A Research Study to Compare a New Weekly Insulin, Insulin Icodec, and an Available Daily Insulin, Insulin Degludec, Both in Combination With Mealtime Insulin in People With Type 1 Diabetes (ONWARDS 6)

NCT04848480 — Phase 3, Completed, 582 participants, Novo Nordisk A/S

ClinicalTrials Daily · Areas · Conditions · Drugs · Sponsors ·

Efficacy and Safety of Once Weekly Insulin Icodec Compared to Once Daily Insulin Degludec 100 Units/mL, Both in Combination With Insulin Aspart, in Adults With Type 1 Diabetes. A 26-week, Randomised, Multicentre, Open-label, Active-controlled, Parallel Group, Two Armed, Treat-to-target Trial Investigating the Effect on Glycaemic Control and Safety of Treatment With Once Weekly Insulin Icodec Compared to Once Daily Insulin Degludec, Both in Combination With Insulin Aspart in Adults With Type 1 Diabetes, With a 26-week Extension Investigating Long Term Safety

Registry	NCT04848480, acronym ONWARDS 6
Status	Completed
Phase	Phase 3
Study type	Interventional; randomized, parallel, masking: none, treatment
Enrollment	582 (Actual)
Sponsor	Novo Nordisk A/S (Industry)
Conditions	Diabetes Mellitus, Type 1
Interventions	insulin icodec, insulin degludec, insulin aspart (Drug)
Dates	start 2021-04-30, primary completion 2022-04-28, completion 2022-12-02, first posted 2021-04-19, last updated 2025-12-04
Locations	130 sites in United States, Austria, Canada, Germany, India, Italy, Japan, Netherlands and 4 more countries

-Summary

This study compares insulin icodec (a new insulin) to insulin degludec (an insulin already available on the market) in people with type 1 diabetes.

The study will look at how well insulin icodec taken weekly controls blood sugar compared to insulin degludec 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 degludec that participants will have to inject once a day at the same time every day. Which treatment participants get is decided at random. 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 1 year and 2 months. Participants will have 28 clinic visits and 28 phone calls with the study doctor. At 11 clinic visits participants will have blood samples taken.

At 6 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 your blood sugar all the time. Participants will be asked to wear it for a total of 57 weeks (around 1 year).

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

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+Arms and interventions

Arm	Type	Interventions	Description
Insulin icodec + insulin aspart	Experimental	Drug: insulin icodec; Drug: insulin aspart	insulin icodec once a week in combination with 2-4 times daily injections of insulin aspart at meal times.
Insulin degludec + insulin aspart	Active comparator	Drug: insulin degludec; Drug: insulin aspart	insulin degludec once a day in combination with 2-4 times daily injections of insulin aspart at meal times.

insulin icodec (Drug): insulin icodec 700 units/mL, subcutaneously (under the skin), solution for injection once weekly
insulin degludec (Drug): insulin degludec 100 units/mL, subcutaneously (under the skin), solution for injection once daily
insulin aspart (Drug): insulin aspart 100 units/mL, subcutaneously (under the skin), solution for injection daily

+Outcome measures

Primary outcomes

Change in Glycosylated Haemoglobin (HbA1c) at Week 26 [Baseline (week 0), week 26]: Change in HbA1c from baseline to week 26 is presented. Data is reported for 'in-trial' 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); death for participants who died before any of the above.

