Trial Outcomes & Findings for Treadmill Exercise and GM-CSF Study to Improving Functioning in Peripheral Artery Disease (PAD) (NCT NCT01408901)

NCT ID: NCT01408901

Last Updated: 2020-01-21

Results Overview

In the six-minute walk, participants walk back and forth along a 100-ft hallway for six minutes after standardized instructions to complete as many laps as possible. Distance covered in six minutes is recorded.

• Recruitment status: COMPLETED
• Study phase: NA
• Target enrollment: 210 participants
• Primary outcome timeframe: change from baseline to week 12
• Results posted on: 2020-01-21

Participant Flow

Participant milestones

Measure	A: GM-CSF + Supervised Treadmill Exercise Therapy Supervised Treadmill Exercise Therapy: Exercise intervention will be delivered three times weekly for 26 weeks. In the first week, participants will be asked to exercise 15 minutes per session (excluding rest periods). Walking exercise duration will be increased to 25 minutes minutes per session during week 2. Week 3 and 4 sessions will also be 25 minutes long, but the intensity will be increased either to produce leg symptoms or at a target rate of perceived exertion (RPE)of 12-14 on the Borg's 6-20 scale. For weeks 5-8, walking duration will be increased to 40 to 50 minutes while maintaining intensity. For weeks 9-26, exercise duration will continue to be 40 to 50 minutes but we will increase intensity up to a maximum of 4.0 miles per hour at 10% grade. granulocyte macrophage colony stimulating factor (GM-CSF): The dose of GM-CSF will be 250 ug/M\^2 subcutaneously three times weekly for two weeks.	B: GM-CSF + Attention Control Group Health education sessions (Control): Participants randomized to the attention control group will attend weekly one-hour educational sessions at Northwestern University for six months. These educational sessions are on topics of interest to the typical PAD patient and are led by physicians and other health care workers. Topics include Medicare Part D, nutritional supplements, C-reactive protein, and hypertension. Sessions do not include information about exercise. granulocyte macrophage colony stimulating factor (GM-CSF): The dose of GM-CSF will be 250 ug/M\^2 subcutaneously three times weekly for two weeks.	C: Placebo + Supervised Exercise Therapy Supervised Treadmill Exercise Therapy: Exercise intervention will be delivered three times weekly for 26 weeks. In the first week, participants will be asked to exercise 15 minutes per session (excluding rest periods). Walking exercise duration will be increased to 25 minutes minutes per session during week 2. Week 3 and 4 sessions will also be 25 minutes long, but the intensity will be increased either to produce leg symptoms or at a target rate of perceived exertion (RPE)of 12-14 on the Borg's 6-20 scale. For weeks 5-8, walking duration will be increased to 40 to 50 minutes while maintaining intensity. For weeks 9-26, exercise duration will continue to be 40 to 50 minutes but we will increase intensity up to a maximum of 4.0 miles per hour at 10% grade.	D: Placebo + Attention Control Group Health education sessions (Control): Participants randomized to the attention control group will attend weekly one-hour educational sessions at Northwestern University for six months. These educational sessions are on topics of interest to the typical PAD patient and are led by physicians and other health care workers. Topics include Medicare Part D, nutritional supplements, C-reactive protein, and hypertension. Sessions do not include information about exercise.
6-Week Follow-Up STARTED	53	53	53	51
6-Week Follow-Up COMPLETED	50	51	50	47
6-Week Follow-Up NOT COMPLETED	3	2	3	4
12-Week Follow-Up (Primary Endpoint) STARTED	50	52	50	49
12-Week Follow-Up (Primary Endpoint) COMPLETED	49	50	50	46
12-Week Follow-Up (Primary Endpoint) NOT COMPLETED	1	2	0	3
26-Week Follow-Up STARTED	49	52	50	47
26-Week Follow-Up COMPLETED	48	50	50	46
26-Week Follow-Up NOT COMPLETED	1	2	0	1

Reasons for withdrawal

Measure	A: GM-CSF + Supervised Treadmill Exercise Therapy Supervised Treadmill Exercise Therapy: Exercise intervention will be delivered three times weekly for 26 weeks. In the first week, participants will be asked to exercise 15 minutes per session (excluding rest periods). Walking exercise duration will be increased to 25 minutes minutes per session during week 2. Week 3 and 4 sessions will also be 25 minutes long, but the intensity will be increased either to produce leg symptoms or at a target rate of perceived exertion (RPE)of 12-14 on the Borg's 6-20 scale. For weeks 5-8, walking duration will be increased to 40 to 50 minutes while maintaining intensity. For weeks 9-26, exercise duration will continue to be 40 to 50 minutes but we will increase intensity up to a maximum of 4.0 miles per hour at 10% grade. granulocyte macrophage colony stimulating factor (GM-CSF): The dose of GM-CSF will be 250 ug/M\^2 subcutaneously three times weekly for two weeks.	B: GM-CSF + Attention Control Group Health education sessions (Control): Participants randomized to the attention control group will attend weekly one-hour educational sessions at Northwestern University for six months. These educational sessions are on topics of interest to the typical PAD patient and are led by physicians and other health care workers. Topics include Medicare Part D, nutritional supplements, C-reactive protein, and hypertension. Sessions do not include information about exercise. granulocyte macrophage colony stimulating factor (GM-CSF): The dose of GM-CSF will be 250 ug/M\^2 subcutaneously three times weekly for two weeks.	C: Placebo + Supervised Exercise Therapy Supervised Treadmill Exercise Therapy: Exercise intervention will be delivered three times weekly for 26 weeks. In the first week, participants will be asked to exercise 15 minutes per session (excluding rest periods). Walking exercise duration will be increased to 25 minutes minutes per session during week 2. Week 3 and 4 sessions will also be 25 minutes long, but the intensity will be increased either to produce leg symptoms or at a target rate of perceived exertion (RPE)of 12-14 on the Borg's 6-20 scale. For weeks 5-8, walking duration will be increased to 40 to 50 minutes while maintaining intensity. For weeks 9-26, exercise duration will continue to be 40 to 50 minutes but we will increase intensity up to a maximum of 4.0 miles per hour at 10% grade.	D: Placebo + Attention Control Group Health education sessions (Control): Participants randomized to the attention control group will attend weekly one-hour educational sessions at Northwestern University for six months. These educational sessions are on topics of interest to the typical PAD patient and are led by physicians and other health care workers. Topics include Medicare Part D, nutritional supplements, C-reactive protein, and hypertension. Sessions do not include information about exercise.
6-Week Follow-Up Lost to Follow-up	2	1	3	2
6-Week Follow-Up Death	1	0	0	0
6-Week Follow-Up Cancelled visit	0	1	0	2
12-Week Follow-Up (Primary Endpoint) Lost to Follow-up	0	0	0	2
12-Week Follow-Up (Primary Endpoint) Death	1	0	0	0
12-Week Follow-Up (Primary Endpoint) Cancelled visit	0	2	0	1
26-Week Follow-Up Lost to Follow-up	1	1	0	1
26-Week Follow-Up Death	0	1	0	0

Baseline Characteristics

Treadmill Exercise and GM-CSF Study to Improving Functioning in Peripheral Artery Disease (PAD)

