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

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

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.

Study Overview

• Status: Completed
• Conditions: Diabetes; Type 2 Diabetes Mellitus
• Intervention / Treatment: Drug: biphasic insulin aspart 30

• Study Type: Interventional
• Enrollment (Actual): 437
• Phase: Phase 4

Contacts and Locations

Study Locations

• Algeria
  • Algiers, Algeria, 16000
    • Novo Nordisk Investigational Site
  • Algiers, Algeria, 16049
    • Novo Nordisk Investigational Site
  • Oran, Algeria, 31000
    • Novo Nordisk Investigational Site
• China
  • Anhui
    • Hefei, Anhui, China, 230001
      • Novo Nordisk Investigational Site
  • Beijing
    • Beijing, Beijing, China, 100029
      • Novo Nordisk Investigational Site
    • Beijing, Beijing, China, 100730
      • Novo Nordisk Investigational Site
    • Beijing, Beijing, China, 100071
      • Novo Nordisk Investigational Site
    • Beijing, Beijing, China, 100144
      • Novo Nordisk Investigational Site
    • Beijing, Beijing, China, 100191
      • Novo Nordisk Investigational Site
  • Chongqing
    • ChongQing, Chongqing, China, 404000
      • Novo Nordisk Investigational Site
  • Fujian
    • Fuzhou, Fujian, China, 350001
      • Novo Nordisk Investigational Site
  • Guangdong
    • Guangzhou, Guangdong, China, 510515
      • Novo Nordisk Investigational Site
    • Shenzhen, Guangdong, China, 518035
      • Novo Nordisk Investigational Site
  • Hebei
    • Shijiazhuang, Hebei, China, 050000
      • Novo Nordisk Investigational Site
  • Jiangsu
    • Changzhou, Jiangsu, China, 213003
      • Novo Nordisk Investigational Site
    • Nanjing, Jiangsu, China, 210011
      • Novo Nordisk Investigational Site
    • Nanjing, Jiangsu, China, 210012
      • Novo Nordisk Investigational Site
    • Nanjing, Jiangsu, China, 210029
      • Novo Nordisk Investigational Site
    • Suzhou, Jiangsu, China, 215006
      • Novo Nordisk Investigational Site
    • Wuxi, Jiangsu, China, 214023
      • Novo Nordisk Investigational Site
    • Zhenjiang, Jiangsu, China, 212001
      • Novo Nordisk Investigational Site
  • Jiangxi
    • Nanchang, Jiangxi, China, 330006
      • Novo Nordisk Investigational Site
  • Jilin
    • Changchun, Jilin, China, 130021
      • Novo Nordisk Investigational Site
  • Liaoning
    • Dalian, Liaoning, China, 116011
      • Novo Nordisk Investigational Site
  • Shanghai
    • Shanghai, Shanghai, China, 200240
      • Novo Nordisk Investigational Site
    • Shanghai, Shanghai, China, 200072
      • Novo Nordisk Investigational Site
  • Sichuan
    • Chengdu, Sichuan, China, 610071
      • Novo Nordisk Investigational Site
  • Tianjin
    • Tianjin, Tianjin, China, 300052
      • Novo Nordisk Investigational Site
• Hong Kong
  • Shatin, New Territories, Hong Kong
    • Novo Nordisk Investigational Site
• India
  • New Delhi, India, 110088
    • Novo Nordisk Investigational Site
  • Andhra Pradesh
    • Visakhapatnam, Andhra Pradesh, India, 530002
      • Novo Nordisk Investigational Site
  • Assam
    • Guwahati, Assam, India, 781006
      • Novo Nordisk Investigational Site
  • Karnataka
    • Bangalore, Karnataka, India, 560002
      • Novo Nordisk Investigational Site
    • Bangalore, Karnataka, India, 560038
      • Novo Nordisk Investigational Site
    • Mysore, Karnataka, India, 570001
      • Novo Nordisk Investigational Site
  • Tamil Nadu
    • Madurai, Tamil Nadu, India, 625 020
      • Novo Nordisk Investigational Site
  • West Bengal
    • Kolkata, West Bengal, India, 700080
      • Novo Nordisk Investigational Site
• Taiwan
  • Kaohsiung, Taiwan, 813
    • Novo Nordisk Investigational Site
  • Taichung City, Taiwan, 407
    • Novo Nordisk Investigational Site
  • Taipei, Taiwan, 114
    • Novo Nordisk Investigational Site
  • Taipei, Taiwan, 11217
    • Novo Nordisk Investigational Site
• Turkey
  • Adana, Turkey, 01130
    • Novo Nordisk Investigational Site
  • Bursa, Turkey, 16059
    • Novo Nordisk Investigational Site
  • Istanbul, Turkey, 34390
    • Novo Nordisk Investigational Site
  • Istanbul, Turkey, 34093
    • Novo Nordisk Investigational Site
  • Kahramanmaras, Turkey, 46000
    • Novo Nordisk Investigational Site
• Ukraine
  • Dnipro, Ukraine, 49005
    • Novo Nordisk Investigational Site
  • Kiev, Ukraine, 01004
    • Novo Nordisk Investigational Site
  • Lviv, Ukraine, 79010
    • Novo Nordisk Investigational Site
  • Ternopil, Ukraine, 46002
    • Novo Nordisk Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: BIAsp 30 BID	Drug: biphasic insulin aspart 30; Administered subcutaneously (s.c., under the skin) thrice daily or twice daily. Subjects will continue with metformin all throughout the trial.
Experimental: BIAsp 30 TID	Drug: biphasic insulin aspart 30; Administered subcutaneously (s.c., under the skin) thrice daily or twice daily. Subjects will continue with metformin all throughout the trial.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Novo Nordisk A/S

Publications and helpful links

General Publications

• Yang W, Ersoy C, Wang G, Ye S, Liu J, Miao H, Asirvatham A, Werther S, Kadu P, Chow F. Efficacy and safety of three-times-daily versus twice-daily biphasic insulin aspart 30 in patients with type 2 diabetes mellitus inadequately controlled with basal insulin combined with oral antidiabetic drugs. Diabetes Res Clin Pract. 2019 Apr;150:158-166. doi: 10.1016/j.diabres.2019.02.023. Epub 2019 Mar 11.

Helpful Links

• Clinical Trials at Novo Nordisk

Study record dates

Study Major Dates

• Study Start (Actual): October 19, 2015
• Primary Completion (Actual): March 18, 2017
• Study Completion (Actual): April 18, 2017

Study Registration Dates

• First Submitted: October 16, 2015
• First Submitted That Met QC Criteria: October 19, 2015
• First Posted (Estimate): October 21, 2015

Study Record Updates

• Last Update Posted (Actual): June 11, 2019
• Last Update Submitted That Met QC Criteria: May 28, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Insulin Aspart; Biphasic Insulins; Insulin aspart, insulin aspart protamine drug combination 30:70
• Other Study ID Numbers: BIASP-4200; U1111-1162-5508 (Other Identifier: WHO)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: According to the Novo Nordisk disclosure commitment on novonordisk-trials.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes