Critical Limb Ischemia
Conditions
Keywords
CLI, Peripheral arterial disease
Brief summary
The purpose of this study is to evaluate the safety and efficacy of the concentrated autologous bone marrow derived stem cells for the treatment of Critical Limb Ischemia patients.
Detailed description
A total of 15 patients suffering from end stage IV and V Rutherford /CLI in whom all previous therapeutic strategies failed (e.g. surgical revascularization) will be selected and undergo local transplantation of autologous BMMNCs. Conventional treatments include angioplasty and /or bypass to remove blood vessel blockage for restoring blood supply, along with prescribed medicines that aid in ulcer recovery and wound healing and debridement of damaged/infected tissue. Amputation is inevitable in many cases because some blood capillaries cannot be corrected and restenosis of vessels is very common. Cell therapies with mononuclear cells from patients own bone marrow is promising because these stem cells are capable of stimulating and regenerating capillaries and blood vessels (neovascularization). This is a Phase Ib (feasibility study), prospective, non randomized and open labeled study aimed to find out the safety and efficacy of intramuscular autologous bone marrow mononuclear cells implantation in patients with chronic critical limb ischemia. The efficacy/safety of this therapy will be assessed by using several endpoints such as (a) prevention of amputation, (b) wound healing and (c) degree of angiogenesis. In order to assess the limb ischemia, the measurements will be performed at pre- and post transplantation at a variety of time intervals. The measurements include: ABI-ankle brachial index, Transcutaneous partial pressure of Oxygen (TcPO2), 6 min walk test, Rest pain and intermittent Claudication assessment, Healing of ulcers/ wounds and angiography of the affected limb.
Interventions
OTHERAutologous Bone Marrow Mononuclear cells (BMMNCs)
Multiple intramuscular injections of concentrated bone marrow derived mononuclear cells (0.5 cc/injection) into the ischemic muscle of the affected limb.
Sponsors
Thermogenesis Corp.
TotipotentSC Scientific Product Pvt. Ltd.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Atherosclerotic ischemic peripheral vascular disease (PVD) or Thromboangiitis Obliterans with severe Critical Limb Ischemia (Rutherford Category 4 and 5: ischemic pain at rest and minor tissue loss and Fontaine Class 4: Ischemic ulcers or gangrene, whivh may be dry or humid). * A non-surgical candidate for revascularization e.g. prior vascular reconstruction, inability to locate a suitable vein for grafting, diffuse multi- segment disease, or extensive infra-popliteal disease not amenable to a vascular graft. * Major amputation recommended patients due to severe life threatening PAD. * Subjects must be on maximal tolerated medical therapy for peripheral vascular disease including A) Cessation of smoking B) Referral to endocrinologist for control of HgA1c to \< 8% mg/dl, C) control of hyperlipidemia with statins or other anti-hyperlipidemic drugs as indicated, D) control of hypertension as indicated E) Antiplatelet therapy with aspirin and / or cilostazol (unless medically contraindicated, e.g. bleeding or allergy). * Ankle Brachial Pressure Index (ABI) ≤ 0.6 or ankle systolic pressure ≤ 60 mm Hg or TcPO2 ≤ 35 mmHg in the foot. * Subjects who are able to understand the requirements of the study, and willing to provide voluntary written informed consent, which abide by the study requirements, and agree to return for required follow-up visits.
