Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted in Asia, Europe and the United States of America (USA). The aim of the trial is to investigate efficacy and safety of semaglutide once weekly versus placebo as add-on to basal insulin alone or basal insulin in combination with metformin in subjects with type 2 diabetes.
Interventions
DRUGsemaglutide
Injected subcutaneously (s.c. under the skin) once-weekly. As add-on to the pre-trial background medication.
DRUGplacebo
Injected subcutaneously (s.c. under the skin) once-weekly. As add-on to the pre-trial background 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
- Male or female, age at least 18 years at the time of signing inform consent. For Japan: Male or female, age at least 20 years at the time of signing informed consent - Subjects diagnosed with T2DM (type 2 diabetes mellitus) and on stable diabetes treatment (plus/minus 20 percent change in total daily dose) with basal insulin (minimum of 0.25 IU/kg/day and/or 20 IU/day of: insulin glargine, insulin detemir, insulin degludec and/or NPH insulin) alone or in combination with metformin (minimum of 1500 mg/day or maximal tolerable dose) for 90 days prior to screening - HbA1c (glycosylated haemoglobin) 7.0 - 10.0 percent (53 - 86 mmol/mol) both inclusive
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 throughout the trial including the 5 weeks follow-up period (adequate contraceptive measures as required by local regulation or practice). Germany: Only highly effective methods of birth control are accepted (ie one that results in less than 1% per year failure rate when used consistently and correctly such as implants, injectables, combined oral contraceptives, some intrauterine device), or sexual abstinence or vasectomised partner. Japan: Adequate contraceptive measures are abstinence (not having sex), diaphragm, condom (by the partner), intrauterine device, sponge, spermicide or oral contraceptives - Treatment with any glucose lowering agents 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 bolus insulin in connection with intercurrent illness - Experienced more than 3 episodes of severe hypoglycaemia within 6 months prior to screening, and/or hypoglycaemia unawareness - History of pancreatitis (acute or chronic) - 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 2 (MEN 2) - Severe renal impairment defined as eGFR (estimated glomerular filtration rate) 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 - Heart failure, New York Heart Association (NYHA) Class IV
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in HbA1c (Glycosylated Haemoglobin) | Week 0, week 30 | Estimated mean change from baseline in HbA1c at week 30. The post-baseline responses are analysed using a mixed model for repeated measurements with treatment, country and stratification variable (HbA1c level at screening \[\<= 8.0% or \> 8.0%\] crossed with use of metformin \[yes or no\]; 2 by 2 levels) as fixed factors and baseline value as covariate, all nested within visit. Mean estimates are adjusted according to observed baseline distribution. Missing data was imputed using mixed model for repeated measurements. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Fasting Plasma Glucose (FPG) | week 0, week 30 | Estimated mean change from baseline in FPG at week 30. The post-baseline responses are analysed using a mixed model for repeated measurements with treatment, country and stratification variable (HbA1c level at screening \[\<= 8.0% or \> 8.0%\] crossed with use of metformin \[yes or no\]; 2 by 2 levels) as fixed factors and baseline value as covariate, all nested within visit. Mean estimates are adjusted according to observed baseline distribution. Missing data was imputed using mixed model for repeated measurements. |
| Change in Insulin Dose | week 0, week 30 | Estimated mean change from baseline in insulin dose at week 30 was measured in terms of ratio to baseline. Responses at week 30 are analysed using an Analysis of covariance model with treatment, country and stratification variable (HbA1c level at screening \[\<= 8.0% or \> 8.0%\] crossed with use of metformin \[yes or no\]; 2 by 2 levels) as fixed factors and baseline value as covariate. Mean estimates are adjusted according to observed baseline distribution. Missing data was imputed using last observation carried forward. |
