Efficacy and Safety of Semaglutide Versus Canagliflozin as add-on to Metformin in Subjects With Type 2 Diabetes (SUSTAIN 8)

• ClinicalTrials.gov Identifier: NCT03136484
• Recruitment Status: Completed
• First Posted: May 2, 2017
• Results First Posted: December 17, 2019
• Last Update Posted: January 21, 2020
• Sponsor: Novo Nordisk A/S
• Information provided by (Responsible Party): Novo Nordisk A/S

Study Description

Brief Summary:

This trial is conducted in Africa, Asia, Europe, North and South America. The aim of the trial is to compare the effect of once-weekly (OW) dosing of subcutaneous semaglutide (1.0 mg) versus once-daily dosing of oral canagliflozin (300 mg) on glycaemic control in subjects with type 2 diabetes (T2D) on a background treatment of metformin

Condition or disease	Intervention/treatment	Phase
Diabetes; Diabetes Mellitus, Type 2	Drug: Semaglutide; Drug: Canagliflozin; Drug: Placebo (canagliflozin); Drug: Placebo (semaglutide)	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 788 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Efficacy and Safety of Semaglutide Versus Canagliflozin as add-on to Metformin in Subjects With Type 2 Diabetes
• Actual Study Start Date: March 15, 2017
• Actual Primary Completion Date: October 16, 2018
• Actual Study Completion Date: November 16, 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: Semaglutide + canagliflozin placebo	Drug: Semaglutide; Following a dose escalation phase of 8 weeks, semaglutide 1.0 mg once-weekly(administered subcutaneously, s.c., under the skin) and canagliflozin placebo once-daily (administered orally, as a tablet). Subjects will continue on their pre-trial daily dose of metformin.; Drug: Placebo (canagliflozin); Following a dose escalation phase of 8 weeks, semaglutide 1.0 mg once-weekly(administered subcutaneously, s.c., under the skin) and canagliflozin placebo once-daily (administered orally, as a tablet). Subjects will continue on their pre-trial daily dose of metformin.
Active Comparator: Canagliflozin + semaglutide placebo	Drug: Canagliflozin; Following a dose escalation phase of 8 weeks, canagliflozin 300 mg once-daily (administered orally, as a tablet) and semaglutide placebo (administered subcutaneously, s.c., under the skin). Subjects will continue on their pre-trial daily dose of metformin.; Drug: Placebo (semaglutide); Following a dose escalation phase of 8 weeks, canagliflozin 300 mg once-daily (administered orally, as a tablet) and semaglutide placebo (administered subcutaneously, s.c., under the skin). Subjects will continue on their pre-trial daily dose of metformin.

Outcome Measures

Primary Outcome Measures :

1. Change in HbA1c [ Time Frame: Week 0, week 52 ]
   Change from baseline (week 0) to week 52 in HbA1c (glycosylated haemoglobin) was evaluated. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose to either the day of last dose plus 7 days or first initiation of rescue medication, whichever came first; and 'In-trial' observation period which started at the date of randomisation and include the period after initiation of rescue medication and/or premature trial product discontinuation, if any and ended at the last contact, withdrawal of consent or death, whichever came first.

Secondary Outcome Measures :

