GM-CSF for Peripheral Arterial Disease

(GPAD-3 Trial)

Overseen By Kiran Ejaz

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Emory University

Must be taking: Statins

Must not be taking: Immunosuppressants

Disqualifiers: Active infections, Cancer, Heart failure, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 24

176 Participants Needed

Trial Summary

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop taking your current medications. However, you must be on stable medical therapy for atherosclerosis and statin therapy for at least 2-3 months before joining. If you are taking immunosuppressant drugs, you cannot participate.

What data supports the effectiveness of the drug GM-CSF for treating peripheral arterial disease?

Research suggests that GM-CSF may help improve walking distance and exercise capacity in patients with peripheral arterial disease by mobilizing progenitor cells, which are cells that can help repair blood vessels. Some studies have shown promising results in improving symptoms like claudication (pain caused by too little blood flow) in these patients. ^{1 2 3 4 5}

Is GM-CSF safe for humans?

GM-CSF (Granulocyte-Macrophage Colony-Stimulating Factor) is generally safe for humans when used at appropriate doses, with mild-to-moderate side effects like fever, muscle pain, and rash occurring in 20-30% of patients. High doses can cause severe side effects, so careful monitoring is needed, especially in certain patient groups. ^{1 2 6 7 8}

How does the drug GM-CSF differ from other treatments for peripheral arterial disease?

GM-CSF is unique because it works by mobilizing progenitor cells from the bone marrow to improve blood vessel function and increase walking distance in patients with peripheral arterial disease, offering a non-invasive alternative to surgery or angioplasty. ^{1 2 4 5 6}

What is the purpose of this trial?

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.

Research Team

Arshed Quyyumi, MD

Principal Investigator

Emory University

Eligibility Criteria

This trial is for people with Peripheral Arterial Disease (PAD) who have been on statin therapy, can consent to the study, and have stable PAD symptoms. They must not have severe heart failure, recent major cardiovascular events or surgeries, uncontrolled diabetes, active cancer treatment, or any condition that would limit participation.

Inclusion Criteria

My walking impairment has been stable for the last 2 months.

I have been on statin therapy for the last 3 months or I cannot tolerate statins.

I am a woman who is either post-menopausal, surgically sterile, not pregnant, using birth control, and not breastfeeding.

Exclusion Criteria

I have had a blood cancer affecting my bone marrow before.

I have had an amputation below or above the knee, or I use a wheelchair.

I use a walking aid that is not a cane.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

4 weeks

1 visit (in-person)

Initial Treatment

Participants receive injections of GM-CSF or placebo three times a week for three weeks

3 weeks

9 visits (in-person)

Interim Follow-up

Participants are monitored for changes in walking performance and other health metrics

3 months

1 visit (in-person)

Second Treatment

Participants receive a second round of injections of GM-CSF or placebo three times a week for three weeks

3 weeks

9 visits (in-person)

Final Follow-up

Participants are monitored for changes in walking performance and other health metrics

3 months

1 visit (in-person)

Long-term Follow-up

Participants are contacted via telephone to administer questionnaires and collect adverse event data

3 years

3 visits (telephone)

Treatment Details

Interventions

• GM-CSF
• Placebo

Trial Overview The trial tests if GM-CSF injections improve blood flow and symptoms in PAD patients compared to a placebo. Participants will receive either GM-CSF or placebo shots three times weekly for two three-week periods with a follow-up at six months to assess improvement.

Participant Groups

Group I: GM-CSF Experimental Treatment 1 Intervention

Participants receiving 500µg of granulocyte-macrophage colony stimulating factor (GM-CSF), administered subcutaneously. Prior to randomization to a study arm, eligible participants will be 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.

Group II: Placebo Placebo Group 1 Intervention

Participants receiving 500µg of a placebo, administered subcutaneously. Prior to randomization to a study arm, eligible participants will be 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.

GM-CSF is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Leukine for:

• Neutropenia
• Bone Marrow Transplantation
• Leukemia
• Lymphoma
• HIV Infection

Approved in European Union as Sargramostim for:

• Neutropenia
• Bone Marrow Transplantation
• Leukemia
• Lymphoma

Approved in Canada as Leukine for:

• Neutropenia
• Bone Marrow Transplantation
• Leukemia
• Lymphoma

Who Is Running the Clinical Trial?

Emory University

Lead Sponsor

Trials

1,735

Recruited

2,605,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Findings from Research

In a study involving 45 patients with peripheral arterial disease (PAD), GM-CSF administration was found to be safe and led to significant increases in progenitor cells and improvements in endothelial function and exercise capacity after 12 weeks.

Patients receiving GM-CSF showed a 59% improvement in flow-mediated vasodilation and increased walking times on a treadmill, indicating enhanced exercise capacity, while no such improvements were seen in the placebo group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bone marrow mobilization with granulocyte macrophage colony-stimulating factor improves endothelial dysfunction and exercise capacity in patients with peripheral arterial disease. Subramaniyam, V., Waller, EK., Murrow, JR., et al.[2015]

The START-trial will investigate the effectiveness of granulocyte/macrophage colony stimulating factor (GM-CSF) in improving walking distance for patients with peripheral arterial disease (PAD), specifically those with intermittent claudication who are not suitable for standard invasive treatments.

