Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase II Double-Blind, Randomized, Placebo-Controlled Study to Assess the Safety and Efficacy of AMG0001 to Improve Perfusion in Critical Leg Ischemia
Brief Summary: The primary purpose of this study was to assess the overall safety of different dose regimens of AMG0001 (HGF transferred via plasmid vector) as well as evaluate the improvement of blood perfusion in subjects with critical limb ischemia (CLI). This study also evaluated the improvement in wound healing without adverse effects on the quality of life, as well as the potential reduction of amputation, mortality and rest pain in the CLI population.


Options:
A: Inclusion Criteria:

* Having peripheral artery disease at the stage of Critical Limb Ischemia (CLI) with skin lesions (either ulcer(s) or gangrene);
* With objective evidence of CLI such as ankle systolic pressure \<70 mmHg and/or toe systolic pressure \<50 mmHg or transcutaneous oxygen pressure (TcPO2) \<30 mmHg;
* Unsuitable for standard revascularization of his/her peripheral arterial disease;
* Having a negative screening for cancer.

Exclusion Criteria:

* Previous major amputation on the leg to be treated or planned major amputation within the first month following randomization;
* Known Buerger's disease;
* Successful lower extremity revascularization procedure within 3 months prior randomization;
* Uncontrolled blood pressure defined as systolic blood pressure (SBP) ≥180 mmHg or diastolic blood pressure (DBP) ≥110 mmHg despite adequate antihypertensive treatment;
* Acute cardiovascular events within 3 months prior to randomization;
* Active proliferative retinopathy and severe macular oedema;
* Previous or current history of malignant disease within the past 5 years;
* Previous treatment with systemic angiogenic factors or with stem cells therapy;
* Pregnant or breast-feeding woman or woman of childbearing potential not protected by an effective contraceptive method of birth control. Man not following effective contraceptive method with his partner of childbearing potential during the course of the study.

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.
B: Inclusion Criteria:

* Subjects will have one or more clinical indications diagnostic of CLI such as: distal extremity pain at rest that requires the subject to use analgesics for \>2 weeks; or peripheral ischemic ulcer(s); or areas of gangrene.
* The subject will have a TcPO2 of \</= 40 mmHg.
* Subjects will have one or both of the following hemodynamic indicators of severe peripheral arterial occlusive disease: (a) Ankle systolic pressure of \</= 70 mmHg; (b)Toe systolic pressure \</= 50 mmHg.
* 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.
* Subject has signed an informed consent form either directly or through a legally authorized representative
* If female, the subject must be (a) at least one year post-menopausal, or (b) surgically sterile, or (c) if the subject is of child-bearing potential, she must have been practicing contraception for at least 12 weeks prior to entering the study.
* If subject is of reproductive potential, he or she must be using an accepted and effective (barrier) form of birth control during the study.
* Subjects will be on a statin and an anti-platelet agent as part of their standard of care and must be stable on these regimens for at least 4 weeks prior to treatment.

Exclusion Criteria:

* 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.
* Subjects with a diagnosis of Buerger's disease (Thromboangitis Obliterans).
* Subjects with hemodynamically significant aorto-iliac occlusive disease.
* 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 for \>2 weeks prior to treatment initiation are acceptable.
* Subjects who require a change in their hypertension medication as part of their standard of care within 4 weeks prior to treatment.
* Evidence or history of malignant neoplasm (clinical, laboratory or imaging), except for basal cell carcinoma of the skin.
* Subjects who have proliferative diabetic retinopathy or severe, non-proliferative retinopathy
* Subjects with end stage renal disease (ESRD) defined as significant renal dysfunction evidenced by a creatinine of \> 2.5, or receiving chronic hemodialysis therapy.
* A subject who has hepatic cirrhosis, viral hepatitis, or is HIV positive.
* 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% the upper limit of normal).
* Subjects requiring the use of hyperbaric oxygen treatment for wound healing during the screening and 6 month follow-up period.
C: Inclusion Criteria:

* Male or female person aged 40 or older
* Subject with diagnosed lower limb ischemia (Fontaine-Pokrovsky Stages IIa-III of chronic limb ischemia)
* Signed informed consent

Exclusion Criteria:

* Any disease that can, in the opinion of the treating physician, affect the outcome of the study
* Patients with addictive disorders or substance abuse
* Pregnancy or nursing
* All other exclusion criteria listed in the summary of product characteristics (SmPC)
D: Inclusion Criteria:

