Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted in Africa, Asia, Europe and South America. The aim of the trial is to evaluate efficacy and safety of semaglutide once-weekly versus sitagliptin once-daily as add-on to metformin and/or TZD (thiazolidinedione) in subjects with type 2 diabetes.
Interventions
DRUGsemaglutide
For subcutaneous injection (s.c., under the skin) once weekly. Will follow a fixed dose escalation regimen. The trial drug will be added on to the subject's stable pre-trial medication.
DRUGsitagliptin
Tablets for oral administration once daily. The trial drug will be added on to the subject's stable pre-trial medication.
DRUGplacebo
Tablets for oral administration once daily. The trial drug will be added on to the subject's stable pre-trial medication.
Sponsors
Novo Nordisk A/S
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
- Japan: Age minimum 20 years - Subjects diagnosed with type 2 diabetes and on stable treatment in a period of 90 days prior to screening with either metformin above or equal to 1500 mg (or maximum tolerated dose), pioglitazone above or equal to 30 mg (or maximum tolerated dose), rosiglitazone above or equal to 4 mg (or maximum tolerated dose) or a combination of either metformin/pioglitazone or metformin/rosiglitazone (doses as for individual therapies). 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 weeks 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 (below or equal to 7 days in total) with insulin in connection with inter-current illness - History of chronic or idiopathic acute pancreatitis - Screening calcitonin value above or equal to 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 m2 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 in HbA1c (Glycosylated Haemoglobin) From Baseline | Week 0, week 56 | Change in HbA1c from baseline until week 56.Full analysis set (FAS=1225) included all randomised subjects who had received at least one dose of randomised semaglutide or sitagliptin. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Body Weight From Baseline | Week 0, week 56 | Change in body weight from baseline to week 56. Full analysis set (FAS=1225) included all randomised subjects who had received at least one dose of semaglutide or sitagliptin. |
| Change in Fasting Plasma Glucose (FPG) From Baseline | Week 0, week 56 | Change in fasting plasma glucose from baseline to week 56. Full analysis set (FAS=1225) included all randomised subjects who had received at least one dose of semaglutide or sitagliptin. |
| Change in Systolic and Diastolic Blood Pressure From Baseline | Week 0, week 56 | Change in systolic and diastolic blood pressure from baseline to week 56. Full analysis set (FAS=1225) included all randomised subjects who had received at least one dose of semaglutide or sitagliptin |
| Change in Patient Reported Outcome (PRO) Questionnaire Diabetes Treatment Satisfaction Questionnaire Status (DTSQs) From Baseline | Week 0, week 56 | Full analysis set (FAS=1225) included all randomised subjects who had received at least one dose of semaglutide or sitagliptin. The DTSQs questionnaire was used to assess subjects' treatment satisfaction. This questionnaire contained 8 components and evaluates the diabetes treatment (including insulin, tablets and/or diet) in terms of convenience, flexibility and general feelings towards the treatment. The result 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 Achieved HbA1c Below or Equal to 6.5% (48 mmol/Mol) American Association of Clinical Endocrinologists (AACE) Target (Yes/no) | After 56 weeks treatment | Subjects who achieved HbA1c ≤6.5% (48 mmol/mol) American Association of Clinical Endocrinologists (AACE) target (yes/no) after week 56 weeks of treatment. |
Countries
Argentina, Bulgaria, Czechia, Hong Kong, Hungary, India, Japan, Mexico, Norway, Portugal, Romania, Russia, South Africa, Spain, Sweden, Thailand, Turkey (Türkiye), Ukraine
Participant flow
Recruitment details
The trial was conducted at 124 sites in 18 countries: Argentina: 4; Bulgaria: 10; Czech Republic: 5; Hong Kong: 1; Hungary: 4; India: 11; Japan: 14; Mexico: 5 Norway: 5; Portugal: 6; Romania: 5; Russian Federation: 17; South Africa: 7; Spain: 7: Sweden: 4; Thailand: 4; Turkey: 9; and Ukraine: 6 sites.
