Arterial Occlusive Disease, Ischemia, Peripheral Vascular Disease, Ulcers
Conditions
Keywords
Ischemic ulcers, Critical Limb Ischemia
Brief summary
The objective of this study is to test the hypothesis that AMG0001 treatment is safe and induces angiogenesis as detected by improved wound healing, reduction in amputation, improved pain at rest and hemodynamic measurement and to assess the effectiveness of the administrative method.
Detailed description
The primary goals of this study evaluating AMG0001 administration in CLI subjects will be to investigate the efficacy and safety of AMG0001. Specifically, the objectives are: 1. Assess efficacy of a dosing regimen of 4.0mg/3 mL AMG0001, administered on Days 0, 14, and 28 as measured by reduction in total wound area at Month 3. 2. Assess potential effects of angiogenesis associated with a dosing regimen of 4.0mg/3 mL AMG0001, administered on Days 0, 14, and 28 as measured by reduction in total wound area at Months 6 and 12, along with reduction in major amputations and improved pain at rest as measured on the VAS and hemodynamic measures (ABI/TBI) at Month 3 and Month 6. 3. Assess overall safety of AMG0001 in the Critical Limb Ischemia subject population as determined by physical examination, blood and urine analyses, electrocardiogram, vital signs, and by evaluation of adverse experiences during and after the course of treatment.
Interventions
GENETICPlacebo
Intramuscular injections into the index leg on days 0, 14, and 28
GENETICHGF plasmid
Intramuscular injections into the index leg on days 0, 14, and 28
Sponsors
AnGes USA, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Subjects will have an appropriately sized peripheral ischemic ulcer(s). 2. Subjects will have one or both of the following hemodynamic indicators of severe peripheral arterial occlusive disease: 1. Ankle systolic pressure (in either the dorsalis pedis or posterior tibial arteries) of \< 70 mmHg 2. Toe systolic pressure \< 50 mmHg 3. The subject is a poor candidate for standard revascularization treatment options for peripheral arterial disease, based on inadequate bypass conduit, unfavorable anatomy, or poor operative risk. 4. Subjects 40 years or older of either sex who have signed an informed consent form either directly or through a legally authorized representative. 5. Subjects will be on a statin and an anti-platelet agent (e.g., clopidogrel, ticlopidine, aspirin, etc.) as part of their standard of care, unless contraindicated. Subjects for which these agents are contraindicated will have this restriction recorded in their case report form (CRF). Subjects must be stable on these medical regimens for at least 4 weeks prior to the start of treatment. 6. If female, the subjects must be: 1. at least one year post-menopausal, or 2. surgically sterile, or 3. if the subject is of child-bearing potential, she must have been practicing adequate contraception for at least 12 weeks prior to entering the study and have a negative urine pregnancy test result prior to study enrollment and agree to periodic pregnancy screening tests during the study. 4. If female, the subject must not be breastfeeding for 30 days following administration of HGF. 7. If subject is of reproductive potential, he or she must be using an accepted and effective (barrier) form of birth control during the study.
