Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted in Japan. The purpose is to compare the safety of once-weekly dosing of semaglutide (0.5 and 1.0 mg) versus sitagliptin (100 mg) once daily, both as monotherapy during 30 weeks of treatment in Japanese subjects with type 2 diabetes.
Interventions
DRUGsemaglutide
Once weekly doses of 0.5 mg semaglutide after an initial dose escalation step of 0.25 mg (4 weeks). Total duration of treatment is 30 weeks. Administered subcutaneously (s.c. under the skin).
DRUGsitagliptin
Daily doses of 100 mg sitagliptin. Total duration of treatment is 30 weeks. Administered as oral tablets.
Sponsors
Novo Nordisk A/S
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female, age 20 years or older at the time of signing informed consent * Glycated hemoglobin (HbA1c) between 6.5% and 9.5% (48-80 mmol/mol) (both inclusive) for subjects treated with oral antidiabetic drug (OAD) monotherapy and between 7.0% and 10.5% (53-91 mmol/mol) (both inclusive) for subjects treated with diet and exercise therapy at screening * Japanese subjects diagnosed with type 2 diabetes who are: a) on stable OAD monotherapy at a half-maximum dose or below according to the approved Japanese labelling in addition to diet and exercise therapy for at least 30 days prior to screening (week -8) (For metformin only: the maximum dose of 750 mg/day is allowed except for METGLUCO®. For METGLUCO®, the allowable half-max dose of 1125 mg/day must be applied.). 'Stable' is defined as unchanged medication and unchanged dose, or b) on stable diet and exercise therapy for at least 30 days prior to screening (week -2)
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 (e.g. abstinence, diaphragm, condom \[by the partner\], intrauterine device, sponge, spermicide or oral contraceptives) throughout the trial including the 5-week follow-up period * Treatment with once-weekly glucagon-like peptide-1 (GLP-1) receptor agonists within 90 days prior to screening * Treatment with any glucose lowering agent(s) (except for pre-trial OAD for subject treated with OAD monotherapy) in a period of 60 days prior to screening. An exception is short-term treatment (7 days or less in total) with insulin in connection with inter-current illness * Any disorder which, in the opinion of the investigator, might jeopardise subject's safety or compliance with the protocol * History of chronic or idiopathic acute pancreatitis * Screening calcitonin value of 50 ng/L (pg/mL) or greater * Personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2 (MEN2) * Impaired renal function defined as estimated glomerular filtration rate (eGFR) less than 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 |
|---|---|---|
| Number of Treatment Emergent Adverse Events (TEAEs) | Weeks 0-30 | An adverse events (AEs) was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of a product, whether or not considered related to the product. All AEs mentioned here are treatment emergent adverse events (TEAE) defined as an event that had onset date (or increase in severity) on or after the first day of exposure to randomised treatment (week 0-30 treatment period) and no later than the follow-up visit during the on-treatment observation period (date of last dose + 42 days). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Severe or Blood Glucose (BG) Confirmed Symptomatic Hypoglycaemic Episodes | Weeks 0-30 | Severe or blood glucose (BG) confirmed symptomatic hypoglycaemic episodes were defined as episodes that were severe and/or BG confirmed by a plasma glucose value of \<56 mg/dL (3.1 mmol/L), with symptoms consistent with hypoglycaemia. Severe hypoglycaemia was an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions. The episodes mentioned here are treatment emergent hypoglycaemic episodes and defined as an event that had onset date (or increase in severity) on or after the first day of exposure to randomised treatment (week 0-30 treatment period) and no later than the follow-up visit during the on-treatment observation period (date of last dose + 42 days). |
| Change in Glycosylated Haemoglobin A1c (HbA1c) | Week 0 and week 30 | Mean changes in HbA1c values from baseline after 30 weeks of treatment. Changes in HbA1c were analysed using a mixed model for repeated measurements (MMRM) with treatment and pre-trial treatment at screening as fixed factors and baseline value as covariate. The data were analysed for the on-treatment without rescue medication observation period which includes observations noted at or after the date of first dose of randomised treatment and not after the last dose of the trial product (+ a 7-day visit window) or initiation of rescue medication. |
Countries
Japan
Participant flow
Recruitment details
The trial was conducted at 25 sites in Japan. These sites randomised/assigned subjects to treatment.
Pre-assignment details
Subjects were either on stable diet and exercise therapy only or on stable oral anti-diabetic drug (OAD) monotherapy (a maximum dose of 750 mg metformin or 2250 mg METGLUCO according to approved Japanese labelling) in addition to stable diet and exercise therapy for at least 30 days prior to screening (week -8 or week -2).