Exclusion criteria
* Subjects with CLI suitable for surgical or percutaneous revascularization and Subjects with acute and chronic inflammatory condition. * CLI patient requiring amputation proximal to trans-metatarsal level * Subjects with spreading (wet) gangrene * Subjects with gait disturbance for reasons other than CLI. * Subjects with poorly controlled diabetes mellitus. * Subjects diagnosed with Thromboangiitis Obliterans (Buerger's Disease) who are smokers and are unwilling or unable to quit smoking or the physician feels the smoking cessation is doubtful. * Subjects having moderate to severe COPD with GOLD Classification IIb or III. * Uncontrolled congestive heart failure or Subjects with left ventricular ejection fraction \< 25% or AHA Stage C or D heart failure or NYHA Class IV CHF * Stroke or myocardial infarction within last 3 months. * Subjects who are contraindicated for CT Angiogram. * Illnesses or conditions that are uncontrolled or whose control, in the opinion of the Principal Investigator, may be jeopardized by participation in this study or by the complications of this therapy. * Documented terminal illness or cancer or any concomitant disease process with a life expectancy of less than 1 year. * Subjects already enrolled in another investigational drug trial or completed within 3 months. * History of severe alcohol or drug abuse within 3 months of screening. * Hb% \< 10 gm%; Serum creatinine ≥ 2.0mg%; Serum total bilirubin ≥2.0mg%; HbA1c \> 8.0%. * Women of child bearing potential; pregnant and lactating women. * Subjects with a) myocardial infarction within the last 30 days or left ventricular ejection fraction \< 35%, B) Subjects with a cerebrovascular accident within the last 6 months. * INR \> 1.5 at the time of Bone Marrow harvest.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events as a Measure of Safety and Major Limb Amputation Free Survival Post BMMNC Administration | 1, 3, 6 and 12 Months | The Primary objective of this study was to determine the safety of intramuscular administration of concentrated autologous BMMNCs harvested, and processed using the Res-Q 60 technology (a point-of-care system). Safety measurements included close vigilance for major limb amputation free survival at 1, 3, 6 and 12 months post BMMNCs administration and stringent reporting of AEs and SAEs. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Measurement of Mean Change in Ankle Brachial Index From Baseline to 12 Months | Baseline, 1, 3, 6 and 12 months | ABI was used to provide a measure of blood flow in the lower limbs. It is the ratio of the blood pressure in the lower limbs to the blood pressure in the upper limbs. Compared to the upper limb, lower blood pressure in the lower limb is an indication of blocked arteries (peripheral vascular disease). The ABI was calculated by dividing the systolic blood pressure at the ankle by the systolic blood pressures in the arm. ABI test was performed at baseline, 1 month, 3 months, 6 months, and 12 months. |
| Measurement of Change in Transcutaneous Oxygen Pressure (TcPO2) From Baseline to 12 Months | Baseline, 1, 3, 6 and 12 months | TcPO2 was used to assess the partial pressure (tension) of oxygen in the capillaries of tissues of lower limbs. It was measured by applying a special set of electrodes to the skin. These electrodes contain photoelectric sensors capable of detecting the specific wavelengths of radiation emitted by oxygenated versus reduced hemoglobin. |
| Degree of Angiogenesis Measured by the Number of Collateral Blood Vessels Formed at 12 Months | Baseline and 12 month | Measurement of blood supply facilitated by the formation of collateral blood vessels assessed by CT angiography after the procedure. |
| Clinical Evaluation for the Presence of Ulcer and/or Gangrene in the Affected Limb From Baseline to 12 Months | Baseline, 1, 3, 6 and 12 months | Evaluation of the integument for ulceration, gangrene and other skin changes in the affected limb was performed at baseline and follow-up visits at 1 month, 3 months, 6 months, and 12 months.The ulceration and gangrene in the affected limb of the subjects was evaluated by visual clinical inspection. |
| Number of Participants Able to Walk From Baseline to 12 Months as Measured by 6-Minute Walk Test | Baseline, 1, 3, 6 and 12 months | Subjects were analyzed to see if they were able to walk any distance and the distance covered by patients in 6 minutes was measured to assess the functional changes from baseline. The American Thoracic Society has issued guidelines for the 6-minute walk test (6 MWT). The 6 MWT is safe, easy to administer, well tolerated, and reflects activities of daily living. |
| Change in Rest Pain and Intermittent Claudication Assessment From Baseline to 12 Months | Baseline, 1, 3, 6 and 12 months | Rest pain is a burning sensation felt at rest, usually in the skin of the foot. It is a symptom of critical ischemia due to severe, chronic, and occlusive peripheral arterial disease (PAD). While, Intermittent Claudication is a crampy leg pain that occurs during exercise, especially walking. The pain is due to the insufficient blood flow in the legs (caused by blocked arteries). Intermittent claudication is the most prominent symptom of PAD. Both Rest Pain assessment and Intermittent Claudication assessment was performed through Visual Analog Scale or Visual Analogue Scale (VAS). VAS is a psychometric (self-report) response scale that ranges from 0 to 10, where a mark of zero indicates no pain and a mark of 10 indicates worst possible pain. |
Countries
India
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| BMMNC Treated Group All the subjects enrolled in the study were treated using autologous Bone Marrow Mononuclear Cells concentrate (BMMNCs) prepared using the Res-Q 60 technology (a point of care system) and injected intra-muscularly into multiple sites in the ischemic muscle of the affected limb at 0.5 cc/injection for a total of 15-20 cc. | 17 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 2 |
Baseline characteristics
| Characteristic | BMMNC Treated Group |
|---|---|
| Age, Continuous | 48.8 years STANDARD_DEVIATION 13.07 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 17 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Region of Enrollment India | 17 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 17 |
| serious Total, serious adverse events | 7 / 17 |
Outcome results
Primary
Number of Participants With Adverse Events as a Measure of Safety and Major Limb Amputation Free Survival Post BMMNC Administration
The Primary objective of this study was to determine the safety of intramuscular administration of concentrated autologous BMMNCs harvested, and processed using the Res-Q 60 technology (a point-of-care system). Safety measurements included close vigilance for major limb amputation free survival at 1, 3, 6 and 12 months post BMMNCs administration and stringent reporting of AEs and SAEs.
