Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted in Europe and North and South America. The aim of the trial is to investigate the efficacy and safety of semaglutide once-weekly versus exenatide ER (extended release) 2.0 mg once-weekly as add-on to 1-2 oral antidiabetic drugs (OADs) in subjects with type 2 diabetes.
Interventions
DRUGsemaglutide
One dose of 1.0 mg semaglutide administered subcutaneously (s.c., under the skin) once-weekly
DRUGexenatide
One dose of 2.0 mg exenatide ER administered subcutaneously (s.c., under the skin) once-weekly
Sponsors
Novo Nordisk A/S
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
- Subjects diagnosed with type 2 diabetes and on stable diabetes treatment with 1-2 OADs (Metformin equal to or above 1500 mg or maximum tolerated dose and/or thiazolidinedione (TZD) and sulfonylureas (SUs) equal to or above half of maximum dose allowed according to national label) for at least 90 days prior to screening. Stable is defined as unchanged medication and unchanged dose - HbA1c 7.0 - 10.5 % (53 - 91 mmol/mol) (both inclusive)
Exclusion criteria
- Females of childbearing potential who are pregnant, breast-feeding or intend to become pregnant or are not using an adequate contraceptive method throughout the trial including the 5 week follow-up period (adequate contraceptive measures as required by local law or practice) - Any chronic disorder or severe disease which, in the opinion of the investigator, might jeopardise subject's safety or compliance with the protocol - Treatment with glucose lowering agent(s) other than stated in the inclusion criteria in a period of 90 days before screening. An exception is short-term treatment (7 days or less in total) with insulin in connection with inter-current illness - History of chronic or idiopathic acute pancreatitis - Screening calcitonin value equal to or above 50 ng/L (pg/mL) - Personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2 (MEN 2) - Impaired renal function defined as estimated glomerular filtration rate (eGFR) below 60 ml/min/1.73 m\^2 per modification of diet in renal disease (MDRD) formula (4 variable version) - Acute coronary or cerebrovascular event within 90 days before randomisation - Heart failure, New York Heart Association (NYHA) class IV
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in HbA1c (Glycosylated Haemoglobin) | Week 0, week 56 | Mean change in HbA1c from baseline to week 56. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Body Weight | Week 0, week 56 | Mean change in body weight from baseline to week 56. |
| Change From Baseline in Fasting Plasma Glucose (FPG) | Week 0, week 56 | Mean change in FPG from baseline to week 56. |
| Change From Baseline in Systolic and Diastolic Blood Pressure | Week 0, week 56 | Mean changes in systolic and diastolic blood pressure from baseline to week 56. |
| Change From Baseline in Patient Reported Outcome (PRO) Questionnaire Diabetes Treatment Satisfaction Questionnaire Status (DTSQs) | Week 0, week 56 | The Diabetes Treatment Satisfaction Questionnaire (DTSQs) was used to assess a subject's treatment satisfaction. This questionnaire contained 8 components and measures the treatment for diabetes (including insulin, tablets and/or diet) in terms of convenience, flexibility and general feelings regarding treatment. The value presented is the 'Treatment Satisfaction' summary score, which is the sum of 6 of the 8 items of the DTSQs questionnaire. Response options range from 6 (best case) to 0 (worst case). Total scores for treatment satisfaction range from 0-36. Higher scores indicate higher satisfaction. |
| Subjects Who Achieve HbA1c Equal to or Below 6.5% (48 mmol/Mol) American Association of Clinical Endocrinologists (AACE) Target: (Yes/no) | After 56 weeks' treatment | The endpoint considered HbA1c ≤6.5% (48 mmol/mol) as per the AACE target after 56 weeks of treatment. |
Countries
Argentina, Croatia, Finland, France, Germany, Greece, Italy, Netherlands, Puerto Rico, Serbia, Switzerland, United Kingdom, United States
Participant flow
Recruitment details
Out of 146 sites selected for recruitment, 138 sites in 12 countries randomised subjects to the treatment viz. Argentina: 4 sites; Croatia: 5 sites; Finland: 5 sites; France: 7 sites; Germany: 7 sites; Greece: 5 sites; Italy: 6 sites; Netherlands: 8 sites; Serbia: 5 sites; Switzerland: 5 sites; United Kingdom: 6 sites and United States: 75 sites
Participants by arm
| Arm | Count |
|---|---|
