A Research Study to Compare Insulin 287 Once a Week to Insulin Glargine (100 Units/mL) Once a Day in People With Type 2 Diabetes.

Study Overview
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Brief Summary
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The study compares 2 medicines for people with type 2 diabetes: insulin 287 (a new medicine) and insulin glargine (a medicine doctors can already prescribe). The study doctors will test insulin 287 to see how well it works compared to insulin glargine. The study will also test if insulin 287 is safe. The study participants will either get insulin 287 or insulin glargine (100 units/mL) - which treatment the participants get is decided by chance. The participants will need to inject their selves every day about the same time. Once a week the participant will need to take 1 extra injection on the same day of the week. The participants will have 16 clinic visits and 14 phone calls with the study doctor. During the study, the doctors will ask you to: 1) measure your blood sugar every day with a blood glucose meter using a finger prick, 2) write down different information in a paper diary daily and return this to your doctor, 3) wear a medical device to measure your blood sugar all the time for 2 weeks 5 times during the study.

Official Title
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An Investigational Trial Comparing the Efficacy and Safety of Once Weekly NNC0148-0287 C (Insulin 287) Versus Once Daily Insulin Glargine, Both in Combination With Metformin, With or Without DPP-4 Inhibitors, in Insulin naïve Subjects With Type 2 Diabetes Mellitus

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Insulin icodec
* Drug: Placebo (insulin 287)
* Drug: Metformin
* Drug: Dipeptidyl peptidase-4 inhibitors
* Drug: Insulin glargine
* Drug: Placebo (insulin glargine)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, aged 18-75 years (both inclusive) at the time of signing informed consent Diagnosed with type 2 diabetes mellitus greater than or equal to 180 days prior to the day of screening HbA1c of 7.0-9.5% (53-80 mmol/mol) (both inclusive) as assessed by central laboratory Stable daily dose(s) for 90 days prior to the day of screening of any of the following antidiabetic drug(s) or combination regime(s): Any metformin formulations greater than or equal to 1500 mg or maximum tolerated or effective dose (as documented in subject's medical record) OR Any metformin formulations greater than or equal to 1500 mg or maximum tolerated or effective dose (as documented in subject medical record) with Dipeptidyl peptidase-4 inhibitor (DPP4i) (greater than or equal to half of the maximum approved dose according to local label or maximum tolerated or effective dose (as documented in subject's medical records) 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 Body mass index (BMI) less than or equal to 40.0 kg/m^2 Exclusion Criteria: Any episodes of diabetic ketoacidosis within the past 90 days prior to the day of screening and between screening and randomisation Myocardial infarction, stroke, hospitalisation for unstable angina pectoris or transient ischaemic attack within 180 days prior to the day of screening and between screening and randomisation Presently classified as being in New York Heart Association (NYHA) Class IV Treatment with any medication for the indication of diabetes or obesity other than stated in the inclusion criteria within the past 90 days prior to the day of screening. 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 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 pharmacologically pupil-dilated fundus examination performed by an ophthalmologist or another suitably qualified health care provider within the past 90 days prior to screening or in the period between screening and randomisation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Insulin 287<br>Participants will receive once weekly insulin 287 and once daily placebo in combination with metformin with or without dipeptidyl peptidase-4 inhibitors (DPP4i) during 26 weeks of treatment period. | Drug: Insulin icodec<br>* Insulin 287 once weekly subcutaneous (s.c.) injections at the starting dose of 70 units. Dose adjustment was done for the individual patient based on the three pre-breakfast self-measured plasma glucose values measured on two days prior to titration and on the day of the contact. The insulin dose adjustment should aim to reach an SMPG of 3.9-6.0 mmol/L (70-108 mg/dL)<br>* Other names: Insulin 287;Drug: Metformin<br>* Metformin is considered as non investigational medicinal product. Subject will continue metformin at stable pre-trial dose.<br>Drug: Dipeptidyl peptidase-4 inhibitors<br>* Dipeptidyl peptidase-4 inhibitors are considered as non investigational medicinal products. Subject will continue dipeptidyl peptidase-4 inhibitor at stable pre-trial dose.<br>Drug: Placebo (insulin glargine)<br>* Participants will receive once daily s.c. injections of placebo equivalent to insulin glargine.<br>|
