Safety and Efficacy of Oral Semaglutide Versus Dulaglutide Both in Combination With One OAD (Oral Antidiabetic Drug) in Japanese Subjects With Type 2 Diabetes

Study Overview
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Brief Summary
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This trial is conducted in Asia. The aim of this trial is to investigate Safety and efficacy of oral semaglutide versus dulaglutide both in combination with one OAD (oral antidiabetic drug) in Japanese subjects with type 2 diabetes.

Official Title
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Safety and Efficacy of Oral Semaglutide Versus Dulaglutide Both in Combination With One OAD in Japanese Subjects With Type 2 Diabetes

Conditions
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Diabetes, Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Semaglutide
* Drug: Dulaglutide


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 Japanese male or female, age above or equal to 20 years at the time of signing informed consent Diagnosed with type 2 diabetes mellitus for at least 60 days prior to day of screening HbA1c (glycosylated haemoglobin) between 7.0%-10.5% (53-91 mmol/mol) (both inclusive) OAD (oral antidiabetic drug) monotherapy with stable daily dose for at least 60 days prior to the day of screening of one of SU (sulphonylurea) glinide , TZD (thiazolidinedione), α-GI (alpha-glucosidase inhibitor) or SGLT-2 (sodium-glucose cotransporter-2) inhibitor according to Japanese labelling 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 measures are abstinence (not having sex), diaphragm, condom (by the partner), intrauterine device, sponge, spermicide or oral contraceptives Any disorder, which in the investigator's opinion might jeopardise subject's safety or compliance with the protocol Family or personal history of multiple endocrine neoplasia type 2 (MEN 2) or medullary thyroid carcinoma (MTC) History of pancreatitis (acute or chronic) History of major surgical procedures involving the stomach potentially affecting absorption of trial product (e.g. subtotal and total gastrectomy, sleeve gastrectomy, gastric bypass surgery) Any of the following: myocardial infarction, stroke or hospitalisation for unstable angina or transient ischaemic attack (TIA) within the past 180 days prior to the day of screening and randomisation Subjects presently classified as being in New York Heart Association (NYHA) Class IV Planned coronary, carotid or peripheral artery revascularisation known on the day of screening Subjects with alanine aminotransferase (ALT) above 2.5 x upper normal limit (UNL) Renal impairment defined as estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m^2 as per Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI) Treatment with once-weekly glucagon-like peptide-1 receptor agonists (GLP-1 RA) or once weekly dipeptidyl peptidase-4 (DPP-4) inhibitor in a period of 90 days before the day of screening For subjects treated with an OAD other than TZD at screening: Treatment with TZD in a period of 90 days before the day of screening Treatment with any medication for the indication of diabetes or obesity in addition to background OAD medication (SU, glinide, TZD, α-GI or SGLT-2 inhibitor) in a period of 60 days before the day of screening with the exception of short-term insulin treatment for acute illness for a total of at least 14 days Proliferative retinopathy or maculopathy requiring acute treatment. Verified by fundus photography or dilated fundoscopy performed within 90 days prior to randomisation History or presence of malignant neoplasms within the last 5 years (except basal and squamous cell skin cancer and in situ carcinomas) History of diabetic ketoacidosis

Ages Eligible for Study
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Minimum Age: 20 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: Oral semaglutide 3 mg<br> | Drug: Semaglutide<br>* Oral administration once-daily, as add-on to pre-trial oral antidiabetic drug (OAD).<br>|
| Experimental: Oral semaglutide 7 mg<br> | Drug: Semaglutide<br>* Oral administration once-daily, as add-on to pre-trial oral antidiabetic drug (OAD).<br>|
| Experimental: Oral semaglutide 14 mg<br> | Drug: Semaglutide<br>* Oral administration once-daily, as add-on to pre-trial oral antidiabetic drug (OAD).<br>|
