Diabetes Mellitus, Type 2
Conditions
Brief summary
This study compares the effect of two doses of semaglutide (1.0 mg and 2.0 mg) in people with type 2 diabetes (T2D). People taking part in the study will take the medicine together with their current diabetes medicine (sulphonylurea and/or metformin). Participants will get a dose of either 1.0 mg or 2.0 mg semaglutide once a week - which dose is decided by chance. Participants will inject semaglutide under the skin once a week. The study will last for about 49 weeks. Participants will have 9 clinic visits and 2 phone calls with the study doctor. At the visits participants will have blood taken and eye tests done. Women cannot take part if pregnant, breast-feeding or planning to become pregnant during the study period. Female participants who can get pregnant will be checked 11 times for pregnancy via urine tests.
Interventions
DRUGSemaglutide
Semaglutide injected subcutaneously (s.c., under the skin) once-weekly. Participants will keep taking their pre-study diabetes tablets throughout the study.
DRUGPlacebo (semaglutide)
Semaglutide placebo injected once-weekly from week 13 to week 40.
Sponsors
Novo Nordisk A/S
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Sponsor staff involved in the clinical trial is masked according to company standard procedures
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female, age equal to or above18 years at the time of signing informed consent * Diagnosed with T2D at least 180 days prior to the day of screening * HbA1c of 8-10% (64-86 mmol/mol) (both inclusive) * Stable daily dose(s) for 90 days prior to the day of screening of: * Any metformin formulations (equal to or above1500 mg or maximum tolerated or effective dose) alone or in combination with sulfonylureas (SU) (equal to or above half of the maximum approved dose according to local label or maximum tolerated or effective dose)
Exclusion criteria
* 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, as is prior insulin treatment for gestational diabetes * Renal impairment measured as estimated glomerular filtration rate (eGFR) value of \<30 mL/min/1.73 m\^2 according to the Chronic Kidney Disease Epidemiology Collaboration (CKDEPI) creatinine equation as defined by KDIGO 2012 classification * Uncontrolled and potentially unstable diabetic retinopathy or maculopathy. Verified by a fundus examination performed within the past 90 days prior to screening or in the period between screening and randomisation. Pharmacological pupil-dilation is a requirement unless using a digital fundus photography camera specified for non-dilated examination
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in HbA1c | Week 0, week 40 | Change from baseline (week 0) to week 40 in glycosylated haemoglobin (HbA1c) was evaluated. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose of trial product to either first initiation of rescue medication or the day of last dose of trial product, whichever came first; and 'In-trial' observation period which started at the date of randomisation and ended at the first of the following dates, both inclusive: end-of-treatment visit (week 40), death, participant withdrew informed consent, last contact for participant lost to follow-up. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Fasting Plasma Glucose (FPG) | Week 0, week 40 | Change from baseline (week 0) to week 40 in FPG was evaluated. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose of trial product to either first initiation of rescue medication or the day of last dose of trial product, whichever came first. |
| Change in Body Mass Index (BMI) | Week 0, week 40 | Change from baseline (week 0) to week 40 in BMI was evaluated. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose of trial product to either first initiation of rescue medication or the day of last dose of trial product, whichever came first. |
| Change in Waist Circumference | Week 0, week 40 | Change from baseline (week 0) to week 40 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 of trial product to either first initiation of rescue medication or the day of last dose of trial product, whichever came first. |
| Participants Who Achieved HbA1c < 7.0% | Week 40 | Percentage of participants who achieved HbA1c \< 7.0% is presented. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose of trial product to either first initiation of rescue medication or the day of last dose of trial product, whichever came first. Missing HbA1c assessment at week 40 was imputed using observed data from participants within same treatment group. |
| Change in Body Weight | Week 0, week 40 | Change from baseline (week 0) to week 40 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 of trial product to either first initiation of rescue medication or the day of last dose of trial product, whichever came first; and 'In-trial' observation period which started at the date of randomisation and ended at the first of the following dates, both inclusive: end-of-treatment visit (week 40), death, participant withdrew informed consent, last contact for participant lost to follow-up. |
| Participants Who Achieved Weight Loss ≥5% | Week 40 | Percentage of participants who achieved weight loss ≥5% is presented. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose of trial product to either first initiation of rescue medication or the day of last dose of trial product, whichever came first. Missing body weight assessment at week 40 was imputed using observed data from participants within same treatment group. |
