HEALIT Bauer Sumpio Yale University Suephy C Chen

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

HEAL-IT HEALing of Ischemic Foot Ulcers With Cilostazol Trial 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 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 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 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 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 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 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 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 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 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 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 HEALing of Ischemic Foot Ulcers With Cilostazol Trial

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

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

HEAL-IT Patient Demographics Variable Mean (SD, N) Age (years) 70 (13, 22) Height (cm) 169. 6 (19. 8, 21) Weight (kg) 81. 2 (21. 2, 21) Toe Pressure (mm. Hg) 31. 5 (7. 3, 8) Chest TCPO 2 48. 8 (8. 8, 14) Dorsum TCPO 2 29. 7 (7. 0, 15) HEALing of Ischemic Foot Ulcers With Cilostazol Trial

HEAL-IT Patient Demographics Variable Male Gender N (%) 16 (73) Caucasian Race 17 (77) Diabetes 15 (68) Hypertension 14 (64) Renal Insufficiency 3 (14) HEALing of Ischemic Foot Ulcers With Cilostazol Trial

HEAL-IT Patient Demographics Variable Cardiac Disease HEALing of Ischemic Foot Ulcers With Cilostazol Trial N (%) 10 (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 Patient Demographics Variable N (%) Cerebrovascular Disease 4 (18) Prior Stroke 3 (75) Prior Stroke denotes those patients with cerebrovascular disease who had a prior stroke.

HEAL-IT Ulcer Location N Digit 12 MTP Joint 1 Mid-Plantar Arch 3 Metatarsal Head 4 Other Location 5 HEALing of Ischemic Foot Ulcers With Cilostazol Trial Multiple Locations are possible. Example: Metatarsal Head and Digit.

HEAL-IT Ulcer Location Medial Aspect Right Side 1+ Edema Number of Ulcers 1 2 3 N (%) 13 (59) 11 (50) 4 (19) 13 (59) 8 (36) 1 (5) HEALing of Ischemic Foot Ulcers With Cilostazol Trial

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