| Active Comparator: Dulaglutide 0.75 mg<br> | Drug: Dulaglutide<br>* Subcutaneously administration (s.c., under the skin) once-weekly, as add-on to pre-trial oral antidiabetic drug (OAD).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Treatment-emergent Adverse Events (TEAEs) | Treatment emergent adverse events (TEAEs) were recorded from week 0 to week 57 (52-week treatment period plus the 5-week follow-up period). Adverse events (AEs) with onset during the on-treatment observation period were considered treatment-emergent. On-treatment observation period: Time period when a participant was on treatment with trial product, including any period after initiation of rescue medication. | Weeks 0-57 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in HbA1c | Change from baseline (week 0) in glycosylated haemoglobin (HbA1c) was evaluated at weeks 26 and 52. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Week 0, week 26, week 52 | 
| Change in Fasting Plasma Glucose | Change from baseline (week 0) in fasting plasma glucose (FPG) was evaluated at weeks 26 and 52. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Week 0, week 26, week 52 | 
| Change in Self-measured Plasma Glucose 7-point Profile (SMPG) - Mean 7-point Profile | Change from baseline (week 0) in mean 7-point SMPG profile was evaluated at weeks 26 and 52. SMPG was recorded at the following 7 time points: before breakfast, 90 minutes after start of breakfast, before lunch, 90 minutes after start of lunch, before dinner, 90 minutes after dinner and at bedtime. Mean 7-point profile was defined as the area under the profile, calculated using the trapezoidal method, divided by the measurement time. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Week 0, week 26, week 52 | 
| Change in Self-measured Plasma Glucose (SMPG) - Mean Postprandial Increment Over All Meals | Change from baseline (week 0) in the average of the post-prandial increments over all meals was evaluated at weeks 26 and 52. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Week 0, week 26, week 52 | 
| Change in Body Weight (kg) | Change from baseline (week 0) in body weight was evaluated at weeks 26 and 52. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Week 0, week 26, week 52 | 
| Change in Body Weight (%) | Relative change from baseline (week 0) in body weight (kg) was evaluated at weeks 26 and 52. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Week 0, week 26, week 52 | 
| Change in Body Mass Index (BMI) | Change from baseline (week 0) in BMI was evaluated at weeks 26 and 52. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Week 0, week 26, week 52 | 
| Change in Waist Circumference | Change from baseline (week 0) in waist circumference was evaluated at weeks 26 and 52. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Week 0, week 26, week 52 | 
| Change in Fasting Total Cholesterol (Ratio to Baseline) | Change from baseline (week 0) in fasting total cholesterol (mmol/L) at weeks 26 and 52 is presented as ratio to baseline. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Week 0, week 26, week 52 | 
| Change in Fasting Low-density Lipoprotein (LDL) - Cholesterol (Ratio to Baseline) | Change from baseline (week 0) in fasting low-density lipoprotein (LDL) (mmol/L) at weeks 26 and 52 is presented as ratio to baseline. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Week 0, week 26, week 52 | 
| Change in Fasting High-density Lipoprotein (HDL) - Cholesterol (Ratio to Baseline) | Change from baseline (week 0) in fasting high-density lipoprotein (HDL) (mmol/L) at weeks 26 and 52 is presented as ratio to baseline. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Week 0, week 26, week 52 | 
| Change in Fasting Very-low Density Lipoprotein (VLDL) - Cholesterol (Ratio to Baseline) | Change from baseline (week 0) in fasting very-low density lipoprotein (VLDL) (mmol/L) at weeks 26 and 52 is presented as ratio to baseline. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Week 0, week 26, week 52 | 
| Change in Fasting Triglyceride (Ratio to Baseline) | Change from baseline (week 0) in fasting triglycerides (mmol/L) at weeks 26 and 52 is presented as ratio to baseline. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Week 0, week 26, week 52 | 
| Participants Who Achieve HbA1c Below 7% (53 mmol/Mol), American Diabetes Association Target (Yes/No) | Participants who achieved HbA1c below 7.0% (53 millimoles per mole [mmol/mol]) according to American Diabetes Association (ADA) target (yes/no) at weeks 26 and 52 are presented. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Week 26, week 52 | 
| Participants Who Achieve HbA1c Below or Equal to 6.5% (48 mmol/Mol), American Association of Clinical Endocrinologists Target (Yes/No) | Participants who achieved HbA1c below or equal to 6.5% (48 mmol/mol), American Association of Clinical Endocrinologists (AACE) target (yes/no) at weeks 26 and 52 are presented. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Week 26, week 52 | 
