Critical Limb Ischemia
Conditions
Keywords
CLI
Brief summary
Study to Evaluate the Efficacy and Safety of AMG0001 in Subjects with Critical Limb Ischemia.
Detailed description
This is a double-blind, randomized, placebo-controlled, phase 3, multinational, multicenter study of AMG0001 (HGF plasmid) in subjects with Critical Limb Ischemia (CLI).
Interventions
BIOLOGICALHGF Plasmid (AMG0001)
IM
BIOLOGICALMatching Placebo
IM
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 90 Years
Healthy volunteers
No
Inclusion criteria
1. Subjects with CLI (Severe Rutherford 4 and Rutherford 5) who have: * No option for revascularization by endovascular intervention or surgical bypass or * Poor option (high risk) for revascularization by surgery and no option for an endovascular intervention (see Section 3.1 Study Population for full definition for appropriate inclusions). 2. Subjects 40-90 years of either gender who have signed an informed consent form either directly or through a legally authorized representative. 3. Subjects currently are taking a statin and an anti-platelet agent (e.g., clopidogrel, ticlopidine, aspirin, etc.) for 2 weeks or more prior to Day 0 as part of their standard of care, unless contraindicated. Subjects for whom these agents are contraindicated will have the reason for contraindication recorded in their case report form (CRF). 4. If female, the subjects must not be of child bearing potential, e.g., post-menopausal or surgically sterile. 5. If a male subject is of reproductive potential, he must agree to use an accepted and effective (barrier) form of birth control starting with the first dose of study product and continue for 12 weeks from the last dose of study product. This applies to both courses of treatment. 6. Subjects with a previous medical history of myocardial infarction and/or stroke should have adequate management of risk factors to prevent secondary occurrence. (See Section 4.2 Medical History for guidelines on appropriate secondary prevention.) 7. Subjects should have the ability to understand the requirements of the protocol and agree to return for the required study visits, assessments and follow up. * The index leg will be the leg with the greater severity of CLI disease. Entry requirements apply to the index leg. The index leg may also be referred to as the treated leg or affected leg in the text of this protocol or other study documents. If the subject has two legs that have the same Rutherford classification (severe Rutherford 4 or Rutherford 5) and are both eligible for treatment, the leg with greater disease severity (based on more extensive necrosis or more extensive/deeper ulceration(s), difference in ABI (ankle brachial index) or TBI (toe brachial index) ≥ 0.1, and/or more extensive vascular disease based on the angiogram) will be chosen as the index leg. If there is no clinical, hemodynamic or angiographic or other evidence to determine which leg has greater disease severity, the subject will be excluded from the study. * These entry criteria will be enforced (prior to randomization) by the Sponsor, as well as an Entry Committee who will review all relevant clinical data including but not limited to medical illness, CLI status, the findings of an angiogram, ulcer photographs and measurements and hemodynamic data.
Exclusion criteria
1. Subjects whose CLI status is unstable (spontaneous marked improvement or marked worsening during the screening period) or who have excessive tissue necrosis that is unlikely to benefit from medication, or those poor option subjects requiring immediate revascularization by surgery. Stability of the CLI status will be confirmed by the Principal Investigator prior to randomization and retrospectively reviewed by the Adjudication Committee. 2. Subjects who may require a major amputation (amputation at or above the ankle) within 4 weeks of Day 0 (± 4 weeks of Day 0). 3. Subjects with ulcers with exposure of tendons, osteomyelitis or uncontrolled infection or with the largest ulcer that is greater than 20 cm2 in area (\>10 cm2 area if on the heel). 4. Subjects with purely neuropathic, or with venous ulcers. 5. Subjects in Rutherford 6 class. 6. Subjects who have had revascularization by surgery or angioplasty within 3 months, unless the procedure has failed based on the anatomy or the hemodynamic measurements. 7. Subjects with a diagnosis of Buerger's disease (Thrombo-angiitis Obliterans). 8. Subjects currently receiving immunosuppressive, chemo or radiation therapy. 9. Evidence or history of malignant neoplasm (clinical, laboratory or imaging) except for successfully excised basal cell or squamous cell carcinoma, or successfully excised early melanoma of the skin. Subjects, 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. Subjects, who had successful tumor resection or radio-chemotherapy of all other tumor types and have been in remission for more than 5 years prior to inclusion in the study, and with no recurrence, may be enrolled in the study. A dermatological exam will have ruled out any skin cancer. 10. Subjects who have proliferative retinopathy, or moderate or severe non-proliferative retinopathy, from any cause (ETDRS Score \> 35), clinically significant macular oedema or previous panretinal photocoagulation therapy (Results from the Early Treatment Diabetic Retinopathy Study. Ophthalmology May 1991 Supplement 98: 823-833). 11. Females of child-bearing potential defined as subjects that are not surgically sterile or post-menopausal. 12. Subjects with severe renal disease defined as significant renal dysfunction evidenced by an estimated creatinine clearance of \<30 mL/minute (calculated using the Cockcroft Gault formula), or receiving chronic hemodialysis therapy. 13. Any co-morbid condition likely to interfere with assessment of safety or efficacy endpoints, acute cardiovascular events (i.e., CVA (cardiovascular accident), MI (myocardial infarction), etc.) within 3 months of treatment, or any disease that in the opinion of the Investigator may result in subject mortality in less than 3 months. 14. Subjects with known liver disease (e.g., hepatitis B or C or cirrhosis of the liver). 15. A subject with HIV, AIDS, severe uncontrolled inflammatory disease or severe uncontrolled autoimmune disease (e.g., ulcerative colitis, Crohn's disease, etc). 16. Subjects who have a significant psychiatric disorder or mental disability that could interfere with the subject's ability to provide informed consent or comply with study procedures. 17. Subjects with a current, uncorrected history of alcohol or substance abuse. 18. Diabetic subjects with an uncorrected HbA1c \> 9.0% during the screening period. 19. Subjects that have been administered rhPDGF (e.g, becaplermin) or other growth factors locally within one month of randomization. 20. Subjects who have received another investigational drug within 30 days of randomization or have previously received any gene transfer therapy within 3 years of entering the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Major Amputation or Revascularization (of the Index Leg), All-cause Death, and Incidence of Stroke and Myocardial Infarction (MI) | 18 months | A frequency table for Day 0 to 6 months, Day 0 to 12 months and Day 0 to 18 months intervals by treatment group; the Fisher's Exact test was used for treatment comparison. |
| Change in Ischemic Rest Pain (in the Index Leg) From Baseline Using a 10 cm Visual Analog Scale (VAS) Scale | 18 months | The severity of rest pain (based on the average over previous 7 days) recorded using the 10 cm visual analog scale (VAS). VAS is a 10-cm line (with score ranges 0 to 10), oriented horizontally; the left end of the line (0 mark) indicates no pain; the right end indicates pain as bad as it can be. 1. The subject is asked to mark a place on the line corresponding to the average pain intensity experienced in the last 7 days. 2. The distance along the scale is converted into a numeric reading by measuring the distance of the subjects mark in cm from the beginning of the scale (the 0 mark). |
| Ulcer Improvement | 18 months | A table showing the number of subjects with complete healing of the target ulcer by treatment. Ulcer healing of the largest ulcer on the index limb was assessed clinically by the Principal Investigator by direct visual inspection at each study visit. If the largest ulcer on the index leg was considered completely healed, photographs of the healed ulcer area was captured. If an ulcer healed completely during the study period, the ulcer was re-evaluated 2 weeks later to confirm it has remained healed. Confirmation of complete ulcer healing was made by an outside physician unconnected with the study and nominated for this purpose. |
| VAS Improvement | 18 months | A table showing the number of subjects with improvement in VAS (≥ 20 mm) by treatment. |
