The Effects of Pulsed Elelectro-Magnetic Fields ("PEMF") in the Treatment of Venous Stasis Leg Ulcers

A Sham Controlled Study to Compare the Effectiveness of Three Different Power Levels of PEMF Devices in the Treatment and Resolution of Venous Stasis Leg Ulcers

The purpose of this study is to determine the clinical effectiveness of a low-power PEMF device, a medium-power PEMF device and a high-power PEMF device as compared to a sham device to treat leg ulcers resulting from venous stasis ("VSLU").

This study will demonstrate whether PEMF therapy is an effective adjunct treatment to the traditional treatment protocol used for the resolution of VSLU and of the pain associated with them. This is a 4 arm study done by comparing the outcomes of treatment with a low-power PEMF device, a medium-power PEMF device and a high-power PEMF device against those obtained from the control group treated with a sham PEMF device.

A device usability study is included in the study protocol to evaluate the participants' understanding of the device packaging, the User Manual, the device labeling, the controls and the directions for use. An un-blinded assistant ("UA") will manage the device usability study and hand out all informational literature and instructions to each participant, in accordance with the randomization protocol. Participants' success will be rated and their perception on the ease of use and how to make the device easier to use will be solicited.

Safety precautions and contraindications are specifically defined, and adverse/ unexpected events and reactions, if any, will be documented as they arise.

The primary aims of the study are to assess the effects of 16 weeks of PEMF treatment on the VSLU with one of three PEMF devices of different power levels against a sham PEMF device. The study has 3 specific aims:

Aim 1 (Primary) Determine if the use of specific PEMFs affect the time for healing trajectory of VSLU. Healing trajectory over the 16 week of the study protocol will be measured as the area under the curve for total lesion area expressed as a percentage of the baseline area.

Aim 2 (Secondary) Determine if VSLU and serum levels of three inflammatory cytokines: IL-1, IL-6 and TNF-alpha are affected by the use of specific PEMFs.

Aim 3 (Secondary) Determine if VSLU pain is improved by the use of specific PEMFs. Pain levels will be assessed with the use of allowed pain medication use by each participant. Pain will also be assessed with the five (5) pain scales from the National Initiative on Pain Control pain assessment scales ("NIPC scales") that will help each participant describe his/her pain levels and characteristics both quantitatively and qualitatively.

Eighty participants will be enrolled on the basis of leg ulcers due to venous insufficiency (VSLU) alone unless there are exclusions factors. The 80 participants will be divided in four groups of 20 participants: three treatment groups and a control group. Of the initial 80 participants at the investigation site approved to participate in this study, the outcome data of a net total of 72 participants, 18 per group, will be considered for analysis. The randomization protocol used for this study will occur in two stages: first with the blinding of the participants and the random assignment of a unique record number ("URN") to each of them and, second, with the random allocation of one of the PEMF or sham devices to each participant. Device allocation will be done according to a computer-generated table of random permutations designed to balance the number of participants in each group. All the data from the follow-ups, various assessments and testing procedures will be collected under the study URN for each participant. The URNs will be kept in a URN Record Log and kept in a locked cabinet in the principal investigator ("PI") 's office. Aside from the UA who will not be involved in data collection, monitoring or analysis, the investigators will be blinded to the URN assignment and to the PEMF or sham treatment protocol followed by each participant during the study. The randomization will not be broken until all eighty participants have completed the study.

The required effect sizes are all large; however, the PEMF effects are expected to be very large. The sample size of 80 participants provides required large effect sizes. Twenty patients will be enrolled per group and 18 are expected to have enough data to be included in the analysis.

Aim 1 With 20 participants enrolled in each of four arms, and a net sample size of 18 per group (accounting for 10% with incomplete data) and a p-value of 0.017 required for significance, there will be 80% power for a t-test to detect an effect size of 1.1 (i.e. a difference in mean area under the curve equal to 1.1 standard deviations). The secondary analysis for time to complete healing will have 80% power to detect a hazard ratio of 3.0.

Aim 2 and 3 The power for the multivariate test will be approximated by that available for a two sample t-test. With a net sample size of 18 per group and a p-value of 0.017 required for significance, the effect size will need to be 1.1 in order to have 80% power for a t-test. For the Wilcoxon rank sum test, the effect size may be expressed by the quantity Prob(X < Y) where X and Y are drug usage values from a random control group patient and a random patient from one of the PEMF groups. Under the null hypothesis, Prob(X < Y) = 0.5. With a sample size of 18 per group and alpha = 0.017, there will be 80% power to detect Prob(X < Y) = 0.81.

The Project Director, a direct agent of the company sponsoring the study, will periodically visit the research site to ensure the study is conducted in compliance with the approved Clinical Investigation Protocol and that the PI, the research assistant ("RA") and the UA adhere to the Protocol.

A record of the number of all screened participants, participants who refuse entry, and those entered in the study will be kept by the UA to follow CONSORT guidelines. He or she will also be informed and keep a record of any dropouts and the reason the participant was dropped from the study.

