republic of
  • Honam
    • Gwangju, Honam, Korea, Republic of
  • Hoseo
    • Daejeon, Hoseo, Korea, Republic of
  • Yeongnam
    • Daegu, Yeongnam, Korea, Republic of
• Latvia
  • Daugavpils, Latvia
  • Liepaja, Latvia
  • Limbazi, Latvia
  • Ogre, Latvia
  • Riga, Latvia
  • Talsi, Latvia
  • Tukums, Latvia
  • Valmiera, Latvia
• Lithuania
  • Alytus, Lithuania
  • Kaunas, Lithuania
  • Kedainiai, Lithuania
  • Klaipeda, Lithuania
  • Palanga, Lithuania
  • Panevezys, Lithuania
  • Vilnius, Lithuania
• Malaysia
  • Ipoh, Malaysia
  • Kajang, Malaysia
  • Kota Bahru, Malaysia
  • Kota Bharu, Malaysia
  • Kuala Terengganu, Malaysia
  • Kuantan, Malaysia
  • Melaka, Malaysia
  • Taiping, Malaysia
• Mexico
  • Huixquilucan Edo. de Mexico, Mexico
  • Mexico City, Mexico
  • Distrito Federal
    • Mexico, Distrito Federal, Mexico
  • Edo de Mexico
    • Tlalnepantla, Edo de Mexico, Mexico
  • Jalisco
    • Guadalajara, Jalisco, Mexico
  • Nuevo Leon
    • Monterrey, Nuevo Leon, Mexico
• New Zealand
  • Auckland, New Zealand
  • Christchurch, New Zealand
  • Hamilton, New Zealand
  • Otahuhu, New Zealand
  • Palmerston North, New Zealand
  • Takapuna, New Zealand
  • Tauranga, New Zealand
  • Wellington, New Zealand
• Peru
  • Ica, Peru
  • Lambayeque
    • Chiclayo, Lambayeque, Peru
  • San Juan de Miraflores
    • Lima, San Juan de Miraflores, Peru
• Philippines
  • Manila, Philippines
• Poland
  • Bytom, Poland
  • Gniewkowo, Poland
  • Krakow, Poland
  • Radom, Poland
  • Rzeszow, Poland
  • Tychy, Poland
  • Warszawa, Poland
• Puerto Rico
  • Ponce, Puerto Rico
  • San Juan, Puerto Rico
• Romania
  • Bacau, Romania
  • Bucharest, Romania
  • Galati, Romania
  • Oradea, Romania
  • Sibiu, Romania
  • Targu Mures, Romania
• Russian Federation
  • Arkhangelsk, Russian Federation
  • Irkutsk, Russian Federation
  • Moscow, Russian Federation
  • Samara, Russian Federation
  • Smolensk, Russian Federation
  • St Petersburg, Russian Federation
  • Yaroslavl, Russian Federation
• Singapore
  • Singapore, Singapore
• South Africa
  • Eastern Cape
    • Port Elizabeth, Eastern Cape, South Africa
  • Gauteng
    • Johannesburg, Gauteng, South Africa
    • Pretoria, Gauteng, South Africa
  • Kwazulu-Natal
    • Durban, Kwazulu-Natal, South Africa
    • Tongaat, Kwazulu-Natal, South Africa
  • Western Cape
    • Cape Town, Western Cape, South Africa
• Spain
  • Alicante, Spain
  • Cataluña
    • Barcelona, Cataluña, Spain
  • Galicia
    • Santiago de Compostela, Galicia, Spain
• Thailand
  • Amphure Muang, Thailand
  • Bangkok, Thailand
  • Chiangmai, Thailand
  • Khon Kaen, Thailand
• Ukraine
  • Dnepropertovsk, Ukraine
  • Dnipropetrovsk, Ukraine
  • Donetsk, Ukraine
  • Kharkiv, Ukraine
  • Kyiv, Ukraine
  • Lviv, Ukraine
  • Vinnytsa, Ukraine
  • Vinnytsya, Ukraine
  • Zaporizhye, Ukraine
  • Zaporizhzhya, Ukraine
• United Kingdom
  • Aintree-Liverpool, United Kingdom
  • Bath, United Kingdom
  • Bournemouth, United Kingdom
  • Dundee, United Kingdom
  • London, United Kingdom
  • Stevenage, United Kingdom
  • Swansea, United Kingdom
• United States
  • Alabama
    • Montgomery, Alabama, United States
    • Muscle Shoals, Alabama, United States
    • Pell City, Alabama, United States
  • Arizona
    • Mesa, Arizona, United States
    • Peoria, Arizona, United States
    • Phoenix, Arizona, United States
    • Sierra Vista, Arizona, United States
    • Tempe, Arizona, United States
    • Tucson, Arizona, United States
  • California
    • Anaheim, California, United States
    • Artesia, California, United States
    • Chico, California, United States
    • Los Alamitos, California, United States
    • Mission Viejo, California, United States
    • National City, California, United States
    • Northridge, California, United States
    • Pismo Beach, California, United States
    • Riverside, California, United States
    • Roseville, California, United States
    • Sacramento, California, United States
    • San Diego, California, United States
    • Santa Monica, California, United States
    • Tustin, California, United States
  • Colorado
    • Arvada, Colorado, United States
    • Colorado Springs, Colorado, United States
  • Connecticut
    • Ridgefield, Connecticut, United States
    • Waterbury, Connecticut, United States
  • Florida
    • Brooksville, Florida, United States
    • New Port Richey, Florida, United States
    • North Miami Beach, Florida, United States
    • Ocala, Florida, United States
    • Opa Locka, Florida, United States
    • Orlando, Florida, United States
  • Georgia
    • Augusta, Georgia, United States
    • Savannah, Georgia, United States
  • Illinois
    • Addison, Illinois, United States
    • Chicago, Illinois, United States
  • Indiana
    • Bloomington, Indiana, United States
    • Evansville, Indiana, United States
    • Indianapolis, Indiana, United States
    • Mishawaka, Indiana, United States
    • South Bend, Indiana, United States
  • Kentucky
    • Lexington, Kentucky, United States
    • Munfordville, Kentucky, United States
  • Louisiana
    • Marrero, Louisiana, United States
  • Maine
    • Bangor, Maine, United States
  • Maryland
    • Elkridge, Maryland, United States
    • Oxon Hill, Maryland, United States
  • Massachusetts
    • North Dartmouth, Massachusetts, United States
  • Michigan
    • Ann Arbor, Michigan, United States
    • Flint, Michigan, United States
  • Mississippi
    • Picayune, Mississippi, United States
  • Missouri
    • Springfield, Missouri, United States
    • St Peters, Missouri, United States
    • St. Louis, Missouri, United States
  • Nebraska
    • Omaha, Nebraska, United States
  • Nevada
    • Las Vegas, Nevada, United States
  • New Mexico
    • Albuquerque, New Mexico, United States
  • New York
    • New Windsor, New York, United States
    • New York, New York, United States
    • Rochester, New York, United States
  • North Dakota
    • Fargo, North Dakota, United States
  • Ohio
    • Beachwood, Ohio, United States
    • Cincinnati, Ohio, United States
    • Dayton, Ohio, United States
    • Willoughby Hills, Ohio, United States
    • Zanesville, Ohio, United States
  • Oklahoma
    • Norman, Oklahoma, United States
    • Oklahoma City, Oklahoma, United States
  • Oregon
    • Medford, Oregon, United States
  • Pennsylvania
    • Havertown, Pennsylvania, United States
    • Norristown, Pennsylvania, United States
    • Philadelphia, Pennsylvania, United States
    • Pittsburgh, Pennsylvania, United States
    • Tipton, Pennsylvania, United States
  • South Carolina
    • Anderson, South Carolina, United States
    • Charleston, South Carolina, United States
    • Greer, South Carolina, United States
  • South Dakota
    • Rapid City, South Dakota, United States
  • Tennessee
    • New Tazewell, Tennessee, United States
  • Texas
    • Arlington, Texas, United States
    • Carrollton, Texas, United States
    • Dallas, Texas, United States
    • Fort Worth, Texas, United States
    • Houston, Texas, United States
    • Hurst, Texas, United States
    • Katy, Texas, United States
    • San Antonio, Texas, United States
    • Spring, Texas, United States
    • Temple, Texas, United States
  • Utah
    • Midvale, Utah, United States
  • Virginia
    • Hampton, Virginia, United States
  • West Virginia
    • Lewisburg, West Virginia, United States
  • Wisconsin
    • Milwaukee, Wisconsin, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Has a diagnosis of type 2 diabetes mellitus.

