NCT04795531: ONWARDS 3

A Research Study to Compare Two Types of Insulin, a New Insulin, Insulin Icodec and an Available Insulin, Insulin Degludec, in People With Type 2 Diabetes Who Have Not Used Insulin Before (ONWARDS 3)

Completed Phase 3 Results posted Last updated 4 December 2024

What this trial tests

Phase 3 trial testing Insulin icodec in Diabetes Mellitus, Type 2 in 588 participants. Completed in 23 June 2022.

Timeline

24 March 2021

Primary endpoint
23 June 2022

23 June 2022

Quick facts

Lead sponsor	Novo Nordisk A/S
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	quadruple
Primary purpose	treatment
Enrollment	588
Start date	24 March 2021
Primary completion	23 June 2022
Estimated completion	23 June 2022
Sites	93 locations across Denmark, France, Austria, Taiwan, Mexico, Argentina, Canada, Puerto Rico

Drugs / interventions tested

• Insulin icodec — full drug profile →
• Placebo insulin icodec — full drug profile →
• Insulin degludec (INSULIN DEGLUDEC) — full drug profile →
• Placebo insulin degludec

Conditions studied

• Diabetes Mellitus, Type 2 — all drugs for Diabetes Mellitus, Type 2 →

Sponsor

Novo Nordisk A/S — full company profile →

Who can join

18 and older, any sex, with Diabetes Mellitus, Type 2. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Change in Glycated Haemoglobin (HbA1c) Primary · Baseline (Week 0), Week 26

Change in HbA1c from baseline (week 0) to week 26 is presented. The outcome data is evaluated based on the in-trial observation period. The in-trial 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.

Group	Value	95% CI
Insulin Icodec	-1.57	± 0.05
Insulin Degludec	-1.36	± 0.05

Change in Fasting Plasma Glucose (FPG) Secondary · Baseline (Week 0), Week 26

Change in FPG from baseline (week 0) to week 26 is presented. The outcome data was evaluated based on the in-trial observation period. The in-trial 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.

Group	Value	95% CI
Insulin Icodec	-3.01	± 0.11
Insulin Degludec	-2.99	± 0.11

Number of Severe Hypoglycaemic Episodes (Level 3) Secondary · From baseline (week 0) to week 31

Number of severe hypoglycaemic episodes (level 3) is presented. Severe hypoglycaemia (level 3) is defined as hypoglycaemia with severe cognitive impairment requiring external assistance for recovery. The outcome data was evaluated based on the on-tratment period. The on-treatment period started at the date of first dose of trial product as recorded on the electronic case report form (eCRF), and ended at the first date of any of the following: The end of trial visit (V30), the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin (corresponding to 5 w

Group	Value	95% CI
Insulin Icodec	0
Insulin Degludec	2

Number of Clinically Significant Hypoglycaemic Episodes (Level 2) (< 3.0 mmol/L (54 Milligrams Per Deciliter [mg/dL]), Confirmed by Blood Glucose [BG] Meter) Secondary · From baseline (week 0) to week 31

Number of clinically significant hypoglycaemic episodes (level 2) (less than \[\<\] 3.0 millimoles per liter (mmol/L) (54 mg/dL), confirmed by BG meter) is presented. Clinically significant hypoglycaemia (level 2) is defined as plasma glucose value of less than 3.0 mmol/L (54 mg/dL) confirmed by BG meter. The outcome data was evaluated based on the on-treatment period. The on-treatment period started at the date of first dose of trial product as recorded on the electronic case report form (eCRF), and ended at the first date of any of the following: The end of trial visit (V30), the last date o

Group	Value	95% CI
Insulin Icodec	53
Insulin Degludec	23

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) Secondary · From baseline (week 0) to week 31

