Exenatide Compared With Twice-Daily Biphasic Insulin Aspart in Patients With Type 2 Diabetes Using Sulfonylurea and Metformin

Efficacy of Exenatide (AC2993, Synthetic Exendin-4, LY2148568) Compared With Twice-Daily Biphasic Insulin Aspart in Patients With Type 2 Diabetes Using Sulfonylurea and Metformin

This is a Phase 3, multicenter, open-label, comparator-controlled trial comparing the effect of exenatide twice daily to twice daily biphasic insulin aspart on glycemic control, as measured by hemoglobin A1c (HbA1c).

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2
• Intervention / Treatment: Drug: exenatide; Drug: biphasic insulin aspart

• Study Type: Interventional
• Enrollment (Actual): 505
• Phase: Phase 3

Contacts and Locations

Study Locations

• Croatia
  • Osijek, Croatia, 31000
    • Clinical Hospital Osijek
  • Zagreb, Croatia, 10000
    • Klinica bolnica Dubrava
  • Zagreb, Croatia, 10000
    • Klinicki Bolnicki Centar Zagreb-Rebro
  • Zagreb, Croatia, 10000
    • Opca bolnica "Sveti Duh"
• Germany
  • Augsburg, Germany, 86150
    • Internistische Gemeinschaftspraxis
  • Beckum, Germany, 59269
    • Dr. Karlheinz Hehemann
  • Dortmund, Germany, 44137
    • Dr. Klaus Busch
  • Giessen, Germany, 35392
    • Medical Clinic and Policlinic 3
  • Hamburg, Germany, 21073
    • Diabetologische Schwerpunktpraxis
  • Mainz, Germany, 55119
    • IKFE GmbH
  • Munich, Germany, 80804
    • Institut for diabetic research
  • Neuss, Germany, 41460
    • Profil, Institut fur Stoffwechselstorungen
  • Neuwied, Germany, 56564
    • Dr. Thomas Behnke
  • Oschatz, Germany, 04758
    • Dr. Bernd Donaubauer
  • Osnabruck, Germany, 49074
    • Marienhospital Osnabrück
  • Schkeuditz, Germany, 04435
    • Dr. Joerg Steindorf
  • Wiesbaden, Germany, 65183
    • Dr. Jerzi Jasinski
• Greece
  • Athens, Greece, 10552
    • "Polyclinic" General Hospital of Athens
  • Athens, Greece, 10676
    • Department of Endocrinology
  • Athens, Greece, 11527
    • Diabetes Center
  • Patras, Greece, 26500
    • University Hospital of Patras
  • Thessaloniki, Greece, 56429
    • 1st Internal Medicine Department "Papagergiou"
• Italy
  • Catania, Italy, 95124
    • Instituto di Endocrinologia
  • Florence, Italy, 50134
    • Dipartimento di fisiopatologia clinica
  • Milan, Italy, 60-20132
    • U.O. Medicina Generale
  • Padova, Italy, 35128
    • Ospedale Civile di Padova
  • Palermo, Italy, 90127
    • Policlinico Univarsitario P. Giaccone
  • Torino, Italy
    • U.O. Universita di Malattie del Metabolismo e Diabetologia
• Netherlands
  • Apeldoorn, Netherlands, 7300 DS
    • Gelre Ziekenhuizen
  • Arnhem, Netherlands, 6815 AD
    • Rijnstate Ziekenhuis
  • Eindhoven, Netherlands, 5631 BM
    • Maxima Medisch Centrum Location Eindhoven
• Portugal
  • Coimbra, Portugal, 3000-076
    • Hospitais da universidade de Coimbra
  • Leiria, Portugal, 2410-197
    • Hospital de Santo Andre
  • Lisboa, Portugal, 1250-203
    • Associacao Protectora dos Diabeticos de Portugal
  • Matosinhos, Portugal, 4454-509
    • Hospital Pedro Hispano
• Romania
  • Brasov, Romania, 500326
    • Spitalul Judetean Brasov
  • Bucuresti, Romania, 020475
    • Institutul de Diabet
  • Judet Timis, Romania, 300723
    • Spitalul Clinic nr. 1 Judetean
• Russian Federation
  • Moscow, Russian Federation, 117036
    • National Endocrinology Research Center
  • Moscow, Russian Federation, 119881
    • Setchenov Moscow Medical Academy
  • Moscow, Russian Federation, 123448
    • Moscow State Medical Stomatological
  • Moscow, Russian Federation, 125315
    • Russian Medical Academy for Advanced Medical Studies, Ministry of Health
  • St. Petersburg, Russian Federation, 193257
    • Hospital of St. Elizabeth's
  • St. Petersburg, Russian Federation, 194354
    • City Clinical Hospital #2
  • St. Petersburg, Russian Federation, 198013
    • Medical Military Academy
• Slovenia
  • Ljubljana, Slovenia, 1000
    • Univerzitetni klinicni center Ljubljana
  • Maribor, Slovenia, 2000
    • Splosna bolnisnica Maribor
• Spain
  • Alicante, Spain, 03300
    • Hospital Vega Baja
  • Barcelona, Spain, 08036
    • Hospital Clinic i Provincial de Barcelona
  • Palma de Mallorca, Spain, 07198
    • Endocrinology Service (Planta Baja)
  • Sevilla, Spain, 41014
    • Hospital Virgen de Valme
  • Teruel, Spain, 44002
    • Hospital General de Teruel
  • Valencia, Spain, 46600 Alzira
    • Hospital la Ribera Alzira
• Taiwan
  • Changhua, Taiwan, 500
    • Changhua Christian Hospital
  • Hualien, Taiwan
    • Tzu Chi General Hospital
  • Taichung, Taiwan, 407
    • Veteran General Hospital-Taichung
  • Taipei, Taiwan
    • Tri-Service General Hospital
• United Kingdom
  • Birmingham, United Kingdom, B9 5SS
    • Diabetes Research, Ward 34, Birmingham Heartlands Hospital
  • Blackburn, United Kingdom, BB2 3LR
    • Diabetes Unit, Blackburn Royal Infirmary
  • Colchester, United Kingdom, CO4 5JL
    • Colchester General Hospital
  • Edinburgh, United Kingdom, EH3 9YW
    • Royal Infirmary of Edinburgh
  • Glasgow, United Kingdom, G4 0SF
    • Glasgow Royal Infirmary
  • Hull, United Kingdom, HU3 2JZ
    • The Michael White Center for Diabetes and Endocrinology
  • Liverpool, United Kingdom, L7 8XP
    • Clinical Sciences Centre
  • Middlesbrough, United Kingdom, TS4 3BW
    • Education Centre, James Cook University Hospital
  • Newcastle upon Tyne, United Kingdom, NE1 4LP
    • Wellcome Labs, Royal Victoria Infirmary
  • Nottingham, United Kingdom, NG7 2UH
    • Queens Medical Centre
  • Oxford, United Kingdom, OX3 7LJ
    • Diabetes Trial Unit OCDEM, Churchill Hospital
  • Wrexham, United Kingdom, LL13 7TD
    • Diabetes Unit, Gladsone Centre, Maelor Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients have been treated with a stable dose of the following for at least 3 months prior to screening: 1. >=1500 mg/day immediate-release metformin or extended-release metformin and at least an optimally effective dose for brand of sulfonylurea, or 2. a fixed-dose sulfonylurea/metformin combination therapy with the same sulfonylurea and metformin requirements as for the individual components
• HbA1c between 7.0% and 11.0%, inclusive.
• Patients have a body mass index >25kg/m2 and <40 kg/m2.
• Female patients are not breastfeeding, and female patients of childbearing potential test negative for pregnancy, do not intend to become pregnant during the study, and agree to continue using a reliable method of birth control

Exclusion Criteria:

• Patients are investigator site personnel directly affiliated with the study, or are immediate family of investigator site personnel directly affiliated with the study.
• Patients are employed by Lilly or Amylin.
• Patients have previously, in this or any other study, received exenatide or glucagon-like peptide-1 analogs.
• Patients have participated in an interventional medical, surgical, or pharmaceutical study within 30 days prior to screening. This criterion includes drugs that have not received regulatory approval for any indication at the time of study entry.
• Patients have had greater than three episodes of severe hypoglycemia within 6 months prior to screening.
• Patients have less than 5 years of remission history from any malignancy (other than basal cell or squamous cell skin cancer, in situ carcinomas of the cervix, or in situ prostate cancer).
• Patients have cardiac disease that is Class III or IV, according to the New York Heart Association criteria.
• Patients have a known allergy or hypersensitivity to biphasic insulin aspart, exenatide, or excipients contained in these agents.
• Patients have characteristics contraindicating metformin or sulfonylurea use, according to product-specific label.
• Patients have a history of renal transplantation or are currently receiving renal dialysis or have serum creatinine >=1.5 mg/dL for males and >=1.2 mg/dL for females.
• Patients have obvious clinical signs or symptoms of liver disease, acute or chronic hepatitis, or alanine aminotransferase/serum glutamic pyruvic transaminase greater than three times the upper limit of the reference range.
• Patients have known hemoglobinopathy or chronic anemia.
• Patients have active proliferative retinopathy or macular edema.
• Patients are receiving treatment for gastrointestinal disease with a drug directly affecting gastrointestinal motility, including but not limited to metoclopramide, cisapride, and chronic macrolide antibiotics.
• Patients are receiving chronic (lasting longer than 2 weeks) systemic glucocorticoid therapy (excluding topical and inhaled preparations) or have received such therapy within 2 weeks immediately prior to screening.
• Patients have used any prescription drug to promote weight loss within 3 months prior to screening.
• Patients have been treated for longer than 2 weeks with any of the following excluded medications within 3 months prior to screening: insulin, thiazolidinediones, alpha-glucosidase inhibitors, meglitinides.
• Patients have any other condition (including known drug or alcohol abuse or psychiatric disorder) that precludes them from following and completing the protocol, in the opinion of the investigator.
• Patients fail to satisfy the investigator of suitability to participate for any other reason.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Exenatide Arm; subcutaneous injection, twice daily; 5 mcg for 4 weeks followed by 10 mcg for 48 weeks	Drug: exenatide; subcutaneous injection, twice daily; 5 mcg for 4 weeks followed by 10 mcg for 48 weeks; Other Names: Byetta
ACTIVE_COMPARATOR: Biphasic Insulin Aspart Arm; subcutaneous injection, twice daily; titration to target blood glucose level	Drug: biphasic insulin aspart; subcutaneous injection, twice daily; titration to target blood glucose level; Other Names: NovoLog

