Rationale and Design for PACE: Patients with Intermittent Claudication Injected with ALDH Bright Cells

Perin, Emerson C.; Murphy, Michael P.; Cooke, John P.; Moyé, Lem; Henry, Timothy D.; Bettencourt, Judy; Gahremanpour, Amir; Leeper, Nicholas J.; Anderson, R. David; Hiatt, William R.; Lima, João A.C.; Venkatesh, Bharath Ambale; Sayre, Shelly L.; Vojvodic, Rachel W.; Taylor, Doris A.; Ebert, Ray F.; Hirsch, Alan T.

doi:10.1016/j.ahj.2014.07.021

Cited by 24 publications

(19 citation statements)

References 28 publications

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“…The detailed study design, including the inclusion and exclusion criteria, sample size, and outcomes have been previously published. (5) Primary study outcomes include both clinical endpoint (change in peak walking time) and physiologic MRI-derived measurements of leg collateral arterial anatomy, arterial blood flow, and capillary perfusion at six months compared to baseline. (5)…”

Section: Methodsmentioning

confidence: 99%

Baseline assessment and comparison of arterial anatomy, hyperemic flow, and skeletal muscle perfusion in peripheral artery disease: The Cardiovascular Cell Therapy Research Network “Patients with Intermittent Claudication Injected with ALDH Bright Cells” (CCTRN PACE) study

Ambale-Venkatesh

Nauffal

Noda

et al. 2017

American Heart Journal

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Background Peripheral artery disease (PAD) is important to public health as a major contributor to cardiovascular morbidity and mortality. Recent developments in MRI techniques permit improved assessment of PAD anatomy and physiology, and may serve as surrogate endpoints after pro-angiogenic therapies. Methods The “Patients with Intermittent Claudication Injected with ALDH Bright Cells” (PACE) study is a randomized, double-blind, placebo-controlled clinical trial designed to assess the physiologic impact and potential clinical efficacy of autologous bone marrow-derived ALDHbr stem cells. The primary MRI endpoints of the study are; 1) total collateral count, 2) calf muscle plasma volume (a measure of capillary perfusion) by dynamic contrast-enhanced MRI, and 3) peak hyperemic popliteal flow by phase contrast MRI. Results The inter- and intra-reader and test-retest results demonstrated good-to-excellent reproducibility (ICC range: 0.61–0.98) for all MR measures. The PAD participants (n=82) had lower capillary perfusion measured by calf muscle plasma volume (3.8 vs 5.6%), and peak hyperemic popliteal flow (4.1 vs 13.5 ml/s) as compared to the normal participants (n=16), with a significant level of collateralization. Conclusions Reproducibility of the MRI primary endpoints in PACE was very good to excellent. The PAD participants exhibited decreased calf muscle capillary perfusion as well as arterial flow reserve when compared to normal participants. The MRI tools utilized in PACE may advance PAD science by enabling accurate measurement of PAD microvascular anatomy and perfusion before and after stem cell or other PAD therapies.

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Section: Methodsmentioning

confidence: 99%

Baseline assessment and comparison of arterial anatomy, hyperemic flow, and skeletal muscle perfusion in peripheral artery disease: The Cardiovascular Cell Therapy Research Network “Patients with Intermittent Claudication Injected with ALDH Bright Cells” (CCTRN PACE) study

Ambale-Venkatesh

Nauffal

Noda

et al. 2017

American Heart Journal

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“…122 An ongoing study of ALDH bright cells is being conducted by the National Institutes of Health–sponsored Cardiovascular Cell Therapy Research Network. 123 …”

Section: Trials Of Cell-based Therapiesmentioning

confidence: 99%

Modulating the Vascular Response to Limb Ischemia

Cooke

Losordo

2015

Circulation Research

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151

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The age-adjusted prevalence of peripheral arterial disease in the US population has been estimated to approach 12%. The clinical consequences of occlusive peripheral arterial disease include pain on walking (claudication), pain at rest, and loss of tissue integrity in the distal limbs; the latter may ultimately lead to amputation of a portion of the lower extremity. Surgical bypass techniques and percutaneous catheter-based interventions may successfully reperfuse the limbs of certain patients with peripheral arterial disease. In many patients, however, the anatomic extent and distribution of arterial occlusion is too severe to permit relief of pain and healing of ischemic ulcers. No effective medical therapy is available for the treatment of such patients, for many of whom amputation represents the only hope for alleviation of symptoms. The ultimate failure of medical treatment and procedural revascularization in significant numbers of patients has led to attempts to develop alternative therapies for ischemic disease. These strategies include administration of angiogenic cytokines, either as recombinant protein or as gene therapy, and more recently, to investigations of stem/progenitor cell therapy. The purpose of this review is to provide an outline of the preclinical basis for angiogenic and stem cell therapies, review the clinical research that has been done, summarize the lessons learned, identify gaps in knowledge, and suggest a course toward successfully addressing an unmet medical need in a large and growing patient population.