| Hemodynamic Measurements - Mean Change From Baseline in Brachial (Right/Left) Systolic Pressure | 18 months | Summary statistics were provided for baseline and change from baseline for right/left brachial systolic pressure by visit and treatment (only subjects with non-missing baseline and visit values). A two-way analysis of covariance (ANCOVA) with treatment and region as fixed factors and baseline as a covariate were performed for each visit and LOCF. |
| Hemodynamic Measurements - Mean Change From Baseline in Ankle (Dorsalis Pedis/Posterior Tibial) Systolic Pressure | 18 months | Summary statistics were provided for baseline and change from baseline for ankle systolic pressure measured at dorsalis pedis and posterior tibial by visit and treatment (only subjects with non-missing baseline and visit values). A two-way analysis of covariance (ANCOVA) with treatment and region as fixed factors and baseline as a covariate were performed for each visit and LOCF. |
| Hemodynamic Measurements - Mean Change From Baseline in Toe Systolic Pressure | 18 months | Summary statistics were provided for baseline and change from baseline for toe systolic pressure by visit and treatment (only subjects with non-missing baseline and visit values). A two-way analysis of covariance (ANCOVA) with treatment and region as fixed factors and baseline as a covariate were performed for each visit and LOCF. |
| Hemodynamic Measurements - Mean Change From Baseline in ABI of Index Leg | 18 months | Summary statistics were provided for baseline and change from baseline for calculated ABI by visit and treatment (only subjects with non-missing baseline and visit values). A two-way analysis of covariance (ANCOVA) with treatment and region as fixed factors and baseline as a covariate were performed for each visit and LOCF. |
| Hemodynamic Measurements - Mean Change From Baseline in TBI of Index Leg | 18 months | Summary statistics were provided for baseline and change from baseline for calculated TBI by visit and treatment (only subjects with non-missing baseline and visit values). A two-way analysis of covariance (ANCOVA) with treatment and region as fixed factors and baseline as a covariate were performed for each visit and LOCF. |
| Changes in the Quality of Life Using the Vascular Quality of Life Questionnaire (VascuQol) Over 18 Months | 18 months | The VascuQol contains 5 domains (pain, symptom, activities, social, and emotional functioning); responses were scored from 0 (lowest QOL, death) to 7 (best QOL, maximum health). Responses were averaged for composite overall and domain-specific scores, giving equal weight to each question and domain. The composite overall is the average of domain-specific scores. Responses after revascularization or major amputation were included in the analysis. In the event of death, subjects were scored as 0. For the effect of treatment on individual domains, pain, symptoms, and activities were considered the most important of the 5 domains. Summary statistics were provided for baseline and change from baseline by visit and treatment for VascuQol, including subscore, for subjects who had a non-missing value at both baseline and the specific visit. A two-way ANCOVA with treatment and region as fixed factors and baseline as a covariate were performed for each visit and LOCF. |
| Changes in the Quality of Life From Baseline Using the EQ-5D-5L Over 18 Months | 18 months | The EQ-5D-5L descriptive system covers 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Each dimension has 5 levels: no problems (1), slight problems (2), moderate problems (3), severe problems (4), and extreme problems (5); death was coded as a worst case. The EQ-5D-5L health state for each subject, referred to as a 5 digit code that combines 1 level from each of the 5 dimensions, was converted into a single index value using a published weighing system. The index value ranges from -0.109 to 1, where 1 indicates no problems in all 5 dimensions, and is reduced when a patient reports increasing problems. Summary statistics were provided for baseline and change from baseline by visit and treatment for EQ-5D-5L, including subscore, for subjects who had a non-missing value at both baseline and the specific visit. A two-way ANCOVA with treatment and region as fixed factors and baseline as a covariate were performed for each visit and LOCF. |
Countries
Belgium, Canada, Denmark, Finland, France, Hungary, Italy, Netherlands, Poland, Sweden, United States
Participant flow
Recruitment details
This study enrolled patients with critical limb ischemia from 69 sites across the United States, Canada, and Europe. The last patient completed in November 28, 2016.
Pre-assignment details
Of the 98 subjects screened, 46 met the entry criteria and were randomized (1:1) into the study to receive AMG0001 or placebo as 4 sets of injections 2 weeks apart at Day 0, Month 3, Month 9, and Month 12.
Participants by arm
| Arm | Count |
|---|---|
| Gene Therapy HGF Plasmid (AMG0001) Randomized subjects will receive 4 sets of intramuscular injections of HGF plasmid two weeks apart starting at Day 0 and again at Month 3 (first cycle) and at Month 9 and again at Month 12 (second cycle) in muscles of the affected lower limb.
HGF Plasmid (AMG0001): IM | 23 |
| Placebo Randomized subjects will receive 4 sets of intramuscular injections of matching placebo two weeks apart starting at Day 0 and again at Month 3 (first cycle) and at Month 9 and again at Month 12 (second cycle) in muscles of the affected lower limb.
Matching Placebo: IM | 23 |
| Total | 46 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 2 | 2 |
| Overall Study | Other | 0 | 1 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Study Discontinuation by Sponsor | 19 | 14 |
| Overall Study | Withdrawal by Subject | 1 | 5 |
Baseline characteristics
| Characteristic | Gene Therapy HGF Plasmid (AMG0001) | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 14 Participants | 14 Participants | 28 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants | 9 Participants | 18 Participants |
| Age, Continuous | 67.5 years STANDARD_DEVIATION 12 | 67 years STANDARD_DEVIATION 9.79 | 67.3 years STANDARD_DEVIATION 10.83 |
| Alcohol Use No | 15 Participants | 17 Participants | 32 Participants |
| Alcohol Use Yes | 8 Participants | 6 Participants | 14 Participants |
| Ankle-brachial index (ABI) at baseline | 0.449 ratio STANDARD_DEVIATION 0.1944 | 0.360 ratio STANDARD_DEVIATION 0.2239 | 0.392 ratio STANDARD_DEVIATION 0.218 |
| Current Tobacco Use No | 17 Participants | 17 Participants | 34 Participants |
| Current Tobacco Use Yes | 6 Participants | 6 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 23 Participants | 23 Participants | 46 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Ischemic Rest Pain (cm) | 5.03 cm STANDARD_DEVIATION 2.92 | 6.04 cm STANDARD_DEVIATION 2.82 | 5.52 cm STANDARD_DEVIATION 2.89 |
| Past Tobacco Use No | 9 Participants | 5 Participants | 14 Participants |
| Past Tobacco Use Yes | 14 Participants | 18 Participants | 32 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 | 3 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 18 Participants | 21 Participants | 39 Participants |
| Region of Enrollment Belgium | 1 participants | 1 participants | 2 participants |
| Region of Enrollment Canada | 1 participants | 1 participants | 2 participants |
| Region of Enrollment France | 1 participants | 2 participants | 3 participants |
| Region of Enrollment Hungary | 8 participants | 6 participants | 14 participants |
| Region of Enrollment Poland | 0 participants | 1 participants | 1 participants |
| Region of Enrollment United States | 12 participants | 12 participants | 24 participants |
| Sex: Female, Male Female | 6 Participants | 7 Participants | 13 Participants |
| Sex: Female, Male Male | 17 Participants | 16 Participants | 33 Participants |
| Toe-brachial index (TBI) at baseline | 0.134 ratio STANDARD_DEVIATION 0.128 | 0.167 ratio STANDARD_DEVIATION 0.166 | 0.149 ratio STANDARD_DEVIATION 0.146 |
| Ulcer Present | 11 Participants | 13 Participants | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 23 | 2 / 23 |
| other Total, other adverse events | 5 / 23 | 7 / 23 |
| serious Total, serious adverse events | 7 / 23 | 9 / 23 |
Outcome results
Primary
Change in Ischemic Rest Pain (in the Index Leg) From Baseline Using a 10 cm Visual Analog Scale (VAS) Scale
The severity of rest pain (based on the average over previous 7 days) recorded using the 10 cm visual analog scale (VAS). VAS is a 10-cm line (with score ranges 0 to 10), oriented horizontally; the left end of the line (0 mark) indicates no pain; the right end indicates pain as bad as it can be. 1. The subject is asked to mark a place on the line corresponding to the average pain intensity experienced in the last 7 days. 2. The distance along the scale is converted into a numeric reading by measuring the distance of the subjects mark in cm from the beginning of the scale (the 0 mark).
