Peripheral Artery Disease
Conditions
Keywords
PAD
Brief summary
HI-PAD is a placebo controlled double-blind randomized pilot clinical trial to determine whether VM202 may improve walking ability in people with lower extremity peripheral artery disease (PAD).
Detailed description
The HI-PAD study will randomize 39 people age 55 and older with PAD who do not have critical limb ischemia. The primary outcome is change in the six-minute walk distance at 6-month follow-up after the first study drug injection. A secondary outcome in change in six-minute walk distance at 3-month follow-up. Additional secondary outcomes are pain-free and maximal treadmill walking distance, calf biopsy measures of skeletal muscle regeneration, capillary density, and autophagy, and MRI-measured calf muscle perfusion at three-month follow-up. Investigators will also measure change in six-minute walk distance at 12-month follow-up.
Interventions
DRUGVM202
Participants randomized to VM202 will receive calf muscle injections of VM202 to each leg with evidence of PAD. Injections of VM202 are administered by a physician in a double-blinded fashion after randomization on Day 0, Day 14, Day 28, and Day 42, for a total of four treatment days. Therefore, participants randomized to VM202 will receive 4 mgs of VM202 in each calf muscle on each treatment day. Injections are placed beginning 2 cm below the popliteal crease, and are administered in a pre-designed sequence and pattern, at a measured distance 2 cm apart. Note: Participants who have a evidence of PAD in only one leg will only receive injections in the leg with evidence of PAD.
OTHERPlacebo
Participants randomized to placebo will receive calf muscle injections of placebo (the excipient buffer formulation minus the VM202) to each leg with evidence of PAD. Injections of placebo are administered by a physician in a double-blinded fashion after randomization on Day 0, Day 14, Day 28, and Day 42, for a total of four treatment days. Placebo appears identical to the VM202 study drug and is administered in a pattern on the calf identical to that of the VM202 injections. Note: Participants who have a evidence of PAD in only one leg will only receive injections in the leg with evidence of PAD.
Sponsors
National Institute on Aging (NIA)
Helixmith Co., Ltd.
Northwestern University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
55 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age 55 or above * Symptomatic PAD, defined as exertion-induced ischemic calf muscle symptoms during the six-minute walk, during the baseline exercise stress test, or during daily walking activities. PAD will be defined as an ankle brachial index (ABI) \< or = 0.90 at the baseline study visit or vascular lab evidence of PAD or angiographic evidence of significant PAD.
Exclusion criteria
* Above- or below-knee amputation. * Critical limb ischemia, including individuals with gangrene and lower extremity ulcers. * Wheelchair-bound or requiring a cane or walker to ambulate. * Walking is limited by a symptom other than PAD. * Lower extremity revascularization, orthopedic surgery, cardiovascular event, coronary revascularization, or other major surgery in the previous three months and planned revascularization or major surgery during the next six months. * Major medical illness including renal disease requiring dialysis, lung disease requiring oxygen, Parkinson's disease, or a life-threatening illness with life expectancy less than six months. \[NOTE: Participants who only use oxygen at night may still qualify\] * History of cancer within the last 5 years or incomplete cancer screening as recommended by the American Cancer Society. Specifically, participants will be asked to provide documentation regarding screening history for colon cancer and breast and cervical cancer (women), according to the American Cancer Society guidelines. Screening for colon cancer may consist of stool testing for blood in the past year. Men must either provide documentation regarding prostate cancer screening history or indicate after a telephone or in-person discussion with Dr. McDermott that they have elected to decline prostate cancer screening. A chest computed tomography will be performed for participants 55 to 74 years old with \>30 pack year history of smoking, unless they have not smoked within the past 15 years, to screen for lung cancer that may exclude them. The study team may also perform colon, breast, and/or cervical cancer screenings as part of study participation. The study team will provide stool testing for blood for colon cancer screening, mammogram for breast cancer screening, and a Pap test for cervical cancer screening according to the participant's eligibility for these screening tests, using the American Cancer Society guidelines. Men who elect to have prostate cancer screening who have not had this completed with their physician can have a prostate specific antigen (PSA) test performed by study investigators. Participants who have a history of non-melanoma skin cancer (i.e.had basal cell carcinoma or squamous cell carcinoma of the skin) may still be eligible if the lesion was completely removed and there has been no evidence of recurrence in the past year. * Evidence of proliferative retinopathy. Participants who were treated for retinopathy at least 5 years prior to their