Granulocyte-Macrophage Stimulating Factor (GM-CSF) in Peripheral Arterial Disease: The GPAD-3 Study
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 114
- 试验地点
- 1
- 主要终点
- Change in 6-minute walk distance
研究概览
简要总结
Peripheral artery disease (PAD) is a disease in which plaque builds up in the arteries that carry blood to the head, organs, and limbs. PAD usually occurs in the arteries in the legs, but can affect any arteries. Over time, plaque can harden and narrow the arteries which limits the flow of oxygen-rich blood to organs and other parts of the body. Blocked blood flow to the arteries can cause pain and numbness. The pain is usually worse with exercise and gets better with rest. PAD can raise the risk of getting an infection which could lead to tissue death and amputation. This study is investigating whether granulocyte-macrophage colony stimulating factor (GM-CSF) improves symptoms and blood flow in people with PAD. GM-CSF is a drug that is used to stimulate the bone marrow to release stem cells. Participants in the study will be randomly selected to receive GM-CSF or a placebo. After a four-week screening phase, participants will receive injections of GM-CSF or a placebo three times a week for three-weeks. Three months later, participants will again receive injections of GM-CSF or placebo three times a week for three-weeks. At six months, the study team will follow up to see if the group that received GM-CSF had more improvement than the group that received placebo.
详细描述
Atherosclerotic peripheral artery disease (PAD) of the lower extremities afflicts up to 8% of the U.S. population and lack of adequate sustainable therapies necessarily results in severe morbidity and increased mortality. Both experimental and current clinical data indicate that GM-CSF has the capacity to mobilize a variety of progenitor cells (PCs), including endothelial PCs that appear to improve ischemia.
This study builds on the findings of prior research which showed improvements in claudication symptoms after treatment with GM-CSF. This study aims to answer whether repeat administration of GM-CSF at 3 months will further improve symptoms. The researchers will investigate in a double-blind placebo-controlled randomized study whether 3 weeks of three-times-a-week injection of GM-CSF will improve measures of ischemia in patients with intermittent claudication.
This study will recruit 176 participants with atherosclerotic PAD and claudication. After screening for inclusion and exclusion criteria, eligible subjects will be trained to perform subcutaneous injections and instructed to walk until they develop claudication or symptomatic limitation at least three times a day for 4 weeks. At the end of the 4-week period, subjects will undergo baseline testing and will be randomized to receive 500 μg/day of GM-CSF thrice weekly for 3 weeks (group A) or a placebo (group B). After 3 months, follow-up endpoint testing will be performed. Subjects in group A will then receive the second administration of 500 μg/day of subcutaneous GM-CSF thrice weekly for another 3 weeks and be followed for another 3 months for endpoint measurements, while Group B subjects will receive a matching placebo. The primary outcome is change in walking performance in the active treatment group after 6 months compared to the placebo group. The secondary outcome includes change in peak walking time at 6 months, changes in circulating progenitor cell levels, ankle brachial index (ABI), walking impairment questionnaire (WIQ) scores, and 36-item Short-Form Health Survey (SF-36) scores. Long-term follow up, by way of a telephone call, will occur with each participant one, two and three years after they enrolled in the study to administer questionnaires and collect adverse event data.
In response to the Coronavirus Disease 2019 (COVID-19) crisis on April 3, 2020 the Institutional Review Board (IRB) approved temporary modifications to this study to postpone study visits that do not involve active drug/placebo use.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
盲法说明
Participants and the primary investigator will be blinded to group assignment. Blinding will be maintained by Investigational Pharmacy and blood counts will be reviewed by one of the study co-investigators who will make dose-modifications, when necessary.
入排标准
- 年龄范围
- 21 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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 symptomatic PAD
- •Clinically stable (at least 2 months prior to enrollment) history of intermittent claudication or walking impairment (Rutherford Class II) with no change in symptom severity in the 2 months prior to screening.
- •On statin therapy for previous 3 months prior to enrollment, unless statin intolerant.
- •Peak Walking Time (PWT) between 1 and 12 minutes on a standardized Gardner treadmill protocol or modified Gardner protocol or less than 12 minutes on a modified Bruce protocol in case PWT on Gardner protocol is more than 12 minutes.
- •A Doppler-derived ankle-brachial index (ABI) of < 0.90 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 > 0.9 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 prior to enrollment.
- •Able to give informed consent.
- •Diabetics with a dilated eye exam excluding proliferative retinopathy in the previous 12 months prior to enrollment.
