Treatment Intensification With Biphasic Insulin Aspart 30 in Subjects With Type 2 Diabetes Inadequately Controlled on Sitagliptin and Metformin (SIT2MIX)

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

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.

Study Overview

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

• Study Type: Interventional
• Enrollment (Actual): 582
• Phase: Phase 4

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1250AAN
    • Novo Nordisk Investigational Site
  • Buenos Aires, Argentina, B1704ETD
    • Novo Nordisk Investigational Site
  • Caba, Argentina, C1179AAB
    • Novo Nordisk Investigational Site
  • Caba, Argentina, C1440AAD
    • Novo Nordisk Investigational Site
  • Mar del Plata, Argentina, B7600FZN
    • Novo Nordisk Investigational Site
  • Morón, Argentina, B1708IFF
    • Novo Nordisk Investigational Site
• Australia
  • New South Wales
    • Broadmeadow, New South Wales, Australia, 2292
      • Novo Nordisk Investigational Site
    • Coffs Harbour, New South Wales, Australia, 2450
      • Novo Nordisk Investigational Site
• Brazil
  • Brasília, Brazil, 71625-009
    • Novo Nordisk Investigational Site
  • Curitiba, Brazil, 80810-040
    • Novo Nordisk Investigational Site
  • Fortaleza, Brazil, 60430-350
    • Novo Nordisk Investigational Site
  • Porto Alegre, Brazil, 90035-170
    • Novo Nordisk Investigational Site
  • Sao Paulo
    • São Paulo, Sao Paulo, Brazil, 01244-030
      • Novo Nordisk Investigational Site
• Greece
  • Alexandroupolis, Greece, GR-68100
    • Novo Nordisk Investigational Site
  • Athens, Greece, GR-17562
    • Novo Nordisk Investigational Site
  • Athens, Greece, 151 23
    • Novo Nordisk Investigational Site
  • Thessaloniki, Greece, GR-57010
    • Novo Nordisk Investigational Site
  • Thessaloniki, Greece, GR-57001
    • Novo Nordisk Investigational Site
  • Thessaloniki, Greece, GR-54642
    • Novo Nordisk Investigational Site
• India
  • New Delhi, India, 110001
    • Novo Nordisk Investigational Site
  • Andhra Pradesh
    • Hyderabad, Andhra Pradesh, India, 500082
      • Novo Nordisk Investigational Site
    • Hyderabad, Andhra Pradesh, India, 500034
      • Novo Nordisk Investigational Site
    • Hyderabad, Andhra Pradesh, India, 500003
      • Novo Nordisk Investigational Site
    • Visakhapatnam, Andhra Pradesh, India, 530002
      • Novo Nordisk Investigational Site
  • Gujarat
    • Ahmedabad, Gujarat, India, 380006
      • Novo Nordisk Investigational Site
    • Ahmedabad, Gujarat, India, 380016
      • Novo Nordisk Investigational Site
  • Karnataka
    • Bangalore, Karnataka, India, 560002
      • Novo Nordisk Investigational Site
    • Bangalore, Karnataka, India, 560092
      • Novo Nordisk Investigational Site
    • Bangalore, Karnataka, India, 560 017
      • Novo Nordisk Investigational Site
    • Bangalore, Karnataka, India, 560043
      • Novo Nordisk Investigational Site
  • Kerala
    • Calicut, Kerala, India, 673016
      • Novo Nordisk Investigational Site
    • Trivandrum, Kerala, India, 695607
      • Novo Nordisk Investigational Site
  • Maharashtra
    • Nagpur, Maharashtra, India, 440010
      • Novo Nordisk Investigational Site
  • Punjab
    • Amritsar, Punjab, India, 143001
      • Novo Nordisk Investigational Site
  • Tamil Nadu
    • Chennai, Tamil Nadu, India, 600040
      • Novo Nordisk Investigational Site
    • Chennai, Tamil Nadu, India, 600003
      • Novo Nordisk Investigational Site
    • Chennai, Tamil Nadu, India, 600006
      • Novo Nordisk Investigational Site
    • Coimbatore, Tamil Nadu, India, 641009
      • Novo Nordisk Investigational Site
    • Trichy, Tamil Nadu, India, 620018
      • Novo Nordisk Investigational Site
  • Uttar Pradesh
    • Kanpur, Uttar Pradesh, India, 208005
      • Novo Nordisk Investigational Site
    • Noida, Uttar Pradesh, India, 201301
      • Novo Nordisk Investigational Site
    • Varanasi, Uttar Pradesh, India, 221105
      • Novo Nordisk Investigational Site
  • West Bengal
    • Kolkata, West Bengal, India, 700038
      • Novo Nordisk Investigational Site
    • Kolkata, West Bengal, India, 700019
      • Novo Nordisk Investigational Site
• Korea, Republic of
  • Goyang, Korea, Republic of, 10380
    • Novo Nordisk Investigational Site
  • Jeonju, Korea, Republic of, 561-712
    • Novo Nordisk Investigational Site
  • Pusan, Korea, Republic of, 602-739
    • Novo Nordisk Investigational Site
  • Pyungchon-Dong 896, Dongan-Gu, Korea, Republic of, 431-796
    • Novo Nordisk Investigational Site
  • Seoul, Korea, Republic of, 03080
    • Novo Nordisk Investigational Site
  • Seoul, Korea, Republic of, 150-713
    • Novo Nordisk Investigational Site
  • Suwon, Korea, Republic of, 16247
    • Novo Nordisk Investigational Site
  • Ulsan, Korea, Republic of, 682-060
    • Novo Nordisk Investigational Site
• Malaysia
  • Penang, Malaysia, 10459
    • Novo Nordisk Investigational Site
  • Seremban, Malaysia, 70300
    • Novo Nordisk Investigational Site
• Portugal
  • Coimbra, Portugal, 3000-561
    • Novo Nordisk Investigational Site
  • Lisboa, Portugal, 1500-650
    • Novo Nordisk Investigational Site
  • Lisboa, Portugal, 1649-035
    • Novo Nordisk Investigational Site
  • Lisboa, Portugal, 1250-230
    • Novo Nordisk Investigational Site
  • Matosinhos, Portugal, 4464-513
    • Novo Nordisk Investigational Site
  • Porto, Portugal, 4200-319
    • Novo Nordisk Investigational Site
• Thailand
  • Bangkok, Thailand, 10400
    • Novo Nordisk Investigational Site
  • Bangkok, Thailand, 10330
    • Novo Nordisk Investigational Site
  • Chiang Mai, Thailand, 50200
    • Novo Nordisk Investigational Site
  • Khon Kaen, Thailand, 40002
    • Novo Nordisk Investigational Site
• Turkey
  • Antalya, Turkey, 07058
    • Novo Nordisk Investigational Site
  • Istanbul, Turkey, 34722
    • Novo Nordisk Investigational Site
  • Istanbul, Turkey, 34718
    • Novo Nordisk Investigational Site
  • Istanbul, Turkey, 34371
    • Novo Nordisk Investigational Site
  • Istanbul, Turkey, 34890
    • 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:

