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

A 78-week Trial Comparing the Effect and Safety of Once Weekly Insulin Icodec and Once Daily Insulin Glargine 100 Units/mL, Both in Combination With Non-insulin Anti-diabetic Treatment, in Insulin naïve Subjects With Type 2 Diabetes

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04460885

Acronym

ONWARDS 1

Enrollment

984

Registered

2020-07-08

Start date

2020-11-25

Completion date

2022-12-01

Last updated

2025-12-04

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 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 get is decided by chance. 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 ½ years. Participants will have 37 clinic visits and 26 phone calls with the study doctor. At 11 clinic visits participant will have blood samples taken. At 8 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 the blood sugar all the time in 5 periods of about one month during the study (about 5 months in total). Women cannot take part if pregnant, breast-feeding or plan to become pregnant during the study period.

Interventions

DRUGInsulin icodec

Participants will receive subcutaneous (s.c.) injections of insulin icodec once weekly for 78 weeks.

DRUGInsulin glargine

Participants will receive subcutaneous (s.c.) injections of insulin glargine once daily for 78 weeks

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

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 type 2 diabetes mellitus (T2D) 180 days or more prior to the day of screening. * HbA1c 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) 90 days or more prior to the day of screening of any of the following anti-diabetic drug(s) or combination regimen(s): a. Any metformin formulations at least or greater than 1500 mg or maximum tolerated or effective dose. b. Any metformin combination formulations equal to or above 1500 mg or maximum tolerated or effective dose. c. Any of the following oral anti-diabetic drug classes including combinations ((equal to or above half of the maximum approved dose according to local label or maximum tolerated or effective dose): Sulfonylureas, Meglitinides (glinides), dipeptidyl peptidase-4 (DPP-4) inhibitors, Sodium-glucose co-transporter-2 (SGLT2) inhibitors, Thiazolidinediones, Alpha-glucosidase inhibitors, Oral combination products (for the allowed individual oral anti-diabetic drugs), Oral or injectable glucagon-like peptide 1 (GLP-1) receptor agonists * Body mass index (BMI) equal to or below 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 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 52	Change in HbA1c from baseline (week 0) to week 52 is presented. The outcome data was evaluated based on the in-trial observation period. The in-trial period started at randomization 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