Secondary outcomes

Change in Glycosylated Haemoglobin (HbA1c) at Week 52 [Baseline (week 0), week 52]: Change in HbA1c from baseline to week 52 is presented. Data is reported for 'in-trial' 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); death for participants who died before any of the above.
Change in Fasting Plasma Glucose (FPG) [Baseline (week 0), week 26]: Change in FPG from baseline to week 26 is presented. Data is reported for 'in-trial' 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); death for participants who died before any of the above.
Percentage of Time in Range 3.9-10.0 mmol/L (70-180 Milligrams Per Deciliter [mg/dL]) Using Continuous Glucose Monitoring (CGM) System [From week 22 to week 26]: Percentage of time in range 3.9-10.0 mmol/L (70-180 mg/dL) using CGM system from week 22 to week 26 is presented. Time in range is defined as 100 times the number of recorded measurements in glycaemic range 3.9-10.0 mmol/L (70-180 mg/dL), both inclusive, divided by the total number of recorded measurements. Data is reported for 'in-trial' 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); death for participants who died before any of the above.
Change in Diabetes Treatment Satisfaction Questionnaire (DTSQs) in Total Treatment Satisfaction [Baseline (week 0), week 26]: Change in DTSQs in total treatment satisfaction from baseline to week 26 is presented. The sum score for DTSQ in total treatment satisfaction was calculated by adding the six item scores of items 1, 4, 5, 6, 7 and 8. The sum score for DTSQ can range from 0 to 36, with 0 being the lowest and 36 being the highest score in total treatment satisfaction. Higher scores on the DTSQ total score indicate higher treatment satisfaction. Data is reported for 'in-trial' 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); death for participants who died before any of the above.
Number of Severe Hypoglycaemic Episodes (Level 3): From Baseline (Week 0) to Week 26 [From baseline (week 0) to week 26]: Number of severe hypoglycaemic episodes (level 3) from baseline to week 26 are presented. Severe hypoglycaemia (level 3) is defined as hypoglycaemia with severe cognitive impairment requiring external assistance for recovery. Data is reported for 'main-on-treatment' period. The main-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 date of the on-treatment period; week 26. On-treatment: Onset date on or after the first dose of trial product and no later than the first date of either the follow-up visit, the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin or the end-date for the in-trial period. Data reflects total number of episodes across all participants within the arm.
Number of Severe Hypoglycaemic Episodes (Level 3): From Baseline (Week 0) to Week 57 [From baseline (week 0) to week 57]: Number of severe hypoglycaemic episodes (level 3) from baseline to week 57 are presented. Severe hypoglycaemia (level 3) is defined as hypoglycaemia with severe cognitive impairment requiring external assistance for recovery. Data is reported for 'on-treatment' period. The on-treatment period: Onset date on or after the first dose of trial product and no later than the first date of either the follow-up visit (FU2), the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin or the end-date for the in-trial period. Data reflects total number of episodes across all participants within the arm.
Number of Clinically Significant Hypoglycaemic Episodes (Level 2) (Less Than 3.0 mmol/L (54 mg/dL) Confirmed by Blood Glucose [BG] Meter): From Baseline (Week 0) to Week 26 [From baseline (week 0) to week 26]: Number of clinically significant hypoglycaemic episodes (level 2) from baseline to week 26 are 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. Data is reported for 'main-on-treatment' period. The main-on-treatment period started at the date of first dose of trial product as recorded on the eCRF, and ended at the first date of any of the following: the end date of the on-treatment period; week 26. The on-treatment period: Onset date on or after the first dose of trial product and no later than the first date of either the follow-up visit (FU2), the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin or the end-date for the in-trial period. Data reflects total number of episodes across all participants within the arm.
Number of Clinically Significant Hypoglycaemic Episodes (Level 2) (Less Than 3.0 mmol/L (54 mg/dL) Confirmed by BG Meter): From Baseline (Week 0) to Week 57 [From baseline (week 0) to week 57]: Number of clinically significant hypoglycaemic episodes (level 2) from baseline to week 57 are 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. Data is reported for 'on-treatment' period. The on-treatment period: Onset date on or after the first dose of trial product and no later than the first date of either the follow-up visit (FU2), the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin or the end-date for the in-trial period. Data reflects total number of episodes across all participants within the arm.
Number of Clinically Significant Hypoglycaemic Episodes (Level 2) (Less Than 3.0 mmol/L (54 mg/dL), Confirmed by BG Meter) or Severe Hypoglycaemic Episodes (Level 3): From Baseline (Week 0) to Week 26 [From baseline (week 0) to week 26]: Number of clinically significant hypoglycaemic episodes (level 2) or severe hypoglycaemic episodes (level 3) from baseline to week 26 presented. Clinically significant hypoglycaemia (level 2) is de-fined as plasma glucose value of < 3.0 mmol/L (54 mg/dL) confirmed by BG meter. Severe hypo-glycaemia (level 3) is defined as hypoglycaemia with severe cognitive impairment requiring ex-ternal assistance for recovery. Data is reported for 'main-on-treatment' period, started at date of first dose of trial product as recorded on eCRF, and ended at first date of any of following: end date of on-treatment period; week 26. On-treatment period: Onset date on or after the first dose of trial product and no later than first date of either the follow-up visit (FU2), the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin or the end-date for the in-trial period. Data reflects total number of episodes across all participants within the arm.