Time frame: 1, 3, 6 and 12 Months
Population: All the safety end points in the study were analyzed on the ITT population. Out of 17 subjects, adverse events were reported for seven subjects. Of the seven subjects, three underwent major amputation, two reported minor amputation, and two died due to cardiac arrest (unrelated death). Furthermore, major limb amputation free survival rate was 14.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BMMNC Treated Group | Number of Participants With Adverse Events as a Measure of Safety and Major Limb Amputation Free Survival Post BMMNC Administration | Major Limb Amputation Free Survival Rate | 14 participants |
| BMMNC Treated Group | Number of Participants With Adverse Events as a Measure of Safety and Major Limb Amputation Free Survival Post BMMNC Administration | Major Amputation | 3 participants |
| BMMNC Treated Group | Number of Participants With Adverse Events as a Measure of Safety and Major Limb Amputation Free Survival Post BMMNC Administration | Minor Amputation | 2 participants |
| BMMNC Treated Group | Number of Participants With Adverse Events as a Measure of Safety and Major Limb Amputation Free Survival Post BMMNC Administration | Unrelated Death | 2 participants |
| BMMNC Treated Group | Number of Participants With Adverse Events as a Measure of Safety and Major Limb Amputation Free Survival Post BMMNC Administration | Total Adverse Events | 7 participants |
Secondary
Change in Rest Pain and Intermittent Claudication Assessment From Baseline to 12 Months
Rest pain is a burning sensation felt at rest, usually in the skin of the foot. It is a symptom of critical ischemia due to severe, chronic, and occlusive peripheral arterial disease (PAD). While, Intermittent Claudication is a crampy leg pain that occurs during exercise, especially walking. The pain is due to the insufficient blood flow in the legs (caused by blocked arteries). Intermittent claudication is the most prominent symptom of PAD. Both Rest Pain assessment and Intermittent Claudication assessment was performed through Visual Analog Scale or Visual Analogue Scale (VAS). VAS is a psychometric (self-report) response scale that ranges from 0 to 10, where a mark of zero indicates no pain and a mark of 10 indicates worst possible pain.
Time frame: Baseline, 1, 3, 6 and 12 months
Population: Efficacy measures were established by assessing CLI symptoms known to be reliable and valid. The efficacy endpoints were analyzed on per protocol (PP) basis (N=14).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BMMNC Treated Group | Change in Rest Pain and Intermittent Claudication Assessment From Baseline to 12 Months | Rest Pain Score at Baseline | 2.80 scores on a scale | Standard Deviation 0.8 |
| BMMNC Treated Group | Change in Rest Pain and Intermittent Claudication Assessment From Baseline to 12 Months | Rest Pain Score at 1 Month | 1.2 scores on a scale | Standard Deviation 1.17 |
| BMMNC Treated Group | Change in Rest Pain and Intermittent Claudication Assessment From Baseline to 12 Months | Rest Pain Score at 3 Months | 0.6 scores on a scale | Standard Deviation 0.87 |
| BMMNC Treated Group | Change in Rest Pain and Intermittent Claudication Assessment From Baseline to 12 Months | Rest Pain Score at 6 Months | 0.4 scores on a scale | Standard Deviation 0.9 |
| BMMNC Treated Group | Change in Rest Pain and Intermittent Claudication Assessment From Baseline to 12 Months | Rest Pain Score at 12 Months | 0.0 scores on a scale | Standard Deviation 0 |
| BMMNC Treated Group | Change in Rest Pain and Intermittent Claudication Assessment From Baseline to 12 Months | Intermittent Claudication Pain Score at Baseline | 7.80 scores on a scale | Standard Deviation 0.97 |