1. Change in Body Weight (kg) [ Time Frame: Week 0, week 52 ]
   Change from baseline (week 0) to week 52 in body weight was evaluated. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose to either the day of last dose plus 7 days or first initiation of rescue medication, whichever came first.
2. Change in Total Fat Mass (kg) [ Time Frame: Week 0, week 52 ]
   Change from baseline (week 0) to week 52 in total fat mass was evaluated. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose to either the day of last dose plus 7 days or first initiation of rescue medication, whichever came first.
3. Change in FPG (Fasting Plasma Glucose) [ Time Frame: Week 0, week 52 ]
   Change from baseline (week 0) to week 52 in FPG was evaluated. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose to either the day of last dose plus 7 days or first initiation of rescue medication, whichever came first.
4. Change in SMPG (Self-measured Plasma Glucose)- Mean 7-point Profile [ Time Frame: Week 0, week 52 ]
   Change from baseline (week 0) to week 52 in SMPG- mean 7-point profile was evaluated. 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 'on-treatment without rescue medication' observation period, which started at the date of first dose to either the day of last dose plus 7 days or first initiation of rescue medication, whichever came first.
5. Change in SMPG- Mean Postprandial Increment Over All Meals [ Time Frame: Week 0, week 52 ]
   Change from baseline (week 0) to week 52 in SMPG- mean postprandial increment over all meals was evaluated. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose to either the day of last dose plus 7 days or first initiation of rescue medication, whichever came first.
6. Change in Fasting Total Cholesterol [ Time Frame: Week 0, week 52 ]
   Change from baseline (week 0) to week 52 in fasting total cholesterol (mmol/L) is presented as ratio to baseline. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose to either the day of last dose plus 7 days or first initiation of rescue medication, whichever came first.
7. Change in Fasting LDL-cholesterol [ Time Frame: Week 0, week 52 ]
   Change from baseline (week 0) to week 52 in fasting low-density lipoprotein (LDL) cholesterol (mmol/L) is presented as ratio to baseline. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose to either the day of last dose plus 7 days or first initiation of rescue medication, whichever came first.
8. Change in Fasting HDL-cholesterol [ Time Frame: Week 0, week 52 ]
   Change from baseline (week 0) to week 52 in fasting high-density lipoprotein (HDL) cholesterol (mmol/L) is presented as ratio to baseline. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose to either the day of last dose plus 7 days or first initiation of rescue medication, whichever came first.
9. Change in Fasting Triglycerides [ Time Frame: Week 0, week 52 ]
   Change from baseline (week 0) to week 52 in fasting triglycerides (mmol/L) is presented as ratio to baseline. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose to either the day of last dose plus 7 days or first initiation of rescue medication, whichever came first.
10. Change in Vital Signs (Systolic Blood Pressure and Diastolic Blood Pressure) [ Time Frame: Week 0, week 52 ]
    Change from baseline (week 0) to week 52 in systolic blood pressure and diastolic blood pressure. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose to either the day of last dose plus 7 days or first initiation of rescue medication, whichever came first.
11. Percentage Change in Body Weight (%) [ Time Frame: Week 0, week 52 ]
    Change from baseline (week 0) to week 52 in body weight was evaluated. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose to either the day of last dose plus 7 days or first initiation of rescue medication, whichever came first.
12. Change in Body Mass Index (BMI) [ Time Frame: Week 0, week 52 ]
    Change from baseline (week 0) to week 52 in BMI was evaluated. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose to either the day of last dose plus 7 days or first initiation of rescue medication, whichever came first.
13. Change in Waist Circumference [ Time Frame: Week 0, week 52 ]
    Change from baseline (week 0) to week 52 in waist circumference was evaluated. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose to either the day of last dose plus 7 days or first initiation of rescue medication, whichever came first.
14. Percentage Change in Total Fat Mass (%) [ Time Frame: Week 0, week 52 ]
    Change from baseline (week 0) to week 52 in total fat mass was evaluated. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose to either the day of last dose plus 7 days or first initiation of rescue medication, whichever came first.
15. Change in Total Lean Mass (kg) [ Time Frame: Week 0, week 52 ]
    Change from baseline (week 0) to week 52 in total lean mass was evaluated. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose to either the day of last dose plus 7 days or first initiation of rescue medication, whichever came first.
16. Percentage Change in Total Lean Mass (%) [ Time Frame: Week 0, week 52 ]
    Change from baseline (week 0) to week 52 in total lean mass was evaluated. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose to either the day of last dose plus 7 days or first initiation of rescue medication, whichever came first.
17. Change in Visceral Fat Mass (kg) [ Time Frame: Week 0, week 52 ]
    Change from baseline (week 0) to week 52 in visceral fat mass was evaluated. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose to either the day of last dose plus 7 days or first initiation of rescue medication, whichever came first.
18. Percentage Change in Visceral Fat Mass (%) [ Time Frame: Week 0, week 52 ]
    Change from baseline (week 0) to week 52 in visceral fat mass was evaluated. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose to either the day of last dose plus 7 days or first initiation of rescue medication, whichever came first.
