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)

A 26-week Double Blinded, Multiregional, Trial Comparing the Effect and Safety of Once Weekly Insulin Icodec and Once Daily Insulin Degludec 100 Units/mL, Both in Combination With Non-insulin Anti-diabetic Drugs, in Insulin naïve Subjects With Type 2 Diabetes.

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04795531

Acronym

ONWARDS 3

Enrollment

588

Registered

2021-03-12

Start date

2021-03-24

Completion date

2022-06-23

Last updated

2026-06-12

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Diabetes Mellitus, Type 2

Brief summary

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.

Interventions

DRUGInsulin icodec

You will get a pen for weekly injection and one for daily injection. One will be icodec 700 units/mL and the other will be placebo. Subcutaneously (under the skin) injections

DRUGPlacebo insulin icodec

You will get a pen for weekly injection and one for daily injection. One will be insulin degludec 100 units/mL and the other will be placebo. Subcutaneously (under the skin) injections

DRUGInsulin degludec

You will get a pen for weekly injection and one for daily injection. One will be degludec 100 units/mL and the other will be placebo. Subcutaneously (under the skin) injections

DRUGPlacebo insulin degludec

You will get a pen for weekly injection and one for daily injection. One will be icodec 700 units/mL and the other will be placebo. Subcutaneously (under the skin) injections

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* Male or female aged above or equal to 18 years at the time of signing informed consent. * Diagnosed with T2D (type 2 diabetes) greater than or equal to 180 days prior to the day of screening. * HbA1c (glycated haemoglobin) from 7.0-11.0% (53.0-96.7 mmol/mol) both inclusive at screening confirmed by central laboratory analysis. * Insulin naïve. However, short term insulin treatment for a maximum of 14 days prior to the day of screening is allowed, as is prior insulin treatment for gestational diabetes. * Stable daily dose(s) greater than or equal to 90 days prior to the day of screening of any of the following anti-diabetic drug(s) or combination regimen(s): a.) Any metformin formulations greater than or equal to 1500 mg or maximum tolerated or effective dose. b.) Any metformin combination formulations greater than or equal to 1500 mg or maximum tolerated or effective dose. c.) Any of the following oral anti-diabetic drug classes including combinations (greater than or equal to half of the maximum approved dose according to local label or maximum tolerated or effective dose).:Sulfonylureas - Meglitinides (glinides) - DPP-4 inhibitors - SGLT2 inhibitors - Thiazolidinediones - Alpha-glucosidase inhibitors - Oral combination products (for the allowed individual Oral Anti-diabetic Drugs (OADs)) - 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 (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.

Design outcomes

Primary

Measure	Time frame	Description
Change in Glycated Haemoglobin (HbA1c)	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.

Secondary

Measure	Time frame	Description
Change in Fasting Plasma Glucose (FPG)	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.
Number of Severe Hypoglycaemic Episodes (Level 3)	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 weeks after the end of the dosing interval for both treatment arms) and the end-date for the in-trial observation period. The on-treatment period represented the time period in which a participant was considered exposed to trial product.
Number of Clinically Significant Hypoglycaemic Episodes (Level 2) (< 3.0 mmol/L (54 Milligrams Per Deciliter [mg/dL]), Confirmed by Blood Glucose [BG] Meter)	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 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 the in-trial observation period. The on-treatment period represented the time period in which a participant was considered exposed to trial product.
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	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 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 the in-trial observation period.
Number of Clinically Significant Hypoglycaemic Episodes (Level 2) (<3.0 mmol/L (54 mg/dL), Confirmed by BG Meter)	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.
Change in Body Weight	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.
Mean Weekly Insulin Dose	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 the in-trial observation period. The on-treatment period represented the time period in which a participant was considered exposed to trial product.

Countries

Argentina, Austria, Brazil, Canada, China, Czechia, Denmark, France, Mexico, Puerto Rico, Taiwan, United States

Contacts

STUDY_DIRECTORClinical Transparency (dept. 1452)

Novo Nordisk A/S

Participant flow

Recruitment details

The trial was conducted at 89 sites in 11 countries as follows (number of sites that screened participants/ number of sites that randomised participants): Argentina (4/4), Austria (3/3), Brazil (4/4), Canada (14/13), China mainland (13/13), Czech Republic (6/6), Denmark (4/4), France (9/8), Mexico (2/2), Taiwan (5/5), United States (28/27).

Pre-assignment details

After randomisation participants continued their pre-trial non-insulin anti-diabetic background medication throughout the entire trial except for sulfonylureas and glinides, which had to be reduced at randomisation by approximately 50% at the discretion of the investigator.

