…in an academic collaboration with ISRCTN

4-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 Committee Overall responsibility for scientific, professional and operational conduct of the study Diabetes Trials Unit Study Design & Protocol Co-ordinating Centre Web-based data collection Clinical queries Statistical analyses Publication Novo Nordisk Study Design & Protocol Site initiation & monitoring Investigator agreements Ethical & regulatory aspects Study medication SAE reporting DTU Central Laboratory Clinical Centres 4-T Trial Organisation

Steering Committee Remit  Main 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 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 Randomisation 700 T2DM on OAD Add twice daily biphasic insulin * Add once (or twice) daily basal insulin * Add thrice daily prandial insulin * Randomisation visit One year * progress to more intensive insulin regimen only if clinically necessary † stop sulphonylurea if taken Glycaemic target: HbA 1c ≤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 † Two years Three years

4-T Main Study Objectives Impact of adding a single insulin preparation to OHA Ability of the three different analogue insulin preparations to achieve good glycaemic control, defined as HbA 1C levels ≤ 6.5 %, evaluated over 12 months Need for more complex insulin regimens Longer 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 calculator Study data will be used to derive algorithms that estimate individual insulin requirements, starting doses and titration steps

Major 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/m 2  HbA 1c 7.0 % to 10.0 % inclusive  Written informed consent

Major 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 trial within the last three months  Lactating or potentially pregnant females

Primary Outcome and Sample Size  The primary objective is to compare the HbA 1c 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 HbA 1c standard deviation of 1.1 and a dropout rate that does not exceed 15%

Three-level Hypoglycaemia Classification Hypoglycaemic episode Plasma glucose ≥3.1 mmol/L, (≥56 mg/dl) or not measured Grade 1: Symptoms only Treated by subject alone Grade 3: Major episode Assistance required Plasma glucose <3.1 mmol/L (<56 mg/dl) Grade 2: Minor episode

Safety Assessments  Incidence of major hypoglycaemic episodes  Incidence of unexpected and/or serious 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 Schedule

Co-ordinating Centre First point of contact/triage for all queries   Phone:  Fax:  Web site: