Patients With Intermittent Claudication Injected With ALDH Bright Cells

Peripheral Artery Disease Clinical Trial

— PACE  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01774097
• Other study ID #: HSC-SPH-12-0785
• Secondary ID: UM1HL087318-06
• Status: Active, not recruiting
• Phase: Phase 2
• First received: January 18, 2013
• Last updated: October 13, 2016
• Start date: June 2013
• Est. completion date: March 2017

Study information

• Verified date: September 2016
• Source: The University of Texas Health Science Center, Houston
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationUnited States: Data and Safety Monitoring BoardUnited States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 82
• Est. completion date: March 2017
• Est. primary completion date: August 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 40 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Intermittent Claudication
• Peripheral Arterial Disease
• Peripheral Artery Disease

Intervention

Biological:
• ALD-301
Ten 1ml injections of ALD-301 in the index calf and posterior, lower thigh
• Placebo (vehicle)
Ten 1ml injections of placebo in the index calf and posterior, lower thigh

Locations

Country	Name	City	State
United States	University of Florida-Department of Medicine	Gainesville	Florida
United States	Texas Heart Institute	Houston	Texas
United States	Indiana Center for Vascular Biology and Medicine	Indianapolis	Indiana
United States	University of Louisville	Louisville	Kentucky
United States	University of Miami-Interdisciplinary Stem Cell Institute	Miami	Florida
United States	Clinical and Translational Science Institute at University of Minnesota	Minneapolis	Minnesota
United States	Minneapolis Heart Institute Foundation	Minneapolis	Minnesota
United States	Orlando Health Inc.	Orlando	Florida
United States	Stanford University School of Medicine (Falk Cardiovascular Research Center)	Stanford	California

Sponsors (4)

Lead Sponsor	Collaborator
The University of Texas Health Science Center, Houston	Aldagen, Center for Cell and Gene Therapy, Baylor College of Medicine, National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

References & Publications (3)

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. Review. — View Citation

Perin EC, Murphy M, Cooke JP, Moyé 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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Primary	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	No
Primary	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	No
Primary	Capillary Perfusion	The placebo adjusted average change in capillary perfusion over time.	Assessed at baseline and 6 months	No
Secondary	Pre-exercise Ankle-Brachial Index (ABI)	The placebo adjusted average change over time in arm and pedal blood pressure will be obtained routinely with the patient supine immediately prior to the treadmill test.	Assessed at baseline and 3 months	No
Secondary	Pre-exercise Ankle-Brachial Index (ABI)	The placebo adjusted average change over time in arm and pedal blood pressure will be obtained routinely with the patient supine immediately prior to the treadmill test.	Assessed at baseline and 6 months	No
Secondary	Post-exercise Ankle-Brachial Index (ABI)	The placebo adjusted average change over time in arm and pedal blood pressure will be obtained routinely with the patient supine immediately following the treadmill test.	Assessed at baseline and 3 months	No
Secondary	Post-exercise Ankle-Brachial Index (ABI)	The placebo adjusted average change over time in arm and pedal blood pressure will be obtained routinely with the patient supine immediately following the treadmill test.	Assessed at baseline and 6 months	No
Secondary	Claudication Onset Time (COT)	The 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.	Assessed at baseline and 3 months	No
Secondary	Claudication Onset Time (COT)	The 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.	Assessed at baseline and 6 months	No
Secondary	Peak Walking Time (PWT)	The placebo adjusted 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	No
Secondary	Relationship between PWT and leg collateral count	Quantitate the relationship between the placebo adjusted change over time in PWT and the change over time in leg collateral count.	Assessed at baseline and 6 months	No
Secondary	Relationship between PWT and peak hyperemic popliteal flow	Quantitate the relationship between the placebo adjusted change over time in PWT and the change over time in peak hyperemic popliteal flow.	Assessed at baseline and 6 months	No
Secondary	Relationship between PWT and capillary perfusion	Quantitate the relationship between the placebo adjusted change over time in PWT and the change over time in capillary perfusion.	Assessed at baseline and 6 months	No
Secondary	Walking Impairment Questionnaire (WIQ)	The placebo adjusted average change in WIQ score over time.	Assessed at baseline and 1 month	No
Secondary	Peripheral Artery Questionnaire (PAQ)	The placebo adjusted average change in PAQ score over time.	Assessed at baseline and 1 month	No
Secondary	Walking Impairment Questionnaire (WIQ)	The placebo adjusted average change in WIQ score assessed over time	Assessed at baseline and 3 months	No
Secondary	Peripheral Artery Questionnaire (PAQ)	The placebo adjusted average change in PAQ score over time	Assessed at baseline and 3 months	No
Secondary	Walking Impairment Questionnaire (WIQ)	The placebo adjusted average change in WIQ score over time	Assessed at baseline and 6 months	No
Secondary	Peripheral Artery Questionnaire (PAQ)	The placebo adjusted average change in PAQ score over time.	Assessed at baseline and 6 months	No

External Links

•   Cardiovascular Cell Therapy Research Network
•   National Heart, Lung, and Blood Institute