Time frame: 18 months
Population: The number analyzed in one or more rows differs from overall number analyzed due to early discontinuation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gene Therapy HGF Plasmid (AMG0001) | Change in Ischemic Rest Pain (in the Index Leg) From Baseline Using a 10 cm Visual Analog Scale (VAS) Scale | Change from Baseline at Month 3 | 0.40 score on a scale | Standard Deviation 2.31 |
| Gene Therapy HGF Plasmid (AMG0001) | Change in Ischemic Rest Pain (in the Index Leg) From Baseline Using a 10 cm Visual Analog Scale (VAS) Scale | Change from Baseline at Month 6 | 0.20 score on a scale | Standard Deviation 3.002 |
| Gene Therapy HGF Plasmid (AMG0001) | Change in Ischemic Rest Pain (in the Index Leg) From Baseline Using a 10 cm Visual Analog Scale (VAS) Scale | Change from Baseline at Month 9 | -0.15 score on a scale | Standard Deviation 2.281 |
| Gene Therapy HGF Plasmid (AMG0001) | Change in Ischemic Rest Pain (in the Index Leg) From Baseline Using a 10 cm Visual Analog Scale (VAS) Scale | Change from Baseline at Month 12 | -2.39 score on a scale | Standard Deviation 2.156 |
| Gene Therapy HGF Plasmid (AMG0001) | Change in Ischemic Rest Pain (in the Index Leg) From Baseline Using a 10 cm Visual Analog Scale (VAS) Scale | Change from Baseline at Month 15 | -0.80 score on a scale | Standard Deviation 1.825 |
| Gene Therapy HGF Plasmid (AMG0001) | Change in Ischemic Rest Pain (in the Index Leg) From Baseline Using a 10 cm Visual Analog Scale (VAS) Scale | Change from Baseline at LOCF | -1.61 score on a scale | Standard Deviation 2.863 |
| Placebo | Change in Ischemic Rest Pain (in the Index Leg) From Baseline Using a 10 cm Visual Analog Scale (VAS) Scale | Change from Baseline at Month 15 | 2.40 score on a scale | Standard Deviation 1.98 |
| Placebo | Change in Ischemic Rest Pain (in the Index Leg) From Baseline Using a 10 cm Visual Analog Scale (VAS) Scale | Change from Baseline at Month 3 | -0.79 score on a scale | Standard Deviation 2.889 |
| Placebo | Change in Ischemic Rest Pain (in the Index Leg) From Baseline Using a 10 cm Visual Analog Scale (VAS) Scale | Change from Baseline at Month 12 | 0.00 score on a scale | Standard Deviation 0.2 |
| Placebo | Change in Ischemic Rest Pain (in the Index Leg) From Baseline Using a 10 cm Visual Analog Scale (VAS) Scale | Change from Baseline at Month 6 | -1.65 score on a scale | Standard Deviation 2.704 |
| Placebo | Change in Ischemic Rest Pain (in the Index Leg) From Baseline Using a 10 cm Visual Analog Scale (VAS) Scale | Change from Baseline at LOCF | -0.20 score on a scale | Standard Deviation 3.087 |
| Placebo | Change in Ischemic Rest Pain (in the Index Leg) From Baseline Using a 10 cm Visual Analog Scale (VAS) Scale | Change from Baseline at Month 9 | -0.90 score on a scale | Standard Deviation 2.801 |
Comparison: Change from Baseline at Month 3p-value: 0.514ANCOVA
Comparison: Change from Baseline at Month 6p-value: 0.445ANCOVA
Comparison: Change from Baseline at Month 9p-value: 0.863ANCOVA
Comparison: Change from Baseline at Month 12p-value: 0.111ANCOVA
Comparison: Change from Baseline at Month 15p-value: 0.153ANCOVA
Comparison: Change from Baseline at last observation carried forward (LOCF)p-value: 0.002ANCOVA
Primary
Changes in the Quality of Life From Baseline Using the EQ-5D-5L Over 18 Months
The EQ-5D-5L descriptive system covers 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Each dimension has 5 levels: no problems (1), slight problems (2), moderate problems (3), severe problems (4), and extreme problems (5); death was coded as a worst case. The EQ-5D-5L health state for each subject, referred to as a 5 digit code that combines 1 level from each of the 5 dimensions, was converted into a single index value using a published weighing system. The index value ranges from -0.109 to 1, where 1 indicates no problems in all 5 dimensions, and is reduced when a patient reports increasing problems. Summary statistics were provided for baseline and change from baseline by visit and treatment for EQ-5D-5L, including subscore, for subjects who had a non-missing value at both baseline and the specific visit. A two-way ANCOVA with treatment and region as fixed factors and baseline as a covariate were performed for each visit and LOCF.
Time frame: 18 months
Population: The number analyzed in one or more rows differs from overall number analyzed due to early discontinuation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gene Therapy HGF Plasmid (AMG0001) | Changes in the Quality of Life From Baseline Using the EQ-5D-5L Over 18 Months | Change from Baseline at Month 3 | 0.03 score on a scale | Standard Deviation 0.13 |
| Gene Therapy HGF Plasmid (AMG0001) | Changes in the Quality of Life From Baseline Using the EQ-5D-5L Over 18 Months | Change from Baseline at Month 6 | 0.01 score on a scale | Standard Deviation 0.127 |
| Gene Therapy HGF Plasmid (AMG0001) | Changes in the Quality of Life From Baseline Using the EQ-5D-5L Over 18 Months | Change from Baseline at Month 9 | -0.06 score on a scale | Standard Deviation 0.168 |
| Gene Therapy HGF Plasmid (AMG0001) | Changes in the Quality of Life From Baseline Using the EQ-5D-5L Over 18 Months | Change from Baseline at Month 12 | 0.08 score on a scale | Standard Deviation 0.193 |
| Gene Therapy HGF Plasmid (AMG0001) | Changes in the Quality of Life From Baseline Using the EQ-5D-5L Over 18 Months | Change from Baseline at Month 15 | -0.03 score on a scale | Standard Deviation 0.043 |
| Gene Therapy HGF Plasmid (AMG0001) | Changes in the Quality of Life From Baseline Using the EQ-5D-5L Over 18 Months | Change from Baseline at LOCF | 0.04 score on a scale | Standard Deviation 0.194 |
| Placebo | Changes in the Quality of Life From Baseline Using the EQ-5D-5L Over 18 Months | Change from Baseline at Month 18 | -0.02 score on a scale | — |
| Placebo | Changes in the Quality of Life From Baseline Using the EQ-5D-5L Over 18 Months | Change from Baseline at Month 12 | 0.08 score on a scale | Standard Deviation 0.097 |
| Placebo | Changes in the Quality of Life From Baseline Using the EQ-5D-5L Over 18 Months | Change from Baseline at Month 3 | 0.03 score on a scale | Standard Deviation 0.149 |
| Placebo | Changes in the Quality of Life From Baseline Using the EQ-5D-5L Over 18 Months | Change from Baseline at LOCF | 0.03 score on a scale | Standard Deviation 0.153 |
| Placebo | Changes in the Quality of Life From Baseline Using the EQ-5D-5L Over 18 Months | Change from Baseline at Month 6 | 0.04 score on a scale | Standard Deviation 0.114 |
| Placebo | Changes in the Quality of Life From Baseline Using the EQ-5D-5L Over 18 Months | Change from Baseline at Month 15 | 0.05 score on a scale | Standard Deviation 0.156 |
| Placebo | Changes in the Quality of Life From Baseline Using the EQ-5D-5L Over 18 Months | Change from Baseline at Month 9 | 0.07 score on a scale | Standard Deviation 0.092 |
Comparison: Change from Baseline at Month 3p-value: 0.941ANCOVA
Comparison: Change from Baseline at Month 6p-value: 0.584ANCOVA
Comparison: Change from Baseline at Month 9p-value: 0.1ANCOVA
Comparison: Change from Baseline at Month 12p-value: 0.916ANCOVA
Comparison: Change from Baseline at Month 15p-value: 0.486ANCOVA
Comparison: Change from Baseline at LOCFp-value: 0.835ANCOVA
Primary
Changes in the Quality of Life Using the Vascular Quality of Life Questionnaire (VascuQol) Over 18 Months
The VascuQol contains 5 domains (pain, symptom, activities, social, and emotional functioning); responses were scored from 0 (lowest QOL, death) to 7 (best QOL, maximum health). Responses were averaged for composite overall and domain-specific scores, giving equal weight to each question and domain. The composite overall is the average of domain-specific scores. Responses after revascularization or major amputation were included in the analysis. In the event of death, subjects were scored as 0. For the effect of treatment on individual domains, pain, symptoms, and activities were considered the most important of the 5 domains. Summary statistics were provided for baseline and change from baseline by visit and treatment for VascuQol, including subscore, for subjects who had a non-missing value at both baseline and the specific visit. A two-way ANCOVA with treatment and region as fixed factors and baseline as a covariate were performed for each visit and LOCF.