| Change in Systolic and Diastolic Blood Pressure | week 0, week 30 | Estimated mean change from baseline in systolic and diastolic blood pressure at week 30. The post-baseline responses are analysed using a mixed model for repeated measurements with treatment, country and stratification variable (HbA1c level at screening \[\<= 8.0% or \> 8.0%\] crossed with use of metformin \[yes or no\]; 2 by 2 levels) as fixed factors and baseline value as covariate, all nested within visit. Mean estimates are adjusted according to observed baseline distribution. Missing data was imputed using mixed model for repeated measurements. |
| Change in Body Weight | Week 0, week 30 | Estimated mean change from baseline in body weight at week 30. The post-baseline responses are analysed using a mixed model for repeated measurements with treatment, country and stratification variable (HbA1c level at screening \[\<= 8.0% or \> 8.0%\] crossed with use of metformin \[yes or no\]; 2 by 2 levels) as fixed factors and baseline value as covariate, all nested within visit. Mean estimates are adjusted according to observed baseline distribution. Missing data was imputed using mixed model for repeated measurements. |
| HbA1c Below 7.0% (53 mmol/Mol) American Diabetes Association (ADA) Target | After 30 weeks treatment | Percentage of subjects with HbA1C below 7.0% after 30 weeks treatment. Missing data imputed from a mixed model for repeated measurements with treatment, country and stratification variable (HbA1c level at screening \[\<= 8.0% or \> 8.0%\] crossed with use of metformin \[yes or no\]; 2 by 2 levels) as fixed factors and baseline value as covariate, all nested within visit. |
| HbA1c Below or Equal to 6.5% (48 mmol/Mol) American Association of Clinical Endocrinologists (AACE) Target | After 30 weeks treatment | Percentage of participants with HbA1c below or equal to 6.5% after 30 weeks treatment. Missing data imputed from a mixed model for repeated measurements with treatment, country and stratification variable (HbA1c level at screening \[\<= 8.0% or \> 8.0%\] crossed with use of metformin \[yes or no\]; 2 by 2 levels) as fixed factors and baseline value as covariate, all nested within visit. |
| Patient Reported Outcomes, Diabetes Treatment Satisfaction Questionnaire (DTSQ) | week 0, week 30 | The DTSQs questionnaire was used to assess subjects' treatment satisfaction and 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. The post-baseline responses are analysed using an ANCOVA model with treatment, country and stratification variables (HbA1c level at screening \[\<= 8.0% or \> 8.0%\] and use of metformin \[yes or no\]) as fixed factors and baseline value as covariate. Mean estimates are adjusted according to observed baseline distribution. Missing data was imputed using last observation carried forward. |
Countries
Germany, Japan, Puerto Rico, Serbia, Slovakia, United States
Participant flow
Recruitment details
The trial was conducted at 90 sites in 5 countries, as follows: Germany: 10 sites; Japan: 6 sites; Serbia: 4 sites; Slovakia: 5 sites; United States: 65.
Participants by arm
| Arm | Count |
|---|---|
| Semaglutide 0.5 mg Subjects received semaglutide 0.25 mg sc injection once weekly for 4 weeks followed by semaglutide 0.5 mg once weekly up to week 30. Semaglutide injection was administered in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same day of the week during the trial. | 132 |
| Semaglutide 1.0 mg Subjects received semaglutide 0.25 mg sc injection once weekly for 4 weeks followed by semaglutide 0.5 mg once weekly for next 4 weeks and then semaglutide 1.0 mg once weekly up to week 30. Semaglutide injection was administered in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same day of the week during the trial. | 131 |
| Placebo Subjects received placebo (matched to semaglutide) sc injection once weekly for 30 weeks. Placebo injection was administered in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same day of the week during the trial. | 133 |
| Total | 396 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Unclassified | 5 | 5 | 7 |
Baseline characteristics
| Characteristic | Semaglutide 1.0 mg | Total | Placebo | Semaglutide 0.5 mg |
|---|---|---|---|---|
| Age, Continuous | 58.5 years STANDARD_DEVIATION 9 | 58.8 years STANDARD_DEVIATION 10.1 | 58.8 years STANDARD_DEVIATION 10.9 | 59.1 years STANDARD_DEVIATION 10.3 |
| Age, Customized 85 years and over | 0 participants | 1 participants | 1 participants | 0 participants |
| Age, Customized Adults (18-64 years) | 102 participants | 281 participants | 86 participants | 93 participants |
| Age, Customized From 65-84 years | 29 participants | 114 participants | 46 participants | 39 participants |
| Body weight | 92.49 kg STANDARD_DEVIATION 22.23 | 91.70 kg STANDARD_DEVIATION 20.97 | 89.88 kg STANDARD_DEVIATION 21.06 | 92.74 kg STANDARD_DEVIATION 19.57 |
| Diabetes Treatment Satisfaction Questionnaire | 28.62 scores on scale STANDARD_DEVIATION 6.45 | 28.34 scores on scale STANDARD_DEVIATION 6.46 | 27.54 scores on scale STANDARD_DEVIATION 6.55 | 28.86 scores on scale STANDARD_DEVIATION 6.35 |
| Diastolic Blood Pressure | 78.73 mm Hg STANDARD_DEVIATION 9.98 | 78.99 mm Hg STANDARD_DEVIATION 9.79 | 79.35 mm Hg STANDARD_DEVIATION 9.71 | 78.89 mm Hg STANDARD_DEVIATION 9.72 |
| Fasting plasma glucose | 152.5 mg/dL STANDARD_DEVIATION 50.91 | 155.9 mg/dL STANDARD_DEVIATION 53.68 | 154.1 mg/dL STANDARD_DEVIATION 46.66 | 161.0 mg/dL STANDARD_DEVIATION 62.38 |
| Glycosylated haemoglobin | 8.31 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.82 | 8.37 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.84 | 8.42 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.88 | 8.36 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.83 |
| Insulin dose | 36.00 international unit | 36.00 international unit | 36.00 international unit | 35.00 international unit |
| Sex: Female, Male Female | 54 Participants | 174 Participants | 62 Participants | 58 Participants |
| Sex: Female, Male Male | 77 Participants | 222 Participants | 71 Participants | 74 Participants |
| Systolic Blood Pressure | 134.40 mm Hg STANDARD_DEVIATION 16.32 | 134.76 mm Hg STANDARD_DEVIATION 15.98 | 134.99 mm Hg STANDARD_DEVIATION 16.68 | 134.87 mm Hg STANDARD_DEVIATION 15 |
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 | 52 / 132 | 54 / 131 | 34 / 133 |
| serious Total, serious adverse events | 8 / 132 | 12 / 131 | 9 / 133 |
Outcome results
Primary
Change in HbA1c (Glycosylated Haemoglobin)
Estimated mean change from baseline in HbA1c at week 30. The post-baseline responses are analysed using a mixed model for repeated measurements with treatment, country and stratification variable (HbA1c level at screening \[\<= 8.0% or \> 8.0%\] crossed with use of metformin \[yes or no\]; 2 by 2 levels) as fixed factors and baseline value as covariate, all nested within visit. Mean estimates are adjusted according to observed baseline distribution. Missing data was imputed using mixed model for repeated measurements.
Time frame: Week 0, week 30
Population: Full analysis set included all randomised subjects who had received at least 1 dose of randomised semaglutide or placebo.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Semaglutide 0.5 mg | Change in HbA1c (Glycosylated Haemoglobin) | -1.45 percentage of glycosylated hemoglobin | Standard Error 0.09 |
| Semaglutide 1.0 mg | Change in HbA1c (Glycosylated Haemoglobin) | -1.85 percentage of glycosylated hemoglobin | Standard Error 0.09 |
| Placebo | Change in HbA1c (Glycosylated Haemoglobin) | -0.09 percentage of glycosylated hemoglobin | Standard Error 0.09 |
Comparison: Hierarchical testing was performed as per sequence listed below:Change in HbA1c: semaglutide 1.0 mg vs placebo. Change in HbA1c: semaglutide 0.5 mg vs placebo. Change in body weight: semaglutide 1.0 mg vs placebo. Change in body weight: semaglutide 0.5 mg vs placebo. Analysis was performed using MMRM with treatment, country and stratification variable (HbA1c at screening \[≤8.0% or \>8.0%\] crossed with use of metformin \[yes or no\]; 2 by 2 levels) as fixed factors and baseline value as covariatep-value: <0.000195% CI: [-2.01, -1.5]Mixed Models Analysis
Comparison: Hierarchical testing was performed as per sequence listed below:Change in HbA1c: semaglutide 1.0 mg vs placebo. Change in HbA1c: semaglutide 0.5 mg vs placebo. Change in body weight: semaglutide 1.0 mg vs placebo. Change in body weight: semaglutide 0.5 mg vs placebo. Analysis was performed using MMRM with treatment, country and stratification variable (HbA1c at screening \[≤8.0% or \>8.0%\] crossed with use of metformin \[yes or no\]; 2 by 2 levels) as fixed factors and baseline value as covariatep-value: <0.000195% CI: [-1.61, -1.1]Mixed Models Analysis
Secondary
Change in Body Weight
Estimated mean change from baseline in body weight at week 30. The post-baseline responses are analysed using a mixed model for repeated measurements with treatment, country and stratification variable (HbA1c level at screening \[\<= 8.0% or \> 8.0%\] crossed with use of metformin \[yes or no\]; 2 by 2 levels) as fixed factors and baseline value as covariate, all nested within visit. Mean estimates are adjusted according to observed baseline distribution. Missing data was imputed using mixed model for repeated measurements.
