Type 2 Diabetes
Conditions
Keywords
Insulin icodec, Once-weekly insulin, Basal insulin, Insulin initiation, Fasting blood glucose, Glycemic target attainment, Supplemental dosing, Factorial trial, Continuous glucose monitoring, Diabetes management
Brief summary
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
DRUGInsulin 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 the starting dose, while Group B receives no supplemental dose. A standardized weekly titration algorithm is applied through Week 12.
Sponsors
Xi'an International Medical Center Hospital
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of participants achieving target fasting blood glucose (4.4 to 7.0 mmol/L) at the end of Week 1 | 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) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Absolute reduction in fasting blood glucose from baseline at the end of Week 1 | Baseline and Day 8 | The absolute change in fasting blood glucose (mmol/L) from baseline to Day 8, compared among the three initiation strategies. |
| Percentage reduction in fasting blood glucose from baseline at the end of Week 1 | Baseline and Day 8 | The percentage change in fasting blood glucose from baseline to Day 8, compared among the three initiation strategies. |
| Safe target attainment rate at the end of Week 1 | Day 8 (end of Week 1) | The proportion of participants with fasting blood glucose within 4.4 to 7.0 mmol/L on the morning of Day 8 and without any level 2 (below 3.0 mmol/L) or level 3 hypoglycemia during Week 1. |
| Fasting blood glucose target attainment rate at Week 12 | Week 12 | The proportion of participants with fasting blood glucose within 4.4 to 7.0 mmol/L at the end of Week 12. |
| Sustained fasting blood glucose target attainment rate | From Week 1 through Week 12 | The proportion of participants whose fasting blood glucose remains within 4.4 to 7.0 mmol/L at every weekly assessment from the end of Week 1 through Week 12. |
| Discriminative ability of Day-4 fasting blood glucose for Week-1 target attainment | Day 4 and Day 8 | The discriminative ability of Day-4 fasting blood glucose (cutoff 6.8 mmol/L) for predicting fasting blood glucose target attainment at the end of Week 1, assessed by area under the ROC curve, sensitivity, and specificity, to prospectively test the reproducibility of the early-warning finding from the previous retrospective study. Time Frame: 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) | Among participants with Day-4 fasting blood glucose at or above 6.8 mmol/L, the effect of a one-time supplemental dose equal to 50% of the starting dose on fasting blood glucose target attainment at the end of Week 1, compared between Group A and Group B. |
| Incidence and event rate of hypoglycemia by severity level | From Day 1 through Week 17 (including the 5-week safety follow-up) | The proportion of participants with hypoglycemia and the number of events per exposure, by capillary glucose using ADA levels (level 1 below 3.9 mmol/L, level 2 below 3.0 mmol/L, level 3 requiring assistance), across treatment. |
| Incidence and event rate of nocturnal hypoglycemia | From Day 1 through Week 17 (including the 5-week safety follow-up) | The proportion of participants with nocturnal hypoglycemia (00:00 to 06:00) and the number of events per exposure. |
| Time in range measured by blinded continuous glucose monitoring | Weeks 1-2 and Weeks 11-12 | Percentage of time with glucose in the target range of 4.4 to 10.0 mmol/L, measured by blinded continuous glucose monitoring during the first 2 weeks and the last 2 weeks. |
| Time below range measured by blinded continuous glucose monitoring | Weeks 1-2 and Weeks 11-12 | Percentage of time with glucose below 4.4 mmol/L, measured by blinded continuous glucose monitoring during the first 2 weeks and the last 2 weeks. |
| Time above range measured by blinded continuous glucose monitoring | Weeks 1-2 and Weeks 11-12 | Percentage of time with glucose above 10.0 mmol/L, measured by blinded continuous glucose monitoring during the first 2 weeks and the last 2 weeks. |
| Glycemic variability measured by blinded continuous glucose monitoring | Weeks 1-2 and Weeks 11-12 | Glycemic variability assessed as coefficient of variation and standard deviation, measured by blinded continuous glucose monitoring during the first 2 weeks and the last 2 weeks. |
| Change in HbA1c from baseline at Week 12 | Baseline and Week 12 | The change in HbA1c from baseline to the end of Week 12. |
Countries
China
Contacts
CONTACTTao Liu
PRINCIPAL_INVESTIGATORQiuhe Ji
Xi'an International Medical Center Hospital
Outcome results
None listed