Number of Clinically Significant Hypoglycaemic Episodes (Level 2) (Less Than 3.0 mmol/L (54 mg/dL), Confirmed by BG Meter) or Severe Hypoglycaemic Episodes (Level 3): From Baseline (Week 0) to Week 57 [From baseline (week 0) to week 57]: Number of clinically significant hypoglycaemic episodes (level 2) or severe hypoglycaemic episodes (level 3) from baseline to week 57 are 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. Severe hypoglycaemia (level 3) is defined as hypoglycaemia with severe cognitive impairment requiring external assistance for recovery. Data is reported for 'on-treatment' period. The on-treatment period: Onset date on or after the first dose of trial product and no later than the first date of either the follow-up visit (FU2), the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin or the end-date for the in-trial period. Data reflects total number of episodes across all participants within the arm.
Number of Nocturnal Clinically Significant Hypoglycaemic Episodes (Level 2) (Less Than 3.0 mmol/L (54 mg/dL), Confirmed by BG Meter) or Severe Hypoglycaemic Episodes (Level 3): From Baseline (Week 0) to Week 26 [From baseline (week 0) to week 26]: Number of nocturnal clinically significant hypoglycaemic episodes (level 2) or severe hypogly-caemic episodes (level 3) from baseline to week 26 presented. Nocturnal: Period between 00:01 and 05:59 (both included). Clinically significant hypoglycaemia (level 2): Plasma glucose value of < 3.0 mmol/L (54 mg/dL) confirmed by BG meter. Severe hypoglycaemia (level 3): Hypoglycaemia with severe cognitive impairment requiring external assistance for recovery. Data is reported for 'main-on-treatment' period, started at date of first dose of trial product as recorded on eCRF, and ended at first date of any of following: end date of on-treatment period; week 26. On-treatment period: Onset date on or after first dose of trial product and no later than first date of either fol-low-up visit, last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin or end-date for in-trial period. Data reflects total number of episodes across all participants within the arm.
Number of Nocturnal Clinically Significant Hypoglycaemic Episodes (Level 2) (Less Than 3.0 mmol/L (54 mg/dL), Confirmed by BG Meter) or Severe Hypoglycaemic Episodes (Level 3): From Baseline (Week 0) to Week 57 [From baseline (week 0) to week 57]: Number of nocturnal clinically significant hypoglycaemic episodes (level 2) or severe hypoglycaemic episodes (level 3) from baseline to week 57 are presented. Nocturnal: The period between 00:01 and 05:59 (both included). Clinically significant hypoglycaemia (level 2): Plasma glucose value of < 3.0 mmol/L (54 mg/dL) confirmed by BG meter. Severe hypoglycaemia (level 3): Hypoglycaemia with severe cognitive impairment requiring external assistance for recovery. Data is reported for 'on-treatment' period. The on-treatment period: Onset date on or after the first dose of trial product and no later than the first date of either the follow-up visit (FU2), the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin or the end-date for the in-trial period. Data reflects total number of episodes across all participants within the arm.
Percentage of Time Spent Less Than (<) 3.0 mmol/L (54 mg/dL) Using Continuous Glucose Monitoring (CGM) System [From week 22 to week 26]: Percentage of time spent < 3.0 mmol/L using CGM system from week 22 to week 26 is presented. Time spent below threshold (< 3.0 mmol/L \[54 mg/dL\]) was defined as 100 times the number of recorded measurements below the threshold, divided by the total number of recorded measurements. Data is reported for 'in-trial' 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); death for participants who died before any of the above.
Percentage of Time Spent Greater Than (>) 10 mmol/L (180 mg/dL) Using Continuous Glucose Monitoring (CGM) System [From week 22 to week 26]: Percentage of time spent > 10 mmol/L using CGM system from week 22 to week 26 is presented. Time spent above threshold (> 10 mmol/L \[180 mg/dL\]) was defined as 100 times the number of recorded measurements above the threshold, divided by the total number of recorded measurements. Data is reported for 'in-trial' 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); death for participants who died before any of the above.
Mean Total Weekly Insulin Dose: From Week 24 to Week 26 [From week 24 to week 26]: Mean total weekly insulin dose from week 24 to week 26 is presented. Data is reported for 'main-on-treatment' period. The main-on-treatment period started at the date of first dose of trial product as recorded on the eCRF, and ended at the first date of any of the following: the end date of the on-treatment period; week 26. The on-treatment period: Onset date on or after the first dose of trial product and no later than the first date of either the follow-up visit (FU2), the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin or the end-date for the in-trial period.
Mean Total Weekly Insulin Dose: From Week 50 to Week 52 [From week 50 to week 52]: Mean total weekly insulin dose from week 50 to week 52 is presented. Data is reported for 'on-treatment' period. The on-treatment period: Onset date on or after the first dose of trial product and no later than the first date of either the follow-up visit (FU2), the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin or the end-date for the in-trial period.
Change in Body Weight [Baseline (week 0), week 26]: Change in body weight from baseline to week 26 is presented. Data is reported for 'in-trial' 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); death for participants who died before any of the above.