Time frame: Week 0, week 30
Population: Full analysis set.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Semaglutide 0.5 mg | Change in Body Weight | -3.67 kg | Standard Error 0.36 |
| Semaglutide 1.0 mg | Change in Body Weight | -6.42 kg | Standard Error 0.36 |
| Placebo | Change in Body Weight | -1.36 kg | Standard Error 0.37 |
Secondary
Change in Fasting Plasma Glucose (FPG)
Estimated mean change from baseline in FPG at week 30. The post-baseline responses are analysed using a mixed model for repeated measurements with treatment, country and stratification variable (HbA1c level at screening \[\<= 8.0% or \> 8.0%\] crossed with use of metformin \[yes or no\]; 2 by 2 levels) as fixed factors and baseline value as covariate, all nested within visit. Mean estimates are adjusted according to observed baseline distribution. Missing data was imputed using mixed model for repeated measurements.
Time frame: week 0, week 30
Population: Full analysis set.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Semaglutide 0.5 mg | Change in Fasting Plasma Glucose (FPG) | -29.14 mg/dL | Standard Error 3.74 |
| Semaglutide 1.0 mg | Change in Fasting Plasma Glucose (FPG) | -42.38 mg/dL | Standard Error 3.76 |
| Placebo | Change in Fasting Plasma Glucose (FPG) | -8.51 mg/dL | Standard Error 4.02 |
Secondary
Change in Insulin Dose
Estimated mean change from baseline in insulin dose at week 30 was measured in terms of ratio to baseline. Responses at week 30 are analysed using an Analysis of covariance model with treatment, country and stratification variable (HbA1c level at screening \[\<= 8.0% or \> 8.0%\] crossed with use of metformin \[yes or no\]; 2 by 2 levels) as fixed factors and baseline value as covariate. Mean estimates are adjusted according to observed baseline distribution. Missing data was imputed using last observation carried forward.
Time frame: week 0, week 30
Population: Full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Semaglutide 0.5 mg | Change in Insulin Dose | 0.90 ratio | Standard Error 0.01 |
| Semaglutide 1.0 mg | Change in Insulin Dose | 0.85 ratio | Standard Error 0.01 |
| Placebo | Change in Insulin Dose | 0.96 ratio | Standard Error 0.01 |
Secondary
Change in Systolic and Diastolic Blood Pressure
Estimated mean change from baseline in systolic and diastolic blood pressure at week 30. The post-baseline responses are analysed using a mixed model for repeated measurements with treatment, country and stratification variable (HbA1c level at screening \[\<= 8.0% or \> 8.0%\] crossed with use of metformin \[yes or no\]; 2 by 2 levels) as fixed factors and baseline value as covariate, all nested within visit. Mean estimates are adjusted according to observed baseline distribution. Missing data was imputed using mixed model for repeated measurements.
