Critical Limb Ischemia, Peripheral Arterial Disease, Peripheral Vascular Disease
Conditions
Keywords
Critical Limb Ischemia, Peripheral Arterial Disease, Peripheral Vascular Disease, CLI, PAD, PVD, Angiogenesis, Stem Cells, Cell Therapy, Limb Salvage, Amputation, Leg Pain
Brief summary
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).
Detailed description
This is a prospective, randomized, double-blind, placebo controlled, multicenter trial intended for subjects with critical limb ischemia (CLI) that are unsuitable for revascularization. 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).
Interventions
Concentration of autologous bone marrow aspirate for intramuscular delivery to affected limb
PROCEDUREPlacebo procedure (sham)
Sham bone marrow aspiration, sham delivery to affected limb
Sponsors
Zimmer Biomet
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Unilateral or bilateral lower extremity ischemia due to advanced peripheral arterial disease * Unsuitable for revascularization * 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 * Competent to give consent * No current malignancy or history of previous malignancy within the last five years, with the exception of adequately treated non-melanoma skin cancer (evidence of standard preventative cancer screenings required)
Exclusion criteria
* Major tissue loss (Rutherford Category 6) * Diabetics on oral or insulin therapy with uncontrolled or untreated proliferative retinopathy (evidence of retinal exam required) * Poorly controlled diabetes mellitus with HbA1C \> 10% (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 * Current infection of index leg * Pregnant women (negative urine pregnancy test required) * Lower extremity venous disease with pitting edema in index leg * Recent history (in the 6 months prior to screening) of bone marrow disease or treatment with any medication or procedure which adversely affects the bone marrow and would prohibit transplantation * Current 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 * Major amputation required within 30 days * Inclusion in any other clinical study that may affect the outcome of this study * Uncorrected stenosis(es) of greater than 50% in the common and/or external iliac artery and/or common femoral artery of the index leg.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Occurrence of Major Amputation or Death | 52 weeks | Occurrence of major amputation (above the ankle joint) or death. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Visual Analog Scale (VAS) - Pain | 52 weeks | Pain reported at the 52-week follow-up visit as assessed on the visual analog scale (VAS). Scores are recorded by making a handwritten mark on a 10-cm line that represents a continuum between no pain and worst pain. The distance from the beginning of the line is measured and reported in centimeters (cm), with 0 representing no pain and 10 representing the worst possible pain. |
| Six-Minute Walk Test | 52 weeks | Measurement (in meters) of the total distance a participant is able to walk in 6 minutes. Since ability to walk is related to the condition of the affected limb, this measure is tied to limb pain and function. If a participant had multiple limbs included in the study, each limb was evaluated separately. Only one limb could be included in the study at a time. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Occurrence of Major Amputation or Death | 5 years | Occurrence of major amputation (above the ankle joint) or death for all participants through final follow-up. |
Countries
United States
Participant flow
Recruitment details
Enrollment in the study occurred between June 2010 and June 2015. Until February 2014, participants completing the initial 52-week follow-up period could choose to have their second limb randomized if the participant and limb continued to meet all study inclusion and exclusion criteria. Three (3) limbs were enrolled during this time, resulting in a total of 155 limbs in 152 participants that were included in the final intent-to treat analysis for the primary endpoint.
Pre-assignment details
Participants that provided informed consent, completed all screening assessments, and met all inclusion and exclusion criteria for the study went on to be randomized and undergo the study procedure.
Participants by arm
| Arm | Count |
|---|---|
| Concentrated Bone Marrow Aspirate (cBMA) Bone marrow concentration device: Concentration of autologous bone marrow aspirate for intramuscular delivery to affected limb | 117 |
| Concentrated Bone Marrow Aspirate (cBMA) Bone marrow concentration device: Concentration of autologous bone marrow aspirate for intramuscular delivery to affected limb | 119 |
| Placebo Control (Sham) Placebo procedure (sham): Sham bone marrow aspiration, sham delivery to affected limb | 36 |
| Placebo Control (Sham) Placebo procedure (sham): Sham bone marrow aspiration, sham delivery to affected limb | 36 |
| Total | 308 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Early study termination by sponsor. | 2 | 0 |
| Overall Study | Lost to Follow-up | 6 | 1 |
| Overall Study | Met study endpoint (major amputation, death) | 36 | 16 |
| Overall Study | Physician Decision | 2 | 0 |
| Overall Study | Received 2nd treatment via compassionate use | 1 | 0 |
| Overall Study | Withdrawal by Subject | 5 | 0 |
Baseline characteristics
| Characteristic | Concentrated Bone Marrow Aspirate (cBMA) | Placebo Control (Sham) | Total |
|---|---|---|---|
| Age, Continuous | 64.7 years STANDARD_DEVIATION 11.9 | 66.7 years STANDARD_DEVIATION 12.2 | 65.0 years STANDARD_DEVIATION 11.9 |
| Diabetic Status Diabetes = No | 70 Limbs | 22 Limbs | 92 Limbs |
| Diabetic Status Diabetes = Yes | 49 Limbs | 14 Limbs | 63 Limbs |
| Race/Ethnicity, Customized African-American | 24 Limbs | 4 Limbs | 28 Limbs |
| Race/Ethnicity, Customized Other | 1 Limbs | 1 Limbs | 2 Limbs |
| Race/Ethnicity, Customized White (Hispanic) | 3 Limbs | 4 Limbs | 7 Limbs |
| Race/Ethnicity, Customized White (non-Hispanic) | 91 Limbs | 27 Limbs | 118 Limbs |
| Region of Enrollment United States | 117 participants | 36 participants | 153 participants |
| Rutherford Score Rutherford Score = 4 | 65 Limbs | 19 Limbs | 84 Limbs |
| Rutherford Score Rutherford Score = 5 | 54 Limbs | 17 Limbs | 71 Limbs |
| Sex: Female, Male Female | 48 Limbs | 16 Limbs | 64 Limbs |
| Sex: Female, Male Male | 71 Limbs | 20 Limbs | 91 Limbs |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 11 / 119 | 7 / 36 |
| other Total, other adverse events | 117 / 119 | 35 / 36 |
| serious Total, serious adverse events | 66 / 119 | 24 / 36 |
Outcome results
Primary
Occurrence of Major Amputation or Death
Occurrence of major amputation (above the ankle joint) or death.
