A Randomised Controlled Clinical Trial in Type 2 Diabetes Comparing Semaglutide to Placebo and Liraglutide

Study Overview
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Brief Summary
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This trial was conducted in Europe,Asia and Africa. Study participants were randomised evenly to treatment with semaglutide (0.1 mg QW - 1.6 mg QW, 6 treatment arms, placebo or liraglutide (1.2 mg QD, or 1.8 mg QD).Treatment allocation to semaglutide or placebo was double-blind, whereas liraglutide treatment was administered open-label.Primary efficacy parameter was HbA1c and the treatment duration was 12 weeks.

Official Title
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Investigation of Safety and Efficacy of Five Doses of Semaglutide Versus Placebo and Open-label Liraglutide, as Add on Therapy, in Subjects Diagnosed With Type 2 Diabetes Currently Treated With Metformin or Controlled With Diet and Exercise A 12 Week Multi-centre, Multi National, Double-blind, Placebo-controlled, Randomised, Nine Armed Parallel Group, Dose Finding Trial

Conditions
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Diabetes, Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: semaglutide
* Drug: semaglutide
* Drug: semaglutide
* Drug: semaglutide
* Drug: semaglutide
* Drug: semaglutide
* Drug: placebo
* Drug: placebo
* Drug: placebo
* Drug: placebo
* Drug: placebo
* Drug: liraglutide
* Drug: liraglutide


Participation Criteria
=================
Eligibility Criteria
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Inclusion Criteria: Men and women-not-of-childbearing potential diagnosed with type 2 diabetes for at least three months Stable treatment regimen with either metformin (at least 1500 mg) or diet and exercise alone for at least three months HbA1c: 7.0-10.0 % (both inclusive) Body weight between 60 kg and 110 kg Exclusion Criteria: Treatment with insulin, GLP-1 receptor agonists (including liraglutide), dipeptidyl peptidase-4 inhibitors, sulphonylurea, thiazolidinediones, Alpha-GIs, or any investigational drug, within the last three months Impaired liver or kidney function Proliferative retinopathy or maculopathy requiring acute treatment Clinically significant active cardiovascular disease and uncontrolled treated/untreated hypertension Recurrent major hypoglycaemia or hypoglycaemic unawareness Present or planned use of any drug which could interfere with the glucose levels (e.g. systemic corticosteroids)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br> | Drug: semaglutide<br>* 0.1 mg, once weekly, s.c. injection<br>* Other names: NN9535;|
| Experimental: B<br> | Drug: semaglutide<br>* 0.2 mg, once weekly, s.c. injection<br>* Other names: NN9535;|
| Experimental: C<br> | Drug: semaglutide<br>* 0.4 mg, once weekly, s.c. injection<br>* Other names: NN9535;|
| Experimental: D<br> | Drug: semaglutide<br>* 0.8 mg, once weekly, s.c. injection<br>* Other names: NN9535;|
| Experimental: E<br> | Drug: semaglutide<br>* 0.8 mg with titration, once weekly, s.c. injection<br>* Other names: NN9535;|
| Experimental: F<br> | Drug: semaglutide<br>* 1.6 mg with titration, once weekly, s.c. injection<br>* Other names: NN9535;|
| Placebo Comparator: G1<br> | Drug: placebo<br>* 0.1 mg, once weekly, s.c. injection<br>|
| Placebo Comparator: G2<br> | Drug: placebo<br>* 0.2 mg, once weekly, s.c. injection<br>|
| Placebo Comparator: G3<br> | Drug: placebo<br>* 0.4 mg, once weekly, s.c. injection<br>|
| Placebo Comparator: G4<br> | Drug: placebo<br>* 0.8 mg with titration, once weekly, s.c. injection<br>|
| Placebo Comparator: G5<br> | Drug: placebo<br>* 0.8 mg with titration, once weekly, s.c. injection<br>|
| Placebo Comparator: G6<br> | Drug: placebo<br>* 1.6 mg, once weekly, s.c. injection<br>|
| Experimental: H<br> | Drug: liraglutide<br>* 1.2 mg with titration, once daily, s.c. injection<br>|
| Experimental: I<br> | Drug: liraglutide<br>* 1.8 mg with titration, once daily, s.c. injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HbA1c | Change from baseline in HbA1c was evaluated after 12 weeks of treatment. Post baseline (week 0) missing values were replaced using the last observation carried forward (LOCF) approach. | After 12 weeks of treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects With an Adverse Events | The results of adverse event presented here are treatment emergent, i.e., TEAE. A TEAE was defined as an event that had onset on or after the first date (week 0) on trial product and no later than 5 weeks after the last date on trial product (week 17), or that had onset before the first date on trial product and increases in severity during the treatment period until 5 weeks after the last date on trial product. | After 12 weeks of treatment. | 