| Participants Who Achieved Weight Loss ≥10% | Week 40 | Percentage of participants who achieved weight loss ≥10% is presented. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose of trial product to either first initiation of rescue medication or the day of last dose of trial product, whichever came first. Missing body weight assessment at week 40 was imputed using observed data from participants within same treatment group. |
| Number of Treatment-emergent Severe or Blood Glucose (BG) Confirmed Symptomatic Hypoglycaemic Episodes | Week 0 to week 47 | 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 required assistance from another person for recovery and blood glucose-confirmed by a plasma glucose value \<3.1 mmol/L (56 milligrams per deciliter (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 ended at the first date of any of the following: the follow-up visit (week 47), the treatment discontinuation follow-up visit (end of treatment + 7 weeks), the date of last dose of trial product +49 days or the end-date for the 'in-trial' observation period. |
| Change in Pulse Rate | Week 0, week 40 | Change from baseline (week 0) to week 40 in pulse rate is presented. Results are based on the 'on-treatment' observation period, which started at the date of first dose of trial product and ended at the endpoint-specific end-date. |
| Participants Who Achieved HbA1c ≤ 6.5% | Week 40 | Percentage of participants who achieved HbA1c ≤ 6.5% is presented. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose of trial product to either first initiation of rescue medication or the day of last dose of trial product, whichever came first. Missing HbA1c assessment at week 40 was imputed using observed data from participants within same treatment group. |
Countries
Bulgaria, Canada, Czechia, Greece, Hungary, Japan, Poland, Puerto Rico, Slovakia, Ukraine, United States
Participant flow
Recruitment details
The trial was conducted at 125 sites in Bulgaria (9), Canada (8), Czech Republic (4), Greece (6), Hungary (12), Japan (2), Poland (10), Slovakia (11), Ukraine (5) and the United States (58). In addition to these sites, 4 sites in the US screened but did not randomize participants, and 3 sites were approved by the IRB/IEC but did not screen or assign any participants to treatment.
Pre-assignment details
Participants with type 2 diabetes (T2D) treated with stable doses of metformin only, or metformin in combination with sulfonylurea (SU), in need of the treatment intensification were randomized 1:1 to once-weekly treatment with semaglutide 2.0 milligrams (mg) or once-weekly treatment with semaglutide 1.0 mg.
Participants by arm
| Arm | Count |
|---|---|
| Semaglutide 1.0 mg Participants received subcutaneous (s.c.) injection of semaglutide once-weekly for 40 weeks in a fixed-dose escalation regimen, with dose doubling every 4 weeks until the target dose of 1.0 mg was reached: 0.25 mg during 0-4 weeks followed by 0.5 mg during 4-8 weeks followed by 1.0 mg during 8-12 weeks and then 1.0 mg semaglutide along with s.c. injection of placebo matched to semaglutide 1.0 mg during 12-40 weeks. | 481 |
| Semaglutide 2.0 mg Participants received s.c. injection of semaglutide once-weekly for 40 weeks in a fixed-dose escalation regimen, with dose doubling every 4 weeks until the target maintenance dose of 2.0 mg was reached: 0.25 mg during 0-4 weeks followed by 0.5 mg during 4-8 weeks followed by 1.0 mg during 8-12 weeks and then 2.0 mg during 12-40 weeks. | 480 |
| Total | 961 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 2 |
| Overall Study | Lost to Follow-up | 3 | 10 |
| Overall Study | Withdrawal by Subject | 6 | 6 |
Baseline characteristics
| Characteristic | Semaglutide 2.0 mg | Total | Semaglutide 1.0 mg |
|---|---|---|---|
| Age, Continuous | 57.9 Years STANDARD_DEVIATION 10 | 58.0 Years STANDARD_DEVIATION 10 | 58.2 Years STANDARD_DEVIATION 9.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 52 Participants | 111 Participants | 59 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 428 Participants | 850 Participants | 422 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska native | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 33 Participants | 69 Participants | 36 Participants |
| Race/Ethnicity, Customized Black or African American | 26 Participants | 43 Participants | 17 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 420 Participants | 847 Participants | 427 Participants |
| Sex: Female, Male Female | 201 Participants | 398 Participants | 197 Participants |
| Sex: Female, Male Male | 279 Participants | 563 Participants | 284 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 480 | 2 / 479 |
| other Total, other adverse events | 126 / 480 | 132 / 479 |
| serious Total, serious adverse events | 25 / 480 | 21 / 479 |
Outcome results
Primary
Change in HbA1c
Change from baseline (week 0) to week 40 in glycosylated haemoglobin (HbA1c) was evaluated. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose of trial product to either first initiation of rescue medication or the day of last dose of trial product, whichever came first; and 'In-trial' observation period which started at the date of randomisation and ended at the first of the following dates, both inclusive: end-of-treatment visit (week 40), death, participant withdrew informed consent, last contact for participant lost to follow-up.
