CLINICAL TRIAL UPDATES

Results for our initial Phase 1 PAD/PVD
Our Phase I study was designed to test safety, not effectiveness. While safety was the primary endpoint, we did do some measurements of safety and demonstrated an 86% amputation-free survival rate (compared to 50% expected amputation rate in this population). We also demonstrated significant improvement in the blood flow measurement at the level of the great toe. There is no published data yet for the Phase I study, though it will be coming out soon in the Journal of Vascular Surgery.  With the success of the Phase I trial, the FDA approved moving to a Phase III trial to test efficacy.  This trial will evaluate the safety and efficacy of concentrated bone marrow aspirate (cBMA) to prevent or delay major amputation and/or death in subjects with critical limb ischemia (CLI) due to severe peripheral arterial disease (PAD).

Results for our initial Phase 1 study

There is no published data yet for the Phase I study, though it will be coming out soon in the Journal of Vascular Surgery. A Phase I study is designed to test safety, not effectiveness. While safety was the primary endpoint, we did do some measurements of safety and demonstrated an 86% amputation-free survival rate
(compared to 50% expected amputation rate in this population). We also demonstrated significant improvement in the blood flow measurement at the level of the great toe. With the success of the Phase I trial, the FDA approved moving to a Phase III trial to test efficacy.

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Submitted to journal for publication

Autologous Bone Marrow Cell Therapy
PromotesLong Term Limb Salvage
in Patients with Critical Limb Ischemia

OBJECTIVES.

Approximately 20-30% of patients with critical limb ischemia (CLI) will not be candidates for conventional methods of revascularization with endovascular or surgical approaches. For these patients the only remaining option for relief of rest pain and infection is amputation. There is accumulating evidence that bone marrow mononuclear cells promote angiogenesis in ischemic tissue. Here we report the results of a phase I clinical trial using autologous bone marrow mononuclear cells (ABMC) to promote limb salvage in patients with no option CLI.
METHODS. Patients (ages 21-85) with Rutherford Class 4, 5 peripheral arterial disease were enrolled and treated with ABMC. The primary safety endpoint was accumulation of serious adverse events. The primary efficacy endpoint was amputation-free survival at one year. Secondary endpoints were changes in ankle-brachial index (ABI), toe-brachial index (TBI), transcutaneous oxygen measurements (TcPO2), and rest pain (RP) using a 10 cm. visual analog scale. Other measures included PET-CT H2O15 blood perfusion (BP) and ulcer healing.
RESULTS. Between September 2005 and March 2009 twenty-nine patients (30 limbs) (Table 1) were enrolled and treated with an average dose of 1.9 + 0.7 x 109 ABMC injected intramuscularly into the index limb. One patient developed ST segment changes that resolved without myocardial infarction. There were no other serious adverse events. Survival to the primary endpoint (amputation-free survival) was 86.2%. There was a significant increase in the mean TBI by 0.11 + 0.04 (p=0.02) from baseline (Figure 1). The mean ABI did increase after treatment by 0.08 + 0.04, however this did not reach statistical significance (Figure 2) and there was no change in TcPO2 (data not shown). RP significantly decreased on average by 2.24 + 0.6 cm. (p=0.02) (Figure 3). Changes in PET-CT H2O15 BP correlated with changes in ABI and TBI (Figure 4). There was complete healing of an ulcer in 4 patients (n= 9, 44%).
CONCLUSIONS. This phase I study has demonstrated safety and the amputation-free survival rates suggest efficacy of ABMC in promoting limb salvage in CLI (Figure 5). Based on these results we are currently conducting a phase III randomized, double-blinded multicenter trial to determine if ABMC are an effective therapy in preventing amputation in this patient population.

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Current efforts in our Phase III PAD/PVD trial

In order to test efficacy, you need a control group, hence the placebo-controlled design of the Phase III trial. We have fielded 77 inquiries so far for the Phase III trial and have enrolled 5 patients. We've had one screen failure. We treated our first subject in June 2010. Cleveland Clinic has treated 2 subjects and two other centers have each treated one subject. We are the lead site for recruitment and are a resource for all other sites since we have the added experience of conducting the Phase I trial here. It will take about 3 years to enroll all subjects and then another year to complete all their follow up, then more time to analyze the data.

