Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted in Asia. The aim of the trial is to investigate safety and efficacy of semaglutide once weekly in monotherapy or in combination with one OAD (oral anti-diabetic drug) in Japanese subjects with type 2 diabetes who are insufficiently controlled on diet/exercise therapy or OAD monotherapy. All subjects will continue their pre-trial treatment (diet and exercise therapy or OAD monotherapy in addition to diet and exercise therapy) during the trial.
Interventions
DRUGsemaglutide
Subject will receive either a dose of 0.5 or 1.0 mg of semaglutide once weekly (subcutaneous (s.c.) injection).Treatment duration 56 weeks.
DRUGDPP-4 inhibitor
Subjects will receive one DPP-4 inhibitor in addition to pre-trial OAD monotherapy, if any, for 56 weeks.
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 at least 20 years at the time of signing informed consent * HbA1c (glycosylated haemoglobin A1c) between 7.0% and 10.5% (53-91 mmol/mol) (both inclusive) * Japanese subjects with type 2 diabetes mellitus (diagnosed clinically) and on stable treatment (defined as unchanged medication and unchanged dose) who are: a) on diet and exercise therapy for at least 30 days before Visit 1 (week -2). or b) on OAD monotherapy (either of SU (sulfonylurea), glinide, a-GI (a-glucosidase inhibitor) or TZD (thiazolidinediones)) within approved Japanese labelling in addition to diet and exercise therapy for at least 60 days before Visit 1 (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 \[not having sex\], diaphragm, condom \[by the partner\], intrauterine device, sponge, spermicide or oral contraceptives) throughout the trial including the 5 week follow-up period * Treatment with glucose lowering agent(s) other than stated in the inclusion criteria within 60 days before Visit 1 (week -2) and treatment with once weekly glucagon-like peptide-1 (GLP-1) receptor agonists within 90 days before Visit 1 (week -2). An exception is short-term treatment (below or equal to 7 days 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 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 (MEN2) * Impaired renal function defined as estimated glomerular filtration rate (eGFR) below 30 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 (Visit 2 \[week 0\]) * Heart failure, New York Heart Association (NYHA) class IV
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Treatment Emergent Adverse Events (TEAEs) | Weeks 0-56 | An adverse event (AEs) was defined as any unfavorable 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 0-56 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 0-56 | 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 0-56 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, week 56 | The observed mean change in HbA1c values from baseline after 56 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 41 sites in Japan.
Pre-assignment details
Subjects were either on diet and exercise therapy only or on stable treatment on oral anti-diabetic drugs (OADs) mono-therapy \[either of sulphonyl urea (SU), glinide, alpha-glucosidase inhibitor (α-GI) or thiazolidinediones (TZD)\] within approved Japanese labelling in addition to diet and exercise therapy before 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 period up to 56 weeks. The treatment period was divided into the dose escalation and the dose maintenance period. Subjects followed a fixed dose escalation pattern to mitigate tolerability concerns, starting with once-weekly doses of 0.25 mg for 4 weeks (4 doses), then escalated to once weekly 0.5 mg maintenance dose for 52 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. All subjects continued their pre-trial treatment of either diet and exercise therapy or OAD monotherapy in addition to diet and exercise throughout the trial. | 239 |
| 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 period up to 56 weeks. The treatment period was divided into the dose escalation and the dose maintenance period. Subjects followed a fixed dose escalation pattern to mitigate tolerability concerns, starting with once-weekly doses of 0.25 mg for 4 weeks (4 doses), then escalated to once weekly doses of 0.5 mg for 4 weeks, and finally escalated to once weekly 1.0 mg maintenance dose for 48 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. All subjects continued their pre-trial treatment of either diet and exercise therapy or OAD monotherapy in addition to diet and exercise throughout the trial. | 241 |