* Males and females 40 to 80 years of age, inclusive.
* Clinical diagnosis of PAD, secondary to atherosclerosis, in both lower limbs, confirmed by objective evidence: An ankle-brachial index (ABI) of ≤ 0.90 at rest in at least 1 lower limb (Note: The index limb must be ≤ 0.90 at rest.); The ABI after exercise must be reduced by ≥ 20% from the ABI at rest in the index leg (the most symptomatic leg during the treadmill testing). The post-exercise ABI will also be performed on the other leg if the resting ABI \> 0.90. A patient may be eligible for the study with a resting ABI in the non-index limb \> 0.90 if: a. The post-exercise ABI in the non-index leg is also reduced by greater than or equal to 20% OR; b. A medically significant stenosis (defined as ≥ 50%) of a femoropopliteal or infrapopliteal artery is present, as documented via an imaging study (such as MR, conventional angiography, duplex ultrasound, or CT); If the ABI cannot be measured in either leg (due to non-compressible arteries), then a toe-brachial index (TBI) of ≤ 0.70 may be used in its place to confirm PAD.
* Symptoms of severe intermittent claudication (IC) in at least 1 lower limb persisting for ≥ 6 months
* Patients with a peak walking time (PWT) of 1 to 12 minutes (inclusive) using the standardized exercise treadmill test at each of the 2 consecutive treadmill tests performed at least a week apart during the Screening period.
* During Screening, patients must demonstrate consistency of PWTs between 2 standardized exercise treadmill tests (Walk 1 and Walk 2) performed at least 1 week apart.
* Consistency of the PWT between the 2 visits is achieved if the difference between PWT at Walk 1 and Walk 2 is ≤ 25% of the higher of the 2 PWTs (\[higher PWT - lower PWT\]/higher PWT).
* If the difference between PWT at Walk 1 and Walk 2 is \> 25% of the higher of the 2 PWTs, a third treadmill test (Walk 3) may be performed at the discretion of the Principal Investigator between 7 and 14 days following Walk 2. The variability in PWT warranting the performance of Walk 3 must be secondary to circumstances that may contribute to the observed variation (e.g., prior exertion, inconsistent timing, ingestion of a meal within 4 hours, etc). To qualify for the study, the difference between PWT of either Walk 1 or Walk 2 as compared with Walk 3 must be ≤ 25% of the higher of the 2 PWTs (\[higher PWT - lower PWT\]/higher PWT). The decision whether Walk 1 or Walk 2 will be used for comparison with Walk 3 will be made prospectively and reviewed with the Sponsor.
* An acceptable mean PWT must be achieved within 4 weeks of treatment administration.
* Patients have been considered for other potential treatment options including exercise rehabilitation, smoking cessation, and pharmacological therapy prior to Enrollment.
* Claudication severity, concomitant medications for the treatment of CAD, PAD, and IC, smoking status and exercise habits should be clinically stable for 3 months prior to Enrollment.
* Patients who are committed to following the protocol requirements as evidenced by written informed consent.

Exclusion Criteria:

* Patients with either current or any history of Critical Limb Ischemia (CLI; that is, patients classified as Rutherford Category 4 \[ischemic rest pain\], Rutherford Category 5 \[non-healing ischemic ulcers and minor tissue loss\], or Rutherford Category 6 \[non-healing ischemic ulcers and major tissue loss\]).
* Patients in whom arterial insufficiency in the lower extremity is the result of acute limb ischemia or an immunological or inflammatory non-atherosclerotic disorder (eg, thromboangiitis obliterans \[Buerger's Disease\]) and systemic sclerosis \[both limited and diffuse forms\]).
* A PAD-specific surgical revascularization procedure within 6 months of enrollment or a PAD-specific percutaneous procedure within 3 months of enrollment, or patients likely to require a PAD-specific revascularization procedure within 6 months after Enrollment.
* Patients with aortoiliac disease that limits inflow in either leg: a. Patients with concomitant aortoiliac disease (i.e., patients with a significant component of inflow disease in the distal aorta, common or external iliac, or proximal common femoral artery) as assessed by an imaging modality (e.g., segmental limb pressures and waveform analysis, duplex ultrasound scanning, magnetic resonance angiography, or radio-contrast arteriogram) performed within 1 year prior to Enrollment. If subject has had a bypass after the imaging study, then documentation of graft patency is required within 6 months prior to Enrollment; b. If it is suspected at Screening that a patient has aortoiliac disease based on vascular examination, an imaging modality (e.g., segmental limb pressures and waveform analysis, duplex ultrasound scanning, magnetic resonance angiography, or radio-contrast arteriogram) must be performed to rule it out if there is not one available within the times specified above. If there is no suspicion of aortoiliac disease in the Principal Investigator's judgment, an imaging test at Screening is not required for study purposes.
* Patients in whom walking impairment due to pain in the index leg is the result of these nonatherosclerotic comorbid conditions: venous claudication, chronic compartment syndrome, peripheral nerve pain (e.g., severe peripheral neuropathy), pseudoclaudication caused by spinal cord compression, or acute limb ischemia which, in the Principal Investigator's judgment are severe enough to confound the assessment of the patient's IC.
* Conditions other than IC of significant severity that could confound PWT on the standardized exercise treadmill test causing premature or inconsistent termination of exercise (e.g., angina pectoris, heart failure \[New York Heart Association {NYHA} Classes III and IV\], respiratory disease \[e.g., chronic obstructive pulmonary disease\], orthopedic disease, neurological disorders, rheumatologic disorders \[e.g., severe degenerative joint diseases\], dyspnea, fatigue, prior lower limb amputation, including amputations proximal to the metatarsal or phalangeal joints).
* Presence or history of cancer within 5 years of enrollment or not current with recommended screening guidelines for colorectal, lung, prostate, breast, cervical, and uterine cancers, with the exception of low grade and fully resolved non-melanoma skin malignancy.
* Patients with a well-defined clinical or genetic disorder predisposing to malignancy should be excluded (e.g., von Hippel Lindau, familial polyposis coli, BRCA1, BRCA2, etc).
* Patients with baseline funduscopic evidence of active proliferative diabetic retinopathy, preproliferative diabetic retinopathy, or wet AMD AND/OR Patients with a history of treatment for active proliferative diabetic retinopathy or wet AMD within 5 years of enrollment.
* Diabetes type 1 (juvenile onset)
* Poorly controlled type 2 diabetes (ie, HbA1C \>10%) at Screening
* Active hepatitis defined as clinically significant increase in liver enzymes (ie, 3 times the ULN) or other current infectious disease
* Patients with symptoms of respiratory infection at time of Screening and/or randomization period and/or patients who have been on systemic or oral antibiotics for active infection within 2 weeks of study drug administration.
* Patients with clinically significant abnormal hematology (eg, hematocrit \< 30%, white blood cell count \> 14,000), blood chemistry, renal, hepatic, or other laboratory parameters that could be the result of an underlying malignancy or systemic infection (e.g., serum creatinine ≥ 2.5 mg/dL), as judged by the investigator.
* Patients with the following comorbidities who may not be healthy enough to successfully complete all protocol requirements or in whom results may be particularly difficult to assess: Concurrent severe congestive heart failure (NYHA Classes III and IV); Life-threatening ventricular arrhythmias, unstable angina (characterized by increasingly frequent episodes with modest exertion or at rest, worsening severity, and prolonged duration), and/or myocardial infarction within 4 weeks before enrollment; Coronary artery bypass grafting or percutaneous coronary intervention within 3 months before enrollment; A renal and/or carotid revascularization procedure within 1 month of enrollment; Transient ischemic attack within 3 months before enrollment; Deep vein thrombosis within 3 months before enrollment; Severe chronic obstructive pulmonary disease (room air arterial PO2 \< 60 mmHg or PCO2 \> 50 mmHg, or abnormal pulmonary function tests (FEV1 \< 1.2 L/sec); Thrombocytopenia (defined as platelet count \< 100,000/mm3); Undergoing hemodialysis; Patients with immunocompromised conditions, organ transplant recipients and/or need for immunosuppressive therapy; Neurological dementia (i.e., Alzheimer's Disease); Hemorrhagic stroke
* Patients with a known allergy to the vehicle, placebo control, or any other medications or imaging agents required for participation in this study.
* Fertile women who are pregnant (as confirmed by a serum pregnancy test at the Screening Visit and a urine pregnancy test at Day 0 prior to study drug administration), nursing, or using either no or an inadequate form of contraception.
* Fertile men and women who are not willing to use barrier-type contraception for at least 90 days post-treatment.
* Patients with a recent history of alcoholism or drug abuse, or severe emotional, behavioral or psychiatric problems, who may not be able to adequately comply with the requirements of the study.
* Patients receiving experimental medications or participating in another study using an experimental drug or experimental procedure within 30 days of enrollment into this study.
* Patients previously enrolled in a prior angiogenic gene therapy clinical study, unless patient was a known placebo patient.

Answer: B