Time frame: 18 months
Population: The number analyzed in one or more rows differs from overall number analyzed due to early discontinuation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gene Therapy HGF Plasmid (AMG0001) | Changes in the Quality of Life Using the Vascular Quality of Life Questionnaire (VascuQol) Over 18 Months | Pain (LOCF) | 1.46 score on a scale | Standard Deviation 1.158 |
| Gene Therapy HGF Plasmid (AMG0001) | Changes in the Quality of Life Using the Vascular Quality of Life Questionnaire (VascuQol) Over 18 Months | Symptom (LOCF) | 0.79 score on a scale | Standard Deviation 1.475 |
| Gene Therapy HGF Plasmid (AMG0001) | Changes in the Quality of Life Using the Vascular Quality of Life Questionnaire (VascuQol) Over 18 Months | Activities (LOCF) | 0.59 score on a scale | Standard Deviation 0.95 |
| Gene Therapy HGF Plasmid (AMG0001) | Changes in the Quality of Life Using the Vascular Quality of Life Questionnaire (VascuQol) Over 18 Months | Social (LOCF) | 0.53 score on a scale | Standard Deviation 1.086 |
| Gene Therapy HGF Plasmid (AMG0001) | Changes in the Quality of Life Using the Vascular Quality of Life Questionnaire (VascuQol) Over 18 Months | Emotional Functioning (LOCF) | 0.77 score on a scale | Standard Deviation 1.247 |
| Gene Therapy HGF Plasmid (AMG0001) | Changes in the Quality of Life Using the Vascular Quality of Life Questionnaire (VascuQol) Over 18 Months | Composite Overall (LOCF) | 0.81 score on a scale | Standard Deviation 0.843 |
| Placebo | Changes in the Quality of Life Using the Vascular Quality of Life Questionnaire (VascuQol) Over 18 Months | Emotional Functioning (LOCF) | 0.83 score on a scale | Standard Deviation 1.458 |
| Placebo | Changes in the Quality of Life Using the Vascular Quality of Life Questionnaire (VascuQol) Over 18 Months | Pain (LOCF) | 0.83 score on a scale | Standard Deviation 1.557 |
| Placebo | Changes in the Quality of Life Using the Vascular Quality of Life Questionnaire (VascuQol) Over 18 Months | Social (LOCF) | 0.39 score on a scale | Standard Deviation 1.852 |
| Placebo | Changes in the Quality of Life Using the Vascular Quality of Life Questionnaire (VascuQol) Over 18 Months | Symptom (LOCF) | 0.71 score on a scale | Standard Deviation 1.468 |
| Placebo | Changes in the Quality of Life Using the Vascular Quality of Life Questionnaire (VascuQol) Over 18 Months | Composite Overall (LOCF) | 0.74 score on a scale | Standard Deviation 1.068 |
| Placebo | Changes in the Quality of Life Using the Vascular Quality of Life Questionnaire (VascuQol) Over 18 Months | Activities (LOCF) | 0.66 score on a scale | Standard Deviation 0.981 |
Comparison: Pain (LOCF)p-value: 0.105ANCOVA
Comparison: Symptom (LOCF)p-value: 0.557ANCOVA
Comparison: Activities (LOCF)p-value: 0.94ANCOVA
Comparison: Social (LOCF)p-value: 0.905ANCOVA
Comparison: Emotional Functioning (LOCF)p-value: 0.782ANCOVA
Comparison: Composite Overall (LOCF)p-value: 0.802ANCOVA
Primary
Hemodynamic Measurements - Mean Change From Baseline in ABI of Index Leg
Summary statistics were provided for baseline and change from baseline for calculated ABI by visit and treatment (only subjects with non-missing baseline and visit values). A two-way analysis of covariance (ANCOVA) with treatment and region as fixed factors and baseline as a covariate were performed for each visit and LOCF.
Time frame: 18 months
Population: The number analyzed in one or more rows differs from overall number analyzed due to early discontinuation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gene Therapy HGF Plasmid (AMG0001) | Hemodynamic Measurements - Mean Change From Baseline in ABI of Index Leg | Change from Baseline at Month 3 | -0.009 ratio | Standard Deviation 0.2612 |
| Gene Therapy HGF Plasmid (AMG0001) | Hemodynamic Measurements - Mean Change From Baseline in ABI of Index Leg | Change from Baseline at Month 6 | 0.097 ratio | Standard Deviation 0.092 |
| Gene Therapy HGF Plasmid (AMG0001) | Hemodynamic Measurements - Mean Change From Baseline in ABI of Index Leg | Change from Baseline at Month 9 | 0.098 ratio | Standard Deviation 0.1001 |
| Gene Therapy HGF Plasmid (AMG0001) | Hemodynamic Measurements - Mean Change From Baseline in ABI of Index Leg | Change from Baseline at Month 12 | 0.303 ratio | Standard Deviation 0.3481 |
| Gene Therapy HGF Plasmid (AMG0001) | Hemodynamic Measurements - Mean Change From Baseline in ABI of Index Leg | Change from Baseline at Month 15 | -0.077 ratio | Standard Deviation 0.2101 |
| Gene Therapy HGF Plasmid (AMG0001) | Hemodynamic Measurements - Mean Change From Baseline in ABI of Index Leg | Change from Baseline at LOCF | 0.115 ratio | Standard Deviation 0.3662 |
| Placebo | Hemodynamic Measurements - Mean Change From Baseline in ABI of Index Leg | Change from Baseline at Month 15 | 0.090 ratio | Standard Deviation 0.1556 |
| Placebo | Hemodynamic Measurements - Mean Change From Baseline in ABI of Index Leg | Change from Baseline at Month 3 | 0.105 ratio | Standard Deviation 0.1661 |
| Placebo | Hemodynamic Measurements - Mean Change From Baseline in ABI of Index Leg | Change from Baseline at Month 12 | 0.098 ratio | Standard Deviation 0.0964 |
| Placebo | Hemodynamic Measurements - Mean Change From Baseline in ABI of Index Leg | Change from Baseline at Month 6 | 0.028 ratio | Standard Deviation 0.2257 |
| Placebo | Hemodynamic Measurements - Mean Change From Baseline in ABI of Index Leg | Change from Baseline at LOCF | 0.111 ratio | Standard Deviation 0.1855 |
| Placebo | Hemodynamic Measurements - Mean Change From Baseline in ABI of Index Leg | Change from Baseline at Month 9 | 0.246 ratio | Standard Deviation 0.3272 |
Comparison: Change from Baseline at Month 3p-value: 0.268ANCOVA
Comparison: Change from Baseline at Month 6p-value: 0.32ANCOVA
Comparison: Change from Baseline at Month 9p-value: 0.315ANCOVA
Comparison: Change from Baseline at Month 12p-value: 0.327ANCOVA
Comparison: Change from Baseline at Month 15p-value: 0.643ANCOVA
Comparison: Change from Baseline at LOCFp-value: 0.74ANCOVA
Primary
Hemodynamic Measurements - Mean Change From Baseline in Ankle (Dorsalis Pedis/Posterior Tibial) Systolic Pressure
Summary statistics were provided for baseline and change from baseline for ankle systolic pressure measured at dorsalis pedis and posterior tibial by visit and treatment (only subjects with non-missing baseline and visit values). A two-way analysis of covariance (ANCOVA) with treatment and region as fixed factors and baseline as a covariate were performed for each visit and LOCF.
Time frame: 18 months
Population: The number analyzed in one or more rows differs from overall number analyzed due to early discontinuation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gene Therapy HGF Plasmid (AMG0001) | Hemodynamic Measurements - Mean Change From Baseline in Ankle (Dorsalis Pedis/Posterior Tibial) Systolic Pressure | Change from Baseline at Month 3 (Dorsalis Pedis) | 4.2 mmHg | Standard Deviation 35.66 |
| Gene Therapy HGF Plasmid (AMG0001) | Hemodynamic Measurements - Mean Change From Baseline in Ankle (Dorsalis Pedis/Posterior Tibial) Systolic Pressure | Change from Baseline at Month 6 (Dorsalis Pedis) | 12.7 mmHg | Standard Deviation 19.96 |
| Gene Therapy HGF Plasmid (AMG0001) | Hemodynamic Measurements - Mean Change From Baseline in Ankle (Dorsalis Pedis/Posterior Tibial) Systolic Pressure | Change from Baseline at Month 9 (Dorsalis Pedis) | 3.4 mmHg | Standard Deviation 40.59 |
| Gene Therapy HGF Plasmid (AMG0001) | Hemodynamic Measurements - Mean Change From Baseline in Ankle (Dorsalis Pedis/Posterior Tibial) Systolic Pressure | Change from Baseline at Month 12 (Dorsalis Pedis) | 59.4 mmHg | Standard Deviation 47 |
| Gene Therapy HGF Plasmid (AMG0001) | Hemodynamic Measurements - Mean Change From Baseline in Ankle (Dorsalis Pedis/Posterior Tibial) Systolic Pressure | Change from Baseline at Month 15 (Dorsalis Pedis) | 18.5 mmHg | Standard Deviation 10.61 |
