1. HEAL-IT Bauer Sumpio Yale University Suephy C. Chen, William S. Weintraub Emory University Sponsor: Otsuka America

2. Facts of The Trial William S. Weintraub, MD Professor of Medicine Emory University Director, Emory Center for Outcomes Research HEAL-IT HEALing of Ischemic Foot Ulcers With Cilostazol Trial

3. Specific Aim: To evaluate the ability of cilostazol (Pletal®) to improve wound healing of ischemic foot ulcers in combination with standard local wound care compared to local wound care alone. HEAL-IT HEALing of Ischemic Foot Ulcers With Cilostazol Trial

4. Background: Foot ulcer prevalence- 1-2% in over-50 age group PVD accounts for up to 2/3 of the etiology Cilostazol originally utilized for healing ischemic ulcers in Japan but only anecdotal reports Cilostazol approved by FDA for claudication 1999 HEAL-IT HEALing of Ischemic Foot Ulcers With Cilostazol Trial

5. Hypothesis: Cilostazol will improve wound healing in ischemic leg ulcers in combination with standard local wound care compared to local wound care alone. HEAL-IT HEALing of Ischemic Foot Ulcers With Cilostazol Trial

6. Primary Endpoint: Mean rate of healing of target ulcer (% per month, where a month is 30 days) HEAL-IT HEALing of Ischemic Foot Ulcers With Cilostazol Trial

7. Secondary Endpoints: 1)Change in target ulcer area (cm 2 ) 2)Target ulcer completely healed (yes/no) 3)Time to complete healing of target ulcer 4)Percent healing of target ulcer 5)Number of ulcers on leg where target ulcer resides 6)Quality of life improvement 7)Cost HEAL-IT HEALing of Ischemic Foot Ulcers With Cilostazol Trial

8. Design: 1)Multicenter, randomized double blind clinical trial 2)300 patients at 20 sites (15-20 per site) HEAL-IT HEALing of Ischemic Foot Ulcers With Cilostazol Trial

9. Study Drug Handling: 1)Be sure that patient number on study drug and patient number on CRF match. Be sure to go in order, i.e. do not skip numbers. 2)Patients will be given a full 6-month supply of study drug in a kit containing pill bottles and a daily dispenser 3)Study drug is in bottles containing 132 tablets. 4)At three month and six month visits patients should bring their kit and all pill bottles, empty, partially full and full for pill count. 5)Patients be resupplied if they lose their original supply. 6)All remaining drug supplies should be returned to ECOR at the end of the study HEAL-IT HEALing of Ischemic Foot Ulcers With Cilostazol Trial

10. Follow-up: 1)Clinical follow-up every month 2)Place a dated, signed copy of follow-ups in the medical record 3)Ulcer counts, target ulcer border tracing and digital photographs will be done at each visit 4)Quality of life assessments done at baseline and at 6 months HEAL-IT HEALing of Ischemic Foot Ulcers With Cilostazol Trial

11. Site monitoring: All sites will be monitored via CRF & photos. Sites will be asked for copies of source documentation after the first 2 patients are enrolled, or 1 month after initiation of the trial, whichever occurs first. HEAL-IT HEALing of Ischemic Foot Ulcers With Cilostazol Trial

12. Case Report Forms: 1)Case report forms is made up in Teleform  2)Copy pages and save copy. 3)Send originals to ECOR every month 4)FAX randomization form to ECOR at randomization: 404-727-6495 5)FAX SAE forms to ECOR after event HEAL-IT HEALing of Ischemic Foot Ulcers With Cilostazol Trial

13. Communications: Reporting will include: 1)DCFs 2)Summary reporting 3)Newsletter 4)Website HEAL-IT HEALing of Ischemic Foot Ulcers With Cilostazol Trial

14. HEAL-IT website: http://www.emory.edu/WHSC/CARDIOLOGY/CVEC/HealIT Login: healit Password: woundhealing HEAL-IT HEALing of Ischemic Foot Ulcers With Cilostazol Trial

18. Patient Demographics VariableMean (SD, N) Age (years)70 (13, 22) Height (cm)169.6 (19.8, 21) Weight (kg)81.2 (21.2, 21) Toe Pressure (mmHg)31.5 (7.3, 8) Chest TCPO248.8 (8.8, 14) Dorsum TCPO229.7 (7.0, 15) HEAL-IT HEALing of Ischemic Foot Ulcers With Cilostazol Trial

19. Patient Demographics VariableN (%) Male Gender16 (73) Caucasian Race17 (77) Diabetes15 (68) Hypertension14 (64) Renal Insufficiency3 (14) HEAL-IT HEALing of Ischemic Foot Ulcers With Cilostazol Trial

20. Patient Demographics VariableN (%) Cardiac Disease10 (45) CABG 3 (30) MI 7 (70) PCI 3 (30) CABG, MI, and PCI denotes those patients who had cardiac disease and CABG, MI, and/or PCI. HEAL-IT HEALing of Ischemic Foot Ulcers With Cilostazol Trial

21. Patient Demographics VariableN (%) Cerebrovascular Disease4 (18) Prior Stroke 3 (75) Prior Stroke denotes those patients with cerebrovascular disease who had a prior stroke. HEAL-IT HEALing of Ischemic Foot Ulcers With Cilostazol Trial

22. Ulcer Location LocationN Digit12 MTP Joint1 Mid-Plantar Arch3 Metatarsal Head4 Other Location5 Multiple Locations are possible. Example: Metatarsal Head and Digit. HEAL-IT HEALing of Ischemic Foot Ulcers With Cilostazol Trial

23. Ulcer Location LocationN (%) Medial Aspect13 (59) Right Side11 (50) 1+ Edema4 (19) Number of Ulcers 1 2 3 13 (59) 8 (36) 1 (5) HEAL-IT HEALing of Ischemic Foot Ulcers With Cilostazol Trial

24. So where are we? 23 patients randomized Sample size 300 We are 8% of the way there To finish enrollment by end of October we need 21 a week Or about one patient per site per week HEAL-IT HEALing of Ischemic Foot Ulcers With Cilostazol Trial

25. Can we have a meaningful trial with fewer patients? Yes (so don’t give up) However, the more patients we randomize, the stronger the study HEAL-IT HEALing of Ischemic Foot Ulcers With Cilostazol Trial

26. Why this trial is important: Arterial ulcers are a serious problem in patients with PVD Anecdotal evidence support the use of Pletal for wound healing Pletal will not become routine for wound healing without this trial If positive, HEAL-IT will offer patients a beneficial new therapy HEAL-IT HEALing of Ischemic Foot Ulcers With Cilostazol Trial

27. What do we need to do? Randomize, Randomize, Randomize HEAL-IT HEALing of Ischemic Foot Ulcers With Cilostazol Trial