IMPORTANCE: Benefits of granulocyte-macrophage colony-stimulating factor (GM-CSF) for improving walking ability in people with lower extremity peripheral artery disease (PAD) are unclear. Walking exercise may augment the effects of GM-CSF in PAD, since exercise-induced ischemia enhances progenitor cell release and may promote progenitor cell homing to ischemic calf muscle. OBJECTIVES: To determine whether GM-CSF combined with supervised treadmill exercise improves 6-minute walk distance, compared with exercise alone and compared with GM-CSF alone; to determine whether GM-CSF alone improves 6-minute walk more than placebo and whether exercise improves 6-minute walk more than an attention control intervention. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial with 2x2 factorial design. Participants were identified from the Chicago metropolitan area and randomized between January 6, 2012, and December 22, 2016, to 1 of 4 groups: supervised exercise plus GM-CSF (exercise+GM-CSF) (n = 53), supervised exercise plus placebo (exercise alone) (n = 53), attention control plus GM-CSF (GM-CSF alone) (n = 53), attention control plus placebo (n = 51). The final follow-up visit was on August 15, 2017. INTERVENTIONS: Supervised exercise consisted of treadmill exercise 3 times weekly for 6 months. The attention control consisted of weekly educational lectures by clinicians for 6 months. GM-CSF (250 micro-g/m2/d) or placebo were administered subcutaneously (double-blinded) 3 times/wk for the first 2 weeks of the intervention. MAIN OUTCOMES AND MEASURES: The primary outcome was change in 6-minute walk distance at 12-week follow-up (minimum clinically important difference, 20 m). P values were adjusted based on the Hochberg step-up method. RESULTS: Of 827 persons evaluated, 210 participants with PAD were randomized (mean age 67.0 (SD 8.6) years; 141 (67%) black, 82 (39%) women). One hundred ninety-five (93%) completed 12-week follow-up. At 12-week follow-up, exercise+GM-CSF did not significantly improve 6-minute walk distance more than exercise alone (mean difference -6.3 m (95% CI -30.2 to +17.6); p = 0.61) or more than GM-CSF alone (mean difference +28.7 m (95% CI +5.1 to +52.3); Hochberg-adjusted p = 0.052). GM-CSF alone did not improve 6-minute walk more than attention control plus placebo (mean difference -1.4 m (95% CI -25.2 to +22.4); p = 0.91). Exercise alone improved 6-minute walk compared with attention control plus placebo (mean difference +33.6 m (95% CI +9.4 to +57.7); Hochberg-adjusted p = 0.02). CONCLUSIONS AND RELEVANCE: Among patients with PAD, supervised treadmill exercise significantly improved 6-minute walk distance compared with attention control plus placebo, whereas GM-CSF did not significantly improve walking performance, either when used alone or when combined with supervised treadmill exercise. These results confirm the benefits of exercise but do not support using GM-CSF to treat walking impairment in patients with PAD. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01408901.

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