HEALing of Ischemic Foot Ulcers With Cilostazol Trial
Protocol 21-01-334
Confidential, do not disseminate
Bauer E. Sumpio, MD, PhD
Department of Vascular Surgery
Yale University
Suephy C. Chen, MD, MS
Department of Dermatology
Emory Center for Outcomes Research
Emory University
William S. Weintraub, MD
Director, Emory Center for Outcomes Research
Emory University
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.
Background:
Ischemic foot ulcers are caused by breakage in the skin followed by poor healing due to peripheral arterial disease. Cutaneous breakdown occurs frequently with the shear forces of walking. Decreased sensation due to neuropathy from diseases such as diabetes contributes to the risk of cutaneous breakdown. Once the skin is compromised, normal healing forces can be impaired from decreased arterial supply, neuropathy, musculoskeletal deformities or a combination of these factors.1 Ischemic ulcers are often preceded by symptoms of chronic arterial occlusion, which include leg claudication and rest pain.2 Intermittent leg claudication, often the first sign of peripheral arterial disease, occurs when the leg becomes painful upon exercise. Rest pain, a sign of progressive peripheral vascular disease, describes the situation when leg pain occurs at rest.
The prevalence of ischemic foot ulcers is high. Investigators estimate prevalence of leg ulcers of all etiologies to be around 1 to 2% in the over-50 age group in developed countries.3-5 Peripheral vascular disease contributes up to 42% of all ulcerated legs in non-diabetic patients and up to 67% in the diabetic population.6-8
Ischemic foot ulcers are debilitating from both an individual and societal perspective. Complications of foot ulcers account for one-quarter of hospital days in the diabetic population. Also, failure of ulcers to heal has led to 50,000 to 60,000 amputations per year in the diabetic population. Nearly half of the amputees develop limb-threatening ischemia in the opposite limb within 18 months of amputation and more than half will require amputation of that opposite limb within 5 years.9 The quality of life of chronic leg ulcers patients is significantly affected. While the ischemic foot ulcer population has not been specifically studied, investigators that have found that leg ulcer patients of all etiologies have significant impact on emotions, functional impairment and symptoms. Emotional impact includes anxiety, depression, hostility, negative self-esteem and negative affect.1011 In one study there was a strong correlation between time spent on ulcer care and feelings of anger and resentment.12 Functional impairment included decreased mobility and activity11, 12, specifically interference with leisure or social activities, social isolation, and physical restrictions.10, 13 Patients with arterial ulcers, in contrast with venous ulcers, also frequently complained of pain. 10
While there is a lack of cost analysis specifically for ischemic foot ulcers, the financial impact of chronic leg ulcers is known to be costly.12 In addition to treatment costs, patients are affected by job loss, time lost from work and transportation costs. Ulcer care given by a visiting nurse has been estimated to amount to approximately $40,000 per patient.14 Approximately 2 million work days are lost annually in the United States because of leg ulcers.15
The common therapeutic interventions for ischemic foot ulcers have been geared toward both local wound care and interventions that improve arterial supply. Local wound care includes mechanical, chemical, and/or enzymatic debridement, systemic antibiotic therapy, and moist dressings. Plastic reconstructive techniques may be necessary to expedite closure of the ulcers after bacterial contamination has been controlled.1 If the arterial supply is severely compromised, revascularization of the ischemic area by vascular-bypass surgery is standard. Investigators have found pentoxifylline to be beneficial in healing diabetic foot ulcers after eight weeks of treatment.16 Ticlopidine, a platelet aggregation inhibitor, also appears to be beneficial in small ischemic ulcers.17 However, it is associated with significant and sometimes fatal adverse reactions, specifically neutropenia and bone marrow aplasia.18
Cilostazol is an antiplatelet and vasodilatory medication. By selectively blocking phosphodiesterase type III, cilostazol increases cyclic AMP within platelets and vascular smooth muscle cells, thereby inhibiting platelet cell aggregation19-20 and causing vasodilation.21-23
Clinical trials have been performed using cilostazol for intermittent claudication with such success that the Food and Drug Administration approved it for relief of intermittent claudication in patients with stable peripheral arterial disease.24 In a placebo-controlled randomized trial, Dawson et.al.25demonstrated on treadmill testing a 35% increase in initial claudication distance and a 41% increase in maximal walking distance in patients treated with cilostazol. Dawson et. al. also showed significantly greater benefit in patients with moderate-to-severe claudication compared to pentoxifylline, which did not differ from placebo.26 Other indices of improvement with cilostazol in claudicants include quality of life, patient reports of walking impairment, and ankle-brachial indexes.27 Investigators have also demonstrated an increased in blood flow and cross-sectional area in dorsalis pedis with cilostazol in an open trial.22, 28-30
There is some experience with cilostazol in the treatment of skin ulcers. Kondo et.al. treated 24 patients with ulcers from collagen diseases in an open label study and found significant decrease in the size of the ulcer.31 Another study32 evaluated the efficacy of cilostazol 100 mg b.i.d. in patients with intractable skin ulcers or other dermatologic symptoms arising from vascular disorders. The patients were either treatment failures or treatment-naive. Disease states included diabetic skin lesions, insufficient peripheral circulation, arteriosclerosis obliterans, ulcers with vasculitis, metabolic disorders, systemic lupus erythematosus, and progressive systemic sclerosis. Twenty-one subjects were treated for a minimum of 6 weeks. Improvement was seen in pressure pain, numbness, pain at rest, and erythema at 2 weeks. Subjects with diabetic ulcer showed the greatest improvement. Overall, 48% showed marked improvement of symptoms, 24% showed improvement, 10% showed slight improvement, and 19% worsened. The authors concluded that PLETAL may be useful in the treatment of skin ulcer secondary to vascular disorders.