| Participants Who Achieve HbA1c Below 7.0% (53 mmol/Mol) Without Severe or Blood Glucose Confirmed Symptomatic Hypoglycaemia Episodes and no Weight Gain (Yes/No) | Participants who achieved HbA1c below 7.0% (53 mmol/mol) without severe or blood glucose (BG) confirmed symptomatic hypoglycaemia episodes and without weight gain (yes/no) at weeks 26 and 52 are presented. Severe hypoglycaemia was defined as an episode requiring assistance of another person to actively administer carbohydrate or glucagon, or take other corrective actions. BG-confirmed symptomatic hypoglycaemia was defined as an episode with plasma glucose value <3.1 mmol/L with symptoms consistent with hypoglycaemia. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Week 26, week 52 | 
| Participants Who Achieve HbA1c Reduction More Than or Equal to 1% (10.9 mmol/Mol) and Weight Loss More Than or Equal to 3% (Yes/No) | Participants who achieved HbA1c reduction more than or equal to 1% (10.9 mmol/mol) and weight loss more than or equal to 3% (yes/no) at weeks 26 and 52 are presented. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Week 26, week 52 | 
| Participants Who Achieve Weight Loss More Than or Equal to 5% (Yes/No). | Participants who achieved weight loss more than or equal to 5% (yes/no) at weeks 26 and 52 are presented. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Week 26, week 52 | 
| Participants Who Achieve Weight Loss More Than or Equal to 10% (Yes/No) | Participants who achieved weight loss more than or equal to 10% (yes/no) at weeks 26 and 52 are presented. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Week 26, week 52 | 
| Time to Additional Anti-diabetic Medication | Presented results are the number of participants who had taken additional anti-diabetic medication anytime during the periods, from week 0 to week 26 and week 0 to week 52. Additional anti-diabetic medication was defined as any new anti-diabetic medication used for more than 21 days with the initiation at or after randomisation (week 0) and before (planned) end-of-treatment, and/or intensification of anti-diabetic medication (a more than 20% increase in dose relative to baseline) for more than 21 days with the intensification at or after randomisation and before (planned) end-of-treatment. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Weeks 0-52 | 
| Time to Rescue Medication | Presented results are the number of participants who had taken rescue medication anytime during the periods, from week 0 to week 26 and week 0 to week 52. Rescue medication was defined as any new anti-diabetic medication used as add-on to trial product and used for more than 21 days with the initiation at or after randomisation (week 0) and before last day on trial product, and/or intensification of anti-diabetic medication (a more than 20% increase in dose relative to baseline) for more than 21 days with the intensification at or after randomisation and before last day on trial product. Results are based on the data from the on-treatment without rescue medication observation period, which was the time period when a participant was on treatment with trial product, excluding any period after initiation of rescue medication and/or premature trial product discontinuation. | Weeks 0-52 | 
| Change in Amylase (Ratio to Baseline) | Change from baseline (week 0) in amylase (measured as units per liter [U/L]) at weeks 26 and 52 is presented as ratio to baseline. Results are based on the data from the on-treatment observation period which was the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication. | Week 0, week 26, week 52 | 
| Change in Lipase (Ratio to Baseline) | Change from baseline (week 0) in lipase (measured as U/L) at weeks 26 and 52 is presented as ratio to baseline. Results are based on the data from the on-treatment observation period which was the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication. | Week 0, week 26, week 52 | 
| Change in Pulse Rate | Change from baseline (week 0) in pulse rate was evaluated at weeks 26 and 52. Results are based on the data from the on-treatment observation period which was the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication. | Week 0, week 26, week 52 | 
| Change in Blood Pressure | Change from baseline (week 0) in blood pressure (systolic blood pressure [SBP] and diastolic blood pressure [DBP]) was evaluated at weeks 26 and 52. Results are based on the data from the on-treatment observation period which was the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication. | Week 0, week 26, week 52 | 
| Change in ECG Evaluation | Change from baseline (week 0) in electrocardiogram (ECG) was evaluated at weeks 26 and 52. Change from baseline results are presented as shift in findings (normal, abnormal and not clinically significant (NCS) and abnormal and clinically significant (CS)) from week 0 to week 26 and 52. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Week 0, week 26, week 52 | 
