Insulin Icodec Initiation Strategies and Day-4 Supplemental Dosing in Type 2 Diabetes

Official title

Effects of Different Insulin Icodec Initiation Strategies and a Day-4 Supplemental Dosing Decision on Early Fasting Blood Glucose Target Attainment in Type 2 Diabetes: A Multicenter, Randomized, Open-Label, 3x2 Factorial Trial

Overview

The goal of this clinical trial is to find the best way to start once-weekly insulin icodec in adults with type 2 diabetes who have not used insulin in the past 3 months, so that their fasting blood glucose reaches the target range within the first week. The main questions it aims to answer are: * Which of three starting-dose methods brings the most people to their fasting blood glucose target by the end of the first week? * On day 4 after starting, if fasting blood glucose is still high, does giving one extra half-dose of insulin help more people reach target safely? Participants will be randomly placed into one of three starting-dose groups: a fixed weekly dose, a dose based on their fasting blood glucose, or a dose based on their body weight. Within each group, participants will also be randomly assigned either to receive an extra insulin dose on day 4 if their fasting blood glucose is at or above a set level, or to receive no extra dose. Participants will: * Start once-weekly insulin icodec and continue their current non-insulin diabetes medicines * Check their fasting blood glucose, including on day 4 after starting * Wear a blinded continuous glucose monitor during the first 2 weeks and the last 2 weeks * Attend weekly visits for dose adjustment and safety checks over 12 weeks, followed by a 5-week safety follow-up

Detailed description

Background and rationale: Once-weekly insulin icodec has a half-life of approximately 196 hours, so its pharmacokinetic steady state is not reached until 3 to 4 weeks after initiation. This creates a mismatch with the clinical need to assess and achieve early fasting blood glucose (FBG) control within the first week. The glucose-lowering effect of icodec peaks on days 2 to 3 and remains near-maximal on day 4, offering an early time point to identify patients at risk of not reaching target. However, no prospective trial has compared icodec initiation strategies for early glycemic control or validated an early marker to guide supplemental dosing. This trial addresses that gap.

Design: This is a multicenter, randomized, open-label trial with a 3-by-2 factorial structure. Insulin-naive adults with type 2 diabetes who have not received insulin in the past 3 months are randomized 1:1:1 (stratified by center and baseline FBG) to one of three icodec initiation strategies: a fixed dose of 70 units per week; a dose based on fasting blood glucose (FBG in mmol/L multiplied by 7); or a dose based on body weight (body weight in kg multiplied by 0.15, then by 7). Within each initiation arm, participants are further randomized 1:1 to one of two day-4 management groups. In Group A, FBG is measured on day 4; if FBG is at or above 6.8 mmol/L, a one-time supplemental dose equal to 50% of the starting dose is given that day. In Group B, FBG is measured on day 4 but no supplemental dose is given. Because day-4 management is randomized independently of the day-4 FBG value, the comparison remains a valid randomized comparison.

Treatment and titration: Icodec is injected once weekly, on a fixed weekday, between 6:00 and 9:00 in the morning, in addition to the participant's existing non-insulin glucose-lowering therapy. The first injection defines study Day 1. From Day 15 (for participants who received a day-4 supplemental dose, whose Day 8 dose returns to the original starting dose) or from Day 8 (for those who did not), a standardized weekly titration algorithm adapted from the ONWARDS program is applied through Week 12. A blinded continuous glucose monitor is worn during the first 2 weeks and the last 2 weeks; it is not used for real-time titration decisions.

Primary endpoints: This trial has two independent co-primary endpoints, each tested at a two-sided alpha of 0.05 without alpha splitting across objectives. The first is the proportion of participants achieving target FBG (4.4 to 7.0 mmol/L) at the end of Week 1 (Day 8, before the second injection), compared across the three initiation strategies, with Bonferroni correction for the three pairwise comparisons. The second is the effectiveness of the day-4 threshold-based supplemental dosing rule, evaluated by comparing target attainment between the pooled Group A and Group B.

Follow-up: The randomized treatment period lasts 12 weeks, followed by a 5-week safety follow-up (Weeks 13 to 17) to capture delayed hypoglycemia after the last dose, given the prolonged action of icodec.

Interventions

• Drug Insulin icodec
  Once-weekly subcutaneous insulin icodec, injected on a fixed weekday between 6:00 and 9:00 in the morning, added to existing non-insulin glucose-lowering therapy. The starting dose is determined by the assigned initiation strategy: a fixed 70 units per week; fasting blood glucose (mmol/L) multiplied by 7; or body weight (kg) multiplied by 0.15 and then by 7. On day 4, participants in Group A with fasting blood glucose at or above 6.8 mmol/L receive a one-time supplemental dose equal to 50% of th

Primary outcome measures

• Proportion of participants achieving target fasting blood glucose (4.4 to 7.0 mmol/L) at the end of Week 1 [Time frame: Day 8 (end of Week 1)]
• Proportion of participants achieving target fasting blood glucose (4.4 to 7.0 mmol/L) at the end of Week 1, compared between the day-4 supplemental dosing decision groups (Group A vs Group B) [Time frame: Day 8 (end of Week 1)]

Secondary outcome measures (12)