+Eligibility

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Male or female aged greater than or equal to 18 years at the time of signing informed consent.
* Diagnosed with type 1 diabetes mellitus greater than or equal to 1 year prior to the day of screening.
* Treated with multiple daily insulin injections (basal and bolus insulin analogue regimes) greater than or equal to 1 year prior to the day of screening.
* HbA1c below10% at screening visit based on analysis from central laboratory.

Exclusion Criteria:

* Myocardial infarction, stroke, hospitalization for unstable angina pectoris or transient ischaemic attack within 180 days prior to the day of screening.
* Chronic heart failure classified as New York Heart Association (NYHA) 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.

+Posted results

Participant flow

Milestone	Insulin Icodec + Insulin Aspart	Insulin Degludec + Insulin Aspart
Started	290	292
Completed	279	284
Not completed	11	8

Outcome results

Change in Glycosylated Haemoglobin (HbA1c) at Week 26 (Primary), Least squares mean, Percentage of HbA1c: Insulin Icodec + Insulin Aspart -0.47 +/- 0.07; Insulin Degludec + Insulin Aspart -0.51 +/- 0.06 (p 0.0065)
Change in Glycosylated Haemoglobin (HbA1c) at Week 52 (Secondary), Least squares mean, Percentage of HbA1c: Insulin Icodec + Insulin Aspart -0.37 +/- 0.05; Insulin Degludec + Insulin Aspart -0.54 +/- 0.05
Change in Fasting Plasma Glucose (FPG) (Secondary), Least squares mean, millimoles per liter (mmol/l): Insulin Icodec + Insulin Aspart -0.84 +/- 0.20; Insulin Degludec + Insulin Aspart -1.87 +/- 0.20
Percentage of Time in Range 3.9-10.0 mmol/L (70-180 Milligrams Per Deciliter [mg/dL]) Using Continuous Glucose Monitoring (CGM) System (Secondary), Mean, Percentage of time: Insulin Icodec + Insulin Aspart 59.10 +/- 15.66; Insulin Degludec + Insulin Aspart 60.85 +/- 15.03
Change in Diabetes Treatment Satisfaction Questionnaire (DTSQs) in Total Treatment Satisfaction (Secondary), Least squares mean, Score on a scale: Insulin Icodec + Insulin Aspart 1.97 +/- 0.27; Insulin Degludec + Insulin Aspart 3.06 +/- 0.27
Number of Severe Hypoglycaemic Episodes (Level 3): From Baseline (Week 0) to Week 26 (Secondary), Number, Episodes: Insulin Icodec + Insulin Aspart 47; Insulin Degludec + Insulin Aspart 17
Number of Severe Hypoglycaemic Episodes (Level 3): From Baseline (Week 0) to Week 57 (Secondary), Number, Episodes: Insulin Icodec + Insulin Aspart 56; Insulin Degludec + Insulin Aspart 25
Number of Clinically Significant Hypoglycaemic Episodes (Level 2) (Less Than 3.0 mmol/L (54 mg/dL) Confirmed by Blood Glucose [BG] Meter): From Baseline (Week 0) to Week 26 (Secondary), Number, Episodes: Insulin Icodec + Insulin Aspart 2789; Insulin Degludec + Insulin Aspart 1478
