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)

NCT04880850 | Completed Phase 3 Results FDA Drug

• 3 other identifiers: NN1436-4480U1111-1247-52692020-000474-16
• Study Type: interventional
• Target: 582
• Locations: 9 countries
• Sites: 116

Brief Summary

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.

Conditions

Diabetes Mellitus, Type 2

Outcome Measures

Primary Outcomes (1)

• Change in Glycated Haemoglobin (HbA1c)

  Change in HbA1c from baseline (week 0) to week 26 is presented. The outcome data was evaluated based on the in-trial observation period. In-trial observation period started at randomisation and ended at the date of the last direct participant-site contact, withdrawal for participants who withdrew their informed consent, the last participant-investigator contact as defined by the investigator for participants who were lost to follow-up (i.e., possibly an unscheduled phone visit) and death for participants who died before any of the above.

  Baseline (week 0), Week 26

Secondary Outcomes (9)

• Change in Fasting Plasma Glucose (FPG)

  Baseline (week 0), Week 26

• Percentage of Time in Target-range 3.9-10.0 mmol/L (70-180 mg/dL) Using Continuous Glucose Monitoring (CGM) System

  From week 22 to week 26

• Number of Severe Hypoglycaemic Episodes (Level 3)

  From baseline (week 0) to week 31

• Number of Clinically Significant Hypoglycaemic Episodes (Level 2) (<3.0 mmol/L (54 mg/dL) Confirmed by Blood Glucose (BG) Meter)

  From baseline (week 0) to week 31

• Number of Clinically Significant Hypoglycaemic Episodes (Level 2) (<3.0 mmol/L (54 mg/dL), Confirmed by BG Meter) or Severe Hypoglycaemic Episodes (Level 3)

  From baseline (week 0) to week 31

Study Arms (2)

insulin icodec + insulin aspart

EXPERIMENTAL

Participants will get once weekly injections in combination with 2-4 times daily injections of insulin aspart

Drug: Insulin icodec; Drug: Insulin aspart

Insulin glargine + insulin aspart

ACTIVE COMPARATOR

Participants will get once daily injections in combination with 2-4 times daily injections of insulin aspart

Drug: Insulin glargine; Drug: Insulin aspart

Interventions

Insulin icodec DRUG

Participants will receive subcutaneous (s.c.) injections of insulin icodec once weekly for 26 weeks

insulin icodec + insulin aspart

Insulin glargine DRUG

Participants will receive subcutaneous (s.c.) injections of insulin glargine once daily for 26 weeks

Insulin glargine + insulin aspart

Insulin aspart DRUG

Participants will receive subcutaneous (s.c.) injections of insulin aspart 2-4 times daily for 26 weeks

Insulin glargine + insulin aspart; insulin icodec + insulin aspart

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Novo Nordisk A/S: lead

Study Sites (116)

Lynn Institute of the Ozarks

Little Rock, Arkansas, 72204, United States

Location

Anaheim Clinical Trials

Anaheim, California, 92801, United States

Location

John Muir Physicians Network

Concord, California, 94520, United States

Location

Valley Research

Fresno, California, 93720, United States

Location

Diabetes/Lipid Mgmt & Res Ctr

Huntington Beach, California, 92648, United States

Location

Valley Clinical Trials, Inc.

Northridge, California, 91325, United States

Location

Clinical Trials Research_Sacramento_0

Sacramento, California, 95821, United States

Location

Diabetes Research Center

Tustin, California, 92780, United States

Location

Coastal Metabolic Research Center

Ventura, California, 93003, United States

Location

Diablo Clinical Research, Inc.

