Patients With Intermittent Claudication Injected With ALDH Bright Cells

NCT ID: NCT01774097

Last Updated: 2017-04-21

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 82 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-06-30
• Study Completion Date: 2017-03-31

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.

Conditions

Peripheral Artery Disease; Intermittent Claudication

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

ALD-301

Participants will receive ALD-301 via intramuscular injection

Group Type: EXPERIMENTAL

ALD-301

Intervention Type: BIOLOGICAL

Ten 1ml injections of ALD-301 in the index calf and posterior, lower thigh

Placebo (vehicle)

Participants will receive placebo (vehicle)via intramuscular injection

Group Type: PLACEBO_COMPARATOR

Placebo (vehicle)

Intervention Type: BIOLOGICAL

Ten 1ml injections of placebo in the index calf and posterior, lower thigh

Interventions

ALD-301

Ten 1ml injections of ALD-301 in the index calf and posterior, lower thigh

Intervention Type: BIOLOGICAL

Placebo (vehicle)

Ten 1ml injections of placebo in the index calf and posterior, lower thigh

Intervention Type: BIOLOGICAL

Other Intervention Names

ALDH Bright Cells; ALDHbr; Aldehyde dehydrogenase-bright cells; Placebo; Vehicle; HSA; Human Serum Albumin

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

• Minimum Eligible Age: 40 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

Aldagen

INDUSTRY

Sponsor Role: collaborator

Center for Cell and Gene Therapy, Baylor College of Medicine

OTHER

Sponsor Role: collaborator

The University of Texas Health Science Center, Houston

OTHER

Sponsor Role: lead

Responsible Party

Dr Lemuel A Moye III

Professor - School of Public Health

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Robert Simari, MD

Role: STUDY_CHAIR

Cardiovascular Cell Therapy Research Network

Locations

Stanford University School of Medicine (Falk Cardiovascular Research Center)

Stanford, California, United States

University of Florida-Department of Medicine

Gainesville, Florida, United States

University of Miami-Interdisciplinary Stem Cell Institute

Miami, Florida, United States

Orlando Health Inc.

Orlando, Florida, United States

Indiana Center for Vascular Biology and Medicine

Indianapolis, Indiana, United States

University of Louisville

Louisville, Kentucky, United States

Minneapolis Heart Institute Foundation

Minneapolis, Minnesota, United States

Clinical and Translational Science Institute at University of Minnesota

Minneapolis, Minnesota, United States

Texas Heart Institute

Houston, Texas, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 16549646 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 21594960 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 25440794 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 28209728 (View on PubMed)

Related Links

http://www.cctrn.org

Cardiovascular Cell Therapy Research Network

http://www.nhlbi.nih.gov/

National Heart, Lung, and Blood Institute

Other Identifiers

UM1HL087318-06

Identifier Type: NIH

Identifier Source: secondary_id

View Link

HSC-SPH-12-0785

Identifier Type: -

Identifier Source: org_study_id