Participants by arm
| Arm | Count |
|---|---|
| Semaglutide 0.5 mg + Sitagliptin Placebo Semaglutide 0.5 mg administered subcutaneously (s.c., under the skin) once weekly, in the thigh, abdomen, or upper arm, at any time of day irrespective of meals. Sitagliptin placebo (0 mg) administered orally once daily. | 409 |
| Semaglutide 1.0 mg + Sitagliptin Placebo Semaglutide 1.0 mg administered subcutaneously (s.c., under the skin) once weekly, in the thigh, abdomen, or upper arm, at any time of day irrespective of meals. Sitagliptin placebo (0 mg) administered orally once daily. | 409 |
| Sitagliptin + Semaglutide Placebo Subjects were randomised to 2 different placebo arms (sitagliptin + semaglutide placebo 0.5 mg and sitagliptin + semaglutide placebo 1.0 mg). Both arms were pooled together for data analysis. Semaglutide placebo administered subcutaneously (s.c., under the skin) once weekly, in the thigh, abdomen, or upper arm, at any time of day irrespective of meals. Sitagliptin (100 mg) administered orally once daily. | 407 |
| Total | 1,225 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 2 | 1 | 3 |
| Overall Study | Lost to Follow-up | 5 | 2 | 2 |
| Overall Study | Missing follow-up information | 2 | 2 | 3 |
| Overall Study | unclassified | 4 | 5 | 3 |
| Overall Study | Withdrawal by Subject | 9 | 11 | 8 |
Baseline characteristics
| Characteristic | Semaglutide 0.5 mg + Sitagliptin Placebo | Semaglutide 1.0 mg + Sitagliptin Placebo | Sitagliptin + Semaglutide Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 54.8 years STANDARD_DEVIATION 10.2 | 56.0 years STANDARD_DEVIATION 9.4 | 54.6 years STANDARD_DEVIATION 10.4 | 55.1 years STANDARD_DEVIATION 10 |
| Body Weight | 89.93 kilograms STANDARD_DEVIATION 20.39 | 89.21 kilograms STANDARD_DEVIATION 20.74 | 89.29 kilograms STANDARD_DEVIATION 19.67 | 89.48 kilograms STANDARD_DEVIATION 20.26 |
| Diastolic and Systolic Blood Pressure Diastolic Blood pressure | 80.63 mmHg STANDARD_DEVIATION 9.76 | 80.87 mmHg STANDARD_DEVIATION 9.08 | 80.48 mmHg STANDARD_DEVIATION 8.7 | 80.66 mmHg STANDARD_DEVIATION 9.19 |
| Diastolic and Systolic Blood Pressure Systolic Blood pressure | 132.73 mmHg STANDARD_DEVIATION 16.09 | 132.56 mmHg STANDARD_DEVIATION 13.93 | 132.66 mmHg STANDARD_DEVIATION 14.58 | 132.65 mmHg STANDARD_DEVIATION 14.88 |
| Fasting Plasma Glucose | 9.33 mmol/L STANDARD_DEVIATION 2.38 | 9.29 mmol/L STANDARD_DEVIATION 2.22 | 9.60 mmol/L STANDARD_DEVIATION 2.16 | 9.40 mmol/L STANDARD_DEVIATION 2.26 |
| HbA1c | 8.01 percentage STANDARD_DEVIATION 0.92 | 8.04 percentage STANDARD_DEVIATION 0.93 | 8.17 percentage STANDARD_DEVIATION 0.92 | 8.07 percentage STANDARD_DEVIATION 0.93 |
| Sex: Female, Male Female | 202 Participants | 204 Participants | 199 Participants | 605 Participants |
| Sex: Female, Male Male | 207 Participants | 205 Participants | 208 Participants | 620 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 197 / 409 | 208 / 409 | 75 / 204 | 85 / 203 |
| serious Total, serious adverse events | 30 / 409 | 30 / 409 | 13 / 204 | 16 / 203 |
Outcome results
Primary
Change in HbA1c (Glycosylated Haemoglobin) From Baseline
Change in HbA1c from baseline until week 56.Full analysis set (FAS=1225) included all randomised subjects who had received at least one dose of randomised semaglutide or sitagliptin.