Measure	Time frame	Description
Change in Fasting Plasma Glucose (FPG)	Baseline (week 0), Week 52	Change in FPG from baseline (week 0) to week 52 is presented. The outcome data was evaluated based on the in-trial observation period. The in-trial period started at randomization 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) Until Week 52	From baseline (week 0) to week 52	Number of severe hypoglycaemic episodes (level 3) is presented. Severe hypoglycaemic episode is defined as hypoglycaemia with severe cognitive impairment requiring external assistance for recovery. The outcome data was evaluated based on main-on-treatment period. Main-on-treatment period started with onset date on or after the first dose of trial product and no later than the first date of either the end-date of the on-treatment period or week 52. On-treatment period started with 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.
Number of Clinically Significant Hypoglycaemic Episodes (Level 2) (Less Than [<] 3.0 mmol/L [54 mg/dL] Confirmed by Blood Glucose [BG] Meter) Until Week 52	From baseline (week 0) to week 52	Number of clinically significant hypoglycaemic episodes (level 2) (\<3.0 mmol/L (54 mg/dL) confirmed by BG meter) is presented. Clinically significant hypoglycaemia 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 main-on-treatment period. Main-on-treatment period started with onset date on or after the first dose of trial product and no later than the first date of either the end-date of the on-treatment period or week 52. On-treatment period started with 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.
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) Until Week 52	From baseline (week 0) to week 52	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. Clinically significant hypoglycaemia is defined as plasma glucose value of \< 3.0 mmol/L (54 mg/dL) confirmed by BG meter. Severe hypoglycaemic episode is defined as hypoglycaemia with severe cognitive impairment requiring external assistance for recovery. The outcome data was evaluated based on main-on-treatment period. Main-on-treatment period started with onset date on or after the first dose of trial product and no later than the first date of either the end-date of the on-treatment period or week 52. On-treatment period started with 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.
Number of Severe Hypoglycaemic Episodes (Level 3) Until Week 83	From baseline (week 0) to week 83	Number of severe hypoglycaemic episodes (level 3) is presented. Severe hypoglycaemic episode is defined as hypoglycaemia with severe cognitive impairment requiring external assistance for recovery. The outcome data was evaluated based on on-treatment period. The 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 of trial visit (V63), 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 subject was considered exposed to trial product.
Percentage of Time in Target Range 3.9-10.0 mmol/L (70-180 mg/dL) Using Continuous Glucose Monitoring (CGM) System	From week 48 to week 52	Percentage of time in target range 3.9-10.0 mmol/L (70-180 mg/dL) using CGM system from week 48 to week 52 is presented. Time in target range is defined as 100 times the number of recorded measurements in glycaemic target range 3.9-10.0 mmol/L (70-180 mg/dL), both inclusive, divided by the total number of recorded measurements. The outcome data was evaluated based on the in-trial observation period. The in-trial period started at randomization 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 Clinically Significant Hypoglycaemic Episodes (Level 2) (<3.0 mmol/L (54 mg/dL), Confirmed by BG Meter) or Severe Hypoglycaemic Episodes (Level 3) Until Week 83	From baseline (week 0) to week 83	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. Clinically significant hypoglycaemia is defined as plasma glucose value of \< 3.0 mmol/L (54 mg/dL) confirmed by BG meter. Severe hypoglycaemic episode is defined as hypoglycaemia with severe cognitive impairment requiring external assistance for recovery. The outcome data was evaluated based on on-treatment period. 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 of trial visit (V63), 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. On-treatment period was the period in which a participant was exposed to trial product.
Mean Weekly Insulin Dose	From week 50 to week 52	Mean weekly insulin dose from week 50 to week 52 is presented. The outcome data was evaluated based on main on treatment period. Main-on-treatment period started with onset date on or after the first dose of trial product and no later than the first date of either the end-date of the on-treatment period or week 52. On-treatment period started with 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.
Change in Body Weight	Baseline (week 0), Week 52	Change in body weight from baseline (week 0) to week 52 is presented. The outcome data was evaluated based on the in-trial observation period. The in-trial period started at randomization 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 < 3.0 mmol/L (54 mg/dL) Using Continuous Glucose Monitoring (CGM) System	From week 48 to week 52	Percentage of time spent \< 3.0 mmol/L (54 mg/dL) from week 48 to week 52 is presented. Time spent below threshold is defined as 100 times the number of recorded measurements below the threshold, divided by the total number of recorded measurements. The outcome data was evaluated based on the in-trial observation period. The in-trial period started at randomization 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 > 10 mmol/L (180 mg/dL) Using Continuous Glucose Monitoring (CGM) System	From week 48 to week 52	Percentage of time spent \> 10 mmol/L (180 mg/dL) is presented. Time spent above threshold is defined as 100 times the number of recorded measurements above the threshold, divided by the total number of recorded measurements. The outcome data was evaluated based on the in-trial observation period. The in-trial period started at randomization 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 Clinically Significant Hypoglycaemic Episodes (Level 2) (<3.0 mmol/L (54 mg/dL) Confirmed by BG Meter) Until Week 83	From baseline (week 0) to week 83	Number of clinically significant hypoglycaemic episodes (level 2) (\<3.0 mmol/L (54 mg/dL) confirmed by BG meter) is presented. Clinically significant hypoglycaemia 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 on-treatment period. The 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 of trial visit (V63), 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 subject was considered exposed to trial product.

Countries

Croatia, India, Israel, Italy, Japan, Mexico, Poland, Puerto Rico, Russia, Slovakia, Spain, United Kingdom, United States

Participant flow

Recruitment details

The trial was conducted at 137 sites in 12 countries while 141 sites screened participants. The total number of sites per country that screened and randomised participants are as follows (number of sites that screened participants/number of sites that randomised participants): Croatia (4/4), India (9/9), Israel (5/5), Italy (5/5), Japan (14/14), Mexico (3/3), Poland (8/8), Russia (14/14), Slovakia (7/7), Spain (5/5), United Kingdom (11/11), United States (56/52)