| Percentage of Subjects With Hypoglycaemic Episode | The results of hypoglycaemic episode presented here are treatment emergent. Hypoglycaemic episodes were defined as treatment emergent if they had onset on or after the first day of randomised treatment (in week 0) and no later than 5 weeks after the last date on trial product (week 17). Hypoglycaemic episodes are classified as follows: Major: If the subject was not able to treat himself or herself and was needed to be administered food, glucagon or intravenous (i.v.) glucose by another person. Minor: If the subject was able to treat himself or herself and measured plasma glucose was <3.1 mmol/L (56 mg/dL). Symptoms only: If the subject was able to treat himself or herself and measured plasma glucose was >=3.1 mmol/L (56 mg/dL) or no plasma glucose measurement was done. | After 12 weeks of treatment | 
| Change From Baseline in ECG | A standard 12 lead electrocardiogram (ECG) with a 10-second rhythm strip was performed at screening (week -2) and at the end of treatment (week 12). The time frame should be read as week -2, week 12. Change from baseline in ECG was measured in terms of number of subjects in each category (normal, abnormal, not clinically significant [NCS] or abnormal clinically significant [CS]) at week -2 and week 12 (i.e., change in each category in terms of number of subjects from week -2 to week 12). | Week 0, week 12. | 
| Change From Baseline in Vital Signs (Pulse) | Change from baseline in pulse was evaluated after 12 weeks of treatment. Post baseline (week 0) missing values were replaced using the LOCF approach. | Week 0, week 12 | 
| Change From Baseline in Vital Signs (Blood Pressure; SBP) | Change from baseline in systolic blood pressure (SBP) was evaluated after 12 weeks of treatment. Post baseline (week 0) missing values were replaced using the LOCF approach. | Week 0, week 12 | 
| Change From Baseline in Vital Signs (Blood Pressure; DBP) | Change from baseline in diastolic blood pressure (DBP) was evaluated after 12 weeks of treatment. Post baseline (week 0) missing values were replaced using the LOCF approach. | Week 0, week 12 | 
| Change From Baseline in Standard Safety Laboratory Parameter (Haematology; Basophils) | Change from baseline in basophils was evaluated after 12 weeks of treatment. Post baseline (week 0) missing values were replaced using the LOCF approach. | Week 0, week 12 | 
| Change From Baseline in Standard Safety Laboratory Parameter (Haematology; Eosinophils) | Change from baseline in eosinophils was evaluated after 12 weeks of treatment. Post baseline (week 0) missing values were replaced using the LOCF approach. | Week 0, week 12 | 
| Change From Baseline in Standard Safety Laboratory Parameter (Haematology; Haematocrit) | Change from baseline in haematocrit (the proportion of blood that consists of red blood cells) was evaluated after 12 weeks of treatment. Post baseline (week 0) missing values were replaced using the LOCF approach. | Week 0, week 12 | 
| Change From Baseline in Standard Safety Laboratory Parameter (Haematology; Haemoglobin) | Change from baseline in haemoglobin was evaluated after 12 weeks of treatment. Post baseline (week 0) missing values were replaced using the LOCF approach. | Week 0, week 12 | 
| Change From Baseline in Standard Safety Laboratory Parameter (Haematology; Lymphocytes) | Change from baseline in lymphocytes was evaluated after 12 weeks of treatment. Post baseline (week 0) missing values were replaced using the LOCF approach. | Week 0, week 12 | 
| Change From Baseline in Standard Safety Laboratory Parameter (Haematology; Monocytes) | Change from baseline in monocytes was evaluated after 12 weeks of treatment. Post baseline (week 0) missing values were replaced using the LOCF approach. | Week 0, week 12 | 
| Change From Baseline in Standard Safety Laboratory Parameter (Haematology; Neutrophils) | Change from baseline in neutrophils was evaluated after 12 weeks of treatment. Post baseline (week 0) missing values were replaced using the LOCF approach. | Week 0, week 12 | 
| Change From Baseline in Standard Safety Laboratory Parameter (Haematology; Thrombocytes) | Change from baseline in thrombocytes was evaluated after 12 weeks of treatment. Post baseline (week 0) missing values were replaced using the LOCF approach. | Week 0, week 12 | 
| Change From Baseline in Standard Safety Laboratory Parameter (Haematology; Erythrocytes) | Change from baseline in erythrocytes was evaluated after 12 weeks of treatment. Post baseline (week 0) missing values were replaced using the LOCF approach. | Week 0, week 12 | 
| Change From Baseline in Standard Safety Laboratory Parameter (Haematology; Leukocytes) | Change from baseline in leukocytes was evaluated after 12 weeks of treatment. Post baseline (week 0) missing values were replaced using the LOCF approach. | Week 0, week 12 | 
| Change From Baseline in Standard Safety Laboratory Parameter (Biochemistry; Albumin) | Change from baseline in albumin was evaluated after 12 weeks of treatment. Post baseline (week 0) missing values were replaced using the LOCF approach. | Week 0, week 12. | 
| Change From Baseline in Standard Safety Laboratory Parameter (Biochemistry; Alkaline Phosphatase) | Change from baseline in alkaline phosphatase was evaluated after 12 weeks of treatment. Post baseline (week 0) missing values were replaced using the LOCF approach. | Week 0, week 12. | 
