Patients With Intermittent Claudication Injected With ALDH Bright Cells (PACE)

• ClinicalTrials.gov Identifier: NCT01774097
• Recruitment Status: Completed
• First Posted: January 23, 2013
• Results First Posted: April 21, 2017
• Last Update Posted: April 21, 2017
• Sponsor: The University of Texas Health Science Center, Houston
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); Aldagen; Center for Cell and Gene Therapy, Baylor College of Medicine
• Information provided by (Responsible Party): Dr Lemuel A Moye III, The University of Texas Health Science Center, Houston

Tracking Information

• First Submitted Date: January 18, 2013
• First Posted Date: January 23, 2013
• Results First Submitted Date: January 3, 2017
• Results First Posted Date: April 21, 2017
• Last Update Posted Date: April 21, 2017
• Actual Study Start Date: June 2013
• Actual Primary Completion Date: August 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 10, 2017)

• Peak Walking Time (PWT) [ Time Frame: Assessed at baseline and 6 months ]
  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.
• Leg Collateral Count (Via Contrast Enhanced-MR) [ Time Frame: Assessed at baseline and 6 months ]
  The placebo adjusted average change in the number of collateral vessels over time.
• Peak Hyperemic Popliteal Flow (Phase Contrast MRA) [ Time Frame: Assessed at baseline and 6 months ]
  The placebo adjusted average change in peak hyperemic popliteal flow (mL/s) over time.
• Capillary Perfusion [ Time Frame: Assessed at baseline and 6 months ]
  The placebo adjusted average change in capillary perfusion over time.

Original Primary Outcome Measures (submitted: January 18, 2013)

• Peak Walking Time (PWT) [ Time Frame: Assessed at baseline and 6 months ]
  The average change over time in the maximum time (in seconds) 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.
• Leg collateral artery anatomy (via contrast enhanced-MR) [ Time Frame: Assessed at baseline and 6 months ]
  The average change in the number of patent vessels over time.
• Vascular Flow (Phase Contrast MRA) [ Time Frame: Assessed at baseline and 6 months ]
  The average change in peak flow (mL/s) over time.
• Perfusion (Cuff-induced Ischemia using Perfusion MR) [ Time Frame: Assessed at baseline and 6 months ]
  The average change in hyperemic fractional microvascular blood plasma volume over time.

Current Secondary Outcome Measures (submitted: March 10, 2017)

• Pre-exercise Ankle-Brachial Index (ABI) [ Time Frame: Assessed as a trajectory (baseline, 3mos, and 6 mos) ]
  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.
• Post-exercise Ankle-Brachial Index (ABI) [ Time Frame: Assessed as a trajectory (baseline, 3mos, and 6 mos) ]
  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.
• Claudication Onset Time (COT) [ Time Frame: Assessed as a trajectory (baseline, 3mos, and 6 mos) ]
  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.
• Peak Walking Time (PWT) [ Time Frame: Assessed at baseline and 3 months ]
  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.
• Peripheral Artery Questionnaire (PAQ) [ Time Frame: Assessed as a trajectory (baseline, 1mos, 3mos, and 6 mos) ]
  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.
• Walking Impairment Questionnaire (WIQ)-Walking Distance Score [ Time Frame: Assessed as a trajectory (baseline, 1mos, 3mos, and 6 mos) ]
  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.
• Walking Impairment Questionnaire (WIQ)- Walking Speed Score [ Time Frame: Assessed as a trajectory (baseline, 1mos, 3mos, and 6 mos) ]
  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.
• Walking Impairment Questionnaire (WIQ)-Ability to Climb Stairs Score [ Time Frame: Assessed as a trajectory (baseline, 1mos, 3mos, and 6 mos) ]
  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.

Original Secondary Outcome Measures (submitted: January 18, 2013)