19. Change in Ratio Between Total Fat Mass and Total Lean Mass [ Time Frame: Week 0, week 52 ]
    Change from baseline (week 0) to week 52 in ratio between total fat mass and total lean mass was evaluated. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose to either the day of last dose plus 7 days or first initiation of rescue medication, whichever came first.
20. Participants Who Achieved HbA1c < 7.0% (53 mmol/Mol), American Diabetes Association (ADA) Target (Yes/no) [ Time Frame: Week 52 ]
    Percentage of participants who achieved HbA1c < 7.0% (53 millimoles per mole [mmol/mol]), ADA target (yes/no) is presented. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose to either the day of last dose plus 7 days or first initiation of rescue medication, whichever came first.
21. Participants Who Achieved HbA1c ≤ 6.5% (48 mmol/Mol), American Association of Clinical Endocrinologists (AACE) Target (Yes/no) [ Time Frame: Week 52 ]
    Percentage of participants who achieved HbA1c ≤ 6.5% (48 mmol/mol), AACE target (yes/no) is presented. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose to either the day of last dose plus 7 days or first initiation of rescue medication, whichever came first.
22. Participants Who Achieved HbA1c Reduction ≥1% (Yes/no) [ Time Frame: Week 0, week 52 ]
    Percentage of participants who achieved ≥1% reduction of baseline HbA1c (yes/no) is presented. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose to either the day of last dose plus 7 days or first initiation of rescue medication, whichever came first.
23. Participants Who Achieved Weight Loss ≥3% (Yes/no) [ Time Frame: Week 0, week 52 ]
    Percentage of participants losing ≥3% of baseline body weight (yes/no) is presented. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose to either the day of last dose plus 7 days or first initiation of rescue medication, whichever came first.
24. Participants Who Achieved Weight Loss ≥5% (Yes/no) [ Time Frame: Week 0, week 52 ]
    Percentage of participants losing ≥5% of baseline body weight (yes/no) is presented. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose to either the day of last dose plus 7 days or first initiation of rescue medication, whichever came first.
25. Participants Who Achieved Weight Loss ≥10% (Yes/no) [ Time Frame: Week 0, week 52 ]
    Percentage of participants losing ≥10% of baseline body weight is presented. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose to either the day of last dose plus 7 days or first initiation of rescue medication, whichever came first.
26. Participants Who Achieved HbA1c Below 7.0% (53 mmol/Mol) Without Severe or Blood Glucose (BG)-Confirmed Symptomatic Hypoglycaemia Episodes and no Weight Gain (Yes/no) [ Time Frame: Week 0, week 52 ]
    Severe or BG-confirmed symptomatic hypoglycaemia is an episode that is severe according to the American Diabetes Association classification or blood glucose-confirmed by a plasma glucose value <3.1 mmol/L (56 milligrams per deciliter [mg/dL]) with symptoms consistent with hypoglycaemia. Percentage of participants who achieved HbA1c below 7.0% (53 mmol/mol) without severe or blood glucose confirmed symptomatic hypoglycaemia episodes and no weight gain (yes/no) is presented. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose to either the day of last dose plus 7 days or first initiation of rescue medication, whichever came first.
27. Participants Who Achieved HbA1c Reduction ≥1% and Weight Loss ≥3% (Yes/no) [ Time Frame: Week 0, week 52 ]
    Percentage of participants who achieved ≥1% reduction of baseline HbA1c and losing ≥3% of baseline body weight (yes/no) is presented. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose to either the day of last dose plus 7 days or first initiation of rescue medication, whichever came first.
28. Participants Who Achieved HbA1c Reduction ≥1% and Weight Loss ≥5% (Yes/no) [ Time Frame: Week 0, week 52 ]
    Percentage of participants who achieved ≥1% reduction of baseline HbA1c and losing ≥5% of baseline body weight (yes/no) is presented. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose to either the day of last dose plus 7 days or first initiation of rescue medication, whichever came first.
29. Participants Who Achieved HbA1c Reduction ≥1% and Weight Loss ≥10% (Yes/no) [ Time Frame: Week 0, week 52 ]
    Percentage of participants who achieved ≥1% reduction of baseline HbA1c and losing ≥10% of baseline body weight (yes/no) is presented. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose to either the day of last dose plus 7 days or first initiation of rescue medication, whichever came first.
30. Total Number of Treatment Emergent Adverse Events (TEAEs) [ Time Frame: Weeks 0-57 ]
    A TEAE is defined as an adverse event with onset in the on-treatment observation period (which started at the date of first dose of trial product and included the period after initiation of rescue medication, if any and excluded the period after premature trial product discontinuation, if any. TEAEs assessed up to approximately 57 weeks is presented.
31. Change in Haematological Parameter- Haemoglobin [ Time Frame: Week 0, week 52 ]
    Change from baseline (week 0) to week 52 in haemoglobin (mmol/L) is presented as ratio to baseline. Results are based on the 'on-treatment' observation period which started at the date of first dose of trial product and include the period after initiation of rescue medication, if any and excludes the period after premature trial product discontinuation, if any.
32. Change in Haematological Parameter- Haematocrit [ Time Frame: Week 0, week 52 ]
    Change from baseline (week 0) to week 52 in haematocrit (%) is presented as ratio to baseline. Results are based on the 'on-treatment' observation period which started at the date of first dose of trial product and include the period after initiation of rescue medication, if any and excludes the period after premature trial product discontinuation, if any.
33. Change in Haematological Parameter- Erythrocytes [ Time Frame: Week 0, week 52 ]
