Clinical trial NCT01041417: Granulocyte-Macrophage Stimulating Factor in the Treatment of Peripheral Arterial Disease
Official title: Granulocyte-Macrophage Stimulating Factor (GM-CSF) and Mobilization of Progenitor Cells in Peripheral Arterial Disease: A Phase II Randomized Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Peripheral Arterial Disease
Keywords: claudication
Lead sponsor: Emory University
Sponsor class: OTHER
Collaborators: name: National Institutes of Health (NIH)
name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2009-12-31
Enrollment: 159
Sex: ALL
Minimum age (years): 21
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Peripheral arterial disease is a common condition in older adults involving poor arterial circulation in the legs leading to leg pain and debility. The body's own circulating blood vessel stem cells may help to improve circulation. This study will test whether treatment with the drug granulocyte macrophage colony stimulating factor (GM-CSF) will improve symptoms and signs of peripheral arterial disease over placebo after four weeks of therapy. As well this study will examine whether improvements in blood vessel function can be observed. Finally, we will measure blood vessel function and stem cell levels in order to determine whether they can help to predict whether patients wither peripheral arterial disease will suffer further cardiovascular complications.

Detailed description: Peripheral artery disease (PAD) affects more than 8 million Americans. Although exercise, smoking cessation, anti-platelet therapy, cilostazol, statins and revascularization are used to treat PAD, men and women with PAD have significantly greater functional impairment and fasterfunctional decline than those without PAD. Stem and progenitor cell (PC) therapy that promotes neoangiogenesis is an emerging treatment modality in PAD. Progenitor cells, particularly those of endothelial origin, are involved in vascular repair and regeneration. They originate primarily but not exclusively from the bone marrow, differentiate into endothelial and other vascular cells, and contribute to neovascularization during tissue repair by direct and paracrine mechanisms. Endogenous, pharmacologically-stimulated, and exogenous PCs contribute to re-endothelialization and neovascularization. Granulocyte colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) stimulate mobilization of hematopoietic and other PCs from the bone marrow.In the murine hind limb ischemia model, GM-CSF administered by injection or by plasmid transfer augments circulating levels of PCs, increases capillary density, and promotes arteriogenesis.GM-CSF also augments neo-endothelialization of denuded arteries, promotes proliferation, differentiation and survival of hematopoietic cells, monocytes and macrophages.

Eligibility criteria: Inclusion Criteria:

* 160 males or post-menopausal females between 21 and 80 years of age. Female subjects must be (a) post-menopausal, (b) surgically sterile or (c) use adequate birth control and have a negative pregnancy test within 3 days prior to administration of study drug and should not be breastfeeding.
* Documented PAD (By Ankle-Brachial Indices or Angiographically)
* Clinically stable (at least 2 months) history of intermittent claudication with no change in symptom severity in the 2 months prior to screening.
* On stable statin therapy for previous 3 months.
* Peak Walking Time (PWT) between 1 and 12 minutes on a standardized Gardner treadmill protocol.
* A Doppler-derived ankle-brachial index (ABI) of \< 0.85 in the symptomatic limb after 10 minutes of rest at screening. For subjects with an ABI of \>1.3 (non-compressible arteries) a Toe-Brachial Index (TBI) of \< 0.70 must be obtained for subject qualification, or if ABI is \> 0.85 to 1.0 , and a reduction of 20% in ABI measured within 1 minute of treadmill testing.
* On appropriate and stable medical therapy for atherosclerosis for at least 2 months.
* Able to give informed consent.
* Diabetics with a dilated eye exam excluding proliferative retinopathy in the previous 12 months.