| Gene Therapy HGF Plasmid (AMG0001) | Hemodynamic Measurements - Mean Change From Baseline in Ankle (Dorsalis Pedis/Posterior Tibial) Systolic Pressure | Change from Baseline at LOCF (Dorsalis Pedis) | 32.9 mmHg | Standard Deviation 41.55 |
| Gene Therapy HGF Plasmid (AMG0001) | Hemodynamic Measurements - Mean Change From Baseline in Ankle (Dorsalis Pedis/Posterior Tibial) Systolic Pressure | Change from Baseline at Month 3 (Posterior Tibial) | 15.2 mmHg | Standard Deviation 35.02 |
| Gene Therapy HGF Plasmid (AMG0001) | Hemodynamic Measurements - Mean Change From Baseline in Ankle (Dorsalis Pedis/Posterior Tibial) Systolic Pressure | Change from Baseline at Month 6 (Posterior Tibial) | 28.4 mmHg | Standard Deviation 28.32 |
| Gene Therapy HGF Plasmid (AMG0001) | Hemodynamic Measurements - Mean Change From Baseline in Ankle (Dorsalis Pedis/Posterior Tibial) Systolic Pressure | Change from Baseline at Month 9 (Posterior Tibial) | 4.5 mmHg | Standard Deviation 24.64 |
| Gene Therapy HGF Plasmid (AMG0001) | Hemodynamic Measurements - Mean Change From Baseline in Ankle (Dorsalis Pedis/Posterior Tibial) Systolic Pressure | Change from Baseline atMonth 12 (Posterior Tibial) | 45.0 mmHg | Standard Deviation 28.86 |
| Gene Therapy HGF Plasmid (AMG0001) | Hemodynamic Measurements - Mean Change From Baseline in Ankle (Dorsalis Pedis/Posterior Tibial) Systolic Pressure | Change from Baseline atMonth 15 (Posterior Tibial) | 40.5 mmHg | Standard Deviation 51.62 |
| Gene Therapy HGF Plasmid (AMG0001) | Hemodynamic Measurements - Mean Change From Baseline in Ankle (Dorsalis Pedis/Posterior Tibial) Systolic Pressure | Change from Baseline at LOCF (Posterior Tibial) | 35.1 mmHg | Standard Deviation 33.97 |
| Placebo | Hemodynamic Measurements - Mean Change From Baseline in Ankle (Dorsalis Pedis/Posterior Tibial) Systolic Pressure | Change from Baseline atMonth 15 (Posterior Tibial) | -10.0 mmHg | — |
| Placebo | Hemodynamic Measurements - Mean Change From Baseline in Ankle (Dorsalis Pedis/Posterior Tibial) Systolic Pressure | Change from Baseline at Month 3 (Dorsalis Pedis) | 11.2 mmHg | Standard Deviation 30.15 |
| Placebo | Hemodynamic Measurements - Mean Change From Baseline in Ankle (Dorsalis Pedis/Posterior Tibial) Systolic Pressure | Change from Baseline at Month 3 (Posterior Tibial) | 16.1 mmHg | Standard Deviation 31.81 |
| Placebo | Hemodynamic Measurements - Mean Change From Baseline in Ankle (Dorsalis Pedis/Posterior Tibial) Systolic Pressure | Change from Baseline at Month 6 (Dorsalis Pedis) | 9.9 mmHg | Standard Deviation 22.73 |
| Placebo | Hemodynamic Measurements - Mean Change From Baseline in Ankle (Dorsalis Pedis/Posterior Tibial) Systolic Pressure | Change from Baseline atMonth 12 (Posterior Tibial) | 4.3 mmHg | Standard Deviation 5.86 |
| Placebo | Hemodynamic Measurements - Mean Change From Baseline in Ankle (Dorsalis Pedis/Posterior Tibial) Systolic Pressure | Change from Baseline at Month 9 (Dorsalis Pedis) | 3.0 mmHg | Standard Deviation 57.86 |
| Placebo | Hemodynamic Measurements - Mean Change From Baseline in Ankle (Dorsalis Pedis/Posterior Tibial) Systolic Pressure | Change from Baseline at Month 6 (Posterior Tibial) | 19.2 mmHg | Standard Deviation 37.04 |
| Placebo | Hemodynamic Measurements - Mean Change From Baseline in Ankle (Dorsalis Pedis/Posterior Tibial) Systolic Pressure | Change from Baseline at Month 12 (Dorsalis Pedis) | 12.0 mmHg | Standard Deviation 15.62 |
| Placebo | Hemodynamic Measurements - Mean Change From Baseline in Ankle (Dorsalis Pedis/Posterior Tibial) Systolic Pressure | Change from Baseline at LOCF (Posterior Tibial) | 13.2 mmHg | Standard Deviation 24.98 |
| Placebo | Hemodynamic Measurements - Mean Change From Baseline in Ankle (Dorsalis Pedis/Posterior Tibial) Systolic Pressure | Change from Baseline at Month 15 (Dorsalis Pedis) | 3.0 mmHg | — |
| Placebo | Hemodynamic Measurements - Mean Change From Baseline in Ankle (Dorsalis Pedis/Posterior Tibial) Systolic Pressure | Change from Baseline at Month 9 (Posterior Tibial) | -3.5 mmHg | Standard Deviation 15.5 |
| Placebo | Hemodynamic Measurements - Mean Change From Baseline in Ankle (Dorsalis Pedis/Posterior Tibial) Systolic Pressure | Change from Baseline at LOCF (Dorsalis Pedis) | 16.7 mmHg | Standard Deviation 34.25 |
Comparison: Change from Baseline at Month 3 (Dorsalis Pedis)p-value: 0.803ANCOVA
Comparison: Change from Baseline at Month 6 (Dorsalis Pedis)p-value: 0.668ANCOVA
Comparison: Change from Baseline at Month 9 (Dorsalis Pedis)p-value: 0.789ANCOVA
Comparison: Change from Baseline at Month 12 (Dorsalis Pedis)p-value: 0.28ANCOVA
Comparison: Change from Baseline at LOCF (Dorsalis Pedis)p-value: 0.324ANCOVA
Comparison: Change from Baseline at Month 3 (Posterior Tibial)p-value: 0.759ANCOVA
Comparison: Change from Baseline at Month 6 (Posterior Tibial)p-value: 0.414ANCOVA
Comparison: Change from Baseline at Month 9 (Posterior Tibial)p-value: 0.886ANCOVA
Comparison: Change from Baseline at Month 12 (Posterior Tibial)p-value: 0.114ANCOVA
Comparison: Change from Baseline at LOCF (Posterior Tibial)p-value: 0.051ANCOVA
Primary
Hemodynamic Measurements - Mean Change From Baseline in Brachial (Right/Left) Systolic Pressure
Summary statistics were provided for baseline and change from baseline for right/left brachial systolic pressure by visit and treatment (only subjects with non-missing baseline and visit values). A two-way analysis of covariance (ANCOVA) with treatment and region as fixed factors and baseline as a covariate were performed for each visit and LOCF.
Time frame: 18 months
Population: The number analyzed in one or more rows differs from overall number analyzed due to early discontinuation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gene Therapy HGF Plasmid (AMG0001) | Hemodynamic Measurements - Mean Change From Baseline in Brachial (Right/Left) Systolic Pressure | Change from Baseline at Month 3 (right) | 0.7 mmHg | Standard Deviation 27.27 |
| Gene Therapy HGF Plasmid (AMG0001) | Hemodynamic Measurements - Mean Change From Baseline in Brachial (Right/Left) Systolic Pressure | Change from Baseline at Month 6 (right) | -2.4 mmHg | Standard Deviation 23.49 |
| Gene Therapy HGF Plasmid (AMG0001) | Hemodynamic Measurements - Mean Change From Baseline in Brachial (Right/Left) Systolic Pressure | Change from Baseline at Month 9 (right) | 2.3 mmHg | Standard Deviation 14.5 |
| Gene Therapy HGF Plasmid (AMG0001) | Hemodynamic Measurements - Mean Change From Baseline in Brachial (Right/Left) Systolic Pressure | Change from Baseline at Month 12 (right) | -5.8 mmHg | Standard Deviation 16.76 |
| Gene Therapy HGF Plasmid (AMG0001) | Hemodynamic Measurements - Mean Change From Baseline in Brachial (Right/Left) Systolic Pressure | Change from Baseline at Month 15 (right) | 5.7 mmHg | Standard Deviation 22.81 |
| Gene Therapy HGF Plasmid (AMG0001) | Hemodynamic Measurements - Mean Change From Baseline in Brachial (Right/Left) Systolic Pressure | Change from Baseline at LOCF (right) | -2.3 mmHg | Standard Deviation 24.36 |
| Gene Therapy HGF Plasmid (AMG0001) | Hemodynamic Measurements - Mean Change From Baseline in Brachial (Right/Left) Systolic Pressure | Change from Baseline at Month 3 (left) | 7.9 mmHg | Standard Deviation 27.37 |
| Gene Therapy HGF Plasmid (AMG0001) | Hemodynamic Measurements - Mean Change From Baseline in Brachial (Right/Left) Systolic Pressure | Change from Baseline at Month 6 (left) | -1.1 mmHg | Standard Deviation 28.61 |
| Gene Therapy HGF Plasmid (AMG0001) | Hemodynamic Measurements - Mean Change From Baseline in Brachial (Right/Left) Systolic Pressure | Change from Baseline at Month 9 (left) | -0.8 mmHg | Standard Deviation 14.52 |
