Treatment Intensification With Biphasic Insulin Aspart 30 in Subjects With Type 2 Diabetes Inadequately Controlled on Sitagliptin and Metformin

Study Overview
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Brief Summary
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This trial is conducted in Asia, Europe, Oceania and South America. The aim of this clinical trial is to generate data demonstrating how to intensify diabetes treatment using BIAsp 30 (biphasic insulin aspart 30) by adding or substituting BIAsp 30 to sitagliptin in various regimens for type 2 patients inadequately controlled on sitagliptin and metformin (with or without other oral anti-diabetic drugs (OADs)). The trial is conducted as a phase 4 trial in the majority of the participating countries. However, in some countries the trial is conducted as phase 3b.

Official Title
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A 24 Week Randomised, Open Label, 3 Parallel-group Comparison of Once and Twice Daily Biphasic Insulin Aspart (BIAsp) 30 Plus Sitagliptin and Twice Daily BIAsp 30, All in Combination With Metformin in Insulin naïve Type 2 Diabetic Subjects Inadequately Controlled on Sitagliptin and Metformin

Conditions
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Diabetes, Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: biphasic insulin aspart 30
* Drug: biphasic insulin aspart 30
* Drug: sitagliptin
* Drug: metformin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosed with type 2 diabetes for a minimum of 6 months prior to screening (Visit 1) Stable treatment with a total daily dose of at least 1000 mg of metformin (with or without additional oral anti-diabetic drugs (OADs) treatment). The metformin dose must have been unchanged for at least 3 months prior to screening (Visit 1) Stable treatment with a total daily dose of at least 100 mg sitagliptin. The sitagliptin dose must have been unchanged for at least 3 months prior to screening (Visit 1) Subject is insulin-naïve (never previously treated with insulin). (However, short term insulin use due to intermittent illness of up to 14 days or insulin treatment for gestational diabetes is allowed) HbA1c (glycosylated haemoglobin) between 7.0 to 10.0 % (53-86 mmol/mol) (both inclusive) by central laboratory analysis demonstrating inadequate control on sitagliptin and metformin (with or without other OADs) Body Mass Index (BMI) below or equal to 40.0 kg/m^2 Able and willing to eat at least 2 meals (breakfast and dinner) every day during the trial Exclusion Criteria: Treatment with thiazolidinedione (TZD) or glucagon-like-peptide-1 (GLP-1) receptor agonist within the last 3 months prior to screening (Visit 1) Cardiac disease within the last 6 months prior to screening (Visit 1), defined as: decompensated heart failure New York Heart Association (NYHA) class III or IV; unstable angina pectoris; or myocardial infarction Severe hypertension, systolic blood pressure equal to or above 180 mm Hg or diastolic blood pressure equal to or above 100 mm Hg, after 5 minutes rest in the sitting position using mean value of 3 measurements at screening (Visit 1) Anticipated change of dose of any systemic treatment with products, which in the trial physician's opinion could interfere with glucose metabolism (e.g., systemic corticosteroids) Clinically significant diseases (except for conditions associated with type 2 diabetes) which, in the trial physician's opinion may confound the results of the trial or pose additional risk in administering trial product(s) Impaired hepatic function as indicated by aspartate aminotransferase (ASAT) or alanine aminotransferase (ALAT) above 2.5 times the upper normal range, according to central laboratory reference ranges Impaired renal function as indicated by serum creatinine levels equal to or above 133 micromol/L (1.5 mg/dL) for males and equal to or above 124 micromol/L (1.4 mg/dL) for females or estimated creatinine clearance below 60 mL/min, based on the Cockroft & Gault formula and according to local practise for metformin use

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: BIAsp 30 BID + sitagliptin + metformin<br> | Drug: biphasic insulin aspart 30<br>* BIAsp 30 will be injected subcutaneously (under the skin) twice daily. Individually adjusted dose.<br>Drug: sitagliptin<br>* Subjects will continue on their pre-trial sitagliptin treatment.<br>Drug: metformin<br>* Subjects will continue on their pre-trial metformin treatment.<br>|
| Active Comparator: BIAsp 30 BID + metformin<br> | Drug: biphasic insulin aspart 30<br>* BIAsp 30 will be injected subcutaneously (under the skin) twice daily. Individually adjusted dose.<br>Drug: metformin<br>* Subjects will continue on their pre-trial metformin treatment.<br>|
| Active Comparator: BIAsp 30 OD + sitagliptin + metformin<br> | Drug: biphasic insulin aspart 30<br>* BIAsp 30 will be injected subcutaneously (under the skin) once daily. Individually adjusted dose.<br>Drug: sitagliptin<br>* Subjects will continue on their pre-trial sitagliptin treatment.<br>Drug: metformin<br>* Subjects will continue on their pre-trial metformin treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in HbA1c (Glycosylated Haemoglobin) | Estimated mean change from baseline in HbA1c after 24 weeks of treatment. | Week 0 to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Responder for HbA1c, Proportion of Subjects Achieving Pre-defined HbA1c Targets (HbA1c < 7.0%) | Proportion of subjects achieving HbA1c below 7.0% after 24 weeks of treatment | After 24 weeks of treatment | 
| Responder for HbA1c, Proportion of Subjects Achieving Pre-defined HbA1c Targets (HbA1c ≤ 6.5%) | Proportion of subjects achieving HbA1c equal to or below 6.5% after 24 weeks of treatment. | After 24 weeks of treatment | 
| Change From Baseline in Fasting Plasma Glucose (FPG) | Estimated mean change from baseline in fasting plasma glucose (FPG) | Week 0 to Week 24 | 
| Prandial Plasma Glucose (PPG) Increments at Breakfast | Estimated mean post prandial increments at breakfast after 24 weeks of treatment. | After 24 weeks of treatment | 
| Prandial Plasma Glucose (PPG) Increments at Lunch. | Estimated mean post prandial increments at lunch after 24 weeks of treatment. | After 24 weeks of treatment | 
| Prandial Plasma Glucose (PPG) Increments at Dinner. | Estimated mean post prandial increments at dinner after 24 weeks of treatment. | After 24 weeks of treatment | 
| Prandial Plasma Glucose (PPG) Overall Mean Increment. | Estimated overall mean post prandial increment after 24 weeks of treatment. | After 24 weeks of treatment | 
| Adverse Events (AEs) | Rate of AEs per 100 years of patient exposure. An adverse event was defined as treatment emergent if the event had onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. | Week 0 to Week 24 | 
| Number of Treatment Emergent Hypoglycaemic Episodes (Nocturnal and Day-time) Classified Both According to the American Diabetes Association (ADA) Definition and to an Additional Definition for Minor Episodes. | Number of treatment emergent hypoglycaemic episodes. Treatment emergent hypoglycaemic episode: if the onset of the episode was on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Nocturnal: Time of onset between 00:01 and 05:59 a.m. (both included). Additional minor hypoglycaemic episode: symptomatic or asymptomatic hypoglycaemia with blood glucose (BG) values < 2.8 mmol/L (50 mg/dL) or plasma glucose (PG) < 3.1 mmol/L (56 mg/dL), and which was handled by the subject him/herself. | Week 0 to Week 24 | 
| Change From Baseline in Patient Reported Outcome by Use of the Treatment Related Impact Measure - Diabetes. | Estimated mean change from baseline in Treatment Related Impact Measure - Diabetes (TRIM-D) 'total score' to end of trial. The score measured treatment satisfaction. The scores were transformed to a 0-100 scale with higher scores indicating greater satisfaction. | Week 0 to Week 24 |