Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase 2, Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter, Dose-Selection Study of Ad2/Hypoxia Inducible Factor (HIF)-1α/VP16 in Patients With Intermittent Claudication
Brief Summary: The purpose of this Phase 2 clinical research study is to examine the safety of an experimental gene transfer agent, Ad2/HIF-1α/VP16, and its ability to stimulate the growth of new blood vessels from existing blood vessels (a process called angiogenesis) in an attempt to improve the flow of blood in the legs of patients with peripheral arterial disease (PAD).

Specifically, this study will enroll patients with severe intermittent claudication (IC) which is the stage of PAD in which a patient's walking ability is severely limited, causing pain in the legs upon exercise due to inadequate blood flow to the muscles of the lower limbs.


Options:
A: Inclusion Criteria:

* Outpatients with severe Peripheral Artery Occlusive Disease defined as Rutherford's Grade III, category 5 or 6, or Fontaine's stage IV.
* Trophic lesions with no signs of healing (no reduction in ulcer size or depth) for at least 2 weeks prior to first study treatment administration (Day 1).
* Patients with objective evidence of peripheral vascular disease (resting ankle pressure \< 70 mmHg and/or toe pressure \< 50 mmHg, and/or resting ankle-brachial index (ABI) \< 0.4 and/or resting toe-brachial index (TBI) \< 0.3 and/or metatarsal pulse volume recording (PVR) flat or barely pulsatile) in the diseased limb on two consecutive examinations performed at least 1 week apart.
* Demonstration or documentation (historical data not older than 6 months prior to first study treatment administration) of total occlusion of the affected limb of one or more of the iliac, superficial femoral, popliteal and/or one or more infrapopliteal arteries as assessed by angiography.
* Life expectancy \> 6 months from the first study treatment administration.
* Poor/not candidates for revascularization (patients suitable for revascularization but with a high risk of failure/ amputation/ or patients not suitable for revascularization).

Exclusion Criteria:

* Previous or current history of malignant disease. Patients who had successful tumor resection or radio-chemotherapy more than 5 years prior to inclusion in the study and no recurrence will be allowed for inclusion.
* Suspicion of malignant disease (abnormal X ray,positive. stool hemoccult, positive Prostate Specific Antigen , abnormal mammography, papanicolaou smear of Class IV or Class V characterization.
* Lower extremity surgery : bypass/angioplasty of the leg to be treated within 2 months prior to the first administration of study treatment (Day 1).
* Active proliferative retinopathy.
* Buerger's disease
B: Inclusion Criteria:

* Males or females older than 18 years of age.
* Limb ischemia with ABI of \< 0.7 in the index lower extremity in two consecutive examinations done at least 1 week apart.
* Limb ischemia with resting ischemic pain and/or claudication at 100 meters and/or non-healing ulcers.
* Claudication
* Patients not considered candidates for surgical or percutaneous revascularization, due to poor target vessels, inability to cross total occlusions, or a morbidity which precludes general anesthesia.

Exclusion Criteria:

* Inability to provide informed consent.
* Previous angiogenic therapy.
* Known sensitivity to gentamycin and/or amphotericin B.
* Use or expected use of antineoplastic drugs.
* Any illness, which might affect the patient's survival after enrollment in the protocol.
* Any illness or significant laboratory abnormality, which in the investigator's judgment will interfere with the patient's ability to comply with the protocol, compromise the patient's safety, or interfere with the interpretation of the study results.
* No evidence of acute infection
* WBC \> 15000.
* WBC \< 4000.
* Serum Creatinine \> 3.0 mg/dL in patients who are not in hemodialysis.
* Pregnant women or women planning to become pregnant or unwilling to use appropriate birth control methods before and 2 months after cell infusion.
* Recent myocardial infarction within 3 months prior to screening.
C: Inclusion criteria:

* Age\>40 years
* History of typical intermittent claudication lasting for at least 3 months, showing no improvement and consistent with treadmill test findings
* Objective evidence of Peripheral Arterial Occlusive Disease. After 10 minutes of rest, either by Ankle brachial index measure (ABI) \<0.8 or Systolic ankle pressure (AP) \< 50 mmHg or Systolic toe pressure \<50 mmHg
* Patent femoral inflow above the level of injections recently (\<2 weeks) documented either with Doppler ultrasonography or Magnetic Resonance Angiography or Angiography

Exclusion criteria:

* Evidence of other causes for leg pain other than intermittent claudication.
* Illnesses limiting subject exercise capacity (angina pectoris, heart failure, respiratory disease, orthopaedic disease, neurological disorders...)
* Pain at rest
* Buerger's disease
* Positive serology for HIV 1 or 2, positive serology hepatitis B or C.
* Subjects with serum creatinine \> 2 mg/dl (176 µmol/l) and subjects on dialysis.
* Active proliferative retinopathy defined by the presence of new vessel formation and scarring.
* Subjects who had a stroke or neurologic deficit presumed to be due to stroke within 3 months prior to the first administration of study treatment
* Previous treatment with any angiogenic growth factor
* Pregnant or breast feeding women or who disagree to practice a medically accepted method of birth control. Men and women who do not agree to use condoms as the only accepted protection barrier, for the entire study period
* Serious concomitant medical conditions not adequately controlled.
* Current alcohol or drug abuse

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