Efficacy and Safety of Semaglutide Once-weekly Versus Placebo as add-on to SGLT-2i in Subjects With Type 2 Diabetes Mellitus

Study Overview
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Brief Summary
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This trial is conducted in Asia, Europe and North America. The aim of the trial is to compare the effect of semaglutide s.c. 1.0 mg once-weekly versus placebo as add-on to sodium glucose co-transporter-2 inhibitor (SGLT-2i) monotherapy or in combination with either metformin or sulfonylurea on glycaemic control after 30 weeks of treatment in subjects with type 2 diabetes. Subjects will remain on their pre-trial medication.

Official Title
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Efficacy and Safety of Semaglutide Once-weekly Versus Placebo as add-on to SGLT-2i in Subjects With Type 2 Diabetes Mellitus. A 30-week Randomised, Double-blind, Placebo-controlled Trial

Conditions
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Diabetes, Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Semaglutide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent obtained before any trial-related activities. Trial-related activities are any procedures that are carried out as part of the trial, including activities to determine suitability for the trial Male or female, above or equal to 18 years at the time of signing informed consent. For Japan only: Male or female, age equal to or above 20 years at the time of signing informed consent Diagnosed with type 2 diabetes mellitus HbA1c of 7.0-10.0% (53-86 mmol/mol) (both inclusive) Stable dose of an SGLT-2 inhibitor as monotherapy or in combination (including fixed-dose drug combination) with a stable dose of metformin (equal to or above 1500 mg or maximum tolerated dose) or a SU for at least 90 days prior to the day of screening. All medications in compliance with current local label Exclusion Criteria: Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing potential and not using an adequate contraceptive method (adequate contraceptive measure as required by local regulation or practice) Any disorder which in the investigator's opinion might jeopardise subject's safety or compliance with the protocol 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 Subjects with alanine aminotransferase above 2.5 x upper normal limit Family or personal history of multiple endocrine neoplasia type 2 or medullary thyroid carcinoma. Family is defined as a first degree relative History or presence of pancreatitis (acute or chronic) History of diabetic ketoacidosis Any of the following: myocardial infarction, stroke, hospitalization for unstable angina or transient ischaemic attack within the past 180 days prior to the day of screening Subjects presently classified as being in New York Heart Association Class IV Planned coronary, carotid or peripheral artery revascularisation known on the day of screening Renal impairment measured as estimated Glomerular Filtration Rate value of eGFR below 60 ml/min/1.73 m^2 as defined by KDIGO 2012 classification using isotope dilution mass spectrometry for serum creatinine measured at screening Proliferative retinopathy or maculopathy requiring acute treatment. Verified by fundus photography or dilated fundoscopy performed within the past 90 days prior to randomisation Presence or history of malignant neoplasms within the past 5 years prior to the day of screening. Basal and squamous cell skin cancer and any carcinoma in-situ is allowed

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Semaglutide<br> | Drug: Semaglutide<br>* Semaglutide, gradually increased to 1.0 mg, injected once weekly under the skin (subcutaneously, s.c.) for 30 weeks<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Semaglutide placebo, gradually increased to 1.0 mg, injected once weekly under the skin (subcutaneously, s.c.) for 30 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in HbA1c | Change from baseline (week 0) in HbA1c was evaluated at week 30. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose of trial product and ended at the first date of any of the following: 1) the last dose of trial product + 7 days or 2) initiation of rescue medication. | Week 0, week 30 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Body Weight (kg) | Change from baseline (week 0) in body weight was evaluated at week 30. Results are based on the 'on-treatment without rescue medication' observation period. | Week 0, week 30 | 
| Change in Fasting Plasma Glucose (FPG) | Change from baseline (week 0) in FPG was evaluated at week 30. Results are based on the 'on-treatment without rescue medication' observation period. | Week 0, week 30 | 
| Change in Self-measured Plasma Glucose (SMPG), 7-point Profile: Mean 7-point Profile | Change from baseline (week 0) in mean of the SMPG, 7-point profile was evaluated at week 30. Mean 7-point profile (the area under the profile) was calculated using the trapezoidal method and divided by the measurement time. Results are based on the 'on-treatment without rescue medication' observation period. Participants measured their plasma glucose at 7 different time points: before breakfast, 90 minutes after start of breakfast, before lunch, 90 minutes after start of lunch, before dinner, 90 minutes after start of dinner and at bedtime. | Week 0, week 30 | 