| BMMNC Treated Group | Change in Rest Pain and Intermittent Claudication Assessment From Baseline to 12 Months | Intermittent Claudication Pain Score at 1 Month | 4.9 scores on a scale | Standard Deviation 2.22 |
| BMMNC Treated Group | Change in Rest Pain and Intermittent Claudication Assessment From Baseline to 12 Months | Intermittent Claudication Pain Score at 3 Months | 2.8 scores on a scale | Standard Deviation 2.61 |
| BMMNC Treated Group | Change in Rest Pain and Intermittent Claudication Assessment From Baseline to 12 Months | Intermittent Claudication Pain Score at 6 Months | 1.1 scores on a scale | Standard Deviation 1.44 |
| BMMNC Treated Group | Change in Rest Pain and Intermittent Claudication Assessment From Baseline to 12 Months | Intermittent Claudication Pain Score at 12 Months | 0.2 scores on a scale | Standard Deviation 0.58 |
Secondary
Clinical Evaluation for the Presence of Ulcer and/or Gangrene in the Affected Limb From Baseline to 12 Months
Evaluation of the integument for ulceration, gangrene and other skin changes in the affected limb was performed at baseline and follow-up visits at 1 month, 3 months, 6 months, and 12 months.The ulceration and gangrene in the affected limb of the subjects was evaluated by visual clinical inspection.
Time frame: Baseline, 1, 3, 6 and 12 months
Population: Efficacy measures were established by assessing CLI symptoms known to be reliable and valid. The efficacy endpoints were analyzed on per protocol (PP) basis (N=14).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BMMNC Treated Group | Clinical Evaluation for the Presence of Ulcer and/or Gangrene in the Affected Limb From Baseline to 12 Months | Ulcer and/ or Gangrene present at Baseline | 11 Participants |
| BMMNC Treated Group | Clinical Evaluation for the Presence of Ulcer and/or Gangrene in the Affected Limb From Baseline to 12 Months | Ulcer and/or Gangrene present at 1 Month | 10 Participants |
| BMMNC Treated Group | Clinical Evaluation for the Presence of Ulcer and/or Gangrene in the Affected Limb From Baseline to 12 Months | Ulcer and/or Gangrene present at 3 Months | 6 Participants |
| BMMNC Treated Group | Clinical Evaluation for the Presence of Ulcer and/or Gangrene in the Affected Limb From Baseline to 12 Months | Ulcer and/or Gangrene present at 6 Months | 2 Participants |
| BMMNC Treated Group | Clinical Evaluation for the Presence of Ulcer and/or Gangrene in the Affected Limb From Baseline to 12 Months | Ulcer and/ or Gangrene present at 12 Months | 0 Participants |
Secondary
Degree of Angiogenesis Measured by the Number of Collateral Blood Vessels Formed at 12 Months
Measurement of blood supply facilitated by the formation of collateral blood vessels assessed by CT angiography after the procedure.
Time frame: Baseline and 12 month
Population: Efficacy measures were established by assessing CLI symptoms known to be reliable and valid. The efficacy endpoints were analyzed on per protocol (PP) basis (N=14).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BMMNC Treated Group | Degree of Angiogenesis Measured by the Number of Collateral Blood Vessels Formed at 12 Months | Number of Collateral vessels at Baseline | 2.42 Number of Vessels | Standard Deviation 0.775 |
| BMMNC Treated Group | Degree of Angiogenesis Measured by the Number of Collateral Blood Vessels Formed at 12 Months | Number of Collateral vessels at 12 months | 5.59 Number of Vessels | Standard Deviation 1.146 |
Secondary
Measurement of Change in Transcutaneous Oxygen Pressure (TcPO2) From Baseline to 12 Months
TcPO2 was used to assess the partial pressure (tension) of oxygen in the capillaries of tissues of lower limbs. It was measured by applying a special set of electrodes to the skin. These electrodes contain photoelectric sensors capable of detecting the specific wavelengths of radiation emitted by oxygenated versus reduced hemoglobin.
