Efficacy and Safety of Dapagliflozin, Added to Therapy of Patients With Type 2 Diabetes With Inadequate Glycemic Control on Insulin

A 24-week International, Randomized, Parallel-group, Double-blind, Placebo-controlled Phase III Study With a 80-week Extension Period to Evaluate the Efficacy and Safety of Dapagliflozin Therapy When Added to the Therapy of Patients With Type 2 Diabetes With Inadequate Glycaemic Control on Insulin

This study is being carried out to see if Dapagliflozin in addition to insulin is effective and safe in treating patients with type 2 diabetes when compared to placebo (identical looking inactive treatment) in addition to insulin

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes
• Intervention / Treatment: Drug: Placebo; Drug: Dapagliflozin; Drug: Dapagliflozin; Drug: Dapagliflozin; Drug: Dapagliflozin; Drug: Dapagliflozin

• Study Type: Interventional
• Enrollment (Actual): 1240
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Salzburg, Austria
    • Research Site
  • Wien, Austria
    • Research Site
• Bulgaria
  • Pleven, Bulgaria
    • Research Site
  • Russe, Bulgaria
    • Research Site
  • Sofia, Bulgaria
    • Research Site
  • Varna, Bulgaria
    • Research Site
• Canada
  • Alberta
    • Calgary, Alberta, Canada
      • Research Site
  • British Columbia
    • Kelowna, British Columbia, Canada
      • Research Site
    • Langley, British Columbia, Canada
      • Research Site
  • Manitoba
    • Winnipeg, Manitoba, Canada
      • Research Site
  • New Brunswick
    • Moncton, New Brunswick, Canada
      • Research Site
  • Newfoundland and Labrador
    • Mount Pearl, Newfoundland and Labrador, Canada
      • Research Site
    • St. John's, Newfoundland and Labrador, Canada
      • Research Site
  • Nova Scotia
    • Halifax, Nova Scotia, Canada
      • Research Site
  • Ontario
    • Etobicoke, Ontario, Canada
      • Research Site
    • Kingston, Ontario, Canada
      • Research Site
    • London, Ontario, Canada
      • Research Site
    • Oakville, Ontario, Canada
      • Research Site
    • Scarborough, Ontario, Canada
      • Research Site
    • Thornhill, Ontario, Canada
      • Research Site
  • Quebec
    • Chicoutimi, Quebec, Canada
      • Research Site
    • Longueuil, Quebec, Canada
      • Research Site
    • Mirabel, Quebec, Canada
      • Research Site
    • Sherbrooke, Quebec, Canada
      • Research Site
• Finland
  • Helsinki, Finland
    • Research Site
  • Joensuu, Finland
    • Research Site
  • Jyvaskyla, Finland
    • Research Site
  • Kuopio, Finland
    • Research Site
  • Lahti, Finland
    • Research Site
  • Oulu, Finland
    • Research Site
  • Seinajoki, Finland
    • Research Site
  • Turku, Finland
    • Research Site
• Germany
  • Bad Oeynhausen, Germany
    • Research Site
  • Dortmund, Germany
    • Research Site
  • Dresden, Germany
    • Research Site
  • Essen, Germany
    • Research Site
  • Frankfurt, Germany
    • Research Site
  • Magdeburg, Germany
    • Research Site
  • Münster, Germany
    • Research Site
  • Riesa, Germany
    • Research Site
  • Wolmirstedt, Germany
    • Research Site
• Hungary
  • Csongrad, Hungary