| Change in Self-measured Plasma Glucose (SMPG), 7-point Profile: Mean Post Prandial Increment (Over All Meals) | Change from baseline (week 0) in mean post prandial increment (over all meals) in the SMPG, 7-point profile was evaluated at week 30. The mean increment over all meals was derived as the mean of all available meal increments. Results are based on the 'on-treatment without rescue medication' observation period. | Week 0, week 30 | 
| Change in Fasting Blood Lipid, Total Cholesterol | Change from baseline (week 0) in total cholesterol (measured in mmol/L and presented as ratio to baseline) was evaluated at week 30. Results are based on the 'on-treatment without rescue medication' observation period. | Week 0, week 30 | 
| Change in Fasting Blood Lipid, Low-density Lipoprotein (LDL) Cholesterol | Change from baseline (week 0) in LDL (measured in mmol/L and presented as ratio to baseline) was evaluated at week 30. Results are based on the 'on-treatment without rescue medication' observation period. | Week 0, week 30 | 
| Change in Fasting Blood Lipid, High-density Lipoprotein (HDL) Cholesterol | Change from baseline (week 0) in HDL (measured in mmol/L and presented as ratio to baseline) was evaluated at week 30. Results are based on the 'on-treatment without rescue medication' observation period. | Week 0, week 30 | 
| Change in Fasting Blood Lipid, Triglycerides | Change from baseline (week 0) in triglycerides (measured in mmol/L and presented as ratio to baseline) was evaluated at week 30. Results are based on the 'on-treatment without rescue medication' observation period. | Week 0, week 30 | 
| Change in Body Weight (%) | Percent (%) change from baseline (week 0) in body weight (measured in kilogram (kg)) was evaluated at week 30. Results are based on the 'on-treatment without rescue medication' observation period. | Week 0, week 30 | 
| Change in Body Mass Index | Change from baseline (week 0) in body mass index (BMI) was evaluated at week 30. Results are based on the 'on-treatment without rescue medication' observation period. BMI was calculated as 'body weight in kg/(height in meters) x (height in meters)'. | Week 0, week 30 | 
| Change in Waist Circumference | Change from baseline (week 0) in waist circumference was evaluated at week 30. Results are based on the 'on-treatment without rescue medication' observation period. | Week 0, week 30 | 
| Change in Systolic Blood Pressure | Change from baseline (week 0) in systolic blood pressure was evaluated at week 30. Results are based on the 'on-treatment without rescue medication' observation period. | Week 0, week 30 | 
| Change in Diastolic Blood Pressure | Change from baseline (week 0) in diastolic blood pressure was evaluated at week 30. Results are based on the 'on-treatment without rescue medication' observation period. | Week 0, week 30 | 
| Change in Scores for Selected Patient Reported Outcomes: Short-form Health Survey (SF-36v2TM): Total Scores (Physical Component and Mental Component) and Scores From the 8 Domains | Change from baseline (week 0) in patient reported outcome (PRO) questionnaire, SF-36v2TM was evaluated at week 30. The SF-36v2™ questionnaire was used to assess the overall health related quality of life of participants. This questionnaire contains 36 items and measures the individual overall health related quality of life on 8 domains: 1) Physical functioning, 2) Role functioning, 3) Bodily pain, 4) General health, 5) Vitality, 6) Social functioning, 7) Role emotional and 8) Mental health. Each item is scored on a scale from 1 to either 2, 3, 5, or 6; each item score is then converted to a scale of 0-100, representing the percentage of total possible score achieved and with higher scores indicating a higher health status; items on the same scale are then averaged to obtain the 8 scale scores. Physical component summary (PCS) includes domains 1-4 and mental component summary (MCS) includes domains 5-8. Higher PCS and MCS scores on a scale of 0-100 indicate a higher health status. | Week 0, week 30 | 
| Change in Scores for Selected Patient Reported Outcomes: Diabetes Treatment Satisfaction Questionnaire (DTSQ): Treatment Satisfaction Score (Sum of 6 of 8 Items) and the 8 Items Separately | Change from baseline (week 0) in PRO questionnaire, DTSQ was evaluated at week 30. Results are based on the 'on-treatment without rescue medication' observation period. The DTSQ measures satisfaction with diabetes treatment. The DTSQ consists of 8 items evaluating 6 aspects of treatment satisfaction and 2 perceived recent event rates of hyperglycemia/hypoglycemia. Each item is scored on a 7- point Likert scale ranging from 0 (very dissatisfied) to 6 (very satisfied). Items evaluating 6 aspects (items 3-8) of treatment satisfaction are summed to produce a total treatment satisfaction score; DTSQ status total scores range from 0-36, with higher scores indicating greater satisfaction; the perceived frequency of hyperglycemia/hypoglycemia items are scored separately, with lower scores indicating better perceived blood glucose control. | Week 0, week 30 | 
