Patients With Intermittent Claudication Injected With ALDH Bright Cells

Study Overview
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Brief Summary
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The purpose of this study is to find out if aldehyde dehydrogenase bright (ALDHbr) cells taken from a patient's bone marrow can be placed safely, via intramuscular injections, into their affected calf and lower thigh muscles and improve blood flow and/or peak walking time in patients experiencing pain associated with blocked blood vessels in the leg.

Detailed Description
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Peripheral Artery Disease (PAD) occurs when arteries in the arms and legs (most often the legs) become narrowed by plaque. Because of this plaque, patients with PAD are also at increased risk for heart attacks and strokes. Those with PAD often have intermittent claudication (blockage of blood vessels in the leg). This blockage decreases blood flow to the leg muscles, which can cause pain in one or both legs during exercise (such as during walking). Intermittent means the pain comes and goes. Because PAD interferes with circulation, worsening of this condition can increase pain in the leg; sometimes even during periods of rest. Bone marrow contains special stem cells that may promote blood vessel growth, prevent cell death, and transform themselves into a number of tissues including new muscle. There is a small subpopulation of bone marrow mononuclear cells, called aldehyde dehydrogenase-bright (ALDHbr) cells, that is highly enriched in these types of stem cells. The enzyme in ALDHbr cells responds to damage signals and may play an important role in tissue repair. In this study we investigate the safety and efficacy of bone marrow derived stem cells with particular characteristics in PAD patients with intermittent claudication and explore new end-points to evaluate therapeutic effects using novel MRI imaging modalities as well as traditional endpoints.

Official Title
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Clinical and MR Imaging Assessments in Patients With Intermittent Claudication Following Injection of Bone Marrow Derived ALDH Bright Cells

Conditions
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Peripheral Artery Disease, Intermittent Claudication

Intervention / Treatment
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* Biological: ALD-301
* Biological: Placebo (vehicle)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with atherosclerotic peripheral artery disease with classic claudication (exercise-induced pain, cramps, fatigue, or other equivalent discomfort involving large muscle groups of the leg(s) that is consistently relieved by rest) or atypical leg pain (exertional leg pain that does not begin at rest or does not resolve consistently with rest) as defined by the San Diego Claudication Questionnaire. Age ≥40 years Resting ankle-brachial index <0.90 or a resting toe-brachial index of <0.70 at baseline testing Presence of significant stenosis or occlusion of infrainguinal arteries including the superficial femoral artery, popliteal artery and/or infrapopliteal arteries as determined by: Duplex ultrasound imaging (occlusion or focal doubling of peak systolic velocity of one or more affected segments) OR lower extremity computed Tomography Angiography (CTA) OR lower extremity magnetic resonance angiography (MRA) OR lower extremity catheter-based contrast arteriography. Each of these noninvasive and invasive anatomic assessments will identify patients with at least a 50% stenosis in the affected segment. Exclusion Criteria: Presence of any musculoskeletal disease, cardiac or pulmonary disease, or neurological disease that limits the patient's ability to walk to fulfill protocol requirements (claudication must be the consistent primary exercise limitation) Inability to complete treadmill testing per protocol requirements. Ability to walk for more than 12 minutes on the treadmill during treadmill testing. Patients who identify both legs as equivocally symptomatic or alternate between symptomatic legs on the baseline treadmill tests. Patients with critical limb ischemia (ischemic rest pain or ischemia-related non healing wounds or tissue loss (Rutherford categories 4-6). Recent (<3 months) infrainguinal revascularization (surgery or endovascular revascularization) or revascularization planned during study period Patients with a patent infrainguinal bypass graft in the index limb, with or without evidence of a hemodynamically significant stenosis or other defect (kinking, pseudoaneurysm, or fistula). Patients with an occluded infrainguinal bypass graft or a patent aortobifemoral or femoral-femoral bypass graft are NOT excluded. Patients with >2+ lower extremity pitting edema Patients with myelodysplastic syndrome (MDS) Patients who are pregnant or lactating, planning to become pregnant in the next 12 months, or are unwilling to use acceptable forms of birth control during study participation. Congestive Heart Failure hospitalization within the last 1 month prior to enrollment Acute coronary syndrome in the last 1 month prior to enrollment Human Immunodeficiency Virus positive, active Hepatitis B Virus or Hepatitis C Virus Disease History of cancer within the last 5 years, except basal cell skin carcinoma Any bleeding diathesis defined as an International Normalized Ratio ≥ 2.0 (off anticoagulation therapy) or history of platelet count less than 100,000 or hemophilia Contraindication to magnetic resonance imaging (MRI) (including knee/tibial/fibular replacement hardware in the index leg) or known allergy to MRI contrast media Chronic kidney disease [effective Glomerular Filtration Rate <30 by modification of diet in renal disease (MDRD) or Mayo or Cockcroft-Gault formula] Uncontrolled diabetes [Hemoglobin A1C (HbA1C)>8.5] Planned change to (initiate or terminate) active involvement in a supervised exercise program (e.g., with a trainer, exercise protocol, and goals, such as in a peripheral arterial disease, cardiac or pulmonary rehabilitation program) during study participation Plans to change medical therapy during the duration of the study, (i.e. patients who use cilostazol should remain on a stable dose for four weeks prior to enrollment and should not change doses for the 6 months of the study duration.) As always, cilostazol can be discontinued if new heart failure or intolerance occurs during study participation. Any condition requiring immunosuppressant medications (e.g., for treatment of organ transplants, psoriasis, Crohn's disease, alopecia areata). History of inflammatory or progressively fibrotic conditions (e.g. rheumatoid arthritis, systemic lupus erythematosis, vasculitic disorders, idiopathic pulmonary fibrosis, retroperitoneal fibrosis). Patients with any untreated stenosis > 70% of the distal aorta, common iliac, or external iliac arteries by CT, Angiography or MRI imaging will be excluded from enrollment (patients with previously successfully revascularized inflow stenoses may enroll in PACE). Subjects who were screen failures for a flow-limiting proximal lesion may be rescreened 3 months after successful angioplasty/stenting. Inability to provide written informed consent due to cognitive or language barriers (interpreter permitted) Concurrent enrollment in another clinical interventional investigative trial. Presence of any clinical condition that in the opinion of the principal Investigator or the sponsor makes the patient not suitable to participate in the trial

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ALD-301<br>Participants will receive ALD-301 via intramuscular injection | Biological: ALD-301<br>* Ten 1ml injections of ALD-301 in the index calf and posterior, lower thigh<br>* Other names: Aldehyde dehydrogenase-bright cells;|
| Placebo Comparator: Placebo (vehicle)<br>Participants will receive placebo (vehicle)via intramuscular injection | Biological: Placebo (vehicle)<br>* Ten 1ml injections of placebo in the index calf and posterior, lower thigh<br>* Other names: Human Serum Albumin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak Walking Time (PWT) | The placebo adjusted average change over time in the maximum time (in minutes) walked by a patient on a treadmill under standardized conditions. The patient continues the test until walking can no longer be tolerated because of claudication symptoms. | Assessed at baseline and 6 months | 
| Leg Collateral Count (Via Contrast Enhanced-MR) | The placebo adjusted average change in the number of collateral vessels over time. | Assessed at baseline and 6 months | 
| Peak Hyperemic Popliteal Flow (Phase Contrast MRA) | The placebo adjusted average change in peak hyperemic popliteal flow (mL/s) over time. | Assessed at baseline and 6 months | 
| Capillary Perfusion | The placebo adjusted average change in capillary perfusion over time. | Assessed at baseline and 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pre-exercise Ankle-Brachial Index (ABI) | ABI is the ratio of the blood pressure at the ankle to the blood pressure of the upper arm. Pre-exercise ABI is collected routinely with the patient supine immediately prior to a treadmill test. This measure represents the placebo adjusted average change over time in arm and pedal (ankle) blood pressure. The reported value is the estimate from regression analysis of the slope of the placebo adjusted measure over the time course of the trial adjusted for baseline weight. | Assessed as a trajectory (baseline, 3mos, and 6 mos) | 
| Post-exercise Ankle-Brachial Index (ABI) | ABI is the ratio of the blood pressure at the ankle to the blood pressure of the upper arm. Post-exercise ABI is collected routinely with the patient supine immediately following a treadmill test. This measure represents the placebo adjusted average change over time in arm and pedal (ankle) blood pressure. The reported value is the estimate from regression analysis of the slope of the placebo adjusted measure over the time course of the trial adjusted for baseline weight. | Assessed as a trajectory (baseline, 3mos, and 6 mos) | 
| Claudication Onset Time (COT) | Claudication Onset Time (COT) is the walking time at which patients first experience leg pain during a treadmill test. The measure represents placebo adjusted average change over time (in minutes) in the time walked by a patient on a treadmill under standardized conditions before the onset of claudication symptoms, regardless of whether this is manifested or characterized as muscle pain, ache, cramp, numbness or fatigue. This does not include joint pain or other pain not associated with claudication. The reported value is the estimate from regression analysis of the slope of the placebo adjusted measure over the time course of the trial adjusted for baseline weight. | Assessed as a trajectory (baseline, 3mos, and 6 mos) | 
| Peak Walking Time (PWT) | The average change in maximum time (in minutes) walked by a patient on a treadmill under standardized conditions. The patient continues the test until walking can no longer be tolerated because of claudication symptoms. | Assessed at baseline and 3 months | 
| Peripheral Artery Questionnaire (PAQ) | The Peripheral Artery Questionnaire (PAQ) assesses subjective physical limitations, leg symptoms, social function, treatment satisfaction, and quality of life. It is administered as a self report. Higher scores are indicative of better outcome. The summary scores is compiled by taking the mean of five subscales generated from the original questions. Range: Minimum score is 11.1, maximum 85. The measure represents placebo adjusted average change in Peripheral Artery Questionnaire (PAQ) summary score assessed over time. The reported value is the estimate from regression analysis of the slope of the placebo adjusted measure over the time course of the trial adjusted for baseline weight. | Assessed as a trajectory (baseline, 1mos, 3mos, and 6 mos) | 
| Walking Impairment Questionnaire (WIQ)-Walking Distance Score | The Walking Impairment Questionnaire (WIQ) assesses the severity of the subjective walking impairment on distance, speed, and stair climbing scales. It is administered as a self report. Range: Minimum score is 0.2, maximum 100. The measure represents the placebo adjusted average change in WIQ walking distance score assessed over time. The reported value is the estimate from regression analysis of the slope of the placebo adjusted measure over the time course of the trial adjusted for baseline weight. | Assessed as a trajectory (baseline, 1mos, 3mos, and 6 mos) | 
| Walking Impairment Questionnaire (WIQ)- Walking Speed Score | The Walking Impairment Questionnaire (WIQ) assesses the severity of the subjective walking impairment on distance, speed, and stair climbing scales. It is administered as a self report. Range: Minimum score is 0, maximum 87. The measure represents the placebo adjusted average change in WIQ walking speed score assessed over time. The reported value is the estimate from regression analysis of the slope of the placebo adjusted measure over the time course of the trial adjusted for baseline weight. | Assessed as a trajectory (baseline, 1mos, 3mos, and 6 mos) | 
| Walking Impairment Questionnaire (WIQ)-Ability to Climb Stairs Score | The Walking Impairment Questionnaire (WIQ) assesses the severity of the subjective walking impairment on distance, speed, and stair climbing scales. It is administered as a self report. Range: Minimum score is 0, maximum 100. The measure represents the placebo adjusted average change in WIQ ability to climb stairs score assessed over time. The reported value is the estimate from regression analysis of the slope of the placebo adjusted measure over the time course of the trial adjusted for baseline weight. | Assessed as a trajectory (baseline, 1mos, 3mos, and 6 mos) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MRI, PAD, Autologous Stem Cells, Claudicants, Peak Walking Time, Vascular Flow, Anatomy, Perfusion, Peripheral Artery Disease, Intermittent Claudication, ALDH cells