    Change from baseline (week 0) to week 52 in erythrocytes (10^12 cells/L) is presented as ratio to baseline. Results are based on the 'on-treatment' observation period which started at the date of first dose of trial product and include the period after initiation of rescue medication, if any and excludes the period after premature trial product discontinuation, if any.
34. Change in Haematological Parameter- Leukocytes [ Time Frame: Week 0, week 52 ]
    Change from baseline (week 0) to week 52 in leukocytes (10^9 cells/L) is presented as ratio to baseline. Results are based on the 'on-treatment' observation period which started at the date of first dose of trial product and include the period after initiation of rescue medication, if any and excludes the period after premature trial product discontinuation, if any.
35. Change in Haematological Parameter- Thrombocytes [ Time Frame: Week 0, week 52 ]
    Change from baseline (week 0) to week 52 in thrombocytes (10^9 cells/L) is presented as ratio to baseline. Results are based on the 'on-treatment' observation period which started at the date of first dose of trial product and include the period after initiation of rescue medication, if any and excludes the period after premature trial product discontinuation, if any.
36. Change in Biochemistry Parameter- Amylase [ Time Frame: Week 0, week 52 ]
    Change from baseline (week 0) to week 52 in amylase (units per liter [U/L]) is presented as ratio to baseline. Results are based on the 'on-treatment' observation period which started at the date of first dose of trial product and include the period after initiation of rescue medication, if any and excludes the period after premature trial product discontinuation, if any.
37. Change in Biochemistry Parameter- Lipase [ Time Frame: Week 0, week 52 ]
    Change from baseline (week 0) to week 52 in lipase (U/L) is presented as ratio to baseline. Results are based on the 'on-treatment' observation period which started at the date of first dose of trial product and include the period after initiation of rescue medication, if any and excludes the period after premature trial product discontinuation, if any.
38. Change in Biochemistry Parameter- ALT [ Time Frame: Week 0, week 52 ]
    Change from baseline (week 0) to week 52 in alanine aminotransferase (ALT) (U/L) is presented as ratio to baseline. Results are based on the 'on-treatment' observation period which started at the date of first dose of trial product and include the period after initiation of rescue medication, if any and excludes the period after premature trial product discontinuation, if any.
39. Change in Biochemistry Parameter- AST [ Time Frame: Week 0, week 52 ]
    Change from baseline (week 0) to week 52 in aspartate aminotransferase (AST) (U/L) is presented as ratio to baseline. Results are based on the 'on-treatment' observation period which started at the date of first dose of trial product and include the period after initiation of rescue medication, if any and excludes the period after premature trial product discontinuation, if any.
40. Change in Biochemistry Parameter- ALP [ Time Frame: Week 0, week 52 ]
    Change from baseline (week 0) to week 52 in alkaline phosphatase (ALP) (U/L) is presented as ratio to baseline. Results are based on the 'on-treatment' observation period which started at the date of first dose of trial product and include the period after initiation of rescue medication, if any and excludes the period after premature trial product discontinuation, if any.
41. Change in Biochemistry Parameter- Total Bilirubin [ Time Frame: Week 0, week 52 ]
    Change from baseline (week 0) to week 52 in total bilirubin (U/L) is presented as ratio to baseline. Results are based on the 'on-treatment' observation period which started at the date of first dose of trial product and include the period after initiation of rescue medication, if any and excludes the period after premature trial product discontinuation, if any.
42. Change in Biochemistry Parameter- Creatinine [ Time Frame: Week 0, week 52 ]
    Change from baseline (week 0) to week 52 in creatinine (micromoles per liter [umol/L]) is presented as ratio to baseline. Results are based on the 'on-treatment' observation period which started at the date of first dose of trial product and include the period after initiation of rescue medication, if any and excludes the period after premature trial product discontinuation, if any.
43. Change in Biochemistry Parameter- eGFR [ Time Frame: Week 0, week 52 ]
    Estimated glomerular filtration rate (eGFR) (milliliters per minute per 1.73 square meters [mL/min/1.73m^2])is calculated using the equation from the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI). Change from baseline (week 0) to week 52 in eGFR is presented as ratio to baseline. Results are based on the 'on-treatment' observation period which started at the date of first dose of trial product and include the period after initiation of rescue medication, if any and excludes the period after premature trial product discontinuation, if any.
44. Change in Biochemistry Parameter- Albumin [ Time Frame: Week 0, week 52 ]
    Change from baseline (week 0) to week 52 in albumin (g/dL) is presented as ratio to baseline. Results are based on the 'on-treatment' observation period which started at the date of first dose of trial product and include the period after initiation of rescue medication, if any and excludes the period after premature trial product discontinuation, if any.
45. Change in Biochemistry Parameter- Calcium [ Time Frame: Week 0, week 52 ]
    Change from baseline (week 0) to week 52 in calcium (mmol/L) is presented as ratio to baseline. Results are based on the 'on-treatment' observation period which started at the date of first dose of trial product and include the period after initiation of rescue medication, if any and excludes the period after premature trial product discontinuation, if any.
