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
试验速览
- 阶段
- 4 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 462
- 试验地点
- 1
- 主要终点
- Proportion of participants achieving target fasting blood glucose (4.4 to 7.0 mmol/L) at the end of Week 1
研究概览
简要总结
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
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Factorial
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Fixed 70 U/Week + Day-4 Supplement (Group A)
Insulin icodec is initiated at a fixed dose of 70 units once weekly, injected subcutaneously on a fixed weekday between 6:00 and 9:00 in the morning, added to existing non-insulin glucose-lowering therapy. On day 4, fasting blood glucose is measured; if it is at or above 6.8 mmol/L, a one-time supplemental dose equal to 50% of the starting dose (35 units) is given that day. For participants who received the supplemental dose, the day 8 dose returns to the starting dose, and a standardized weekly titration algorithm is applied from day 15 through Week 12.
干预措施: Insulin icodec (Drug)
Fixed 70 U/Week + No Day-4 Supplement (Group B)
Insulin icodec is initiated at a fixed dose of 70 units once weekly, injected subcutaneously on a fixed weekday between 6:00 and 9:00 in the morning, added to existing non-insulin glucose-lowering therapy. On day 4, fasting blood glucose is measured for recording only; no supplemental dose is given. A standardized weekly titration algorithm is applied from day 8 through Week 12.
干预措施: Insulin icodec (Drug)
FBG-Based Dose (FBG×7) + Day-4 Supplement (Group A)
Insulin icodec is initiated at a dose calculated as fasting blood glucose (mmol/L) multiplied by 7, given once weekly, injected subcutaneously on a fixed weekday between 6:00 and 9:00 in the morning, added to existing non-insulin glucose-lowering therapy. On day 4, fasting blood glucose is measured; if it is at or above 6.8 mmol/L, a one-time supplemental dose equal to 50% of the starting dose is given that day. For participants who received the supplemental dose, the day 8 dose returns to the starting dose, and a standardized weekly titration algorithm is applied from day 15 through Week 12.
干预措施: Insulin icodec (Drug)
FBG-Based Dose (FBG×7) + No Day-4 Supplement (Group B)
Insulin icodec is initiated at a dose calculated as fasting blood glucose (mmol/L) multiplied by 7, given once weekly, injected subcutaneously on a fixed weekday between 6:00 and 9:00 in the morning, added to existing non-insulin glucose-lowering therapy. On day 4, fasting blood glucose is measured for recording only; no supplemental dose is given. A standardized weekly titration algorithm is applied from day 8 through Week 12.
干预措施: Insulin icodec (Drug)
Weight-Based Dose (BW×0.15×7) + Day-4 Supplement (Group A)
Insulin icodec is initiated at a dose calculated as body weight (kg) multiplied by 0.15 and then by 7, given once weekly, injected subcutaneously on a fixed weekday between 6:00 and 9:00 in the morning, added to existing non-insulin glucose-lowering therapy. On day 4, fasting blood glucose is measured; if it is at or above 6.8 mmol/L, a one-time supplemental dose equal to 50% of the starting dose is given that day. For participants who received the supplemental dose, the day 8 dose returns to the starting dose, and a standardized weekly titration algorithm is applied from day 15 through Week 12.
干预措施: Insulin icodec (Drug)
Weight-Based Dose (BW×0.15×7) + No Day-4 Supplement (Group B)
Insulin icodec is initiated at a dose calculated as body weight (kg) multiplied by 0.15 and then by 7, given once weekly, injected subcutaneously on a fixed weekday between 6:00 and 9:00 in the morning, added to existing non-insulin glucose-lowering therapy. On day 4, fasting blood glucose is measured for recording only; no supplemental dose is given. A standardized weekly titration algorithm is applied from day 8 through Week 12.
干预措施: Insulin icodec (Drug)
结局指标
主要结局
Proportion of participants achieving target fasting blood glucose (4.4 to 7.0 mmol/L) at the end of Week 1
时间窗: Day 8 (end of Week 1)
The proportion of participants whose fasting blood glucose is within the target range of 4.4 to 7.0 mmol/L, measured on the morning of Day 8 before the second weekly injection and any dose adjustment. This endpoint is compared among the three insulin icodec initiation strategies (fixed 70 U/week, FBGx7, and BWx0.15x7) to identify the strategy that best promotes early target attainment. Fasting blood glucose is assessed by capillary measurement.
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)
时间窗: Day 8 (end of Week 1)
The effectiveness of the day-4 threshold-based supplemental dosing rule, evaluated as the proportion of participants achieving target fasting blood glucose (4.4 to 7.0 mmol/L) on the morning of Day 8. All three initiation arms are pooled, and Group A (fasting blood glucose measured on Day 4; a one-time supplemental dose equal to 50% of the starting dose given if the value is at or above 6.8 mmol/L) is compared with Group B (fasting blood glucose measured on Day 4 but no supplemental dose given). Fasting blood glucose is assessed by capillary measurement.
次要结局
- Sustained fasting blood glucose target attainment rate(From Week 1 through Week 12)
- Absolute reduction in fasting blood glucose from baseline at the end of Week 1(Baseline and Day 8)
- Percentage reduction in fasting blood glucose from baseline at the end of Week 1(Baseline and Day 8)
- Safe target attainment rate at the end of Week 1(Day 8 (end of Week 1))
- Fasting blood glucose target attainment rate at Week 12(Week 12)
- Discriminative ability of Day-4 fasting blood glucose for Week-1 target attainment(Day 4 and Day 8)
- Effectiveness of the 50% supplemental dose on target attainment in participants above the Day-4 threshold(Day 8 (end of Week 1))
- Incidence and event rate of hypoglycemia by severity level(From Day 1 through Week 17 (including the 5-week safety follow-up))
- Incidence and event rate of nocturnal hypoglycemia(From Day 1 through Week 17 (including the 5-week safety follow-up))
- Time in range measured by blinded continuous glucose monitoring(Weeks 1-2 and Weeks 11-12)
- Time below range measured by blinded continuous glucose monitoring(Weeks 1-2 and Weeks 11-12)
- Time above range measured by blinded continuous glucose monitoring(Weeks 1-2 and Weeks 11-12)
- Glycemic variability measured by blinded continuous glucose monitoring(Weeks 1-2 and Weeks 11-12)
- Change in HbA1c from baseline at Week 12(Baseline and Week 12)