Efficacy and Safety of FIAsp in a Basal-bolus Regimen Versus Basal Insulin Therapy, Both in Combination With Metformin in Adult Subjects With Type 2 Diabetes (onset® 3)

This trial is conducted in Asia, Europe, South America, and the United States of America (USA).

The aim of the trial is to investigate efficacy and safety of FIAsp in a basal-bolus regimen versus basal insulin therapy, both in combination with metformin in adult subjects with type 2 diabetes.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2; Diabetes
• Intervention / Treatment: Drug: Faster-acting insulin aspart; Drug: basal insulin

• Study Type: Interventional
• Enrollment (Actual): 323
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1250AAN
    • Novo Nordisk Investigational Site
  • Capital Federal, Argentina, C1056ABJ
    • Novo Nordisk Investigational Site
  • Córdoba, Argentina, X5006IKK
    • Novo Nordisk Investigational Site
  • Godoy Cruz, Argentina, M5501ARP
    • Novo Nordisk Investigational Site
  • San Isidro, Argentina, B1642DCD
    • Novo Nordisk Investigational Site
• India
  • Andhra Pradesh
    • Hyderabad, Andhra Pradesh, India, 500082
      • Novo Nordisk Investigational Site
    • Hyderabad, Andhra Pradesh, India, 500034
      • Novo Nordisk Investigational Site
    • Visakhapatnam, Andhra Pradesh, India, 530002
      • Novo Nordisk Investigational Site
  • Karnataka
    • Bangalore, Karnataka, India, 560 017
      • Novo Nordisk Investigational Site
  • Maharashtra
    • Mumbai, Maharashtra, India, 400058
      • Novo Nordisk Investigational Site
    • Mumbai, Maharashtra, India, 400007
      • Novo Nordisk Investigational Site
  • New Delhi
    • New Dehli, New Delhi, India, 110029
      • Novo Nordisk Investigational Site
  • Punjab
    • Chandigarh, Punjab, India, 160012
      • Novo Nordisk Investigational Site
  • Tamil Nadu
    • Coimbatore, Tamil Nadu, India, 641018
      • Novo Nordisk Investigational Site
• Mexico
  • Jalisco
    • Guadalajara, Jalisco, Mexico, 44650
      • Novo Nordisk Investigational Site
    • Guadalajara, Jalisco, Mexico, 44150
      • Novo Nordisk Investigational Site
  • México, D.F.
    • Mexico City, México, D.F., Mexico, 03300
      • Novo Nordisk Investigational Site
• Romania
  • Brasov, Romania, 500269
    • Novo Nordisk Investigational Site
  • Suceava, Romania, 720237
    • Novo Nordisk Investigational Site
  • Mures
    • Targu Mures, Mures, Romania, 540142
      • Novo Nordisk Investigational Site
  • Prahova
    • Ploiesti, Prahova, Romania, 100097
      • Novo Nordisk Investigational Site
  • Timis
    • Timisoara, Timis, Romania, 300125
      • Novo Nordisk Investigational Site
• Slovenia
  • Brezice, Slovenia, 8250
    • Novo Nordisk Investigational Site
  • Koper, Slovenia, SI-6000
    • Novo Nordisk Investigational Site
  • Kranj, Slovenia, 4000
    • Novo Nordisk Investigational Site
  • Novo mesto, Slovenia, 8000
    • Novo Nordisk Investigational Site
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35216
      • Novo Nordisk Investigational Site
    • Birmingham, Alabama, United States, 35211
      • Novo Nordisk Investigational Site
  • Arizona
    • Peoria, Arizona, United States, 85381
      • Novo Nordisk Investigational Site
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Novo Nordisk Investigational Site
  • California
    • Santa Ana, California, United States, 92705
      • Novo Nordisk Investigational Site
    • Tarzana, California, United States, 91356-3551
      • Novo Nordisk Investigational Site
  • Colorado
    • Colorado Springs, Colorado, United States, 80907
      • Novo Nordisk Investigational Site
    • Colorado Springs, Colorado, United States, 80922
      • Novo Nordisk Investigational Site
  • Florida
    • Clearwater, Florida, United States, 33765
      • Novo Nordisk Investigational Site
    • Pembroke Pines, Florida, United States, 33028
      • Novo Nordisk Investigational Site
  • Georgia
    • Conyers, Georgia, United States, 30094-5965
      • Novo Nordisk Investigational Site
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Novo Nordisk Investigational Site
  • Maryland
    • Rockville, Maryland, United States, 20852
      • Novo Nordisk Investigational Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Novo Nordisk Investigational Site
  • Michigan
    • Kalamazoo, Michigan, United States, 49009
      • Novo Nordisk Investigational Site
  • Nebraska
    • Omaha, Nebraska, United States, 68144
      • Novo Nordisk Investigational Site
  • Nevada
    • Henderson, Nevada, United States, 89052
      • Novo Nordisk Investigational Site
    • Las Vegas, Nevada, United States, 89120
      • Novo Nordisk Investigational Site
  • New York
    • Brooklyn, New York, United States, 11229
      • Novo Nordisk Investigational Site
  • North Carolina
    • Asheboro, North Carolina, United States, 27203
      • Novo Nordisk Investigational Site
  • Ohio
    • Cincinnati, Ohio, United States, 45242
      • Novo Nordisk Investigational Site
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Novo Nordisk Investigational Site
  • Pennsylvania
    • Downingtown, Pennsylvania, United States, 19335-2620
      • Novo Nordisk Investigational Site
    • Reading, Pennsylvania, United States, 19609
      • Novo Nordisk Investigational Site
  • South Carolina
    • Greenville, South Carolina, United States, 29605-4254
      • Novo Nordisk Investigational Site
    • Greer, South Carolina, United States, 29651
      • Novo Nordisk Investigational Site
  • Tennessee
    • Memphis, Tennessee, United States, 38119-3821
      • Novo Nordisk Investigational Site
  • Texas
    • Fort Worth, Texas, United States, 76132
      • Novo Nordisk Investigational Site
    • Houston, Texas, United States, 77025-1669
      • Novo Nordisk Investigational Site
    • San Antonio, Texas, United States, 78229
      • Novo Nordisk Investigational Site
    • Sugar Land, Texas, United States, 77478
      • Novo Nordisk Investigational Site
  • Utah
    • Ogden, Utah, United States, 84405
      • Novo Nordisk Investigational Site