46. Change in Biochemistry Parameter- Potassium [ Time Frame: Week 0, week 52 ]
    Change from baseline (week 0) to week 52 in potassium (mmol/L) is presented as ratio to baseline. Results are based on the 'on-treatment' observation period which started at the date of first dose of trial product and include the period after initiation of rescue medication, if any and excludes the period after premature trial product discontinuation, if any.
47. Change in Biochemistry Parameter- Sodium [ Time Frame: Week 0, week 52 ]
    Change from baseline (week 0) to week 52 in sodium (mmol/L) is presented as ratio to baseline. Results are based on the 'on-treatment' observation period which started at the date of first dose of trial product and include the period after initiation of rescue medication, if any and excludes the period after premature trial product discontinuation, if any.
48. Change in Calcitonin [ Time Frame: Week 0, week 52 ]
    Change from baseline (week 0) to week 52 in calcitonin (nanograms per liter) is presented as ratio to baseline. Results are based on the 'on-treatment' observation period which started at the date of first dose of trial product and include the period after initiation of rescue medication, if any and excludes the period after premature trial product discontinuation, if any.
49. Change in Pulse [ Time Frame: Week 0, week 52 ]
    Change from baseline (week 0) to week 52 in pulse is presented based on the 'on-treatment' observation period which started at the date of first dose of trial product and include the period after initiation of rescue medication, if any and excludes the period after premature trial product discontinuation, if any.
50. Change in ECG [ Time Frame: Week 0, week 52 ]
    The electrocardiogram (ECG) was assessed by the investigator at baseline (week 0) and week 52 and categorised as normal, abnormal NCS or abnormal CS. Number of participants in each ECG category at baseline and week 52 were presented. Results are based on the 'on-treatment' observation period which started at the date of first dose of trial product and include the period after initiation of rescue medication, if any and excludes the period after premature trial product discontinuation, if any.
51. Change in Physical Examination [ Time Frame: Week -2, week 52 ]
    Physical examination parameters are categorised as general appearance; nervous system (central and peripheral); cardiovascular system; gastrointestinal system; skin; respiratory system; lymph node palpation; thyroid gland; left foot; right foot; left leg and right leg. The number of participants assessed as normal, abnormal not clinically significant (NCS) and abnormal clinically significant (CS) at baseline (week -2) and week 52 is presented based on the 'on-treatment' observation period which started at the date of first dose of trial product and include the period after initiation of rescue medication, if any and excludes the period after premature trial product discontinuation, if any.
52. Eye Examination [ Time Frame: Week 0, week 52 ]
    Fundus photography or a dilated fundoscopy was performed by the investigator at baseline (week 0) and week 52. The results of the examination were interpreted for each eye (left/right) are categorised as normal, abnormal NCS or abnormal CS. Number of participants in each category at baseline and week 52 were presented. Results are based on the 'on-treatment' observation period which started at the date of first dose of trial product and include the period after initiation of rescue medication, if any and excludes the period after premature trial product discontinuation, if any.
53. Total Number of Treatment-emergent Severe or Blood Glucose-confirmed Symptomatic Hypoglycaemic Episodes [ Time Frame: Weeks 0-57 ]
    Hypoglycaemic episodes defined as treatment-emergent if the onset of the episode occurs within the on-treatment observation period. Severe or BG-confirmed symptomatic hypoglycaemia is an episode that is severe according to the American Diabetes Association classification or blood glucose-confirmed by a plasma glucose value <3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia. Results are based on the 'on-treatment' observation period which started at the date of first dose of trial product and include the period after initiation of rescue medication, if any and excludes the period after premature trial product discontinuation, if any.
54. Participants With Treatment-emergent Severe or Blood Glucose-confirmed Symptomatic Hypoglycaemic Episodes [ Time Frame: Weeks 0-57 ]
    Number of participants with treatment emergent severe or blood glucose-confirmed symptomatic hypoglycaemic episodes. Hypoglycaemic episodes defined as treatment-emergent if the onset of the episode occurs within the on-treatment observation period. Severe or BG-confirmed symptomatic hypoglycaemia is an episode that is severe according to the American Diabetes Association classification or blood glucose-confirmed by a plasma glucose value <3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia. Results are based on the 'on-treatment' observation period which started at the date of first dose of trial product and include the period after initiation of rescue medication, if any and excludes the period after premature trial product discontinuation, if any.
55. Change in Short Form 36 Health Survey (SF-36): Sub-domains [ Time Frame: Week 0, week 52 ]
    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™ questionnaire measured the HRQoL on 8 domains on individual scale ranges. The scores 0-100 (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. A norm-based score of 50 corresponds to the mean score and 10 corresponds to the standard deviation of the 2009 U.S. general population. Change from baseline (week 0) to week 52 in the sub-domain scores is presented. A positive change score indicate an improvement since baseline. Results are based on the 'on-treatment without rescue medication' observation period.
56. Change in SF-36: Physical Component Summary (PCS) [ Time Frame: Week 0, week 52 ]