    • Research Site
  • Esztergom, Hungary
    • Research Site
  • Gyor, Hungary
    • Research Site
  • Kaposvar, Hungary
    • Research Site
  • Kecskemet, Hungary
    • Research Site
  • Komarom, Hungary
    • Research Site
  • Miskolc, Hungary
    • Research Site
  • Szekesfehervar, Hungary
    • Research Site
  • Veszprem, Hungary
    • Research Site
• Netherlands
  • Amersfoort, Netherlands
    • Research Site
  • Den Helder, Netherlands
    • Research Site
  • Leiden, Netherlands
    • Research Site
  • Rotterdam, Netherlands
    • Research Site
• Romania
  • Brasov, Romania
    • Research Site
  • Bucuresti, Romania
    • Research Site
  • Mures
    • Tg Mures, Mures, Romania
      • Research Site
• Russian Federation
  • Moscow, Russian Federation
    • Research Site
  • Nizhnii Novgorod, Russian Federation
    • Research Site
  • Saint- Petersburg, Russian Federation
    • Research Site
  • St Petersburg, Russian Federation
    • Research Site
  • St. Petersburg, Russian Federation
    • Research Site
  • St.-petersburg, Russian Federation
    • Research Site
  • St.petersburg, Russian Federation
    • Research Site
• Slovakia
  • Bratislava, Slovakia
    • Research Site
  • Dolny Kubin, Slovakia
    • Research Site
  • Kosice, Slovakia
    • Research Site
  • Levice, Slovakia
    • Research Site
  • Lucenec, Slovakia
    • Research Site
  • Povazska Bystrica, Slovakia
    • Research Site
  • Presov, Slovakia
    • Research Site
• Spain
  • Andalucia
    • Sevilla, Andalucia, Spain
      • Research Site
  • Cataluna
    • Sabadell (barcelona), Cataluna, Spain
      • Research Site
  • Comunidad Valenciana
    • Alicante, Comunidad Valenciana, Spain
      • Research Site
  • Comunidad de Madrid
    • Madrid, Comunidad de Madrid, Spain
      • Research Site
• United Kingdom
  • Ashford, United Kingdom
    • Research Site
  • Birmingham, United Kingdom
    • Research Site
  • Cardiff, United Kingdom
    • Research Site
  • Liverpool, United Kingdom
    • Research Site
  • Reading, United Kingdom
    • Research Site
  • Swansea, United Kingdom
    • Research Site
  • Berks
    • Reading, Berks, United Kingdom
      • Research Site
  • Bucks
    • Aylesbury, Bucks, United Kingdom
      • Research Site
• United States
  • California
    • Fresno, California, United States
      • Research Site
    • Greenbrae, California, United States
      • Research Site
  • Georgia
    • Roswell, Georgia, United States
      • Research Site
  • Illinois
    • Chicago, Illinois, United States
      • Research Site
    • Springfield, Illinois, United States
      • Research Site
  • Indiana
    • Indianapolis, Indiana, United States
      • Research Site
  • Nebraska
    • Omaha, Nebraska, United States
      • Research Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States
      • Research Site
  • Texas
    • Corpus Christi, Texas, United States
      • Research Site
    • Dallas, Texas, United States
      • Research Site
  • Virginia
    • Norfolk, Virginia, United States
      • Research Site
    • Richmond, Virginia, United States
      • Research Site
  • Washington
    • Tacoma, Washington, United States
      • Research Site