Time frame: Week 0, week 56
Population: Missing data imputed from a mixed model for repeated measurements for treatment and country as fixed factors and baseline value as covariate, all nested within visit.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Semaglutide 0.5 mg + Sitagliptin Placebo | Change in HbA1c (Glycosylated Haemoglobin) From Baseline | -1.32 percentage of glycosylated haemoglobin | Standard Error 0.05 |
| Semaglutide 1.0 mg + Sitagliptin Placebo | Change in HbA1c (Glycosylated Haemoglobin) From Baseline | -1.61 percentage of glycosylated haemoglobin | Standard Error 0.05 |
| Sitagliptin + Semaglutide Placebo | Change in HbA1c (Glycosylated Haemoglobin) From Baseline | -0.55 percentage of glycosylated haemoglobin | Standard Error 0.05 |
p-value: <0.000195% CI: [-1.21, -0.91]Mixed Models Analysis
p-value: <0.000195% CI: [-1.21, -0.62]Mixed Models Analysis
Secondary
Change in Body Weight From Baseline
Change in body weight from baseline to week 56. Full analysis set (FAS=1225) included all randomised subjects who had received at least one dose of semaglutide or sitagliptin.
Time frame: Week 0, week 56
Population: Missing data imputed from a mixed model for repeated measurements for treatment and country as fixed factors and baseline value as covariate, all nested within visit.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Semaglutide 0.5 mg + Sitagliptin Placebo | Change in Body Weight From Baseline | -4.28 kilograms | Standard Error 0.25 |
| Semaglutide 1.0 mg + Sitagliptin Placebo | Change in Body Weight From Baseline | -6.13 kilograms | Standard Error 0.25 |
| Sitagliptin + Semaglutide Placebo | Change in Body Weight From Baseline | -1.93 kilograms | Standard Error 0.26 |
Secondary
Change in Fasting Plasma Glucose (FPG) From Baseline
Change in fasting plasma glucose from baseline to week 56. Full analysis set (FAS=1225) included all randomised subjects who had received at least one dose of semaglutide or sitagliptin.
Time frame: Week 0, week 56
Population: Missing data imputed from a mixed model for repeated measurements for treatment and country as fixed factors and baseline value as covariate, all nested within visit
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Semaglutide 0.5 mg + Sitagliptin Placebo | Change in Fasting Plasma Glucose (FPG) From Baseline | -37.38 mg/dL | Standard Error 1.79 |
| Semaglutide 1.0 mg + Sitagliptin Placebo | Change in Fasting Plasma Glucose (FPG) From Baseline | -46.72 mg/dL | Standard Error 1.78 |
| Sitagliptin + Semaglutide Placebo | Change in Fasting Plasma Glucose (FPG) From Baseline | -19.85 mg/dL | Standard Error 1.88 |
Secondary
Change in Patient Reported Outcome (PRO) Questionnaire Diabetes Treatment Satisfaction Questionnaire Status (DTSQs) From Baseline
Full analysis set (FAS=1225) included all randomised subjects who had received at least one dose of semaglutide or sitagliptin. The DTSQs questionnaire was used to assess subjects' treatment satisfaction. This questionnaire contained 8 components and evaluates the diabetes treatment (including insulin, tablets and/or diet) in terms of convenience, flexibility and general feelings towards the treatment. The result 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: Out of the 1225 subjects in FAS, 76 in semaglutide 0.5 mg arm, 76 in semaglutide 1.0 mg arm, and 113 in placebo arm had missing data for the endpoint. Missing data imputed from a mixed model for repeated measurements for treatment and country as fixed factors and baseline value as covariate, all nested within visit.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Semaglutide 0.5 mg + Sitagliptin Placebo | Change in Patient Reported Outcome (PRO) Questionnaire Diabetes Treatment Satisfaction Questionnaire Status (DTSQs) From Baseline | 5.28 Units on a scale | Standard Error 0.23 |
