A Trial Investigating the Efficacy and Safety of Flexible vs. Fixed Dosing and Simple vs. Stepwise Titration With Once Daily (OD) Insulin Degludec in Inadequately Treated Subjects With Type 2 Diabetes

• ClinicalTrials.gov Identifier: NCT01880736
• Recruitment Status: Completed
• First Posted: June 19, 2013
• Results First Posted: March 17, 2016
• Last Update Posted: February 10, 2017
• Sponsor: Novo Nordisk A/S
• Information provided by (Responsible Party): Novo Nordisk A/S

Study Description

Brief Summary:

This trial is conducted in Asia. The aim of the trial is to investigate the efficacy and safety of flexible versus fixed dosing and simple versus stepwise titration with OD insulin degludec in inadequately treated subjects with type 2 diabetes.

Condition or disease	Intervention/treatment	Phase
Diabetes; Diabetes Mellitus, Type 2	Drug: insulin degludec	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 458 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Trial Investigating the Efficacy and Safety of Flexible vs. Fixed Dosing and Simple vs. Stepwise Titration With Once Daily Insulin Degludec in Inadequately Treated Subjects With Type 2 Diabetes
• Study Start Date: June 2013
• Actual Primary Completion Date: April 2014
• Actual Study Completion Date: April 2014

Arms and Interventions

Arm	Intervention/treatment
Experimental: IDeg OD Flexible Dose	Drug: insulin degludec; Individual dose adjusted once weekly. IDeg (100 U/mL, 3 mL FlexTouch® pen PDS290) to be administered under the skin OD with the option to vary time of administration within a window of plus/minus 8 hours. A maximum of 3 pre-trial OADs are allowed during the trial at an unchanged, stable dose level and dosing frequency.; Drug: insulin degludec; Individual dose adjusted once weekly. IDeg (100 U/mL, 3 mL FlexTouch® pen PDS290) to be administered under the skin OD at the same time each day. A maximum of 3 pre-trial OADs are allowed during the trial at an unchanged, stable dose level and dosing frequency.; Drug: insulin degludec; Individual dose adjusted once weekly. IDeg (100 U/mL, 3 mL FlexTouch® pen PDS290) to be administered subcutaneously (under the skin) OD at the same time each day. A maximum of 3 pre-trial oral anti-diabetic drugs (OADs) are allowed during the trial at an unchanged, stable dose level and dosing frequency.
Experimental: IDeg OD Fixed Dose	Drug: insulin degludec; Individual dose adjusted once weekly. IDeg (100 U/mL, 3 mL FlexTouch® pen PDS290) to be administered under the skin OD with the option to vary time of administration within a window of plus/minus 8 hours. A maximum of 3 pre-trial OADs are allowed during the trial at an unchanged, stable dose level and dosing frequency.; Drug: insulin degludec; Individual dose adjusted once weekly. IDeg (100 U/mL, 3 mL FlexTouch® pen PDS290) to be administered under the skin OD at the same time each day. A maximum of 3 pre-trial OADs are allowed during the trial at an unchanged, stable dose level and dosing frequency.; Drug: insulin degludec; Individual dose adjusted once weekly. IDeg (100 U/mL, 3 mL FlexTouch® pen PDS290) to be administered subcutaneously (under the skin) OD at the same time each day. A maximum of 3 pre-trial oral anti-diabetic drugs (OADs) are allowed during the trial at an unchanged, stable dose level and dosing frequency.
Experimental: IDeg OD Simple	Drug: insulin degludec; Individual dose adjusted once weekly. IDeg (100 U/mL, 3 mL FlexTouch® pen PDS290) to be administered under the skin OD with the option to vary time of administration within a window of plus/minus 8 hours. A maximum of 3 pre-trial OADs are allowed during the trial at an unchanged, stable dose level and dosing frequency.; Drug: insulin degludec; Individual dose adjusted once weekly. IDeg (100 U/mL, 3 mL FlexTouch® pen PDS290) to be administered under the skin OD at the same time each day. A maximum of 3 pre-trial OADs are allowed during the trial at an unchanged, stable dose level and dosing frequency.; Drug: insulin degludec; Individual dose adjusted once weekly. IDeg (100 U/mL, 3 mL FlexTouch® pen PDS290) to be administered subcutaneously (under the skin) OD at the same time each day. A maximum of 3 pre-trial oral anti-diabetic drugs (OADs) are allowed during the trial at an unchanged, stable dose level and dosing frequency.
Experimental: IDeg OD Stepwise	Drug: insulin degludec; Individual dose adjusted once weekly. IDeg (100 U/mL, 3 mL FlexTouch® pen PDS290) to be administered under the skin OD with the option to vary time of administration within a window of plus/minus 8 hours. A maximum of 3 pre-trial OADs are allowed during the trial at an unchanged, stable dose level and dosing frequency.; Drug: insulin degludec; Individual dose adjusted once weekly. IDeg (100 U/mL, 3 mL FlexTouch® pen PDS290) to be administered under the skin OD at the same time each day. A maximum of 3 pre-trial OADs are allowed during the trial at an unchanged, stable dose level and dosing frequency.; Drug: insulin degludec; Individual dose adjusted once weekly. IDeg (100 U/mL, 3 mL FlexTouch® pen PDS290) to be administered subcutaneously (under the skin) OD at the same time each day. A maximum of 3 pre-trial oral anti-diabetic drugs (OADs) are allowed during the trial at an unchanged, stable dose level and dosing frequency.

