WALK: Safety and Efficacy Study of Ad2/Hypoxia Inducible Factor (HIF)-1α/VP16 Gene Transfer in Patients With Intermittent Claudication

Sponsor

Genzyme, a Sanofi Company (Industry)

Overall Status

Completed

CT.gov ID

NCT00117650

Collaborator

(none)

289

Enrollment

Locations

Arms

60.9

Duration (Months)

6.1

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Intermittent Claudication Peripheral Vascular Disease Atherosclerosis	Biological: Ad2/HIF-1α/VP16 Biological: Ad2/HIF-1α/VP16 Biological: Ad2/HIF-1α/VP16 Other: Saline (Placebo Control)	Phase 2

Detailed Description

This Phase 2 gene transfer study will look at whether different doses of Ad2/HIF-1α/VP16 can be tolerated safely by direct injection into the leg muscles where the blood flow is not sufficient to meet the oxygen demands of the leg muscles. The study will also assess whether patients who receive the investigational drug product are able to increase their maximal walking time using a standardized treadmill walking test.

The study design is a randomized, double-blind, placebo-controlled, parallel group, multi-center, Phase 2 dose-selection study. Seventy-five patients will be enrolled into each of 4 study drug groups (3 groups of Ad2/HIF-1α/VP16 gene transfer and 1 placebo group) for a total of 300 patients overall. Three different doses of Ad2/HIF-1α/VP16 gene transfer will be studied. The dose range was previously tested in animals and in the Phase 1 human studies. A placebo group is included in the study to compare safety and efficacy of different doses of Ad2/HIF-1α/VP16 with placebo. Each patient will receive a single set of 20 injections (100 μL each) of gene transfer or placebo in one administration to each leg for a total of 40 injections.

Study Design

Study Type:

Interventional

Actual Enrollment :

289 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official 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

Study Start Date :

Feb 1, 2005

Actual Primary Completion Date :

Sep 1, 2008

Actual Study Completion Date :

Mar 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Low Dose 2 x 10^9 vp (viral particles)	Biological: Ad2/HIF-1α/VP16 a one time treatment of 20 IM injections of 0.01 ML each into each leg for a total of 40 injections Other Names: HIF-1alpha
Active Comparator: Middle Dose 2 x 10^10 vp	Biological: Ad2/HIF-1α/VP16 one time treatment of 20 IM injections of 0.01 ML each into each leg for a total of 40 injections. Other Names: HIF-1alpha
Active Comparator: High Dose 2 x 10^11 vp	Biological: Ad2/HIF-1α/VP16 a one time treatment of 20 IM injections of 0.01 ML each into each leg for a total of 40 injections. Other Names: HIF-1alpha
Placebo Comparator: Placebo (PBS + 10% sucrose + 0.02% polysorbate 80)	Other: Saline (Placebo Control) a one time treatment of 20 IM injections of 0.01 ML each into each leg for a total of 40 injections.

Outcome Measures

Primary Outcome Measures

Peak Walking Time [at 6 months]

Secondary Outcome Measures

Peak walking time [at 3 months and at 1 year]
Claudication onset time [at 3 months, 6 months, and at 1 year]
Quality of life questionnaires [at 3 months, 6 months, 1 year]
Resting ankle brachial index [at 3 months, 6 months, 1 year]

Eligibility Criteria

Criteria

Ages Eligible for Study:

40 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Baptist Medical Center Princeton	Birmingham	Alabama	United States	35211
2	VA Palo Alto Health Care System	Palo Alto	California	United States	94304
3	University of California at Davis	Sacramento	California	United States	95817
4	Stanford University School of Medicine	Stanford	California	United States	94305
5	University of Colorado Health Sciences Center	Denver	Colorado	United States	80262
6	The Washington Hospital Center	Washington	District of Columbia	United States	20010
7	Palm Beach Heart Institute	Atlantis	Florida	United States	33462
8	Baptist Health Care	Pensacola	Florida	United States	32522
9	University of South Florida	Tampa	Florida	United States	33606
10	Saint Joseph's Research Institute	Atlanta	Georgia	United States	30342
11	Rush University Medical Center	Chicago	Illinois	United States	60612
12	Prairie Cardiovascular Consultants, Ltd.	Springfield	Illinois	United States	32701
13	The Care Group at the Heart Center	Indianapolis	Indiana	United States	46290
14	Ochsner Clinic Foundation	Metairie	Louisiana	United States	70002
15	The Johns Hopkins Hospital	Baltimore	Maryland	United States	21287
16	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
17	Boston Medical Center	Boston	Massachusetts	United States	02118
18	Caritas St. Elizabeth's Medical Center, CCP4C	Boston	Massachusetts	United States	02135
19	Henry Ford Hospital	Detroit	Michigan	United States	48126
20	Minneapolis Heart Institute Foundation	Minneapolis	Minnesota	United States	55415
21	Saint Louis University Hospital	St. Louis	Missouri	United States	63104
22	Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
23	New York University School of Medicine	New York	New York	United States	10003
24	Mount Sinai School of Medicine	New York	New York	United States	10029
25	University of Rochester Medical Center	Rochester	New York	United States	14642
26	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina	United States	27599
27	Duke University Medical Center	Durham	North Carolina	United States	27705
28	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
29	Jobst Vascular Center	Toledo	Ohio	United States	43606
30	Medical University of Ohio	Toledo	Ohio	United States	43614
31	University of Oklahoma, Health Sciences Center	Oklahoma City	Oklahoma	United States	73190
32	Oregon Health & Science University	Portland	Oregon	United States	97239
33	Baylor University Medical Center	Dallas	Texas	United States	75246
34	Baylor College of Medicine	Houston	Texas	United States	77030
35	Peripheral Vascular Associates	San Antonio	Texas	United States	78205
36	Ev. Krankenhaus Königin Elisabeth	Berlin		Germany	10365
37	Charité Campus Benjamin Franklin	Berlin		Germany	12203
38	Klinikum Karlsbad Langensteinbach gGmbH	Karlsbad		Germany	76307
39	Universitätsklinikum Schleswig Holstein/Campus Luebeck	Luebeck		Germany	23538
40	Klinikum Grosshadern	Munich		Germany	81377
41	Universitätsklinikum Munster	Munster		Germany	48149
42	Belfast City Hospital	Belfast		United Kingdom	BT9 7AB
43	Selly Oak Hospital	Birmingham		United Kingdom	B29 6JD
44	Ninewells Hospital & Medical School	Dundee		United Kingdom	DD1 9SY
45	Hull Royal Infirmary	Hull		United Kingdom	HU3 2JZ
46	St. George's Hospital and Medical School	London		United Kingdom	SW17 0QT
47	Ealing Hospital	Southall, Middlesex		United Kingdom	UB1 3HW