| Semaglutide 1.0 mg + Sitagliptin Placebo | Change in Patient Reported Outcome (PRO) Questionnaire Diabetes Treatment Satisfaction Questionnaire Status (DTSQs) From Baseline | 5.91 Units on a scale | Standard Error 0.23 |
| Sitagliptin + Semaglutide Placebo | Change in Patient Reported Outcome (PRO) Questionnaire Diabetes Treatment Satisfaction Questionnaire Status (DTSQs) From Baseline | 4.45 Units on a scale | Standard Error 0.24 |
Secondary
Change in Systolic and Diastolic Blood Pressure From Baseline
Change in systolic and diastolic blood pressure from baseline to week 56. Full analysis set (FAS=1225) included all randomised subjects who had received at least one dose of semaglutide or sitagliptin
Time frame: Week 0, week 56
Population: Missing data imputed from a mixed model for repeated measurements for treatment and country as fixed factors and baseline value as covariate, all nested within visit
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Semaglutide 0.5 mg + Sitagliptin Placebo | Change in Systolic and Diastolic Blood Pressure From Baseline | Systolic blood pressure | -5.07 mmHg | Standard Error 0.64 |
| Semaglutide 0.5 mg + Sitagliptin Placebo | Change in Systolic and Diastolic Blood Pressure From Baseline | Diastolic blood pressure | -2.01 mmHg | Standard Error 0.42 |
| Semaglutide 1.0 mg + Sitagliptin Placebo | Change in Systolic and Diastolic Blood Pressure From Baseline | Systolic blood pressure | -5.61 mmHg | Standard Error 0.63 |
| Semaglutide 1.0 mg + Sitagliptin Placebo | Change in Systolic and Diastolic Blood Pressure From Baseline | Diastolic blood pressure | -1.91 mmHg | Standard Error 0.42 |
| Sitagliptin + Semaglutide Placebo | Change in Systolic and Diastolic Blood Pressure From Baseline | Systolic blood pressure | -2.29 mmHg | Standard Error 0.67 |
| Sitagliptin + Semaglutide Placebo | Change in Systolic and Diastolic Blood Pressure From Baseline | Diastolic blood pressure | -1.11 mmHg | Standard Error 0.44 |
Secondary
Subjects Who Achieved HbA1c Below or Equal to 6.5% (48 mmol/Mol) American Association of Clinical Endocrinologists (AACE) Target (Yes/no)
Subjects who achieved HbA1c ≤6.5% (48 mmol/mol) American Association of Clinical Endocrinologists (AACE) target (yes/no) after week 56 weeks of treatment.
Time frame: After 56 weeks treatment
Population: Full analysis set (FAS=1225) included all randomised subjects who had received at least one dose of semaglutide or sitagliptin
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Semaglutide 0.5 mg + Sitagliptin Placebo | Subjects Who Achieved HbA1c Below or Equal to 6.5% (48 mmol/Mol) American Association of Clinical Endocrinologists (AACE) Target (Yes/no) | Yes | 215 Subjects |
| Semaglutide 0.5 mg + Sitagliptin Placebo | Subjects Who Achieved HbA1c Below or Equal to 6.5% (48 mmol/Mol) American Association of Clinical Endocrinologists (AACE) Target (Yes/no) | No | 194 Subjects |
| Semaglutide 1.0 mg + Sitagliptin Placebo | Subjects Who Achieved HbA1c Below or Equal to 6.5% (48 mmol/Mol) American Association of Clinical Endocrinologists (AACE) Target (Yes/no) | Yes | 270 Subjects |
| Semaglutide 1.0 mg + Sitagliptin Placebo | Subjects Who Achieved HbA1c Below or Equal to 6.5% (48 mmol/Mol) American Association of Clinical Endocrinologists (AACE) Target (Yes/no) | No | 139 Subjects |
| Sitagliptin + Semaglutide Placebo | Subjects Who Achieved HbA1c Below or Equal to 6.5% (48 mmol/Mol) American Association of Clinical Endocrinologists (AACE) Target (Yes/no) | Yes | 83 Subjects |
| Sitagliptin + Semaglutide Placebo | Subjects Who Achieved HbA1c Below or Equal to 6.5% (48 mmol/Mol) American Association of Clinical Endocrinologists (AACE) Target (Yes/no) | No | 324 Subjects |