Time frame: Baseline, 1, 3, 6 and 12 months
Population: The efficacy endpoints were analyzed on per protocol (PP) basis (N=14).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BMMNC Treated Group | Measurement of Change in Transcutaneous Oxygen Pressure (TcPO2) From Baseline to 12 Months | TcPO2 at Baseline | 14.66 mmHg | Standard Deviation 6.925 |
| BMMNC Treated Group | Measurement of Change in Transcutaneous Oxygen Pressure (TcPO2) From Baseline to 12 Months | TcPO2 at 1 Month | 25.10 mmHg | Standard Deviation 11.906 |
| BMMNC Treated Group | Measurement of Change in Transcutaneous Oxygen Pressure (TcPO2) From Baseline to 12 Months | TcPO2 at 3 Months | 36.85 mmHg | Standard Deviation 17.892 |
| BMMNC Treated Group | Measurement of Change in Transcutaneous Oxygen Pressure (TcPO2) From Baseline to 12 Months | TcPO2 at 6 Months | 34.58 mmHg | Standard Deviation 15.5 |
| BMMNC Treated Group | Measurement of Change in Transcutaneous Oxygen Pressure (TcPO2) From Baseline to 12 Months | TcPO2 at 12 Months | 35.75 mmHg | Standard Deviation 17.035 |
Secondary
Measurement of Mean Change in Ankle Brachial Index From Baseline to 12 Months
ABI was used to provide a measure of blood flow in the lower limbs. It is the ratio of the blood pressure in the lower limbs to the blood pressure in the upper limbs. Compared to the upper limb, lower blood pressure in the lower limb is an indication of blocked arteries (peripheral vascular disease). The ABI was calculated by dividing the systolic blood pressure at the ankle by the systolic blood pressures in the arm. ABI test was performed at baseline, 1 month, 3 months, 6 months, and 12 months.
Time frame: Baseline, 1, 3, 6 and 12 months
Population: Efficacy measures were established by assessing CLI symptoms known to be reliable and valid. The efficacy endpoints were analyzed on per protocol (PP) basis (N=14).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BMMNC Treated Group | Measurement of Mean Change in Ankle Brachial Index From Baseline to 12 Months | ABI at Baseline | 0.507 Ratio | Standard Deviation 0.0971 |
| BMMNC Treated Group | Measurement of Mean Change in Ankle Brachial Index From Baseline to 12 Months | ABI at 1 Month | 0.612 Ratio | Standard Deviation 0.1653 |
| BMMNC Treated Group | Measurement of Mean Change in Ankle Brachial Index From Baseline to 12 Months | ABI at 3 Months | 0.819 Ratio | Standard Deviation 0.2829 |
| BMMNC Treated Group | Measurement of Mean Change in Ankle Brachial Index From Baseline to 12 Months | ABI at 6 Months | 0.879 Ratio | Standard Deviation 0.2467 |
| BMMNC Treated Group | Measurement of Mean Change in Ankle Brachial Index From Baseline to 12 Months | ABI at 12 Months | 0.696 Ratio | Standard Deviation 0.265 |
Secondary
Number of Participants Able to Walk From Baseline to 12 Months as Measured by 6-Minute Walk Test
Subjects were analyzed to see if they were able to walk any distance and the distance covered by patients in 6 minutes was measured to assess the functional changes from baseline. The American Thoracic Society has issued guidelines for the 6-minute walk test (6 MWT). The 6 MWT is safe, easy to administer, well tolerated, and reflects activities of daily living.
Time frame: Baseline, 1, 3, 6 and 12 months
Population: Efficacy measures were established by assessing CLI symptoms known to be reliable and valid. The efficacy endpoints were analyzed on per protocol (PP) basis (N=14).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BMMNC Treated Group | Number of Participants Able to Walk From Baseline to 12 Months as Measured by 6-Minute Walk Test | Subjects able to walk at baseline | 2 Participants |
| BMMNC Treated Group | Number of Participants Able to Walk From Baseline to 12 Months as Measured by 6-Minute Walk Test | Subjects able to walk at 1 Month | 8 Participants |
| BMMNC Treated Group | Number of Participants Able to Walk From Baseline to 12 Months as Measured by 6-Minute Walk Test | Subjects able to walk at 3 Months | 9 Participants |
| BMMNC Treated Group | Number of Participants Able to Walk From Baseline to 12 Months as Measured by 6-Minute Walk Test | Subjects able to walk at 6 Months | 9 Participants |
| BMMNC Treated Group | Number of Participants Able to Walk From Baseline to 12 Months as Measured by 6-Minute Walk Test | Subjects able to walk at 12 Months | 9 Participants |