| Change From Baseline in Standard Safety Laboratory Parameter (Biochemistry; AST) | Change from baseline in aspartate aminotransferase (AST) was evaluated after 12 weeks of treatment. Post baseline (week 0) missing values were replaced using the LOCF approach. | Week 0, week 12. | 
| Change From Baseline in Standard Safety Laboratory Parameter (Biochemistry; ALAT) | Change from baseline in alanine aminotransferase (ALAT) was evaluated after 12 weeks of treatment. Post baseline (week 0) missing values were replaced using the LOCF approach. | Week 0, week 12. | 
| Change From Baseline in Standard Safety Laboratory Parameter (Biochemistry; Total Bilirubin) | Change from baseline in total bilirubin was evaluated after 12 weeks of treatment. Post baseline (week 0) missing values were replaced using the LOCF approach. | Week 0, week 12. | 
| Change From Baseline in Standard Safety Laboratory Parameter (Biochemistry; Calcium, Total) | Change from baseline in calcium, total was evaluated after 12 weeks of treatment. Post baseline (week 0) missing values were replaced using the LOCF approach. | Week 0, week 12. | 
| Change From Baseline in Standard Safety Laboratory Parameter (Biochemistry; Calcium, Ionised) | Change from baseline in calcium, ionised was evaluated after 12 weeks of treatment. Post baseline (week 0) missing values were replaced using the LOCF approach. | Week 0, week 12. | 
| Change From Baseline in Standard Safety Laboratory Parameter (Biochemistry; Creatinine) | Change from baseline in creatinine was evaluated after 12 weeks of treatment. Post baseline (week 0) missing values were replaced using the LOCF approach. | Week 0, week 12. | 
| Change From Baseline in Standard Safety Laboratory Parameter (Biochemistry; Potassium) | Change from baseline in potassium was evaluated after 12 weeks of treatment. Post baseline (week 0) missing values were replaced using the LOCF approach. | Week 0, week 12. | 
| Change From Baseline in Standard Safety Laboratory Parameter (Biochemistry; Sodium) | Change from baseline in sodium was evaluated after 12 weeks of treatment. Post baseline (week 0) missing values were replaced using the LOCF approach. | Week 0, week 12. | 
| Change From Baseline in Standard Safety Laboratory Parameter (Biochemistry; Urea) | Change from baseline in urea was evaluated after 12 weeks of treatment. Post baseline (week 0) missing values were replaced using the LOCF approach. | Week 0, week 12. | 
| Change From Baseline in Standard Safety Laboratory Parameter (Urinalysis; Glucose) | Change from baseline in urine-glucose was measured in terms of number of subjects in each category (negative, positive, >=55 mmol/L, or missing) at week 0 and week 12 (i.e., change in each category in terms of number of subjects from week 0 to week 12). | Week 0, week 12 | 
| Change From Baseline in Standard Safety Laboratory Parameter (Urinalysis; Haemoglobin) | Change from baseline in urine-haemoglobin was measured in terms of number of subjects in each category (negative, trace, small, moderate/large and missing) at week 0 and week 12 (i.e., change in each category in terms of number of subjects from week 0 to week 12). | Week 0, week 12 | 
| Change From Baseline in Standard Safety Laboratory Parameter (Urinalysis; Ketones) | Change from baseline in urine-ketone was measured in terms of number of subjects in each category (negative, positive, >=55 mmol/L and missing) at week 0 and week 12 (i.e., change in each category in terms of number of subjects from week 0 to week 12). | Week 0, week 12 | 
| Change From Baseline in Standard Safety Laboratory Parameter (Urinalysis; pH) | Change from baseline in urine-pH was measured in terms of number of subjects in each category (pH=6.0, 6.5, 7.0, 7.5, 8.0, >=8.5 and missing) at week 0 and week 12 (i.e., change in each category in terms of number of subjects from week 0 to week 12). | Week 0, week 12 | 
| Change From Baseline in Standard Safety Laboratory Parameter (Urinalysis; Protein) | Change from baseline in urine-protein was measured in terms of number of subjects in each category at week 0 (negative, 0.3 g/L, 1.0 g/L and missing) and week 12 (negative, trace, 0.3 g/L, 1.0 g/L, >=3.0 g/L and missing). i.e., change in each category in terms of number of subjects from week 0 to week 12. | Week 0, week 12 | 
| Change From Baseline in Calcitonin | Change from baseline in calcitonin was evaluated after 12 weeks of treatment. Post baseline (week 0) missing values were replaced using the LOCF approach. | Week 0, week 12. | 
| Percentage of Subjects Developing Anti-semaglutide Antibodies | Antibodies were measured after 12-week of treatment at week 17; percentage of participants with positive anti-semaglutide antibodies are presented here. Assessments of antibodies were not done for subjects allocated to the open-label liraglutide treatment arms. | After 12 weeks of treatment |