Comparing Efficacy and Safety of Thrice Daily Versus Twice Daily NovoMix® 30 (Biphasic Insulin Aspart 30) in Subjects With Type 2 Diabetes Inadequately Controlled With Basal Insulin

Study Overview
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Brief Summary
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This trial is conducted in Asia. The aim of the trial is to compare efficacy and safety of thrice daily versus twice daily NovoMix® 30 (Biphasic insulin aspart 30) in subjects with type 2 diabetes inadequately controlled with basal insulin.

Official Title
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A 24-week, Multinational, Multicentre, Randomised, Open Label, Parallel-group Treat-to-target Trial to Compare Efficacy and Safety of Thrice Daily Versus Twice Daily NovoMix® 30 (Biphasic Insulin Aspart 30) in Subjects With Type 2 Diabetes Inadequately Controlled With Basal Insulin

Conditions
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Diabetes, Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: biphasic insulin aspart 30


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, age at least 18 years at the time of signing informed consent. For Algeria only: age at least 19 years at the time of signing informed consent Type 2 diabetes subjects clinically diagnosed for at least 12 months prior to the day of screening (Visit 1) Treated with basal insulin for at least 90 days prior to the day of screening (Visit 1). The following basal insulin are allowed : insulin analogue once daily (OD) Neutral Protamine Hagedorn (NPH) OD or BID (twice daily) Treatment with metformin with or without one additional OAD (oral antidiabetic drug) for at least 90 days prior to the day of screening (Visit 1) Metformin must be at a stable dose of at least 1500 mg daily or maximum tolerated dose for at least 60 days prior to screening (Visit 1) One additional OAD:Sulphonylurea/Glinides/ a-glucosidase inhibitors/Dipeptidyl-peptidase-4 inhibitors/Sodium glucose co-transporter 2 (SGLT2) inhibitors (if applicable) HbA1c (glycosylated haemoglobin) 7.5%-10.0% (both inclusive) by central laboratory analysis at screening (Visit 1) Able and willing to intake three main meals daily (breakfast, lunch and main evening meal) throughout the trial. Definition of main meal as judged by the investigator Exclusion Criteria: Previous insulin intensification regimen for more than 14 days: premixed insulin thrice daily, basal-bolus regimen or continuous subcutaneous insulin infusion (CSII). Treatment during hospitalisation or during gestational diabetes is allowed for periods longer than 14 days Anticipated initiation or change in concomitant medications for more than 14 consecutive days or on a frequent basis known to affect weight or glucose metabolism (e.g. orlistat, thyroid hormones, systemic corticosteroids) Impaired liver function, defined as alanine aminotransferase (ALT) equal to or above 2.5 times upper normal limit at screening (Visit 1)