Number of Clinically Significant Hypoglycaemic Episodes (Level 2) (Less Than 3.0 mmol/L (54 mg/dL) Confirmed by BG Meter): From Baseline (Week 0) to Week 57 (Secondary), Number, Episodes: Insulin Icodec + Insulin Aspart 5047; Insulin Degludec + Insulin Aspart 2811
Number of Clinically Significant Hypoglycaemic Episodes (Level 2) (Less Than 3.0 mmol/L (54 mg/dL), Confirmed by BG Meter) or Severe Hypoglycaemic Episodes (Level 3): From Baseline (Week 0) to Week 26 (Secondary), Number, Episodes: Insulin Icodec + Insulin Aspart 2836; Insulin Degludec + Insulin Aspart 1495
Number of Clinically Significant Hypoglycaemic Episodes (Level 2) (Less Than 3.0 mmol/L (54 mg/dL), Confirmed by BG Meter) or Severe Hypoglycaemic Episodes (Level 3): From Baseline (Week 0) to Week 57 (Secondary), Number, Episodes: Insulin Icodec + Insulin Aspart 5103; Insulin Degludec + Insulin Aspart 2836
Number of Nocturnal Clinically Significant Hypoglycaemic Episodes (Level 2) (Less Than 3.0 mmol/L (54 mg/dL), Confirmed by BG Meter) or Severe Hypoglycaemic Episodes (Level 3): From Baseline (Week 0) to Week 26 (Secondary), Number, Episodes: Insulin Icodec + Insulin Aspart 481; Insulin Degludec + Insulin Aspart 227
Number of Nocturnal Clinically Significant Hypoglycaemic Episodes (Level 2) (Less Than 3.0 mmol/L (54 mg/dL), Confirmed by BG Meter) or Severe Hypoglycaemic Episodes (Level 3): From Baseline (Week 0) to Week 57 (Secondary), Number, Episodes: Insulin Icodec + Insulin Aspart 870; Insulin Degludec + Insulin Aspart 462
Percentage of Time Spent Less Than (<) 3.0 mmol/L (54 mg/dL) Using Continuous Glucose Monitoring (CGM) System (Secondary), Mean, Percentage of time: Insulin Icodec + Insulin Aspart 1.02 +/- 1.64; Insulin Degludec + Insulin Aspart 0.68 +/- 1.27
Percentage of Time Spent Greater Than (>) 10 mmol/L (180 mg/dL) Using Continuous Glucose Monitoring (CGM) System (Secondary), Mean, Percentage of time: Insulin Icodec + Insulin Aspart 37.03 +/- 16.21; Insulin Degludec + Insulin Aspart 36.25 +/- 15.61
Mean Total Weekly Insulin Dose: From Week 24 to Week 26 (Secondary), Least squares mean, Units of insulin: Insulin Icodec + Insulin Aspart 310.52 (295.70 to 326.08); Insulin Degludec + Insulin Aspart 322.68 (307.46 to 338.66)
Mean Total Weekly Insulin Dose: From Week 50 to Week 52 (Secondary), Least squares mean, Units of insulin: Insulin Icodec + Insulin Aspart 310.14 (294.85 to 326.22); Insulin Degludec + Insulin Aspart 328.90 (312.86 to 345.75)
Change in Body Weight (Secondary), Least squares mean, kilograms: Insulin Icodec + Insulin Aspart 1.29 +/- 0.23; Insulin Degludec + Insulin Aspart 1.01 +/- 0.23

Adverse events

Time frame: Week 1 to week 57

Arm	Deaths	Serious adverse events	Other adverse events
Insulin Icodec + Insulin Aspart	1/290 (0.3%)	24/290 (8.3%)	145/290 (50.0%)
Insulin Degludec + Insulin Aspart	0/292 (0.0%)	20/292 (6.8%)	162/292 (55.5%)