| HbA1c Below 7.0% (53 mmol/Mol) | Percentage of participants with HbA1c below 7.0% (53 mmol/mol) was evaluated at week 30. Results are based on the 'on-treatment without rescue medication' observation period. | After 30 weeks | 
| HbA1c Equal to or Below 6.5% (48 mmol/Mol) | Percentage of participants with HbA1c equal to or below 6.5% (48 mmol/mol) was evaluated at week 30. Results are based on the 'on-treatment without rescue medication' observation period. | After 30 weeks | 
| Weight Loss Equal to or Above 3% | Percentage of participants with weight loss equal to or above 3% of their baseline (week 0) body weight was evaluated at week 30. Results are based on the 'on-treatment without rescue medication' observation period. | After 30 weeks | 
| Weight Loss Equal to or Above 5% | Percentage of participants with weight loss equal to or above 5% of their baseline (week 0) body weight was evaluated at week 30. Results are based on the 'on-treatment without rescue medication' observation period. | After 30 weeks | 
| Weight Loss Equal to or Above 10% | Percentage of participants with weight loss equal to or above 10% of their baseline (week 0) body weight was evaluated at week 30. Results are based on the 'on-treatment without rescue medication' observation period. | After 30 weeks | 
| HbA1c Below 7.0% (53 mmol/Mol) Without Severe or BG Confirmed Symptomatic Hypoglycaemia Episodes and no Weight Gain | Percentage of participants with HbA1c below 7.0% (53 mmol/mol) without severe or BG confirmed symptomatic hypoglycaemia episodes and no weight gain from their baseline (week 0) body weight was evaluated at week 30. Severe or blood glucose (BG)-confirmed symptomatic hypoglycaemia: an episode that was severe according to the American Diabetes Association (ADA) classification or confirmed by a plasma glucose (PG) value below 3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia. Results are based on the 'on-treatment without rescue medication' observation period. | After 30 weeks | 
| HbA1c Reduction Equal to or Above 1%-Point | Percentage of participants with HbA1c reduction equal to or above 1%-point was evaluated at week 30. Results are based on the 'on-treatment without rescue medication' observation period. | After 30 weeks | 
| HbA1c Reduction Equal to or Above 1%-Point and Weight Loss Equal to or Above 3% | Percentage of participants with HbA1c reduction equal to or above 1%-point and weight loss equal to or above 3% of their baseline (week 0) body weight was evaluated at week 30. Results are based on the 'on-treatment without rescue medication' observation period. | After 30 weeks | 
| HbA1c Reduction Equal to or Above 1%-Point and Weight Loss Equal to or Above 5% | Percentage of participants with HbA1c reduction equal to or above 1%-point and weight loss equal to or above 5% of their baseline (week 0) body weight was evaluated at week 30. Results are based on the 'on-treatment without rescue medication' observation period. | After 30 weeks | 
| HbA1c Reduction Equal to or Above 1%-Point and Weight Loss Equal to or Above 10% | Percentage of participants with HbA1c reduction equal to or above 1%-point and weight loss equal to or above 10% of their baseline (week 0) body weight was evaluated at week 30. Results are based on the 'on-treatment without rescue medication' observation period. | After 30 weeks | 
| Number of Treatment-emergent Adverse Events (TEAEs) | A TEAE was defined as an event that has onset date (or increase in severity) during the on-treatment observation period, which started at the date of first dose of trial product and ended at the last date on trial product + 42 days. | Week 0 - week 30 | 
| Number of Treatment Emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes | Hypoglycaemic episodes were defined as treatment emergent if the onset of the episode occurred within the on-treatment observation period, which started at the date of first dose of trial product and ended at the last date on trial product + 42 days. Severe or BG-confirmed symptomatic hypoglycaemia: an episode that was severe according to the ADA classification or confirmed by a PG value below 3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia. | Week 0 - week 30 | 
| Change in Haematology: Haemoglobin | Change from baseline (week 0) in haemoglobin was evaluated at week 30. Results are based on the on-treatment observation period, which started at the date of first dose of trial product and ended at the last date on trial product + 7 days. | Week 0, week 30 | 
| Change in Haematology: Haematocrit | Change from baseline (week 0) in haematocrit was evaluated at week 30. Results are based on the on-treatment observation period, which started at the date of first dose of trial product and ended at the last date on trial product + 7 days. | Week 0, week 30 | 