    Change from baseline (week 0) to week 52 in short form 36 v2.0 acute domain PCS. SF-36v2™ questionnaire measured the HRQoL on 8 domains on individual scale ranges. It consists of 2 component summary measures that further summarize 8 health domain scales. The PCS measure is derived from domain scales of physical functioning, role-physical, bodily pain, and general health. The scores 0-100 (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. A norm-based score of 50 corresponds to the mean score and 10 corresponds to the standard deviation of the 2009 U.S. general population. A positive change score indicates an improvement since baseline. Results are based on the 'on-treatment without rescue medication' observation period.
57. Change in SF-36: Mental Component Summary (MCS) [ Time Frame: Week 0, week 52 ]
    Change from baseline (week 0) to week 52 in short form 36 v2.0 acute domain MCS. SF- 36v2™ questionnaire measured the HRQoL on 8 domains on individual scale ranges. The MCS measure is derived from domain scales of vitality, social functioning, role emotional and mental health. The scores 0-100 (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. A norm-based score of 50 corresponds to the mean score and 10 corresponds to the standard deviation of the 2009 U.S. general population. A positive change score indicates an improvement since baseline. Results are based on the 'on-treatment without rescue medication' observation period.
58. Change in Diabetes Treatment Satisfaction Questionnaire (DTSQ): Treatment Satisfaction Summary Score (Sum of 6 of 8 Items) and the 8 Items Separately [ Time Frame: Week 0, week 52 ]
    Change from baseline (week 0) in DTSQ was evaluated at week 52. The DTSQs items are scored on a 7-point graded response scale ranging from 6 to 0. Higher scores indicate higher levels of treatment satisfaction for DTSQs items 1, 4 -8. For items 2 and 3 a higher score indicates a higher patient perceived experience of high blood sugars and low blood sugars, respectively. Thus, lower scores indicate a perception of blood glucose levels being "none of the time" unacceptably high (item 2) or low (item 3). The domain score of total treatment satisfaction (total treatment satisfaction score) was computed by adding the six items scores 1, 4-8. The score ranges 0-36. A higher treatment satisfaction score indicates a higher level of treatment satisfaction. Results are based on the 'on-treatment without rescue medication' observation period.
59. Change in Control of Eating Questionnaire (CoEQ): Domains [ Time Frame: Week 0, week 52 ]
    The CoEQ comprised 19 items to assess the intensity and type of food cravings, as well as subjective sensation of appetite and mood, with the 4 domains: 'craving control', 'craving for sweet', 'craving for savoury' and 'positive mood'. The 19 items were scored on an 11-point graded response scale ranging from 10 to 0, with items relating to each of the 4 domains being averaged to create a final score. A low score in the domains 'craving for sweet and 'craving for savoury' represents a low level of craving; whereas a high score in the domains 'craving control' and 'positive mood' represents good control and a good mood, respectively. Results are based on the 'on-treatment without rescue medication' observation period.
60. Change in CoEQ: Individual Items [ Time Frame: Week 0, week 52 ]
    The CoEQ comprised 19 items to assess the intensity and type of food cravings, as well as subjective sensation of appetite and mood, with the 4 domains: 'craving control', 'craving for sweet', 'craving for savoury' and 'positive mood'. The 19 items were scored on an 11-point graded response scale ranging from 10 to 0, with items relating to each of the 4 domains being averaged to create a final score. A low score in the domains 'craving for sweet and 'craving for savoury' represents a low level of craving; whereas a high score in the domains 'craving control' and 'positive mood' represents good control and a good mood, respectively. Results are based on the 'on-treatment without rescue medication' observation period.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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, age equal to or above18 years at the time of signing informed consent - Diagnosed with type 2 diabetes mellitus (T2D) - HbA1c of 7.0-10.5% (53-91 mmol/mol, both inclusive) - Stable daily dose of metformin (equal to or above1500 mg or maximum tolerated dose as documented in the subject medical record and in compliance with current local label) for at least 90 days prior to the day of screening Exclusion Criteria: - Known or suspected hypersensitivity to trial product(s) or related products - Previous participation in this trial. Participation is defined as signed informed consent - 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) - Participation in any clinical trial of an approved or non-approved investigational medicinal product within 90 days prior to the day of screening - Any disorder which in the investigator's opinion might jeopardise subject's safety or compliance with the protocol - Subject with alanine aminotransferase (ALT) above 2.5 x upper normal limit (UNL) - 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 (DKA) - Any of the following: myocardial infarction (MI), 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 (NYHA) Class IV - Planned coronary, carotid or peripheral artery revascularisation known on the day of screening - Renal impairment measured as eGFR below 60 ml/min/1.73 m^2 as defined by Kidney Disease Improving global outcomes (KDIGO 2012) classification using isotope dilution mass spectrometry (IDMS) for serum creatinine measured at screening - 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 - 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 - Medical history of diabetes-related lower limb amputations or signs of critical lower limb ischemia, (e.g. skin ulcer, osteomyelitis, or gangrene) within the last 26 weeks prior to screening