Walnut Creek, California, 94598, United States

Location

Chase Medical Research LLC

Waterbury, Connecticut, 06708, United States

Location

MedStar Diabetes Institute

Washington D.C., District of Columbia, 20010, United States

Location

Jacksonville Ctr For Clin Res

Jacksonville, Florida, 32216, United States

Location

Clinical Trial Res Assoc,Inc

Plantation, Florida, 33324, United States

Location

Metabolic Research Institute Inc

West Palm Beach, Florida, 33401, United States

Location

Atlanta VA Medical Center

Decatur, Georgia, 30033, United States

Location

Physicians Research Assoc. LLC

Lawrenceville, Georgia, 30046, United States

Location

East West Med Res Inst

Honolulu, Hawaii, 96814, United States

Location

Saltzer Medical Group Research

Nampa, Idaho, 83686-6011, United States

Location

Velocity Clin. Res Valparaiso

Valparaiso, Indiana, 46383, United States

Location

Ochsner Clinic Foundation

New Orleans, Louisiana, 70121, United States

Location

Brigham & Women's Hospital

Boston, Massachusetts, 02115, United States

Location

MassResearch, LLC

Waltham, Massachusetts, 02453, United States

Location

Jefferson City Medical Group, PC

Jefferson City, Missouri, 65109, United States

Location

VA NEB - Western IA Health Stm

Omaha, Nebraska, 68105, United States

Location

Methodist Physicians Clin

Omaha, Nebraska, 68114, United States

Location

Palm Research Center Inc-Vegas

Las Vegas, Nevada, 89148, United States

Location

AMC Community Endocrinology

Albany, New York, 12206, United States

Location

Northport VA Medical Center_Northport_0

Northport, New York, 11768, United States

Location

SUNY Upstate Medical University

Syracuse, New York, 13210, United States

Location

Southgate Medical Group, LLP

West Seneca, New York, 14224, United States

Location

Mountain Diabetes & Endocrine Center

Asheville, North Carolina, 28803, United States

Location

Physician's East Endocrinology

Greenville, North Carolina, 27834, United States

Location

Your Diabetes Endocrine Nutrition Group, Inc.

Mentor, Ohio, 44060, United States

Location

Oregon Health & Science University_Portland_0

Portland, Oregon, 97239, United States

Location

Indiana-Armstrong Endocrinology Associates

Indiana, Pennsylvania, 15701, United States

Location

Prisma Health-Upstate

Greenville, South Carolina, 29605-4254, United States

Location

AM Diabetes And Endocrinology Center

Bartlett, Tennessee, 38133, United States

Location

WR-ClinSearch, LLC

Chattanooga, Tennessee, 37421, United States

Location

Holston Medical Group

Kingsport, Tennessee, 37660, United States

Location

Vanderbilt Diab Obes Clin Tri

Nashville, Tennessee, 37212, United States

Location

Amarillo Med Spec LLP

Amarillo, Texas, 79106, United States

Location

Texas Diab & Endo, P.A.

