A Clinical Trial Comparing Glycaemic Control and Safety of Insulin Degludec/Liraglutide (IDegLira) Versus Insulin Glargine (IGlar) as add-on Therapy to SGLT2i in Subjects With Type 2 Diabetes Mellitus

Study Overview
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Brief Summary
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This trial is conducted globally. The aim of this trial is comparing glycaemic control and safety of insulin degludec/liraglutide (IDegLira) versus insulin glargine (IGlar) as add-on therapy to SGLT2i (sodium-glucose cotransporter 2 inhibitors) in subjects with type 2 diabetes mellitus.

Official Title
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A Clinical Trial Comparing Glycaemic Control and Safety of Insulin Degludec/Liraglutide (IDegLira) Versus Insulin Glargine (IGlar) as add-on Therapy to SGLT2i in Subjects With Type 2 Diabetes Mellitus. DUALTM IX - Add-on to SGLT2i

Conditions
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Diabetes, Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: insulin degludec/liraglutide
* Drug: insulin glargine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Male or female, age at least 18 years at the time of signing informed consent - Subjects diagnosed (clinically) with type 2 diabetes mellitus - HbA1c 7.0-11.0% [53-97 mmol/mol] (both inclusive) by central laboratory analysis - Body mass index (BMI) equal to or above 20 kg/m^2 and below 40 kg/m^2 - Insulin naïve subjects; however short term insulin treatment for a maximum of 14 days prior to the day of screening is allowed, as well as prior insulin treatment for gestational diabetes - A stable daily dose for at least 90 days prior to the day of screening of any SGLT2i in monotherapy or in combination with metformin ± DPP4i ± pioglitazone. Use of pioglitazone is not allowed in subjects treated with dapagliflozin Exclusion Criteria: - Receipt of any investigational medicinal product within 90 days prior to screening - Use of any OADs (other than SGLT2i in monotherapy or in combination with metformin or DPP4i or pioglitazone as described in the inclusion criteria) within 90 days prior to the day of screening - Use of glucagon-like peptide-1 (GLP-1) receptor agonist (e.g., exenatide or liraglutide) within 90 days prior to the day of screening - Acute decompensation of glycaemic control requiring immediate intensification of treatment to prevent severe metabolic dysregulation (e.g., diabetes ketoacidosis) in the previous 90 days prior to the day of the screening - Subjects presently classified as being in NYHA (New York Heart Association) Class III or IV1 - Renal impairment estimated Glomerular Filtration Rate 60 mL/min/1.73 m2 as per CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) - Impaired liver function, defined as ALT (alanine aminotransferase) equal to or above 2.5 times upper normal limit at screening - Known or suspected hypersensitivity to trial product(s) or related products

Ages Eligible for Study
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Minimum Age: 18 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IDegLira<br> | Drug: insulin degludec/liraglutide<br>* IDegLira will be given subcutaneously ( s.c., under the skin) once daily.<br>|
| Active Comparator: IGlar<br> | Drug: insulin glargine<br>* IGlar will be given subcutaneously ( s.c., under the skin) once daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in HbA1c (Glycosylated Haemoglobin) | The mean change from baseline (week 0) in HbA1c values evaluated after 26 weeks of randomised treatment. The results presented included retrieved data at week 26 for subjects who prematurely discontinued the trial product. | Week 0, Week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Body Weight | The mean change from baseline (week 0) in body weight evaluated after 26 weeks of randomised treatment. The results presented included retrieved data at week 26 for subjects who prematurely discontinued the trial product. | Week 0, Week 26 | 
| Number of Treatment-emergent Severe or BG (Blood Glucose) Confirmed Symptomatic Hypoglycaemic Episodes | Severe or BG confirmed symptomatic hypoglycaemic episodes were defined as episodes that were severe (subjects who were not able to self-treat) and/or BG confirmed by a plasma glucose values <3.1 mmol/L (56 mg/dL) with accompanied symptoms consistent with hypoglycaemia. | Week 0-26 | 
| Insulin Dose, Total Daily Dose (U) | Actual daily total insulin dose (Units) was evaluated after 26 weeks of randomised treatment. The results presented included retrieved data at week 26 for subjects who prematurely discontinued the trial product. | After 26 weeks | 
| Change in Fasting Plasma Glucose (FPG) | Change from baseline (week 0) in FPG was evaluated after 26 weeks of randomised treatment. | Week 0, Week 26 | 
| Number of Treatment-emergent Adverse Events | Treatment emergent adverse events (TEAEs) were recorded from week 0 to week 26. TEAE was defined as an event that has onset date on or after the first day of exposure to randomised treatment and no later than 7 days after the last day of randomised treatment. | Week 0-26 | 