• 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

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

3

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Novo Nordisk A/S

Publications and helpful links

General Publications

• Linjawi S, Sothiratnam R, Sari R, Andersen H, Hiort LC, Rao P. The study of once- and twice-daily biphasic insulin aspart 30 (BIAsp 30) with sitagliptin, and twice-daily BIAsp 30 without sitagliptin, in patients with type 2 diabetes uncontrolled on sitagliptin and metformin-The Sit2Mix trial. Prim Care Diabetes. 2015 Oct;9(5):370-6. doi: 10.1016/j.pcd.2014.11.001. Epub 2014 Dec 3.

Helpful Links

• Clinical Trials at Novo Nordisk

Study record dates

Study Major Dates

• Study Start: June 1, 2012
• Primary Completion (Actual): October 1, 2013
• Study Completion (Actual): October 1, 2013

Study Registration Dates

• First Submitted: January 24, 2012
• First Submitted That Met QC Criteria: January 24, 2012
• First Posted (Estimate): January 27, 2012

Study Record Updates

• Last Update Posted (Actual): February 24, 2017
• Last Update Submitted That Met QC Criteria: January 10, 2017
• Last Verified: January 1, 2017

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; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Incretins; Dipeptidyl-Peptidase IV Inhibitors; Insulin; Insulin, Globin Zinc; Insulin Aspart; Insulin, Long-Acting; Insulin degludec, insulin aspart drug combination; Metformin; Sitagliptin Phosphate; Biphasic Insulins; Insulin aspart, insulin aspart protamine drug combination 30:70; Insulin, Isophane
• Other Study ID Numbers: BIASP-3963; U1111-1125-0850 (Other Identifier: WHO); 2011-004930-33 (EudraCT Number)