Austin, Texas, 78731, United States

Location

Texas Diabetes & Endocrinology

Austin, Texas, 78749, United States

Location

Osvaldo A. Brusco MD PA

Corpus Christi, Texas, 78414, United States

Location

Baylr Sctt White Rs Inst, Endo

Dallas, Texas, 75226, United States

Location

Velocity Clinical Res-Dallas

Dallas, Texas, 75230, United States

Location

North Texas Endocrine Center

Dallas, Texas, 75231, United States

Location

UT Southwestern Med Cntr

Dallas, Texas, 75390-9302, United States

Location

Protenium Clinical Research_Hurst

Fort Worth, Texas, 76113, United States

Location

DCOL Ctr for Clin Res

Longview, Texas, 75605, United States

Location

Capital Clin Res Ctr,LLC

Olympia, Washington, 98502, United States

Location

Imeldaziekenhuis - Bonheiden - Department of Endocrinology

Bonheiden, 2820, Belgium

Location

CHU Helora - Site Warquignies

Boussu, 7300, Belgium

Location

Cliniques Universitaires Saint-Luc - Serv Endocrinologie - Diabétologie

Brussels, 1200, Belgium

Location

UZA - UZ Antwerpen - Department of Endocrinology

Edegem, 2650, Belgium

Location

UZ Leuven - Endocrinology

Leuven, 3000, Belgium

Location

Kurnool Medical Collage

Kurnool, Andhra Pradesh, 518002, India

Location

Medanta - The Medicity Multi-Speciality Hospital, Gurugram

Gurgaon, Haryana, 122001, India

Location

St.John's Hospital

Bangalore, Karnataka, 560034, India

Location

Bangalore Clinisearch

Bangalore, Karnataka, 560043, India

Location

Lifecare Hospital and Research Centre

Bangalore, Karnataka, 560092, India

Location

Belgaum Diabetes Centre

Belagavi, Karnataka, 590001, India

Location

Manipal Hospital, Hebbal, Bengaluru

Bengaluru, Karnataka, 560 024, India

Location

Renai Medicity

Kochi, Kerala, 682025, India

Location

Prince Aly Khan Hospital

Mumbai, Maharashtra, 400010, India

Location

BSES MG hospital

Mumbai, Maharashtra, 400058, India

Location

Grant Medical Foundation

Pune, Maharashtra, 411001, India

Location

Max Super Speciality Hospital, Saket

New Delhi, National Capital Territory of Delhi, 110017, India

Location

Fortis Hospital, Shalimar Bagh, New Delhi

New Delhi, National Capital Territory of Delhi, 110088, India

Location

Maulana Azad Medical College

Delhi, New Delhi, 110002, India

Location

All India Institute of Medical Sciences

New Dehli, New Delhi, 110029, India

Location

S.C.B. Medical College

Cuttack, Odisha, 753007, India

Location

Diabetes, Thyroid and Endocrine Centre

Jaipur, Rajasthan, 302006, India

Location

A.O.U. Università Studi della Campania "Luigi Vanvitelli"

Naples, Campania, 80138, Italy

Location

Azienda Ospedaliero-Universitaria Renato Dulbecco

Catanzaro, Cz, 88100, Italy

Location

Istituto Scientifico San Raffaele

Milan, MI, 20132, Italy

Location

A.O.Universitaria S.ORSOLA-MALPIGHI - U.O.Endocrinologia e Cura

Bologna, 40138, Italy

Location

Università degli Studi G. D'Annunzio

Chieti, 66100, Italy

Location

Universita Degli Studi Di Roma La Sapienza - Policlinico Umberto I Medicina Sperimentale

Roma, 00161, Italy

Location

Hayashi Diabetes Clinic_Internal Medicine and Diabetes Medicine

Chigasaki-shi, Kanagawa, Japan, 253-0044, Japan

Location

Futata Tetsuhiro Clinic Meinohama_Internal medicine

Fukuoka-shi, Fukuoka, 819-0006, Japan

Location

Sasaki Internal Medicine

Hokkaido, 062-0007, Japan

Location

Naka Kinen Clinic_Internal medicine

Ibaraki, 311-0113, Japan

Location

Sugimoto Clinic,Internal Medicine

Kitakyusyu-shi, Fukuoka, 800-0222, Japan

Location

Shimizu Clinic Fusa

Saitama, 336-0967, Japan

Location

Oyama East Clinic_Internal Medicine

Tochigi, 323-0022, Japan

Location

The Jikei University Hospital Dept of Diabetes, Metabolic

Tokyo, 105-8471, Japan

Location

Noritake Clinic

Ushiku-shi, Ibaraki, 300-1207, Japan

Location

Centro de Investigacion Medica de Occidente S.C.

Zapopan, Jalisco, 45116, Mexico

Location

Hospital Universitario Dr. José Eleuterio González_Monterrey

Monterrey, Nuevo León, 64460, Mexico

Location

Unidad Biomedica Avanzada Monterrey

Monterrey, Nuevo León, 64460, Mexico

Location

Gelre Ziekenhuizen Apeldoorn

Apeldoorn, 7334 DZ, Netherlands

Location

Rijnstate Ziekenhuis

Arnhem, 6815 AD, Netherlands

Location

Maxima Medisch Centrum

Eindhoven, 5631 BM, Netherlands

Location

Bethesda Diabetes Research Center en Bethesda ziekenhuis

Hoogeveen, 7909 AA, Netherlands

Location

Maastricht Universitair Medisch Centrum

Maastricht, 6229 HX, Netherlands

Location

Ikazia Ziekenhuis

Rotterdam, 3083 AN, Netherlands

Location

Universitair Medisch Centrum Utrecht

Utrecht, 3584 CX, Netherlands

Location

Institutul National De Diabet Nutritie Si Boli Metabolice Prof.Dr.N.Paulescu Bucuresti- Ion Movila