Baseline characteristics by cohort

Measure	A: GM-CSF + Supervised Treadmill Exercise Therapy n=53 Participants Supervised Treadmill Exercise Therapy: Exercise intervention will be delivered three times weekly for 26 weeks. In the first week, participants will be asked to exercise 15 minutes per session (excluding rest periods). Walking exercise duration will be increased to 25 minutes minutes per session during week 2. Week 3 and 4 sessions will also be 25 minutes long, but the intensity will be increased either to produce leg symptoms or at a target rate of perceived exertion (RPE)of 12-14 on the Borg's 6-20 scale. For weeks 5-8, walking duration will be increased to 40 to 50 minutes while maintaining intensity. For weeks 9-26, exercise duration will continue to be 40 to 50 minutes but we will increase intensity up to a maximum of 4.0 miles per hour at 10% grade. granulocyte macrophage colony stimulating factor (GM-CSF): The dose of GM-CSF will be 250 ug/M\^2 subcutaneously three times weekly for two weeks.	B: GM-CSF + Attention Control Group n=53 Participants Health education sessions (Control): Participants randomized to the attention control group will attend weekly one-hour educational sessions at Northwestern University for six months. These educational sessions are on topics of interest to the typical PAD patient and are led by physicians and other health care workers. Topics include Medicare Part D, nutritional supplements, C-reactive protein, and hypertension. Sessions do not include information about exercise. granulocyte macrophage colony stimulating factor (GM-CSF): The dose of GM-CSF will be 250 ug/M\^2 subcutaneously three times weekly for two weeks.	C: Placebo + Supervised Exercise Therapy n=53 Participants Supervised Treadmill Exercise Therapy: Exercise intervention will be delivered three times weekly for 26 weeks. In the first week, participants will be asked to exercise 15 minutes per session (excluding rest periods). Walking exercise duration will be increased to 25 minutes minutes per session during week 2. Week 3 and 4 sessions will also be 25 minutes long, but the intensity will be increased either to produce leg symptoms or at a target rate of perceived exertion (RPE)of 12-14 on the Borg's 6-20 scale. For weeks 5-8, walking duration will be increased to 40 to 50 minutes while maintaining intensity. For weeks 9-26, exercise duration will continue to be 40 to 50 minutes but we will increase intensity up to a maximum of 4.0 miles per hour at 10% grade.	D: Placebo + Attention Control Group n=51 Participants Health education sessions (Control): Participants randomized to the attention control group will attend weekly one-hour educational sessions at Northwestern University for six months. These educational sessions are on topics of interest to the typical PAD patient and are led by physicians and other health care workers. Topics include Medicare Part D, nutritional supplements, C-reactive protein, and hypertension. Sessions do not include information about exercise.	Total n=210 Participants Total of all reporting groups
Age, Continuous	66.6 years STANDARD_DEVIATION 9.5 • n=5 Participants	67.9 years STANDARD_DEVIATION 7.5 • n=7 Participants	67.5 years STANDARD_DEVIATION 8.7 • n=5 Participants	66.0 years STANDARD_DEVIATION 8.6 • n=4 Participants	67.0 years STANDARD_DEVIATION 8.6 • n=21 Participants
Sex: Female, Male Female	20 Participants n=5 Participants	19 Participants n=7 Participants	23 Participants n=5 Participants	20 Participants n=4 Participants	82 Participants n=21 Participants
Sex: Female, Male Male	33 Participants n=5 Participants	34 Participants n=7 Participants	30 Participants n=5 Participants	31 Participants n=4 Participants	128 Participants n=21 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants	3 Participants n=4 Participants	9 Participants n=21 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	51 Participants n=5 Participants	51 Participants n=7 Participants	51 Participants n=5 Participants	48 Participants n=4 Participants	201 Participants n=21 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants	2 Participants n=21 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	2 Participants n=21 Participants
Race (NIH/OMB) Black or African American	35 Participants n=5 Participants	35 Participants n=7 Participants	33 Participants n=5 Participants	38 Participants n=4 Participants	141 Participants n=21 Participants
Race (NIH/OMB) White	18 Participants n=5 Participants	16 Participants n=7 Participants	19 Participants n=5 Participants	11 Participants n=4 Participants	64 Participants n=21 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Ankle-brachial index (ABI)	0.70 ratio STANDARD_DEVIATION 0.20 • n=5 Participants	0.71 ratio STANDARD_DEVIATION 0.17 • n=7 Participants	0.69 ratio STANDARD_DEVIATION 0.19 • n=5 Participants	0.69 ratio STANDARD_DEVIATION 0.19 • n=4 Participants	0.70 ratio STANDARD_DEVIATION 0.19 • n=21 Participants
Body Mass Index (BMI)	29.7 kg/m^2 STANDARD_DEVIATION 6.5 • n=5 Participants	30.7 kg/m^2 STANDARD_DEVIATION 6.9 • n=7 Participants	31.7 kg/m^2 STANDARD_DEVIATION 6.0 • n=5 Participants	29.9 kg/m^2 STANDARD_DEVIATION 6.8 • n=4 Participants	30.5 kg/m^2 STANDARD_DEVIATION 6.6 • n=21 Participants
Six-minute walk distance	336.4 meters STANDARD_DEVIATION 109.5 • n=5 Participants	339.8 meters STANDARD_DEVIATION 101.0 • n=7 Participants	338.7 meters STANDARD_DEVIATION 95.6 • n=5 Participants	339.1 meters STANDARD_DEVIATION 92.0 • n=4 Participants	338.5 meters STANDARD_DEVIATION 99.1 • n=21 Participants

PRIMARY outcome

Timeframe: change from baseline to week 12

Population: Data were imputed for participants who were lost to follow-up or who canceled the visit. Variables used for imputation were age, ankle brachial index, body mass index, sex, race, smoking status, baseline outcome values, leg symptoms, and comorbidities. SAS procedure MI was used to obtain 20 imputed data sets.

In the six-minute walk, participants walk back and forth along a 100-ft hallway for six minutes after standardized instructions to complete as many laps as possible. Distance covered in six minutes is recorded.

Outcome measures

Measure	A: GM-CSF + Supervised Treadmill Exercise Therapy n=51 Participants Supervised Treadmill Exercise Therapy: Exercise intervention will be delivered three times weekly for 26 weeks. In the first week, participants will be asked to exercise 15 minutes per session (excluding rest periods). Walking exercise duration will be increased to 25 minutes minutes per session during week 2. Week 3 and 4 sessions will also be 25 minutes long, but the intensity will be increased either to produce leg symptoms or at a target rate of perceived exertion (RPE)of 12-14 on the Borg's 6-20 scale. For weeks 5-8, walking duration will be increased to 40 to 50 minutes while maintaining intensity. For weeks 9-26, exercise duration will continue to be 40 to 50 minutes but we will increase intensity up to a maximum of 4.0 miles per hour at 10% grade. granulocyte macrophage colony stimulating factor (GM-CSF): The dose of GM-CSF will be 250 ug/M\^2 subcutaneously three times weekly for two weeks.	B: GM-CSF + Attention Control Group n=53 Participants Health education sessions (Control): Participants randomized to the attention control group will attend weekly one-hour educational sessions at Northwestern University for six months. These educational sessions are on topics of interest to the typical PAD patient and are led by physicians and other health care workers. Topics include Medicare Part D, nutritional supplements, C-reactive protein, and hypertension. Sessions do not include information about exercise. granulocyte macrophage colony stimulating factor (GM-CSF): The dose of GM-CSF will be 250 ug/M\^2 subcutaneously three times weekly for two weeks.	C: Placebo + Supervised Exercise Therapy n=53 Participants Supervised Treadmill Exercise Therapy: Exercise intervention will be delivered three times weekly for 26 weeks. In the first week, participants will be asked to exercise 15 minutes per session (excluding rest periods). Walking exercise duration will be increased to 25 minutes minutes per session during week 2. Week 3 and 4 sessions will also be 25 minutes long, but the intensity will be increased either to produce leg symptoms or at a target rate of perceived exertion (RPE)of 12-14 on the Borg's 6-20 scale. For weeks 5-8, walking duration will be increased to 40 to 50 minutes while maintaining intensity. For weeks 9-26, exercise duration will continue to be 40 to 50 minutes but we will increase intensity up to a maximum of 4.0 miles per hour at 10% grade.	D: Placebo + Attention Control Group n=51 Participants Health education sessions (Control): Participants randomized to the attention control group will attend weekly one-hour educational sessions at Northwestern University for six months. These educational sessions are on topics of interest to the typical PAD patient and are led by physicians and other health care workers. Topics include Medicare Part D, nutritional supplements, C-reactive protein, and hypertension. Sessions do not include information about exercise.
Change in Six-Minute Walk Performance at 12-week Follow-up	22.2 meters Interval 5.4 to 39.0	-6.4 meters Interval -23.0 to 10.1	28.5 meters Interval 11.7 to 45.4	-5.0 meters Interval -22.3 to 12.2