Time frame: Week 0, week 40
Population: The FAS included all randomized participants. Number analyzed=number of participants contributed to the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Semaglutide 1.0 mg | Change in HbA1c | On-treatment without rescue medication | -2.0 Percentage change | Standard Deviation 1 |
| Semaglutide 1.0 mg | Change in HbA1c | In-trial | -1.9 Percentage change | Standard Deviation 1 |
| Semaglutide 2.0 mg | Change in HbA1c | On-treatment without rescue medication | -2.2 Percentage change | Standard Deviation 1 |
| Semaglutide 2.0 mg | Change in HbA1c | In-trial | -2.2 Percentage change | Standard Deviation 1.1 |
Comparison: On-treatment without rescue medication observation period: Imputation of missing data was handled by multiple imputation (MI) assuming that missing data were missed at random (MAR). The imputation was performed separately within each treatment group defined by randomised treatment.p-value: 0.000395% CI: [-0.36, -0.11]ANCOVA
Comparison: In-trial observation period: Imputation of missing data was handled by MI assuming that missing data were missed at random. The imputation was performed by imputing missing week 40 data separately within groups defined by randomised treatment and treatment status at week 40.p-value: 0.009895% CI: [-0.31, -0.04]ANCOVA
Secondary
Change in Body Mass Index (BMI)
Change from baseline (week 0) to week 40 in BMI was evaluated. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose of trial product to either first initiation of rescue medication or the day of last dose of trial product, whichever came first.
Time frame: Week 0, week 40
Population: The FAS included all randomized participants. Overall number of participants analyzed=number of participants contributed to the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Semaglutide 1.0 mg | Change in Body Mass Index (BMI) | -2.1 Kilogram per squaremeter (Kg/m^2) | Standard Deviation 2.1 |
| Semaglutide 2.0 mg | Change in Body Mass Index (BMI) | -2.5 Kilogram per squaremeter (Kg/m^2) | Standard Deviation 2.1 |
Secondary
Change in Body Weight
Change from baseline (week 0) to week 40 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 of trial product to either first initiation of rescue medication or the day of last dose of trial product, whichever came first; and 'In-trial' observation period which started at the date of randomisation and ended at the first of the following dates, both inclusive: end-of-treatment visit (week 40), death, participant withdrew informed consent, last contact for participant lost to follow-up.
Time frame: Week 0, week 40
Population: The FAS included all randomized participants. Number analyzed=number of participants contributed to the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Semaglutide 1.0 mg | Change in Body Weight | On-treatment without rescue medication | -6.0 Kilogram (kg) | Standard Deviation 5.8 |
| Semaglutide 1.0 mg | Change in Body Weight | In-trial | -5.7 Kilogram (kg) | Standard Deviation 5.9 |
| Semaglutide 2.0 mg | Change in Body Weight | On-treatment without rescue medication | -7.0 Kilogram (kg) | Standard Deviation 5.8 |
| Semaglutide 2.0 mg | Change in Body Weight | In-trial | -6.7 Kilogram (kg) | Standard Deviation 5.9 |
Secondary
Change in Fasting Plasma Glucose (FPG)
Change from baseline (week 0) to week 40 in FPG was evaluated. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose of trial product to either first initiation of rescue medication or the day of last dose of trial product, whichever came first.
Time frame: Week 0, week 40
Population: The FAS included all randomized participants. Overall number of participants analyzed=number of participants contributed to the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Semaglutide 1.0 mg | Change in Fasting Plasma Glucose (FPG) | -3.2 Millimoles per liter (mmol/L) | Standard Deviation 2.8 |
| Semaglutide 2.0 mg | Change in Fasting Plasma Glucose (FPG) | -3.4 Millimoles per liter (mmol/L) | Standard Deviation 3.1 |
Secondary
Change in Pulse Rate
Change from baseline (week 0) to week 40 in pulse rate is presented. Results are based on the 'on-treatment' observation period, which started at the date of first dose of trial product and ended at the endpoint-specific end-date.