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“…Quality of life (QOL) measures and telephone communications with the participants were described in the PACE design manuscript. 16 Treadmill and ABI or toe-brachial index (TBI) testing were conducted at three and six months. MRI measurements were performed at six months for the primary endpoint assessment.…”

Section: Methodsmentioning

confidence: 99%

“…16 Fisher exact tests for categorical variables and Student’s t -tests for continuous variables assessed between group compatibility of baseline variables. Within group results are reported as mean ± SD.…”

Section: Methodsmentioning

confidence: 99%

Evaluation of Cell Therapy on Exercise Performance and Limb Perfusion in Peripheral Artery Disease

Perin¹,

Murphy²,

March³

et al. 2017

Circulation

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Background Atherosclerotic peripheral artery disease (PAD) affects 8–12% of Americans over 65 and is associated with a major decline in functional status, increased myocardial infarction and stroke rates, and increased risk of ischemic amputation. Current treatment strategies for claudication have limitations. PACE is an NHLBI-sponsored, randomized, double-blind, placebo-controlled phase 2, exploratory clinical trial designed to assess safety and efficacy of autologous bone marrow–derived aldehyde dehydrogenase bright (ALDHbr) cells in PAD patients and to explore associated claudication physiologic mechanisms. Methods All participants, randomized 1:1 to receive ALDHbr cells or placebo, underwent bone marrow aspiration and isolation of ALDHbr cells, followed by ten injections into the thigh and calf of the index leg. The co-primary endpoints were: change from baseline to six months in peak walking time (PWT), collateral count, peak hyperemic popliteal flow, and capillary perfusion measured by magnetic resonance imaging (MRI); as well as safety. Results A total of 82 patients with claudication and infra-inguinal PAD were randomized at nine sites, of which 78 had analyzable data (57 male, 21 female; mean age 66±9 years). The mean differences in the change over six months between study groups for PWT (mean ± standard error of the mean [SEM]) (0.9±0.8 minutes; 95% CI −0.6 to 2.5; p=0.238), collateral count (0.9±0.6 arteries; 95% CI −0.2 to 2.1; p=0.116), peak hyperemic popliteal flow (0.0±0.4 mL/sec; 95% CI −0.8 to 0.8; p=0.978), and capillary perfusion (−0.2±0.6%; 95% CI −1.3 to 0.9; p=0.752) were not significant. Additionally, there were no significant differences for the secondary endpoints, including quality of life measures. There were no adverse safety outcomes. Correlative relationships between MRI measures and PWT were not significant. A post-hoc exploratory analysis suggested that ALDHbr cell administration might be associated with an increase in the number of collateral arteries (1.5±0.7; 95% CI 0.1 to 2.9; p=0.047) in participants with completely occluded femoral arteries. Conclusions ALDHbr cell administration did not improve PWT or MR outcomes, and the changes in PWT were not associated with the anatomic or physiologic MRI endpoints. Future PAD cell therapy investigational trial design may be informed by new anatomic and perfusion insights.

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Rationale and Design for PACE: Patients with Intermittent Claudication Injected with ALDH Bright Cells

Cited by 24 publications

References 28 publications

Baseline assessment and comparison of arterial anatomy, hyperemic flow, and skeletal muscle perfusion in peripheral artery disease: The Cardiovascular Cell Therapy Research Network “Patients with Intermittent Claudication Injected with ALDH Bright Cells” (CCTRN PACE) study

Baseline assessment and comparison of arterial anatomy, hyperemic flow, and skeletal muscle perfusion in peripheral artery disease: The Cardiovascular Cell Therapy Research Network “Patients with Intermittent Claudication Injected with ALDH Bright Cells” (CCTRN PACE) study

Modulating the Vascular Response to Limb Ischemia

Evaluation of Cell Therapy on Exercise Performance and Limb Perfusion in Peripheral Artery Disease

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