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Granulocyte-Macrophage Stimulating Factor in the Treatment of Peripheral Arterial Disease (GPAD-2)

Primary Purpose

Peripheral Arterial Disease

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Granulocyte-Macrophage Stimulating Factor (GM-CSF)
Placebo
Sponsored by
Emory University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Peripheral Arterial Disease focused on measuring claudication

Eligibility Criteria

21 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Emory University

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

GM-CSF

Placebo

Arm Description

Subjects will receive GM-CSF 500μg (Sargramostim (Leukine), Sanofi Aventis) by a self-administered subcutaneous injection thrice weekly on Monday, Wednesday, and Friday for four weeks

Subjects will receive a saline injection (placebo) by a self-administered subcutaneous injection thrice weekly on Monday, Wednesday, and Friday for four weeks

Outcomes

Primary Outcome Measures

Change in Peak Walking Time During Treadmill Exercise Tolerance Test From Baseline to 3 Months
Exercise Tolerance Test (ETT) was conducted using the Gardner protocol. Participants exercised on a treadmill, starting at 2.0 mph. The intensity of exercise (speed) was increased in grade of 2% every 2 minutes. Participants were asked to exercise until symptom limitation and the time measured in seconds from the ETT was used for data analysis.

Secondary Outcome Measures

Change in Peak Walking Time During Treadmill Exercise Tolerance Test From Baseline to 6 Months
Exercise Tolerance Test (ETT) was conducted using the Gardner protocol. Participants exercised on a treadmill, starting at 2.0 mph. The intensity of exercise (speed) was increased in grade of 2% every 2 minutes. Participants were asked to exercise until symptom limitation and the time measured in seconds from the ETT was used for data analysis.
Change in Claudication Onset Time (COT) From Baseline to 3 Months
Claudication is pain, tired or weak feeling that occurs in the legs, usually during activity such as walking. The COT was measured as the time to onset of the participant's typical claudication as the maximum distance the patient could walk on the treadmill.
Change in Claudication Onset Time (COT) From Baseline to 6 Months
Claudication is pain, tired or weak feeling that occurs in the legs, usually during activity such as walking. The COT was measured as the time to onset of the participant's typical claudication as the maximum distance the patient could walk on the treadmill.
Change in Walking Distance Scores on Walking Impairment Questionnaire (WIQ) From Baseline to 3 Months
The WIQ quantifies walking difficulty on a 100-point scale, in which 0 indicates extreme difficulty and 100 indicates no difficulty with walking distance.
Change in Walking Distance Scores on Walking Impairment Questionnaire (WIQ) From Baseline to 6 Months
The WIQ quantifies walking difficulty on a 100-point scale, in which 0 indicates extreme difficulty and 100 indicates no difficulty with walking distance.
Change in Walking Speed Score on Walking Impairment Questionnaire (WIQ) From Baseline to 3 Months
The WIQ quantifies walking difficulty on a 100-point scale, in which 0 indicates extreme difficulty and 100 indicates no difficulty with walking speed.
Change in Walking Speed Score on Walking Impairment Questionnaire (WIQ) From Baseline to 6 Months
The WIQ quantifies walking difficulty on a 100-point scale, in which 0 indicates extreme difficulty and 100 indicates no difficulty with walking speed.
Change in Stair Climbing Score on Walking Impairment Questionnaire (WIQ) From Baseline to 3 Months
The WIQ quantifies walking difficulty on a 100-point scale, in which 0 indicates extreme difficulty and 100 indicates no difficulty with stair climbing elements.
Change in Stair Climbing Score on Walking Impairment Questionnaire (WIQ) From Baseline to 6 Months
The WIQ quantifies walking difficulty on a 100-point scale, in which 0 indicates extreme difficulty and 100 indicates no difficulty with stair climbing elements.
Change in Score on Physical Composite Score (PCS) Subscale of the Short Form 36 Health Survey (SF-36) From Baseline to 3 Months
The SF-36 is a standard quality of life instrument. The PCS represents the the physical burden on quality of life and is a summary of questions related to physical impact of a disease or condition (physical function, role physical, bodily pain, and general health). PCS is a summary measure derived from 8 scale score and the score ranges from 0-100; higher scores indicate better performance.
Change in Score on Physical Composite Score (PCS) Subscale of the Short Form 36 Health Survey (SF-36) From Baseline to 6 Months
The SF-36 is a standard quality of life instrument. The PCS represents the the physical burden on quality of life and is a summary of questions related to physical impact of a disease or condition (physical function, role physical, bodily pain, and general health). PCS is a summary measure derived from 8 scale score and the score ranges from 0-100; higher scores indicate better performance.
Change in Score on Mental Composite Score (MCS) Subscale of the Short Form 36 Health Survey (SF-36) From Baseline to 3 Months
The SF-36 is a standard quality of life instrument. The MCS represents the the mental burden on quality of life and is a summary of questions related to mental impact of a disease or condition (mental function, role emotional, vitality, and mental health). MCS is a summary measure derived from 8 scale score and the score ranges from 0-100; higher scores indicate better performance.
Change in Score on Mental Composite Score (MCS) Subscale of the Short Form 36 Health Survey (SF-36) From Baseline to 6 Months
The SF-36 is a standard quality of life instrument. The MCS represents the the mental burden on quality of life and is a summary of questions related to mental impact of a disease or condition (mental function, role emotional, vitality, and mental health). MCS is a summary measure derived from 8 scale score and the score ranges from 0-100; higher scores indicate better performance.
Change in Score on Physical Functioning Subscale of the Short Form 36 Health Survey (SF-36) From Baseline to 3 Months
The SF-36 is a standard quality of life instrument. The physical functioning represents limitations in physical activities because of health problems. Physical functioning is a summary measure derived from 8 scale scores and the score ranges from 0-100; higher scores indicate better performance.
Change in Score on Physical Functioning Subscale of the Short Form 36 Health Survey (SF-36) From Baseline to 6 Months
The SF-36 is a standard quality of life instrument. The physical functioning represents limitations in physical activities because of health problems. Physical functioning is a summary measure derived from 8 scale scores and the score ranges from 0-100; higher scores indicate better performance.