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:

• Type 2 Diabetes
• Patients with HbA1c ≥7.5% and ≤10.5% and who are on a stable insulin regimen of at least 30 IU of injectable insulin per day either without any other oral antidiabetic drug or with a stable dose of oral antidiabetic drugs

Exclusion Criteria:

• Type 1 Diabetes
• Treatment with more than two additional oral antidiabetic drugs
• Moderate and severe renal (kidney) failure or dysfunction

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: 4	Drug: Placebo; Placebo
EXPERIMENTAL: 1; 2.5mg	Drug: Dapagliflozin; tablet oral 2.5 mg total daily dose once daily 48 weeks (= 24 week randomised treatment period + 24 week study extension period I); Drug: Dapagliflozin; Tablet oral 5 mg total daily dose once daily 48 weeks (= 24 week randomised treatment period + 24 week study extension period I); Drug: Dapagliflozin; Tablet oral 10 mg total daily dose once daily 48 weeks (= 24 week randomised treatment period + 24 week study extension period I); Drug: Dapagliflozin; tablet oral 2.5 total daily dose once daily 56 weeks (= 56 week study extension period II); Drug: Dapagliflozin; tablet oral 10 mg total daily dose once daily 56 weeks (= 56 week study extension period II)patients that have been treated with 5 mg during the 24 week randomised treatment period and extension I period will during extension II period switched to 10 mg
EXPERIMENTAL: 2; 5mg	Drug: Dapagliflozin; tablet oral 2.5 mg total daily dose once daily 48 weeks (= 24 week randomised treatment period + 24 week study extension period I); Drug: Dapagliflozin; Tablet oral 5 mg total daily dose once daily 48 weeks (= 24 week randomised treatment period + 24 week study extension period I); Drug: Dapagliflozin; Tablet oral 10 mg total daily dose once daily 48 weeks (= 24 week randomised treatment period + 24 week study extension period I); Drug: Dapagliflozin; tablet oral 2.5 total daily dose once daily 56 weeks (= 56 week study extension period II); Drug: Dapagliflozin; tablet oral 10 mg total daily dose once daily 56 weeks (= 56 week study extension period II)patients that have been treated with 5 mg during the 24 week randomised treatment period and extension I period will during extension II period switched to 10 mg
EXPERIMENTAL: 3; 10mg	Drug: Dapagliflozin; tablet oral 2.5 mg total daily dose once daily 48 weeks (= 24 week randomised treatment period + 24 week study extension period I); Drug: Dapagliflozin; Tablet oral 5 mg total daily dose once daily 48 weeks (= 24 week randomised treatment period + 24 week study extension period I); Drug: Dapagliflozin; Tablet oral 10 mg total daily dose once daily 48 weeks (= 24 week randomised treatment period + 24 week study extension period I); Drug: Dapagliflozin; tablet oral 2.5 total daily dose once daily 56 weeks (= 56 week study extension period II); Drug: Dapagliflozin; tablet oral 10 mg total daily dose once daily 56 weeks (= 56 week study extension period II)patients that have been treated with 5 mg during the 24 week randomised treatment period and extension I period will during extension II period switched to 10 mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adjusted Mean Change in HbA1c Levels	To assess the efficacy of 2.5 mg, 5 mg and 10 mg dapagliflozin compared to placebo as add-on therapy to insulin in improving glycaemic control in participants with type 2 diabetes who have inadequate glycaemic control on ≥ 30 IU injectable insulin daily for at least 8 weeks prior to enrolment, as determined by the change in HbA1c levels from baseline to Week 24, excluding data after insulin up-titration.	Baseline to Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adjusted Mean Change in Body Weight	To examine whether treatment with dapagliflozin in combination with insulin is superior in reducing body weight or causing less weight gain as compared to placebo added to insulin treatment after 24 weeks of treatment (LOCF), excluding data after insulin up-titration.	Baseline to Week 24
Adjusted Mean Change in Calculated Mean Daily Insulin Dose	To examine whether treatment with dapagliflozin in combination with insulin leads to a lower absolute calculated mean daily insulin dose as compared to placebo added to insulin treatment alone, from baseline to week 24, including data after insulin up-titration.	Baseline to Week 24
Proportion of Participants With Calculated Mean Daily Insulin Dose Reduction	To examine whether treatment with dapagliflozin in combination with insulin leads to higher percentage of participants with calculated mean daily insulin dose reduction from baseline to week 24 (i.e. reduction >= 10%) as compared to placebo added to insulin treatment.	Baseline to Week 24
Adjusted Mean Change in Fasting Plasma Glucose (FPG)	To examine whether treatment with dapagliflozin in combination with insulin is superior in reducing Fasting Plasma Glucose (FPG) as compared to placebo added to insulin treatment after 24 weeks of treatment, excluding data after insulin up-titration.	Baseline to Week 24