| Responder (Yes/No) for HbA1c Below 7.0% | The proportion of subjects achieving pre-defined HbA1c targets <7.0% after 26 weeks of randomised treatment. The results presented included retrieved data at week 26 for subjects who prematurely discontinued the trial product. | After 26 weeks | 
| Responder After 26 Weeks (Yes/No) for: HbA1c < 7.0% Without Weight Gain | The proportion of subjects achieving pre-defined HbA1c targets <7.0% without weight gain after 26 weeks of randomised treatment. The results presented included retrieved data at week 26 for subjects who prematurely discontinued the trial product. | After 26 weeks | 
| Responder After 26 Weeks (Yes/No) for: HbA1c < 7.0% Without Treatment-emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes During the Last 12 Weeks of Treatment | The proportion of subjects achieving pre-defined HbA1c targets <7.0% without treatment-emergent severe or BG confirmed symptomatic hypoglycaemic episodes during the last 12 weeks of treatment. The results presented included retrieved data at week 26 for subjects who prematurely discontinued the trial product. | After 26 weeks | 
| Responder After 26 Weeks (Yes/No) for: HbA1c < 7.0% Without Treatment-emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes During the Last 12 Weeks of Treatment and Without Weight Gain | The proportion of subjects achieving pre-defined HbA1c targets <7.0% without treatment-emergent severe or BG confirmed symptomatic hypoglycaemic episodes during the last 12 weeks of treatment and without weight gain. The results presented included retrieved data at week 26 for subjects who prematurely discontinued the trial product. | After 26 weeks | 
| Responder After 26 Weeks (Yes/No) for: HbA1c ≤ 6.5% | The proportion of subjects achieving pre-defined HbA1c targets ≤ 6.5% after 26 weeks of randomised treatment. The results presented included retrieved data at week 26 for subjects who prematurely discontinued the trial product. | After 26 weeks | 
| Responder After 26 Weeks (Yes/No) for: HbA1c ≤ 6.5% Without Weight Gain | The proportion of subjects achieving pre-defined HbA1c targets ≤ 6.5% without weight gain after 26 weeks of randomised treatment. The results are based on retrieved data at week 26 for subjects who prematurely discontinued the trial product. | After 26 weeks | 
| Responder After 26 Weeks (Yes/No) for: HbA1c ≤ 6.5% Without Treatment-emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes During the Last 12 Weeks of Treatment | The proportion of subjects achieving pre-defined HbA1c targets ≤ 6.5%without treatment-emergent severe or BG confirmed symptomatic hypoglycaemic episodes during the last 12 weeks of treatment. The results presented included retrieved data at week 26 for subjects who prematurely discontinued the trial product. | After 26 weeks | 
| Responder After 26 Weeks (Yes/No) for: HbA1c ≤ 6.5% Without Treatment-emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes During the Last 12 Weeks of Treatment and Without Weight Gain | The proportion of subjects achieving pre-defined HbA1c targets ≤ 6.5%without treatment-emergent severe or BG confirmed symptomatic hypoglycaemic episodes during the last 12 weeks of treatment and without weight gain. The results presented included retrieved data at week 26 for subjects who prematurely discontinued the trial product. | After 26 weeks | 
| Change From Baseline After 26 Weeks in Waist Circumference | Mean change from baseline in waist circumference after 26 weeks of randomised treatment. | After 26 weeks | 
| Change From Baseline in Fasting Lipid Profile: Cholesterol | The values of total cholesterol from fasting lipid profile after 26 weeks of randomised treatment. | After 26 weeks | 
| Change From Baseline in Fasting Lipid Profile: Low-density Lipoprotein Cholesterol (LDL Cholesterol) | The values of LDL cholesterol from fasting lipid profile after 26 weeks of randomised treatment. | After 26 weeks | 
| Change From Baseline in Fasting Lipid Profile: High-density Lipoprotein Cholesterol (HDL Cholesterol) | The values of HDL cholesterol from fasting lipid profile after 26 weeks of randomised treatment. | After 26 weeks | 
| Change From Baseline in Fasting Lipid Profile: Very-low-density Lipoprotein Cholesterol (VLDL Cholesterol) | The values of VLDL cholesterol from fasting lipid profile after 26 weeks of randomised treatment. | After 26 weeks | 
| Change From Baseline in Fasting Lipid Profile: Triglycerides | The values of triglycerides from fasting lipid profile after 26 weeks of randomised treatment. | After 26 weeks | 
| Change From Baseline in Fasting Lipid Profile: Free Fatty Acids | The values of free fatty acids from fasting lipid profile after 26 weeks of randomised treatment. | After 26 weeks | 
| Change From Baseline in the 9-point Self-measured Plasma Glucose (SMPG) Profile | Change in 9-point SMPG profile was evaluated after 26 weeks of randomised treatment. SMPG measurements at baseline and week 26 are presented here at the following mentioned time points:1) Before breakfast, 2) 90 mins after the start of Breakfast, 3) Before lunch, 4) 90 mins after the start of lunch, 5) Before dinner, 6) 90 mins after the start of dinner, 7) At bedtime, 8) At 4 AM, 9) Before breakfast the following day. | After 26 weeks | 