| Semaglutide 1.0 mg Subjects randomised to semaglutide followed a fixed dose-escalation regimen for a period of 56 weeks. Subjects started with once-weekly doses of 0.25 mg for 4 weeks, then escalated to doses of 0.5 mg once weekly for 4 weeks, and finally escalated to 1.0 mg once weekly (maximum dose). Doses were not changed during the trial after the maintenance dose was reached. Semaglutide 1.34 mg/mL was supplied in a 1.5 mL pre-filled PDS290 pen-injector and was to be administered subcutaneously (s.c.; under the skin) either in the thigh, abdomen or upper arm at the same weekday. All subjects continued their pre-trial treatment of 1-2 oral anti-diabetes drug (OAD) therapy throughout the trial, unless rescue medication was needed. | 404 |
| Exenatide ER 2.0 mg Subjects randomised to exenatide extended release (ER) 2.0 mg (Bydureon®) were treated with the same 2.0 mg dose for a period of 56 weeks. Exenatide one vial of 2 mg exenatide ER was supplied in a pre-filled syringe of 0.65 mL solvent and to be administrated subcutaneously (s.c.; under the skin) once weekly through out the trial. All subjects continued their pre-trial treatment of 1-2 OAD therapy entire trial, unless rescue medication was needed. | 405 |
| Total | 809 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Unclassified | 32 | 38 |
Baseline characteristics
| Characteristic | Semaglutide 1.0 mg | Exenatide ER 2.0 mg | Total |
|---|---|---|---|
| Age, Continuous | 56.4 years STANDARD_DEVIATION 10.3 | 56.7 years STANDARD_DEVIATION 11.1 | 56.6 years STANDARD_DEVIATION 10.7 |
| Body Weight | 96.21 kilogram (s) STANDARD_DEVIATION 22.5 | 95.37 kilogram (s) STANDARD_DEVIATION 20.46 | 95.79 kilogram (s) STANDARD_DEVIATION 21.49 |
| Diastolic blood pressure | 80.23 mm Hg STANDARD_DEVIATION 8.67 | 79.57 mm Hg STANDARD_DEVIATION 8.8 | 79.90 mm Hg STANDARD_DEVIATION 8.73 |
| Fasting Plasma Glucose | 190.5 mg/ dL STANDARD_DEVIATION 48.06 | 187.5 mg/ dL STANDARD_DEVIATION 49.41 | 189.0 mg/ dL STANDARD_DEVIATION 48.74 |
| Glycosylated haemoglobin (HbA1c) | 8.36 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.95 | 8.33 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.96 | 8.35 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.95 |
| Patient-reported outcome: Diabetes Treatment Satisfaction Questionnaire (DTSQ) | 27.35 Units on a scale STANDARD_DEVIATION 6.55 | 27.23 Units on a scale STANDARD_DEVIATION 6.62 | 27.29 Units on a scale STANDARD_DEVIATION 6.58 |
| Sex: Female, Male Female | 185 Participants | 177 Participants | 362 Participants |
| Sex: Female, Male Male | 219 Participants | 228 Participants | 447 Participants |
| Systolic blood pressure | 133.35 mm Hg STANDARD_DEVIATION 14.87 | 133.66 mm Hg STANDARD_DEVIATION 14.25 | 133.51 mm Hg STANDARD_DEVIATION 14.55 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 194 / 404 | 187 / 405 |
| serious Total, serious adverse events | 38 / 404 | 24 / 405 |
Outcome results
Primary
Change From Baseline in HbA1c (Glycosylated Haemoglobin)
Mean change in HbA1c from baseline to week 56.
Time frame: Week 0, week 56
Population: The full analysis set (FAS) included all randomised subjects who had received at least one dose of randomised semaglutide 1.0 mg or exenatide ER 2.0 mg.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Semaglutide 1.0 mg | Change From Baseline in HbA1c (Glycosylated Haemoglobin) | -1.54 percentage of glycosylated haemoglobin | Standard Error 0.06 |
| Exenatide ER 2.0 mg | Change From Baseline in HbA1c (Glycosylated Haemoglobin) | -0.92 percentage of glycosylated haemoglobin | Standard Error 0.06 |
Comparison: The post-baseline responses were analysed using a mixed model for repeated measurements with treatment and country as fixed factors and baseline value as covariate, all nested within visit.p-value: <0.000195% CI: [-0.8, -0.44]Mixed Models Analysis
Comparison: The post-baseline responses were analysed using a mixed model for repeated measurements with treatment and country as fixed factors and baseline value as covariate, all nested within visit.p-value: <0.000195% CI: [-0.8, -0.44]Mixed Models Analysis
Secondary
Change From Baseline in Body Weight
Mean change in body weight from baseline to week 56.
Time frame: Week 0, week 56
Population: The full analysis set (FAS) included all randomised subjects who had received at least one dose of randomised semaglutide 1.0 mg or exenatide ER 2.0 mg.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Semaglutide 1.0 mg | Change From Baseline in Body Weight | -5.63 kilograms | Standard Error 0.29 |
| Exenatide ER 2.0 mg | Change From Baseline in Body Weight | -1.85 kilograms | Standard Error 0.29 |
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG)
Mean change in FPG from baseline to week 56.
