Condition category
Nutritional, Metabolic, Endocrine
Date applied
02/08/2004
Date assigned
14/09/2004
Last edited
17/08/2010
Prospective/Retrospective
Prospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Plain English Summary

Not provided at time of registration

Trial website

http://www.dtu.ox.ac.uk/4-T

Contact information

Type

Scientific

Primary contact

Prof Rury Holman

ORCID ID

Contact details

Diabetes Trials Unit
Oxford Centre for Diabetes
Endocrinology and Metabolism (OCDEM)
Churchill Hospital
Old Road
Headington
Oxford
OX3 7LJ
United Kingdom
+44 (0)1865 857240
4-T@dtu.ox.ac.uk

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

NN304-1613

Study information

Scientific title

Acronym

4-T

Study hypothesis

Current hypothesis as of 06/07/07:
The United Kingdom Prospective Diabetes Study (UKPDS) demonstrated that improved glycaemic control reduces the risk of complications in type 2 diabetes. It showed also that type 2 diabetes is a progressive condition in which HbA1c levels rise inexorably, secondary to declining beta cell function. As a result, oral therapy needs to be escalated repeatedly with the majority of patients requiring insulin in the longer term.

There remains, however, considerable uncertainty as to which insulin regimen should be used when oral therapy becomes insufficient. Analogue insulin preparations have been shown to reduce the risk of hypoglycaemia whilst minimising weight gain, but there is no consensus about whether to commence therapy with a short acting, a long acting or a biphasic preparation. It is also uncertain how best to select an appropriate starting dose given that insulin requirements are often 2 - 3 times higher in type 2 than in type 1 diabetes.

The 4-T trial is a three-year, randomised controlled study in 57 centres that is comparing the efficacy and safety of three different analogue insulin regimens in 708 patients with type 2 diabetes inadequately controlled on maximally tolerated sulphonylurea and metformin therapy (not glitazones).

Patients are allocated to open-label therapy with:
1. Twice-daily biphasic insulin aspart 30
2. Once-daily determir insulin (twice if required)
3. Aspart insulin with meals three times daily

During the first year of the trial (Phase 1) insulin therapy is restricted to a single insulin formulation (unless unacceptable hyperglycaemia occurs), aiming to achieve HbA1c levels less than or equal to 6.5%. During the second and third years (Phase 2) more complex insulin regimens will be introduced if HbA1c levels are greater than 6.5%. 4-T is designed to provide the evidence base that will assist:
1. The choice of an appropriate insulin regimen when treatment with sulphonylurea and/or metformin becomes insufficient
2. Determination of an appropriate insulin starting dose for individual patients
3. Managing cessation of sulphonylurea therapy and transition to a more complex insulin regimen should hyperglycaemia recur

Previous hypothesis:
In year one, to determine the degree to which the randomised addition to existing oral therapies of:
1. Long-acting analogue insulin once-daily (or twice if needed)
2. Prandial rapid-acting analogue insulin thrice-daily
3. Pre-mixed long and rapid acting (biphasic) analogue insulin twice-daily can achieve HbA1c values less than 6.5%.

In years two and three, to determine the degree to which HbA1c values less than 6.5% can be achieved when existing sulphonylurea therapy is replaced by a second insulin preparation.
To derive algorithms that predict likely starting and adjustment doses of insulin for Type 2 diabetic patients with inadequate glycaemic control on oral agents.

Ethics approval

Ethics approval received from West Hertfordshire Local Research Ethics Committee on 13th September 2004 (ref: 04/Q0203/33)

Study design

Multicentre open-label randomised parallel-group trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Not specified

Trial type

Treatment

Patient information sheet

Condition

Type 2 diabetes

Intervention

Please note that, as of 6 July 2007, the anticipated end date of this trial was extended from 30 December 2008 to 31 July 2009.

1. Insulin detemir (Levemir)
2. Insulin Aspart (NovoRapid)
3. Biphasic Insulin Aspart (NovoMix30)

Intervention type

Drug

Phase

Phase I/II

Drug names

Antidiabetic drugs (OADs) (metformin and/or a sulphonylurea)

Primary outcome measures

Current primary outcomes measures as of 06/07/07:
The 4-T study will explore the efficacy and safety of treatment with biphasic, basal and prandial analogue insulin regimens in participants with type 2 diabetes mellitus (T2DM) inadequately controlled by two OADs. As this is an HbA1c treat-to-target study it is expected that the HbA1c levels in the three treatment groups will be similar but that there may be substantive differences in concomitant measures such as rates of hypoglycaemia, changes in weight and Quality of Life scores.

Co-primary objective at one year:
To compare the ability of three different single insulin formulation regimens to achieve good glycaemic control, defined as HbA1C levels less than or equal to 6.5 %, when added to current OAD treatment in subjects with inadequately controlled type 2 diabetes.

Co-primary objective at three years:
To determine the efficacy and durability of the three different insulin regimens in the longer term, and to assess the need for the addition of a second insulin formulation to achieve good glycaemic control.

Co-primary objective at one year:
To derive algorithms to estimate individual starting insulin dose requirements and insulin adjustment scales in populations such as this.

