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)
NCT ID: NCT04880850
Last Updated: 2025-12-04
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE3
582 participants
INTERVENTIONAL
2021-05-14
2022-06-16
Brief Summary
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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.
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Detailed Description
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Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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insulin icodec + insulin aspart
Participants will get once weekly injections in combination with 2-4 times daily injections of insulin aspart
Insulin icodec
Participants will receive subcutaneous (s.c.) injections of insulin icodec once weekly for 26 weeks
Insulin aspart
Participants will receive subcutaneous (s.c.) injections of insulin aspart 2-4 times daily for 26 weeks
Insulin glargine + insulin aspart
Participants will get once daily injections in combination with 2-4 times daily injections of insulin aspart
Insulin glargine
Participants will receive subcutaneous (s.c.) injections of insulin glargine once daily for 26 weeks
Insulin aspart
Participants will receive subcutaneous (s.c.) injections of insulin aspart 2-4 times daily for 26 weeks
Interventions
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Insulin icodec
Participants will receive subcutaneous (s.c.) injections of insulin icodec once weekly for 26 weeks
Insulin glargine
Participants will receive subcutaneous (s.c.) injections of insulin glargine once daily for 26 weeks
Insulin aspart
Participants will receive subcutaneous (s.c.) injections of insulin aspart 2-4 times daily for 26 weeks
Eligibility Criteria
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Inclusion Criteria
* 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
* 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.
ALL
No
Sponsors
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Novo Nordisk A/S
INDUSTRY
Responsible Party
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Principal Investigators
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Clinical Transparency (dept. 1452)
Role: STUDY_DIRECTOR
Novo Nordisk A/S
Locations
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City Hospital #5
Barnaul, , Russia
Lynn Institute of the Ozarks
Little Rock, Arkansas, United States
Anaheim Clinical Trials
Anaheim, California, United States
John Muir Physicians Network
Concord, California, United States
Valley Research
Fresno, California, United States
Diabetes/Lipid Mgmt & Res Ctr
Huntington Beach, California, United States
Valley Clinical Trials, Inc.
Northridge, California, United States
Clinical Trials Research_Sacramento_0
Sacramento, California, United States
Diabetes Research Center
Tustin, California, United States
Coastal Metabolic Research Center
Ventura, California, United States
Diablo Clinical Research, Inc.
Walnut Creek, California, United States
Chase Medical Research LLC
Waterbury, Connecticut, United States
MedStar Diabetes Institute
Washington D.C., District of Columbia, United States
Jacksonville Ctr For Clin Res
Jacksonville, Florida, United States
Clinical Trial Res Assoc,Inc
Plantation, Florida, United States
Metabolic Research Institute Inc
West Palm Beach, Florida, United States
Atlanta VA Medical Center
Decatur, Georgia, United States
Physicians Research Assoc. LLC
Lawrenceville, Georgia, United States
East West Med Res Inst
Honolulu, Hawaii, United States
Saltzer Medical Group Research
Nampa, Idaho, United States
Velocity Clin. Res Valparaiso
Valparaiso, Indiana, United States
Ochsner Clinic Foundation
New Orleans, Louisiana, United States
Brigham & Women's Hospital
Boston, Massachusetts, United States
MassResearch, LLC
Waltham, Massachusetts, United States
Jefferson City Medical Group, PC
Jefferson City, Missouri, United States
VA NEB - Western IA Health Stm
Omaha, Nebraska, United States
Methodist Physicians Clin
Omaha, Nebraska, United States
Palm Research Center Inc-Vegas
Las Vegas, Nevada, United States
AMC Community Endocrinology
Albany, New York, United States
Northport VA Medical Center_Northport_0
Northport, New York, United States
SUNY Upstate Medical University
Syracuse, New York, United States
Southgate Medical Group, LLP
West Seneca, New York, United States
Mountain Diabetes & Endocrine Center
Asheville, North Carolina, United States
Physician's East Endocrinology
Greenville, North Carolina, United States
Your Diabetes Endocrine Nutrition Group, Inc.
Mentor, Ohio, United States
Oregon Health & Science University_Portland_0
Portland, Oregon, United States
Indiana-Armstrong Endocrinology Associates
Indiana, Pennsylvania, United States
Prisma Health-Upstate
Greenville, South Carolina, United States
AM Diabetes And Endocrinology Center
Bartlett, Tennessee, United States
WR-ClinSearch, LLC
Chattanooga, Tennessee, United States
Holston Medical Group
Kingsport, Tennessee, United States
Vanderbilt Diab Obes Clin Tri
Nashville, Tennessee, United States
Amarillo Med Spec LLP
Amarillo, Texas, United States
Texas Diab & Endo, P.A.