Serious adverse events by term

Term	Organ system	Insulin Icodec + Insulin Aspart	Insulin Degludec + Insulin Aspart
Abortion spontaneous	Pregnancy, puerperium and perinatal conditions	1/290	0/292
Abortion threatened	Pregnancy, puerperium and perinatal conditions	1/290	0/292
Acute kidney injury	Renal and urinary disorders	1/290	0/292
Acute myocardial infarction	Cardiac disorders	1/290	0/292
Acute respiratory failure	Respiratory, thoracic and mediastinal disorders	1/290	0/292
Alcohol abuse	Psychiatric disorders	0/290	1/292
Angina unstable	Cardiac disorders	0/290	2/292
Ankle fracture	Injury, poisoning and procedural complications	1/290	0/292
Asthenia	General disorders	0/290	1/292
Benign prostatic hyperplasia	Reproductive system and breast disorders	1/290	0/292
Blood glucose fluctuation	Investigations	0/290	1/292
Blood glucose increased	Investigations	0/290	1/292
Brachiocephalic artery stenosis	Vascular disorders	0/290	1/292
COVID-19	Infections and infestations	1/290	1/292
COVID-19 pneumonia	Infections and infestations	1/290	0/292
Cardiac ablation	Surgical and medical procedures	1/290	0/292
Cardiac failure congestive	Cardiac disorders	1/290	0/292
Cerebral haemorrhage	Nervous system disorders	1/290	0/292
Cystitis escherichia	Infections and infestations	0/290	1/292
Diabetic ketoacidosis	Metabolism and nutrition disorders	1/290	0/292
Haemorrhage intracranial	Nervous system disorders	1/290	0/292
Haemorrhoids	Gastrointestinal disorders	0/290	1/292
Hypertension	Vascular disorders	0/290	1/292
Hypertensive crisis	Vascular disorders	0/290	1/292
Hypoglycaemia	Metabolism and nutrition disorders	8/290	1/292
Hypoglycaemic seizure	Nervous system disorders	1/290	1/292
Hypoglycaemic unconsciousness	Nervous system disorders	0/290	1/292
Hypokalaemia	Metabolism and nutrition disorders	1/290	0/292
Hypotension	Vascular disorders	1/290	0/292
Influenza	Infections and infestations	0/290	1/292
Ischaemic stroke	Nervous system disorders	0/290	1/292
Ligament rupture	Injury, poisoning and procedural complications	1/290	0/292
Lumbar hernia	Gastrointestinal disorders	0/290	1/292
Major depression	Psychiatric disorders	1/290	0/292
Medical device site dermatitis	General disorders	0/290	1/292
Myocardial ischaemia	Cardiac disorders	0/290	1/292
Obesity	Metabolism and nutrition disorders	0/290	1/292
Optic neuritis	Nervous system disorders	0/290	1/292
Pneumonia	Infections and infestations	0/290	1/292
Proctitis ulcerative	Gastrointestinal disorders	0/290	1/292
Product administration error	Injury, poisoning and procedural complications	1/290	0/292
Pyelonephritis acute	Infections and infestations	1/290	0/292
Respiratory tract infection viral	Infections and infestations	1/290	0/292
Rotator cuff syndrome	Musculoskeletal and connective tissue disorders	1/290	0/292
Sepsis	Infections and infestations	1/290	0/292
Tendon rupture	Injury, poisoning and procedural complications	1/290	0/292
Uterine leiomyoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	0/290	1/292
Vomiting	Gastrointestinal disorders	1/290	0/292

Other adverse events by term

Term	Organ system	Insulin Icodec + Insulin Aspart	Insulin Degludec + Insulin Aspart
Arthralgia	Musculoskeletal and connective tissue disorders	12/290	15/292
Back pain	Musculoskeletal and connective tissue disorders	5/290	17/292
COVID-19	Infections and infestations	74/290	83/292
Diabetic retinopathy	Eye disorders	24/290	26/292
Headache	Nervous system disorders	17/290	16/292
Nasopharyngitis	Infections and infestations	48/290	61/292
Pyrexia	General disorders	16/290	20/292
Upper respiratory tract infection	Infections and infestations	15/290	11/292

+Locations (130)