| Gene Therapy HGF Plasmid (AMG0001) | Hemodynamic Measurements - Mean Change From Baseline in Brachial (Right/Left) Systolic Pressure | Change from Baseline at Month 12 (left) | 0.6 mmHg | Standard Deviation 14 |
| Gene Therapy HGF Plasmid (AMG0001) | Hemodynamic Measurements - Mean Change From Baseline in Brachial (Right/Left) Systolic Pressure | Change from Baseline at Month 15 (left | 4.7 mmHg | Standard Deviation 21.01 |
| Gene Therapy HGF Plasmid (AMG0001) | Hemodynamic Measurements - Mean Change From Baseline in Brachial (Right/Left) Systolic Pressure | Change from Baseline at LOCF (left) | 2.6 mmHg | Standard Deviation 26.68 |
| Placebo | Hemodynamic Measurements - Mean Change From Baseline in Brachial (Right/Left) Systolic Pressure | Change from Baseline at LOCF (right) | 8.2 mmHg | Standard Deviation 23.94 |
| Placebo | Hemodynamic Measurements - Mean Change From Baseline in Brachial (Right/Left) Systolic Pressure | Change from Baseline at Month 12 (left) | 10.0 mmHg | Standard Deviation 11.36 |
| Placebo | Hemodynamic Measurements - Mean Change From Baseline in Brachial (Right/Left) Systolic Pressure | Change from Baseline at Month 3 (left) | -5.7 mmHg | Standard Deviation 22.24 |
| Placebo | Hemodynamic Measurements - Mean Change From Baseline in Brachial (Right/Left) Systolic Pressure | Change from Baseline at Month 3 (right) | 2.4 mmHg | Standard Deviation 18.78 |
| Placebo | Hemodynamic Measurements - Mean Change From Baseline in Brachial (Right/Left) Systolic Pressure | Change from Baseline at LOCF (left) | -0.9 mmHg | Standard Deviation 19.2 |
| Placebo | Hemodynamic Measurements - Mean Change From Baseline in Brachial (Right/Left) Systolic Pressure | Change from Baseline at Month 6 (right) | 0.7 mmHg | Standard Deviation 33.58 |
| Placebo | Hemodynamic Measurements - Mean Change From Baseline in Brachial (Right/Left) Systolic Pressure | Change from Baseline at Month 6 (left) | -15.8 mmHg | Standard Deviation 30.04 |
| Placebo | Hemodynamic Measurements - Mean Change From Baseline in Brachial (Right/Left) Systolic Pressure | Change from Baseline at Month 9 (right) | -7.2 mmHg | Standard Deviation 26.52 |
| Placebo | Hemodynamic Measurements - Mean Change From Baseline in Brachial (Right/Left) Systolic Pressure | Change from Baseline at Month 15 (left | -18.5 mmHg | Standard Deviation 38.89 |
| Placebo | Hemodynamic Measurements - Mean Change From Baseline in Brachial (Right/Left) Systolic Pressure | Change from Baseline at Month 12 (right) | 5.0 mmHg | Standard Deviation 15.6 |
| Placebo | Hemodynamic Measurements - Mean Change From Baseline in Brachial (Right/Left) Systolic Pressure | Change from Baseline at Month 9 (left) | -25.8 mmHg | Standard Deviation 30.78 |
| Placebo | Hemodynamic Measurements - Mean Change From Baseline in Brachial (Right/Left) Systolic Pressure | Change from Baseline at Month 15 (right) | 13.0 mmHg | Standard Deviation 6.08 |
| Placebo | Hemodynamic Measurements - Mean Change From Baseline in Brachial (Right/Left) Systolic Pressure | Change from Baseline at Month 18 (right) | 23.0 mmHg | — |
| Placebo | Hemodynamic Measurements - Mean Change From Baseline in Brachial (Right/Left) Systolic Pressure | Change from Baseline at Month 18 (left) | -2.0 mmHg | — |
Comparison: Change from baseline at Month 3 (right brachial)p-value: 0.733ANCOVA
Comparison: Change from baseline at Month 6 (right brachial)p-value: 0.808ANCOVA
Comparison: Change from baseline at Month 9 (right brachial)p-value: 0.487ANCOVA
Comparison: Change from baseline at Month 12 (right brachial)p-value: 0.216ANCOVA
Comparison: Change from baseline at Month 15 (right brachial)p-value: 0.896ANCOVA
Comparison: Change from baseline at last observation carried forward (LOCF) (right brachial)p-value: 0.167ANCOVA
Comparison: Change from baseline at Month 3 (left brachial)p-value: 0.378ANCOVA
Comparison: Change from baseline at Month 6 (left brachial)p-value: 0.39ANCOVA
Comparison: Change from baseline at Month 9 (left brachial)p-value: 0.521ANCOVA
Comparison: Change from baseline at Month 12 (left brachial)p-value: 0.044ANCOVA
Comparison: Change from baseline at Month 15 (left brachial)p-value: 0.423ANCOVA
Comparison: Change from baseline at LOCF (left brachial)p-value: 0.989ANCOVA
Primary
Hemodynamic Measurements - Mean Change From Baseline in TBI of Index Leg
Summary statistics were provided for baseline and change from baseline for calculated TBI by visit and treatment (only subjects with non-missing baseline and visit values). A two-way analysis of covariance (ANCOVA) with treatment and region as fixed factors and baseline as a covariate were performed for each visit and LOCF.
Time frame: 18 months
Population: The number analyzed in one or more rows differs from overall number analyzed due to early discontinuation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gene Therapy HGF Plasmid (AMG0001) | Hemodynamic Measurements - Mean Change From Baseline in TBI of Index Leg | Change from Baseline at Month 3 | 0.024 ratio | Standard Deviation 0.1661 |
| Gene Therapy HGF Plasmid (AMG0001) | Hemodynamic Measurements - Mean Change From Baseline in TBI of Index Leg | Change from Baseline at Month 6 | 0.133 ratio | Standard Deviation 0.1398 |
| Gene Therapy HGF Plasmid (AMG0001) | Hemodynamic Measurements - Mean Change From Baseline in TBI of Index Leg | Change from Baseline at Month 9 | 0.134 ratio | Standard Deviation 0.1493 |
| Gene Therapy HGF Plasmid (AMG0001) | Hemodynamic Measurements - Mean Change From Baseline in TBI of Index Leg | Change from Baseline at Month 12 | 0.303 ratio | Standard Deviation 0.2945 |
| Gene Therapy HGF Plasmid (AMG0001) | Hemodynamic Measurements - Mean Change From Baseline in TBI of Index Leg | Change from Baseline at Month 15 | 0.110 ratio | Standard Deviation 0.2261 |
| Gene Therapy HGF Plasmid (AMG0001) | Hemodynamic Measurements - Mean Change From Baseline in TBI of Index Leg | Change from Baseline at LOCF | 0.168 ratio | Standard Deviation 0.2692 |
| Placebo | Hemodynamic Measurements - Mean Change From Baseline in TBI of Index Leg | Change from Baseline at Month 18 | 0.070 ratio | — |
| Placebo | Hemodynamic Measurements - Mean Change From Baseline in TBI of Index Leg | Change from Baseline at Month 12 | 0.238 ratio | Standard Deviation 0.2045 |
| Placebo | Hemodynamic Measurements - Mean Change From Baseline in TBI of Index Leg | Change from Baseline at Month 3 | -0.078 ratio | Standard Deviation 0.1536 |
| Placebo | Hemodynamic Measurements - Mean Change From Baseline in TBI of Index Leg | Change from Baseline at LOCF | -0.044 ratio | Standard Deviation 0.1846 |
| Placebo | Hemodynamic Measurements - Mean Change From Baseline in TBI of Index Leg | Change from Baseline at Month 6 | -0.037 ratio | Standard Deviation 0.2175 |
| Placebo | Hemodynamic Measurements - Mean Change From Baseline in TBI of Index Leg | Change from Baseline at Month 15 | 0.035 ratio | Standard Deviation 0.0495 |
| Placebo | Hemodynamic Measurements - Mean Change From Baseline in TBI of Index Leg | Change from Baseline at Month 9 | 0.112 ratio | Standard Deviation 0.1747 |
Comparison: Change from Baseline at Month 3p-value: 0.147ANCOVA
Comparison: Change from Baseline at Month 6p-value: 0.032ANCOVA
Comparison: Change from Baseline at Month 9p-value: 0.709ANCOVA
Comparison: Change from Baseline at Month 12p-value: 0.771ANCOVA
Comparison: Change from Baseline at Month 15p-value: 0.83ANCOVA
Comparison: Change from Baseline at LOCFp-value: 0.033ANCOVA
Primary
Hemodynamic Measurements - Mean Change From Baseline in Toe Systolic Pressure
Summary statistics were provided for baseline and change from baseline for toe systolic pressure by visit and treatment (only subjects with non-missing baseline and visit values). A two-way analysis of covariance (ANCOVA) with treatment and region as fixed factors and baseline as a covariate were performed for each visit and LOCF.