Austin, Texas, United States
Texas Diabetes & Endocrinology
Austin, Texas, United States
Osvaldo A. Brusco MD PA
Corpus Christi, Texas, United States
Baylr Sctt White Rs Inst, Endo
Dallas, Texas, United States
Velocity Clinical Res-Dallas
Dallas, Texas, United States
North Texas Endocrine Center
Dallas, Texas, United States
UT Southwestern Med Cntr
Dallas, Texas, United States
Protenium Clinical Research_Hurst
Fort Worth, Texas, United States
DCOL Ctr for Clin Res
Longview, Texas, United States
Capital Clin Res Ctr,LLC
Olympia, Washington, United States
Imeldaziekenhuis - Bonheiden - Department of Endocrinology
Bonheiden, , Belgium
CHU Helora - Site Warquignies
Boussu, , Belgium
Cliniques Universitaires Saint-Luc - Serv Endocrinologie - Diabétologie
Brussels, , Belgium
UZA - UZ Antwerpen - Department of Endocrinology
Edegem, , Belgium
UZ Leuven - Endocrinology
Leuven, , Belgium
Kurnool Medical Collage
Kurnool, Andhra Pradesh, India
Medanta - The Medicity Multi-Speciality Hospital, Gurugram
Gurgaon, Haryana, India
St.John's Hospital
Bangalore, Karnataka, India
Bangalore Clinisearch
Bangalore, Karnataka, India
Lifecare Hospital and Research Centre
Bangalore, Karnataka, India
Belgaum Diabetes Centre
Belagavi, Karnataka, India
Manipal Hospital, Hebbal, Bengaluru
Bengaluru, Karnataka, India
Renai Medicity
Kochi, Kerala, India
Prince Aly Khan Hospital
Mumbai, Maharashtra, India
BSES MG hospital
Mumbai, Maharashtra, India
Grant Medical Foundation
Pune, Maharashtra, India
Max Super Speciality Hospital, Saket
New Delhi, National Capital Territory of Delhi, India
Fortis Hospital, Shalimar Bagh, New Delhi
New Delhi, National Capital Territory of Delhi, India
Maulana Azad Medical College
Delhi, New Delhi, India
All India Institute of Medical Sciences
New Dehli, New Delhi, India
S.C.B. Medical College
Cuttack, Odisha, India
Diabetes, Thyroid and Endocrine Centre
Jaipur, Rajasthan, India
A.O.U. Università Studi della Campania "Luigi Vanvitelli"
Napoli, Campania, Italy
Azienda Ospedaliero-Universitaria Renato Dulbecco
Catanzaro, Cz, Italy
Istituto Scientifico San Raffaele
Milan, MI, Italy
A.O.Universitaria S.ORSOLA-MALPIGHI - U.O.Endocrinologia e Cura
Bologna, , Italy
Università degli Studi G. D'Annunzio
Chieti, , Italy
Universita Degli Studi Di Roma La Sapienza - Policlinico Umberto I Medicina Sperimentale
Roma, , Italy
Hayashi Diabetes Clinic_Internal Medicine and Diabetes Medicine
Chigasaki-shi, Kanagawa, Japan, Japan
Futata Tetsuhiro Clinic Meinohama_Internal medicine
Fukuoka-shi, Fukuoka, , Japan
Sasaki Internal Medicine
Hokkaido, , Japan
Naka Kinen Clinic_Internal medicine
Ibaraki, , Japan
Sugimoto Clinic,Internal Medicine
Kitakyusyu-shi, Fukuoka, , Japan
Shimizu Clinic Fusa
Saitama, , Japan
Oyama East Clinic_Internal Medicine
Tochigi, , Japan
The Jikei University Hospital Dept of Diabetes, Metabolic
Tokyo, , Japan
Noritake Clinic
Ushiku-shi, Ibaraki, , Japan
Centro de Investigacion Medica de Occidente S.C.
Zapopan, Jalisco, Mexico
Hospital Universitario Dr. José Eleuterio González_Monterrey
Monterrey, Nuevo León, Mexico
Unidad Biomedica Avanzada Monterrey
Monterrey, Nuevo León, Mexico
Gelre Ziekenhuizen Apeldoorn
Apeldoorn, , Netherlands
Rijnstate Ziekenhuis
Arnhem, , Netherlands
Maxima Medisch Centrum
Eindhoven, , Netherlands
Bethesda Diabetes Research Center en Bethesda ziekenhuis
Hoogeveen, , Netherlands
Maastricht Universitair Medisch Centrum
Maastricht, , Netherlands
Ikazia Ziekenhuis
Rotterdam, , Netherlands
Universitair Medisch Centrum Utrecht
Utrecht, , Netherlands
Institutul National De Diabet Nutritie Si Boli Metabolice Prof.Dr.N.Paulescu Bucuresti- Ion Movila
Bucharest, Bucurestii, Romania
Spitalul Judetean de Urgenta Targoviste
Târgovişte, Dâmbovița County, Romania
Sc Mediab Srl
Târgu Mureş, Mureș County, Romania
Mariodiab Clinic SRL
Brasov, , Romania
S.C. Medcon S.R.L
Buzău, , Romania
Clinical Emergency Sf. Apostol Andrei Hospital
Galati, , Romania
Tumen State Medical University
Tyumen, Russia, Russia
Arkhangelsk Regional Clinical Hospital
Arkhangelsk, , Russia
KSFMU, Inrereginal Clinical Diagnostic center
Kazan', , Russia
Kirov Clinical Hospital #7
Kirov, , Russia
Limited Liability Company "AriVa-Med"
Kursk, , Russia
City Clinical Hospital №52
Moscow, , Russia
LLC "Centr Targetnoy Terapii"
Moscow, , Russia
Limited Law Company "Healthy Family" Medicine Center"
Novosibirsk, , Russia
SPb SBHI City Outpatient clinic #37
Saint Petersburg, , Russia
Regional clinical cardiology dispensary
Saratov, , Russia
Countries
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References
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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.
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.
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.
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.
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.
Provided Documents
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Document Type: Study Protocol
Document Type: Statistical Analysis Plan
Other Identifiers
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U1111-1247-5269
Identifier Type: OTHER
Identifier Source: secondary_id
2020-000474-16
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
NN1436-4480
Identifier Type: -
Identifier Source: org_study_id
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