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Participants With Lack of Glycemic Control	Participants with lack of glycemic control or insulin up-titration for failing to achieve pre-specified glycemic targets	Baseline to Week 24

Collaborators and Investigators

• Sponsor: AstraZeneca
• Collaborators: Bristol-Myers Squibb
• Investigators: Principal Investigator: John Wilding, MD, Clinical Sciences CentreUniversity Hospital AintreeLongmoor LaneLiverpool, UK

Publications and helpful links

General Publications

• Aberle J, Menzen M, Schmid SM, Terkamp C, Jaeckel E, Rohwedder K, Scheerer MF, Xu J, Tang W, Birkenfeld AL. Dapagliflozin effects on haematocrit, red blood cell count and reticulocytes in insulin-treated patients with type 2 diabetes. Sci Rep. 2020 Dec 28;10(1):22396. doi: 10.1038/s41598-020-78734-z.
• Shah M, Stolbov L, Yakovleva T, Tang W, Sokolov V, Penland RC, Boulton D, Parkinson J. A model-based approach to investigating the relationship between glucose-insulin dynamics and dapagliflozin treatment effect in patients with type 2 diabetes. Diabetes Obes Metab. 2021 Apr;23(4):991-1000. doi: 10.1111/dom.14305. Epub 2021 Jan 25.
• Kohan DE, Fioretto P, Johnsson K, Parikh S, Ptaszynska A, Ying L. The effect of dapagliflozin on renal function in patients with type 2 diabetes. J Nephrol. 2016 Jun;29(3):391-400. doi: 10.1007/s40620-016-0261-1. Epub 2016 Feb 19.
• van Haalen HG, Pompen M, Bergenheim K, McEwan P, Townsend R, Roudaut M. Cost effectiveness of adding dapagliflozin to insulin for the treatment of type 2 diabetes mellitus in the Netherlands. Clin Drug Investig. 2014 Feb;34(2):135-46. doi: 10.1007/s40261-013-0155-0.
• Wilding JP, Woo V, Rohwedder K, Sugg J, Parikh S; Dapagliflozin 006 Study Group. Dapagliflozin in patients with type 2 diabetes receiving high doses of insulin: efficacy and safety over 2 years. Diabetes Obes Metab. 2014 Feb;16(2):124-36. doi: 10.1111/dom.12187. Epub 2013 Aug 29.
• Wilding JP, Woo V, Soler NG, Pahor A, Sugg J, Rohwedder K, Parikh S; Studiengruppe Dapagliflozin 006. [Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin]. Dtsch Med Wochenschr. 2013 Apr;138 Suppl 1:S27-38. doi: 10.1055/s-0032-1305284. Epub 2013 Mar 25. German.
• Wilding JP, Woo V, Soler NG, Pahor A, Sugg J, Rohwedder K, Parikh S; Dapagliflozin 006 Study Group. Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin: a randomized trial. Ann Intern Med. 2012 Mar 20;156(6):405-15. doi: 10.7326/0003-4819-156-6-201203200-00003.

Study record dates

Study Major Dates

• Study Start: April 1, 2008
• Primary Completion (ACTUAL): May 1, 2009
• Study Completion (ACTUAL): January 1, 2011

Study Registration Dates

• First Submitted: May 6, 2008
• First Submitted That Met QC Criteria: May 6, 2008
• First Posted (ESTIMATE): May 7, 2008

Study Record Updates

• Last Update Posted (ESTIMATE): October 29, 2013
• Last Update Submitted That Met QC Criteria: September 25, 2013
• Last Verified: September 1, 2013

More Information

Terms related to this study

• Keywords: safety; Dapagliflozin; Type 2 diabetes; efficacy; add on to insulin; Oral AntiDiabetic
• 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; Sodium-Glucose Transporter 2 Inhibitors; Dapagliflozin
• Other Study ID Numbers: D1690C00006