Contacts and Locations

Locations

United States, California

Novo Nordisk Investigational Site

Anaheim, California, United States, 92801

Novo Nordisk Investigational Site

La Mesa, California, United States, 91942

Novo Nordisk Investigational Site

Los Angeles, California, United States, 90057

Novo Nordisk Investigational Site

Montclair, California, United States, 91763

Novo Nordisk Investigational Site

San Diego, California, United States, 92111

Novo Nordisk Investigational Site

Spring Valley, California, United States, 91978

Novo Nordisk Investigational Site

Tustin, California, United States, 92780

Novo Nordisk Investigational Site

Walnut Creek, California, United States, 94598

United States, Florida

Novo Nordisk Investigational Site

Fleming Island, Florida, United States, 32003

Novo Nordisk Investigational Site

Hallandale Beach, Florida, United States, 33009

Novo Nordisk Investigational Site

Hialeah, Florida, United States, 33012

Novo Nordisk Investigational Site

Miami, Florida, United States, 33135

Novo Nordisk Investigational Site

Miami, Florida, United States, 33155

Novo Nordisk Investigational Site

Miami, Florida, United States, 33174

Novo Nordisk Investigational Site

Miami, Florida, United States, 33175

Novo Nordisk Investigational Site

Miami, Florida, United States, 33186

Novo Nordisk Investigational Site

Spring Hill, Florida, United States, 34609

United States, Georgia

Novo Nordisk Investigational Site

Conyers, Georgia, United States, 30094-5965

Novo Nordisk Investigational Site

Marietta, Georgia, United States, 30060

United States, Idaho

Novo Nordisk Investigational Site

Meridian, Idaho, United States, 83646

United States, Iowa

Novo Nordisk Investigational Site

Council Bluffs, Iowa, United States, 51501

United States, Kentucky

Novo Nordisk Investigational Site

Lexington, Kentucky, United States, 40503

United States, Louisiana

Novo Nordisk Investigational Site

Lake Charles, Louisiana, United States, 70601

Novo Nordisk Investigational Site

Metairie, Louisiana, United States, 70002

United States, Maryland

Novo Nordisk Investigational Site

Baltimore, Maryland, United States, 21239

Novo Nordisk Investigational Site

Hyattsville, Maryland, United States, 20782

United States, Michigan

Novo Nordisk Investigational Site

Detroit, Michigan, United States, 48202

Novo Nordisk Investigational Site

Flint, Michigan, United States, 48504

Novo Nordisk Investigational Site

Flint, Michigan, United States, 48532

Novo Nordisk Investigational Site

Sterling Heights, Michigan, United States, 48310-3503

Novo Nordisk Investigational Site

Troy, Michigan, United States, 48098

United States, New Jersey

Novo Nordisk Investigational Site

Trenton, New Jersey, United States, 08611

United States, New York

Novo Nordisk Investigational Site

Brooklyn, New York, United States, 11229

Novo Nordisk Investigational Site

New Windsor, New York, United States, 12553

United States, North Carolina

Novo Nordisk Investigational Site

Greensboro, North Carolina, United States, 27408

United States, Ohio

Novo Nordisk Investigational Site

Cincinnati, Ohio, United States, 45212

Novo Nordisk Investigational Site

Maumee, Ohio, United States, 43537

Novo Nordisk Investigational Site

Toledo, Ohio, United States, 43614

Novo Nordisk Investigational Site

Toledo, Ohio, United States, 43623

United States, Oregon

Novo Nordisk Investigational Site

Corvallis, Oregon, United States, 97330-3737

United States, South Carolina

Novo Nordisk Investigational Site

Anderson, South Carolina, United States, 29621

United States, Texas

Novo Nordisk Investigational Site

Amarillo, Texas, United States, 79106

Novo Nordisk Investigational Site

Corpus Christi, Texas, United States, 78404

Novo Nordisk Investigational Site

Corpus Christi, Texas, United States, 78413

Novo Nordisk Investigational Site

Dallas, Texas, United States, 75230

Novo Nordisk Investigational Site

Dallas, Texas, United States, 75251

Novo Nordisk Investigational Site

Dallas, Texas, United States, 75390-9302

Novo Nordisk Investigational Site

Houston, Texas, United States, 77058

Novo Nordisk Investigational Site

Houston, Texas, United States, 77074

Novo Nordisk Investigational Site

Houston, Texas, United States, 77081

Novo Nordisk Investigational Site

Katy, Texas, United States, 77450

Novo Nordisk Investigational Site

San Antonio, Texas, United States, 78230

Novo Nordisk Investigational Site

Splendora, Texas, United States, 77372

United States, Utah

Novo Nordisk Investigational Site

Saint George, Utah, United States, 84790

United States, Virginia

Novo Nordisk Investigational Site

Herndon, Virginia, United States, 20171

United States, Washington

Novo Nordisk Investigational Site

Olympia, Washington, United States, 98502

Novo Nordisk Investigational Site

Wenatchee, Washington, United States, 98801-2028

Argentina

Novo Nordisk Investigational Site

Buenos Aires, Argentina, C1250AAN

Novo Nordisk Investigational Site

Caba, Argentina, C1093AAS

Novo Nordisk Investigational Site

Caba, Argentina, C1430CKE

Novo Nordisk Investigational Site

Rosario, Argentina, S2000CUD

Novo Nordisk Investigational Site

Salta, Argentina, 4400

Brazil

Novo Nordisk Investigational Site

Porto Alegre, Brazil, 90035-170

Novo Nordisk Investigational Site

Rio de Janeiro, Brazil, 22271-100

Canada, British Columbia

Novo Nordisk Investigational Site

Surrey, British Columbia, Canada, V3S 2N6

Canada, Ontario

Novo Nordisk Investigational Site

Brampton, Ontario, Canada, L6T 0G1

Novo Nordisk Investigational Site