Exclusion criteria
1. Subjects who, in the opinion of the investigator, have a vascular disease prognosis that indicates they would require a major amputation (at or above the ankle) within 4 weeks of start of treatment. 2. Subjects with a diagnosis of Buerger's disease (thromboangiitis obliterans). 3. Subjects with hemodynamically significant aorto-iliac occlusive disease. 4. Subjects who have had a revascularization procedure within 12 weeks prior to treatment initiation that remains patent. Revascularization procedures that are evidenced to have failed (completely occluded) for \>2 weeks prior to treatment initiation are acceptable. 5. Subjects who require a change in their hypertension medication (other than dosage change) as part of their standard of care within 4 weeks prior to treatment initiation. 6. Subjects with deep ulcerations with bone or tendon exposure, or clinical evidence of invasive infection (e.g., cellulitis, osteomyelitis, etc.) uncontrollable by antibiotics. 7. Subjects currently receiving immuno-suppressive medication, chemo or radiation therapy. 8. Evidence or history of malignant neoplasm (clinical, laboratory or imaging), except for fully resolved basal cell carcinoma of the skin. Patient's who had successful tumor resection or radio-chemotherapy of breast cancer more than 10 years prior to inclusion in the study, and with no recurrence, may be enrolled in the study. Patient's who had successful tumor resection or radio-chemotherapy of all other tumor types more than 5 years prior to inclusion in the study, and with no recurrence, may be enrolled in the study. 9. Subjects who have proliferative diabetic retinopathy, severe non-proliferative retinopathy, recent (within 6 months) retinal vein occlusion, macular degeneration with choroidal neovascularization, macular edema on fundus evaluation by ophthalmologist, or intraocular surgery within 3 months. 10. Subjects with end stage renal disease (ESRD) defined as significant renal dysfunction evidenced by a creatinine of \> 2.5 mg/dL, or receiving chronic hemodialysis therapy. 11. Any co-morbid condition likely to interfere with assessment of safety or efficacy endpoints, acute cardiovascular events (i.e. cerebrovascular accident \[CVA\], myocardial infarction \[MI\], etc.) within 12 weeks of treatment, or non-cardiovascular diseases that in the opinion of the investigator may result in \< 3 month subject mortality. 12. A subject who has a history of hepatic cirrhosis, viral hepatitis, or HIV. 13. Subjects with a clinically significant liver enzyme abnormality (i.e., AST or ALT more than two times the upper limit of normal and/or bilirubin more than 50% above the upper limit of normal). 14. Subjects taking cilostazol (Pletal®) are eligible for inclusion, but the subject must have been taking the medication for at least 4 weeks prior to test material administration. 15. Subject who received another investigational drug for peripheral arterial disease within 90 days of randomization, have previously received any gene transfer therapy or growth factor product not approved by the United States Food and Drug Administration (FDA) or received any investigational Drug Product in another clinical trial in the 30 days prior to administration of HGF. 16. Unreliable or uncooperative subject or other severe concomitant disease(s), which the clinical investigator feels constitute(s) criteria for exclusion of a particular subject.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Wound Healing (Change in Total Wound Area of All Ischemic Ulcers) | Baseline, Month 3, Month 6 | Wound healing measured by change in mean total wound area of all ischemic ulcers at Month 3 and Month 6 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Where All Ulcers Healed | Month 3 and Month 6 | This outcome is a percentage of participants where all of their baseline ulcers healed. |
| Change in Pain at Rest as Measured on the Visual Analog Scale (VAS) | Baseline, Month 3 and Month 6 | The mean VAS score where 0 = no pain; 10 = worst possible pain. |
| Number of Subjects Who Undergo a Major Amputation | Month 3 and Month 6 | — |
| Change in Hemodynamic Measurements - Mean Change in Ankle Brachial Index (ABI) | Baseline, Month 3, Month 6 | — |
| Change in Hemodynamic Measurements - Mean Change in Toe Brachial Index (TBI) | Baseline, Month 3, Month 6 | — |
Countries
United States
Participant flow
Pre-assignment details
Screening was up to 30 days
Participants by arm
| Arm | Count |
|---|---|
| Active Group 4.0 mg AMG0001 via IM injections on days 0, 14, and 28 | 21 |
| Placebo Group Placebo (saline)via IM injections on days 0, 14, and 28 | 6 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 4 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 0 |