Time frame: 18 months
Population: The number analyzed in one or more rows differs from overall number analyzed due to early discontinuation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gene Therapy HGF Plasmid (AMG0001) | Hemodynamic Measurements - Mean Change From Baseline in Toe Systolic Pressure | Change from Baseline at Month 3 | 4.4 mmHg | Standard Deviation 19.96 |
| Gene Therapy HGF Plasmid (AMG0001) | Hemodynamic Measurements - Mean Change From Baseline in Toe Systolic Pressure | Change from Baseline at Month 6 | 19.5 mmHg | Standard Deviation 18.44 |
| Gene Therapy HGF Plasmid (AMG0001) | Hemodynamic Measurements - Mean Change From Baseline in Toe Systolic Pressure | Change from Baseline at Month 9 | 20.7 mmHg | Standard Deviation 20.38 |
| Gene Therapy HGF Plasmid (AMG0001) | Hemodynamic Measurements - Mean Change From Baseline in Toe Systolic Pressure | Change from Baseline at Month 12 | 34.8 mmHg | Standard Deviation 37.38 |
| Gene Therapy HGF Plasmid (AMG0001) | Hemodynamic Measurements - Mean Change From Baseline in Toe Systolic Pressure | Change from Baseline at Month 15 | 16.0 mmHg | Standard Deviation 33.05 |
| Gene Therapy HGF Plasmid (AMG0001) | Hemodynamic Measurements - Mean Change From Baseline in Toe Systolic Pressure | Change from Baseline at LOCF | 18.5 mmHg | Standard Deviation 32.51 |
| Placebo | Hemodynamic Measurements - Mean Change From Baseline in Toe Systolic Pressure | Change from Baseline at Month 18 | 14.0 mmHg | — |
| Placebo | Hemodynamic Measurements - Mean Change From Baseline in Toe Systolic Pressure | Change from Baseline at Month 12 | 39.3 mmHg | Standard Deviation 19.63 |
| Placebo | Hemodynamic Measurements - Mean Change From Baseline in Toe Systolic Pressure | Change from Baseline at Month 3 | -9.9 mmHg | Standard Deviation 25.07 |
| Placebo | Hemodynamic Measurements - Mean Change From Baseline in Toe Systolic Pressure | Change from Baseline at LOCF | -2.9 mmHg | Standard Deviation 30.04 |
| Placebo | Hemodynamic Measurements - Mean Change From Baseline in Toe Systolic Pressure | Change from Baseline at Month 6 | -6.3 mmHg | Standard Deviation 33.76 |
| Placebo | Hemodynamic Measurements - Mean Change From Baseline in Toe Systolic Pressure | Change from Baseline at Month 15 | 6.5 mmHg | Standard Deviation 9.19 |
| Placebo | Hemodynamic Measurements - Mean Change From Baseline in Toe Systolic Pressure | Change from Baseline at Month 9 | 29.3 mmHg | Standard Deviation 28.79 |
Comparison: Change from Baseline at Month 3p-value: 0.211ANCOVA
Comparison: Change from Baseline at Month 6p-value: 0.036ANCOVA
Comparison: Change from Baseline at Month 9p-value: 0.725ANCOVA
Comparison: Change from Baseline at Month 12p-value: 0.468ANCOVA
Comparison: Change from Baseline at Month 15p-value: 0.854ANCOVA
Comparison: Change from Baseline at LOCFp-value: 0.233ANCOVA
Primary
Major Amputation or Revascularization (of the Index Leg), All-cause Death, and Incidence of Stroke and Myocardial Infarction (MI)
A frequency table for Day 0 to 6 months, Day 0 to 12 months and Day 0 to 18 months intervals by treatment group; the Fisher's Exact test was used for treatment comparison.
Time frame: 18 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Gene Therapy HGF Plasmid (AMG0001) | Major Amputation or Revascularization (of the Index Leg), All-cause Death, and Incidence of Stroke and Myocardial Infarction (MI) | 0-6 Months (MI) | 1 Participants |
| Gene Therapy HGF Plasmid (AMG0001) | Major Amputation or Revascularization (of the Index Leg), All-cause Death, and Incidence of Stroke and Myocardial Infarction (MI) | 0-12 Months (MI) | 2 Participants |
| Gene Therapy HGF Plasmid (AMG0001) | Major Amputation or Revascularization (of the Index Leg), All-cause Death, and Incidence of Stroke and Myocardial Infarction (MI) | 0-18 Months (MI) | 2 Participants |
| Gene Therapy HGF Plasmid (AMG0001) | Major Amputation or Revascularization (of the Index Leg), All-cause Death, and Incidence of Stroke and Myocardial Infarction (MI) | 0-6 Months (Stroke) | 0 Participants |
| Gene Therapy HGF Plasmid (AMG0001) | Major Amputation or Revascularization (of the Index Leg), All-cause Death, and Incidence of Stroke and Myocardial Infarction (MI) | 0-12 Months (Stroke) | 1 Participants |
| Gene Therapy HGF Plasmid (AMG0001) | Major Amputation or Revascularization (of the Index Leg), All-cause Death, and Incidence of Stroke and Myocardial Infarction (MI) | 0-18 Months (Stroke) | 1 Participants |
| Gene Therapy HGF Plasmid (AMG0001) | Major Amputation or Revascularization (of the Index Leg), All-cause Death, and Incidence of Stroke and Myocardial Infarction (MI) | 0-6 Months (Major Amputation) | 5 Participants |
| Gene Therapy HGF Plasmid (AMG0001) | Major Amputation or Revascularization (of the Index Leg), All-cause Death, and Incidence of Stroke and Myocardial Infarction (MI) | 0-12 Months (Major Amputation) | 6 Participants |
| Gene Therapy HGF Plasmid (AMG0001) | Major Amputation or Revascularization (of the Index Leg), All-cause Death, and Incidence of Stroke and Myocardial Infarction (MI) | 0-18 Months (Major Amputation) | 6 Participants |
| Gene Therapy HGF Plasmid (AMG0001) | Major Amputation or Revascularization (of the Index Leg), All-cause Death, and Incidence of Stroke and Myocardial Infarction (MI) | 0-6 Months (Revascularization) | 3 Participants |
| Gene Therapy HGF Plasmid (AMG0001) | Major Amputation or Revascularization (of the Index Leg), All-cause Death, and Incidence of Stroke and Myocardial Infarction (MI) | 0-12 Months (Revascularization) | 6 Participants |
| Gene Therapy HGF Plasmid (AMG0001) | Major Amputation or Revascularization (of the Index Leg), All-cause Death, and Incidence of Stroke and Myocardial Infarction (MI) | 0-18 Months (Revascularization) | 6 Participants |
| Gene Therapy HGF Plasmid (AMG0001) | Major Amputation or Revascularization (of the Index Leg), All-cause Death, and Incidence of Stroke and Myocardial Infarction (MI) | 0-6 Months (All-cause Death) | 0 Participants |
| Gene Therapy HGF Plasmid (AMG0001) | Major Amputation or Revascularization (of the Index Leg), All-cause Death, and Incidence of Stroke and Myocardial Infarction (MI) | 0-12 Months (All-cause Death) | 2 Participants |
| Gene Therapy HGF Plasmid (AMG0001) | Major Amputation or Revascularization (of the Index Leg), All-cause Death, and Incidence of Stroke and Myocardial Infarction (MI) | 0-18 Months (All-cause Death) | 3 Participants |
| Gene Therapy HGF Plasmid (AMG0001) | Major Amputation or Revascularization (of the Index Leg), All-cause Death, and Incidence of Stroke and Myocardial Infarction (MI) | 0-6 Months (Major Amputation or Death) | 5 Participants |
| Gene Therapy HGF Plasmid (AMG0001) | Major Amputation or Revascularization (of the Index Leg), All-cause Death, and Incidence of Stroke and Myocardial Infarction (MI) | 0-12 Months (Major Amputation or Death) | 7 Participants |
| Gene Therapy HGF Plasmid (AMG0001) | Major Amputation or Revascularization (of the Index Leg), All-cause Death, and Incidence of Stroke and Myocardial Infarction (MI) | 0-18 Months (Major Amputation or Death) | 8 Participants |
| Gene Therapy HGF Plasmid (AMG0001) | Major Amputation or Revascularization (of the Index Leg), All-cause Death, and Incidence of Stroke and Myocardial Infarction (MI) | 0-6 Months (Major Amputation or Revascularization) | 7 Participants |
| Gene Therapy HGF Plasmid (AMG0001) | Major Amputation or Revascularization (of the Index Leg), All-cause Death, and Incidence of Stroke and Myocardial Infarction (MI) | 0-12 Month (Major Amputation or Revascularization) | 11 Participants |
| Gene Therapy HGF Plasmid (AMG0001) | Major Amputation or Revascularization (of the Index Leg), All-cause Death, and Incidence of Stroke and Myocardial Infarction (MI) | 0-18 Month (Major Amputation or Revascularization) | 11 Participants |
| Placebo | Major Amputation or Revascularization (of the Index Leg), All-cause Death, and Incidence of Stroke and Myocardial Infarction (MI) | 0-12 Months (Revascularization) | 3 Participants |