Burlington, Ontario, Canada, L7M 4Y1

Novo Nordisk Investigational Site

London, Ontario, Canada, N5W 6A2

Novo Nordisk Investigational Site

Sarnia, Ontario, Canada, N7T 4X3

Novo Nordisk Investigational Site

Toronto, Ontario, Canada, M9V 4B4

Canada, Quebec

Novo Nordisk Investigational Site

Pointe Claire, Quebec, Canada, H9R 4S3

Novo Nordisk Investigational Site

Pointe-Claire, Quebec, Canada, H9R 3J1

India

Novo Nordisk Investigational Site

Hyderabad, Andhra Pradesh, India, 500034

Novo Nordisk Investigational Site

Rohtak, Haryana, India, 124001

Novo Nordisk Investigational Site

Bangalore, Karnataka, India, 560054

Novo Nordisk Investigational Site

Kochi, Kerala, India, 682041

Novo Nordisk Investigational Site

Mumbai, Maharashtra, India, 400008

Novo Nordisk Investigational Site

Nagpur, Maharashtra, India, 440008

Novo Nordisk Investigational Site

Jaipur, Rajasthan, India, 302006

Novo Nordisk Investigational Site

Chennai, Tamil Nadu, India, 600 013

Novo Nordisk Investigational Site

Chennai, Tamil Nadu, India, 600001

Novo Nordisk Investigational Site

Kolkata, West Bengal, India, 700020

Novo Nordisk Investigational Site

Kolkata, West Bengal, India, 700054

Ireland

Novo Nordisk Investigational Site

Dublin, Ireland, DUBLIN 15

Novo Nordisk Investigational Site

Dublin, Ireland, DUBLIN 4

Novo Nordisk Investigational Site

Dublin, Ireland, DUBLIN 7

Novo Nordisk Investigational Site

Galway, Ireland, H91 YR71

Novo Nordisk Investigational Site

Mallow, Ireland, P51Y8EC

Italy

Novo Nordisk Investigational Site

Milano, Italy, 20100

Lebanon

Novo Nordisk Investigational Site

Achrafieh, Lebanon

Novo Nordisk Investigational Site

Hazmieh, Lebanon

Novo Nordisk Investigational Site

Lebanon - Beirut, Lebanon, 9611

Novo Nordisk Investigational Site

Mansourieh, Lebanon

Novo Nordisk Investigational Site

Zgharta, Lebanon, 9616

Malaysia

Novo Nordisk Investigational Site

Alor Gajah, Malaysia, 78300

Novo Nordisk Investigational Site

Ipoh, Malaysia, 30450

Novo Nordisk Investigational Site

Melaka, Malaysia, 75400

Novo Nordisk Investigational Site

Penang, Malaysia, 10450

Novo Nordisk Investigational Site

Sandakan, Malaysia, 90000

Novo Nordisk Investigational Site

Seremban, Malaysia, 70300

Mexico

Novo Nordisk Investigational Site

Cuernavaca, Morelos, Mexico, 62250

Novo Nordisk Investigational Site

Mexico City, México, D.F., Mexico, 02230

Novo Nordisk Investigational Site

Monterrey, Nuevo León, Mexico, 64620

Sweden

Novo Nordisk Investigational Site

Eksjö, Sweden, 575 35

Novo Nordisk Investigational Site

Kristianstad, Sweden, 291 85

Novo Nordisk Investigational Site

Lund, Sweden, 221 85

Novo Nordisk Investigational Site

Malmö, Sweden, 205 02

Novo Nordisk Investigational Site

Örebro, Sweden, 701 85

United Kingdom

Novo Nordisk Investigational Site

Basingstoke, United Kingdom, RG24 9GT

Novo Nordisk Investigational Site

Bradford-on-Avon, United Kingdom, BA15 1DQ

Novo Nordisk Investigational Site

Dundee, United Kingdom, DD1 9SY

Novo Nordisk Investigational Site

Haxey, United Kingdom, DN9 2HY

Novo Nordisk Investigational Site

Nottingham, United Kingdom, NG7 2UH

Novo Nordisk Investigational Site

Plymouth, United Kingdom, PL8 8DQ

Novo Nordisk Investigational Site

Soham, United Kingdom, CB7 5JD

Novo Nordisk Investigational Site

Southampton, United Kingdom, SO30 3JB

Novo Nordisk Investigational Site

Stevenage, United Kingdom, SG1 4AB

Novo Nordisk Investigational Site

Torquay, United Kingdom, TQ2 7AA

Novo Nordisk Investigational Site

Wellingborough, United Kingdom, NN8 4RW

Sponsors and Collaborators

Novo Nordisk A/S

  Study Documents (Full-Text)

Documents provided by Novo Nordisk A/S:

Study Protocol  [PDF] June 3, 2019

Statistical Analysis Plan  [PDF] June 3, 2019

More Information

Publications of Results:

Lingvay I, Catarig AM, Frias JP, Kumar H, Lausvig NL, le Roux CW, Thielke D, Viljoen A, McCrimmon RJ. Efficacy and safety of once-weekly semaglutide versus daily canagliflozin as add-on to metformin in patients with type 2 diabetes (SUSTAIN 8): a double-blind, phase 3b, randomised controlled trial. Lancet Diabetes Endocrinol. 2019 Nov;7(11):834-844. doi: 10.1016/S2213-8587(19)30311-0. Epub 2019 Sep 17.

McCrimmon RJ, Catarig AM, Frias JP, Lausvig NL, le Roux CW, Thielke D, Lingvay I. Effects of once-weekly semaglutide vs once-daily canagliflozin on body composition in type 2 diabetes: a substudy of the SUSTAIN 8 randomised controlled clinical trial. Diabetologia. 2020 Mar;63(3):473-485. doi: 10.1007/s00125-019-05065-8. Epub 2020 Jan 2.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Lingvay I, Capehorn MS, Catarig AM, Johansen P, Lawson J, Sandberg A, Shaw R, Paine A. Efficacy of Once-Weekly Semaglutide vs Empagliflozin Added to Metformin in Type 2 Diabetes: Patient-Level Meta-analysis. J Clin Endocrinol Metab. 2020 Dec 1;105(12):e4593-604. doi: 10.1210/clinem/dgaa577.

• Responsible Party: Novo Nordisk A/S
• ClinicalTrials.gov Identifier: NCT03136484
• Other Study ID Numbers: NN9535-4270; 2016-000989-35 ( EudraCT Number ); U1111-1180-3651 ( Other Identifier: World Health Organization (WHO) )
• First Posted: May 2, 2017
• Results First Posted: December 17, 2019
• Last Update Posted: January 21, 2020
• Last Verified: January 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: According to the Novo Nordisk disclosure commitment on novonordisk-trials.com

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Canagliflozin; Sodium-Glucose Transporter 2 Inhibitors; Molecular Mechanisms of Pharmacological Action; Hypoglycemic Agents; Physiological Effects of Drugs