Facility	City	Country
John Muir Physicians Network	Concord, California	United States
Headlands Research California, LLC	Escondido, California	United States
Valley Research	Fresno, California	United States
Scripps Whittier Diabetes Inst	La Jolla, California	United States
Diabetes & Endocrine Associates	La Mesa, California	United States
Mills-Peninsula Hlth Services	San Mateo, California	United States
Diablo Clinical Research, Inc.	Walnut Creek, California	United States
Barbara Davis Center	Aurora, Colorado	United States
Creekside Endocrine Associates, PC	Denver, Colorado	United States
Christiana Care Health Services, Inc.	Newark, Delaware	United States
Northeast Research Institute	Fleming Island, Florida	United States
Center For Diabetes & Endo Care	Fort Lauderdale, Florida	United States
Hanson Clinical Research Center	Port Charlotte, Florida	United States
Northeast Research Institute	Saint Augustine, Florida	United States
Physicians Research Assoc. LLC	Lawrenceville, Georgia	United States
Endo Res Solutions Inc	Roswell, Georgia	United States
Northwestern University_Chicago	Chicago, Illinois	United States
The University of Chicago	Chicago, Illinois	United States
Cotton-O'Neil Diab & Endo Ctr	Topeka, Kansas	United States
Endo and Metab Consultants	Rockville, Maryland	United States
Brigham & Women's Hospital	Boston, Massachusetts	United States
MassResearch, LLC	Waltham, Massachusetts	United States
Minn Center For Obesity Met & Endocrinology	Eagan, Minnesota	United States
International Diabetes Center	Minneapolis, Minnesota	United States
Jefferson City Medical Group, PC	Jefferson City, Missouri	United States
Mercy Research	Springfield, Missouri	United States
Methodist Physicians Clin	Omaha, Nebraska	United States
Palm Research Center Inc-Vegas	Las Vegas, Nevada	United States
Southern NH Diabetes and Endo_Nashua	Nashua, New Hampshire	United States
John J Shelmet, MD	Lawrenceville, New Jersey	United States
AMC Community Endocrinology	Albany, New York	United States
Accellacare	Wilmington, North Carolina	United States
Prisma Health-Upstate	Greenville, South Carolina	United States
Univ Diab & Endo Consultants	Chattanooga, Tennessee	United States
Amarillo Med Spec LLP	Amarillo, Texas	United States
Texas Diab & Endo, P.A.	Austin, Texas	United States
Texas Diab & Endo, P.A.	Austin, Texas	United States
Velocity Clinical Res-Dallas	Dallas, Texas	United States
North Texas Endocrine Center	Dallas, Texas	United States
PlanIt Research, PLLC	Houston, Texas	United States
NE Clin Res of San Antonio	San Antonio, Texas	United States
Rainier Clin Res Ctr Inc	Renton, Washington	United States
Univ.-Klinik für Innere Medizin	Graz	Austria
Univ.-Klinik für Innere Medizin I	Innsbruck	Austria
Fließer-Görzer [Ordination]	Saint Stefan	Austria
Klinik Landstraße	Vienna	Austria
Universitätsklinikum AKH Wien	Vienna	Austria
Klinik Hietzing	Vienna	Austria
Winnipeg Clinic	Winnipeg, Manitoba	Canada
Eastern Health Authority	St. John's, Newfoundland and Labrador	Canada
Nova Scotia Hlth Halifax	Halifax, Nova Scotia	Canada
LMC Clinical Res Thornhill	Concord, Ontario	Canada
St. Joseph's Health Care	London, Ontario	Canada
Centricity Research LMC	Toronto, Ontario	Canada
Ctr de rech Clin de Laval	Laval, Quebec	Canada
IRCM	Montreal, Quebec	Canada
Centre de recherché du CHUS	Sherbrooke, Quebec	Canada
CHU de Quebec-Universite Laval	Québec	Canada
Medizinisches Versorgungszentrum Am Bahnhof Spandau GbR	Berlin	Germany
InnoDiab Forschung GmbH	Essen	Germany
Zentrum für klinische Forschung, Dr. med. Lüdemann	Falkensee	Germany
Diabetologische Gemeinschaftspraxis Dr. Staudenmeyer und Dr. Schiwietz	Lingen	Germany
Die Praxis am Ludwigsplatz	Ludwigshafen	Germany
Uniklinik Schleswig-Holstein - Medizinischen Klinik I am Campus Lübeck	Lübeck	Germany
Institut für Diabetesforschung GmbH Münster - Dr. med. Rose	Münster	Germany
RED-Institut für medizinische Studien und Fortbildung GmbH	Oldenburg I. Holst	Germany
RED-Institut für medizinische Forschung und Fortbildung GmbH	Oldenburg in Holstein	Germany
Zentrum für klinische Studien Alexander Segner	Saint Ingbert-Oberwürzbach	Germany
Diacare diabetes Hormonal Clinic	Ahmedabad, Gujarat	India
Calicut Medical College	Kozhikode, Kerala	India
All India Institute of Medical Sciences	New Dehli, New Delhi	India
Post Graduate Institute of Medical Education & Research	Chandigarh, Punjab	India
Fortis Heart Institute and Multispeciality Hospital	Mohali, Punjab	India
Care Hospital	Hyderabad	India
Lady Hardinge Medical College	New Delhi	India
Jothydev's Diabetes & Research Center	Thriruvananthapuram	India
Azienda Ospedaliera di Perugia;Ospedale S. Maria della Misericordia	Perugia, Umbria	Italy
Policlinico Mater Domini Università di Catanzaro	Catanzaro	Italy
Azienda Ospedaliero Universitaria Careggi MASTER	Florence	Italy
Osp. San Raffaele Diabetes Research Institute, Dibit 1	Milan	Italy
Policlinico Umberto I Clinica Medica DH Diabetologia	Roma	Italy
Master Centre for Italy	Rome	Italy
Fondazione Policlinico Universitario Agostino Gemelli IRCCS - Dipartimento di scienze Mediche e Chirurgiche	Rome	Italy
Seino Internal Medicine Clinic_Internal medicine	Koriyama-shi, Fukushima, Japan	Japan
Manda Memorial Hospital_Internal Medicine	Sapporo-shi, Hokkaido, Hokkaido, Japan	Japan
Jinnouchi Hospital_Internal Medicine	Kumamoto, Kumamoto, Japan	Japan
The Institute of Medical Science, Asahi Life Foundation_Internal Medicine	Chuo-ku, Tokyo	Japan
H.E.C Science Clinic	Kanagawa	Japan
Yuri Ono Clinic	Sapporo-shi, Hokkaido	Japan
Tokyo Women's Medical University_Metabolism and Diabetology	Tokyo	Japan
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
Volosevich First City Clinical Hospital	Arkhangelsk	Russia
LLC "Clinic of new technologies in Medicine"	Dzerzhinskiy	Russia
FSBI 'I.I. Dedov National Medical Research Center of Endocrinology' of the MH of Russia	Moscow	Russia