baseline assessment who do not have evidence of proliferative retinopathy at the time of baseline assessment may still be eligible. * Positive test for active Human Immunodeficiency Virus (HIV), hepatitis B virus, hepatitis C virus or Human T-lymphotropic virus. Patients who have positive antibodies for HIV, hepatitis B, or hepatitis C who do not have detectable viral load will be eligible for participation. * Mini-Mental Status Examination (MMSE) score \<23 or dementia. * Participation in or completion of a clinical trial in the previous three months. \[NOTE: after completing a stem cell or gene therapy intervention, participants will become eligible after the final study follow-up visit of the stem cell or gene therapy study so long as at least six months have passed since the final intervention administration. After completing a supplement or drug therapy (other than stem cell or gene therapy), participants will be eligible after the final study follow-up visit as long as at least three months have passed since the final intervention of the trial.\] * Increase in angina or angina at rest. * Premenopausal women. * Non-English speaking. * Visual impairment that limits walking ability. * In addition to the above criteria, investigator discretion will be used to determine if the trial is unsafe or not a good fit for the potential participant. * Potential participants who have had symptoms from peripheral artery disease for less than six months will be excluded. * Potential participants who, after being advised of therapeutic options available for people with PAD, prefer to return to their physician to discuss alternative treatment (e.g. supervised exercise or revascularization). Potential participants may participate in the study after 12 weeks has passed since their last supervised exercise session or revascularization if they meet inclusion criteria. * Potential participants with a baseline six-minute walk value \< 595 or \> 1,520 feet will be excluded. * Potential participants with the following laboratory values will be excluded: a hemoglobin value \< 8.0 g/dL, a white blood cell count \< 3,000 cells per microliter, platelet count \< 75,000/mm3, GFR \< 20 mL/minute/1.73 M2, AST or ALT value \> 3 times the upper limit of normal, or any other clinically significant laboratory abnormality which, in the opinion of the investigator, should exclude the participant. Participants may undergo a serum electrophoresis and an immunofixation blood test if indicated to further evaluate abnormalities on the complete blood count if needed to assess study eligibility. * Potential participants started on cilostazol within the past three months will be excluded. They may be evaluated for eligibility once three months has passed since beginning cilostazol. * Vulnerable populations (fetuses, pregnant women, children, prisoners, and institutionalized persons) and adults unable to consent will not be included in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Six-minute Walk Distance | Change from baseline to six-month follow-up in six-minute walk distance | Participants walking up and down a 100 foot hallway for six minutes following a standardized protocol. The goal is for them to walk as far as possible in six minutes |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximal Treadmill Walking Time | Change from baseline to three-month follow-up | A Gardner or Modified Gardner treadmill exercise protocol will be used |
| Calf Muscle Perfusion | Change from baseline to three-month follow-up | Calf muscle perfusion is measured by Magnetic Resonance Imaging (MRI) Unit of measure is ml/minute per 100 gms tissue |
| Calf Muscle Biopsy Biochemical Measures (Satellite Cells - Total SCs/100 Fibers) | Change from baseline to three-month follow-up | A skeletal muscle sample will be obtained from the calf muscle. The outcome is the number of satellite cells per 100 muscle fibers |
| The Short-Form-36 Physical Functioning Score | Change from baseline to three-month follow-up | This well validated quality of life measure will be used to assess changes in patient perceived quality of life. The SF-36 is scored from 0-100, with 100 being the best score. |
| Six-minute Walk Distance | Change in six-minute walk distance from baseline to three-month follow-up | Participants walking up and down a 100 foot hallway for six minutes following a standardized protocol. The goal is for them to walk as far as possible in six minutes |
| Pain-free Treadmill Walking Time | Change from baseline to three-month follow-up | A Gardner or Modified Gardner treadmill exercise protocol will be used |
| Walking Impairment Questionnaire - Distance Score | Change from baseline to three-month follow-up | The well validated Walking Impairment Questionnaire will be used to measure patient- perceived walking performance. The WIQ is scored from 0-100, with 100 being the best score. We will use distance and speed sub-components separately. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Six-minute Walk Distance | Change from baseline to 12-month follow-up in six minute walk distance. | See above regarding 6-minute walk protocol |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| VM202 Participants will receive injections of VM202 (4 mgs) in calf skeletal muscle every 14 days for a total of four treatment days.