Number of clinically significant hypoglycaemic episodes (level 2) (less than 3.0 mmol/L) (54 mg/dL), confirmed by blood glucose \[BG\] meter) or severe hypoglycaemic episodes (level 3) is presented. Severe hypoglycaemia (level 3) is defined as hypoglycaemia with severe cognitive impairment requiring external assistance for recovery. Clinically significant hypoglycaemia (level 2) is defined as plasma glucose value of \< 3.0 mmol/L (54 mg/dL) confirmed by BG meter. The outcome data was evaluated based on the on-treatment period. The on-treatment period started at the date of first dose of trial

Group	Value	95% CI
Insulin Icodec	53
Insulin Degludec	25

Number of Severe Hypoglycaemic Episodes (Level 3) Secondary · From baseline (week 0) to week 26

Number of severe hypoglycaemic episodes (level 3) is presented. Severe hypoglycaemia (level 3) is defined as hypoglycaemia with severe cognitive impairment requiring external assistance for recovery.

Group	Value	95% CI
Insulin Icodec	0
Insulin Degludec	0

Number of Clinically Significant Hypoglycaemic Episodes (Level 2) (<3.0 mmol/L (54 mg/dL), Confirmed by BG Meter) Secondary · From baseline (week 0) to week 26

Number of clinically significant hypoglycaemic episodes (level 2) (\< 3.0 mmol/L (54 mg/dL), confirmed by BG meter) is presented. Clinically significant hypoglycaemia (level 2) is defined as plasma glucose value of less than (\<) 3.0 mmol/L (54 mg/dL) confirmed by BG meter.

Group	Value	95% CI
Insulin Icodec	50
Insulin Degludec	17

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) Secondary · From baseline (week 0) to week 26

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) is presented. Severe hypoglycaemia (level 3) is defined as hypoglycaemia with severe cognitive impairment requiring external assistance for recovery. Clinically significant hypoglycaemia (level 2) is defined as plasma glucose value of less than (\<) 3.0 millimoles per liter (mmol/L) (54 milligrams per deciliter \[mg/dL\]) confirmed by blood glucose (BG) meter.

Group	Value	95% CI
Insulin Icodec	50
Insulin Degludec	17

Change in Body Weight Secondary · Baseline (Week 0), Week 26

Change in body weight from baseline (week 0) to week 26 is presented. The outcome data was evaluated based on the in-trial observation period. The in-trial 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.

Group	Value	95% CI
Insulin Icodec	2.77	± 0.22
Insulin Degludec	2.32	± 0.24

Mean Weekly Insulin Dose Secondary · From week 24 to week 26

Estimated mean weekly insulin dose during the last 2 weeks of treatment (from week 24 to week 26) is presented. The outcome data was evaluated based on the on-treatment period. The on-treatment period started at the date of first dose of trial product as recorded on the electronic case report form (eCRF), and ended at the first date of any of the following: The end of trial visit (V30), the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin (corresponding to 5 weeks after the end of the dosing interval for both treatment arms) and the end-date for

Group	Value	95% CI
Insulin Icodec	204.28	189.44 – 220.29
Insulin Degludec	186.52	173.06 – 201.02

Adverse events — posted to ClinicalTrials.gov

Time frame: From baseline (Week 0) to Week 31. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Insulin Icodec

Serious: 15/293 (5%)

Deaths: 2/293

Insulin Degludec

Serious: 15/294 (5%)

Deaths: 1/294

Serious adverse events (39 terms)

Reaction	System	Insulin Icodec	Insulin Degludec
Accidental overdose	Injury, poisoning and procedural complications	—	—
Acute kidney injury	Renal and urinary disorders	—	—
Acute myocardial infarction	Cardiac disorders	—	—
Adenocarcinoma of colon	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Adenocarcinoma pancreas	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Aortic arteriosclerosis	Vascular disorders	—	—
Asthenia	General disorders	—	—
COVID-19	Infections and infestations	—	—
COVID-19 pneumonia	Infections and infestations	—	—
Cardiac failure	Cardiac disorders	—	—
Cardio-respiratory arrest	Cardiac disorders	—	—
Cellulitis	Infections and infestations	—	—
Chest discomfort	General disorders	—	—
Colorectal cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Cystitis	Infections and infestations	—	—
Diabetic neuropathy	Nervous system disorders	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—
Erysipelas	Infections and infestations	—	—
Escherichia bacteraemia	Infections and infestations	—	—
Fall	Injury, poisoning and procedural complications	—	—
Gastritis	Gastrointestinal disorders	—	—
Haematoma	Vascular disorders	—	—
Haemorrhoids	Gastrointestinal disorders	—	—
Hypoglycaemia	Metabolism and nutrition disorders	—	—
Influenza	Infections and infestations	—	—