This double-blind, randomized, placebo-controlled study will involve 40 patients over a 14-day treatment period, with the primary outcome being the change in walking distance measured by an exercise treadmill test, aiming to provide a new therapeutic option for PAD patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design of the START-trial: STimulation of ARTeriogenesis using subcutaneous application of GM-CSF as a new treatment for peripheral vascular disease. A randomized, double-blind, placebo-controlled trial. van Royen, N., Piek, JJ., Legemate, DA., et al.[2017]

The GPAD-3 trial is investigating the efficacy of Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) in improving claudication symptoms in patients with lower extremity peripheral arterial disease (PAD), involving 176 participants in a randomized, double-blind, placebo-controlled Phase IIB study.

The primary goal of the trial is to measure the change in 6-minute walk distance after treatment, which could provide a new therapeutic option for patients who do not respond adequately to existing medical or surgical interventions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rationale and design of the granulocyte-macrophage colony stimulating factor in peripheral arterial disease (GPAD-3) study. Mehta, A., Mavromatis, K., Ko, YA., et al.[2021]

In a study of 39 patients with intractable peripheral artery disease (PAD), treatment with granulocyte colony-stimulating factor (G-CSF) significantly improved clinical symptoms and outcomes, similar to the effects of bone marrow transplantation (BMT).

Both the G-CSF and BMT groups showed significant increases in ankle-brachial pressure index and transcutaneous oxygen pressure, indicating enhanced blood flow and oxygen delivery, while the control group receiving only conventional therapy did not show these improvements.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Granulocyte colony-stimulating factor: a noninvasive regeneration therapy for treating atherosclerotic peripheral artery disease. Arai, M., Misao, Y., Nagai, H., et al.[2022]

In a study involving 210 participants with peripheral artery disease (PAD), supervised treadmill exercise significantly improved walking distance compared to an attention control, highlighting the effectiveness of exercise in enhancing mobility.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) did not show a significant benefit in improving walking ability, whether used alone or in combination with exercise, suggesting it may not be a viable treatment for walking impairment in PAD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Granulocyte-Macrophage Colony-Stimulating Factor With or Without Supervised Exercise on Walking Performance in Patients With Peripheral Artery Disease: The PROPEL Randomized Clinical Trial. McDermott, MM., Ferrucci, L., Tian, L., et al.[2018]

In a double-blinded, randomized, placebo-controlled study of 40 patients with peripheral artery disease, GM-CSF treatment did not show a significant improvement in walking time compared to placebo, indicating it may not be effective for this condition.

While both groups experienced an increase in walking distance after 14 days, GM-CSF did not lead to any changes in ankle-brachial index or microcirculatory flow reserve, suggesting that its effects may differ between coronary and peripheral circulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

START Trial: a pilot study on STimulation of ARTeriogenesis using subcutaneous application of granulocyte-macrophage colony-stimulating factor as a new treatment for peripheral vascular disease. van Royen, N., Schirmer, SH., Atasever, B., et al.[2011]

GM-CSF is effective in preventing or reversing neutropenia, with a recommended dose of 5-10 micrograms/kg/day administered via intravenous infusion or subcutaneous injection, leading to predominantly mild-to-moderate side effects in 20-30% of patients.

High doses of GM-CSF can cause severe adverse effects, including a 'first-dose reaction' in some patients, but with careful monitoring and appropriate dosing, the overall benefit-to-risk ratio has significantly improved.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The side-effect profile of GM-CSF. Stern, AC., Jones, TC.[2019]

In a study analyzing 990 patients treated with sargramostim and matched cohorts receiving filgrastim or pegfilgrastim, sargramostim was associated with a 56% lower risk of infection-related hospitalizations for those undergoing chemotherapy-induced neutropenia.

Patients using sargramostim also experienced significantly lower hospitalization costs, with reductions of 84% compared to filgrastim and 62% compared to pegfilgrastim, highlighting its potential economic benefits in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of hospitalization risk and associated costs among patients receiving sargramostim, filgrastim, and pegfilgrastim for chemotherapy-induced neutropenia. Heaney, ML., Toy, EL., Vekeman, F., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Bone marrow mobilization with granulocyte macrophage colony-stimulating factor improves endothelial dysfunction and exercise capacity in patients with peripheral arterial disease. [2015]

2. England pubmed.ncbi.nlm.nih.gov

Design of the START-trial: STimulation of ARTeriogenesis using subcutaneous application of GM-CSF as a new treatment for peripheral vascular disease. A randomized, double-blind, placebo-controlled trial. [2017]

3. United States pubmed.ncbi.nlm.nih.gov

Rationale and design of the granulocyte-macrophage colony stimulating factor in peripheral arterial disease (GPAD-3) study. [2021]

4. Japan pubmed.ncbi.nlm.nih.gov

Granulocyte colony-stimulating factor: a noninvasive regeneration therapy for treating atherosclerotic peripheral artery disease. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Effect of Granulocyte-Macrophage Colony-Stimulating Factor With or Without Supervised Exercise on Walking Performance in Patients With Peripheral Artery Disease: The PROPEL Randomized Clinical Trial. [2018]

6. United States pubmed.ncbi.nlm.nih.gov

START Trial: a pilot study on STimulation of ARTeriogenesis using subcutaneous application of granulocyte-macrophage colony-stimulating factor as a new treatment for peripheral vascular disease. [2011]

7. Germany pubmed.ncbi.nlm.nih.gov

The side-effect profile of GM-CSF. [2019]

8. United States pubmed.ncbi.nlm.nih.gov

Comparison of hospitalization risk and associated costs among patients receiving sargramostim, filgrastim, and pegfilgrastim for chemotherapy-induced neutropenia. [2022]