• Resting Ankle-Brachial Index (ABI) [ Time Frame: Assessed at baseline and 3 months ]
  The average change over time in arm and pedal blood pressure will be obtained routinely with the patient supine immediately prior to the treadmill test.
• Resting Ankle-Brachial Index (ABI) [ Time Frame: Assessed at baseline and 6 months ]
  The average change over time in arm and pedal blood pressure will be obtained routinely with the patient supine immediately prior to the treadmill test.
• Post-exercise Ankle-Brachial Index (ABI) [ Time Frame: Assessed at baseline and 3 months ]
  The average change over time in arm and pedal blood pressure will be obtained routinely with the patient supine immediately following the treadmill test.
• Post-exercise Ankle-Brachial Index (ABI) [ Time Frame: Assessed at baseline and 6 months ]
  The average change over time in arm and pedal blood pressure will be obtained routinely with the patient supine immediately following the treadmill test.
• Claudication Onset Time (COT) [ Time Frame: Assessed at baseline and 3 months ]
  The average change over time (in seconds) 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.
• Claudication Onset Time (COT) [ Time Frame: Assessed at baseline and 6 months ]
  The average change over time (in seconds) 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.
• Peak Walking Time (PWT) [ Time Frame: Assessed at baseline and 3 months ]
  The average change in maximum time (in seconds) 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.
• Relationship between PWT and leg collateral artery anatomy [ Time Frame: Assessed at baseline and 6 months ]
  Quantitate the relationship between the change over time in PWT and the change over time in leg collateral artery anatomy using the general linear model.
• Relationship between PWT and Vascular Flow [ Time Frame: Assessed at baseline and 6 months ]
  Quantitate the relationship between the change over time in PWT and the change over time in vascular flow using the general linear model.
• Relationship between PWT and Perfusion [ Time Frame: Assessed at baseline and 6 months ]
  Quantitate the relationship between the change over time in PWT and the change over time in perfusion using the general linear model.

• Current Other Pre-specified Outcome Measures: Not Provided

Original Other Pre-specified Outcome Measures (submitted: January 18, 2013)

Oximetry (cuff induced ischemia) [ Time Frame: Assessed at baseline and 6 months ]

The average change over time in washout time (seconds) between the two groups after five minutes cuff-induced ischemia - this experimental endpoint will only be performed at clinical sites that are qualified to participate in this sub-study by the MRI core lab.

Descriptive Information

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

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.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Peripheral Artery Disease
• Intermittent Claudication

Intervention

• Biological: ALD-301
  Ten 1ml injections of ALD-301 in the index calf and posterior, lower thigh
  Other Names:

  • ALDH Bright Cells
  • ALDHbr
  • Aldehyde dehydrogenase-bright cells
• Biological: Placebo (vehicle)
  Ten 1ml injections of placebo in the index calf and posterior, lower thigh
  Other Names:

  • Placebo
  • Vehicle
  • HSA
  • Human Serum Albumin

Study Arms

• Experimental: ALD-301
  Participants will receive ALD-301 via intramuscular injection
  Intervention: Biological: ALD-301
• Placebo Comparator: Placebo (vehicle)
  Participants will receive placebo (vehicle)via intramuscular injection
  Intervention: Biological: Placebo (vehicle)

Publications *

• Hirsch AT, Haskal ZJ, Hertzer NR, Bakal CW, Creager MA, Halperin JL, Hiratzka LF, Murphy WR, Olin JW, Puschett JB, Rosenfield KA, Sacks D, Stanley JC, Taylor LM Jr, White CJ, White J, White RA, Antman EM, Smith SC Jr, Adams CD, Anderson JL, Faxon DP, Fuster V, Gibbons RJ, Hunt SA, Jacobs AK, Nishimura R, Ornato JP, Page RL, Riegel B; American Association for Vascular Surgery; Society for Vascular Surgery; Society for Cardiovascular Angiography and Interventions; Society for Vascular Medicine and Biology; Society of Interventional Radiology; ACC/AHA Task Force on Practice Guidelines Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease; American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; Vascular Disease Foundation. ACC/AHA 2005 Practice Guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease): endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation. Circulation. 2006 Mar 21;113(11):e463-654. doi: 10.1161/CIRCULATIONAHA.106.174526. No abstract available.
• Perin EC, Silva G, Gahremanpour A, Canales J, Zheng Y, Cabreira-Hansen MG, Mendelsohn F, Chronos N, Haley R, Willerson JT, Annex BH. A randomized, controlled study of autologous therapy with bone marrow-derived aldehyde dehydrogenase bright cells in patients with critical limb ischemia. Catheter Cardiovasc Interv. 2011 Dec 1;78(7):1060-7. doi: 10.1002/ccd.23066. Epub 2011 May 18.
• Perin EC, Murphy M, Cooke JP, Moye L, Henry TD, Bettencourt J, Gahremanpour A, Leeper N, Anderson RD, Hiatt WR, Lima JA, Venkatesh B, Sayre SL, Vojvodic RW, Taylor DA, Ebert RF, Hirsch AT; Cardiovascular Cell Therapy Research Network. Rationale and design for PACE: patients with intermittent claudication injected with ALDH bright cells. Am Heart J. 2014 Nov;168(5):667-73. doi: 10.1016/j.ahj.2014.07.021. Epub 2014 Jul 30.
• Perin EC, Murphy MP, March KL, Bolli R, Loughran J, Yang PC, Leeper NJ, Dalman RL, Alexander J, Henry TD, Traverse JH, Pepine CJ, Anderson RD, Berceli S, Willerson JT, Muthupillai R, Gahremanpour A, Raveendran G, Velasquez O, Hare JM, Hernandez Schulman I, Kasi VS, Hiatt WR, Ambale-Venkatesh B, Lima JA, Taylor DA, Resende M, Gee AP, Durett AG, Bloom J, Richman S, G'Sell P, Williams S, Khan F, Gyang Ross E, Santoso MR, Goldman J, Leach D, Handberg E, Cheong B, Piece N, DiFede D, Bruhn-Ding B, Caldwell E, Bettencourt J, Lai D, Piller L, Simpson L, Cohen M, Sayre SL, Vojvodic RW, Moye L, Ebert RF, Simari RD, Hirsch AT; Cardiovascular Cell Therapy Research Network (CCTRN). Evaluation of Cell Therapy on Exercise Performance and Limb Perfusion in Peripheral Artery Disease: The CCTRN PACE Trial (Patients With Intermittent Claudication Injected With ALDH Bright Cells). Circulation. 2017 Apr 11;135(15):1417-1428. doi: 10.1161/CIRCULATIONAHA.116.025707. Epub 2017 Feb 16.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 11, 2016): 82
• Original Estimated Enrollment (submitted: January 18, 2013): 80
• Actual Study Completion Date: March 2017
• Actual Primary Completion Date: August 2016 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. 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.
2. Age ≥40 years
3. Resting ankle-brachial index <0.90 or a resting toe-brachial index of <0.70 at baseline testing
4. 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:

1. 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)
2. Inability to complete treadmill testing per protocol requirements.
3. Ability to walk for more than 12 minutes on the treadmill during treadmill testing.
4. Patients who identify both legs as equivocally symptomatic or alternate between symptomatic legs on the baseline treadmill tests.
5. Patients with critical limb ischemia (ischemic rest pain or ischemia-related non healing wounds or tissue loss (Rutherford categories 4-6).
6. Recent (<3 months) infrainguinal revascularization (surgery or endovascular revascularization) or revascularization planned during study period
7. 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.
8. Patients with >2+ lower extremity pitting edema
9. Patients with myelodysplastic syndrome (MDS)
10. 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.
11. Congestive Heart Failure hospitalization within the last 1 month prior to enrollment
12. Acute coronary syndrome in the last 1 month prior to enrollment
13. Human Immunodeficiency Virus positive, active Hepatitis B Virus or Hepatitis C Virus Disease
14. History of cancer within the last 5 years, except basal cell skin carcinoma
15. 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
16. Contraindication to magnetic resonance imaging (MRI) (including knee/tibial/fibular replacement hardware in the index leg) or known allergy to MRI contrast media
17. Chronic kidney disease [effective Glomerular Filtration Rate <30 by modification of diet in renal disease (MDRD) or Mayo or Cockcroft-Gault formula]
18. Uncontrolled diabetes [Hemoglobin A1C (HbA1C)>8.5]
19. 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
20. 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.
21. Any condition requiring immunosuppressant medications (e.g., for treatment of organ transplants, psoriasis, Crohn's disease, alopecia areata).
22. History of inflammatory or progressively fibrotic conditions (e.g. rheumatoid arthritis, systemic lupus erythematosis, vasculitic disorders, idiopathic pulmonary fibrosis, retroperitoneal fibrosis).
23. 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.
24. Inability to provide written informed consent due to cognitive or language barriers (interpreter permitted)
25. Concurrent enrollment in another clinical interventional investigative trial.
26. 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 40 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01774097
• Other Study ID Numbers: HSC-SPH-12-0785; UM1HL087318-06 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Dr Lemuel A Moye III, The University of Texas Health Science Center, Houston
• Original Responsible Party: Same as current
• Current Study Sponsor: The University of Texas Health Science Center, Houston
• Original Study Sponsor: Same as current

Collaborators

• National Heart, Lung, and Blood Institute (NHLBI)
• Aldagen
• Center for Cell and Gene Therapy, Baylor College of Medicine

Investigators

• Study Chair: Robert Simari, MD; Cardiovascular Cell Therapy Research Network

• PRS Account: The University of Texas Health Science Center, Houston
• Verification Date: March 2017