• Absolute reduction in fasting blood glucose from baseline at the end of Week 1 [Time frame: Baseline and Day 8]
• Percentage reduction in fasting blood glucose from baseline at the end of Week 1 [Time frame: Baseline and Day 8]
• Safe target attainment rate at the end of Week 1 [Time frame: Day 8 (end of Week 1)]
• Fasting blood glucose target attainment rate at Week 12 [Time frame: Week 12]
• Sustained fasting blood glucose target attainment rate [Time frame: From Week 1 through Week 12]
• Discriminative ability of Day-4 fasting blood glucose for Week-1 target attainment [Time frame: Day 4 and Day 8]
• Effectiveness of the 50% supplemental dose on target attainment in participants above the Day-4 threshold [Time frame: Day 8 (end of Week 1)]
• Incidence and event rate of hypoglycemia by severity level [Time frame: From Day 1 through Week 17 (including the 5-week safety follow-up)]
• Incidence and event rate of nocturnal hypoglycemia [Time frame: From Day 1 through Week 17 (including the 5-week safety follow-up)]
• Time in range measured by blinded continuous glucose monitoring [Time frame: Weeks 1-2 and Weeks 11-12]
• Time below range measured by blinded continuous glucose monitoring [Time frame: Weeks 1-2 and Weeks 11-12]
• Time above range measured by blinded continuous glucose monitoring [Time frame: Weeks 1-2 and Weeks 11-12]

Eligibility criteria

Inclusion criteria

• Age 18 years or older
• Diagnosis of type 2 diabetes mellitus for at least 180 days
• No insulin treatment of any kind within the past 3 months
• Currently treated with at least one non-insulin glucose-lowering agent (oral agent or GLP-1 receptor agonist) with inadequate glycemic control, and a clinical indication to start basal insulin
• HbA1c of 7.0% to 11.0% at screening
• Body mass index of 35.0 kg/m2 or lower
• Able and willing to wear a continuous glucose monitor per protocol, to undergo day-4 fasting blood glucose assessment, and to attend all scheduled visits
• Provides written informed consent

Exclusion criteria

• Type 1 diabetes, specific types of diabetes, or recent acute complications such as diabetic ketoacidosis or hyperosmolar hyperglycemic state
• Level 2 or level 3 hypoglycemia within the past 3 months, or hypoglycemia unawareness
• Current use, or use within the past 3 months, of systemic glucocorticoids (excluding inhaled or topical preparations) or other agents that markedly affect blood glucose
• Moderate to severe renal impairment (eGFR below 45 mL/min/1.73 m2 by the CKD-EPI 2021 creatinine equation) or need for dialysis
• Active liver disease, abnormal liver function (ALT or AST above 3 times the upper limit of normal), or decompensated cirrhosis
• Marked edema, large-volume ascites, amputation, or other conditions that may impair accurate body weight measurement or distort weight-based dosing
• Known allergy to insulin icodec or its excipients
• Extensive skin lesions, allergy to continuous glucose monitor adhesive, or anticipated frequent magnetic resonance imaging that may interfere with monitor wear or interpretation
• Active malignancy
• Acute cardiovascular or cerebrovascular event (such as myocardial infarction, stroke, or unstable angina) within the past 6 months, or other major illness with short expected survival or poor compliance
• Pregnancy or lactation, or women of childbearing potential with pregnancy plans
• Participation in another drug or device clinical trial within the past 3 months
• Other conditions judged by the investigator to be unsuitable for enrollment or likely to affect participant safety or data reliability

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Factorial

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Xi'an International Medical Center Hospital — Xi'an

Publications

• Bajaj HS, Aberle J, Davies M, Donatsky AM, Frederiksen M, Yavuz DG, Gowda A, Lingvay I, Bode B. Once-Weekly Insulin Icodec With Dosing Guide App Versus Once-Daily Basal Insulin Analogues in Insulin-Naive Type 2 Diabetes (ONWARDS 5) : A Randomized Trial. Ann Intern Med. 2023 Nov;176(11):1476-1485. doi: 10.7326/M23-1288. Epub 2023 Sep 26. PMID 37748181
• Lingvay I, Asong M, Desouza C, Gourdy P, Kar S, Vianna A, Vilsboll T, Vinther S, Mu Y. Once-Weekly Insulin Icodec vs Once-Daily Insulin Degludec in Adults With Insulin-Naive Type 2 Diabetes: The ONWARDS 3 Randomized Clinical Trial. JAMA. 2023 Jul 18;330(3):228-237. doi: 10.1001/jama.2023.11313. PMID 37354562
• Rosenstock J, Bain SC, Gowda A, Jodar E, Liang B, Lingvay I, Nishida T, Trevisan R, Mosenzon O; ONWARDS 1 Trial Investigators. Weekly Icodec versus Daily Glargine U100 in Type 2 Diabetes without Previous Insulin. N Engl J Med. 2023 Jul 27;389(4):297-308. doi: 10.1056/NEJMoa2303208. Epub 2023 Jun 24. PMID 37356066
• 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
• Nishimura E, Pridal L, Glendorf T, Hansen BF, Hubalek F, Kjeldsen T, Kristensen NR, Lutzen A, Lyby K, Madsen P, Pedersen TA, Ribel-Madsen R, Stidsen CE, Haahr H. Molecular and pharmacological characterization of insulin icodec: a new basal insulin analog designed for once-weekly dosing. BMJ Open Diabetes Res Care. 2021 Aug;9(1):e002301. doi: 10.1136/bmjdrc-2021-002301. PMID 34413118

Identifiers

NCT: NCT07747402 · IIT-2026-NFM-01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