• Must meet one of the following:

  • Has been inadequately controlled on a stable daily dose of ≥1500 mg (or documented maximum tolerated dose) of metformin for at least 2 months prior to Screening.
  • Has been inadequately controlled (as defined by a glycosylated hemoglobin 7.5 - 10%, inclusive) on metformin <1500 mg without documented maximum tolerated dose.
• No treatment with antidiabetic agents other than metformin within 2 months prior to Screening (for Schedule A)/Pre-Screening (for Schedule B).
• Has body mass index within 23 kg/m^2 and 45 kg/m^2 unless the patient is Asian or of Asian descent, for whom the allowable body mass index will be ≥ 20 kg/m^2 and ≤ 35 kg/m^2, inclusive.
• Has fasting C-peptide concentration at least 0.8 ng.
• If regularly using non-excluded medications, must be on a stable dose at least 4 weeks prior to Screening/Pre-screening.
• Females of childbearing potential who are sexually active must agree to use adequate contraception, and can neither be pregnant, lactating or intends to donate ova from Screening throughout the duration of the study.
• Must be able and willing to monitor their blood glucose concentrations with a home monitor, and comply with protocol requirements including scheduled clinic appointments.

Exclusion Criteria:

• Systolic blood pressure greater than or equal to 150 mmHg and/or diastolic pressure greater than or equal to 90.
• Hemoglobin less than or equal to 12 g/dL for males and less than or equal to 10 g/dL for females at Screening Visit.
• Alanine aminotransferase greater than or equal to 2.5 times the upper limit of normal at Screening Visit.
• Serum creatinine greater than or equal to 1.5 mg/dL for males and 1.4 for females, or calculated creatinine clearance less than 60 L/min.
• Males intending to impregnate others or donate sperm before, during or within 1 month after participating in the study.
• A history of cancer other than squamous or basal cell carcinoma of the skin that has not been in full remission for at least 5 years.
• A history of laser treatment for diabetic retinopathy within 6 months of screening.
• Treated for diabetic gastric paresis, gastric banding, or gastric bypass.
• New York Heart Association Class III or IV heart failure.
• History of coronary angioplasty, coronary stent placement, coronary bypass surgery, myocardial infarction, stroke or transient ischemic attack within 3 months prior to screening.
• Known history of human immunodeficiency virus, hepatitis B or C.
• Alcohol or substance abuse within 2 years prior to screening.

• Is required to take or intends to continue taking any disallowed medication, any prescription medication, herbal treatment or over-the counter medication that may interfere with evaluation of the study medication, including:

  • Any investigational drug within 30 days
  • Any investigational diabetic drug within 3 months
  • Any antidiabetic drug in the dipeptidyl peptidase-4 inhibitors or glucagon-like peptide-1 mimetics classes within 90 days prior to Screening other than metformin
  • Prior treatment with alogliptin.
  • Weight-loss drugs
  • Oral or systemically injected glucocorticoids
• A hypersensitivity allergy or anaphylactic reaction to any dipeptidyl peptidase-4 drug, metformin or glipizide.
• Has a documented history or concurrent signs of significant thyroid disease (eg, autoimmune thyroid diseases such as Graves disease and Hashimoto thyroiditis or active thyroid nodules).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Metformin + Alogliptin 12.5 mg; Alogliptin 12.5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.	Drug: Alogliptin; Alogliptin tablets; Other Names: SYR-322; Nesina; Drug: Metformin; Metformin tablets; Other Names: Glucophage
Experimental: Metformin + Alogliptin 25 mg; Alogliptin 25 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.	Drug: Alogliptin; Alogliptin tablets; Other Names: SYR-322; Nesina; Drug: Metformin; Metformin tablets; Other Names: Glucophage
Active Comparator: Metformin + Glipizide; Glipizide 5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks. After at least 2 weeks of treatment but prior to Week 20, participants with persistent hyperglycemia (fasting plasma glucose ≥250 mg/dL) underwent a dose titration of glipizide up to 20 mg in 5-mg increments in 4-week intervals.	Drug: Metformin; Metformin tablets; Other Names: Glucophage; Drug: Glipizide; Glipizide tablets; Other Names: Glucotrol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 52	The change from Baseline to Week 52 in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound). The least squares (LS) means are from an analysis of covariance (ANCOVA) model with treatment, study schedule, and geographic region as class variables, and Baseline metformin dose and Baseline HbA1c as covariates.	Baseline and Week 52
Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 104	The change from Baseline to Week 104 in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound). The least squares (LS) means are from an analysis of covariance (ANCOVA) model with treatment, study schedule, and geographic region as class variables, and Baseline metformin dose and Baseline HbA1c as covariates.	Baseline and Week 104