Other adverse events (3 terms — click to expand)

Reaction	System	Insulin Icodec	Insulin Degludec
COVID-19	Infections and infestations	—	—
Diabetic retinopathy	Eye disorders	—	—
Influenza	Infections and infestations	—	—

Most-reported serious reactions: Accidental overdose, Acute kidney injury, Acute myocardial infarction, Adenocarcinoma of colon, Adenocarcinoma pancreas, Aortic arteriosclerosis, Asthenia, COVID-19.

Data from ClinicalTrials.gov NCT04795531 adverse events section.

Sponsor's own description

This study compares insulin icodec (a new insulin taken once a week) to insulin degludec (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 degludec taken daily.

Participants will get their study medicine in an injection pen. Participants will get a pen for weekly injection and one for daily injection. One will be icodec or degludec and the other will be dummy medicine. The treatment participants get is decided by chance. Participants and the study staff will not know which active medicine they get.

The insulin is injected with a needle in a skin fold in the thigh. The study could last for about 8 months. Participants will have 13 clinic visits and 17 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.

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

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Once-Weekly Insulin Icodec vs Once-Daily Insulin Degludec in Adults With Insulin-Naive Type 2 Diabetes: The ONWARDS 3 Randomized Clinical Trial.
   Lingvay I, Asong M, Desouza C, Gourdy P, et al · · 2023 · cited 95× · PMID 37354562 · DOI 10.1001/jama.2023.11313
2. A Randomized, Open-Label Comparison of Once-Weekly Insulin Icodec Titration Strategies Versus Once-Daily Insulin Glargine U100.
   Lingvay I, Buse JB, Franek E, Hansen MV, et al · · 2021 · cited 61× · PMID 33875484 · DOI 10.2337/dc20-2878
3. Rationale and design of the phase 3a development programme (ONWARDS 1-6 trials) investigating once-weekly insulin icodec in diabetes.
   Philis-Tsimikas A, Bajaj HS, Begtrup K, Cailleteau R, et al · · 2023 · cited 60× · PMID 36106652 · DOI 10.1111/dom.14871
4. The Basis for Weekly Insulin Therapy: Evolving Evidence With Insulin Icodec and Insulin Efsitora Alfa.
   Rosenstock J, Juneja R, Beals JM, Moyers JS, et al · · 2024 · cited 51× · PMID 38224978 · DOI 10.1210/endrev/bnad037
5. Efficacy and Hypoglycemia Profile of Once-weekly Insulin Icodec vs Once-daily Comparators Across Demographic Subgroups.
   Lingvay I, Bache JK, Desouza CV, Fragão-Marques M, et al · · 2025 · cited 5× · PMID 40102962 · DOI 10.1210/clinem/dgaf168
6. Once-Weekly Insulin Icodec in Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomized Clinical Trials (ONWARDS Clinical Program).
   Lisco G, De Tullio A, De Geronimo V, Giagulli VA, et al · · 2024 · cited 5× · PMID 39200316 · DOI 10.3390/biomedicines12081852
7. Pharmacological and Benefit-Risk Profile of Once-Weekly Basal Insulin Administration (Icodec): Addressing Patients' Unmet Needs and Exploring Future Applications.
   Ingrasciotta Y, Vitturi G, Trifirò G. · · 2024 · cited 4× · PMID 38610878 · DOI 10.3390/jcm13072113
8. 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.
   Riddell MC, Heller S, Carstensen L, Rocha TMP, et al · · 2025 · cited 3× · PMID 40186685 · DOI 10.1007/s00125-025-06414-6