Methods
Hypothesis
Cilostazol will improve wound healing in ischemic leg ulcers in combination with standard local wound care compared to local wound care alone.
Primary Endpoint
Mean rate of healing of target ulcer (%/ month, where a month is 30 days)
Secondary Endpoints
1)Change in target ulcer area (cm2)
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
Safety Endpoints
Pharmacokinetic trials have shown that cilostazol is well tolerated in both healthy volunteers and in patients with intermittent claudication resulting from peripheral arterial disease.33 A multicenter trial designed to evaluate the safety of cilostazol for the treatment of intermittent claudication demonstrated that no clinically relevant laboratory changes were seen except for a possible positive change in high-density lipoprotein cholesterol and triglycerides.34 Pharmacokinetic trials have shown that the dose of cilostazol does not have to be adjusted for patients with mild hepatic impairment, but should be used with caution in patients with moderate or severe hepatic impairment.35 Cilostazol doses do not have to be adjusted for patients with renal impairment of all severities.36 Because of the favorable findings of these safety studies, sites will check labs prior to administering medication only if there is a possibility of moderate or severe hepatic impairment or of pregnancy in women of childbearing potential.
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. Target ulcer is full-thickness but does not involve bone. Target ulcer is > 0.25 cm2 and < 12 cm2. Non-target ulcers do not have to fulfill these criteria.
3)Transcutaneous oximetry (TcPO2) and/or toe pressures between 20 to 40 mm Hg
4)Age >18 years
5)Women of child-bearing potential: negative pregnancy and commitment to remain abstinent or use contraception for the duration of the study.
Exclusion Criteria
1)Dominating venous stasis ulcers on foot with target ulcer. Venous stasis ulcers are allowed, if not too dominating.
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 2+ 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. Patients with a history of heart failure are eligible for the study if (1) the PI determines that: a) Heart failure diagnosis was incorrect, or b) The heart failure diagnosis was over 2 years ago, currently asymptomatic, not presently on heart failure medication and has an EF of > 35. Patients with any history of heart failure will have to be adjudicated by Dr. William S. Weintraub.
8)Known thrombocytopenia
9)Known bleeding diathesis
10)Known intolerance or hypersensitivity to cilostazol or any of the ingredients of Pletal®
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 1 month of the trial.
Study Design
The HEAL-IT trial is a multicenter, randomized, double-blind, placebo-controlled clinical trial to test whether cilostazol will improve wound healing in combination with standard local wound care compared to wound care alone. A total of 300 patients at 20 clinical sites will be randomized. Patients will be recruited into the trial after standard wound care is performed on the ulcer to ensure minimal eschar and lack of infection. Standardized good wound care is defined by a clean, moist wound environment, infection control, a non-weight-bearing regimen, and debridement of nonviable or compromised tissue, as needed. No topical medications of any sort are included in this definition.
After informed consent is obtained, a target ulcer will be chosen. The largest ulcer will be defined as the target ulcer. The sites will take a tracing of the target ulcer border as well as a digital image. The tracing will be performed with a thin permanent marker on acetate sheets that will be provided. The tracing will then be sent to ECOR, where the area of the ulcer can be determined and recorded. The digital image will be sent to the Yale Lab to evaluate for signs of significant infection. If the Yale Lab finds the ulcer to be infected at screening, a full course of antibiotic therapy must be completed prior to randomization. However, investigators should note that there will only be a 3-month recruitment period; therefore, if prolonged antibiotic therapy is necessary, the subject may not be eligible before the recruitment period closes.
If there are no signs of infection, the patient will be randomized to cilostazol or placebo. At baseline, the subjects will complete two quality of life questionnaires, the EuroQOL and the Short Form-36 (SF-36). The form of standard wound care (mechanical, chemical, or enzymatic debridement) will also be documented. The dose of cilostazol will be 100 mg twice a day. If the patient cannot tolerate the dose due to adverse effects such as headache and abnormal stools, they will be allowed to take a lower dose (50 mg twice a day). Once the symptoms subside, the patient can be tried on the higher dosing. (The investigators will be provided with recommendations for treating several common adverse effects.) If the patient is taking a medication that inhibits CYP3A4 or CYP2C19, consideration should be given to a dose of 50 mg twice a day for the duration of exposure to the inhibitor plus 5 of its half-lives. A patient will be considered noncompliant, but still included in the analysis by intention-to treat, if the patient falls below 75% compliance of the 50 mg twice-a-day dosage.
