Comparison of Insulin Detemir, Insulin Aspart and Biphasic Insulin Aspart 30 With OAD Treatment in Type 2 Diabetes (4T)

A 36-month, Multi-centre, Open-label, Randomised, Parallel-group Trial Comparing the Safety, Efficacy and Durability of Adding a Basal Insulin Versus a Twice Daily Insulin Mixture Versus a Meal-time Rapid-Acting Insulin in Subjects With Type 2 Diabetes Inadequately Controlled on Therapy With Oral Agents, and Assessing the Requirement for More Complex Insulin Regimens to Achieve and Maintain Glycaemic Control, Their Efficacy and Durability

This trial is conducted in Europe.

The aim of this research study is to compare the efficacy (reduction in HbA1c and in blood glucose levels) of insulin detemir, insulin aspart and biphasic insulin aspart 30, when added to current OAD (oral anti-diabetic drug) treatment in subjects with type 2 diabetes and to verify the safety of use (number and severity of episodes of hypoglycaemia, body weight and side effects).

Study Overview

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

• Study Type: Interventional
• Enrollment (Actual): 708
• Phase: Phase 3

Contacts and Locations

Study Locations

• Ireland
  • Dublin, Ireland, DUBLIN 15
    • Novo Nordisk Investigational Site
  • Dublin, Ireland, DUBLIN 7
    • Novo Nordisk Investigational Site
  • Dublin, Ireland, DUBLIN 8
    • Novo Nordisk Investigational Site
  • Galway, Ireland
    • Novo Nordisk Investigational Site
• United Kingdom
  • Aberdeen, United Kingdom, AB25 1LD
    • Novo Nordisk Investigational Site
  • Addlestone, United Kingdom, KT15 2BH
    • Novo Nordisk Investigational Site
  • Airdrie, United Kingdom, ML6 0JS
    • Novo Nordisk Investigational Site
  • Ashton-Under-Lyne, United Kingdom, OL6 9RW
    • Novo Nordisk Investigational Site
  • Ayr, United Kingdom, KA6 6DX
    • Novo Nordisk Investigational Site
  • Belfast, United Kingdom, BT12 6BA
    • Novo Nordisk Investigational Site
  • Belfast, United Kingdom, BT37 9RH
    • Novo Nordisk Investigational Site
  • Belfast, United Kingdom, BT9 78B
    • Novo Nordisk Investigational Site
  • Berkshire, United Kingdom, RG7 3SQ
    • Novo Nordisk Investigational Site
  • Birmingham, United Kingdom, B9 5SS
    • Novo Nordisk Investigational Site
  • Birmingham, United Kingdom, B71 4HJ
    • Novo Nordisk Investigational Site
  • Bournemouth, United Kingdom, BH7 7DW
    • Novo Nordisk Investigational Site
  • Bradford, United Kingdom, BD9 6RJ
    • Novo Nordisk Investigational Site
  • Bristol, United Kingdom, BS10 5NB
    • Novo Nordisk Investigational Site
  • Bury St Edmunds, United Kingdom, IP30 9QU
    • Novo Nordisk Investigational Site
  • Cambridge, United Kingdom, CB2 2QQ
    • Novo Nordisk Investigational Site
  • Colchester, United Kingdom, CO4 5JL
    • Novo Nordisk Investigational Site
  • Coventry, United Kingdom, CV1 4FH
    • Novo Nordisk Investigational Site
  • Crawley, United Kingdom, RH10 7DH
    • Novo Nordisk Investigational Site
  • Derby, United Kingdom, DE22 3DT
    • Novo Nordisk Investigational Site
  • Dundee, United Kingdom, DD1 9SY
    • Novo Nordisk Investigational Site
  • Edinburgh, United Kingdom, EH16 4SA
    • Novo Nordisk Investigational Site
  • Exeter, United Kingdom, EX2 5AX
    • Novo Nordisk Investigational Site