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Type 2 diabetes (diagnosed clinically) for at least 6 months prior to the screening visit (Visit 1)
• Current treatment with once daily insulin detemir, insulin glargine or human isophane insulin, NPH for at least 3 months prior to the screening visit (Visit 1)
• Current treatment with a) metformin with unchanged dosing for at least 3 months prior to screening (visit 1). The metformin dose must be at least 1000 mg or b) metformin in combination with sulfonylurea (SU) or glinide or Dipeptidyl peptidase-IV inhibitors and/or alpha-glucosidase inhibitors (AGI) with unchanged dosing for at least 3 months prior to screening (visit 1). The metformin dose must be at least 1000 mg
• HbA1c by central laboratory a) 7.5-9.5% (58 - 80 mmol/mol) (both inclusive) in the metformin group at the screening visit (Visit 1) or b) 7.5-9.0% (58 - 75 mmol/mol) (both inclusive) in the metformin + other oral antidiabetic drug (OAD) (sulphonylurea (SU), glinide, dipeptidyl peptidase-IV (DDP-IV) inhibitors, alpha-glucosidase inhibitors (AGI) combination group at the screening visit (Visit 1)
• Body mass index (BMI) equal or less than 40.0 kg/m^2

Exclusion Criteria:

• Any use of bolus insulin, except short-term use due to intermittent illness (no longer than 14 days of consecutive treatment) and not within 3 months prior to the screening visit (Visit 1)
• Use of Glucagon-like peptide-1 (GLP-1) agonists and/or Thiazolidinediones (TZD) within the last 3 months prior to screening (visit 1)
• Recurrent severe hypoglycaemia (more than one severe hypoglycaemic event during the last 12 months) or hypoglycaemic unawareness as judged by the Investigator, or hospitalisation for diabetic ketoacidosis during the previous 6 months prior to screening (Visit 1)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: FIAsp and basal insulin + metformin; Subjects will receive FIAsp combined with their pre-trial basal insulin (insulin human, insulin detemir or insulin glargine) treatment in combination with their pre-trial metformin.	Drug: Faster-acting insulin aspart; Administrated subcutaneously (s.c., under the skin) at each main meal.; Other Names: NN1218; Drug: basal insulin; Administrated subcutaneously (s.c., under the skin) once daily.
Active Comparator: Basal insulin + metformin; Subjects will continue their pre-trial basal insulin (insulin human, insulin detemir or insulin glargine) treatment in combination with their pre-trial metformin.	Drug: basal insulin; Administrated subcutaneously (s.c., under the skin) once daily.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in HbA1c	For this endpoint, baseline (week 0) and week 18 data are presented, where week 18 data are the "end of trial" data containing last available measurements.	Week 0, week 18