Baseline characteristics
| Characteristic | Active Group | Placebo Group | Total |
|---|---|---|---|
| Age, Continuous | 75.7 years STANDARD_DEVIATION 2.49 | 78.0 years STANDARD_DEVIATION 1.86 | 76.2 years STANDARD_DEVIATION 1.97 |
| Sex: Female, Male Female | 8 Participants | 4 Participants | 12 Participants |
| Sex: Female, Male Male | 13 Participants | 2 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 20 / 21 | 5 / 6 |
| serious Total, serious adverse events | 17 / 21 | 3 / 6 |
Outcome results
Primary
Wound Healing (Change in Total Wound Area of All Ischemic Ulcers)
Wound healing measured by change in mean total wound area of all ischemic ulcers at Month 3 and Month 6
Time frame: Baseline, Month 3, Month 6
Population: Per protocol population - Efficacy Evaluable or EE
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active Group | Wound Healing (Change in Total Wound Area of All Ischemic Ulcers) | Baseline | 5.75 total wound area (cm^2) | Standard Error 1.8134 |
| Active Group | Wound Healing (Change in Total Wound Area of All Ischemic Ulcers) | Month 3 | 15.766 total wound area (cm^2) | Standard Error 6.8421 |
| Active Group | Wound Healing (Change in Total Wound Area of All Ischemic Ulcers) | Month 6 | 16.375 total wound area (cm^2) | Standard Error 7.1336 |
| Placebo Group | Wound Healing (Change in Total Wound Area of All Ischemic Ulcers) | Baseline | 12.600 total wound area (cm^2) | Standard Error 9.4435 |
| Placebo Group | Wound Healing (Change in Total Wound Area of All Ischemic Ulcers) | Month 3 | 12.200 total wound area (cm^2) | Standard Error 8.7022 |
| Placebo Group | Wound Healing (Change in Total Wound Area of All Ischemic Ulcers) | Month 6 | 12.700 total wound area (cm^2) | Standard Error 9.719 |
Comparison: Comparison made is the difference from baseline at Month 3.p-value: 0.35ANCOVA
Comparison: Comparison made is the difference from baseline at Month 6.p-value: 0.17ANCOVA
Secondary
Change in Hemodynamic Measurements - Mean Change in Ankle Brachial Index (ABI)
Time frame: Baseline, Month 3, Month 6
Population: Population is per protocol - Efficacy Evaluable (EE)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active Group | Change in Hemodynamic Measurements - Mean Change in Ankle Brachial Index (ABI) | Baseline | 0.492 mm Hg / mm Hg | Standard Error 0.0662 |
| Active Group | Change in Hemodynamic Measurements - Mean Change in Ankle Brachial Index (ABI) | Month 3 | 0.476 mm Hg / mm Hg | Standard Error 0.0657 |
| Active Group | Change in Hemodynamic Measurements - Mean Change in Ankle Brachial Index (ABI) | Month 6 | 0.472 mm Hg / mm Hg | Standard Error 0.0846 |
| Placebo Group | Change in Hemodynamic Measurements - Mean Change in Ankle Brachial Index (ABI) | Month 6 | 0.303 mm Hg / mm Hg | Standard Error 0.1481 |
| Placebo Group | Change in Hemodynamic Measurements - Mean Change in Ankle Brachial Index (ABI) | Baseline | 0.430 mm Hg / mm Hg | Standard Error 0.0957 |
| Placebo Group | Change in Hemodynamic Measurements - Mean Change in Ankle Brachial Index (ABI) | Month 3 | 0.448 mm Hg / mm Hg | Standard Error 0.1248 |
Comparison: Comparison at Month 3p-value: 0.77ANCOVA
Comparison: Comparison at Month 6p-value: 0.45ANCOVA
Secondary
Change in Hemodynamic Measurements - Mean Change in Toe Brachial Index (TBI)
Time frame: Baseline, Month 3, Month 6
Population: Population is per protocol - Efficacy Evaluable (EE)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active Group | Change in Hemodynamic Measurements - Mean Change in Toe Brachial Index (TBI) | Baseline | 0.19 mm Hg / mm Hg | Standard Error 0.04 |
| Active Group | Change in Hemodynamic Measurements - Mean Change in Toe Brachial Index (TBI) | Month 3 | 0.22 mm Hg / mm Hg | Standard Error 0.05 |
| Active Group | Change in Hemodynamic Measurements - Mean Change in Toe Brachial Index (TBI) | Month 6 | 0.24 mm Hg / mm Hg | Standard Error 0.06 |
| Placebo Group | Change in Hemodynamic Measurements - Mean Change in Toe Brachial Index (TBI) | Baseline | 0.28 mm Hg / mm Hg | Standard Error 0.06 |
| Placebo Group | Change in Hemodynamic Measurements - Mean Change in Toe Brachial Index (TBI) | Month 3 | 0.14 mm Hg / mm Hg | Standard Error 0.06 |
| Placebo Group | Change in Hemodynamic Measurements - Mean Change in Toe Brachial Index (TBI) | Month 6 | 0.11 mm Hg / mm Hg | Standard Error 0.07 |
Comparison: Comparison between groups for mean TBI at Month 3 versus baseline.p-value: 0.06ANCOVA
Comparison: Comparison between groups for mean TBI at Month 6 versus baseline.p-value: 0.05ANCOVA
Secondary
Change in Pain at Rest as Measured on the Visual Analog Scale (VAS)
The mean VAS score where 0 = no pain; 10 = worst possible pain.