Full Information

First Posted
December 29, 2009
Last Updated
December 12, 2014
Sponsor
Emory University
Collaborators
National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI)
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1. Study Identification

Unique Protocol Identification Number
NCT01041417
Brief Title
Granulocyte-Macrophage Stimulating Factor in the Treatment of Peripheral Arterial Disease
Acronym
GPAD-2
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

2. Study Status

Record Verification Date
December 2014
Overall Recruitment Status
Completed
Study Start Date
September 2009 (undefined)
Primary Completion Date
March 2014 (Actual)
Study Completion Date
undefined (undefined)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Emory University
Collaborators
National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Peripheral Arterial Disease
Keywords
claudication

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
159 (Actual)

8. Arms, Groups, and Interventions

Arm Title
GM-CSF
Arm Type
Experimental
Arm Description
Subjects will receive GM-CSF 500μg (Sargramostim (Leukine), Sanofi Aventis) by a self-administered subcutaneous injection thrice weekly on Monday, Wednesday, and Friday for four weeks
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Subjects will receive a saline injection (placebo) by a self-administered subcutaneous injection thrice weekly on Monday, Wednesday, and Friday for four weeks
Intervention Type
Drug
Intervention Name(s)
Granulocyte-Macrophage Stimulating Factor (GM-CSF)
Other Intervention Name(s)
GM-CSF, Leukine
Intervention Description
500 micrograms of GM-CSF
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Saline injection
Primary Outcome Measure Information:
Title
Change in Peak Walking Time During Treadmill Exercise Tolerance Test From Baseline to 3 Months
Description
Exercise Tolerance Test (ETT) was conducted using the Gardner protocol. Participants exercised on a treadmill, starting at 2.0 mph. The intensity of exercise (speed) was increased in grade of 2% every 2 minutes. Participants were asked to exercise until symptom limitation and the time measured in seconds from the ETT was used for data analysis.
Time Frame
Baseline, 3 months
Secondary Outcome Measure Information:
Title
Change in Peak Walking Time During Treadmill Exercise Tolerance Test From Baseline to 6 Months
Description
Exercise Tolerance Test (ETT) was conducted using the Gardner protocol. Participants exercised on a treadmill, starting at 2.0 mph. The intensity of exercise (speed) was increased in grade of 2% every 2 minutes. Participants were asked to exercise until symptom limitation and the time measured in seconds from the ETT was used for data analysis.
Time Frame
Baseline, 6 months
Title
Change in Claudication Onset Time (COT) From Baseline to 3 Months
Description
Claudication is pain, tired or weak feeling that occurs in the legs, usually during activity such as walking. The COT was measured as the time to onset of the participant's typical claudication as the maximum distance the patient could walk on the treadmill.
Time Frame
Baseline, 3 months
Title
Change in Claudication Onset Time (COT) From Baseline to 6 Months
Description
Claudication is pain, tired or weak feeling that occurs in the legs, usually during activity such as walking. The COT was measured as the time to onset of the participant's typical claudication as the maximum distance the patient could walk on the treadmill.
Time Frame
Baseline, 6 months
Title
Change in Walking Distance Scores on Walking Impairment Questionnaire (WIQ) From Baseline to 3 Months
Description
The WIQ quantifies walking difficulty on a 100-point scale, in which 0 indicates extreme difficulty and 100 indicates no difficulty with walking distance.
Time Frame
Baseline, 3 months
Title
Change in Walking Distance Scores on Walking Impairment Questionnaire (WIQ) From Baseline to 6 Months
Description
The WIQ quantifies walking difficulty on a 100-point scale, in which 0 indicates extreme difficulty and 100 indicates no difficulty with walking distance.
Time Frame
Baseline, 6 months
Title
Change in Walking Speed Score on Walking Impairment Questionnaire (WIQ) From Baseline to 3 Months
Description
The WIQ quantifies walking difficulty on a 100-point scale, in which 0 indicates extreme difficulty and 100 indicates no difficulty with walking speed.
Time Frame
Baseline, 3 months
Title
Change in Walking Speed Score on Walking Impairment Questionnaire (WIQ) From Baseline to 6 Months
Description
