A Phase IIB Pilot Study of a Modified Dosage Regimen of AMG0001 in Subjects With Critical Limb Ischemia

Study Overview
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Brief Summary
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The purpose of the study is to confirm the feasibility of study procedures and the tolerability of a new dose regimen of AMG0001 in subjects with Critical Limb Ischemia (CLI)

Detailed Description
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The primary objectives of the study are: To confirm the feasibility of study-related activities and the tolerability of a modified dosage regimen of AMG0001 in CLI To evaluate safety of AMG0001

Official Title
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A Phase IIB Pilot Study to Confirm the Feasibility and Tolerability of a Modified Dosage Regimen of AMG0001 in Subjects With Critical Limb Ischemia

Conditions
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Critical Limb Ischemia, Vascular Diseases, Peripheral Arterial Disease

Intervention / Treatment
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* Biological: HGF Plasmid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects with stable CLI (Severe Rutherford 4 and Rutherford 5) who have no option for revascularization by endovascular intervention or surgical bypass or a poor option (high risk) for revascularization by surgery and no option for an endovascular intervention Subjects 40-90 years of either gender who have signed an informed consent Subjects currently are taking a statin and an anti-platelet agent If female, the subjects must not be of child bearing potential, e.g., post-menopausal or surgically sterile. 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. Subjects with a previous medical history of myocardial infarction and/or stroke should have adequate management of risk factors to prevent secondary occurrence. Subjects should have the ability to understand the requirements of the protocol and agree to return for the required study visits and assessments Exclusion Criteria: Subjects whose CLI status is unstable (spontaneous marked improvement or marked worsening during the screening period). Subjects who may require a major amputation (amputation at or above the ankle) within 4 weeks of Day 0 (± 4 weeks of Day 0). 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). Subjects with purely neuropathic or venous ulcers. Subjects in Rutherford 6 class. 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. Subjects with a diagnosis of Buerger's disease (Thrombo-angiitis Obliterans). Subjects currently receiving immunosuppressive, chemo or radiation therapy. 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. 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. 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. A Stroke, TIA or MI within 3 months of entry into the study. Subjects with known liver disease (e.g., hepatitis B or C or cirrhosis of the liver). A subject with HIV, AIDS, or severe uncontrolled ulcerative colitis or Crohn's disease. Subjects with a current, uncorrected history of alcohol or substance abuse. Subjects that have been administered rhPDGF (e.g, becaplermin) or other growth factors locally within one month of randomization. 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.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AMG0001<br>Hepatocyte Growth Factor (HGF) Plasmid | Biological: HGF Plasmid<br>* Intramuscular injection in the affected limb.<br>* Other names: AMG0001;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs) Suspected to be Related to Injections of AMG0001 | All summaries and analyses will be presented in tabular or graphical form. The study is not powered for the statistical inference and the test will be considered to be descriptive. Treatment-emergent adverse events (TEAEs) was evaluated, and a table showing the number and percentage of subjects with occurrences categorized by System Organ Class and Preferred Term was provided by causality (relationship to study drug). | 18 months | 
| Number of Participants Discontinued Due to AEs From the Injections of AMG0001 | All summaries and analyses will be presented in tabular or graphical form. The study is not powered for the statistical inference and the test will be considered to be descriptive. Treatment-emergent adverse events (TEAEs) was evaluated, and a table showing the number and percentage of subjects with occurrences categorized by System Organ Class and Preferred Term was provided by whether the AE led to discontinuation. | up to 18 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants in Whom the Largest Ulcer Healed Completely or Gets Smaller (Photo Confirmation) | All summaries and analyses will be presented in tabular or graphical form. The study is not powered for the statistical inference and the test will be considered to be descriptive. A table showing the number of subjects completely healed in the target ulcer was provided at up to 6 months, > 6 months to 12 months, from >12 months to 18 months. | 18 Months | 