Participants by arm

Arm	Count
Insulin Icodec Participants were to receive once weekly subcutaneous (s.c.) injection of insulin icodec using PDS290 prefilled pen-injector at a starting dose of 70 units (U) and once weekly placebo for 26 weeks. The dose was then adjusted once weekly to reach the glycaemic target of 4.4-7.2 millimoles per liter (mmol/L) based on 3 pre-breakfast self-measured plasma glucose (SMPG) values measured on 2 previous days and on the day of the titration. If at least one pre-breakfast SMPG value was: \< 4.4 mmol/L: dose reduced by 20 U; If the mean was: 4.4-7.2 mmol/L- no adjustment; \> 7.2 mmol/L- dose increased by 20 U.	294
Insulin Degludec Participants were to receive once daily s.c. injection of insulin degludec using PDS290 prefilled pen-injector at a starting dose of 10 U and once daily placebo for 26 weeks. The dose was then adjusted once weekly to reach the glycaemic target of 4.4-7.2 millimoles per liter mmol/L based on 3 pre-breakfast values measured on 2 previous days and on the day of the titration. If at least one pre-breakfast SMPG value was: \< 4.4 mmol/L: dose reduced by 3 U; If the mean was: 4.4-7.2 mmol/L- no adjustment; \> 7.2 mmol/L- dose increased by 3 U.	294
Total	588

Baseline characteristics

Characteristic	Insulin Icodec	Insulin Degludec	Total
Age, Continuous	57.70 Years STANDARD_DEVIATION 10.19	58.56 Years STANDARD_DEVIATION 9.74	58.13 Years STANDARD_DEVIATION 9.97
Ethnicity (NIH/OMB) Hispanic or Latino	76 Participants	88 Participants	164 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	203 Participants	190 Participants	393 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	15 Participants	16 Participants	31 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	1 Participants	1 Participants
Race (NIH/OMB) Asian	80 Participants	85 Participants	165 Participants
Race (NIH/OMB) Black or African American	9 Participants	6 Participants	15 Participants
Race (NIH/OMB) More than one race	11 Participants	11 Participants	22 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	15 Participants	16 Participants	31 Participants
Race (NIH/OMB) White	179 Participants	175 Participants	354 Participants
Sex: Female, Male Female	109 Participants	110 Participants	219 Participants
Sex: Female, Male Male	185 Participants	184 Participants	369 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	2 / 293	1 / 294
other Total, other adverse events	52 / 293	29 / 294
serious Total, serious adverse events	15 / 293	15 / 294

Outcome results

Primary

Change in Glycated Haemoglobin (HbA1c)

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.

Time frame: Baseline (Week 0), Week 26

Population: Full analysis set (FAS) included all randomised participants.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Insulin Icodec	Change in Glycated Haemoglobin (HbA1c)	-1.57 Percentage of HbA1c	Standard Error 0.05
Insulin Degludec	Change in Glycated Haemoglobin (HbA1c)	-1.36 Percentage of HbA1c	Standard Error 0.05

Comparison: The response and change from baseline in response after 26 weeks are analysed using an analysis of covariance (ANCOVA) model with treatment, region and sulfonylureas (SU)/glinides use as fixed factors, and baseline response as covariate.p-value: <0.000195% CI: [-0.34, -0.08]ANCOVA

Secondary

Change in Body Weight

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.

Time frame: Baseline (Week 0), Week 26

Population: Full analysis set included all randomised participants.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Insulin Icodec	Change in Body Weight	2.77 Kilograms (kg)	Standard Error 0.22
Insulin Degludec	Change in Body Weight	2.32 Kilograms (kg)	Standard Error 0.24

Secondary

Change in Fasting Plasma Glucose (FPG)

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.

Time frame: Baseline (Week 0), Week 26

Population: Full analysis set (FAS) included all randomised participants. Overall number of participants analyzed = participants with available data for this outcome measure.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Insulin Icodec	Change in Fasting Plasma Glucose (FPG)	-3.01 millimoles per liter (mmol/L)	Standard Error 0.11
Insulin Degludec	Change in Fasting Plasma Glucose (FPG)	-2.99 millimoles per liter (mmol/L)	Standard Error 0.11

Secondary

Mean Weekly Insulin Dose

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 the in-trial observation period. The on-treatment period represented the time period in which a participant was considered exposed to trial product.

Time frame: From week 24 to week 26

Population: Full analysis set included all randomised participants.

Arm	Measure	Value (LEAST_SQUARES_MEAN)
Insulin Icodec	Mean Weekly Insulin Dose	204.28 Units (U) of insulin
Insulin Degludec	Mean Weekly Insulin Dose	186.52 Units (U) of insulin

Secondary

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

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.

Time frame: From baseline (week 0) to week 26