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Glcosylated Hemoglobin (HbA1c)	Change in HbA1c from baseline to week 52	baseline, week 52

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Patients Achieving HbA1c <=7%	Percentage of patients in each arm who had HbA1c >7% at baseline and had HbA1c <=7% at week 52 (percentage = [number of subjects with HbA1c <=7% at week 52 divided by number of subjects with HbA1c >7% at baseline] * 100%).	52 weeks
Change in Body Weight	Change in body weight from baseline to week 52.	baseline, week 52
Change in Fasting Serum Glucose	Change in fasting serum glucose from baseline to week 52	baseline, week 52
Change in 7-point Self-monitored Blood Glucose (SMBG) Profile	Change in 7-point (pre-breakfast, after breakfast, pre-lunch, after lunch, pre-dinner, after dinner, 0300 hours) SMBG profile from baseline to week 52	baseline, week 52
Percentage of Patients With Hypoglycemic Events	Percentage of patients who experienced at least one episode of hypoglycemia at any point during the 52 week Parent Study (incidence of hypoglycemia = number of patients who experienced at least one episode of hypoglycemia at any point during the 52 week Parent Study divided by the total number of patients who particiapted in the 52 week Parent Study	52 weeks
Change in Rate of Hypoglycemic Events	Change in rate of hypoglycemic events per 30 days per patient from baseline to week 52	baseline, week 52

Collaborators and Investigators

• Sponsor: AstraZeneca
• Collaborators: Eli Lilly and Company

Publications and helpful links

General Publications

• Nauck MA, Duran S, Kim D, Johns D, Northrup J, Festa A, Brodows R, Trautmann M. A comparison of twice-daily exenatide and biphasic insulin aspart in patients with type 2 diabetes who were suboptimally controlled with sulfonylurea and metformin: a non-inferiority study. Diabetologia. 2007 Feb;50(2):259-67. doi: 10.1007/s00125-006-0510-2. Epub 2006 Dec 8.
• Pencek R, Blickensderfer A, Li Y, Brunell SC, Anderson PW. Exenatide twice daily: analysis of effectiveness and safety data stratified by age, sex, race, duration of diabetes, and body mass index. Postgrad Med. 2012 Jul;124(4):21-32. doi: 10.3810/pgm.2012.07.2567.
• Fineman MS, Mace KF, Diamant M, Darsow T, Cirincione BB, Booker Porter TK, Kinninger LA, Trautmann ME. Clinical relevance of anti-exenatide antibodies: safety, efficacy and cross-reactivity with long-term treatment. Diabetes Obes Metab. 2012 Jun;14(6):546-54. doi: 10.1111/j.1463-1326.2012.01561.x. Epub 2012 Feb 10.

Study record dates

Study Major Dates

• Study Start: November 1, 2003
• Primary Completion (ACTUAL): July 1, 2008
• Study Completion (ACTUAL): July 1, 2008

Study Registration Dates

• First Submitted: May 6, 2004
• First Submitted That Met QC Criteria: May 7, 2004
• First Posted (ESTIMATE): May 10, 2004

Study Record Updates

• Last Update Posted (ESTIMATE): April 7, 2015
• Last Update Submitted That Met QC Criteria: March 19, 2015
• Last Verified: March 1, 2015

More Information

Terms related to this study

• Keywords: diabetes; Lilly; Amylin; exendin; insulin aspart
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Anti-Obesity Agents; Incretins; Insulin Aspart; Exenatide; Biphasic Insulins
• Other Study ID Numbers: H8O-MC-GWAD