| Change in Haematology: Thrombocytes | Change from baseline (week 0) in thrombocytes was evaluated at week 30. Results are based on the on-treatment observation period, which started at the date of first dose of trial product and ended at the last date on trial product + 7 days. | Week 0, week 30 | 
| Change in Haematology: Erythrocytes | Change from baseline (week 0) in erythrocytes was evaluated at week 30. Results are based on the on-treatment observation period, which started at the date of first dose of trial product and ended at the last date on trial product + 7 days. | Week 0, week 30 | 
| Change in Haematology: Leucocytes | Change from baseline (week 0) in leucocytes was evaluated at week 30. Results are based on the on-treatment observation period, which started at the date of first dose of trial product and ended at the last date on trial product + 7 days. | Week 0, week 30 | 
| Change in Biochemistry: Amylase | Change from baseline (week 0) in amylase was evaluated at week 30. Results are based on the on-treatment observation period, which started at the date of first dose of trial product and ended at the last date on trial product + 7 days. | Week 0, week 30 | 
| Change in Biochemistry: Lipase | Change from baseline (week 0) in lipase was evaluated at week 30. Results are based on the on-treatment observation period, which started at the date of first dose of trial product and ended at the last date on trial product + 7 days. | Week 0, week 30 | 
| Change in Biochemistry: Alkaline Phosphatase | Change from baseline (week 0) in alkaline phosphatase was evaluated at week 30. Results are based on the on-treatment observation period, which started at the date of first dose of trial product and ended at the last date on trial product + 7 days. | Week 0, week 30 | 
| Change in Biochemistry: Alanine Aminotransferase | Change from baseline (week 0) in alanine aminotransferase was evaluated at week 30. Results are based on the on-treatment observation period, which started at the date of first dose of trial product and ended at the last date on trial product + 7 days. | Week 0, week 30 | 
| Change in Biochemistry: Aspartate Aminotransferase | Change from baseline (week 0) in aspartate aminotransferase was evaluated at week 30. Results are based on the on-treatment observation period, which started at the date of first dose of trial product and ended at the last date on trial product + 7 days. | Week 0, week 30 | 
| Change in Biochemistry: Total Bilirubin | Change from baseline (week 0) in total bilirubin was evaluated at week 30. Results are based on the on-treatment observation period, which started at the date of first dose of trial product and ended at the last date on trial product + 7 days. | Week 0, week 30 | 
| Change in Biochemistry: Albumin | Change from baseline (week 0) in albumin was evaluated at week 30. Results are based on the on-treatment observation period, which started at the date of first dose of trial product and ended at the last date on trial product + 7 days. | Week 0, week 30 | 
| Change in Biochemistry: Calcium (Total) | Change from baseline (week 0) in albumin was evaluated at week 30. Results are based on the on-treatment observation period, which started at the date of first dose of trial product and ended at the last date on trial product + 7 days. | Week 0, week 30 | 
| Change in Biochemistry: Potassium | Change from baseline (week 0) in potassium was evaluated at week 30. Results are based on the on-treatment observation period, which started at the date of first dose of trial product and ended at the last date on trial product + 7 days. | Week 0, week 30 | 
| Change in Biochemistry: Sodium | Change from baseline (week 0) in sodium was evaluated at week 30. Results are based on the on-treatment observation period, which started at the date of first dose of trial product and ended at the last date on trial product + 7 days. | Week 0, week 30 | 
| Change in Biochemistry: Bicarbonate | Change from baseline (week 0) in bicarbonate was evaluated at week 30. Results are based on the on-treatment observation period, which started at the date of first dose of trial product and ended at the last date on trial product + 7 days. | Week 0, week 30 | 
| Change in Biochemistry: Estimated Glomerular Filtration Rate (eGFR) | Change from baseline (week 0) in eGFR was evaluated at week 30. Results are based on the on-treatment observation period, which started at the date of first dose of trial product and ended at the last date on trial product + 7 days. | Week 0, week 30 | 
| Change in Biochemistry: Creatinine | Change from baseline (week 0) in creatinine was evaluated at week 30. Results are based on the on-treatment observation period, which started at the date of first dose of trial product and ended at the last date on trial product + 7 days. | Week 0, week 30 | 