VM202: Participants randomized to VM202 will receive calf muscle injections of VM202 to each leg with evidence of PAD. Injections of VM202 are administered by a physician in a double-blinded fashion after randomization on Day 0, Day 14, Day 28, and Day 42, for a total of four treatment days. Therefore, participants randomized to VM202 will receive 4 mgs of VM202 in each calf muscle on each treatment day. Injections are placed beginning 2 cm below the popliteal crease, and are administered in a pre-designed sequence and pattern, at a measured distance 2 cm apart.
Note: Participants who have a evidence of PAD in only one leg will only receive injections in the leg with evidence of PAD. | 21 |
| Placebo Participants will receive injections of placebo in calf skeletal muscle every 14 days for a total of four treatment days.
Placebo: Participants randomized to placebo will receive calf muscle injections of placebo (the excipient buffer formulation minus the VM202) to each leg with evidence of PAD. Injections of placebo are administered by a physician in a double-blinded fashion after randomization on Day 0, Day 14, Day 28, and Day 42, for a total of four treatment days. Placebo appears identical to the VM202 study drug and is administered in a pattern on the calf identical to that of the VM202 injections.
Note: Participants who have a evidence of PAD in only one leg will only receive injections in the leg with evidence of PAD. | 18 |
| Total | 39 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| 12-month Follow-up | Death | 1 | 1 |
| 12-month Follow-up | Withdrawal by Subject | 1 | 1 |
| 3-month Follow-up | Death | 0 | 1 |
| 6-month Follow-up | Death | 0 | 1 |
| 6-month Follow-up | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | VM202 | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 70.9 years STANDARD_DEVIATION 8.9 | 67.1 years STANDARD_DEVIATION 7 | 69.1 years STANDARD_DEVIATION 8.2 |
| Ankle Brachial Index | 0.61 ratio of systolic pressures STANDARD_DEVIATION 0.12 | 0.63 ratio of systolic pressures STANDARD_DEVIATION 0.13 | 0.62 ratio of systolic pressures STANDARD_DEVIATION 0.12 |
| Body Mass Index | 29.8 kg/m^2 STANDARD_DEVIATION 6.4 | 30.0 kg/m^2 STANDARD_DEVIATION 5.6 | 29.9 kg/m^2 STANDARD_DEVIATION 6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants | 18 Participants | 38 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 15 Participants | 10 Participants | 25 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 5 Participants | 7 Participants | 12 Participants |
| Sex: Female, Male Female | 7 Participants | 4 Participants | 11 Participants |
| Sex: Female, Male Male | 14 Participants | 14 Participants | 28 Participants |
| Six-minute walk distance | 321.7 meters STANDARD_DEVIATION 72.2 | 310.2 meters STANDARD_DEVIATION 77.9 | 316.4 meters STANDARD_DEVIATION 74.1 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 18 | 1 / 21 |
| other Total, other adverse events | 14 / 18 | 17 / 21 |
| serious Total, serious adverse events | 6 / 18 | 6 / 21 |
Outcome results
Primary
Six-minute Walk Distance
Participants walking up and down a 100 foot hallway for six minutes following a standardized protocol. The goal is for them to walk as far as possible in six minutes
Time frame: Change from baseline to six-month follow-up in six-minute walk distance
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Six-minute Walk Distance | 17.01 meters | Standard Error 13.76 |
| VM202 | Six-minute Walk Distance | 3.46 meters | Standard Error 12.7 |
p-value: 0.7586ANCOVA
Secondary
Calf Muscle Biopsy Biochemical Measures (Satellite Cells - Total SCs/100 Fibers)
A skeletal muscle sample will be obtained from the calf muscle. The outcome is the number of satellite cells per 100 muscle fibers
Time frame: Change from baseline to three-month follow-up
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Calf Muscle Biopsy Biochemical Measures (Satellite Cells - Total SCs/100 Fibers) | -4.83 Satellite cells per 100 muscle fibers | Standard Error 8.23 |
| VM202 | Calf Muscle Biopsy Biochemical Measures (Satellite Cells - Total SCs/100 Fibers) | 3.45 Satellite cells per 100 muscle fibers | Standard Error 6.91 |
p-value: 0.208ANCOVA
Secondary
Calf Muscle Perfusion
