Critical Limb Ischemia, Peripheral Artery Disease, Vascular Disease
Conditions
Keywords
BKA, amputation, MarrowStim, below knee amputation, wound complication, vascular disease, critical limb ischemia, peripheral artery disease, AKA, stem cells, bone marrow
Brief summary
Patients scheduled for major extremity lower amputation to receive bone marrow cells (cBMA) injected IM in the leg proximal to the amputation in the index limb to prevent ischemic wound complications after surgery.
Detailed description
Patients scheduled for amputation will receive bone marrow cells concentrated via the MarrowStim device (cBMA) injected IM at 25 sites in the leg proximal to the amputation in the index limb to prevent ischemic wound complications after surgery. cBMA will be injected into the anterior tibialis muscle below the point of amputation in an area approximately 3cm\^2 x 2cm\^2 for analytical purposes. Patients will be scheduled for amputation at Days 7, 14, or 21 post injection. Safety will be evaluated by review of treatment related adverse events (AE) during the 52-week follow-up period. The investigator will compare rates of wound complications and amputation revisions to historical controls at the institution to assess trends in therapeutic efficacy. Patients will undergo amputation and injection sites will be harvested at that time. Immunohistochemical staining (IHC) will determine capillary density and local host immune responses. Angiogenic and inflammatory cytokines will be quantified using a multiplex array system and quantitative polymerase chain reaction (PCR).
Interventions
BIOLOGICALInjection of cBMA aspirate into the index leg
Injection of cBMA into the anterior tibialis muscle and upper index leg of subjects scheduled for semi-elective BKA 7-21 days before surgery
Sponsors
Zimmer Biomet
Michael Murphy
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Autologous bone marrow derived mesenchymal stromal cells will be delivered intramuscularly in the lower extremity of participants undergoing lower extremity major amputation to assess incidence of wound healing and infection prevention.
Eligibility
Sex/Gender
ALL
Age
40 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
1. Be ≥ 40 and ≤90 years of age. 2. Patients requiring below knee amputation, as determined by an independent vascular specialist. 3. If ulceration or gangrene present, it is distal to malleoli (to allow adequate length of ATM for 4 injections 4 cm. apart) 4. BKA can safely be performed up to 30 days after screening, as determined by an independent vascular or orthopedic surgeon. This information will be documented in subjects' case report forms (CRFs). 5. Females of childbearing potential must be willing to use one form of birth control for the duration of the study. Female participants must undergo a blood or urine pregnancy test at screening.
Exclusion criteria
1. Patients who are pregnant, planning to become pregnant in the next 12 months, or lactating. 2. Significant hepatic dysfunction (ALT or AST greater than 2 times normal). 3. CHF hospitalization within the last 1 month prior to enrollment.\* 4. Acute coronary syndrome (ACS) in the last 1 month prior to enrollment.\* 5. HIV positive, or active, untreated HCV. 6. History of cancer within the last 5 years, except basal cell skin carcinoma 7. Any bleeding diathesis defined as an INR ≥ 2.0 (off anticoagulation therapy) or history of platelet count less than 70,000 or hemophilia. 8. Inability to provide written informed consent due to cognitive or language barriers (interpreter permitted). 9. Concurrent enrollment in another clinical investigative trial. 10. Any condition requiring immunosuppressant medications (e.g., for treatment of organ transplants, psoriasis, Crohn's disease, alopecia areata). 11. Presence of any clinical condition that in the opinion of the PI or the sponsor makes the patient not suitable to participate in the trial. * As defined by the standard definitions of CHF and ACS by the American Heart Association.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-related Adverse Events Occurring During the Enrollment Period as Assessed by the Investigator Using the CTCAE 4.0 Scale. | 12 months | Safety will be evaluated by review of treatment related AEs during the 12-month follow-up period. The study will be terminated in the event of a Grade 4-5 unexpected event based on the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Treatment-related AEs will be categorized overlapping systems and severities. Three categories of systems are cardiovascular, respiratory, or infectious. Two categories of severity will be serious adverse (SAE) and major adverse cardiac events (MACE). Binomial confidence Intervals at the 95% confidence level and p-values for these 3 groups will be calculated. Since previous trials have not reported AEs with cBMA treatment, confidence intervals will be generated by the method of the Wilson Score Interval. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Conversion From Below Knee Amputation to Above Knee Amputation as Evidenced by Wound Complications at the Below Knee Amputation Stump Site. | 12 months | Documentation will be collected on wound complications at the below knee amputation surgical site resulting in necessity of revision/conversion to above knee amputation. |
| The Role of Autologous Bone Marrow Cells Injected in Human Skeletal Muscle in Inducing Capillary Vessel Formation at the Time of Below Knee Amputation. | 12 months | Continuous confidence intervals at the 95% level will be constructed to explore differences among the time-tiered administration of MSC for the quantity of capillary density in muscle fibers. |
Countries
United States
Participant flow
Recruitment details
Eligible patients were invited to participate in the study on a first-come basis, recruited from the Investigator's patient population and by referrals from other physicians who have patients recommended for major amputation. The study team received referrals after the patient was seen by their own vascular or orthopedic specialist and the amputation was recommended to them.