Exclusion Criteria:

* Recent or current active infections (treated with antibiotics).
* Recent (3 months) change in statin therapy
* Critical limb ischemia either chronic (category 3 and 4 of SVS classification) or acute ischemia manifested by rest pain, ulceration, or gangrene.
* Lower extremity vascular surgery, angioplasty or lumbar sympathectomy within 3 months of enrollment.
* Participation in a structured exercise treatment protocol within 3 months of enrollment.
* Prior myeloid cancer.
* Unstable angina, myocardial infarction, TIA, stroke or revascularization in the preceding 4 months.
* Severe heart failure (Class III or IV), heart muscle disease or atrial fibrillation.
* Limitation on exercise for symptoms other than intermittent claudication such as arthritis or dyspnea.
* Uncontrolled diabetes mellitus (defined as HbA1c \> 10.0).
* Chronic renal disease (creatinine of \>2.5 mg/dl) or hepatic disease (\> 3 X elevations in AST and ALT).
* Ophthalmologic conditions associated with a neo-vascular response.
* Alcohol or drug abuse, or any other disease process that, in the opinion of the PI, will interfere with the ability of the patient to participate in the study.

Primary outcomes:
measure: Change in Peak Walking Time During Treadmill Exercise Tolerance Test From Baseline to 3 Months
timeFrame: Baseline, 3 months
Secondary outcomes:
measure: Change in Peak Walking Time During Treadmill Exercise Tolerance Test From Baseline to 6 Months
timeFrame: Baseline, 6 months
measure: Change in Claudication Onset Time (COT) From Baseline to 3 Months
timeFrame: Baseline, 3 months
measure: Change in Claudication Onset Time (COT) From Baseline to 6 Months
timeFrame: Baseline, 6 months
measure: Change in Walking Distance Scores on Walking Impairment Questionnaire (WIQ) From Baseline to 3 Months
timeFrame: Baseline, 3 months
measure: Change in Walking Distance Scores on Walking Impairment Questionnaire (WIQ) From Baseline to 6 Months
timeFrame: Baseline, 6 months
measure: Change in Walking Speed Score on Walking Impairment Questionnaire (WIQ) From Baseline to 3 Months
timeFrame: Baseline, 3 months
measure: Change in Walking Speed Score on Walking Impairment Questionnaire (WIQ) From Baseline to 6 Months
timeFrame: Baseline, 6 months
measure: Change in Stair Climbing Score on Walking Impairment Questionnaire (WIQ) From Baseline to 3 Months
timeFrame: Baseline, 3 months
measure: Change in Stair Climbing Score on Walking Impairment Questionnaire (WIQ) From Baseline to 6 Months
timeFrame: Baseline, 6 months
measure: Change in Score on Physical Composite Score (PCS) Subscale of the Short Form 36 Health Survey (SF-36) From Baseline to 3 Months
timeFrame: Baseline, 3 months
measure: Change in Score on Physical Composite Score (PCS) Subscale of the Short Form 36 Health Survey (SF-36) From Baseline to 6 Months
timeFrame: Baseline, 6 months
measure: Change in Score on Mental Composite Score (MCS) Subscale of the Short Form 36 Health Survey (SF-36) From Baseline to 3 Months
timeFrame: Baseline, 3 months
measure: Change in Score on Mental Composite Score (MCS) Subscale of the Short Form 36 Health Survey (SF-36) From Baseline to 6 Months
timeFrame: Baseline, 6 months
measure: Change in Score on Physical Functioning Subscale of the Short Form 36 Health Survey (SF-36) From Baseline to 3 Months
timeFrame: Baseline, 3 months
measure: Change in Score on Physical Functioning Subscale of the Short Form 36 Health Survey (SF-36) From Baseline to 6 Months
timeFrame: Baseline, 6 months
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Emory University
state: Georgia
Study officials:
affiliation: Emory University
name: Arshed Quyyumi, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Poole J, Mavromatis K, Binongo JN, Khan A, Li Q, Khayata M, Rocco E, Topel M, Zhang X, Brown C, Corriere MA, Murrow J, Sher S, Clement S, Ashraf K, Rashed A, Kabbany T, Neuman R, Morris A, Ali A, Hayek S, Oshinski J, Yoon YS, Waller EK, Quyyumi AA. Effect of progenitor cell mobilization with granulocyte-macrophage colony-stimulating factor in patients with peripheral artery disease: a randomized clinical trial. JAMA. 2013 Dec 25;310(24):2631-9. doi: 10.1001/jama.2013.282540.