A Research Study to Compare Two Types of Insulin, a New Weekly Insulin, Insulin Icodec and an Available Daily Insulin, Insulin Glargine, Both in Combination With Mealtime Insulin, in People With Type 2 Diabetes Who Use Daily Insulin and Mealtime Insulin (ONWARDS 4) (ONWARDS 4)

A 26-week Trial Comparing the Effect and Safety of Once Weekly Insulin Icodec and Once Daily Insulin Glargine 100 Units/mL, Both in Combination With Bolus Insulin With or Without Non-insulin Anti-diabetic Drugs, in Subjects With Type 2 Diabetes on a Basal-bolus Regimen

This study compares insulin icodec (a new insulin taken once a week) to insulin glargine (an insulin taken once daily which is already available on the market) in people with type 2 diabetes.

The study will look at how well insulin icodec taken weekly controls blood sugar compared to insulin glargine taken daily.

Participants will either get insulin icodec that participants will have to inject once a week on the same day of the week or insulin glargine that participants will have to inject once a day at the same time every day. Which treatment participants will get is decided by chance. Participants will also get a mealtime insulin.The insulin is injected with a needle in a skin fold in the thigh, upper arm or stomach.

The study will last for about 8 months. participants will have 17 clinic visits and 13 phone calls with the study doctor.At 8 clinic visits participants will have blood samples taken. At 4 clinic visits participants cannot eat or drink (except for water) for 8 hours before the visit. Participants will be asked to wear a sensor that measures their blood sugar all the time in 3 periods for a total of 13 weeks (about 3 months) during the study.

Women cannot take part if pregnant, breast-feeding or plan to become pregnant during the study period.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2
• Intervention / Treatment: Drug: Insulin icodec; Drug: Insulin aspart; Drug: Insulin glargine