排除标准
- •Recent or current active infections (treated with antibiotics)
- •Recent (6 months prior to randomization) or current active cancer undergoing treatment
- •Recent (3 months prior to randomization) change in statin or cilostazol therapy
- •Critical limb ischemia either chronic (Rutherford Class >II) or acute ischemia manifested by rest pain, ulceration, or gangrene
- •Recent (3 months prior to randomization) lower extremity vascular surgery, angioplasty or lumbar sympathectomy
- •Planned participation in a structured exercise treatment protocol in the future or within period of study
- •Prior myeloid malignancy
- •Recent (3 months prior to randomization) Unstable angina, myocardial infarction, transient ischemic attack (TIA), stroke or revascularization
- •Severe heart failure (Class III or IV) or heart muscle disease
- •Limitation on exercise for symptoms other than intermittent claudication such as arthritis or dyspnea
- •Below- or above-knee amputation
- •Wheelchair confinement
- •Use of a walking aid other than a cane
- •Walking impairment for reasons other than PAD e.g. Parkinson's disease
- •Uncontrolled diabetes mellitus (defined as HbA1c > 10.0)
- •Chronic renal disease (creatinine of >2.5 mg/dl) or hepatic disease (> 3 X elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT))
- •White blood cell count < 3k/cmm
- •Hemoglobin (HGB) < 10g/dL
- •Blood Pressure Systolic >180 and/or Diastolic >100
- •Taking Immunosuppressant drugs
- •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
- •Inability to attend study visits
研究组 & 干预措施
Granulocyte-macrophage Colony Stimulating Factor (GM-CSF)
Participants receiving 500µg of granulocyte-macrophage colony stimulating factor (GM-CSF), administered subcutaneously. Prior to randomization to a study arm, eligible participants are trained to perform subcutaneous injections and instructed to walk at least three times a day until they develop claudication or symptomatic limitation for 4 weeks.
干预措施: GM-CSF (Drug)
Placebo
Participants receiving 500µg of a placebo, administered subcutaneously. Prior to randomization to a study arm, eligible participants are trained to perform subcutaneous injections and instructed to walk at least three times a day until they develop claudication or symptomatic limitation for 4 weeks.
干预措施: Placebo (Drug)
结局指标
主要结局
Change in 6-minute walk distance
时间窗: Baseline, Month 3, Month 6, Month 9
Participants will be walk up and down a 100-foot hallway for 6 minutes to cover the maximum distance possible. The distance, measured in feet, completed after 6 minutes will be recorded.
Change in 6-minute walk distance
时间窗: Baseline, Month 6
Participants walk up and down a 100-foot hallway for 6 minutes to cover the maximum distance possible. The distance, measured in meters, completed after 6 minutes will be recorded. The primary outcome examines walking distance following two consecutive 3-monthly administrations of the study treatments.
次要结局
- Change in Walking Impairment Questionnaire (WIQ): Walking Speed Score(Baseline, Month 3, Month 6, Month 9, Follow-up Years 1, 2, and 3)
- Change in Walking Impairment Questionnaire (WIQ): Stair Climbing Score(Baseline, Month 3, Month 6, Month 9, Follow-up Years 1, 2, and 3)
- Change in 36-item Short-Form Health Survey (SF-36) Score(Baseline, Month 3, Month 6, Month 9, Follow-up Years 1, 2, and 3)
- Change in Claudication Onset Time (COT)(Baseline, Month 3, Month 6, Month 9)
- Change in Ankle-Brachial Index (ABI)(Baseline, Month 3, Month 6, Month 9)
- Change in Foot Transcutaneous Oxygen Tension (TcPO2)(Baseline, Month 3, Month 6, Month 9)
- Change in Walking Impairment Questionnaire (WIQ): Walking Distance Score(Baseline, Month 3, Month 6, Month 9, Follow-up Years 1, 2, and 3)
- Change in Peak Walking Time (PWT)(Baseline, Month 3, Month 6, Month 9)
- Change in Peak Walking Time (PWT)(Baseline, Month 6)
- Change in Peak Walking Time (PWT) From First Through Second Treatment(Month 3, Month 6)
- Number of Circulating Mononuclear Cells Expressing VEGF2R (KDR)(Baseline, Week 3, Month 3, Week 15, Month 6, Month 9)
- Change in Peak Walking Time (PWT) After Single Treatment(Baseline, Month 3)
- Change in 6-minute Walk Distance From First Through Second Treatment(Month 3, Month 6)
- Change in 6-minute Walk Distance After Single Treatment(Baseline, Month 3)
- Change in Walking Impairment Questionnaire (WIQ): Walking Distance Score(Baseline, Month 3, Month 6, Month 9, Year 1)
- Change in Walking Impairment Questionnaire (WIQ): Walking Speed Score(Baseline, Month 3, Month 6, Month 9, Year 1)
- Change in Walking Impairment Questionnaire (WIQ): Stair Climbing Score(Baseline, Month 3, Month 6, Month 9, Year 1)
- Change in 36-item Short-Form Health Survey (SF-36) Score(Baseline, Month 3, Month 6, Month 9, Year 1)
- Number of Circulating Mononuclear Cells Expressing CD34(Baseline, Week 3, Month 3, Week 15, Month 6, Month 9)
- Number of Circulating Mononuclear Cells Expressing CD133(Baseline, Week 3, Month 3, Week 15, Month 6, Month 9)
- Number of Circulating Mononuclear Cells Expressing CXCR4(Baseline, Week 3, Month 3, Week 15, Month 6, Month 9)
研究者
Arshed A. Quyyumi
Professor
Emory University