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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.(NN1436-4625) (ONWARDS6)

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. (ONWARDS6)

582

Of the 582 randomised subjects, 42.1% were female, 77.0% were White, 21.1% were Asian, 1.9% were Black/African American and 3.4% were Hispanic/Latino. Their mean baseline characteristics were, age: 44.18 years, HbA1c: 7.61%, FPG: 9.75 mmol/L (175.67 mg/dL), BMI: 26.51 kg/m2, diabetes duration: 19.51 years.

A total of 582 basal-bolus treated subjects with T1D were randomised, 290 in the insulin icodec arm and 292 to insulin degludec. A total of 290 subjects (100%) were exposed to insulin icodec and 292 subjects (100%) were exposed to insulin degludec, while 272 (93.8%) and 283 subjects (96.9%), respectively, completed week 26 visit without permanent discontinuation of trial product. In the extension part, 262 (90.3%) in the insulin icodec arm and 278 (95.2%) subjects in the insulin degludec arm completed the week 52 visit without permanent discontinuation of trial product.

<52-week main part> -Estimated change from baseline to week 26 in body weight was 1.29 kg with insulin icodec and 1.01 kg with insulin degludec. The treatment difference was not statistically significant. ETD 0.28 kg [-0.37;0.92]95% CI -There were 47 episodes of severe (level 3) hypoglycaemia in 9 subjects with insulin icodec and 17 episodes in 9 subjects with insulin degludec. There was no statistically significant difference between insulin icodec and insulin degludec. ERR 2.08 [0.39;10.96]95% CI -The rate of clinically significant (level 2) hypoglycaemia per 100 PYE (patient years of exposure) was 1959.83 with insulin icodec and 1025.53 with insulin degludec. The rate of clinically significant (level 2) hypoglycaemia was statistically significantly higher with insulin icodec vs insulin degludec. ERR 1.88 [1.53;2.32]95% CI -The rate of severe (level 3) or clinically significant (level 2) hypoglycaemia per 100 PYE was 1992.86 with insulin icodec and 1037.33 with insulin degludec. The rate of severe (level 3) or clinically significant (level 2) hypoglycaemia was statistically significantly higher with insulin icodec vs insulin degludec. ERR 1.89 [1.54;2.33]95% CI -The rate of nocturnal severe (level 3) or clinically significant (level 2) hypoglycaemia per 100 PYE was 338.00 with insulin icodec and 157.51 with insulin degludec. The rate of nocturnal severe (level 3) or clinically significant (level 2) hypoglycaemia was statistically significantly higher with insulin icodec vs insulin degludec. ERR 2.13 [1.56;2.91]95% CI - No new safety issues were identified in relation to insulin icodec in the main phase of this trial -No specific pattern in the occurrence and frequency of events between treatment arms was observed -SAEs: -Insulin icodec: 15 SAEs, 8 events were assessed as 'possibly' or 'probably' related to insulin icodec -Insulin degludec: 9 SAEs, 2 events were assessed as 'possibly' related to insulin degludec -Fatal events: 1 event in insulin icodec -Medication errors incl. misuse and abuse: 18 events in insulin icodec and 6 events in insulin degludec -No new safety concern regarding anti-drug antibodies formation was identified <entire trial period including extension part> -Estimated change from baseline to week 52 in body weight was 1.25 kg with insulin icodec and 1.67 kg with insulin degludec. The treatment difference was not statistically significant. ETD -0.42 [-1.20;0.37]95% CI -There were 56 episodes of severe (level 3) hypoglycaemia with insulin icodec and 25 with insulin degludec during the on-treatment period. The rate of severe (level 3) hypoglycaemia was not statistically significantly different between two treatment arms. ERR 1.88 [0.48;7.36]95% CI -The rate of clinically significant (level 2) hypoglycaemia per 100 PYE (patient years of exposure) was 1681.44 with insulin icodec and 908.00 with insulin degludec during the on-treatment period. The rate of clinically significant (level 2) hypoglycaemia was statistically significantly different in favour of insulin degludec. ERR 1.79 [1.48;2.18]95% CI -The rate of severe (level 3) or clinically significant (level 2) hypoglycaemia per 100 PYE (patient years of exposure) was 1700.10 with insulin icodec and 916.07 with insulin degludec during the on-treatment period. The rate of severe (level 3) or clinically significant (level 2) hypoglycaemia was statistically significantly different in favour of insulin degludec. ERR 1.80 [1.48;2.18]95% CI -The rate of nocturnal severe (level 3) or clinically significant (level 2) hypoglycaemia per 100 PYE (patient years of exposure) was 289.85 with insulin icodec and 149.23 with insulin degludec during the on-treatment period. The rate of nocturnal severe (level 3) or clinically significant (level 2) hypoglycaemia was statistically significantly different in favour of insulin degludec. ERR 1.89 [1.44;2.48]95% CI -No new safety issues were identified in relation to insulin icodec in the extension part of this trial -No unexpected pattern in the occurrence and frequency of events between treatment arms was observed -SAEs: -Insulin icodec: 39 SAEs, 15 reactions were assessed as possibly or probably related to insulin icodec -Insulin degludec: 25 SAEs, 4 reactions were assessed as possibly related to insulin degludec -The imbalance in number of SAEs is driven by more serious hypoglycaemic episodes reported by insulin icodec-treated patients -Fatal events: 1 case in insulin icodec -There was no identified safety concern with development of anti-insulin icodec ADA. Almost all ADA positive samples were cross-reactive to human insulin. No clinically relevant consequence of ADA on safety or efficacy parameters were identified. -Medication errors incl. misuse and abuse: 18 events in insulin icodec and 8 events in insulin degludec -Most of the events (15 of 18 events) of medication error in the insulin icodec group happened up until and including study day 8 of main phase coinciding with when the patients in the insulin icodec treatment group received a one-time additional dose