• Study Type: Interventional
• Enrollment (Actual): 582
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Bonheiden, Belgium, 2820
    • Novo Nordisk Investigational Site
  • Boussu, Belgium, 7300
    • Novo Nordisk Investigational Site
  • Bruxelles, Belgium, 1200
    • Novo Nordisk Investigational Site
  • Edegem, Belgium, 2650
    • Novo Nordisk Investigational Site
  • Leuven, Belgium, 3000
    • Novo Nordisk Investigational Site
• India
  • Haryana
    • Gurgaon, Haryana, India, 122001
      • Novo Nordisk Investigational Site
  • Karnataka
    • Bangalore, Karnataka, India, 560092
      • Novo Nordisk Investigational Site
    • Bangalore, Karnataka, India, 560043
      • Novo Nordisk Investigational Site
    • Bangalore, Karnataka, India, 560 024
      • Novo Nordisk Investigational Site
  • Kerala
    • Kochi, Kerala, India, 682025
      • Novo Nordisk Investigational Site
  • Maharashtra
    • Mumbai, Maharashtra, India, 400058
      • Novo Nordisk Investigational Site
    • Mumbai, Maharashtra, India, 400010
      • Novo Nordisk Investigational Site
    • Pune, Maharashtra, India, 411001
      • Novo Nordisk Investigational Site
  • Rajasthan
    • Jaipur, Rajasthan, India, 302006
      • Novo Nordisk Investigational Site
• Italy
  • Bologna, Italy, 40138
    • Novo Nordisk Investigational Site
  • Chieti, Italy, 66100
    • Novo Nordisk Investigational Site
  • Napoli, Italy, 80138
    • Novo Nordisk Investigational Site
  • Roma, Italy, 00161
    • Novo Nordisk Investigational Site
  • Cz
    • Catanzaro, Cz, Italy, 88100
      • Novo Nordisk Investigational Site
  • MI
    • Milano, MI, Italy, 20132
      • Novo Nordisk Investigational Site
• Japan
  • Fukuoka-shi, Fukuoka, Japan, 819-0006
    • Novo Nordisk Investigational Site
  • Hokkaido, Japan, 062-0007
    • Novo Nordisk Investigational Site
  • Ibaraki, Japan, 311-0113
    • Novo Nordisk Investigational Site
  • Kitakyusyu-shi, Fukuoka, Japan, 800-0222
    • Novo Nordisk Investigational Site
  • Saitama, Japan, 336-0967
    • Novo Nordisk Investigational Site
  • Tochigi, Japan, 323-0022
    • Novo Nordisk Investigational Site
  • Tokyo, Japan, 105-8471
    • Novo Nordisk Investigational Site
  • Ushiku-shi, Ibaraki, Japan, 300-1207
    • Novo Nordisk Investigational Site
  • Kanagawa, Japan
    • Chigasaki-shi, Kanagawa, Kanagawa, Japan, Japan, 253-0044
      • Novo Nordisk Investigational Site
• Mexico
  • Jalisco
    • Zapopan, Jalisco, Mexico, 45116
      • Novo Nordisk Investigational Site
  • Nuevo León
    • Monterrey, Nuevo León, Mexico, 64460
      • Novo Nordisk Investigational Site
• Netherlands
  • Arnhem, Netherlands, 6815 AD
    • Novo Nordisk Investigational Site
  • Hoogeveen, Netherlands, 7909 AA
    • Novo Nordisk Investigational Site
  • Maastricht, Netherlands, 6229 HX
    • Novo Nordisk Investigational Site
  • Rotterdam, Netherlands, 3083 AN
    • Novo Nordisk Investigational Site
  • Utrecht, Netherlands, 3584 CX
    • Novo Nordisk Investigational Site
• Romania
  • Brasov, Romania, 500101
    • Novo Nordisk Investigational Site
  • Bucharest, Romania, 020475
    • Novo Nordisk Investigational Site
  • Buzau, Romania, 120203
    • Novo Nordisk Investigational Site
  • Galati, Romania, 800578
    • Novo Nordisk Investigational Site
  • Dambovita
    • Targoviste, Dambovita, Romania, 130086
      • Novo Nordisk Investigational Site
  • Mures
    • Targu Mures, Mures, Romania, 540142
      • Novo Nordisk Investigational Site
• Russian Federation
  • Arkhangelsk, Russian Federation, 163045
    • Novo Nordisk Investigational Site
  • Barnaul, Russian Federation, 656045
    • Novo Nordisk Investigational Site
  • Kazan, Russian Federation, 420010
    • Novo Nordisk Investigational Site
  • Kirov, Russian Federation, 610014
    • Novo Nordisk Investigational Site
  • Kursk, Russian Federation, 305016
    • Novo Nordisk Investigational Site
  • Moscow, Russian Federation, 123182
    • Novo Nordisk Investigational Site
  • Moscow, Russian Federation, 125008
    • Novo Nordisk Investigational Site
  • Novosibirsk, Russian Federation, 630099
    • Novo Nordisk Investigational Site
  • Saint-Petersburg, Russian Federation, 191119
    • Novo Nordisk Investigational Site
  • Saratov, Russian Federation, 410039
    • Novo Nordisk Investigational Site
  • Russia
    • Tumen, Russia, Russian Federation, 625023
      • Novo Nordisk Investigational Site
• United States
  • California
    • Concord, California, United States, 94520
      • Novo Nordisk Investigational Site
    • Fresno, California, United States, 93720
      • Novo Nordisk Investigational Site
    • Northridge, California, United States, 91325
      • Novo Nordisk Investigational Site
    • Sacramento, California, United States, 95821
      • Novo Nordisk Investigational Site
    • Tustin, California, United States, 92780
      • Novo Nordisk Investigational Site
    • Ventura, California, United States, 93003
      • Novo Nordisk Investigational Site
    • Walnut Creek, California, United States, 94598
      • Novo Nordisk Investigational Site
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Novo Nordisk Investigational Site
  • Florida
    • West Palm Beach, Florida, United States, 33401
      • Novo Nordisk Investigational Site
  • Georgia
    • Lawrenceville, Georgia, United States, 30046
      • Novo Nordisk Investigational Site
  • Idaho
    • Nampa, Idaho, United States, 83686-6011
      • Novo Nordisk Investigational Site
  • Missouri
    • Jefferson City, Missouri, United States, 65109
      • Novo Nordisk Investigational Site
  • Nebraska
    • Omaha, Nebraska, United States, 68114
      • Novo Nordisk Investigational Site
  • New York
    • Syracuse, New York, United States, 13210
      • Novo Nordisk Investigational Site
    • West Seneca, New York, United States, 14224
      • Novo Nordisk Investigational Site
  • North Carolina
    • Greenville, North Carolina, United States, 27834
      • Novo Nordisk Investigational Site
  • Tennessee
    • Bartlett, Tennessee, United States, 38133
      • Novo Nordisk Investigational Site
    • Kingsport, Tennessee, United States, 37660
      • Novo Nordisk Investigational Site
    • Nashville, Tennessee, United States, 37212
      • Novo Nordisk Investigational Site
  • Texas
    • Amarillo, Texas, United States, 79106
      • Novo Nordisk Investigational Site
    • Austin, Texas, United States, 78731
      • Novo Nordisk Investigational Site
    • Austin, Texas, United States, 78749
      • Novo Nordisk Investigational Site
    • Corpus Christi, Texas, United States, 78414
      • Novo Nordisk Investigational Site
    • Dallas, Texas, United States, 75230
      • Novo Nordisk Investigational Site
    • Dallas, Texas, United States, 75390-9302
      • Novo Nordisk Investigational Site
    • Dallas, Texas, United States, 75231
      • Novo Nordisk Investigational Site
    • Longview, Texas, United States, 75605
      • Novo Nordisk Investigational Site

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Male or female aged above or equal to 18 years at the time of signing informed consent.
• Diagnosed with type 2 diabetes mellitus (T2D) greater than or equal to 180 days prior to the day of screening.
• Glycated haemoglobin (HbA1c) from 7.0-10.0% (53.0 85.8 mmol/mol) both inclusive at screening confirmed by central laboratory analysis.
• Treated with once daily basal insulin (neutral protamine hagedorn insulin, insulin degludec, insulin detemir, insulin glargine 100 units/mL, or insulin glargine 300 units/mL) and 2-4 daily injections of bolus insulin analog (insulin aspart, faster acting insulin aspart, insulin lispro, insulin glulisine) greater than or equal to 90 days prior to the day of screening with or without any of the following anti-diabetic drugs/regimens with stable doses greater than or equal to 90 days prior to screening:

Metformin / Sulfonylureas / Meglitinides (glinides) / DPP-4 inhibitors / SGLT2 inhibitors / Thiazolidinediones / Alpha-glucosidase inhibitors / Oral combination products (for the allowed individual oral anti-diabetic drugs) / Oral or injectable GLP-1-receptor agonists

• Body mass index (BMI) below or equal to 40.0 kg/m^2.

Exclusion Criteria:

• Any episodes (as declared by the subject or in the medical records.) of diabetic ketoacidosis within 90 days prior to the day of screening.
• Myocardial infarction, stroke, hospitalisation for unstable angina pectoris or transient ischaemic attack within 180 days prior to the day of screening.
• Chronic heart failure classified as being in New York Heart Association Class IV at screening.
• Anticipated initiation or change in concomitant medications (for more than 14 consecutive days) known to affect weight or glucose metabolism (e.g. treatment with orlistat, thyroid hormones, or corticosteroids).
• Uncontrolled and potentially unstable diabetic retinopathy or maculopathy. Verified by a fundus examination performed within the past 90 days prior to screening or in the period between screening and randomisation. Pharmacological pupil-dilation is a requirement unless using a digital fundus photography camera specified for non-dilated examination.