  • Gillingham, United Kingdom, ME7 5NY
    • Novo Nordisk Investigational Site
  • Glasgow, United Kingdom, G4 0SF
    • Novo Nordisk Investigational Site
  • Guildford, United Kingdom, GU2 7XX
    • Novo Nordisk Investigational Site
  • Haywards Heath, United Kingdom, RH16 4EX
    • Novo Nordisk Investigational Site
  • Headington, United Kingdom, OX3 7LE
    • Novo Nordisk Investigational Site
  • High Wycombe, United Kingdom, HP11 2TZ
    • Novo Nordisk Investigational Site
  • Hull, United Kingdom, HU3 2JZ
    • Novo Nordisk Investigational Site
  • Kettering, United Kingdom, NN16 8UZ
    • Novo Nordisk Investigational Site
  • Leeds, United Kingdom, LS9 7TF
    • Novo Nordisk Investigational Site
  • Leicester, United Kingdom, LE1 5WW
    • Novo Nordisk Investigational Site
  • Leicester, United Kingdom, LE5 4PW
    • Novo Nordisk Investigational Site
  • Liverpool, United Kingdom, L7 8XP
    • Novo Nordisk Investigational Site
  • Liverpool, United Kingdom, L9 7AL
    • Novo Nordisk Investigational Site
  • Livingstone, United Kingdom, EH54 6PP
    • Novo Nordisk Investigational Site
  • London, United Kingdom, SE5 9RS
    • Novo Nordisk Investigational Site
  • London, United Kingdom, N19 3UA
    • Novo Nordisk Investigational Site
  • London, United Kingdom
    • Novo Nordisk Investigational Site
  • Manchester, United Kingdom, M8 5RB
    • Novo Nordisk Investigational Site
  • Manchester, United Kingdom, M41 5SL
    • Novo Nordisk Investigational Site
  • Manchester, United Kingdom, M13 0JE
    • Novo Nordisk Investigational Site
  • Manchester, United Kingdom, M23 9LT
    • Novo Nordisk Investigational Site
  • Middlesborough, United Kingdom, TS3 4BW
    • Novo Nordisk Investigational Site
  • Newcastle, United Kingdom, NE29 0LR
    • Novo Nordisk Investigational Site
  • Newcastle, United Kingdom, NE4 6BE
    • Novo Nordisk Investigational Site
  • Norfolk, United Kingdom, NR4 7UZ
    • Novo Nordisk Investigational Site
  • Northampton, United Kingdom, NN1 5BD
    • Novo Nordisk Investigational Site
  • Nottingham, United Kingdom, NG7 2UH
    • Novo Nordisk Investigational Site
  • Plymouth, United Kingdom, PL8 8DQ
    • Novo Nordisk Investigational Site
  • Rugby, United Kingdom, CV22 5PX
    • Novo Nordisk Investigational Site
  • Sheffield, United Kingdom, S5 7AU
    • Novo Nordisk Investigational Site
  • Skipton, United Kingdom, BD23 1EU
    • Novo Nordisk Investigational Site
  • Stevenage, United Kingdom, SG1 4AB
    • Novo Nordisk Investigational Site
  • Torquay, United Kingdom, TQ2 7AA
    • Novo Nordisk Investigational Site
  • Welwyn Garden City, United Kingdom, AL7 4HQ
    • Novo Nordisk Investigational Site
  • Whiston, United Kingdom, L35 5DR
    • Novo Nordisk Investigational Site
  • Wirral, Merseyside, United Kingdom, CH63 4JY
    • 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:

• Type 2 diabetes
• Insulin naive
• On OAD treatment for at least 4 months with metformin, a sulphonylurea or a combination
• Body Mass Index (BMI) below or equal to 40.0 kg/m2
• HbA1c (glycosylated haemoglobin): 7.0%-10% (both inclusive)

Exclusion Criteria:

• Proliferative retinopathy
• Recurrent major hypoglycaemia
• Cardial problems
• Uncontrolled hypertension
• Impaired hepatic or renal function

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Insulin detemir (basal insulin); Individually adjusted insulin detemir injected subcutaneously once daily before bed and administered in combination with current OAD treatment. Subjects had the option to add a second pre-breakfast basal insulin analogue injection if pre-breakfast but not pre-dinner meal plasma glucose targets were met. In the second and third years, a second insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to insulin detemir once (or twice) daily were asked to add insulin aspart three times daily with meals i.e. a basal-bolus insulin analogue regimen.	Drug: insulin detemir; Treat-to-target (individually adjusted dose), subcutaneously (under the skin) injection, once or twice daily plus option for insulin aspart
ACTIVE_COMPARATOR: Insulin aspart (prandial insulin); Individually adjusted insulin aspart injected subcutaneously at meal-times (breakfast, lunch and dinner) and administered in combination with current OAD treatment. In the second and third years, a second insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to insulin aspart three times a day with meals were asked to add insulin detemir once or twice daily i.e. a basal-bolus insulin analogue regimen.	Drug: biphasic insulin aspart; Treat-to-target (individually adjusted dose), subcutaneously (under the skin) injection, once or twice daily plus option for insulin aspart
ACTIVE_COMPARATOR: Biphasic insulin aspart 30 (biphasic insulin); Individually adjusted biphasic insulin aspart 30 injected subcutaneously twice daily with meals (breakfast and dinner) and administered in combination with current OAD treatment. In the second and third years, a second insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to biphasic insulin aspart twice daily were asked to add insulin aspart at lunchtime (midday) i.e. an augmented pre-mixed insulin analogue regimen.	Drug: insulin aspart; Treat-to-target (individually adjusted dose), subcutaneously (under the skin) injection, twice daily plus option for insulin detemir

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
HbA1c (Glycosylated Haemoglobin) at Month 12	HbA1c values offer evidence of the efficacy and durability of the insulin regimens.	Baseline, Month 12
HbA1c (Glycosylated Haemoglobin) at Month 36	HbA1c values offer evidence of the efficacy and durability of the insulin regimens.	Baseline, Month 36

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants (Total Participants and the Subset of Participants Who Did Not Have an Hypoglycaemic Episode) Achieving a Month 12 Value in HbA1c Below or Equal to 6.5%	Two participant counts are listed. The first is the percentage of total participants who achieved the target (HbA1c below or equal to 6.5%) at Month 12. The second is the percentage of subset of participants who achieved the target and did not have either minor or major hypoglycaemic episode within the four weeks prior to the month 12 exam. Minor hypoglycaemic episode is an episode in which the participant was able to treat her/himself and plasma glucose was below 3.1 mmol/L (56 mg/dL). Major hypoglycaemic episode is an episode in which the participant was unable to treat her/himself.	Month 12
Percentage of Participants Achieving a Month 36 Value in HbA1c Below or Equal to 6.5%	Percentage of participants who achieved the target (HbA1c below or equal to 6.5%) at Month 36	Month 36
Number of Hypoglycaemic Events Per Participant Per Year at Month 12 for All Participants and the Subset Who Achieved Target HbA1c Below or Equal to 6.5%	Rate of hypoglycaemic events was calculated as the median number of events per participant per year, defined as grade 1 (symptoms only), 2 (minor) and 3 (major). Symptoms only if self-measured plasma glucose level of 3.1 mmol/L (56 mg/dL) or more. Minor (grade 2) if able to treat her/himself and plasma glucose was below 3.1 mmol/L (56 mg/dL). Major (grade 3) if unable to treat her/himself. Rates are reported for all participants and for the subset of participants who achieved target HbA1c below or equal to 6.5%.	Month 12
Number of Hypoglycaemic Events Per Participant Per Year at Month 36 for All Participants and the Subset Who Achieved Target HbA1c Below or Equal to 6.5%	Rate of hypoglycaemic events was calculated as the median number of events per participant per year, defined as grade 1 (symptoms only), 2 (minor) and 3 (major). Symptoms only if self-measured plasma glucose level of 3.1 mmol/L (56 mg/dL) or more. Minor (grade 2) if able to treat her/himself and plasma glucose was below 3.1 mmol/L (56 mg/dL). Major (grade 3) if unable to treat her/himself. Rates are reported for all participants and for the subset of participants who achieved target HbA1c below or equal to 6.5%.	Month 36
Percentage of Participants Who Required A Second Insulin Therapy by Month 12	Percentage of participants who required a second insulin formulation to be added to their treatment. This outcome offers evidence to the efficacy and durability of the insulin regimens.	Month 12
Percentage of Participants Who Required A Second Insulin Therapy by Month 36	Percentage of participants who required a second insulin formulation to be added to their treatment. This outcome offers evidence to the efficacy and durability of the insulin regimens.	Month 36
Change From Baseline in Body Weight at Month 12		Week 0 (baseline), month 12
Change From Baseline in Body Weight at Month 36		Week 0 (baseline), month 36
Change in Eight-point Capillary Plasma Glucose Profiles (Self-measured) at 12 Months	For each visit and telephone contact, participants were asked to perform in advance three capillary glucose profiles (using blood glucose metre provided for the trial) obtained before breakfast and before the evening meal for participants in the biphasic and basal groups and before meals and two hours after meals and at bedtime in the prandial group.	Baseline, month 12
Change in Eight-point Capillary Plasma Glucose Profiles (Self-measured) at 36 Months	For each visit and telephone contact, participants were asked to perform in advance three capillary glucose profiles (using blood glucose metre provided for the trial) obtained before breakfast and before the evening meal for participants in the biphasic and basal groups and before meals and two hours after meals and at bedtime in the prandial group.	Baseline, month 36
Quality of Life as Measured by the EuroQol Group 5-Dimension Self-Report Questionnaire Score (EQ5D) at 12 Months	The EuroQol Group 5-Dimension Self-Report Questionnaire score (EQ5D) is a standardised instrument for use as a measure of health outcome in medical research. Responses can be used to generate a single numerical value associated with a given health state. The scale of values is graded from -0.59 to 1.00, with lower scores indicating a poorer health status. A score of 0 represents no quality of life and scores less than 0 represent states perceived by the respondent to be worse than death.	Month 12
Quality of Life as Measured by the EuroQol Group 5-Dimension Self-Report Questionnaire Score (EQ5D) at 36 Months	The EuroQol Group 5-Dimension Self-Report Questionnaire score (EQ5D) is a standardised instrument for use as a measure of health outcome in medical research. Responses can be used to generate a single numerical value associated with a given health state. The scale of values is graded from -0.59 to 1.00, with lower scores indicating a poorer health status. A score of 0 represents no quality of life and scores less than 0 represent states perceived by the respondent to be worse than death.	Month 36
Number of Participants Having an 'Other' Adverse Event		Up to month 37 (36 months of treatment plus 1 month follow-up)