Time frame: Week 0, week 40
Population: The SAS included all participants exposed to at least one dose of trial product. Overall number of participants analyzed=number of participants contributed to the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Semaglutide 1.0 mg | Change in Pulse Rate | 2.8 Beats per minute | Standard Deviation 10 |
| Semaglutide 2.0 mg | Change in Pulse Rate | 3.3 Beats per minute | Standard Deviation 9.5 |
Secondary
Change in Waist Circumference
Change from baseline (week 0) to week 40 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 of trial product to either first initiation of rescue medication or the day of last dose of trial product, whichever came first.
Time frame: Week 0, week 40
Population: The FAS included all randomized participants. Overall number of participants analyzed=number of participants contributed to the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Semaglutide 1.0 mg | Change in Waist Circumference | -5.2 Centimeter (cm) | Standard Deviation 6.1 |
| Semaglutide 2.0 mg | Change in Waist Circumference | -5.9 Centimeter (cm) | Standard Deviation 6.2 |
Secondary
Number of Treatment-emergent Severe or Blood Glucose (BG) 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 required assistance from another person for recovery and blood glucose-confirmed by a plasma glucose value \<3.1 mmol/L (56 milligrams per deciliter (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 ended at the first date of any of the following: the follow-up visit (week 47), the treatment discontinuation follow-up visit (end of treatment + 7 weeks), the date of last dose of trial product +49 days or the end-date for the 'in-trial' observation period.
Time frame: Week 0 to week 47
Population: The SAS included all participants exposed to at least one dose of trial product.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Semaglutide 1.0 mg | Number of Treatment-emergent Severe or Blood Glucose (BG) Confirmed Symptomatic Hypoglycaemic Episodes | 28 Episodes |
| Semaglutide 2.0 mg | Number of Treatment-emergent Severe or Blood Glucose (BG) Confirmed Symptomatic Hypoglycaemic Episodes | 21 Episodes |
Secondary
Participants Who Achieved HbA1c ≤ 6.5%
Percentage of participants who achieved HbA1c ≤ 6.5% is presented. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose of trial product to either first initiation of rescue medication or the day of last dose of trial product, whichever came first. Missing HbA1c assessment at week 40 was imputed using observed data from participants within same treatment group.
Time frame: Week 40
Population: The FAS included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Semaglutide 1.0 mg | Participants Who Achieved HbA1c ≤ 6.5% | 38.5 Percentage of participants |
| Semaglutide 2.0 mg | Participants Who Achieved HbA1c ≤ 6.5% | 51.7 Percentage of participants |
Secondary
Participants Who Achieved HbA1c < 7.0%
Percentage of participants who achieved HbA1c \< 7.0% is presented. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose of trial product to either first initiation of rescue medication or the day of last dose of trial product, whichever came first. Missing HbA1c assessment at week 40 was imputed using observed data from participants within same treatment group.
Time frame: Week 40
Population: The FAS included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Semaglutide 1.0 mg | Participants Who Achieved HbA1c < 7.0% | 57.5 Percentage of participants |
| Semaglutide 2.0 mg | Participants Who Achieved HbA1c < 7.0% | 67.6 Percentage of participants |
Secondary
Participants Who Achieved Weight Loss ≥10%
Percentage of participants who achieved weight loss ≥10% is presented. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose of trial product to either first initiation of rescue medication or the day of last dose of trial product, whichever came first. Missing body weight assessment at week 40 was imputed using observed data from participants within same treatment group.
Time frame: Week 40
Population: The FAS included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Semaglutide 1.0 mg | Participants Who Achieved Weight Loss ≥10% | 22.6 Percentage of participants |
| Semaglutide 2.0 mg | Participants Who Achieved Weight Loss ≥10% | 28.4 Percentage of participants |
Secondary
Participants Who Achieved Weight Loss ≥5%
Percentage of participants who achieved weight loss ≥5% is presented. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose of trial product to either first initiation of rescue medication or the day of last dose of trial product, whichever came first. Missing body weight assessment at week 40 was imputed using observed data from participants within same treatment group.
Time frame: Week 40
Population: The FAS included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Semaglutide 1.0 mg | Participants Who Achieved Weight Loss ≥5% | 51.3 Percentage of participants |
| Semaglutide 2.0 mg | Participants Who Achieved Weight Loss ≥5% | 59.2 Percentage of participants |