Statistical data will include 2 series of survey questionnaires at baseline and at the end of the study. The questionnaires include: Your Health in General (SF-36) and pain assessment using the National Initiative on Pain Control pain ("NIPC") assessment scales. A count, measurement and imaging of the VSLU using Silhouette High Tech cameras. Pain levels and pain medication intake will also be obtained weekly using a Caregiver Diary. A fluid and a small blood sample will be collected weekly from the VSLU area and tested for various inflammation biomarkers and growth factors. The data will be noted using a series of case report forms.

The primary tests for a PEMF benefit will be made using a Hochberg adjustment to take into account testing a single primary outcome measure (healing trajectory) measured three times, once for each of three different PEMF variations versus control. Under the Hochberg method, if all three primary test p-values are under 0.05, then all three will be considered significant. However, if only one is under 0.05, it will need to be under 0.05/3 = 0.017 in order to be considered significant. Assuming at least one of the PEMF variations is superior to control for at least one of the outcomes, a secondary analysis will compare each of the PEMF variations to the other two. A Hochberg adjustment will also be made for each of the two sets of secondary comparisons (pain and cytokines).

Aim 1 (Primary) The healing trajectory over 16 weeks will be compared for each PEMF variation versus the control group by t-test. Healing trajectory will be measured as the area under the curve for total lesion area expressed as a percentage of the baseline area.

Secondary analysis will use a log rank test to compare the times to complete healing. Descriptive analysis will plot the number of ulcers and their combined area over time for each subject. Kaplan-Meier survival curves for the time to complete healing will also be produced.

Aim 2 (Secondary) A multivariate test will be made comparing each PEMF group versus control, for a vector made up of the three cytokines: IL-1, IL-6 and TNF-alpha.

Aim 3 (Secondary) A multivariate test will be made comparing each PEMF group versus control, for a vector made up of the five pain scales. Pain medication usage will also be summarized using two quantities: a morphine equivalent dose to summarize all opioid drugs used, and a maximum dose equivalent for NSAIDs. Averages for these two medication use measures will be computed for the 16 weeks of observations and each will be analyzed separately using a Wilcoxon rank sum test.

The blinding assessment will occur at the end of the treatment protocol. Participants and investigators will be probed as to the device and treatment protocol each received.

All data, resulting analyses, and reports will remain proprietary to the sponsor. All case report forms and final data reports will be submitted to the sponsor for review and approval prior to any publication being made.

The data obtained from this study will demonstrate whether treatment with specific PEMFs affect the time for healing trajectory of VSLU; affect VSLU and serum levels of inflammatory cytokines; and if VSLU pain is improved.

A successful resolution of leg ulcers from venous stasis and the associated pain using therapeutic means, such as PEMF therapy, that are conservative, non-invasive, non-pharmacological and with no known undesirable side effects may prove to be quite significant.

Inclusion Criteria:

Participants must also have normal cognitive and communicative abilities to provide comprehensive information for:

1. Health history questionnaire and Your Health in General ("SF-36")
2. The National Initiative on Pain Control pain assessment scales (NIPC scales). The NIPC scales are comprised of four complementary pain assessment rating scales, the Wong-Baker FACES Pain Rating Scale, Numeric Rating Scale (NRS), a pain location chart and a Pain Quality Assessment Scale© (PQAS©)

Exclusion Criteria:

1. Inability to obtain informed consent from participant
2. Prisoners or convicts
3. Hemorrhagic tendencies, Purpura, hemophilia, or any cardiovascular diseases
4. Severe anemia, Hemoglobin < 8.5
5. Severe hypoalbumenemia, serum albumen , 2.6
6. Poorly controlled diabetes, A1cHgb > 12
7. Severe renal failure - serum creatinine > 2.5 or hemodialysis
8. Severe hepatic insufficiency: know cirrhosis, any degree of ascites, serum transaminases more than 3 times the upper limit of normal
9. Pregnancy - women of childbearing potential must agree to use adequate contraception during the study
10. HIV infection unless on retroviral therapy and viral load undetectable by PCR
11. Severe hypoxemia - chronic oxygen or ventilator therapy
12. Known cryoglobulinemia
13. Systemic antibiotic therapy for any indication within 5 days of screening
14. A fracture to the lower extremities in the last 6 weeks
15. Within 24 hours of any surgery or 2 weeks of surgery on internal organs
16. Critically ill patients, patients hospitalized and patients who received transplants in past 2 months or patients in whom over-medication may be contraindicated
17. Active chemotherapy, cancer or malignant tumors
18. Any metal screws, pins and/or metallic implants within 15 inches of the VSLU
19. Participants with specific ulcers originating from sickle cell anemia or clinically significant infections as determined by ulcer culture
20. A history of difficult venipuncture for obtaining blood specimens
21. Current use of systemic agents or immunosuppressive therapy that may influence wound healing, such as Prednisone, Dexamethasone. Topical steroids to a maximum level of 25 mg Hydrocortisone daily applied no closer than 2.5 cm from the VSLU margin. Non steroidal anti-inflammatory drugs (NSAIDs) are not allowed except Ibuprofen maximum daily dose of 1800 mg, Acetaminophen maximum daily dose of 2600 mg (with or w/o opiates) and Naproxen maximum daily dose of 1000 mg
22. Current participation in any other clinical trial or study
23. Current involvement in a medical litigation or malpractice lawsuit.