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 |
| --- | --- |
| Experimental: BIAsp 30 TID<br> | Drug: biphasic insulin aspart 30<br>* Administered subcutaneously (s.c., under the skin) thrice daily or twice daily. Subjects will continue with metformin all throughout the trial.<br>|
| Active Comparator: BIAsp 30 BID<br> | Drug: biphasic insulin aspart 30<br>* Administered subcutaneously (s.c., under the skin) thrice daily or twice daily. Subjects will continue with metformin all throughout the trial.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Glycosylated Haemoglobin (HbA1c) | Change from baseline in HbA1c was evaluated after 24 weeks of treatment. Missing data was imputed using the last observation carried forward (LOCF) method. | Week 0, Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Subjects Achieving HbA1c Below 7.0% | Percentage of subjects achieving HbA1c <7.0% (yes or no) was evaluated after 24 weeks of treatment. | Week 24 | 
| Proportion of Subjects Achieving HbA1c Below 7.0% Without Severe Hypoglycaemic Episodes. | Percentage of subjects achieving HbA1c <7.0% (yes or no) without severe hypoglycaemic episodes was evaluated after 24 weeks of treatment. Severe hypoglycaemia: Episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions. Plasma glucose (PG) concentrations may not be available during event, but neurological recovery following return of PG to normal is considered sufficient evidence that the event was induced by low PG concentration. | Week 24 | 
| Proportion of Subjects Achieving HbA1c Below 7.0% Without Severe or Blood Glucose (BG) Confirmed Hypoglycaemic Episodes (According to the Novo Nordisk Classification) | Percentage of subjects achieving HbA1c <7.0% (yes or no) without severe or BG confirmed hypoglycaemic episodes (according to the Novo Nordisk classification) was evaluated after 24 weeks of treatment. Severe or BG confirmed hypoglycaemia: an episode that is severe according to the American Diabetes Association (ADA) classification or BG confirmed by a plasma glucose (PG) value <3.1 mmol/L (56 mg/dL) with or without symptoms consistent with hypoglycaemia. Severe hypoglycaemia as per ADA: Episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions. PG concentrations may not be available during event, but neurological recovery following return of PG to normal is considered sufficient evidence that the event was induced by low PG concentration. | Week 24 | 
| Number of Treatment Emergent Hypoglycaemic Episodes Classified According to the American Diabetes Association (ADA) Definition | ADA classification of hypoglycaemia: Severe:Episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions. PG concentrations may not be available during event, but neurological recovery following return of PG to normal is considered sufficient evidence that the event was induced by low PG concentration Asymptomatic:Episode not accompanied by typical symptoms of hypoglycaemia, but with a measured PG concentration ≤3.9 mmol/L Documented symptomatic:Episode during which typical symptoms of hypoglycaemia are accompanied by a measured PG concentration ≤3.9 mmol/L Pseudo:Episode during which person with diabetes reports any of the typical symptoms of hypoglycaemia with measured PG concentration >3.9 mmol/L but approaching that level Probable symptomatic:Episode during which symptoms of hypoglycaemia are not accompanied by PG determination but that was presumably caused by a PG concentration ≤3.9 mmol/L | Week 0-24 | 
| Number of Treatment Emergent Hypoglycaemic Episodes Classified According to Novo Nordisk Definition | Treatment emergent hypoglycaemic episodes were defined as the hypoglycaemic episodes, which occurred on or after the first day of trial product administration (in week 0), and no later than 7 days after the last day on trial product. Novo Nordisk (NN) classification of hypoglycaemia: Severe hypoglycaemia: According to the ADA classification. Blood glucose (BG) confirmed hypoglycaemia: an episode that is BG confirmed by a plasma glucose value <3.1 mmol/L (56 mg/dL) with or without symptoms consistent with hypoglycaemia. Severe or BG confirmed hypoglycaemia: an episode that is severe according to the ADA classification or BG confirmed by a plasma glucose value <3.1 mmol/L (56 mg/dL) with or without symptoms consistent with hypoglycaemia. | Week 0-24 | 
| Change From Baseline in FPG by Central Laboratory Analysis | Change from baseline in fasting plasma glucose (FPG) by central laboratory analysis was evaluated after 24 weeks of treatment. Missing data was imputed using the LOCF method. | Week 0, Week 24 | 
| 7-point SMPG Profile | 7-point self-measured plasma glucose (SMPG) profiles was evaluated after 24 weeks of treatment. Subjects were instructed to perform the following SMPG measurements: Before breakfast. 120 minutes after the start of breakfast. Before lunch. 120 minutes after the start of lunch. Before main evening meal. 120 minutes after the start of main evening meal. At bedtime. Missing data was imputed using the LOCF method. | Week 24 | 
| 7-point SMPG Profiles: Change From Baseline in 2-hour PPG at Individual Meal (Breakfast, Lunch and Main Evening Meal) | Change from baseline in 2-hour postprandial glucose (PPG) at individual meal (breakfast, lunch and main evening meal) was evaluated after 24 weeks of treatment. Missing data was imputed using the LOCF method. | Week 0, Week 24 | 
| 7-point SMPG Profiles: Change From Baseline in PPG Increment at Individual Meal (Breakfast, Lunch and Main Evening Meal) | Change from baseline in PPG increment at individual meal (breakfast, lunch and main evening meal) was evaluated after 24 weeks of treatment. Missing data was imputed using the LOCF method. | Week 0, Week 24 | 
| 7-point SMPG Profiles: Change From Baseline in Mean of 2-hour PPG Over 3 Main Meals (Breakfast, Lunch and Main Evening Meal) | Change from baseline in mean of 2-hour PPG at individual meal (breakfast, lunch and main evening meal) was evaluated after 24 weeks of treatment. Missing data was imputed using the LOCF method. | Week 0, Week 24 | 
| 7-point SMPG Profiles: Change From Baseline in Mean of PPG Increment Over 3 Main Meals (Breakfast, Lunch and Main Evening Meal) | Change from baseline in mean of PPG increment at individual meal (breakfast, lunch and main evening meal) was evaluated after 24 weeks of treatment. Missing data was imputed using the LOCF method. | Week 0, Week 24 | 
| 7-point SMPG Profiles: Change From Baseline in Mean of the 7-point Profile | Change from baseline in mean of the 7-point SMPG profiles was evaluated after 24 weeks of treatment. Missing data was imputed using the LOCF method. | Week 0, Week 24 | 
| 7-point SMPG Profiles: Fluctuation in the 7-point Profile | Fluctuation in the 7-point SMPG profile was evaluated after 24 weeks of treatment. Fluctuation in 7-point SMPG profile was the average absolute difference to the mean of the profile of the 7-point SMPG measurements accumulated over the profile. Missing data was imputed using the LOCF method. | Week 24 | 
| Incidence of Treatment Emergent Adverse Events (TEAEs) | Incidence of TEAEs was recorded during 24 weeks of treatment. A TEAE was defined as an event that has onset date (or increase in severity) on or after the first day of exposure to trial product (in week 0) and no later than 7 days after the last day on trial product. | Week 0-24 | 
| Total Daily Insulin Dose | Total daily insulin dose was the sum of doses given before breakfast and before main evening meal for the BID treatment group, and the sum of doses given before breakfast, before lunch and before main evening meal for the TID treatment group. Missing data was imputed using the LOCF method. | Week 1, Week 24 | 
| Change From Baseline in Body Weight | Change from baseline in body weight was evaluated after 24 weeks of treatment. Missing data was imputed using the LOCF method. | Week 0, Week 24 | 
| Change From Baseline in Patient-reported Treatment Satisfaction as Assessed by the Diabetes Treatment Satisfaction Questionnaire (Status) (DTSQs) | Change from baseline in patient-reported treatment satisfaction (as assessed by the DTSQs) was evaluated after 24 weeks of treatment. The DTSQs is a self-completion questionnaire used to investigate the subject's treatment satisfaction. The DTSQ contained 8 questions, which were scored on a scale from 0 to 6. Out of 8 questions, 6 were related to the overall treatment satisfaction and 2 were related to glycaemic control (hypoglycaemia and hyperglycaemia). Results for the 6 questions relating to overall treatment satisfaction are presented together whereas the 2 questions relating to blood glucose are presented separately. For the overall treatment satisfaction, a higher score (0-36) was related to a better perception of treatment satisfaction. For hypoglycaemia and hyperglycaemia, a lower score (0-6) was related to a better blood glucose control. Missing data was imputed using the LOCF method. | Week 0, Week 24 |