Estimated change from baseline to week 26 in HbA1c was -0.47%-point with insulin icodec and -0.51%-point with insulin degludec, confirming non inferiority of insulin icodec vs insulin degludec. ETD 0.05%-point [-0.13; 0.23]95% CI <26-week main part> -Time in range 3.9-10.0 mmol/L from week 22 to week 26 was 59.10% with insulin icodec and 60.85% with insulin degludec. The treatment difference was not statistically significant. ETD -2.00%-point [-4.38; 0.38]95% CI -Time spent <3.0 mmol/L from week 22 to week 26 was 1.02% with insulin icodec and 0.68% with insulin degludec. The treatment ratio was statistically significant in favour of insulin degludec. ETR 1.46 [1.16; 1.85]95% CI -Time spent >10.0 mmol/L from week 22 to week 26 was 37.03% with insulin icodec and 36.25% with insulin degludec. The treatment difference was not statistically significant. ETD 1.14%-point [-1.34; 3.61]95% CI -Estimated proportion of subjects achieving HbA1c<7.0% after 26 weeks was 40.20% with insulin icodec and 45.72% with insulin degludec. The odds of achieving HbA1c<7% were not statistically significantly different between treatment arms. EOR 0.80 [0.53; 1.19]95% CI -Estimated proportion of subjects achieving HbA1c<=6.5% after 26 weeks was 23.95% with insulin icodec and 18.42% with insulin degludec. The odds of achieving HbA1c<=6.5% were not statistically significantly different between treatment arms. EOR 1.39 [0.88; 2.22]95% CI -Estimated change from baseline to week 26 in FPG was -0.84 mmol/L with insulin icodec and -1.87 mmol/L with insulin degludec. The treatment difference was statistically significant in favour of insulin degludec. ETD 1.03 mmol/L [0.48; 1.59]95% CI -Estimated change from baseline to week 26 in DTSQs in total treatment satisfaction was 1.97 with insulin icodec and 3.06 with insulin degludec. The treatment difference was statistically significant in favour of insulin degludec. ETD -1.09 [-1.85; -0.34]95% CI -When adjusting for screening dose, the estimated mean weekly total insulin dose from week 24 to week 26 was 310.52 U with insulin icodec and 322.68 U with insulin degludec. There was no statistically significant difference between insulin icodec and insulin degludec. ETR 0.96 [0.90;1.03]95% CI -When adjusting for screening dose, the estimated mean weekly total basal insulin dose from week 24 to week 26 was 169.96 U with insulin icodec and 151.24 U with insulin degludec. The dose was statistically significantly higher with insulin icodec vs insulin degludec. ETR 1.12 [1.07;1.18]95% CI -When adjusting for screening dose, the estimated mean weekly total bolus insulin dose from week 24 to week 26 was 131.86 U with insulin icodec and 161.42 U with insulin degludec. The dose was statistically significantly lower with insulin icodec vs insulin degludec. ETR 0.82 [0.74;0.90]95% CI <at the end of extension part (52 weeks)> -Estimated change from baseline to week 52 in HbA1c was -0.37%-point with insulin icodec and -0.54%-point with insulin degludec. The difference is statistically significant and in favour of insulin degludec. ETD 0.17%-point [0.02; 0.31]95% CI -Time in range 3.9-10.0 mmol/L from week 48 to week 52 was 57.26% with insulin icodec and 59.60% with insulin degludec. The treatment difference was not statistically significant. ETD -2.42%-point [-4.90; 0.07]95% CI -Time spent <3.0 mmol/L from week 48 to week 52 was 0.84% with insulin icodec and 0.80% with insulin degludec. The treatment ratio was not statistically significant. ETR 1.02 [0.80; 1.30]95% CI -Time spent >10.0 mmol/L from week 48 to week 52 was 39.32% with insulin icodec and 37.25% with insulin degludec. The treatment difference was not statistically significant. ETD 2.27% [-0.39;4.94]95% CI -Estimated proportion of subjects achieving HbA1c<7.0% after 52 weeks was 33.92% with insulin icodec and 36.99% with insulin degludec. The odds of achieving HbA1c<7% were not statistically significantly different between treatment arms. EOR 0.87 [0.57; 1.33]95% CI -Estimated proportion of subjects achieving HbA1c<=6.5% after 52 weeks was 14.65% with insulin icodec and 18.11% with insulin degludec. The odds of achieving HbA1c<=6.5% were not statistically significantly different between treatment arms. EOR 0.78 [0.48; 1.24]95% CI -Estimated change from baseline to week 52 in FPG was -0.58 mmol/L with insulin icodec and -1.88 mmol/L with insulin degludec. The treatment difference was statistically significant in favour of insulin degludec. ETD 1.30 mmol/L [0.73; 1.86]95% CI -Estimated change from baseline to week 52 in DTSQs in total treatment satisfaction was 1.41 with insulin icodec and 3.00 with insulin degludec. The treatment difference was statistically significant in favour of insulin degludec. ETD -1.59 [-2.51; -0.67]95% CI -Estimated mean total weekly insulin dose from week 50 to week 52 was 310.14 U with insulin icodec and 328.90 U with insulin degludec. There was no statistically significant difference between two treatment arms. ETR 0.94 [0.88;1.01]95%CI -Estimated mean total weekly basal insulin dose from week 50 to week 52 was 169.47 U with insulin icodec and 152.78 U with insulin degludec. There was statistically significantly higher basal insulin dose for icodec. ETR 1.11 [1.04;1.18]95% CI -Estimated mean total weekly bolus insulin dose from week 50 to week 52 was 135.72 U with insulin icodec and 161.25 U with insulin degludec. There was statistically significantly lower bolus insulin dose for insulin icodec. ETR 0.84 [0.76;0.93]95% CI