SECONDARY outcome

Timeframe: change from baseline to week 12

Population: Data were imputed for participants who were lost to follow-up or who canceled the visit. Variables used for imputation were age, ankle brachial index, body mass index, sex, race, smoking status, baseline outcome values, leg symptoms, and comorbidities. SAS procedure MI was used to obtain 20 imputed data sets.

The brachial artery is imaged 5 to 9 cm above the antecubital fossa using a linear array vascular ultrasound transducer. Three video sequences are obtained. The first verifies the location and baseline hemodynamic state of the brachial artery. The second begins 20 seconds before cuff inflation and continues for 10 seconds after inflation. The third begins 15 seconds before cuff release and continues for 90 seconds after deflation. Brachial artery FMD is calculated as the percent change in brachial artery diameter at 60 seconds and at 90 seconds after the release of the cuff.

Outcome measures

Measure	A: GM-CSF + Supervised Treadmill Exercise Therapy n=51 Participants Supervised Treadmill Exercise Therapy: Exercise intervention will be delivered three times weekly for 26 weeks. In the first week, participants will be asked to exercise 15 minutes per session (excluding rest periods). Walking exercise duration will be increased to 25 minutes minutes per session during week 2. Week 3 and 4 sessions will also be 25 minutes long, but the intensity will be increased either to produce leg symptoms or at a target rate of perceived exertion (RPE)of 12-14 on the Borg's 6-20 scale. For weeks 5-8, walking duration will be increased to 40 to 50 minutes while maintaining intensity. For weeks 9-26, exercise duration will continue to be 40 to 50 minutes but we will increase intensity up to a maximum of 4.0 miles per hour at 10% grade. granulocyte macrophage colony stimulating factor (GM-CSF): The dose of GM-CSF will be 250 ug/M\^2 subcutaneously three times weekly for two weeks.	B: GM-CSF + Attention Control Group n=53 Participants Health education sessions (Control): Participants randomized to the attention control group will attend weekly one-hour educational sessions at Northwestern University for six months. These educational sessions are on topics of interest to the typical PAD patient and are led by physicians and other health care workers. Topics include Medicare Part D, nutritional supplements, C-reactive protein, and hypertension. Sessions do not include information about exercise. granulocyte macrophage colony stimulating factor (GM-CSF): The dose of GM-CSF will be 250 ug/M\^2 subcutaneously three times weekly for two weeks.	C: Placebo + Supervised Exercise Therapy n=53 Participants Supervised Treadmill Exercise Therapy: Exercise intervention will be delivered three times weekly for 26 weeks. In the first week, participants will be asked to exercise 15 minutes per session (excluding rest periods). Walking exercise duration will be increased to 25 minutes minutes per session during week 2. Week 3 and 4 sessions will also be 25 minutes long, but the intensity will be increased either to produce leg symptoms or at a target rate of perceived exertion (RPE)of 12-14 on the Borg's 6-20 scale. For weeks 5-8, walking duration will be increased to 40 to 50 minutes while maintaining intensity. For weeks 9-26, exercise duration will continue to be 40 to 50 minutes but we will increase intensity up to a maximum of 4.0 miles per hour at 10% grade.	D: Placebo + Attention Control Group n=51 Participants Health education sessions (Control): Participants randomized to the attention control group will attend weekly one-hour educational sessions at Northwestern University for six months. These educational sessions are on topics of interest to the typical PAD patient and are led by physicians and other health care workers. Topics include Medicare Part D, nutritional supplements, C-reactive protein, and hypertension. Sessions do not include information about exercise.
Change in Brachial Artery Flow-mediated Dilation (FMD) at 12-week Follow-up	-0.37 percent change Interval -2.5 to 1.28	0.10 percent change Interval -1.49 to 1.18	0.14 percent change Interval -1.53 to 1.5	-0.72 percent change Interval -2.02 to 1.64

SECONDARY outcome

Timeframe: change from baseline to week 12

Population: Data were imputed for participants who were lost to follow-up or who canceled the visit. Variables used for imputation were age, ankle brachial index, body mass index, sex, race, smoking status, baseline outcome values, leg symptoms, and comorbidities. SAS procedure MI was used to obtain 20 imputed data sets.

The Gardner graded treadmill exercise test is the standard, accepted treadmill protocol for measuring change in maximal treadmill walking time in response to interventions among PAD participants. In the Gardner exercise protocol, speed is maintained at 2.0 miles per hour (mph) and treadmill grade increases by 2.0% every two minutes. If patients cannot begin walking at 2.0 mph, treadmill speed is started at 0.50 mph and increased by 0.50 mph every 2 minutes until the participant reaches 2.0 mph, after which the treadmill grade is increased every two minutes.