| Additional OAD Subjects were randomised to receive one additional OAD in addition to the pre-trial treatment for a duration of 56 weeks. The type and dosage of the additional OAD was selected by the investigator according to the approved Japanese labelling based on drug combinations and contraindications. One of the following OADs was to be selected as the additional OAD therapy: dipeptidyl peptidase-4 (DPP-4) inhibitor, SU, glinide, biguanide, α-GI and TZD. For subjects treated with OAD as pre-trial treatment, the type and dosage of the additional OAD with a different mechanism of action from the pre-trial OAD was to be chosen. The dose of the additional OAD was optimized within approved Japanese labelling until week 8 (dose adjustment period) and the dose remained unchanged until week 56 (maintenance dose) unless rescue medication was needed. The type of the additional OAD remained unchanged during the trial. | 120 |
| Total | 600 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 1 | 0 | 1 |
| Overall Study | Missing follow-up information | 0 | 1 | 1 |
| Overall Study | Withdrawal by Subject | 5 | 9 | 4 |
Baseline characteristics
| Characteristic | Semaglutide 0.5 mg | Semaglutide 1.0 mg | Additional OAD | Total |
|---|---|---|---|---|
| Age, Continuous | 58.0 Years STANDARD_DEVIATION 10.6 | 58.7 Years STANDARD_DEVIATION 10.2 | 59.2 Years STANDARD_DEVIATION 10.1 | 58.5 Years STANDARD_DEVIATION 10.3 |
| Glycosylated haemoglobin (HbA1c) | 8.04 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.89 | 8.14 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.96 | 8.10 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.89 | 8.09 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.92 |
| Sex: Female, Male Female | 73 Participants | 67 Participants | 31 Participants | 171 Participants |
| Sex: Female, Male Male | 166 Participants | 174 Participants | 89 Participants | 429 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 | 160 / 239 | 169 / 241 | 61 / 120 |
| serious Total, serious adverse events | 19 / 239 | 12 / 241 | 8 / 120 |
Outcome results
Primary
Number of Treatment Emergent Adverse Events (TEAEs)
An adverse event (AEs) was defined as any unfavorable 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 0-56 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 0-56
Population: The safety analysis set (SAS) included all randomised subjects who had received at least one dose of semaglutide 0.5 mg (s.c.), semaglutide 1.0 mg (s.c.) or one additional OAD. Subjects in the SAS contributed to the evaluation as treated.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Semaglutide 0.5 mg | Number of Treatment Emergent Adverse Events (TEAEs) | 909 Number of events |
| Semaglutide 1.0 mg | Number of Treatment Emergent Adverse Events (TEAEs) | 954 Number of events |
| Additional OAD | Number of Treatment Emergent Adverse Events (TEAEs) | 269 Number of events |
Secondary
Change in Glycosylated Haemoglobin A1c (HbA1c)
The observed mean change in HbA1c values from baseline after 56 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, week 56
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 56.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Semaglutide 0.5 mg | Change in Glycosylated Haemoglobin A1c (HbA1c) | -1.74 Percentage (%) of HbA1c | Standard Error 0.05 |
| Semaglutide 1.0 mg | Change in Glycosylated Haemoglobin A1c (HbA1c) | -2.03 Percentage (%) of HbA1c | Standard Error 0.05 |
| Additional OAD | Change in Glycosylated Haemoglobin A1c (HbA1c) | -0.67 Percentage (%) of HbA1c | 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 0-56 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 0-56
Population: The safety analysis set (SAS) included all randomised subjects who had received at least one dose of semaglutide 0.5 mg (s.c.), semaglutide 1.0 mg (s.c.) or one additional OAD. Subjects in the SAS 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 | 4 Number of episodes |
| Semaglutide 1.0 mg | Number of Severe or Blood Glucose (BG) Confirmed Symptomatic Hypoglycaemic Episodes | 8 Number of episodes |
| Additional OAD | Number of Severe or Blood Glucose (BG) Confirmed Symptomatic Hypoglycaemic Episodes | 2 Number of episodes |