Outcome Measures

Primary Outcome Measures :

1. Change From Baseline in HbA1c (%) Glycosylated Haemoglobin) [ Time Frame: Week 0, week 26 ]
   Changes from baseline in HbA1c values over time period of Week 0-26 were evaluated by dosing regimen (flexible vs. fixed dosing) and by titration algorithm (simple vs stepwise)

Secondary Outcome Measures :

1. Change From Baseline in Fasting Plasma Glucose (FPG) [ Time Frame: Week 0, week 26 ]
   Changes from baseline in FPG values over the time period of Week 0-26 were evaluated by dosing regimen (flexible vs. fixed dosing) and by titration algorithm (simple vs stepwise).
2. Responder for HbA1c (%) Based on Central Laboratory Assessment: HbA1c Below 7.0% at End of Trial [ Time Frame: After 26 weeks of treatment ]
   The number of subjects who achieved the pre-defined HbA1c target (<7.0%) after 26 weeks of treatment was recorded by dosing regimen (flexible vs. fixed dosing) and by titration algorithm (simple vs stepwise).
3. Incidence of Treatment Emergent Adverse Events (TEAEs) [ Time Frame: Weeks 0-26 ]
   The incidences of treatment emergent adverse events (TEAEs) over the time period of Week 0-26 were recorded by dosing regimen (flexible vs. fixed dosing); and by titration algorithm (simple vs stepwise).
4. Number of Treatment Emergent Confirmed Hypoglycaemic Episodes (Defined as Severe Hypoglycaemia and/or a Measured Plasma Glucose (PG) Less Than 3.1 mmol/L (Less Than 56 mg/dL)) [ Time Frame: Weeks 0-26 ]
   The confirmed hypoglycaemic episodes (defined as severe hypoglycaemia and/or a measured plasma glucose (PG) less than 3.1 mmol/L [less than 56 mg/dL]) over the time period of Week 0-26 was recorded by dosing regimen (flexible vs. fixed dosing); and by titration algorithm (simple vs stepwise).
5. Number of Treatment Emergent Hypoglycaemic Episodes According to the American Diabetes Association (ADA) Definition [ Time Frame: Weeks 0-26 ]
   Number of treatment emergent hypoglycaemic episodes according to the ADA definition (classified as severe hypoglycaemia, documented hypoglycaemia, asymptomatic hypoglycaemia, probable symptomatic hypoglycaemia, relative hypoglycaemia) over the time period of Week 0-26 was recorded by dosing regimen (flexible vs. fixed dosing) and by titration algorithm (simple vs stepwise).
6. Number of Treatment Emergent Confirmed Hypoglycaemic Episodes in the Maintenance Period [ Time Frame: From Week 16 to end of trial (week 27) ]
   The number of treatment mergent confirmed hypoglycaemic episodes in the maintenance period from Week 16 to end of trial (week 27) was recorded by dosing regimen (flexible vs. fixed dosing) and by titration algorithm (simple vs. stepwise). Confirmed hypoglycaemic episodes consisted of severe hypoglycaemia as well as minor hypoglycaemic episodes with a confirmed plasma glucose value of less than 3.1 mmol/L.
7. Number of Treatment Emergent Nocturnal (00:01-05:59 am) Confirmed Hypoglycaemic Episodes [ Time Frame: Weeks 0-26 ]
   The number of treatment emergent nocturnal (00:01-05:59 am) confirmed hypoglycaemic episodes over the time period of Week 0-26 was recorded by dosing regimen (flexible vs. fixed dosing) and by titration algorithm (simple vs stepwise). Confirmed hypoglycaemic episodes consisted of severe hypoglycaemia as well as minor hypoglycaemic episodes with a confirmed plasma glucose value of less than 3.1 mmol/L. Nocturnal hypoglycaemic episodes are defined as occurring between 00:01 and 05:59 a.m.
8. Number of Treatment Emergent Nocturnal (00:01-05:59 am) Confirmed Hypoglycaemic Episodes in the Maintenance Period [ Time Frame: From week 16 to end of trial (week 27) ]
   The number of treatment emergent nocturnal (00:01-05:59 am) confirmed hypoglycaemic episodes in the maintenance period from 16 weeks to end of trial (week 27) was recorded by dosing regimen (flexible vs. fixed dosing); and by titration algorithm (simple vs stepwise). Confirmed hypoglycaemic episodes consisted of severe hypoglycaemia as well as minor hypoglycaemic episodes with a confirmed plasma glucose value of less than 3.1 mmol/L. Nocturnal hypoglycaemic episodes are defined as occurring between 00:01 and 05:59 a.m.