| Placebo | Major Amputation or Revascularization (of the Index Leg), All-cause Death, and Incidence of Stroke and Myocardial Infarction (MI) | 0-6 Months (MI) | 0 Participants |
| Placebo | Major Amputation or Revascularization (of the Index Leg), All-cause Death, and Incidence of Stroke and Myocardial Infarction (MI) | 0-6 Months (Major Amputation or Revascularization) | 9 Participants |
| Placebo | Major Amputation or Revascularization (of the Index Leg), All-cause Death, and Incidence of Stroke and Myocardial Infarction (MI) | 0-12 Months (MI) | 0 Participants |
| Placebo | Major Amputation or Revascularization (of the Index Leg), All-cause Death, and Incidence of Stroke and Myocardial Infarction (MI) | 0-18 Months (Revascularization) | 3 Participants |
| Placebo | Major Amputation or Revascularization (of the Index Leg), All-cause Death, and Incidence of Stroke and Myocardial Infarction (MI) | 0-18 Months (MI) | 0 Participants |
| Placebo | Major Amputation or Revascularization (of the Index Leg), All-cause Death, and Incidence of Stroke and Myocardial Infarction (MI) | 0-12 Months (Major Amputation or Death) | 9 Participants |
| Placebo | Major Amputation or Revascularization (of the Index Leg), All-cause Death, and Incidence of Stroke and Myocardial Infarction (MI) | 0-6 Months (Stroke) | 1 Participants |
| Placebo | Major Amputation or Revascularization (of the Index Leg), All-cause Death, and Incidence of Stroke and Myocardial Infarction (MI) | 0-6 Months (All-cause Death) | 1 Participants |
| Placebo | Major Amputation or Revascularization (of the Index Leg), All-cause Death, and Incidence of Stroke and Myocardial Infarction (MI) | 0-12 Months (Stroke) | 1 Participants |
| Placebo | Major Amputation or Revascularization (of the Index Leg), All-cause Death, and Incidence of Stroke and Myocardial Infarction (MI) | 0-18 Month (Major Amputation or Revascularization) | 10 Participants |
| Placebo | Major Amputation or Revascularization (of the Index Leg), All-cause Death, and Incidence of Stroke and Myocardial Infarction (MI) | 0-18 Months (Stroke) | 1 Participants |
| Placebo | Major Amputation or Revascularization (of the Index Leg), All-cause Death, and Incidence of Stroke and Myocardial Infarction (MI) | 0-12 Months (All-cause Death) | 2 Participants |
| Placebo | Major Amputation or Revascularization (of the Index Leg), All-cause Death, and Incidence of Stroke and Myocardial Infarction (MI) | 0-6 Months (Major Amputation) | 7 Participants |
| Placebo | Major Amputation or Revascularization (of the Index Leg), All-cause Death, and Incidence of Stroke and Myocardial Infarction (MI) | 0-18 Months (Major Amputation or Death) | 9 Participants |
| Placebo | Major Amputation or Revascularization (of the Index Leg), All-cause Death, and Incidence of Stroke and Myocardial Infarction (MI) | 0-12 Months (Major Amputation) | 7 Participants |
| Placebo | Major Amputation or Revascularization (of the Index Leg), All-cause Death, and Incidence of Stroke and Myocardial Infarction (MI) | 0-18 Months (All-cause Death) | 2 Participants |
| Placebo | Major Amputation or Revascularization (of the Index Leg), All-cause Death, and Incidence of Stroke and Myocardial Infarction (MI) | 0-18 Months (Major Amputation) | 7 Participants |
| Placebo | Major Amputation or Revascularization (of the Index Leg), All-cause Death, and Incidence of Stroke and Myocardial Infarction (MI) | 0-12 Month (Major Amputation or Revascularization) | 10 Participants |
| Placebo | Major Amputation or Revascularization (of the Index Leg), All-cause Death, and Incidence of Stroke and Myocardial Infarction (MI) | 0-6 Months (Revascularization) | 2 Participants |
| Placebo | Major Amputation or Revascularization (of the Index Leg), All-cause Death, and Incidence of Stroke and Myocardial Infarction (MI) | 0-6 Months (Major Amputation or Death) | 8 Participants |
Comparison: MI at 0-6 Monthsp-value: >0.999Fisher Exact
Comparison: MI at 0-12 Monthsp-value: 0.4889Fisher Exact
Comparison: MI at 0-18 Monthsp-value: 0.4889Fisher Exact
Comparison: Stroke at 0-6 Monthsp-value: >0.999Fisher Exact
Comparison: Stroke at 0-12 Monthsp-value: >0.999Fisher Exact
Comparison: Stroke at 0-18 Monthsp-value: >0.999Fisher Exact
Comparison: Major amputation at 0-6 Monthsp-value: 0.7381Fisher Exact
Comparison: Major amputation at 0-12 Monthsp-value: >0.999Fisher Exact
Comparison: Major amputation at 0-18 Monthsp-value: >0.999Fisher Exact
Comparison: Revascularization at 0-6 Monthsp-value: >0.999Fisher Exact
Comparison: Revascularization at 0-12 Monthsp-value: 0.4591Fisher Exact
Comparison: Revascularization at 0-18 Monthsp-value: 0.4591Fisher Exact
Comparison: All-cause death at 0-6 Monthsp-value: >0.999Fisher Exact
Comparison: All-cause death at 0-12 Monthsp-value: >0.999Fisher Exact
Comparison: All-cause death at 0-18 Monthsp-value: >0.999Fisher Exact
Comparison: 0-6 Months (Major Amputation or Death)p-value: 0.5136Fisher Exact
Comparison: 0-12 Months (Major Amputation or Death)p-value: 0.7575Fisher Exact
Comparison: 0-18 Months (Major Amputation or Death)p-value: >0.999Fisher Exact
Comparison: 0-6 Months (Major Amputation or Revascularization)p-value: 0.7575Fisher Exact
Comparison: 0-12 Months (Major Amputation or Revascularization)p-value: >0.999Fisher Exact
Comparison: 0-18 Months (Major Amputation or Revascularization)p-value: >0.999Fisher Exact
Primary
Ulcer Improvement
A table showing the number of subjects with complete healing of the target ulcer by treatment. Ulcer healing of the largest ulcer on the index limb was assessed clinically by the Principal Investigator by direct visual inspection at each study visit. If the largest ulcer on the index leg was considered completely healed, photographs of the healed ulcer area was captured. If an ulcer healed completely during the study period, the ulcer was re-evaluated 2 weeks later to confirm it has remained healed. Confirmation of complete ulcer healing was made by an outside physician unconnected with the study and nominated for this purpose.
Time frame: 18 months
Population: The number of participants analyzed are those that have an ulcer on the index leg at the time of enrollment (n=11 in HGF plasmid group, n=13 in placebo group).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Gene Therapy HGF Plasmid (AMG0001) | Ulcer Improvement | Baseline and up to Month 6 | 2 Participants |
| Gene Therapy HGF Plasmid (AMG0001) | Ulcer Improvement | Baseline and up to Month 12 | 3 Participants |
| Gene Therapy HGF Plasmid (AMG0001) | Ulcer Improvement | Baseline and up to Month 18 | 3 Participants |
| Placebo | Ulcer Improvement | Baseline and up to Month 6 | 1 Participants |
| Placebo | Ulcer Improvement | Baseline and up to Month 12 | 1 Participants |
| Placebo | Ulcer Improvement | Baseline and up to Month 18 | 1 Participants |
Primary
VAS Improvement
A table showing the number of subjects with improvement in VAS (≥ 20 mm) by treatment.
Time frame: 18 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Gene Therapy HGF Plasmid (AMG0001) | VAS Improvement | Baseline and up to Month 6 | 4 Participants |
| Gene Therapy HGF Plasmid (AMG0001) | VAS Improvement | Baseline and up to Month 12 | 9 Participants |
| Gene Therapy HGF Plasmid (AMG0001) | VAS Improvement | Baseline and up to Month 18 | 9 Participants |
| Placebo | VAS Improvement | Baseline and up to Month 6 | 6 Participants |
| Placebo | VAS Improvement | Baseline and up to Month 12 | 6 Participants |
| Placebo | VAS Improvement | Baseline and up to Month 18 | 6 Participants |
Post Hoc
Time to Major Amputation (of the Index Leg) or All-cause Death
The median time to major amputation or death was analyzed over the duration of the study as a post-hoc analysis; all reports of major amputation or death were included in this post hoc analysis, irrespective of pre-defined study windows.
Time frame: Month 36
Population: Subjects who had a major amputation or died during the study
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Gene Therapy HGF Plasmid (AMG0001) | Time to Major Amputation (of the Index Leg) or All-cause Death | 505 Days |
| Placebo | Time to Major Amputation (of the Index Leg) or All-cause Death | 381 Days |