Marrow StimTM PAD Kit for the Treatment of Critical Limb Ischemia (CLI) in Subjects with Severe Peripheral Arterial Disease (PAD)

All clinical trials require a sponsor to pay for the study.  Many services and tests do not qualify for insurance of which the patient should not have out of pocket expenses.  Biomet, a company who manufactures supplies and equipment that would be used in the treatments specific to this study, is sponsoring (paying for) all of the Phase III study expenses.  A Phase III trial is to test the efficacy of the treatment. In order to test efficacy, you need a control group, hence the placebo-controlled design of the Phase III trial. We have fielded 77 inquiries so far for the Phase III trial and have enrolled 5 patients. We've had one screen failure. We treated our first subject in June 2010. Cleveland Clinic has treated 2 subjects and two other centers have each treated one subject. We are the lead site for recruitment and are a resource for all other sites since we have the added experience of conducting the Phase I trial here.  It will take about 3 years to enroll all subjects and then another year to complete all their follow up, then more time to analyze the data.    Included in this packet is an example of the “informed consent” each potential patient receives when they are screened for potential enrollment into the study and details about the trial to help you understand the processes involved in the processes.

TRIAL DETAILS

This is a prospective, randomized, double-blind, placebo controlled, multicenter trial intended for subjects with critical limb ischemia (CLI) and no revascularization options. The investigational treatment utilizes autologous concentrated bone marrow aspirate (cBMA) at the point of care. The bone marrow aspirate is obtained from the subject's hip, concentrated with a bone marrow concentration device, and delivered intramuscularly to the affected limb. Subjects meeting the inclusion/exclusion criteria will be randomized to receive either the investigational treatment (cBMA) or a placebo control (sham treatment).

Eligibility

Ages Eligible for Study:   21 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

Inclusion Criteria:

• Lower extremity ischemia due to advanced peripheral arterial disease

• Non-candidates for surgical bypass or percutaneous angioplasty and stenting

• Maximal medical therapy for critical limb ischemia

• Minor tissue loss (Rutherford Category 5) or ischemic rest pain (Rutherford Category 4) with ABI ≤ 0.6, or TBI ≤ 0.4, or TcPO2 ≤ 50 mm Hg

• No history of malignant disease (evidence of standard preventative cancer screenings required)

• Competent to give consent

• Negative urine pregnancy test (women of childbearing potential)

• Unilateral or bilateral lower limb ischemia

Exclusion Criteria:

• Existing malignant disease diagnosis

• Major tissue loss (Rutherford Category 6)

• Diabetics on oral or insulin therapy with active (or history of) proliferative retinopathy (evidence of retinal exam required)

• Poorly controlled diabetes mellitus with HbA1C > 8.5% (evidence of HbA1C test required)

• Uncompensated congestive heart failure (New York Heart Association Class IV) and/or other conditions that preclude general anesthesia

• Myocardial infarction or stroke within last 90 days

• Elevated liver function tests (AST or ALT more than twice normal upper limit)

• Renal disease (creatinine > 2.5 mg/dl) or chronic hemodialysis

• White blood cell count < 3,000/µL or > 15,000/µL, platelet count < 100,000/µL, or hematocrit < 32%

• Topical growth hormone therapy within last 90 days, or injected growth hormone therapy within last 180 days

• Disease of central nervous system and/or other conditions that impair cognitive function

• Two or more episodes of pulmonary embolus with a documented DVT in index leg or history of DVT in index leg without evidence of clot resolution

• Infection of index leg

• Pregnant women

• Lower extremity venous disease with pitting edema in index leg

• History of bone marrow disease prohibiting transplantation

• History of chemotherapy or radiation affecting bone marrow

• Osteomyelitis in index leg

• Existing HIV diagnosis

• Organ transplant recipients

• Known terminal disease process with life expectancy less than one year

• Severe concomitant disease(s) or any additional condition(s) which the investigator feels constitute(s) criteria for exclusion of a particular subject

• Amputation required within 30 days

• Inclusion in any other clinical study that may affect the outcome of this study

The recruitment package can be found at

http://www.biomet.com/patients/clinical_recruitment_padkit.cfm

We, neither ICVBM nor CMMRF, can select what hospitals qualify to run this study.  If you are associated with a medical facility that wishes to inquire into becoming a study site, contact Dr. March or myself after this meeting and we will give you the contact information to start the process. 

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