Time frame: Baseline, Month 3 and Month 6
Population: Per protocol population or Efficacy Evaluable EE
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active Group | Change in Pain at Rest as Measured on the Visual Analog Scale (VAS) | Baseline | 5.31 cm | Standard Error 0.6 |
| Active Group | Change in Pain at Rest as Measured on the Visual Analog Scale (VAS) | Month 3 | 4.26 cm | Standard Error 0.92 |
| Active Group | Change in Pain at Rest as Measured on the Visual Analog Scale (VAS) | Month 6 | 3.40 cm | Standard Error 0.99 |
| Placebo Group | Change in Pain at Rest as Measured on the Visual Analog Scale (VAS) | Baseline | 6.04 cm | Standard Error 1.2 |
| Placebo Group | Change in Pain at Rest as Measured on the Visual Analog Scale (VAS) | Month 3 | 6.52 cm | Standard Error 1.5 |
| Placebo Group | Change in Pain at Rest as Measured on the Visual Analog Scale (VAS) | Month 6 | 6.66 cm | Standard Error 1.3 |
Comparison: Comparison between groups at Month 3p-value: 0.2ANCOVA
Comparison: Comparison between groups at Month 6p-value: 0.04ANCOVA
Secondary
Number of Subjects Who Undergo a Major Amputation
Time frame: Month 3 and Month 6
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Active Group | Number of Subjects Who Undergo a Major Amputation | 3 months | 3 participants |
| Active Group | Number of Subjects Who Undergo a Major Amputation | 6 months | 3 participants |
| Placebo Group | Number of Subjects Who Undergo a Major Amputation | 3 months | 0 participants |
| Placebo Group | Number of Subjects Who Undergo a Major Amputation | 6 months | 0 participants |
p-value: 1Fisher Exact
Secondary
Percentage of Participants Where All Ulcers Healed
This outcome is a percentage of participants where all of their baseline ulcers healed.
Time frame: Month 3 and Month 6
Population: Per protocol population Efficacy Evaluable EE
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Active Group | Percentage of Participants Where All Ulcers Healed | Month 3 | 6 Percentage of Participants |
| Active Group | Percentage of Participants Where All Ulcers Healed | Month 6 | 19 Percentage of Participants |
| Active Group | Percentage of Participants Where All Ulcers Healed | Month 12 | 31 Percentage of Participants |
| Placebo Group | Percentage of Participants Where All Ulcers Healed | Month 3 | 0 Percentage of Participants |
| Placebo Group | Percentage of Participants Where All Ulcers Healed | Month 6 | 0 Percentage of Participants |
| Placebo Group | Percentage of Participants Where All Ulcers Healed | Month 12 | 0 Percentage of Participants |
Comparison: The comparison of groups at Month 3p-value: 0.55Fisher Exact
Comparison: The comparison of groups at Month 6.p-value: 0.28Fisher Exact