Outcome measures

Measure	A: GM-CSF + Supervised Treadmill Exercise Therapy n=51 Participants Supervised Treadmill Exercise Therapy: Exercise intervention will be delivered three times weekly for 26 weeks. In the first week, participants will be asked to exercise 15 minutes per session (excluding rest periods). Walking exercise duration will be increased to 25 minutes minutes per session during week 2. Week 3 and 4 sessions will also be 25 minutes long, but the intensity will be increased either to produce leg symptoms or at a target rate of perceived exertion (RPE)of 12-14 on the Borg's 6-20 scale. For weeks 5-8, walking duration will be increased to 40 to 50 minutes while maintaining intensity. For weeks 9-26, exercise duration will continue to be 40 to 50 minutes but we will increase intensity up to a maximum of 4.0 miles per hour at 10% grade. granulocyte macrophage colony stimulating factor (GM-CSF): The dose of GM-CSF will be 250 ug/M\^2 subcutaneously three times weekly for two weeks.	B: GM-CSF + Attention Control Group n=53 Participants Health education sessions (Control): Participants randomized to the attention control group will attend weekly one-hour educational sessions at Northwestern University for six months. These educational sessions are on topics of interest to the typical PAD patient and are led by physicians and other health care workers. Topics include Medicare Part D, nutritional supplements, C-reactive protein, and hypertension. Sessions do not include information about exercise. granulocyte macrophage colony stimulating factor (GM-CSF): The dose of GM-CSF will be 250 ug/M\^2 subcutaneously three times weekly for two weeks.	C: Placebo + Supervised Exercise Therapy n=53 Participants Supervised Treadmill Exercise Therapy: Exercise intervention will be delivered three times weekly for 26 weeks. In the first week, participants will be asked to exercise 15 minutes per session (excluding rest periods). Walking exercise duration will be increased to 25 minutes minutes per session during week 2. Week 3 and 4 sessions will also be 25 minutes long, but the intensity will be increased either to produce leg symptoms or at a target rate of perceived exertion (RPE)of 12-14 on the Borg's 6-20 scale. For weeks 5-8, walking duration will be increased to 40 to 50 minutes while maintaining intensity. For weeks 9-26, exercise duration will continue to be 40 to 50 minutes but we will increase intensity up to a maximum of 4.0 miles per hour at 10% grade.	D: Placebo + Attention Control Group n=51 Participants Health education sessions (Control): Participants randomized to the attention control group will attend weekly one-hour educational sessions at Northwestern University for six months. These educational sessions are on topics of interest to the typical PAD patient and are led by physicians and other health care workers. Topics include Medicare Part D, nutritional supplements, C-reactive protein, and hypertension. Sessions do not include information about exercise.
Change in Maximal Treadmill Walking Time at 12-week Follow-up	3.5 minutes Interval 2.5 to 4.5	-0.1 minutes Interval -1.1 to 0.9	4.2 minutes Interval 3.2 to 5.2	0.5 minutes Interval -0.6 to 1.6

SECONDARY outcome

Timeframe: change from baseline to week 12

Population: Note: It is pre-specified in the study protocol that investigators will determine whether a supervised treadmill exercise intervention alone (Group C) is associated with greater increases in CD34+ cells at 12-week follow-up, compared to Group D. Therefore, only group C and group D are included here.

Red blood cells are lysed twice with freshly prepared lysis buffer. Remaining cells are stained with LIVE/DEAD® Fixable Dead Cell Stains for 20 minutes at room temperature and Fc receptors are blocked by incubating with Fc receptor blocking reagent for 10 minutes at 4oC. Samples are then stained with the following antibody cocktail for 30 minutes at 4oC: CD34 VioBlue, CD133-APC , CD45 AlexaFluor 700, and CD31 (PECAM-1) APC-eFluor® 780. Stained samples are acquired using a BD LSRII and analyzed using Flowjo software.

The outcome is the absolute change in the percentages of cells.

Outcome measures

Measure	A: GM-CSF + Supervised Treadmill Exercise Therapy n=48 Participants Supervised Treadmill Exercise Therapy: Exercise intervention will be delivered three times weekly for 26 weeks. In the first week, participants will be asked to exercise 15 minutes per session (excluding rest periods). Walking exercise duration will be increased to 25 minutes minutes per session during week 2. Week 3 and 4 sessions will also be 25 minutes long, but the intensity will be increased either to produce leg symptoms or at a target rate of perceived exertion (RPE)of 12-14 on the Borg's 6-20 scale. For weeks 5-8, walking duration will be increased to 40 to 50 minutes while maintaining intensity. For weeks 9-26, exercise duration will continue to be 40 to 50 minutes but we will increase intensity up to a maximum of 4.0 miles per hour at 10% grade. granulocyte macrophage colony stimulating factor (GM-CSF): The dose of GM-CSF will be 250 ug/M\^2 subcutaneously three times weekly for two weeks.	B: GM-CSF + Attention Control Group n=43 Participants Health education sessions (Control): Participants randomized to the attention control group will attend weekly one-hour educational sessions at Northwestern University for six months. These educational sessions are on topics of interest to the typical PAD patient and are led by physicians and other health care workers. Topics include Medicare Part D, nutritional supplements, C-reactive protein, and hypertension. Sessions do not include information about exercise. granulocyte macrophage colony stimulating factor (GM-CSF): The dose of GM-CSF will be 250 ug/M\^2 subcutaneously three times weekly for two weeks.	C: Placebo + Supervised Exercise Therapy Supervised Treadmill Exercise Therapy: Exercise intervention will be delivered three times weekly for 26 weeks. In the first week, participants will be asked to exercise 15 minutes per session (excluding rest periods). Walking exercise duration will be increased to 25 minutes minutes per session during week 2. Week 3 and 4 sessions will also be 25 minutes long, but the intensity will be increased either to produce leg symptoms or at a target rate of perceived exertion (RPE)of 12-14 on the Borg's 6-20 scale. For weeks 5-8, walking duration will be increased to 40 to 50 minutes while maintaining intensity. For weeks 9-26, exercise duration will continue to be 40 to 50 minutes but we will increase intensity up to a maximum of 4.0 miles per hour at 10% grade.	D: Placebo + Attention Control Group Health education sessions (Control): Participants randomized to the attention control group will attend weekly one-hour educational sessions at Northwestern University for six months. These educational sessions are on topics of interest to the typical PAD patient and are led by physicians and other health care workers. Topics include Medicare Part D, nutritional supplements, C-reactive protein, and hypertension. Sessions do not include information about exercise.
Change in CD34_CD45lo at 12-week Follow-up	-0.002 percentage of cells Interval -0.006 to 0.003	0.004 percentage of cells Interval -0.001 to 0.008	—	—

SECONDARY outcome

Timeframe: change from baseline to week 12

Population: Note: It is pre-specified in the study protocol that investigators will determine whether a supervised treadmill exercise intervention alone (Group C) is associated with greater increases in CD34+ cells at 12-week follow-up, compared to Group D. Therefore, only group C and group D are included here.

Red blood cells are lysed twice with freshly prepared lysis buffer. Remaining cells are stained with LIVE/DEAD® Fixable Dead Cell Stains for 20 minutes at room temperature and Fc receptors are blocked by incubating with Fc receptor blocking reagent for 10 minutes at 4oC. Samples are then stained with the following antibody cocktail for 30 minutes at 4oC: CD34 VioBlue, CD133-APC , CD45 AlexaFluor 700, and CD31 (PECAM-1) APC-eFluor® 780. Stained samples are acquired using a BD LSRII and analyzed using Flowjo software.

The outcome is the absolute change in the percentages of cells.