| Change in Calcitonin | Change from baseline (week 0) in calcitonin was evaluated at week 30. Results are based on the on-treatment observation period, which started at the date of first dose of trial product and ended at the last date on trial product + 7 days. | Week 0, week 30 | 
| Change in Pulse | Change from baseline (week 0) in pulse rate was evaluated at week 30. Results are based on the on-treatment observation period, which started at the date of first dose of trial product and ended at the last date on trial product + 7 days. | Week 0, week 30 | 
| Change in Electrocardiogram | Electrocardiogram (ECG) results are presented for week 0 (baseline) and week 30. ECG finding are presented as percentage of participants with normal, abnormal non-clinically significant (NCS) and abnormal clinically significant (CS) ECG values. Results are based on the on-treatment observation period, which started at the date of first dose of trial product and ended at the last date on trial product + 42 days. | Week 0, week 30 | 
| Change in Physical Examination: General Appearance | Physical examination (general appearance) results are presented for week -2 (baseline) and week 30. Results are presented as percentage of participants with normal, abnormal NCS and abnormal CS findings. Results are based on the on-treatment observation period, which started at the date of first dose of trial product and ended at the last date on trial product + 7 days. | Week -2, week 30 | 
| Change in Physical Examination: Central and Peripheral Nervous System | Physical examination (central and peripheral nervous system) results are presented for week -2 (baseline) and week 30. Results are presented as percentage of participants with normal, abnormal NCS and abnormal CS findings. Results are based on the on-treatment observation period, which started at the date of first dose of trial product and ended at the last date on trial product + 7 days. | Week -2, week 30 | 
| Change in Physical Examination: Cardiovascular System | Physical examination (cardiovascular system) results are presented for week -2 (baseline) and week 30. Results are presented as percentage of participants with normal, abnormal NCS and abnormal CS findings. Results are based on the on-treatment observation period, which started at the date of first dose of trial product and ended at the last date on trial product + 7 days. | Week -2, week 30 | 
| Change in Physical Examination: Gastrointestinal System Including Mouth | Physical examination (gastrointestinal system including mouth) results are presented for week -2 (baseline) and week 30. Results are presented as percentage of participants with normal, abnormal NCS and abnormal CS findings. Results are based on the on-treatment observation period, which started at the date of first dose of trial product and ended at the last date on trial product + 7 days. | Week -2, week 30 | 
| Change in Physical Examination: Skin | Physical examination (skin) results are presented for week -2 (baseline) and week 30. Results are presented as percentage of participants with normal, abnormal NCS and abnormal CS findings. Results are based on the on-treatment observation period, which started at the date of first dose of trial product and ended at the last date on trial product + 7 days. | Week -2, week 30 | 
| Change in Physical Examination: Respiratory System | Physical examination (respiratory system) results are presented for week -2 (baseline) and week 30. Results are presented as percentage of participants with normal, abnormal NCS and abnormal CS findings. Results are based on the on-treatment observation period, which started at the date of first dose of trial product and ended at the last date on trial product + 7 days. | Week -2, week 30 | 
| Change in Physical Examination: Lymph Node Palpation | Physical examination (lymph node palpation) results are presented for week -2 (baseline) and week 30. Results are presented as percentage of participants with normal, abnormal NCS and abnormal CS findings. Results are based on the on-treatment observation period, which started at the date of first dose of trial product and ended at the last date on trial product + 7 days. | Week -2, week 30 | 
| Change in Physical Examination: Thyroid Gland | Physical examination (thyroid gland) results are presented for week -2 (baseline) and week 30. Results are presented as percentage of participants with normal, abnormal NCS and abnormal CS findings. Results are based on the on-treatment observation period, which started at the date of first dose of trial product and ended at the last date on trial product + 7 days. | Week -2, week 30 | 
| Change in Fundoscopy | Fundoscopy results for both left and right eyes are presented for week 0 (baseline) and week 30. Results are presented as percentage of participants with normal, abnormal NCS and abnormal CS findings. Results are based on the on-treatment observation period, which started at the date of first dose of trial product and ended at the last date on trial product + 7 days. | Week 0, week 30 |