| Change From Baseline in Self-measured Plasma Glucose (SMPG) 9-point Profile: Mean of the 9-point Profile | Change in mean of the 9-point profile SMPG was evaluated after 26 weeks of randomised treatment. 9-point profile SMPG was measured at the following mentioned time points:1) Before breakfast, 2) 90 mins after the start of Breakfast, 3) Before lunch, 4) 90 mins after the start of lunch, 5) Before dinner, 6) 90 mins after the start of dinner, 7) At bedtime, 8) At 4 AM, 9) Before breakfast the following day. | After 26 weeks | 
| Change From Baseline in SMPG 9-point Profile: Prandial Plasma Glucose Increments (From Before Meal to 90 Min After Breakfast, Lunch and Dinner). The Mean Increment Over All Meals Will be Derived as the Mean of All Available Meal Increments | Mean prandial plasma glucose increments for each meal (from before meal to 90 min after breakfast, lunch and dinner) was evaluated after 26 weeks of randomised treatment. The mean increment over all meals was derived as the mean of all available meal increments are presented here. | After 26 weeks | 
| Change From Baseline in Systolic Blood Pressure | Change from baseline (week 0) in systolic blood pressure (BP) was evaluated after 26 weeks of randomised treatment. | After 26 weeks | 
| Change From Baseline in Diastolic Blood Pressure | Change from baseline (week 0) in diastolic blood pressure was evaluated after 26 weeks of randomised treatment. | After 26 weeks | 
| Number of Treatment-emergent Nocturnal Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes During 26 Weeks | Number of treatment-emergent nocturnal severe or BG confirmed symptomatic hypoglycaemic episodes (00:01-05:59 - inclusive) during 26 weeks of randomised treatment. | Week 0-26 | 
| Number of Treatment-emergent Hypoglycaemic Episodes According to ADA Definition During 26 Weeks | American Diabetes Association (ADA) classification of hypoglycaemic episodes: 1)Severe: Requiring assistance of another person to actively administer carbohydrate/glucagon/take other corrective actions. PG levels may not be available during an event, but neurological recovery following return of PG to normal is considered sufficient evidence that event was induced by a low PG level. 2) Documented symptomatic: PG ≤3.9 mmol/L with symptoms. 3) Asymptomatic: PG ≤3.9 mmol/L without symptoms. 4) Probable symptomatic: No measurement with symptoms. 5) Pseudo: PG >3.9 mmol/L with symptoms. 6) Unclassifiable. | Week 0-26 | 
| Change From Baseline in Clinical Evaluation After 26 Weeks: Electrocardiogram (ECG) | Reported results are ECG findings at screening and week 26 of randomised treatment. Since the values measured at the baseline (week 0) were not collected, the screening data (week -2, which is <= 2 weeks before baseline) is presented here. The findings are categorised as: 1) Normal. 2) Abnormal (not clinically significant [NCS]). 3) Abnormal (clinically significant [CS]). 4) Missing. | After 26 weeks | 
| Change From Baseline in Clinical Evaluation After 26 Weeks: Eye Examination: Fundoscopy/Fundus Photography | Reported results are fundus photography/fundoscopy (for both left and right eye) findings at screening and week 26 of randomised treatment. Since the values measured at the baseline (week 0) were not collected, the screening data (week -2, which is <= 2 weeks before baseline) is presented here. The findings are categorised as: 1) Normal. 2) Abnormal (not clinically significant [NCS]). 3) Abnormal (clinically significant [CS]). 4) Missing. | After 26 weeks | 
| Change From Baseline in Clinical Evaluation After 26 Weeks: Pulse Rate | Change from baseline (week 0) in pulse rate was evaluated after 26 weeks of randomised treatment. | After 26 weeks | 
| Change From Baseline in Patient Reported Outcomes (PROs) After 26 Weeks: Summary Scores of Medical Outcomes Study 36-item Short Form (SF-36v2) | The Short Form (SF)-36v2™ patient reported outcomes (PRO) questionnaire was used to assess the subject's overall health related quality of life (HRQoL). PRO questionnaire (SF-36v2™) measured the HRQoL which contains 36 items covering 8 domains of physical and mental health status. The raw scale scores from the SF-36 were transformed to a 0-100 scale scores (where higher scores indicated a better health status) which is further converted to norm-based scores using a T-score transformation in order to obtain a direct interpretation in relation to the distribution of the scores in the 2009 reference population . The total/overall (SF-36v2™) scores for physical and mental health from baseline to week 26 are presented here. | After 26 weeks | 
| Change From Baseline in Patient Reported Outcomes (PROs) After 26 Weeks: Summary Scores of Treatment Related Impact Measure for Diabetes (TRIM-D) | The patient reported outcomes are calculated based on TRIM-D questionnaire. The TRIM-D questionnaire consists of 5 sub-domains (treatment burden, daily life, diabetes management, compliance and psychological health), where each question is scored to a 1-5-point scale with a higher score indicating a better health state (less negative impact). Mean TRIM-D domain scores and the total scores are later transformed to a 0-100 scale for analysis. Summary scores from baseline and week 26 for total/overall scores are presented here. | After 26 weeks |