Calf muscle perfusion is measured by Magnetic Resonance Imaging (MRI) Unit of measure is ml/minute per 100 gms tissue
Time frame: Change from baseline to three-month follow-up
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Calf Muscle Perfusion | 1.98 ml/minute per 100 gm tissue | Standard Error 1.9 |
| VM202 | Calf Muscle Perfusion | 2.68 ml/minute per 100 gm tissue | Standard Error 1.87 |
p-value: 0.4019ANCOVA
Secondary
Maximal Treadmill Walking Time
A Gardner or Modified Gardner treadmill exercise protocol will be used
Time frame: Change from baseline to three-month follow-up
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Maximal Treadmill Walking Time | -0.59 minutes | Standard Error 0.73 |
| VM202 | Maximal Treadmill Walking Time | 1.66 minutes | Standard Error 0.73 |
p-value: 0.0298ANCOVA
Secondary
Pain-free Treadmill Walking Time
A Gardner or Modified Gardner treadmill exercise protocol will be used
Time frame: Change from baseline to three-month follow-up
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Pain-free Treadmill Walking Time | 0.95 minutes | Standard Error 0.8 |
| VM202 | Pain-free Treadmill Walking Time | 0.45 minutes | Standard Error 0.77 |
p-value: 0.6603ANCOVA
Secondary
Six-minute Walk Distance
Participants walking up and down a 100 foot hallway for six minutes following a standardized protocol. The goal is for them to walk as far as possible in six minutes
Time frame: Change in six-minute walk distance from baseline to three-month follow-up
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Six-minute Walk Distance | -0.48 meters | Standard Error 12.8 |
| VM202 | Six-minute Walk Distance | -2.49 meters | Standard Error 12.01 |
p-value: 0.5442ANCOVA
Secondary
The Short-Form-36 Physical Functioning Score
This well validated quality of life measure will be used to assess changes in patient perceived quality of life. The SF-36 is scored from 0-100, with 100 being the best score.
Time frame: Change from baseline to three-month follow-up
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | The Short-Form-36 Physical Functioning Score | 8.70 score on a scale | Standard Error 4.94 |
| VM202 | The Short-Form-36 Physical Functioning Score | 3.20 score on a scale | Standard Error 4.6 |
p-value: 0.7852ANCOVA
Secondary
The Short-Form-36 Physical Functioning Score
This well validated quality of life measure will be used to assess changes in patient perceived quality of life. Scored on a 0-100 scale, where 100- is best.
Time frame: Change from baseline to six-month follow-up
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | The Short-Form-36 Physical Functioning Score | 11.98 score on a scale | Standard Error 3.67 |
| VM202 | The Short-Form-36 Physical Functioning Score | 6.84 score on a scale | Standard Error 3.32 |
p-value: 0.8414ANCOVA
Secondary
Walking Impairment Questionnaire - Distance Score
The well validated Walking Impairment Questionnaire will be used to measure patient- perceived walking performance.
Time frame: Change from baseline to six-month follow-up
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Walking Impairment Questionnaire - Distance Score | 11.44 score on a scale | Standard Error 6.63 |
| VM202 | Walking Impairment Questionnaire - Distance Score | 9.31 score on a scale | Standard Error 6.01 |
p-value: 0.5912ANCOVA
Secondary
Walking Impairment Questionnaire - Distance Score
The well validated Walking Impairment Questionnaire will be used to measure patient- perceived walking performance. The WIQ is scored from 0-100, with 100 being the best score. We will use distance and speed sub-components separately.
Time frame: Change from baseline to three-month follow-up
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Walking Impairment Questionnaire - Distance Score | 6.28 score on a scale | Standard Error 5.54 |
| VM202 | Walking Impairment Questionnaire - Distance Score | 8.30 score on a scale | Standard Error 5.19 |
p-value: 0.398ANCOVA
Other Pre-specified
Six-minute Walk Distance
See above regarding 6-minute walk protocol
Time frame: Change from baseline to 12-month follow-up in six minute walk distance.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Six-minute Walk Distance | 5.02 meters | Standard Error 12.17 |
| VM202 | Six-minute Walk Distance | 2.24 meters | Standard Error 11.17 |
p-value: 0.5647ANCOVA