Participants by arm

Arm	Count
Insulin Icodec Participants received once-weekly subcutaneous injection of insulin icodec at a starting dose of 70 U for 78 weeks using PDS 290 pre-filled injector in combination with non-insulin anti-diabetic drugs. The dose adjustment was based on the three pre-breakfast self-monitored plasma glucose (SMPG) values measured on two days prior to titration and on the day of the contact. If at least one pre-breakfast SMPG value was: \< 4.4 millimoles per liter (mmol/L): dose reduced by 20 units (U); 4.4-7.2 mmol/L: no adjustment; \> 7.2 mmol/L: dose increased by 20 units.	492
Insulin Glargine Participants received once daily subcutaneous injection of insulin glargine at a starting dose of 10 U for 78 weeks using SoloSTAR pre-filled pen injector in combination with non-insulin anti-diabetic drugs. The dose adjustment was based on the three pre-breakfast self-monitored plasma glucose (SMPG) values measured on two days prior to titration and on the day of the contact. If atleast one pre-breakfast SMPG value was: \< 4.4 mmol/L: the dose was reduced by 3 U; 4.4-7.2: no dose adjustment required and \>7.2 mmol/L: dose was increased by 3 U.	492
Total	984

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Death	5	4
Overall Study	Lost to Follow-up	4	4
Overall Study	Physician Decision	2	1
Overall Study	Site closure	1	0
Overall Study	Withdrawal by Subject	6	8

Baseline characteristics

Characteristic	Insulin Glargine	Total	Insulin Icodec
Age, Continuous	58.85 Years STANDARD_DEVIATION 9.85	58.96 Years STANDARD_DEVIATION 9.95	59.06 Years STANDARD_DEVIATION 10.05
Ethnicity (NIH/OMB) Hispanic or Latino	53 Participants	106 Participants	53 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	439 Participants	878 Participants	439 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	0 Participants	2 Participants	2 Participants
Race/Ethnicity, Customized Asian	145 Participants	274 Participants	129 Participants
Race/Ethnicity, Customized Black or African American	17 Participants	27 Participants	10 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 Participants	2 Participants	2 Participants
Race/Ethnicity, Customized Other	13 Participants	29 Participants	16 Participants
Race/Ethnicity, Customized White	317 Participants	650 Participants	333 Participants
Sex: Female, Male Female	229 Participants	426 Participants	197 Participants
Sex: Female, Male Male	263 Participants	558 Participants	295 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	5 / 492	4 / 492
other Total, other adverse events	221 / 492	216 / 492
serious Total, serious adverse events	64 / 492	71 / 492

Outcome results

Primary

Change in Glycated Haemoglobin (HbA1c)

Change in HbA1c from baseline (week 0) to week 52 is presented. The outcome data was evaluated based on the in-trial observation period. The in-trial period started at randomization 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.

Time frame: Baseline (week 0), Week 52

Population: Full analysis set included all randomized participants.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Insulin Icodec	Change in Glycated Haemoglobin (HbA1c)	-1.55 Percentage of HbA1c	Standard Error 0.06
Insulin Glargine	Change in Glycated Haemoglobin (HbA1c)	-1.35 Percentage of HbA1c	Standard Error 0.05

p-value: <0.000195% CI: [-0.36, -0.03]ANCOVA

Secondary

Change in Body Weight

Change in body weight from baseline (week 0) to week 52 is presented. The outcome data was evaluated based on the in-trial observation period. The in-trial period started at randomization 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.

Time frame: Baseline (week 0), Week 52

Population: Full analysis set included all randomized participants.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Insulin Icodec	Change in Body Weight	2.29 kilograms (kg)	Standard Error 0.21
Insulin Glargine	Change in Body Weight	1.83 kilograms (kg)	Standard Error 0.21

Secondary

Change in Fasting Plasma Glucose (FPG)

Change in FPG from baseline (week 0) to week 52 is presented. The outcome data was evaluated based on the in-trial observation period. The in-trial period started at randomization 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.

Time frame: Baseline (week 0), Week 52

Population: Full analysis set included all randomized participants. Overall number of participants analysed = Participants with available data for the outcome measure.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Insulin Icodec	Change in Fasting Plasma Glucose (FPG)	-3.35 millimoles per liter (mmol/L)	Standard Error 0.09
Insulin Glargine	Change in Fasting Plasma Glucose (FPG)	-3.33 millimoles per liter (mmol/L)	Standard Error 0.09

Secondary

Mean Weekly Insulin Dose

Mean weekly insulin dose from week 50 to week 52 is presented. The outcome data was evaluated based on main on treatment period. Main-on-treatment period started with onset date on or after the first dose of trial product and no later than the first date of either the end-date of the on-treatment period or week 52. On-treatment period started with 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.

Time frame: From week 50 to week 52