Secondary outcome measures

Current secondary outcome measures as of 06/07/07:
At one and three years, to compare the three treatment arms in terms of:
1. Proportions of participants who achieve HbA1c values less than or equal to 6.5%
2. Proportions who achieve HbA1c values of 6.5% or less without grade 2 (minor) or grade 3 (major) hypoglycaemia (as defined in the protocol) in the last four weeks of year one
3. Proportion who have clinically unacceptable hyperglycaemia (defined as two consecutive HbA1c values 8.0 % or more, or a single HbA1c value 10.0 % or more at or after 24 weeks) despite therapy with a single insulin formulation
4. The frequency of grade 1 (symptoms only), grade 2 (minor) or grade 3 (major) hypoglycaemia (as defined in the protocol) in a 24-hour period (00:00 - 24:00)
5. The frequency of grade 1, 2 or 3 nocturnal hypoglycaemia (23:00 - 05:59)
6. The frequency of grade 1, 2 or 3 daytime hypoglycaemia (06:00-22.59)
7. Changes in body weight
8. Changes in eight-point capillary plasma glucose profiles (self-measured)
9. Within-subject variation in pre-breakfast, pre-lunch and pre-dinner capillary plasma glucose levels (self-measured)
10. Changes in urinary albumin-to-creatinine ratio
11. Reasons for inability to achieve target HbA1c levels
12. Changes in quality of life and beliefs about medicines, both generic and disease-specific measures for people with diabetes treated with insulin

Overall trial start date

01/11/2004

Overall trial end date

31/07/2009

Reason abandoned

Eligibility

Participant inclusion criteria

Current inclusion criteria as of 06/07/07:
1. Informed consent
2. People with type 2 diabetes for at least 12 months who are insulin naive
3. On maximally tolerated metformin and sulphonylurea therapy for at least four months
4. Males and females, aged 18 years or more
5. Body mass index of 40.0 kg/m^2 or less
6. HbA1c in the range 7.0 to 10.0% inclusive
7. Able and willing to use insulin injections and perform self-monitoring of plasma glucose for the entire trial period

Previous inclusion criteria:
1. 700 subjects with type 2 diabetes
2. Males and females
3. Aged 18 years or over
4. Body mass index (BMI) less than or equal to 40kg/m^2 currently treated with oral antidiabetic drugs (OADs) (metformin and/or a sulphonylurea) and with an HbA1c in the range 7.0% to 10.0% inclusive

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Target number: 700. As of 6 July 2007, recruitment was completed with 708 participants.

Participant exclusion criteria

Current exclusion criteria as of 06/07/07:
1. Current or previous treatment with thiazolidinediones within the last six months
2. Current or previous treatment with an alpha-glucosidase inhibitor, repaglinide or nateglinide within the past 30 days
3. Oral Antidiabetic (OAD) treatment with three or more OADs within the last six months
4. Diabetes other than type 2 diabetes mellitus
5. Known sight-threatening retinopathy as judged by the investigator
6. Plasma creatinine 130 micromoles/l or more
7. Cardiac disease defined as:
7.1. Unstable angina pectoris within the last six months
7.2. Myocardial infarction (MI) within last six months
7.3. Congestive heart failure New York Heart Association (NYHA) class III and IV
8. Evidence of hepatic disease as determined by alanine aminotransferase (ALT) values of twice the upper limit of normal or more
9. Known hypoglycaemia unawareness or recurrent major hypoglycaemia as judged by the Investigator
10. Anticipated change in dose of concomitant medication, which may interfere with glucose regulation, such as monoamine oxidase inhibitors (MAOI), beta-adrenergic agents, anabolic steroids or systemic glucocorticoids
11. Uncontrolled hypertension with systolic blood pressure repeatedly 180 mmHg or more, or diastolic blood pressure 105 mmHg or more
12. Known or suspected allergy to trial products or related products
13. Any condition that the Investigator and/or the Sponsor feel would interfere with trial participation or the evaluation of results
14. Mental incapacity, unwillingness or language barrier precluding adequate understanding or cooperation
15. Pregnant or planning to become pregnant within the next 36 months, breastfeeding, or judged to be using inadequate contraceptive methods. Adequate contraceptive methods are sterilisation, intrauterine device (IUD), oral contraceptives or consistent use of barrier methods.
16. Receipt of any investigational trial drug within three months prior to participation in this trial
17. Subjects previously screened for participation or having already participated in this trial

Recruitment start date

01/11/2004

Recruitment end date

31/07/2009

Locations

Countries of recruitment

Ireland, United Kingdom

Trial participating centre

Diabetes Trials Unit
Oxford
OX3 7LJ
United Kingdom

Sponsor information

Organisation

Novo Nordisk Limited (UK)

Sponsor details

Broadfield Park
Brighton Road
Crawley
West Sussex
RH11 9RT
United Kingdom

Sponsor type

Industry

Website

http://www.novonordisk.co.uk/documents/home_page/document/index.asp

Funders

Funder type

Industry

Funder name

Novo Nordisk Limited (UK)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

Participant level data

Not provided at time of registration

Results - basic reporting

Publication summary

1. 2007 results in http://www.ncbi.nlm.nih.gov/pubmed/17890232
2. 2009 results in http://www.ncbi.nlm.nih.gov/pubmed/19850703
3. 2010 results in http://www.ncbi.nlm.nih.gov/pubmed/20592050

Publication citations

  1. Results

    Jenkins N, Hallowell N, Farmer AJ, Holman RR, Lawton J, Initiating insulin as part of the Treating To Target in Type 2 Diabetes (4-T) trial: an interview study of patients' and health professionals' experiences., Diabetes Care, 2010, 33, 10, 2178-2180, doi: 10.2337/dc10-0494.

  2. Holman RR, Thorne KI, Farmer AJ, Davies MJ, Keenan JF, Paul S, Levy JC, , Addition of biphasic, prandial, or basal insulin to oral therapy in type 2 diabetes., N. Engl. J. Med., 2007, 357, 17, 1716-1730, doi: 10.1056/NEJMoa075392.

  3. Holman RR, Farmer AJ, Davies MJ, Levy JC, Darbyshire JL, Keenan JF, Paul SK, , Three-year efficacy of complex insulin regimens in type 2 diabetes., N. Engl. J. Med., 2009, 361, 18, 1736-1747, doi: 10.1056/NEJMoa0905479.

Additional files

Editorial Notes