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

2. 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

3. 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

4. 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

5. 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

6. 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

7. Inclusion Criteria: 1)Non-healing ulcer of the foot (ankle forward) 2)Largest (target) ulcer on either foot is > 4 weeks and < 52 weeks old. 3)Target ulcer is full-thickness but does not involve bone. 4)Target ulcer is > 0.25 cm 2 and < 12 cm 2. Non-target ulcers do not have to fulfill these criteria. 5)Transcutaneous oximetry (TcPO2) and/or toe pressures between 20 to 40 mm Hg 6)Age >18 years 7)Women of child-bearing potential: negative pregnancy and commitment to remain abstinent or use contraception for the duration of the study. HEAL-IT HEALing of Ischemic Foot Ulcers With Cilostazol Trial

8. Exclusion Criteria: 1.Venous stasis ulcers on foot with target ulcer 2.Lower extremity arterial revascularization (either bypass surgery or angioplasty) less than 6 weeks prior to screening in leg with target ulcer 3.Charcot feet 4.More than 1+ pitting edema of the leg with the target ulcer 5.Patient has exposed bone and/or osteomyelitis in the leg with the target ulcer 6.Patient is receiving radiation, chemotherapy, corticosteroids or immune system suppressants 7.History of congestive heart failure of any severity 8.Known thrombocytopenia 9.Known bleeding diathesis 10.Known intolerance or hypersensitivity to cilostazol or any of the ingredients of Pletal® Cont’d HEAL-IT HEALing of Ischemic Foot Ulcers With Cilostazol Trial

9. Exclusion Criteria cont’d: 11.Active peptic ulcer disease or GI bleeding 12.Known moderate or severe hepatic dysfunction 13.Current participation in another clinical trial 14.Major life-threatening illness or prognosis of less than 1 year 15.Inability to give informed consent 16.Concurrent use of pentoxifylline 17.Concurrent use of ticlopidine 18.Concurrent use of hyperbaric oxygen 19.Concurrent use of arginine 20.Use of Pletal® within 6 months of the trial. HEAL-IT HEALing of Ischemic Foot Ulcers With Cilostazol Trial

10. 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

11. Randomization and Initiation: 1)Decide if patient requires eschar debridement and treatment of infection 2)Informed consent after standard wound care. 3)Choose target ulcer 4)Tracing of target ulcer border and digital image of target ulcer 5)Send tracing to ECOR 6)Send image to both ECOR and Yale 7)Patient randomized to cilostazol vs placebo 8)Take 2 tablets twice a day, one table twice a day if on concomitant administration of a drug interfering with cytochrome P-450 metabolism (see appendix of protocol) 9)Continue study drug for 6 months HEAL-IT HEALing of Ischemic Foot Ulcers With Cilostazol Trial

12. 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 loose 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

13. 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

14. Data Collection: See table, page 6 of protocol HEAL-IT HEALing of Ischemic Foot Ulcers With Cilostazol Trial

15. 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. All records will be reviewed. HEAL-IT HEALing of Ischemic Foot Ulcers With Cilostazol Trial

16. 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 screening forms 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

17. Target Ulcer Border Tracings and Images 1)Target ulcer border tracings –copy original and save copy at site 2)Send original tracings to ECOR 3) Digital images – send copy (JPG file) to Yale and ECOR. Save a copy. 4)Labels are provided 5)Send Tracings and Images every month HEAL-IT HEALing of Ischemic Foot Ulcers With Cilostazol Trial

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

19. ECOR Contact: Felicia Warren, HEAL-IT Coordinator 1256 Briarcliff Road, Suite 1N Atlanta, GA 30306 404-727-3683 HEAL-IT HEALing of Ischemic Foot Ulcers With Cilostazol Trial

20. Who to call: Bauer Sumpio: 203-737-6066 bauer.sumpio@yale.edu bauer.sumpio@yale.edu Eileen Moran: 203-737-6066 Eileen.Moran@med.va.gov Suephy C. Chen: 404-712-9660 schen2@emory.edu@e William S. Weintraub: 404-712-9652 wweintr@emory.edu Felicia Warren: 404-727-3683 fwarren@emory.edu HEAL-IT HEALing of Ischemic Foot Ulcers With Cilostazol Trial