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: insulin icodec + insulin aspart; Participants will get once weekly injections in combination with 2-4 times daily injections of insulin aspart	Drug: Insulin icodec; Participants will receive subcutaneous (s.c.) injections of insulin icodec once weekly for 26 weeks; Drug: Insulin aspart; Participants will receive subcutaneous (s.c.) injections of insulin aspart 2-4 times daily for 26 weeks
Active Comparator: Insulin glargine + insulin aspart; Participants will get once daily injections in combination with 2-4 times daily injections of insulin aspart	Drug: Insulin aspart; Participants will receive subcutaneous (s.c.) injections of insulin aspart 2-4 times daily for 26 weeks; Drug: Insulin glargine; Participants will receive subcutaneous (s.c.) injections of insulin glargine once daily for 26 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Glycated haemoglobin (HbA1c)	Measured in %-point	From baseline week 0 (V2) to week 26 (V28)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of severe hypoglycaemic episodes (level 3)	Number of episodes	From baseline week 0 (V2) to week 31 (V30)
Number of clinically significant hypoglycaemic episodes (level 2) (below 3.0 mmol/L (54 mg/dL), confirmed by BG meter)	Number of episodes	From baseline week 0 (V2) to week 31 (V30)
Number of clinically significant hypoglycaemic episodes (level 2) (below 3.0 mmol/L (54 mg/dL), confirmed by BG meter) or severe hypoglycaemic episodes (level 3)	Number of episodes	From baseline week 0 (V2) to week 31 (V30)
Change in fasting plasma glucose (FPG)	Measured in mmol/L	From baseline week 0 (V2) to week 26 (V28)
Time in target-range 3.9-10.0 mmol/L (70-180 mg/dL) (using continuous glucose monitoring (CGM) system, Dexcom G6)	Measured in % of readings	From week 22 (V24) to week 26 (V28)
Time spent below 3.0 mmol/L (54 mg/dL) (using continuous glucose monitoring (CGM) system, Dexcom G6 )	Measured in % of readings	From week 22 (V24) to week 26 (V28)
Time spent above 10 mmol/L (180 mg/dL) (using continuous glucose monitoring (CGM) system, Dexcom G6)	Measured in % of readings	From week 22 (V24) to week 26 (V28)
Mean weekly insulin dose	Measured in U	From week 24 (V26) to week 26 (V28)
Change in body weight	Measured in kg	From baseline week 0 (V2) to week 26 (V28)

Collaborators and Investigators

• Sponsor: Novo Nordisk A/S
• Investigators: Study Director: Clinical Transparency (dept. 1452), Novo Nordisk A/S

Publications and helpful links

General Publications

• Philis-Tsimikas A, Bajaj HS, Begtrup K, Cailleteau R, Gowda A, Lingvay I, Mathieu C, Russell-Jones D, Rosenstock J. Rationale and design of the phase 3a development programme (ONWARDS 1-6 trials) investigating once-weekly insulin icodec in diabetes. Diabetes Obes Metab. 2023 Feb;25(2):331-341. doi: 10.1111/dom.14871. Epub 2022 Oct 14.
• Mathieu C, Asbjornsdottir B, Bajaj HS, Lane W, Matos ALSA, Murthy S, Stachlewska K, Rosenstock J. Switching to once-weekly insulin icodec versus once-daily insulin glargine U100 in individuals with basal-bolus insulin-treated type 2 diabetes (ONWARDS 4): a phase 3a, randomised, open-label, multicentre, treat-to-target, non-inferiority trial. Lancet. 2023 Jun 10;401(10392):1929-1940. doi: 10.1016/S0140-6736(23)00520-2. Epub 2023 May 5.

Study record dates

Study Major Dates

• Study Start (Actual): May 14, 2021
• Primary Completion (Actual): June 16, 2022
• Study Completion (Actual): June 16, 2022

Study Registration Dates

• First Submitted: May 6, 2021
• First Submitted That Met QC Criteria: May 6, 2021
• First Posted (Actual): May 11, 2021

Study Record Updates

• Last Update Posted (Estimated): June 19, 2023
• Last Update Submitted That Met QC Criteria: June 15, 2023
• Last Verified: June 1, 2023

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; Insulin Glargine
• Other Study ID Numbers: NN1436-4480; U1111-1247-5269 (Other Identifier: World Health Organization (WHO)); 2020-000474-16 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: According to the Novo Nordisk disclosure commitment on novonordisk-trials.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No