The WIQ quantifies walking difficulty on a 100-point scale, in which 0 indicates extreme difficulty and 100 indicates no difficulty with walking speed.
Time Frame
Baseline, 6 months
Title
Change in Stair Climbing Score on Walking Impairment Questionnaire (WIQ) From Baseline to 3 Months
Description
The WIQ quantifies walking difficulty on a 100-point scale, in which 0 indicates extreme difficulty and 100 indicates no difficulty with stair climbing elements.
Time Frame
Baseline, 3 months
Title
Change in Stair Climbing Score on Walking Impairment Questionnaire (WIQ) From Baseline to 6 Months
Description
The WIQ quantifies walking difficulty on a 100-point scale, in which 0 indicates extreme difficulty and 100 indicates no difficulty with stair climbing elements.
Time Frame
Baseline, 6 months
Title
Change in Score on Physical Composite Score (PCS) Subscale of the Short Form 36 Health Survey (SF-36) From Baseline to 3 Months
Description
The SF-36 is a standard quality of life instrument. The PCS represents the the physical burden on quality of life and is a summary of questions related to physical impact of a disease or condition (physical function, role physical, bodily pain, and general health). PCS is a summary measure derived from 8 scale score and the score ranges from 0-100; higher scores indicate better performance.
Time Frame
Baseline, 3 months
Title
Change in Score on Physical Composite Score (PCS) Subscale of the Short Form 36 Health Survey (SF-36) From Baseline to 6 Months
Description
The SF-36 is a standard quality of life instrument. The PCS represents the the physical burden on quality of life and is a summary of questions related to physical impact of a disease or condition (physical function, role physical, bodily pain, and general health). PCS is a summary measure derived from 8 scale score and the score ranges from 0-100; higher scores indicate better performance.
Time Frame
Baseline, 6 months
Title
Change in Score on Mental Composite Score (MCS) Subscale of the Short Form 36 Health Survey (SF-36) From Baseline to 3 Months
Description
The SF-36 is a standard quality of life instrument. The MCS represents the the mental burden on quality of life and is a summary of questions related to mental impact of a disease or condition (mental function, role emotional, vitality, and mental health). MCS is a summary measure derived from 8 scale score and the score ranges from 0-100; higher scores indicate better performance.
Time Frame
Baseline, 3 months
Title
Change in Score on Mental Composite Score (MCS) Subscale of the Short Form 36 Health Survey (SF-36) From Baseline to 6 Months
Description
The SF-36 is a standard quality of life instrument. The MCS represents the the mental burden on quality of life and is a summary of questions related to mental impact of a disease or condition (mental function, role emotional, vitality, and mental health). MCS is a summary measure derived from 8 scale score and the score ranges from 0-100; higher scores indicate better performance.
Time Frame
Baseline, 6 months
Title
Change in Score on Physical Functioning Subscale of the Short Form 36 Health Survey (SF-36) From Baseline to 3 Months
Description
The SF-36 is a standard quality of life instrument. The physical functioning represents limitations in physical activities because of health problems. Physical functioning is a summary measure derived from 8 scale scores and the score ranges from 0-100; higher scores indicate better performance.
Time Frame
Baseline, 3 months
Title
Change in Score on Physical Functioning Subscale of the Short Form 36 Health Survey (SF-36) From Baseline to 6 Months
Description
The SF-36 is a standard quality of life instrument. The physical functioning represents limitations in physical activities because of health problems. Physical functioning is a summary measure derived from 8 scale scores and the score ranges from 0-100; higher scores indicate better performance.
Time Frame
Baseline, 6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
21 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Arshed Quyyumi, MD
Organizational Affiliation
Emory University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Emory University
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
24247554
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.
Results Reference
derived

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Granulocyte-Macrophage Stimulating Factor in the Treatment of Peripheral Arterial Disease

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