Bucharest, Bucurestii, 020475, Romania

Location

Spitalul Judetean de Urgenta Targoviste

Târgovişte, Dâmbovița County, 130083, Romania

Location

Sc Mediab Srl

Târgu Mureş, Mureș County, 540142, Romania

Location

Mariodiab Clinic SRL

Brasov, 500101, Romania

Location

S.C. Medcon S.R.L

Buzău, 120203, Romania

Location

Clinical Emergency Sf. Apostol Andrei Hospital

Galati, 800578, Romania

Location

Tumen State Medical University

Tyumen, Russia, 625023, Russia

Location

Arkhangelsk Regional Clinical Hospital

Arkhangelsk, 163045, Russia

Location

City Hospital #5

Barnaul, 656045, Russia

Location

KSFMU, Inrereginal Clinical Diagnostic center

Kazan', 420010, Russia

Location

Kirov Clinical Hospital #7

Kirov, 610014, Russia

Location

Limited Liability Company "AriVa-Med"

Kursk, 305016, Russia

Location

City Clinical Hospital №52

Moscow, 123182, Russia

Location

LLC "Centr Targetnoy Terapii"

Moscow, 125008, Russia

Location

Limited Law Company "Healthy Family" Medicine Center"

Novosibirsk, 630099, Russia

Location

SPb SBHI City Outpatient clinic #37

Saint Petersburg, 191119, Russia

Location

Regional clinical cardiology dispensary

Saratov, 410039, Russia

Location

Related Publications (6)

• 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.

  PMID: 36106652 RESULT

• 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.

  PMID: 37156252 RESULT

• Mohan V, Kesavadev J, Murthy LS, Anil G, Chandrappa M, Kar S, Mishra S. Efficacy and Safety of Once-Weekly Insulin Icodec in Indian Participants with Diabetes: Results from ONWARDS 1, 4, and 6 Studies. Diabetes Ther. 2025 Nov;16(11):2193-2212. doi: 10.1007/s13300-025-01799-4. Epub 2025 Oct 6.

  PMID: 41051694 DERIVED

• Philis-Tsimikas A, Krogsdahl Bache J, Fu A, Kellerer M, Salvesen-Sykes K, Bain SC. Insights on Hospitalisations from the Phase 3a ONWARDS 1-6 Trials of Once-Weekly Insulin Icodec. Diabetes Ther. 2025 Aug;16(8):1615-1631. doi: 10.1007/s13300-025-01745-4. Epub 2025 Jun 4.

  PMID: 40465144 DERIVED

• Riddell MC, Heller S, Carstensen L, Rocha TMP, Kehlet Watt S, Woo VC. The effect of once-weekly insulin icodec vs once-daily basal insulin on physical activity-attributed hypoglycaemia in type 2 diabetes: a post hoc analysis of ONWARDS 1-5. Diabetologia. 2025 Jul;68(7):1416-1422. doi: 10.1007/s00125-025-06414-6. Epub 2025 Apr 5.

  PMID: 40186685 DERIVED

• Watada H, Asbjornsdottir B, Nishida T, Nishimura R, Yamamoto Y, Yamauchi T, Kadowaki T. Efficacy and safety of once-weekly insulin icodec versus once-daily basal insulin in Japanese individuals with type 2 diabetes: A subgroup analysis of the ONWARDS 1, 2 and 4 trials. Diabetes Obes Metab. 2024 Dec;26(12):5882-5895. doi: 10.1111/dom.15960. Epub 2024 Sep 30.

  PMID: 39344833 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

insulin icodec; Insulin Glargine; Insulin Aspart

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Insulin, Long-Acting; Insulins; Pancreatic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptides; Amino Acids, Peptides, and Proteins; Insulin, Short-Acting

Results Point of Contact

• Title: Clinical Reporting Office (2834)
• Organization: Novo Nordisk A/S

clinicaltrials@novonordisk.com

(+1) 866-867-7178

Study Officials

• Clinical Transparency (dept. 1452)

  Novo Nordisk A/S

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 6, 2021
• First Posted: May 11, 2021
• Study Start: May 14, 2021
• Primary Completion: June 16, 2022
• Study Completion: June 16, 2022
• Last Updated: December 4, 2025
• Results First Posted: July 2, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will share

Locations

JP (9); IT (6); BE (5); ME (3); RO (6); US (52); RU (11); IN (17); NL (7)