Eligibility Criteria

• Ages Eligible for Study: 20 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Current treatment with IGlar (insulin glargine) with or without OADs (oral antidiabetic drug). All antidiabetic treatments should have been on-going for at least 12 weeks prior to randomisation, and doses of OADs should have been stable in this period of time. - Please note that a maximum of 3 OADs are allowed during this trial: metformin, sulphonylurea (SU)/glinides, dipeptidyl peptidase 4 (DPP-IV) inhibitors, alfa-glucosidaseinhibitors or pioglitazone.
• Diagnosis of T2DM (type 2 diabetes mellitus) at the discretion of the investigator for at least 26 weeks prior to visit 1 (Screening visit)
• HbA1c 7.0-9.5% (both inclusive) by central laboratory analysis
• Body mass index (BMI) equal to or below 35 kg/m^2

Exclusion Criteria:

• Any chronic disorder or severe disease which, in the opinion of the Investigator might jeopardise subject's safety or compliance with the protocol
• Stroke; decompensated heart failure New York Heart Association (NYHA) class III or IV; myocardial infarction; unstable angina pectoris; or coronary arterial bypass graft or angioplasty; all within the last 26 weeks prior to Visit 1 (Screening visit)
• Impaired renal function, defined as serum-creatinine higher than or equal to 1.4 mg/dL for males and higher than or equal to 1.3 mg/dL for females
• Current or past (within the last 5 years) malignant neoplasms (except basal cell and squamous cell skin carcinoma)
• Treatment with glucose-lowering agent(s) other than stated in the inclusion criteria in a period of 12 weeks prior to randomisation

Contacts and Locations

Locations

Japan

Novo Nordisk Investigational Site

Chuo-ku, Tokyo, Japan, 103 0002

Novo Nordisk Investigational Site

Chuo-ku, Tokyo, Japan, 103 0027

Novo Nordisk Investigational Site

Fukui-shi, Fukui, Japan, 918-8503

Novo Nordisk Investigational Site

Fukuoka, Japan, 812 0025

Novo Nordisk Investigational Site

Gifu-shi, Gifu, Japan, 501-1194

Novo Nordisk Investigational Site

Izumisano-shi, Japan, 598 0048

Novo Nordisk Investigational Site

Kagoshima-shi, Kagoshima, Japan, 890-8520

Novo Nordisk Investigational Site

Kamakura-shi, Japan, 247 0056

Novo Nordisk Investigational Site

Kashiwara-shi, Osaka, Japan, 582 0005

Novo Nordisk Investigational Site

Katsushika-ku, Tokyo, Japan, 125 0054

Novo Nordisk Investigational Site

Kawasaki-shi, Kanagawa, Japan, 216-8511

Novo Nordisk Investigational Site

Kitakyushu-shi, Fukuoka, Japan, 800 0252

Novo Nordisk Investigational Site

Kitakyushu-shi, Fukuoka, Japan, 807-8555

Novo Nordisk Investigational Site

Kitakyusyu-shi, Fukuoka, Japan, 800-0222

Novo Nordisk Investigational Site

Koriyama-shi, Fukushima, Japan, 963 8851

Novo Nordisk Investigational Site

Kumamoto-shi,Kumamoto, Japan, 862 0976

Novo Nordisk Investigational Site

Mito-shi, Ibaraki, Japan, 310-0845

Novo Nordisk Investigational Site

Miyazaki-shi, Japan, 880 0034

Novo Nordisk Investigational Site

Naka-shi, Ibaraki, Japan, 311 0113

Novo Nordisk Investigational Site

Niigata-shi, Niigata, Japan, 951-8520

Novo Nordisk Investigational Site

Nishinomiya-shi, Hyogo, Japan, 663-8501

Novo Nordisk Investigational Site

Oita-shi, Japan, 870 0039

Novo Nordisk Investigational Site

Okawa-shi, Fukuoka, Japan, 831 0016

Novo Nordisk Investigational Site

Osaka-shi, Osaka, Japan, 532 0003

Novo Nordisk Investigational Site

Oyama-shi, Tochigi, Japan, 323 0022

Novo Nordisk Investigational Site

Sakaide-shi, Kagawa, Japan, 762-0031

Novo Nordisk Investigational Site

Sapporo-shi, Hokkaido, Japan, 060 0062

Novo Nordisk Investigational Site

Sapporo-shi, Hokkaido, Japan, 060-0001

Novo Nordisk Investigational Site

Sapporo-shi, Hokkaido, Japan, 062 0007

Novo Nordisk Investigational Site

Sendai-shi, Japan, 980 0021

Novo Nordisk Investigational Site

Shimotsuke-shi, Tochigi, Japan, 329 0433

Novo Nordisk Investigational Site

Suita-shi, Osaka, Japan, 565-0853

Novo Nordisk Investigational Site

Takatsuki-shi, Osaka, Japan, 569 1096

Novo Nordisk Investigational Site

Tokyo, Japan, 103-0028

Novo Nordisk Investigational Site

Tokyo, Japan, 113-8655

Novo Nordisk Investigational Site

Tokyo, Japan, 123-0845

Novo Nordisk Investigational Site

Tokyo, Japan, 143-8541

Novo Nordisk Investigational Site

Tokyo, Japan, 144-0051

Novo Nordisk Investigational Site

Tokyo, Japan, 162-8655

Novo Nordisk Investigational Site

Yokkaichi-shi, Mie, Japan, 510-0829

Sponsors and Collaborators

Novo Nordisk A/S

Investigators

• Study Director: Global Clinical Registry (GCR, 1452); Novo Nordisk A/S

More Information

Additional Information:

Clinical Trials at Novo Nordisk 

Publications of Results:

Kadowaki T, Jinnouchi H, Kaku K, Hersløv ML, Hyllested-Winge J, Nakamura S. Insulin degludec in a simple or stepwise titration algorithm in a Japanese population of patients with type 2 diabetes: a randomized, 26-week, treat-to-target trial. Diabetol Int. 2016 Sep 2;8(1):87-94. doi: 10.1007/s13340-016-0284-9. eCollection 2017 Mar.

Kadowaki T, Jinnouchi H, Kaku K, Hersløv ML, Hyllested-Winge J, Nakamura S. Efficacy and safety of once-daily insulin degludec dosed flexibly at convenient times vs fixed dosing at the same time each day in a Japanese cohort with type 2 diabetes: A randomized, 26-week, treat-to-target trial. J Diabetes Investig. 2016 Sep;7(5):711-7. doi: 10.1111/jdi.12502. Epub 2016 Apr 1.

• Responsible Party: Novo Nordisk A/S
• ClinicalTrials.gov Identifier: NCT01880736
• Other Study ID Numbers: NN1250-4060; U1111-1137-0953 ( Other Identifier: WHO ); JapicCTI- 132164 ( Other Identifier: JAPIC )
• First Posted: June 19, 2013
• Results First Posted: March 17, 2016
• Last Update Posted: February 10, 2017
• Last Verified: December 2016

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Insulin; Insulin, Globin Zinc; Insulin, Long-Acting; Hypoglycemic Agents; Physiological Effects of Drugs