Time frame: week 0, week 30
Population: Full analysis set
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Semaglutide 0.5 mg | Change in Systolic and Diastolic Blood Pressure | Diastolic blood pressure | -1.84 mm Hg | Standard Error 0.73 |
| Semaglutide 0.5 mg | Change in Systolic and Diastolic Blood Pressure | Systolic blood pressure | -4.29 mm Hg | Standard Error 1.26 |
| Semaglutide 1.0 mg | Change in Systolic and Diastolic Blood Pressure | Diastolic blood pressure | -1.50 mm Hg | Standard Error 0.74 |
| Semaglutide 1.0 mg | Change in Systolic and Diastolic Blood Pressure | Systolic blood pressure | -7.27 mm Hg | Standard Error 1.27 |
| Placebo | Change in Systolic and Diastolic Blood Pressure | Diastolic blood pressure | -2.17 mm Hg | Standard Error 0.79 |
| Placebo | Change in Systolic and Diastolic Blood Pressure | Systolic blood pressure | -0.99 mm Hg | Standard Error 1.34 |
Secondary
HbA1c Below 7.0% (53 mmol/Mol) American Diabetes Association (ADA) Target
Percentage of subjects with HbA1C below 7.0% after 30 weeks treatment. Missing data imputed from a mixed model for repeated measurements with treatment, country and stratification variable (HbA1c level at screening \[\<= 8.0% or \> 8.0%\] crossed with use of metformin \[yes or no\]; 2 by 2 levels) as fixed factors and baseline value as covariate, all nested within visit.
Time frame: After 30 weeks treatment
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Semaglutide 0.5 mg | HbA1c Below 7.0% (53 mmol/Mol) American Diabetes Association (ADA) Target | 60.6 percentage of subjects |
| Semaglutide 1.0 mg | HbA1c Below 7.0% (53 mmol/Mol) American Diabetes Association (ADA) Target | 78.6 percentage of subjects |
| Placebo | HbA1c Below 7.0% (53 mmol/Mol) American Diabetes Association (ADA) Target | 10.5 percentage of subjects |
Secondary
HbA1c Below or Equal to 6.5% (48 mmol/Mol) American Association of Clinical Endocrinologists (AACE) Target
Percentage of participants with HbA1c below or equal to 6.5% after 30 weeks treatment. Missing data imputed from a mixed model for repeated measurements with treatment, country and stratification variable (HbA1c level at screening \[\<= 8.0% or \> 8.0%\] crossed with use of metformin \[yes or no\]; 2 by 2 levels) as fixed factors and baseline value as covariate, all nested within visit.
Time frame: After 30 weeks treatment
Population: Full analysis set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Semaglutide 0.5 mg | HbA1c Below or Equal to 6.5% (48 mmol/Mol) American Association of Clinical Endocrinologists (AACE) Target | 40.9 percentage of subjects |
| Semaglutide 1.0 mg | HbA1c Below or Equal to 6.5% (48 mmol/Mol) American Association of Clinical Endocrinologists (AACE) Target | 61.1 percentage of subjects |
| Placebo | HbA1c Below or Equal to 6.5% (48 mmol/Mol) American Association of Clinical Endocrinologists (AACE) Target | 4.5 percentage of subjects |
Secondary
Patient Reported Outcomes, Diabetes Treatment Satisfaction Questionnaire (DTSQ)
The DTSQs questionnaire was used to assess subjects' treatment satisfaction and 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. The post-baseline responses are analysed using an ANCOVA model with treatment, country and stratification variables (HbA1c level at screening \[\<= 8.0% or \> 8.0%\] and use of metformin \[yes or no\]) as fixed factors and baseline value as covariate. Mean estimates are adjusted according to observed baseline distribution. Missing data was imputed using last observation carried forward.
Time frame: week 0, week 30
Population: Full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Semaglutide 0.5 mg | Patient Reported Outcomes, Diabetes Treatment Satisfaction Questionnaire (DTSQ) | 2.73 scores on a scale | Standard Error 0.46 |
| Semaglutide 1.0 mg | Patient Reported Outcomes, Diabetes Treatment Satisfaction Questionnaire (DTSQ) | 3.47 scores on a scale | Standard Error 0.46 |
| Placebo | Patient Reported Outcomes, Diabetes Treatment Satisfaction Questionnaire (DTSQ) | 1.25 scores on a scale | Standard Error 0.5 |