Based on this 26-week main phase of the trial comparing once-weekly insulin icodec with once-daily insulin degludec, in type 1 diabetic subjects previously treated with basal-bolus insulin, change in HbA1c for insulin icodec was non-inferior to insulin degludec. There was statistically significant difference in change from baseline to week 52 in HbA1c between two treatment arms in favour of insulin degludec. No new safety issues were identified in relation to insulin icodec in this trial.

Oct. 17, 2023

https://pubmed.ncbi.nlm.nih.gov/37863084/

Yes

According to the Novo Nordisk disclosure commitment on novonordisk-trials.com URL:http://novonordisk-trials.com

https://jrct.mhlw.go.jp/latest-detail/jRCT2031210031

Oyatani Akihito

Novo Nordisk Pharma Ltd.

2-1-1, Marunouchi, Chiyodaku

JPHC_clinical_trials@novonordisk.com

Oyatani Akihito

Novo Nordisk Pharma Ltd.

2-1-1, Marunouchi, Chiyodaku

+81-362661000

JPHC_clinical_trials@novonordisk.com

Complete

April. 30, 2021

Interventional

randomized controlled trial

open(masking not used)

active control

parallel assignment

treatment purpose

1.Male or female aged >=18 years at the time of signing informed consent.
2.Diagnosed with type 1 diabetes mellitus>=1 year prior to the day of screening.
3.Treated with multiple daily insulin injections (basal and bolus insulin analogue regimes) >= 1 year prior to the day of screening.
4.HbA1c <10% at screening visit based on analysis from central laboratory.

1.Myocardial infarction, stroke, hospitalization for unstable angina pectoris or transient ischaemic attack within 180 days prior to the day of screening.
2.Chronic heart failure classified as New York Heart Association (NYHA) Class IV at screening.
3.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).
4.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.

Both

type 1 diabetes

-Two arm for insulin icodec and insulin degludec
-Use insulin aspart as a concomitant medication
-The study will consist of 3 periods: a Screening Period, a Treatment Period, and a Follow-Up Period.
-Implementation of blood sampling tests, etc. specified in the protocol.
Etc.

To confirm the effect on glycaemic control of once weekly insulin icodec in combination with insulin aspart, in subjects with type 1 diabetes. This includes comparing the difference in change from baseline in HbA1c between once weekly insulin icodec and once daily insulin degludec both in combination with insulin aspart after 26 weeks of treatment to a non-inferiority limit of 0.3%.

+81-42-648-5551

Mar. 08, 2021

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