Outcome measures

Measure	A: GM-CSF + Supervised Treadmill Exercise Therapy n=48 Participants Supervised Treadmill Exercise Therapy: Exercise intervention will be delivered three times weekly for 26 weeks. In the first week, participants will be asked to exercise 15 minutes per session (excluding rest periods). Walking exercise duration will be increased to 25 minutes minutes per session during week 2. Week 3 and 4 sessions will also be 25 minutes long, but the intensity will be increased either to produce leg symptoms or at a target rate of perceived exertion (RPE)of 12-14 on the Borg's 6-20 scale. For weeks 5-8, walking duration will be increased to 40 to 50 minutes while maintaining intensity. For weeks 9-26, exercise duration will continue to be 40 to 50 minutes but we will increase intensity up to a maximum of 4.0 miles per hour at 10% grade. granulocyte macrophage colony stimulating factor (GM-CSF): The dose of GM-CSF will be 250 ug/M\^2 subcutaneously three times weekly for two weeks.	B: GM-CSF + Attention Control Group n=43 Participants Health education sessions (Control): Participants randomized to the attention control group will attend weekly one-hour educational sessions at Northwestern University for six months. These educational sessions are on topics of interest to the typical PAD patient and are led by physicians and other health care workers. Topics include Medicare Part D, nutritional supplements, C-reactive protein, and hypertension. Sessions do not include information about exercise. granulocyte macrophage colony stimulating factor (GM-CSF): The dose of GM-CSF will be 250 ug/M\^2 subcutaneously three times weekly for two weeks.	C: Placebo + Supervised Exercise Therapy Supervised Treadmill Exercise Therapy: Exercise intervention will be delivered three times weekly for 26 weeks. In the first week, participants will be asked to exercise 15 minutes per session (excluding rest periods). Walking exercise duration will be increased to 25 minutes minutes per session during week 2. Week 3 and 4 sessions will also be 25 minutes long, but the intensity will be increased either to produce leg symptoms or at a target rate of perceived exertion (RPE)of 12-14 on the Borg's 6-20 scale. For weeks 5-8, walking duration will be increased to 40 to 50 minutes while maintaining intensity. For weeks 9-26, exercise duration will continue to be 40 to 50 minutes but we will increase intensity up to a maximum of 4.0 miles per hour at 10% grade.	D: Placebo + Attention Control Group Health education sessions (Control): Participants randomized to the attention control group will attend weekly one-hour educational sessions at Northwestern University for six months. These educational sessions are on topics of interest to the typical PAD patient and are led by physicians and other health care workers. Topics include Medicare Part D, nutritional supplements, C-reactive protein, and hypertension. Sessions do not include information about exercise.
Change in CD34_CD45loCD133_ at 12-week Follow-up	-0.002 percentage of cells Interval -0.005 to 0.002	0.004 percentage of cells Interval 0.0 to 0.007	—	—

SECONDARY outcome

Timeframe: change from baseline to week 12

Population: Note: It is pre-specified in the study protocol that investigators will determine whether a supervised treadmill exercise intervention alone (Group C) is associated with greater increases in CD34+ cells at 12-week follow-up, compared to Group D. Therefore, only group C and group D are included here.

Red blood cells are lysed twice with freshly prepared lysis buffer. Remaining cells are stained with LIVE/DEAD® Fixable Dead Cell Stains for 20 minutes at room temperature and Fc receptors are blocked by incubating with Fc receptor blocking reagent for 10 minutes at 4oC. Samples are then stained with the following antibody cocktail for 30 minutes at 4oC: CD34 VioBlue, CD133-APC , CD45 AlexaFluor 700, and CD31 (PECAM-1) APC-eFluor® 780. Stained samples are acquired using a BD LSRII and analyzed using Flowjo software.

The outcome is the absolute change in the percentages of cells.

Outcome measures

Measure	A: GM-CSF + Supervised Treadmill Exercise Therapy n=35 Participants Supervised Treadmill Exercise Therapy: Exercise intervention will be delivered three times weekly for 26 weeks. In the first week, participants will be asked to exercise 15 minutes per session (excluding rest periods). Walking exercise duration will be increased to 25 minutes minutes per session during week 2. Week 3 and 4 sessions will also be 25 minutes long, but the intensity will be increased either to produce leg symptoms or at a target rate of perceived exertion (RPE)of 12-14 on the Borg's 6-20 scale. For weeks 5-8, walking duration will be increased to 40 to 50 minutes while maintaining intensity. For weeks 9-26, exercise duration will continue to be 40 to 50 minutes but we will increase intensity up to a maximum of 4.0 miles per hour at 10% grade. granulocyte macrophage colony stimulating factor (GM-CSF): The dose of GM-CSF will be 250 ug/M\^2 subcutaneously three times weekly for two weeks.	B: GM-CSF + Attention Control Group n=30 Participants Health education sessions (Control): Participants randomized to the attention control group will attend weekly one-hour educational sessions at Northwestern University for six months. These educational sessions are on topics of interest to the typical PAD patient and are led by physicians and other health care workers. Topics include Medicare Part D, nutritional supplements, C-reactive protein, and hypertension. Sessions do not include information about exercise. granulocyte macrophage colony stimulating factor (GM-CSF): The dose of GM-CSF will be 250 ug/M\^2 subcutaneously three times weekly for two weeks.	C: Placebo + Supervised Exercise Therapy Supervised Treadmill Exercise Therapy: Exercise intervention will be delivered three times weekly for 26 weeks. In the first week, participants will be asked to exercise 15 minutes per session (excluding rest periods). Walking exercise duration will be increased to 25 minutes minutes per session during week 2. Week 3 and 4 sessions will also be 25 minutes long, but the intensity will be increased either to produce leg symptoms or at a target rate of perceived exertion (RPE)of 12-14 on the Borg's 6-20 scale. For weeks 5-8, walking duration will be increased to 40 to 50 minutes while maintaining intensity. For weeks 9-26, exercise duration will continue to be 40 to 50 minutes but we will increase intensity up to a maximum of 4.0 miles per hour at 10% grade.	D: Placebo + Attention Control Group Health education sessions (Control): Participants randomized to the attention control group will attend weekly one-hour educational sessions at Northwestern University for six months. These educational sessions are on topics of interest to the typical PAD patient and are led by physicians and other health care workers. Topics include Medicare Part D, nutritional supplements, C-reactive protein, and hypertension. Sessions do not include information about exercise.
Change in CD34_CD45lo_CD31_ at 12-week Follow-up	-0.003 percentage of cells Interval -0.007 to 0.001	0.002 percentage of cells Interval -0.002 to 0.007	—	—

SECONDARY outcome

Timeframe: change from baseline to week 12

Population: Note: It is pre-specified in the study protocol that investigators will determine whether a supervised treadmill exercise intervention alone (Group C) is associated with greater increases in CD34+ cells at 12-week follow-up, compared to Group D. Therefore, only group C and group D are included here.

Red blood cells are lysed twice with freshly prepared lysis buffer. Remaining cells are stained with LIVE/DEAD® Fixable Dead Cell Stains for 20 minutes at room temperature and Fc receptors are blocked by incubating with Fc receptor blocking reagent for 10 minutes at 4oC. Samples are then stained with the following antibody cocktail for 30 minutes at 4oC: CD34 VioBlue, CD133-APC , CD45 AlexaFluor 700, and CD31 (PECAM-1) APC-eFluor® 780. Stained samples are acquired using a BD LSRII and analyzed using Flowjo software.

The outcome is the absolute change in the percentages of cells.