Time frame: 52 weeks
Population: All limbs that were randomized to a treatment group were included in the analysis for the primary endpoint.
| Arm | Measure | Value (COUNT_OF_UNITS) |
|---|---|---|
| Concentrated Bone Marrow Aspirate (cBMA) | Occurrence of Major Amputation or Death | 24 Limbs |
| Placebo Control (Sham) | Occurrence of Major Amputation or Death | 11 Limbs |
p-value: 0.22495% CI: [0.31, 1.31]Proportional Hazards Regression
Secondary
Six-Minute Walk Test
Measurement (in meters) of the total distance a participant is able to walk in 6 minutes. Since ability to walk is related to the condition of the affected limb, this measure is tied to limb pain and function. If a participant had multiple limbs included in the study, each limb was evaluated separately. Only one limb could be included in the study at a time.
Time frame: 52 weeks
Population: All limbs that were randomized to a treatment group, did not meet a primary endpoint or otherwise exit from the study, and that had an assessment available at 52 weeks were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Concentrated Bone Marrow Aspirate (cBMA) | Six-Minute Walk Test | Baseline | 158.508 meters | Standard Deviation 115.157 |
| Concentrated Bone Marrow Aspirate (cBMA) | Six-Minute Walk Test | 52 Weeks | 223.545 meters | Standard Deviation 170.015 |
| Placebo Control (Sham) | Six-Minute Walk Test | Baseline | 173.114 meters | Standard Deviation 130.397 |
| Placebo Control (Sham) | Six-Minute Walk Test | 52 Weeks | 218.352 meters | Standard Deviation 148.226 |
p-value: 0.714Repeated measures model
Secondary
Visual Analog Scale (VAS) - Pain
Pain reported at the 52-week follow-up visit as assessed on the visual analog scale (VAS). Scores are recorded by making a handwritten mark on a 10-cm line that represents a continuum between no pain and worst pain. The distance from the beginning of the line is measured and reported in centimeters (cm), with 0 representing no pain and 10 representing the worst possible pain.
Time frame: 52 weeks
Population: All limbs that were randomized to a treatment group, did not meet a primary endpoint or otherwise exit from the study, and that had an assessment available at 52 weeks were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Concentrated Bone Marrow Aspirate (cBMA) | Visual Analog Scale (VAS) - Pain | Baseline | 6.462 score on a scale | Standard Deviation 7.789 |
| Concentrated Bone Marrow Aspirate (cBMA) | Visual Analog Scale (VAS) - Pain | 52 Weeks | 3.651 score on a scale | Standard Deviation 2.964 |
| Placebo Control (Sham) | Visual Analog Scale (VAS) - Pain | Baseline | 5.836 score on a scale | Standard Deviation 2.68 |
| Placebo Control (Sham) | Visual Analog Scale (VAS) - Pain | 52 Weeks | 3.346 score on a scale | Standard Deviation 3.019 |
p-value: 0.671Repeated measures model
Other Pre-specified
Occurrence of Major Amputation or Death
Occurrence of major amputation (above the ankle joint) or death for all participants through final follow-up.
Time frame: 5 years
Population: All randomized participants were included in the analysis. Some participants did not re-consent for follow-up after 52 weeks and as such their long-term status is unknown. For the purposes of this analysis, they are counted with those who completed follow-up. Control participants that received crossover therapy with cBMA after 52 weeks are counted with the control group.
| Arm | Measure | Value (COUNT_OF_UNITS) |
|---|---|---|
| Concentrated Bone Marrow Aspirate (cBMA) | Occurrence of Major Amputation or Death | 36 Limbs |
| Placebo Control (Sham) | Occurrence of Major Amputation or Death | 16 Limbs |
Post Hoc
Occurrence of Major Amputation or Death, Excluding Rutherford 5 Diabetic Subjects
Occurrence of major amputation (above the ankle joint) or death, excluding the subgroup of subjects with Rutherford Category 5 critical limb ischemia and diabetes. The Rutherford score is a classification of severity for peripheral artery disease which ranges from 0 (asymptomatic) to 6 (major tissue loss extending above the transmetatarsal level, functional foot no longer salvageable). The study enrolled participants with Rutherford scores of 4 (ischemic rest pain) and 5 (minor tissue loss, nonhealing ulcer, and/or focal dry gangrene).
Time frame: 52 weeks
Population: All limbs for subjects from the following subgroups that were randomized to a treatment group were included in this post-hoc analysis: Rutherford Category 4 and diabetic, Rutherford Category 4 and non-diabetic, Rutherford Category 5 and non-diabetic.
| Arm | Measure | Value (COUNT_OF_UNITS) |
|---|---|---|
| Concentrated Bone Marrow Aspirate (cBMA) | Occurrence of Major Amputation or Death, Excluding Rutherford 5 Diabetic Subjects | 13 Limbs |
| Placebo Control (Sham) | Occurrence of Major Amputation or Death, Excluding Rutherford 5 Diabetic Subjects | 10 Limbs |
p-value: 0.01895% CI: [0.16, 0.85]Proportional Hazards Regression