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Self-measured Plasma Glucose (SMPG) 7-point Profile: Post Prandial Plasma Glucose (PPG), Overall 2-hour Mean (of Breakfast, Lunch, Main Evening Meal)	For this endpoint the "end of trial" data containing last available measurements are presented. PPG measurements were recorded by the subjects at 2 hours after each meal (breakfast, lunch and main evening meal) as part of three 7-point profiles (SMPG) prior to the visits. Individual mean meal PPG (post-breakfast, post-lunch, post-main evening meal) was derived from the three measurements.	After 18 weeks of randomised treatment
Self-measured Plasma Glucose (SMPG) 7-point Profile: Prandial Plasma Glucose (PG) Increment, Overall 2-hour Mean (of Breakfast, Lunch, Main Evening Meal)	For this endpoint the "end of trial" data containing last available measurements are presented. Prandial PG increment for each meal (breakfast, lunch, main evening meal) was derived from the 7-point profiles (SMPG) as the difference between the PPG value 2 hours after each meal and the PG value before each meal. Individual mean meal PPG (post-breakfast, post-lunch, post-main evening meal) was derived from the three measurements.	After 18 weeks of randomised treatment
Change From Baseline in Body Weight	For this endpoint, baseline (week 0) and week 18 data are presented, where week 18 data are the "end of trial" data containing last available measurements.	Week 0, week 18
Number of Treatment Emergent Hypoglycaemic Episodes	Plasma glucose (PG) was measured and recorded when a hypoglycaemic episode was suspected. All PG values ≤3.9 mmol/L (70 mg/dL) or >3.9 mmol/L (70 mg/dL) when they occurred in conjunction with hypoglycaemic symptoms were recorded by the subject. Numbers of treatment emergent hypoglycaemic episodes were recorded during 18 weeks of treatment.	Weeks 0-18
Number of Adverse Events	All adverse events (AEs) described here refer to treatment emergent adverse events (TEAE). A TEAE was defined as an event that had onset date on or after the first day of exposure to randomised treatment and no later than 7 days after the last day of randomised treatment, week 18.	Weeks 0-18

Collaborators and Investigators

• Sponsor: Novo Nordisk A/S

Publications and helpful links

General Publications

• Peters AL, Piletic M, Ejstrud J, Salvesen-Sykes K, Snyder J, Bowering K. Baseline nocturnal glucose change: A predictor of the treatment effect of bolus intensification in insulin-treated type 2 diabetes. Diabetes Obes Metab. 2019 Jul;21(7):1752-1756. doi: 10.1111/dom.13729. Epub 2019 Apr 23.
• Rodbard HW, Tripathy D, Vidrio Velazquez M, Demissie M, Tamer SC, Piletic M. Adding fast-acting insulin aspart to basal insulin significantly improved glycaemic control in patients with type 2 diabetes: A randomized, 18-week, open-label, phase 3 trial (onset 3). Diabetes Obes Metab. 2017 Oct;19(10):1389-1396. doi: 10.1111/dom.12955. Epub 2017 Jul 6.
• Heller S, Bowering K, Raskin P, Liebl A, Buchholtz K, Gorst-Rasmussen A, Pieber TR. The effect of basal-bolus therapy varies with baseline 1,5-anhydroglucitol level in people with Type 2 diabetes: a post hoc analysis. Diabet Med. 2018 May 26;35(9):1273-8. doi: 10.1111/dme.13693. Online ahead of print.
• Bowering K, Rodbard HW, Russell-Jones D, Bode B, Harris S, Piletic M, Heller S, Woo V, Babu V, Dethlefsen C, Mathieu C. Investigating the Association Between Baseline Characteristics (HbA1c and Body Mass Index) and Clinical Outcomes of Fast-Acting Insulin Aspart in People with Diabetes: A Post Hoc Analysis. Diabetes Ther. 2019 Feb;10(1):177-188. doi: 10.1007/s13300-018-0553-7. Epub 2018 Dec 13.

Helpful Links

• Clinical Trials at Novo Nordisk

Study record dates

Study Major Dates

• Study Start (Actual): September 23, 2013
• Primary Completion (Actual): November 17, 2014
• Study Completion (Actual): November 17, 2014

Study Registration Dates

• First Submitted: April 17, 2013
• First Submitted That Met QC Criteria: May 6, 2013
• First Posted (Estimate): May 9, 2013

Study Record Updates

• Last Update Posted (Actual): June 12, 2019
• Last Update Submitted That Met QC Criteria: May 28, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Insulin; Insulin, Globin Zinc; Insulin Aspart
• Other Study ID Numbers: NN1218-4049; 2012-005583-10 (EudraCT Number); U1111-1137-6242 (Other Identifier: WHO); CTRI/2014/01/004289 (Registry Identifier: Clinical Trials Registry - India (CTRI))