Time frame: Week 0, week 56
Population: The full analysis set (FAS) included all randomised subjects who had received at least one dose of randomised semaglutide 1.0 mg or exenatide ER 2.0 mg.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Semaglutide 1.0 mg | Change From Baseline in Fasting Plasma Glucose (FPG) | -51.22 mg/dL | Standard Error 2.36 |
| Exenatide ER 2.0 mg | Change From Baseline in Fasting Plasma Glucose (FPG) | -36.1 mg/dL | Standard Error 2.45 |
Secondary
Change From Baseline in Patient Reported Outcome (PRO) Questionnaire Diabetes Treatment Satisfaction Questionnaire Status (DTSQs)
The Diabetes Treatment Satisfaction Questionnaire (DTSQs) was used to assess a subject's treatment satisfaction. This questionnaire contained 8 components and measures the treatment for diabetes (including insulin, tablets and/or diet) in terms of convenience, flexibility and general feelings regarding treatment. The value presented is the 'Treatment Satisfaction' summary score, which is the sum of 6 of the 8 items of the DTSQs questionnaire. Response options range from 6 (best case) to 0 (worst case). Total scores for treatment satisfaction range from 0-36. Higher scores indicate higher satisfaction.
Time frame: Week 0, week 56
Population: The full analysis set (FAS) included all randomised subjects who had received at least one dose of randomised semaglutide 1.0 mg or exenatide ER 2.0 mg.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Semaglutide 1.0 mg | Change From Baseline in Patient Reported Outcome (PRO) Questionnaire Diabetes Treatment Satisfaction Questionnaire Status (DTSQs) | 4.98 Units on a scale | Standard Error 0.26 |
| Exenatide ER 2.0 mg | Change From Baseline in Patient Reported Outcome (PRO) Questionnaire Diabetes Treatment Satisfaction Questionnaire Status (DTSQs) | 3.96 Units on a scale | Standard Error 0.27 |
Secondary
Change From Baseline in Systolic and Diastolic Blood Pressure
Mean changes in systolic and diastolic blood pressure from baseline to week 56.
Time frame: Week 0, week 56
Population: The full analysis set (FAS) included all randomised subjects who had received at least one dose of randomised semaglutide 1.0 mg or exenatide ER 2.0 mg.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Semaglutide 1.0 mg | Change From Baseline in Systolic and Diastolic Blood Pressure | Diastolic blood pressure | -1.0 mm Hg | Standard Error 0.45 |
| Semaglutide 1.0 mg | Change From Baseline in Systolic and Diastolic Blood Pressure | Systolic blood pressure | -4.6 mm Hg | Standard Error 0.68 |
| Exenatide ER 2.0 mg | Change From Baseline in Systolic and Diastolic Blood Pressure | Systolic blood pressure | -2.23 mm Hg | Standard Error 0.7 |
| Exenatide ER 2.0 mg | Change From Baseline in Systolic and Diastolic Blood Pressure | Diastolic blood pressure | -0.1 mm Hg | Standard Error 0.46 |
Secondary
Subjects Who Achieve HbA1c Equal to or Below 6.5% (48 mmol/Mol) American Association of Clinical Endocrinologists (AACE) Target: (Yes/no)
The endpoint considered HbA1c ≤6.5% (48 mmol/mol) as per the AACE target after 56 weeks of treatment.
Time frame: After 56 weeks' treatment
Population: The full analysis set (FAS) included all randomised subjects who had received at least one dose of randomised semaglutide 1.0 mg or exenatide ER 2.0 mg.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Semaglutide 1.0 mg | Subjects Who Achieve HbA1c Equal to or Below 6.5% (48 mmol/Mol) American Association of Clinical Endocrinologists (AACE) Target: (Yes/no) | Yes | 190 Participants |
| Semaglutide 1.0 mg | Subjects Who Achieve HbA1c Equal to or Below 6.5% (48 mmol/Mol) American Association of Clinical Endocrinologists (AACE) Target: (Yes/no) | No | 214 Participants |
| Exenatide ER 2.0 mg | Subjects Who Achieve HbA1c Equal to or Below 6.5% (48 mmol/Mol) American Association of Clinical Endocrinologists (AACE) Target: (Yes/no) | Yes | 89 Participants |
| Exenatide ER 2.0 mg | Subjects Who Achieve HbA1c Equal to or Below 6.5% (48 mmol/Mol) American Association of Clinical Endocrinologists (AACE) Target: (Yes/no) | No | 316 Participants |