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Glycosylated Hemoglobin at Other Time Points	The change from Baseline over time in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound). LS means are from an ANCOVA model with treatment, study schedule, and geographic region as class variables, and Baseline metformin dose and Baseline HbA1c as covariates.	Baseline and Weeks 4, 8, 12, 16, 20, 26, 39, 65, 78, and 91.
Change From Baseline in Fasting Plasma Glucose Over Time	The change from Baseline in fasting plasma glucose (FPG) was assessed at Weeks 2, 4, 8, 12, 16, 20, 26, 39, 52, 65, 78, 91, and 104. LS means are from an ANCOVA model with treatment, study schedule, and geographic region as class variables, and Baseline FPG and Baseline metformin dose as covariates.	Baseline and Weeks 2, 4, 8, 12, 16, 20, 26, 39, 52, 65, 78, 91, and 104.
Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 6.5%	The percentage of participants with HbA1c less than or equal to 6.5% at Weeks 26, 52, 78, and 104. Participants who did not complete the scheduled Week 104 visit were assessed based on their response at the time of discontinuation.	Weeks 26, 52, 78, and 104.
Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 7.0%	Percentage of participants with HbA1c ≤ 7.0% at Weeks 26, 52, 78, and 104. Participants who did not complete the scheduled Week 104 visit were assessed based on their response at the time of discontinuation.	Weeks 26, 52, 78, and 104.
Change From Baseline in Body Weight Over Time	LS Means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and Baseline weight and Baseline metformin dose as covariates.	Baseline and Weeks 12, 26, 39, 52, 65, 78, 91, and 104.

Collaborators and Investigators

• Sponsor: Takeda

Publications and helpful links

General Publications

• Gordon J, McEwan P, Hurst M, Puelles J. The Cost-Effectiveness of Alogliptin Versus Sulfonylurea as Add-on Therapy to Metformin in Patients with Uncontrolled Type 2 Diabetes Mellitus. Diabetes Ther. 2016 Dec;7(4):825-845. doi: 10.1007/s13300-016-0206-7. Epub 2016 Oct 27.

Study record dates

Study Major Dates

• Study Start: March 1, 2009
• Primary Completion (Actual): October 1, 2012
• Study Completion (Actual): October 1, 2012

Study Registration Dates

• First Submitted: March 4, 2009
• First Submitted That Met QC Criteria: March 4, 2009
• First Posted (Estimate): March 5, 2009

Study Record Updates

• Last Update Posted (Estimate): December 3, 2013
• Last Update Submitted That Met QC Criteria: September 25, 2013
• Last Verified: September 1, 2013

More Information

Terms related to this study

• Keywords: Drug Therapy; Diabetes Mellitus; Hyperglycemia; Glucose Intolerance; Hyperinsulinism
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Incretins; Dipeptidyl-Peptidase IV Inhibitors; Metformin; Glipizide; Alogliptin
• Other Study ID Numbers: SYR-322_305; 2008-007444-34 (Registry Identifier: EudraCT); U1111-1111-7397 (Registry Identifier: WHO); HKCTR-862 (Registry Identifier: HKUCTR); DOH-27-0709-2825 (Registry Identifier: SANCTR); 09/H0703/66 (Registry Identifier: NRES); NMRR-09-203-3590 (Registry Identifier: NMRR)