Participants by arm
| Arm | Count |
|---|---|
| Semaglutide 0.5 mg Subjects were randomized to receive semaglutide 0.5 mg once weekly subcutaneously (s.c.; under the skin) in the thigh, abdomen, or upper arm for a duration of 30 weeks. Subjects followed a fixed dose escalation pattern to improve tolerability concerns, starting with once-weekly doses of 0.25 mg for 4 weeks (4 doses), then escalated to 0.5 mg once weekly maintenance dose for 26 weeks (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 administered on the same day of every week during the trial. For subjects previously treated with OAD monotherapy, their 8-week pre-trial OAD was washed out before randomisation. All subjects continued their pre-trial treatment of diet and exercise therapy throughout the trial. | 103 |
| Semaglutide 1.0 mg Subjects were randomized to receive semaglutide 1.0 mg once weekly subcutaneously (s.c.; under the skin) in the thigh, abdomen, or upper arm for a duration of 30 weeks. Subjects followed a fixed dose escalation pattern to improve tolerability concerns, starting with once-weekly doses of 0.25 mg for 4 weeks (4 doses), then escalated to 0.5 mg once weekly for 4 weeks, and finally escalated to 1.0 mg once weekly maintenance dose for 22 weeks (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 administered on the same day of every week during the trial. For subjects previously treated with OAD monotherapy, their 8-week pre-trial OAD was washed out before randomisation. All subjects continued their pre-trial treatment of diet and exercise therapy throughout the trial. | 102 |
| Sitagliptin The subjects in this arm received oral fixed dose of sitagliptin 100 mg tablet once daily for a duration of 30 weeks. For subjects previously treated with OAD monotherapy, their pre-trial OAD was washed out before randomisation. Doses of sitagliptin were not changed throughout the trial. All subjects continued their pre-trial treatment of diet and exercise therapy throughout the trial. | 103 |
| Total | 308 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Missing follow-up information | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 3 | 1 |
Baseline characteristics
| Characteristic | Semaglutide 0.5 mg | Semaglutide 1.0 mg | Sitagliptin | Total |
|---|---|---|---|---|
| Age, Continuous | 58.8 years STANDARD_DEVIATION 10.4 | 58.1 years STANDARD_DEVIATION 11.6 | 57.9 years STANDARD_DEVIATION 10.1 | 58.3 years STANDARD_DEVIATION 10.7 |
| Glycosylated haemoglobin (HbA1c) | 8.23 percentage of glycosylated haemoglobin STANDARD_DEVIATION 1.02 | 8.01 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.85 | 8.20 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.89 | 8.15 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.93 |
| Sex: Female, Male Female | 24 Participants | 27 Participants | 22 Participants | 73 Participants |
| Sex: Female, Male Male | 79 Participants | 75 Participants | 81 Participants | 235 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 53 / 103 | 46 / 102 | 36 / 103 |
| serious Total, serious adverse events | 6 / 103 | 2 / 102 | 2 / 103 |
Outcome results
Primary
Number of Treatment Emergent Adverse Events (TEAEs)
An adverse events (AEs) was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of a product, whether or not considered related to the product. All AEs mentioned here are treatment emergent adverse events (TEAE) defined as an event that had onset date (or increase in severity) on or after the first day of exposure to randomised treatment (week 0-30 treatment period) and no later than the follow-up visit during the on-treatment observation period (date of last dose + 42 days).
Time frame: Weeks 0-30
Population: The safety analysis set (SAS) included all subjects receiving at least one dose of trial product and subjects contributed to the evaluation as treated.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Semaglutide 0.5 mg | Number of Treatment Emergent Adverse Events (TEAEs) | 228 Number of events |
| Semaglutide 1.0 mg | Number of Treatment Emergent Adverse Events (TEAEs) | 197 Number of events |
| Sitagliptin | Number of Treatment Emergent Adverse Events (TEAEs) | 186 Number of events |
Secondary
Change in Glycosylated Haemoglobin A1c (HbA1c)
Mean changes in HbA1c values from baseline after 30 weeks of treatment. Changes in HbA1c were analysed using a mixed model for repeated measurements (MMRM) with treatment and pre-trial treatment at screening as fixed factors and baseline value as covariate. The data were analysed for the on-treatment without rescue medication observation period which includes observations noted at or after the date of first dose of randomised treatment and not after the last dose of the trial product (+ a 7-day visit window) or initiation of rescue medication.
Time frame: Week 0 and week 30
Population: The full analysis set (FAS) included all randomised subjects who have received at least one dose of trial product. All subjects contributed to the statistical model of the data analysis, but not all subjects had a value at week 30.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Semaglutide 0.5 mg | Change in Glycosylated Haemoglobin A1c (HbA1c) | -1.87 Percentage of glycosylated haemoglobin | Standard Error 0.07 |
| Semaglutide 1.0 mg | Change in Glycosylated Haemoglobin A1c (HbA1c) | -2.18 Percentage of glycosylated haemoglobin | Standard Error 0.07 |
| Sitagliptin | Change in Glycosylated Haemoglobin A1c (HbA1c) | -0.74 Percentage of glycosylated haemoglobin | Standard Error 0.07 |
Secondary
Number of Severe or Blood Glucose (BG) Confirmed Symptomatic Hypoglycaemic Episodes
Severe or blood glucose (BG) confirmed symptomatic hypoglycaemic episodes were defined as episodes that were severe and/or BG confirmed by a plasma glucose value of \<56 mg/dL (3.1 mmol/L), with symptoms consistent with hypoglycaemia. Severe hypoglycaemia was an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions. The episodes mentioned here are treatment emergent hypoglycaemic episodes and defined as an event that had onset date (or increase in severity) on or after the first day of exposure to randomised treatment (week 0-30 treatment period) and no later than the follow-up visit during the on-treatment observation period (date of last dose + 42 days).
Time frame: Weeks 0-30
Population: The safety analysis set (SAS) included all subjects receiving at least one dose of trial product and subjects contributed to the evaluation as treated.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Semaglutide 0.5 mg | Number of Severe or Blood Glucose (BG) Confirmed Symptomatic Hypoglycaemic Episodes | 0 Number of episodes |
| Semaglutide 1.0 mg | Number of Severe or Blood Glucose (BG) Confirmed Symptomatic Hypoglycaemic Episodes | 1 Number of episodes |
| Sitagliptin | Number of Severe or Blood Glucose (BG) Confirmed Symptomatic Hypoglycaemic Episodes | 0 Number of episodes |