| Number of Participants in Whom Rest Pain (Based on 10 cm VAS Scale) Reduces by 20 mm (2 cm) or More or Was Completely Relieved. | All summaries and analyses will be presented in tabular or graphical form. The study is not powered for the statistical inference and the test will be considered to be descriptive. 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. The subject is asked to mark a place on the line corresponding to the average pain intensity experienced in the last 7 days. 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). | 18 months | 
| Change From Baseline of VascuQol Score for the Index Limb by Visit | 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. | 18 months | 
| Change in Hemodynamic Measurements of Change From Baseline Value of Toe Systolic Pressure (mmHg) | Summary statistics was provided for baseline and change from baseline for toe systolic pressure by visit. At each visit, only subjects who have a non-missing value at both baseline and the specific visit was summarized. Two-sided one-sample t-test was performed for each visit and last observation carried forward (LOCF). | 18 months | 
| Change in Hemodynamic Measurements of Change From Baseline Value of Ankle Systolic Pressure (mmHg) of the Index Leg by Visit | Summary statistics was provided for baseline and change from baseline for ankle systolic pressure by visit. At each visit, only subjects who have a non-missing value at both baseline and the specific visit was summarized. Two-sided one-sample t-test was performed for each visit and last observation carried forward (LOCF). | 18 months | 
| Change in Hemodynamic Measurements of Change From Baseline Value of Brachial Systolic Pressure (mmHg) | Summary statistics was provided for baseline and change from baseline for right/left brachial systolic pressure by visit. At each visit, only subjects who have a non-missing value at both baseline and the specific visit was summarized. Two-sided one-sample t-test was performed for each visit and last observation carried forward (LOCF). | 18 months | 
| Change in Hemodynamic Measurement of Baseline Calculated Toe Brachial Index (TBI) of the Index Leg by Visit | Summary statistics was provided for baseline and change from baseline for toe brachial index (TBI) by visit. At each visit, only subjects who have a non-missing value at both baseline and the specific visit was summarized. Two-sided one-sample t-test was performed for each visit and last observation carried forward (LOCF). TBI was calculated by dividing the toe systolic blood pressure by the brachial systolic blood pressure. TBI was calculated at baseline and at each visit. The change in TBI at each visit compared to the baseline value was recorded. | 18 months | 
| Change in Hemodynamic Measurement of Baseline Calculated ABI of the Index Leg by Visit | Summary statistics was provided for baseline and change from baseline for ankle brachial index (ABI) by visit. At each visit, only subjects who have a non-missing value at both baseline and the specific visit was summarized. Two-sided one-sample t-test was performed for each visit and last observation carried forward (LOCF). ABI was calculated by dividing the ankle systolic blood pressure by the brachial systolic blood pressure. ABI was calculated at baseline and at each visit. The change in ABI at each visit compared to the baseline value was recorded. | 18 months | 
| Subjects Who Had Myocardial Infarction (MI), Stroke, Major Amputation, Revascularization (by Surgical Bypass, Endovascular Intervention, Hybrid Procedure), or All-cause Death | A summary table including counts and percentages was provided for subjects who had MI, stroke, major amputation, revascularization, or all-cause death for the time periods: 0 to Month 6, 0 to Month 12, 0 to Month 18. | 18 months | 
| Number of Participants With Worsening CLI Event of Index Leg | A summary table and listing of worsening CLI-related events of the index leg including any new or worsening events, worsening rest pain, new ulcer or worsening ulcer, new or worsening wound infection, peripheral vascular intervention, complication of a peripheral vascular intervention, cellulitis, and amputation due to worsening CLI was provided. | 18 months | 
| Number of Participants With Shift From Baseline in Rutherford Classification | Shift from baseline in Rutherford classification was summarized by study visit. Patients enrolled in the study were classified as either Rutherford 4 or Rutherford 5 at baseline. Rutherford category (clinical description) 0 (Asymptomatic - no hemodynamically significant occlusive disease) (Mild claudication) (Moderate claudication) (Severe claudication) (Ischemic rest pain) (Minor tissue loss - nonhealing ulcer, focal gangrene with diffuse pedal ischemia) (Major tissue loss - extending above TM level, functional foot no longer salvageable) | 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Peripheral Arterial Disease, Vascular Disease, CLI, Critical Limb Ischemia, PAD, AnGes, HGF Plasmid, HGF, Hepatocyte Growth Factor Plasmid, gene therapy