| Active Comparator: Insulin glargine<br>Participants will receive once daily insulin glargine and once weekly placebo in combination with metformin with or without DPP4i during 26 weeks of treatment period. | Drug: Placebo (insulin 287)<br>* Participants will receive once weekly s.c. injections of placebo equivalent to insulin 287.<br>Drug: Metformin<br>* Metformin is considered as non investigational medicinal product. Subject will continue metformin at stable pre-trial dose.<br>Drug: Dipeptidyl peptidase-4 inhibitors<br>* Dipeptidyl peptidase-4 inhibitors are considered as non investigational medicinal products. Subject will continue dipeptidyl peptidase-4 inhibitor at stable pre-trial dose.<br>Drug: Insulin glargine<br>* Insulin glargine (100 U/mL) once daily s.c. injections at the starting dose of 10 units. Dose adjustment will be done for the individual patient based on the three pre-breakfast self-measured plasma glucose values measured on two days prior to titration and on the day of the contact. The insulin dose adjustment should aim to reach an SMPG of 3.9-6.0 mmol/L (70-108 mg/dL).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Glycated Haemoglobin (HbA1c) [Percentage Point (%-Point)] | Change in HbA1c from baseline (week 0) to week 26 is presented. The endpoint was evaluated based on the data from on-treatment without ancillary treatment period, starting at the date of first dose of trial product until the follow-up visit, or the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin, or initiation of any diabetes treatment other than trial products and metformin +/- DPP4i, or increase of the dose of metformin or DPP4i. | From baseline (Visit 2) to week 26 (Visit 28) | 
| Change in HbA1c [Millimoles/Mole (mmol/Mol)] | Change in HbA1c from baseline (week 0) to week 26 is presented. The endpoint was evaluated based on the data from on-treatment without ancillary treatment period, starting at the date of first dose of trial product until the follow-up visit, or the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin, or initiation of any diabetes treatment other than trial products and metformin +/- DPP4i, or increase of the dose of metformin or DPP4i. | From baseline (Visit 2) to week 26 (Visit 28) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Fasting Plasma Glucose | Change in fasting plasma glucose from baseline (week 0) to week 26 is presented. The endpoint was evaluated based on the data from on-treatment without ancillary treatment period, starting at the date of first dose of trial product until the follow-up visit, or the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin, or initiation of any diabetes treatment other than trial products and metformin +/- DPP4i, or increase of the dose of metformin or DPP4i. | From baseline (Visit 2) to week 26 (Visit 28) | 
| 9-point Profile (Individual SMPG Values) | Participants measured their plasma glucose (PG) levels using blood glucose meters (as plasma equivalent values of capillary whole blood glucose) at 9 time points (before breakfast, 90 minutes after the start of breakfast, before lunch, 90 minutes after the start of lunch, before dinner, 90 minutes after the start of dinner, at bedtime, at 4 am, before breakfast the following day). 9-point SMPG values after 26 weeks are presented. The endpoint was evaluated based on the data from on-treatment without ancillary treatment period, starting at the date of first dose of trial product until the follow-up visit, or the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin, or initiation of any diabetes treatment other than trial products and metformin +/- DPP4i, or increase of the dose of metformin or DPP4i. | Week 26 (Visit 28) | 
| Change in Mean of the 9-point Profile, Defined as the Area Under the Profile Divided by Measurement Time | Participants measured their PG levels using blood glucose meters at 9 time points (before breakfast, 90 minutes after the start of breakfast, before lunch, 90 minutes after the start of lunch, before dinner, 90 minutes after the start of dinner, at bedtime, at 4 am, before breakfast the following day). The endpoint was evaluated based on the data from on-treatment without ancillary treatment period, starting at the date of first dose of trial product until the follow-up visit, or the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin, or initiation of any diabetes treatment other than trial products and metformin +/- DPP4i, or increase of the dose of metformin or DPP4i. | From baseline (Visit 2) to week 26 (Visit 28) | 
| Fluctuations of the 9-point Profile (Defined as the Integrated Absolute Distance From the Mean Profile Value Divided by Measurement Time). | Participants measured their plasma glucose (PG) levels using blood glucose meters at 9 time points (before breakfast, 90 minutes after the start of breakfast, before lunch, 90 minutes after the start of lunch, before dinner, 90 minutes after the start of dinner, at bedtime, at 4 am, before breakfast the following day). Presented fluctuation in 9-point SMPG profile is the integrated absolute distance from the mean profile value divided by measurement time and is calculated using the trapezoidal method. The endpoint was evaluated based on the data from on-treatment without ancillary treatment period, starting at the date of first dose of trial product until the follow-up visit, or the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin, or initiation of any diabetes treatment other than trial products and metformin +/- DPP4i, or increase of the dose of metformin or DPP4i. | Week 26 (Visit 28) | 