| Change in Physical Examination | Participants with physical examination findings, normal, abnormal NCS and abnormal CS at baseline (weeks -2), week 26 and weeks 52 are presented. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. Results are presented for the following examinations: 1) Cardiovascular system; 2) Central and peripheral nervous system; 3) Gastrointestinal system, incl. mouth; 4) General appearance; 5) Head, ears, eyes, nose, throat, neck; 6) Lymph node palpation; 7) Musculoskeletal system; 8) Respiratory system; 9) Skin; 10) Thyroid gland. | Week -2, week 26, week 52 | 
| Change in Eye Examination Category | Participants with eye examination (fundoscopy) findings, normal, abnormal NCS and abnormal CS at baseline (week -2) and week 52 are presented. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Week -2, week 52 | 
| Number of Treatment-emergent Severe or Blood Glucose-confirmed Symptomatic Hypoglycaemic Episodes | Treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes were recorded during weeks 0-57 (52-week treatment period plus the 5-week follow-up period). Hypoglycaemic episodes with onset during the on-treatment observation period were considered treatment-emergent. On-treatment observation period was defined as the time period when a subject was on treatment with trial product, including any period after initiation of rescue medication. Severe hypoglycaemia was defined as an episode requiring assistance of another person to actively administer carbohydrate or glucagon, or take other corrective actions. BG-confirmed symptomatic hypoglycaemia: Confirmed by a glucose value <3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia. | Weeks 0-57 | 
| Participants With Treatment-emergent Severe or BG-confirmed Symptomatic Hypoglycaemic Episodes | Participants with treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes were recorded from week 0 to week 83 (78-week treatment period plus the 5-week follow-up period). Hypoglycaemic episodes with onset during the on-treatment observation period were considered treatment-emergent. On-treatment observation period was defined as the time period when a subject was on treatment with trial product, including any period after initiation of rescue medication. Severe hypoglycaemia was defined as an episode requiring assistance of another person to actively administer carbohydrate or glucagon, or take other corrective actions. BG-confirmed symptomatic hypoglycaemia: Confirmed by a glucose value <3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia. | Weeks 0-57 | 
| Change in SF-36v2 (Acute Version) Health Survey Scores: Scores From the 8 Domains, the Physical Component Summary (PCS) and the Mental Component Summary (MCS) | SF-36 is a 36-item patient-reported survey of patient health that measures the participant's overall health-related quality of life (HRQoL). SF-36v2™ (acute version) questionnaire measured eight domains of functional health and well-being as well as two component summary scores (physical component summary (PCS) and mental component summary (MCS)). The 0-100 scale scores (where higher scores indicated a better HRQoL) from the SF-36 were converted to norm-based scores to enable a direct interpretation in relation to the distribution of the scores in the 2009 U.S. general population. In the metric of norm-based scores, 50 and 10 corresponds to the mean and standard deviation respectively of the 2009 U.S. general population. Change from baseline (week 0) in the domain scores and component summary (PCS and MCS) scores were evaluated at weeks 26 and 52. A positive change score indicates an improvement since baseline. Results are based on the data from the in-trial observation period. | Week 0, week 26, week 52 | 
| Diabetes Therapy-Related Quality of Life (DTR-QoL): Total Score and Scores for the 4 Domains | DTR-QoL questionnaire is a 29-item patient-reported survey of patient health that measures the influence of diabetes treatment on health related-QoL on 4 domains on individual scale ranges: Burden on social activities and daily activities, Anxiety and dissatisfaction with treatment, Hypoglycemia and Satisfaction with treatment on a 7-point graded response scale. The domain score is calculated from the mean score of the attribute items, and the scoring range is converted to 0 - 100 (best-case response = 100; worst case response = 0). The total score, after simple addition of the item scores, is converted to 0 - 100 (best-case response = 100; worst case response = 0). Change from baseline (week 0) in the scores were evaluated at week 26, week 52. Data based on in-trial observation period is presented. W26 and W52 refer to week 26 and week 52 respectively. | week 0, week 26, week 52 |