A torvastatin in F actorial with O mega-3 fatty acid R isk R eduction in D iabetes

1. …in an academic collaboration with Atorvastatin in Factorial withOmega-3 fatty acid RiskReduction in Diabetes

2. Collaborative academic and pharmaceutical study Funded by Pfizer, with data owned, analysed and reported by the University of Oxford Diabetes Trials Unit (DTU) Multi-centre primary prevention trial in 1,000 patients with type 2 diabetes Double-blind, placebo-controlled 2 x 2 factorial randomisation to Atorvastatin (Lipitor 20 mg/day) Omega 3 PUFA (Omacor 2g/day) 70 UK clinical centres, one year follow-up Trial Design

3. Trial Organisation Steering Committee Overall responsibility for scientific, professionaland operational conduct of the study Diabetes Trials Unit Study Design and Protocol Dev. Co-ordinating Centre Investigator agreements Ethical/regulatory approval Data collection and management Protocol/clinical queries Statistical analysis/publication Pfizer UK Protocol development Regulatory aspects Study medication On-site Monitoring SAE reporting 70 Clinical Centres DTU CentralLaboratory

4. To determine the: Range of estimated CHD risk levels typically seen in people with type 2 diabetes in UK general practice Proportion whose estimated ten-year CHD risk can be reduced below 15% with a 20 mg of atorvastatin or 1.8 g omega-3 PUFA/day Degree to which atorvastatin and omega-3 PUFA in combination have additive effects Extent to which therapy adherence can be enhanced using a simple behavioural intervention Aims

5. Aged 18 years and above Have had type 2 diabetes for at least 3 months Not known to have had a cardiovascular event Have provided written informed consent Inclusion Criteria

6. Taking prescribed lipid lowering therapy Triglycerides ≥8.0 mmol/L Have specific contraindications toatorvastatin or omega-3 PUFA Have participated in a clinical trialwithin the last 3 months Are pregnant or lactating females Exclusion Criteria

7. 2 x 2 Factorial Randomisation Atorvastatin (20 mg ) AtorvastatinPlacebo 500 Omega-3 Omega-3Omega-3 (250)(250) AtorvastatinPlacebo500 Placebo Placebo Placebo (250)(250) 500 500 1,000 Atorvastatin Placebo patientsin total Omega-3PUFA (1.8 g)

8. Primary Objectives • Proportion of subjects whose LDL levels are<2.6 mmol/L at four months • Proportion of subjects whose triglycerides are<1.5 mmol/L at four months

9. Secondary Objectives • Proportion of subjects with LDL levels<2.6 mmol/L at one year • Proportion of subjects with triglycerides<1.5 mmol/L at one year • Proportion (%) of subjects with estimated ten-year CHD risk <15% at 16 weeks and one year • Study medication adherenceat 16 weeks and at one year • Health economic assessmentat 16 weeks and at one year

10. Visit 1: week -2 Recruitment Visit 2: week 0 Randomisation Visit 3: week 16 Four month evaluation Visit 4: week 18 Additional medication* Adherence study Visit 5: week 32 Routine Follow up Visit 6: week 52 One year evaluation End of study * Patients whose estimated CHD risk remains greater than 15% at four months will receive an additional tablet containing 20 mg atorvastatin, whilst the remainder will receive an additional placebo tablet, in double-blind fashion. Visit Schedule

11. Trial Schedule • Study commenced in November 2004 • One year recruitment in 70 UK practices • One year follow-up for all subjects • Results expected late 2006 • Contact: • Email: aforrd@dtu.ox.ac.uk • Phone: 01865 857 246 • Fax: 01865 857 256 • Web site: www.dtu.ox.ac.uk/aforrd