Collaborators and Investigators

• Sponsor: Novo Nordisk A/S

Publications and helpful links

General Publications

• Holman RR, Farmer AJ, Davies MJ, Levy JC, Darbyshire JL, Keenan JF, Paul SK; 4-T Study Group. Three-year efficacy of complex insulin regimens in type 2 diabetes. N Engl J Med. 2009 Oct 29;361(18):1736-47. doi: 10.1056/NEJMoa0905479. Epub 2009 Oct 22. Erratum In: N Engl J Med. 2010 Nov 18;363(21):2078.
• Holman RR, Thorne KI, Farmer AJ, Davies MJ, Keenan JF, Paul S, Levy JC; 4-T Study Group. Addition of biphasic, prandial, or basal insulin to oral therapy in type 2 diabetes. N Engl J Med. 2007 Oct 25;357(17):1716-30. doi: 10.1056/NEJMoa075392. Epub 2007 Sep 21.
• Jenkins N, Hallowell N, Farmer AJ, Holman RR, Lawton J. Participants' experiences of intensifying insulin therapy during the Treating to Target in Type 2 Diabetes (4-T) trial: qualitative interview study. Diabet Med. 2011 May;28(5):543-8. doi: 10.1111/j.1464-5491.2010.03200.x.

Helpful Links

• Clinical Trials at Novo Nordisk

Study record dates

Study Major Dates

• Study Start: November 1, 2004
• Primary Completion (ACTUAL): August 1, 2009
• Study Completion (ACTUAL): August 1, 2009

Study Registration Dates

• First Submitted: September 13, 2005
• First Submitted That Met QC Criteria: September 13, 2005
• First Posted (ESTIMATE): September 16, 2005

Study Record Updates

• Last Update Posted (ACTUAL): March 9, 2017
• Last Update Submitted That Met QC Criteria: January 26, 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; Insulin; Insulin, Globin Zinc; Insulin Aspart; Insulin, Long-Acting; Insulin degludec, insulin aspart drug combination; Insulin Detemir; Biphasic Insulins
• Other Study ID Numbers: NN304-1613; 2004-000514-38 (EUDRACT_NUMBER)