30 more sites not listed.

+Publications

Results publication: 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
Results publication: Kristensen NR, Haridas MP, Philis-Tsimikas A, Ribel-Madsen R, Mathieu C. The Effect of Intrinsic Factors on the Pharmacokinetics of Once-Weekly Insulin Icodec in Type 1 and Type 2 Diabetes: A Population Pharmacokinetic Analysis of Phase II and Phase III trials. Clin Pharmacokinet. 2026 Sep 30. doi: 10.1007/s40262-026-01710-9. Online ahead of print. PMID 42814374
Results publication: 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
Results publication: Danne T, Engberg S, Irace C, Kjaersgaard MIS, Klonoff DC, Mathieu C, Kehlet Watt S, Russell-Jones D. Continuous Glucose Monitoring Metrics and Continuous Glucose Monitoring-Based Hypoglycemia, Including Duration, in Individuals with Type 1 Diabetes Switching to Once-Weekly Insulin Icodec: A Post Hoc Evaluation of ONWARDS 6. Diabetes Technol Ther. 2025 Dec;27(12):963-972. doi: 10.1177/15209156251359319. Epub 2025 Jul 18. PMID 40742780
Results publication: 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
Results publication: Russell-Jones D, Babazono T, Cailleteau R, Engberg S, Irace C, Kjaersgaard MIS, Mathieu C, Rosenstock J, Woo V, Klonoff DC. Once-weekly insulin icodec versus once-daily insulin degludec as part of a basal-bolus regimen in individuals with type 1 diabetes (ONWARDS 6): a phase 3a, randomised, open-label, treat-to-target trial. Lancet. 2023 Nov 4;402(10413):1636-1647. doi: 10.1016/S0140-6736(23)02179-7. Epub 2023 Oct 17. PMID 37863084

+Study documents

Study Protocol (PDF, 2022-06-27)
Statistical Analysis Plan (PDF, 2021-04-15)

+Investigators

Clinical Transparency (1452), Study director, Novo Nordisk A/S