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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

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Trial Conditions
  • Intermittent Claudication
  • Peripheral Vascular Disease
  • Atherosclerosis
What is the purpose of this trial?

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.

Date & Status


Who can Participate?


40  - 80 



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

- 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

- 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

- 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

- 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,

- 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

- Patients previously enrolled in a prior angiogenic gene therapy clinical study,
unless patient was a known placebo patient.

Gender: Both
Steward Physician(s)
  • Medical Monitor
  • St. Elizabeth's Medical Center - Completed
Trial Interventions
  • Ad2/HIF-1α/VP16
  • Ad2/HIF-1α/VP16
  • Ad2/HIF-1α/VP16
  • Saline (Placebo Control)
Physician Researcher

Investigator Name:

  • Medical Monitor

Other Information

Sponsor: Genzyme, a Sanofi Company
Phase: Phase 2
Trial ID: NCT00117650
Volunteers:  Not Accepting Healthy Volunteers

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