| Fasting C-peptide | Fasting C-peptide at week 26 is presented. The endpoint was evaluated based on the data from on-treatment without ancillary treatment period, starting at the date of first dose of trial product until the follow-up visit, or the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin, or initiation of any diabetes treatment other than trial products and metformin +/- DPP4i, or increase of the dose of metformin or DPP4i. | At week 26 (Visit 28) | 
| Change in Body Weight | Change in body weight from baseline (week 0) to week 26 is presented. The endpoint was evaluated based on the data from on-treatment without ancillary treatment period, starting at the date of first dose of trial product until the follow-up visit, or the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin, or initiation of any diabetes treatment other than trial products and metformin +/- DPP4i, or increase of the dose of metformin or DPP4i. | From baseline (Visit 2) to week 26 (Visit 28) | 
| Weekly Dose of Insulin 287 and Weekly Dose of Insulin Glargine | Weekly dose of insulin 287 and weekly dose of glargine at week 25 and week 26 are presented.The endpoint was evaluated based on the data from on-treatment without ancillary treatment period, starting at the date of first dose of trial product until the follow-up visit, or the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin, or initiation of any diabetes treatment other than trial products and metformin +/- DPP4i, or increase of the dose of metformin or DPP4i. | week 25 (Visit 27) and 26 (Visit 28) | 
| Number of Treatment Emergent Adverse Events (TEAEs) | An adverse event (AE) is any untoward medical occurrence in a clinical trial subject administered or using a medicinal product, whether or not considered related to the medicinal product or usage. A TEAE was defined as an event that had onset date (or increase in severity) during the on-treatment observation period. The endpoint was evaluated based on the data from on-treatment period, starting at the date of first dose of trial product, and ending at follow-up visit, or the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin. | From baseline (Visit 2) to week 31 (Visit 30) | 
| Number of Hypoglycaemic Alert Episodes (Level 1) (≥3.0 and <3.9 mmol/L (≥54 and <70 mg/dL), Confirmed by BG Meter) | Hypoglycaemia alert value (level 1) was defined as episodes that were sufficiently low for treatment with fast-acting carbohydrate and dose adjustment of glucose-lowering therapy with plasma glucose value of equal to or above (>=) 3.0 and less than (<) 3.9 mmol/L (>= 54 and < 70 mg/dL) confirmed by BG meter. Number of hypoglycaemic alert episodes (level 1) that occurred from week 0 to week 26 are presented. | From baseline (Visit 2) to week 26 (Visit 28) | 
| 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) | Clinically significant hypoglycaemic episodes (level 2) were defined as episodes that were sufficiently low to indicate serious, clinically important hypoglycaemia with plasma glucose value of less than (<) 3.0 mmol/L (54 mg/dL). Severe hypoglycaemic episodes (level 3) were defined as episodes that were associated with severe cognitive impairment requiring external assistance for recovery. Number of clinically significant hypoglycaemic episodes (level 2), confirmed by blood glucose (BG) meter or severe hypoglycaemic episodes (level 3) that occurred from week 0 to week 26 are presented. | From baseline (Visit 2) to week 26 (Visit 28) | 
| Number of Severe Hypoglycaemic Episodes (Level 3) | Severe hypoglycaemic episodes (level 3) were defined as episodes that were associated with severe cognitive impairment requiring external assistance for recovery. Number of severe hypoglycaemic episodes that occurred from week 0 to week 26 are presented. | From baseline (Visit 2) to week 26 (Visit 28) | 
| Change in Anti-insulin 287 Antibody Titres | Samples from the insulin 287 arm of the study were analysed for anti-insulin 287 antibodies. Confirmed anti-insulin 287 antibody positive samples had an antibody titre value determined. The endpoint was evaluated based on the data from in-trial period, starting at randomisation, and ending at the last direct participant-site contact, or when participant withdrew their informed consent, or the last participant-investigator contact for participants lost to follow-up, or death. | From baseline (Visit 2) to week 31 (Visit 30) | 
| Change in Cross-reactive Anti-human Insulin Antibody Status (Positive/Negative) | Anti-insulin 287 or glargine antibodies were classified as negative if % B/T was below a certain cut point. Samples positive for anti-insulin 287 or glargine antibodies were further tested for cross-reactivity to endogenous insulin. Samples not further tested are categorised as not applicable (NA). Unknown refers to samples with insufficient volume to perform analysis. The endpoint was evaluated based on the data from in-trial period, starting at randomisation, and ending at the last direct participant-site contact, or when participant withdrew their informed consent, or the last participant-investigator contact for participants lost to follow-up, or death. | From baseline (Visit 2) to week 31 (Visit 30) | 
| Change in Anti-insulin 287 Antibody Level | Change in anti-insulin 287 antibodies level is not assessed because change in anti-insulin 287 antibody titres is a more meaningful way of describing the change in antibody levels. The results for change in anti-insulin 287 antibody titres are reported as a separate endpoint. | From baseline (Visit 2) to week 31 (Visit 30) |