Baseline(Visit 1) / Weeks 4, 8, 12, 16, and 20) (Visits 2-6) / Final Visit
(Week 24, Visit 7) or ET* / 14 days post Final Visit or ET / As Needed
Randomization / X
Informed Consent / X
Inclusion/exclusion criteria / X
Demographics / X
Ulcer count (of leg with target ulcer) / X / X / X
Target ulcer dimensions (tracing by sites) / X / X / X
Target ulcer completely healed (yes/no) / X / X
Urine HCG (women of childbearing potential only, at investigators discretion) / X
Photograph of target ulcer to
check for infection and need
for debridement / X / X / X
Drug dosing (need to record the dosage) / X / X / X
Unused drug returned and counted / X
(at month 3) / X
Complications/Adverse
effects Assessment / X / X / X / X
Quality of life questionnaires / X / X
Death report / X
Hospitalization report / X
The subjects are to be followed routinely during the study with visits every four weeks. At each visit, a digital photograph and tracing will be taken of the target ulcer after any necessary debridement is done. If a significant amount of eschar forms during the trial, the treating physician will perform debridement according to standard wound care procedure. Information on the ulcer status will also be obtained. If there is an interim hospitalization, sites will be asked to report the event and the reason for admission. A DRG code will be assigned to the hospitalization and costs will be estimated using the Medicare reimbursement rate.
Data to be Collected (*ET = early termination)
Randomization and Study Drug
The randomization scheme will be developed by the coordinating center. Patient allocation to drug or placebo, using a blocked design, will be developed by the coordinating center and sent to the sponsor for drug preparation. The sponsor will prepare matching unmarked bottles of cilostazol 50 mg and placebo. The bottles will be marked with a patient allocation number. The sites will receive an initial shipment of cilostazol or placebo sufficient for 20 patients for eight months of therapy. Note that an additional two months of drug are given to ensure that the subject will not run out of medication in case they cannot make it to their follow-up exactly at the 3-month time point. Should there be more rapid randomization at some sites, supplementary drugs will be made available. Drugs will be made available to patients in the trial according to allocation number. The sites will receive a list of their sequential allocation numbers. The sites will need to carefully enroll patients by allocation number. For the first two weeks, patients will take one tablet twice a day and then two tablets twice a day for the remainder of the study. The pills are to be taken at least a half hour before or two hours after breakfast and dinner. If patients cannot tolerate the higher dose, they will be allowed to take a one-pill-twice-a-day regimen. If patients must be on medications that inhibit the hepatic cytochrome P-450 isozymes 3A4 or 2C19 (including diltiazem, verapamil, nifedipfine and omeprazole, see appendix for a more complete list), consideration will be given to prescribing one tablet of study drug twice a day. Patients will be asked not to drink grapefruit juice on a regular basis for the duration of the study.
Follow-up
Patients will be seen every 4 weeks for ulcer evaluation at which time a digital photograph and tracing will be taken of the target ulcer. A 4-month supply of pills will be dispensed at the first and fourth. At the third and last follow-up appointments, all unused pills will be returned to the site. The site will then count the unused pills and return the pills to ECOR.
Site Monitoring
All sites will be monitored during the trial. 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.
Organizational Structure
The trial will be run by an Executive Committee. The Executive Committee will be chaired by the overall PI of the trial (Bauer Sumpio). Other members of the Executive Committee will be the director of the Coordinating Center (William Weintraub), the co-PI of the Coordinating Center (Suephy Chen), and the director of biostatistics (Elizabeth Mahoney). The Executive Committee will also serve as a publication committee. All data will be reviewed by an independent Data and Safety Monitoring Board. There will a Yale laboratory for evaluation of infection and eschar; the ECOR wound size laboratory will measure and record wound size.
Data Handling and Coordinating Center Activity
The Emory Center for Outcomes Research (ECOR) will function as the data-coordinating center for the trial. All data points for the trial will be defined in a data dictionary. All ulcer tracings will be mailed to ECOR and scanned and analyzed with Image Pro Express to determine their area. The database for the trial will be developed in Microsoft Access. Forms will be developed in Teleform. Case report forms will be developed and sent to the sites. Forms will be filled out on paper and signed by the site PI. Forms will be copied and copies kept at the site. The originals will be sent to the coordinating center at the Emory Center for Outcomes Research. All data will be logged and then scanned into the database. All data will be verified using the Teleform verifier. The data center will develop monthly reports summarizing recruitment and data completeness. Sites will receive data clarification forms (DCF’s) on a regular basis for missing data or incomplete forms.