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

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ClinicalTrials.gov Identifier: NCT00184600
Recruitment Status : Completed
First Posted : September 16, 2005
Results First Posted : July 25, 2011
Last Update Posted : March 9, 2017
Sponsor:
Information provided by (Responsible Party):
Novo Nordisk A/S

Brief Summary:

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).


Condition or disease Intervention/treatment Phase
Diabetes Diabetes Mellitus, Type 2 Drug: biphasic insulin aspart Drug: insulin detemir Drug: insulin aspart Phase 3

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 708 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : November 2004
Actual Primary Completion Date : August 2009
Actual Study Completion Date : August 2009

Resource links provided by the National Library of Medicine


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




Primary Outcome Measures :
  1. HbA1c (Glycosylated Haemoglobin) at Month 12 [ Time Frame: Baseline, Month 12 ]
    HbA1c values offer evidence of the efficacy and durability of the insulin regimens.

  2. HbA1c (Glycosylated Haemoglobin) at Month 36 [ Time Frame: Baseline, Month 36 ]
    HbA1c values offer evidence of the efficacy and durability of the insulin regimens.


Secondary Outcome Measures :
  1. 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% [ Time Frame: Month 12 ]
    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.

  2. Percentage of Participants Achieving a Month 36 Value in HbA1c Below or Equal to 6.5% [ Time Frame: Month 36 ]
    Percentage of participants who achieved the target (HbA1c below or equal to 6.5%) at Month 36

  3. 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% [ Time Frame: Month 12 ]
    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%.

  4. 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% [ Time Frame: Month 36 ]
    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%.

  5. Percentage of Participants Who Required A Second Insulin Therapy by Month 12 [ Time Frame: 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.

  6. Percentage of Participants Who Required A Second Insulin Therapy by Month 36 [ Time Frame: 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.

  7. Change From Baseline in Body Weight at Month 12 [ Time Frame: Week 0 (baseline), month 12 ]
  8. Change From Baseline in Body Weight at Month 36 [ Time Frame: Week 0 (baseline), month 36 ]
  9. Change in Eight-point Capillary Plasma Glucose Profiles (Self-measured) at 12 Months [ Time Frame: Baseline, month 12 ]
    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.

  10. Change in Eight-point Capillary Plasma Glucose Profiles (Self-measured) at 36 Months [ Time Frame: Baseline, month 36 ]
    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.

  11. Quality of Life as Measured by the EuroQol Group 5-Dimension Self-Report Questionnaire Score (EQ5D) at 12 Months [ Time Frame: Month 12 ]
    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.

  12. Quality of Life as Measured by the EuroQol Group 5-Dimension Self-Report Questionnaire Score (EQ5D) at 36 Months [ Time Frame: Month 36 ]
    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.

  13. Number of Participants Having an 'Other' Adverse Event [ Time Frame: Up to month 37 (36 months of treatment plus 1 month follow-up) ]


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00184600


  Hide Study Locations
Locations
Ireland
Novo Nordisk Investigational Site
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
United Kingdom
Novo Nordisk Investigational Site
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, B71 4HJ
Novo Nordisk Investigational Site
Birmingham, United Kingdom, B9 5SS
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, N19 3UA
Novo Nordisk Investigational Site
London, United Kingdom, SE5 9RS
Novo Nordisk Investigational Site
London, United Kingdom
Novo Nordisk Investigational Site
Manchester, United Kingdom, M13 0JE
Novo Nordisk Investigational Site
Manchester, United Kingdom, M23 9LT
Novo Nordisk Investigational Site
Manchester, United Kingdom, M41 5SL
Novo Nordisk Investigational Site
Manchester, United Kingdom, M8 5RB
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
Sponsors and Collaborators
Novo Nordisk A/S
Investigators
Study Director: Global Clinical Registry (GCR, 1452) Novo Nordisk A/S

Additional Information:
Publications of Results:
Responsible Party: Novo Nordisk A/S
ClinicalTrials.gov Identifier: NCT00184600     History of Changes
Other Study ID Numbers: NN304-1613
2004-000514-38 ( EudraCT Number )
First Posted: September 16, 2005    Key Record Dates
Results First Posted: July 25, 2011
Last Update Posted: March 9, 2017
Last Verified: January 2017

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Insulin, Globin Zinc
Insulin degludec, insulin aspart drug combination
Insulin aspart, insulin aspart protamine drug combination 30:70
Insulin
Insulin Aspart
Insulin, Long-Acting
Insulin Detemir
Biphasic Insulins
Insulin, Isophane
Hypoglycemic Agents
Physiological Effects of Drugs