…in an academic collaboration with

ISRCTN 51125379ISRCTN 51125379

www.dtu.ox.ac.uk/4-Twww.dtu.ox.ac.uk/4-T

4-T Design4-T Design Collaborative academic and pharmaceutical study

Three-year, multi-centre trial of addition of anlogue insulin to oral hypoglycaemic agents in 700 patients with Type 2 diabetes

Open-label, three arm comparison of:

Basal insulin, given once (or twice) daily

Prandial insulin, given three times daily

Biphasic insulin, given twice daily

50 secondary-care based UK clinical centres

Funded by Novo Nordisk

Steering CommitteeOverall responsibility for scientific, professional

and operational conduct of the study

Diabetes Trials UnitStudy Design & Protocol

Co-ordinating CentreWeb-based data collection

Clinical queriesStatistical analyses

Publication

Novo NordiskStudy Design & Protocol

Site initiation & monitoring Investigator agreements

Ethical & regulatory aspectsStudy medication

SAE reporting

DTU CentralLaboratory

Clinical Centres

4-T Trial Organisation4-T Trial Organisation

Steering Committee RemitSteering Committee RemitMain decision-making body of the Study

Responsible for protocol design

Ensure overall scientific, professional and operational conduct

Review performance of clinical centres, co-ordinating centre, central laboratory and centre monitors on a monthly basis

Steering Committee MembershipSteering Committee Membership Professor Rury Holman (Chair) Dr Jonathan Levy (Co-chair) Dr Andrew Farmer (Academic GP) Ms Joanne Keenan (DTU Project Manager)

Dr Melanie Davies (Independent Diabetologist) Mr George Nelson (Patient Representative)

Dr Alan McDougall (Novo Nordisk) Dr Henrik Schou (Novo Nordisk) Dr Mari-Anne Gall (Novo Nordisk)

Three Way RandomisationThree Way Randomisation

700 T2DMon OAD

Add twice daily

biphasic insulin*

Add once (or twice)

daily basal insulin*

Add thrice daily

prandial insulin*

Randomisationvisit

Oneyear

* progress to more intensive insulin regimen only if clinically necessary† stop sulphonylurea if taken

Glycaemic target: HbA1c ≤6.5%

R Add midday prandial insulin

if glycaemic target not met†

Add prandial insulin

if glycaemic target not met†

Add basal insulin

if glycaemic target not met†

Twoyears

Threeyears

4-T Main Study Objectives4-T Main Study ObjectivesImpact of adding a single insulin preparation to OHA

Ability of the three different analogue insulin preparations to achieve good glycaemic control, defined as HbA1C levels ≤ 6.5 %, evaluated over 12 months

Need for more complex insulin regimensLonger term efficacy and durability of the three insulin preparations, as well as the need for a second analogue insulin preparation to be added in order to achieve good glycaemic control, evaluated in the second and third years of the study

Insulin dose calculatorStudy data will be used to derive algorithms that estimate individual insulin requirements, starting doses and titration steps

Major Inclusion CriteriaMajor Inclusion Criteria Aged ≥18 years, male and female

Type 2 diabetes for at least 12 months

On maximal tolerated doses of metformin and sulphonylurea for at least four months

Body mass index ≤40 kg/m2

HbA1c 7.0 % to 10.0 % inclusive

Written informed consent

Major Exclusion CriteriaMajor Exclusion Criteria Taking insulin therapy

Taking oral antidiabetic therapy other than sulphonylurea and/or metformin

Plasma creatinine >130 µmol/L

ALT ≥2x upper limit of normal

Life threatening cardiovascular disease

Participation in a clinical drug trialwithin the last three months

Lactating or potentially pregnant females

Primary Outcome and Sample SizePrimary Outcome and Sample Size The primary objective is to compare the HbA1c

levels achieved by the three insulin regimens Formal analyses will be performed at one year

and at three years, without adjustment for multiple comparisons, as the two phases of the study are regarded as separate experiments

4-T has 95% power to show equivalence between groups at the 5% level of significance if 233 patients per group are randomised, assuming an HbA1c standard deviation of 1.1 and a dropout rate that does not exceed 15%

Three-level Hypoglycaemia ClassificationThree-level Hypoglycaemia Classification

Hypoglycaemicepisode

Plasma glucose ≥3.1 mmol/L,(≥56 mg/dl)

or not measured

Grade 1:Symptoms

onlyTreated by

subject alone

Grade 3:Major

episode

Assistancerequired

Plasma glucose<3.1 mmol/L (<56 mg/dl)

Grade 2:Minor

episode

Safety AssessmentsSafety Assessments Incidence of major hypoglycaemic episodes

Incidence of unexpected and/orserious adverse events (SAEs)

Plasma ALT, creatinine and lipid levels

Stop metformin if plasma creatinine ≥150 µmol/L

Blood pressure

The study commenced 1st November 2004

50 UK centres have been enrolled

18 patients per centre will be recruited

One year results expected in 2007

Three year results expected in 2009

ScheduleSchedule

Co-ordinating CentreCo-ordinating Centre

First point of contact/triage for all queries

Email: 4-T@dtu.ox.ac.uk

Phone: 01865 857 239

Fax: 01865 857 248

Web site: www.dtu.ox.ac.uk/4-T