Outcome measures

Measure	A: GM-CSF + Supervised Treadmill Exercise Therapy n=35 Participants Supervised Treadmill Exercise Therapy: Exercise intervention will be delivered three times weekly for 26 weeks. In the first week, participants will be asked to exercise 15 minutes per session (excluding rest periods). Walking exercise duration will be increased to 25 minutes minutes per session during week 2. Week 3 and 4 sessions will also be 25 minutes long, but the intensity will be increased either to produce leg symptoms or at a target rate of perceived exertion (RPE)of 12-14 on the Borg's 6-20 scale. For weeks 5-8, walking duration will be increased to 40 to 50 minutes while maintaining intensity. For weeks 9-26, exercise duration will continue to be 40 to 50 minutes but we will increase intensity up to a maximum of 4.0 miles per hour at 10% grade. granulocyte macrophage colony stimulating factor (GM-CSF): The dose of GM-CSF will be 250 ug/M\^2 subcutaneously three times weekly for two weeks.	B: GM-CSF + Attention Control Group n=30 Participants Health education sessions (Control): Participants randomized to the attention control group will attend weekly one-hour educational sessions at Northwestern University for six months. These educational sessions are on topics of interest to the typical PAD patient and are led by physicians and other health care workers. Topics include Medicare Part D, nutritional supplements, C-reactive protein, and hypertension. Sessions do not include information about exercise. granulocyte macrophage colony stimulating factor (GM-CSF): The dose of GM-CSF will be 250 ug/M\^2 subcutaneously three times weekly for two weeks.	C: Placebo + Supervised Exercise Therapy Supervised Treadmill Exercise Therapy: Exercise intervention will be delivered three times weekly for 26 weeks. In the first week, participants will be asked to exercise 15 minutes per session (excluding rest periods). Walking exercise duration will be increased to 25 minutes minutes per session during week 2. Week 3 and 4 sessions will also be 25 minutes long, but the intensity will be increased either to produce leg symptoms or at a target rate of perceived exertion (RPE)of 12-14 on the Borg's 6-20 scale. For weeks 5-8, walking duration will be increased to 40 to 50 minutes while maintaining intensity. For weeks 9-26, exercise duration will continue to be 40 to 50 minutes but we will increase intensity up to a maximum of 4.0 miles per hour at 10% grade.	D: Placebo + Attention Control Group Health education sessions (Control): Participants randomized to the attention control group will attend weekly one-hour educational sessions at Northwestern University for six months. These educational sessions are on topics of interest to the typical PAD patient and are led by physicians and other health care workers. Topics include Medicare Part D, nutritional supplements, C-reactive protein, and hypertension. Sessions do not include information about exercise.
Change in CD34_CD45lo_CD31_CD133_ at 12-week Follow-up	-0.003 percentage of cells Interval -0.006 to 0.001	0.001 percentage of cells Interval -0.003 to 0.005	—	—

Adverse Events

A: GM-CSF + Supervised Treadmill Exercise Therapy

Serious events: 17 serious events

Other events: 52 other events

Deaths: 2 deaths

B: GM-CSF + Attention Control Group

Serious events: 13 serious events

Other events: 49 other events

Deaths: 1 deaths

C: Placebo + Supervised Exercise Therapy

Serious events: 9 serious events

Other events: 50 other events

Deaths: 0 deaths

D: Placebo + Attention Control Group

Serious events: 12 serious events

Other events: 48 other events

Deaths: 0 deaths

Serious adverse events

Measure	A: GM-CSF + Supervised Treadmill Exercise Therapy n=53 participants at risk Supervised Treadmill Exercise Therapy: Exercise intervention will be delivered three times weekly for 26 weeks. In the first week, participants will be asked to exercise 15 minutes per session (excluding rest periods). Walking exercise duration will be increased to 25 minutes minutes per session during week 2. Week 3 and 4 sessions will also be 25 minutes long, but the intensity will be increased either to produce leg symptoms or at a target rate of perceived exertion (RPE)of 12-14 on the Borg's 6-20 scale. For weeks 5-8, walking duration will be increased to 40 to 50 minutes while maintaining intensity. For weeks 9-26, exercise duration will continue to be 40 to 50 minutes but we will increase intensity up to a maximum of 4.0 miles per hour at 10% grade. granulocyte macrophage colony stimulating factor (GM-CSF): The dose of GM-CSF will be 250 ug/M\^2 subcutaneously three times weekly for two weeks.	B: GM-CSF + Attention Control Group n=53 participants at risk Health education sessions (Control): Participants randomized to the attention control group will attend weekly one-hour educational sessions at Northwestern University for six months. These educational sessions are on topics of interest to the typical PAD patient and are led by physicians and other health care workers. Topics include Medicare Part D, nutritional supplements, C-reactive protein, and hypertension. Sessions do not include information about exercise. granulocyte macrophage colony stimulating factor (GM-CSF): The dose of GM-CSF will be 250 ug/M\^2 subcutaneously three times weekly for two weeks.	C: Placebo + Supervised Exercise Therapy n=53 participants at risk Supervised Treadmill Exercise Therapy: Exercise intervention will be delivered three times weekly for 26 weeks. In the first week, participants will be asked to exercise 15 minutes per session (excluding rest periods). Walking exercise duration will be increased to 25 minutes minutes per session during week 2. Week 3 and 4 sessions will also be 25 minutes long, but the intensity will be increased either to produce leg symptoms or at a target rate of perceived exertion (RPE)of 12-14 on the Borg's 6-20 scale. For weeks 5-8, walking duration will be increased to 40 to 50 minutes while maintaining intensity. For weeks 9-26, exercise duration will continue to be 40 to 50 minutes but we will increase intensity up to a maximum of 4.0 miles per hour at 10% grade.	D: Placebo + Attention Control Group n=51 participants at risk Health education sessions (Control): Participants randomized to the attention control group will attend weekly one-hour educational sessions at Northwestern University for six months. These educational sessions are on topics of interest to the typical PAD patient and are led by physicians and other health care workers. Topics include Medicare Part D, nutritional supplements, C-reactive protein, and hypertension. Sessions do not include information about exercise.
Cardiac disorders Cardiovascular event	7.5% 4/53 • Number of events 4 • Adverse event data was collected between randomization and final 26-week follow-up.	9.4% 5/53 • Number of events 6 • Adverse event data was collected between randomization and final 26-week follow-up.	3.8% 2/53 • Number of events 2 • Adverse event data was collected between randomization and final 26-week follow-up.	5.9% 3/51 • Number of events 3 • Adverse event data was collected between randomization and final 26-week follow-up.
Endocrine disorders Diabetes	1.9% 1/53 • Number of events 3 • Adverse event data was collected between randomization and final 26-week follow-up.	0.00% 0/53 • Adverse event data was collected between randomization and final 26-week follow-up.	0.00% 0/53 • Adverse event data was collected between randomization and final 26-week follow-up.	0.00% 0/51 • Adverse event data was collected between randomization and final 26-week follow-up.
Gastrointestinal disorders Gastrointestinal bleeding	0.00% 0/53 • Adverse event data was collected between randomization and final 26-week follow-up.	1.9% 1/53 • Number of events 1 • Adverse event data was collected between randomization and final 26-week follow-up.	0.00% 0/53 • Adverse event data was collected between randomization and final 26-week follow-up.	0.00% 0/51 • Adverse event data was collected between randomization and final 26-week follow-up.
General disorders General event	13.2% 7/53 • Number of events 10 • Adverse event data was collected between randomization and final 26-week follow-up.	9.4% 5/53 • Number of events 5 • Adverse event data was collected between randomization and final 26-week follow-up.	7.5% 4/53 • Number of events 4 • Adverse event data was collected between randomization and final 26-week follow-up.	11.8% 6/51 • Number of events 6 • Adverse event data was collected between randomization and final 26-week follow-up.
Infections and infestations Infection	5.7% 3/53 • Number of events 3 • Adverse event data was collected between randomization and final 26-week follow-up.	3.8% 2/53 • Number of events 2 • Adverse event data was collected between randomization and final 26-week follow-up.	1.9% 1/53 • Number of events 1 • Adverse event data was collected between randomization and final 26-week follow-up.	3.9% 2/51 • Number of events 2 • Adverse event data was collected between randomization and final 26-week follow-up.
Injury, poisoning and procedural complications Injury	0.00% 0/53 • Adverse event data was collected between randomization and final 26-week follow-up.	1.9% 1/53 • Number of events 1 • Adverse event data was collected between randomization and final 26-week follow-up.	0.00% 0/53 • Adverse event data was collected between randomization and final 26-week follow-up.	2.0% 1/51 • Number of events 1 • Adverse event data was collected between randomization and final 26-week follow-up.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Cancer	1.9% 1/53 • Number of events 1 • Adverse event data was collected between randomization and final 26-week follow-up.	0.00% 0/53 • Adverse event data was collected between randomization and final 26-week follow-up.	0.00% 0/53 • Adverse event data was collected between randomization and final 26-week follow-up.	0.00% 0/51 • Adverse event data was collected between randomization and final 26-week follow-up.
Renal and urinary disorders Renal failure	0.00% 0/53 • Adverse event data was collected between randomization and final 26-week follow-up.	1.9% 1/53 • Number of events 1 • Adverse event data was collected between randomization and final 26-week follow-up.	0.00% 0/53 • Adverse event data was collected between randomization and final 26-week follow-up.	0.00% 0/51 • Adverse event data was collected between randomization and final 26-week follow-up.
Respiratory, thoracic and mediastinal disorders Dyspnea	0.00% 0/53 • Adverse event data was collected between randomization and final 26-week follow-up.	0.00% 0/53 • Adverse event data was collected between randomization and final 26-week follow-up.	0.00% 0/53 • Adverse event data was collected between randomization and final 26-week follow-up.	2.0% 1/51 • Number of events 1 • Adverse event data was collected between randomization and final 26-week follow-up.
Vascular disorders Vascular	3.8% 2/53 • Number of events 2 • Adverse event data was collected between randomization and final 26-week follow-up.	1.9% 1/53 • Number of events 1 • Adverse event data was collected between randomization and final 26-week follow-up.	3.8% 2/53 • Number of events 3 • Adverse event data was collected between randomization and final 26-week follow-up.	3.9% 2/51 • Number of events 5 • Adverse event data was collected between randomization and final 26-week follow-up.