Pre-assignment details
Of 7 screened patients, 6 met inclusion criteria and were treated.
Participants by arm
| Arm | Count |
|---|---|
| Day 7 BKA performed at 7 days post autologous cBMA injection. Injection of cBMA aspirate into the index leg
Injection of cBMA aspirate into the index leg: Injection of cBMA into the anterior tibialis muscle and upper index leg of subjects scheduled for semi-elective BKA 7-21 days before surgery | 5 |
| Day 21 BKA performed at 21 days post autologous cBMA injection. Injection of cBMA aspirate into the index leg
Injection of cBMA aspirate into the index leg: Injection of cBMA into the anterior tibialis muscle and upper index leg of subjects scheduled for semi-elective BKA 7-21 days before surgery | 1 |
| Total | 6 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Physician Decision | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Day 7 | Day 21 |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 2 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 3 Participants | 0 Participants |
| Age, Continuous | 63 years STANDARD_DEVIATION 5.26 | 62.4 years STANDARD_DEVIATION 5.57 | 66 years STANDARD_DEVIATION 0 |
| Body Mass index (BMI) | 30.43 weight in kg/height in meters^2 STANDARD_DEVIATION 4.09 | 31.62 weight in kg/height in meters^2 STANDARD_DEVIATION 3.41 | 24.5 weight in kg/height in meters^2 STANDARD_DEVIATION 0 |
| Current Smoker | 5 participants | 4 participants | 1 participants |
| Diabetes Mellitus | 6 participants | 5 participants | 1 participants |
| Diastolic Blood Pressure | 71.5 Pressure between heartbeats in mmHg STANDARD_DEVIATION 9.2 | 68.8 Pressure between heartbeats in mmHg STANDARD_DEVIATION 71.5 | 85 Pressure between heartbeats in mmHg STANDARD_DEVIATION 0 |
| eGFR | 60.3 Renal filtration rate in mg/mmol STANDARD_DEVIATION 33.17 | 61.96 Renal filtration rate in mg/mmol STANDARD_DEVIATION 36.1 | 52 Renal filtration rate in mg/mmol STANDARD_DEVIATION 0 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 5 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Hgb A1C % | 8.52 percentage of glycated hemoglobin STANDARD_DEVIATION 0.52 | 9.04 percentage of glycated hemoglobin STANDARD_DEVIATION 1.46 | 8.0 percentage of glycated hemoglobin STANDARD_DEVIATION 0 |
| Index Leg TcPO2 | 35.25 Oxygen level at skin in mmHg STANDARD_DEVIATION 21.69 | 35.25 Oxygen level at skin in mmHg STANDARD_DEVIATION 21.69 | 0 Oxygen level at skin in mmHg STANDARD_DEVIATION 0 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 5 Participants | 0 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 6 Participants | 5 Participants | 1 Participants |
| Systolic Blood Pressure | 133 Pressure during heartbeat in mmHg STANDARD_DEVIATION 35 | 122 Pressure during heartbeat in mmHg STANDARD_DEVIATION 27.6 | 187 Pressure during heartbeat in mmHg STANDARD_DEVIATION 0 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 1 |
| other Total, other adverse events | 5 / 5 | 1 / 1 |
| serious Total, serious adverse events | 4 / 5 | 1 / 1 |
Outcome results
Primary
Number of Participants With Treatment-related Adverse Events Occurring During the Enrollment Period as Assessed by the Investigator Using the CTCAE 4.0 Scale.
Safety will be evaluated by review of treatment related AEs during the 12-month follow-up period. The study will be terminated in the event of a Grade 4-5 unexpected event based on the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Treatment-related AEs will be categorized overlapping systems and severities. Three categories of systems are cardiovascular, respiratory, or infectious. Two categories of severity will be serious adverse (SAE) and major adverse cardiac events (MACE). Binomial confidence Intervals at the 95% confidence level and p-values for these 3 groups will be calculated. Since previous trials have not reported AEs with cBMA treatment, confidence intervals will be generated by the method of the Wilson Score Interval.
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Day 7 | Number of Participants With Treatment-related Adverse Events Occurring During the Enrollment Period as Assessed by the Investigator Using the CTCAE 4.0 Scale. | 2 Participants |
| Day 21 | Number of Participants With Treatment-related Adverse Events Occurring During the Enrollment Period as Assessed by the Investigator Using the CTCAE 4.0 Scale. | 0 Participants |
Secondary
Number of Participants With Conversion From Below Knee Amputation to Above Knee Amputation as Evidenced by Wound Complications at the Below Knee Amputation Stump Site.
Documentation will be collected on wound complications at the below knee amputation surgical site resulting in necessity of revision/conversion to above knee amputation.
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Day 7 | Number of Participants With Conversion From Below Knee Amputation to Above Knee Amputation as Evidenced by Wound Complications at the Below Knee Amputation Stump Site. | 0 Participants |
| Day 21 | Number of Participants With Conversion From Below Knee Amputation to Above Knee Amputation as Evidenced by Wound Complications at the Below Knee Amputation Stump Site. | 0 Participants |
Secondary
The Role of Autologous Bone Marrow Cells Injected in Human Skeletal Muscle in Inducing Capillary Vessel Formation at the Time of Below Knee Amputation.
Continuous confidence intervals at the 95% level will be constructed to explore differences among the time-tiered administration of MSC for the quantity of capillary density in muscle fibers.
Time frame: 12 months
Population: Immunostaining for the CD31 antigen was selected to measure the capillary density, reported as CD31-positive features normalized to fiber number. For capillary density quantification, CD31 positive profiles were counted using a custom algorithm and nuclei were counted using a pipeline that we designed in CellProfiler.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Day 7 | The Role of Autologous Bone Marrow Cells Injected in Human Skeletal Muscle in Inducing Capillary Vessel Formation at the Time of Below Knee Amputation. | Distal ATM Segment B | 1.373 CD31-positive capillaries/fiber | Standard Error 0.05 |
| Day 7 | The Role of Autologous Bone Marrow Cells Injected in Human Skeletal Muscle in Inducing Capillary Vessel Formation at the Time of Below Knee Amputation. | Distal ATM Segment D | 1.065 CD31-positive capillaries/fiber | Standard Error 0.064 |
| Day 7 | The Role of Autologous Bone Marrow Cells Injected in Human Skeletal Muscle in Inducing Capillary Vessel Formation at the Time of Below Knee Amputation. | Distal ATM Segment C | 1.064 CD31-positive capillaries/fiber | Standard Error 0.056 |
| Day 7 | The Role of Autologous Bone Marrow Cells Injected in Human Skeletal Muscle in Inducing Capillary Vessel Formation at the Time of Below Knee Amputation. | Control Segment - Soleus | 1.191 CD31-positive capillaries/fiber | Standard Error 0.104 |
| Day 7 | The Role of Autologous Bone Marrow Cells Injected in Human Skeletal Muscle in Inducing Capillary Vessel Formation at the Time of Below Knee Amputation. | Proximal ATM Segment A | 1.089 CD31-positive capillaries/fiber | Standard Error 0.052 |
| Day 21 | The Role of Autologous Bone Marrow Cells Injected in Human Skeletal Muscle in Inducing Capillary Vessel Formation at the Time of Below Knee Amputation. | Control Segment - Soleus | NA CD31-positive capillaries/fiber | — |
| Day 21 | The Role of Autologous Bone Marrow Cells Injected in Human Skeletal Muscle in Inducing Capillary Vessel Formation at the Time of Below Knee Amputation. | Proximal ATM Segment A | 1.431 CD31-positive capillaries/fiber | Standard Error 0.553 |
| Day 21 | The Role of Autologous Bone Marrow Cells Injected in Human Skeletal Muscle in Inducing Capillary Vessel Formation at the Time of Below Knee Amputation. | Distal ATM Segment B | 1.673 CD31-positive capillaries/fiber | Standard Error 0.232 |
| Day 21 | The Role of Autologous Bone Marrow Cells Injected in Human Skeletal Muscle in Inducing Capillary Vessel Formation at the Time of Below Knee Amputation. | Distal ATM Segment C | 1.526 CD31-positive capillaries/fiber | Standard Error 0.508 |
| Day 21 | The Role of Autologous Bone Marrow Cells Injected in Human Skeletal Muscle in Inducing Capillary Vessel Formation at the Time of Below Knee Amputation. | Distal ATM Segment D | 1.197 CD31-positive capillaries/fiber | Standard Error 0.46 |