Other adverse events

Measure	A: GM-CSF + Supervised Treadmill Exercise Therapy n=53 participants at risk Supervised Treadmill Exercise Therapy: Exercise intervention will be delivered three times weekly for 26 weeks. In the first week, participants will be asked to exercise 15 minutes per session (excluding rest periods). Walking exercise duration will be increased to 25 minutes minutes per session during week 2. Week 3 and 4 sessions will also be 25 minutes long, but the intensity will be increased either to produce leg symptoms or at a target rate of perceived exertion (RPE)of 12-14 on the Borg's 6-20 scale. For weeks 5-8, walking duration will be increased to 40 to 50 minutes while maintaining intensity. For weeks 9-26, exercise duration will continue to be 40 to 50 minutes but we will increase intensity up to a maximum of 4.0 miles per hour at 10% grade. granulocyte macrophage colony stimulating factor (GM-CSF): The dose of GM-CSF will be 250 ug/M\^2 subcutaneously three times weekly for two weeks.	B: GM-CSF + Attention Control Group n=53 participants at risk Health education sessions (Control): Participants randomized to the attention control group will attend weekly one-hour educational sessions at Northwestern University for six months. These educational sessions are on topics of interest to the typical PAD patient and are led by physicians and other health care workers. Topics include Medicare Part D, nutritional supplements, C-reactive protein, and hypertension. Sessions do not include information about exercise. granulocyte macrophage colony stimulating factor (GM-CSF): The dose of GM-CSF will be 250 ug/M\^2 subcutaneously three times weekly for two weeks.	C: Placebo + Supervised Exercise Therapy n=53 participants at risk Supervised Treadmill Exercise Therapy: Exercise intervention will be delivered three times weekly for 26 weeks. In the first week, participants will be asked to exercise 15 minutes per session (excluding rest periods). Walking exercise duration will be increased to 25 minutes minutes per session during week 2. Week 3 and 4 sessions will also be 25 minutes long, but the intensity will be increased either to produce leg symptoms or at a target rate of perceived exertion (RPE)of 12-14 on the Borg's 6-20 scale. For weeks 5-8, walking duration will be increased to 40 to 50 minutes while maintaining intensity. For weeks 9-26, exercise duration will continue to be 40 to 50 minutes but we will increase intensity up to a maximum of 4.0 miles per hour at 10% grade.	D: Placebo + Attention Control Group n=51 participants at risk Health education sessions (Control): Participants randomized to the attention control group will attend weekly one-hour educational sessions at Northwestern University for six months. These educational sessions are on topics of interest to the typical PAD patient and are led by physicians and other health care workers. Topics include Medicare Part D, nutritional supplements, C-reactive protein, and hypertension. Sessions do not include information about exercise.
Musculoskeletal and connective tissue disorders Aching or soreness in feet	71.7% 38/53 • Number of events 126 • Adverse event data was collected between randomization and final 26-week follow-up.	67.9% 36/53 • Number of events 103 • Adverse event data was collected between randomization and final 26-week follow-up.	54.7% 29/53 • Number of events 100 • Adverse event data was collected between randomization and final 26-week follow-up.	43.1% 22/51 • Number of events 61 • Adverse event data was collected between randomization and final 26-week follow-up.
Musculoskeletal and connective tissue disorders Aching or soreness in thighs	50.9% 27/53 • Number of events 74 • Adverse event data was collected between randomization and final 26-week follow-up.	50.9% 27/53 • Number of events 53 • Adverse event data was collected between randomization and final 26-week follow-up.	49.1% 26/53 • Number of events 92 • Adverse event data was collected between randomization and final 26-week follow-up.	41.2% 21/51 • Number of events 53 • Adverse event data was collected between randomization and final 26-week follow-up.
Musculoskeletal and connective tissue disorders Aching or soreness in lower back	64.2% 34/53 • Number of events 120 • Adverse event data was collected between randomization and final 26-week follow-up.	69.8% 37/53 • Number of events 115 • Adverse event data was collected between randomization and final 26-week follow-up.	60.4% 32/53 • Number of events 136 • Adverse event data was collected between randomization and final 26-week follow-up.	62.7% 32/51 • Number of events 98 • Adverse event data was collected between randomization and final 26-week follow-up.
Musculoskeletal and connective tissue disorders Aching or soreness in knee joints	50.9% 27/53 • Number of events 82 • Adverse event data was collected between randomization and final 26-week follow-up.	49.1% 26/53 • Number of events 64 • Adverse event data was collected between randomization and final 26-week follow-up.	62.3% 33/53 • Number of events 120 • Adverse event data was collected between randomization and final 26-week follow-up.	43.1% 22/51 • Number of events 83 • Adverse event data was collected between randomization and final 26-week follow-up.
Musculoskeletal and connective tissue disorders Aching or soreness in other joints	26.4% 14/53 • Number of events 32 • Adverse event data was collected between randomization and final 26-week follow-up.	32.1% 17/53 • Number of events 37 • Adverse event data was collected between randomization and final 26-week follow-up.	30.2% 16/53 • Number of events 43 • Adverse event data was collected between randomization and final 26-week follow-up.	23.5% 12/51 • Number of events 25 • Adverse event data was collected between randomization and final 26-week follow-up.
Vascular disorders Aching or soreness in calves	75.5% 40/53 • Number of events 118 • Adverse event data was collected between randomization and final 26-week follow-up.	66.0% 35/53 • Number of events 86 • Adverse event data was collected between randomization and final 26-week follow-up.	67.9% 36/53 • Number of events 128 • Adverse event data was collected between randomization and final 26-week follow-up.	51.0% 26/51 • Number of events 70 • Adverse event data was collected between randomization and final 26-week follow-up.
Vascular disorders Aching or soreness in buttocks	47.2% 25/53 • Number of events 72 • Adverse event data was collected between randomization and final 26-week follow-up.	43.4% 23/53 • Number of events 53 • Adverse event data was collected between randomization and final 26-week follow-up.	41.5% 22/53 • Number of events 63 • Adverse event data was collected between randomization and final 26-week follow-up.	27.5% 14/51 • Number of events 34 • Adverse event data was collected between randomization and final 26-week follow-up.
Musculoskeletal and connective tissue disorders Aching or soreness in other areas	58.5% 31/53 • Number of events 68 • Adverse event data was collected between randomization and final 26-week follow-up.	56.6% 30/53 • Number of events 66 • Adverse event data was collected between randomization and final 26-week follow-up.	52.8% 28/53 • Number of events 61 • Adverse event data was collected between randomization and final 26-week follow-up.	41.2% 21/51 • Number of events 33 • Adverse event data was collected between randomization and final 26-week follow-up.
Musculoskeletal and connective tissue disorders Aching or soreness in hip joints	43.4% 23/53 • Number of events 59 • Adverse event data was collected between randomization and final 26-week follow-up.	43.4% 23/53 • Number of events 63 • Adverse event data was collected between randomization and final 26-week follow-up.	50.9% 27/53 • Number of events 93 • Adverse event data was collected between randomization and final 26-week follow-up.	41.2% 21/51 • Number of events 63 • Adverse event data was collected between randomization and final 26-week follow-up.
Respiratory, thoracic and mediastinal disorders Increase in shortness of breath	18.9% 10/53 • Number of events 13 • Adverse event data was collected between randomization and final 26-week follow-up.	22.6% 12/53 • Number of events 20 • Adverse event data was collected between randomization and final 26-week follow-up.	15.1% 8/53 • Number of events 9 • Adverse event data was collected between randomization and final 26-week follow-up.	21.6% 11/51 • Number of events 14 • Adverse event data was collected between randomization and final 26-week follow-up.
General disorders New chest pain	7.5% 4/53 • Number of events 9 • Adverse event data was collected between randomization and final 26-week follow-up.	9.4% 5/53 • Number of events 6 • Adverse event data was collected between randomization and final 26-week follow-up.	5.7% 3/53 • Number of events 3 • Adverse event data was collected between randomization and final 26-week follow-up.	5.9% 3/51 • Number of events 4 • Adverse event data was collected between randomization and final 26-week follow-up.
General disorders Fever greater than 101 degrees	5.7% 3/53 • Number of events 3 • Adverse event data was collected between randomization and final 26-week follow-up.	5.7% 3/53 • Number of events 4 • Adverse event data was collected between randomization and final 26-week follow-up.	3.8% 2/53 • Number of events 2 • Adverse event data was collected between randomization and final 26-week follow-up.	5.9% 3/51 • Number of events 3 • Adverse event data was collected between randomization and final 26-week follow-up.
General disorders Chills	22.6% 12/53 • Number of events 26 • Adverse event data was collected between randomization and final 26-week follow-up.	41.5% 22/53 • Number of events 43 • Adverse event data was collected between randomization and final 26-week follow-up.	28.3% 15/53 • Number of events 29 • Adverse event data was collected between randomization and final 26-week follow-up.	23.5% 12/51 • Number of events 21 • Adverse event data was collected between randomization and final 26-week follow-up.
General disorders New headaches	47.2% 25/53 • Number of events 57 • Adverse event data was collected between randomization and final 26-week follow-up.	45.3% 24/53 • Number of events 40 • Adverse event data was collected between randomization and final 26-week follow-up.	35.8% 19/53 • Number of events 29 • Adverse event data was collected between randomization and final 26-week follow-up.	39.2% 20/51 • Number of events 39 • Adverse event data was collected between randomization and final 26-week follow-up.
Musculoskeletal and connective tissue disorders Pain in muscles	75.5% 40/53 • Number of events 109 • Adverse event data was collected between randomization and final 26-week follow-up.	71.7% 38/53 • Number of events 90 • Adverse event data was collected between randomization and final 26-week follow-up.	58.5% 31/53 • Number of events 103 • Adverse event data was collected between randomization and final 26-week follow-up.	54.9% 28/51 • Number of events 88 • Adverse event data was collected between randomization and final 26-week follow-up.
Gastrointestinal disorders Nausea or vomiting	24.5% 13/53 • Number of events 16 • Adverse event data was collected between randomization and final 26-week follow-up.	32.1% 17/53 • Number of events 27 • Adverse event data was collected between randomization and final 26-week follow-up.	32.1% 17/53 • Number of events 32 • Adverse event data was collected between randomization and final 26-week follow-up.	23.5% 12/51 • Number of events 19 • Adverse event data was collected between randomization and final 26-week follow-up.
General disorders New rash	20.8% 11/53 • Number of events 16 • Adverse event data was collected between randomization and final 26-week follow-up.	20.8% 11/53 • Number of events 15 • Adverse event data was collected between randomization and final 26-week follow-up.	18.9% 10/53 • Number of events 12 • Adverse event data was collected between randomization and final 26-week follow-up.	13.7% 7/51 • Number of events 12 • Adverse event data was collected between randomization and final 26-week follow-up.
General disorders New swelling in hands or feet	34.0% 18/53 • Number of events 28 • Adverse event data was collected between randomization and final 26-week follow-up.	34.0% 18/53 • Number of events 27 • Adverse event data was collected between randomization and final 26-week follow-up.	32.1% 17/53 • Number of events 23 • Adverse event data was collected between randomization and final 26-week follow-up.	31.4% 16/51 • Number of events 23 • Adverse event data was collected between randomization and final 26-week follow-up.
Musculoskeletal and connective tissue disorders Pain in bones	37.7% 20/53 • Number of events 38 • Adverse event data was collected between randomization and final 26-week follow-up.	35.8% 19/53 • Number of events 39 • Adverse event data was collected between randomization and final 26-week follow-up.	35.8% 19/53 • Number of events 30 • Adverse event data was collected between randomization and final 26-week follow-up.	33.3% 17/51 • Number of events 36 • Adverse event data was collected between randomization and final 26-week follow-up.
Vascular disorders Pulmonary embolism	1.9% 1/53 • Number of events 1 • Adverse event data was collected between randomization and final 26-week follow-up.	0.00% 0/53 • Adverse event data was collected between randomization and final 26-week follow-up.	0.00% 0/53 • Adverse event data was collected between randomization and final 26-week follow-up.	0.00% 0/51 • Adverse event data was collected between randomization and final 26-week follow-up.
Vascular disorders Other type of blood clotting or thrombosis	3.8% 2/53 • Number of events 2 • Adverse event data was collected between randomization and final 26-week follow-up.	1.9% 1/53 • Number of events 1 • Adverse event data was collected between randomization and final 26-week follow-up.	1.9% 1/53 • Number of events 1 • Adverse event data was collected between randomization and final 26-week follow-up.	2.0% 1/51 • Number of events 2 • Adverse event data was collected between randomization and final 26-week follow-up.

Additional Information

Mary McDermott MD

Northwestern University

Phone: 312-503-6419

Email: mdm608@northwestern.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place