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

NCT00117650 | Completed Phase 2 DMC

• 2 other identifiers: PADHIF007042004-002508-13
• Study Type: interventional
• Target: 289
• Locations: 3 countries
• Sites: 47

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.

Conditions

Intermittent Claudication; Peripheral Vascular Disease; Atherosclerosis

Keywords

leg pain; gene transfer; angiogenesis; Phase 2; Genzyme; peripheral arterial disease

Outcome Measures

Primary Outcomes (1)

• Peak Walking Time

  at 6 months

Secondary Outcomes (4)

• 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

Study Arms (4)

Low Dose

ACTIVE COMPARATOR

2 x 10\^9 vp (viral particles)

Biological: Ad2/HIF-1α/VP16

Middle Dose

ACTIVE COMPARATOR

2 x 10\^10 vp

Biological: Ad2/HIF-1α/VP16

High Dose

ACTIVE COMPARATOR

2 x 10\^11 vp

Biological: Ad2/HIF-1α/VP16

Placebo

PLACEBO COMPARATOR

(PBS + 10% sucrose + 0.02% polysorbate 80)

Other: Saline (Placebo Control)

Interventions

Ad2/HIF-1α/VP16 BIOLOGICAL

a one time treatment of 20 IM injections of 0.01 ML each into each leg for a total of 40 injections

Also known as: HIF-1alpha

Low Dose

Saline (Placebo Control) OTHER

a one time treatment of 20 IM injections of 0.01 ML each into each leg for a total of 40 injections.

Placebo

Eligibility Criteria

• Age: 40 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Genzyme, a Sanofi Company: lead

Study Sites (47)

Baptist Medical Center Princeton

Birmingham, Alabama, 35211, United States

Location

VA Palo Alto Health Care System

Palo Alto, California, 94304, United States

Location

University of California at Davis

Sacramento, California, 95817, United States

Location

Stanford University School of Medicine

Stanford, California, 94305, United States

Location

University of Colorado Health Sciences Center

Denver, Colorado, 80262, United States

Location

The Washington Hospital Center

Washington D.C., District of Columbia, 20010, United States

Location

Palm Beach Heart Institute

Atlantis, Florida, 33462, United States

Location

Baptist Health Care

Pensacola, Florida, 32522, United States

Location

University of South Florida

Tampa, Florida, 33606, United States

Location

Saint Joseph's Research Institute

Atlanta, Georgia, 30342, United States

Location

Rush University Medical Center

Chicago, Illinois, 60612, United States

Location

Prairie Cardiovascular Consultants, Ltd.

Springfield, Illinois, 32701, United States

Location

The Care Group at the Heart Center

Indianapolis, Indiana, 46290, United States

Location

Ochsner Clinic Foundation

Metairie, Louisiana, 70002, United States

Location

The Johns Hopkins Hospital

Baltimore, Maryland, 21287, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Boston Medical Center

Boston, Massachusetts, 02118, United States

Location

Caritas St. Elizabeth's Medical Center, CCP4C

Boston, Massachusetts, 02135, United States

Location

Henry Ford Hospital

Detroit, Michigan, 48126, United States

Location

Minneapolis Heart Institute Foundation

Minneapolis, Minnesota, 55415, United States

Location

Saint Louis University Hospital

St Louis, Missouri, 63104, United States

Location

Dartmouth-Hitchcock Medical Center

Lebanon, New Hampshire, 03756, United States

Location

New York University School of Medicine

New York, New York, 10003, United States

Location

Mount Sinai School of Medicine

New York, New York, 10029, United States

Location

University of Rochester Medical Center

Rochester, New York, 14642, United States

Location

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, 27599, United States

Location

Duke University Medical Center

Durham, North Carolina, 27705, United States

Location

Cleveland Clinic Foundation

Cleveland, Ohio, 44195, United States

Location

Jobst Vascular Center

Toledo, Ohio, 43606, United States

Location

Medical University of Ohio

Toledo, Ohio, 43614, United States

Location

University of Oklahoma, Health Sciences Center

Oklahoma City, Oklahoma, 73190, United States

Location

Oregon Health & Science University

Portland, Oregon, 97239, United States

Location

Baylor University Medical Center

Dallas, Texas, 75246, United States

Location

Baylor College of Medicine

Houston, Texas, 77030, United States

Location

Peripheral Vascular Associates

San Antonio, Texas, 78205, United States

Location

Ev. Krankenhaus Königin Elisabeth

Berlin, 10365, Germany

Location

Charité Campus Benjamin Franklin

Berlin, 12203, Germany

Location

Klinikum Karlsbad Langensteinbach gGmbH

Karlsbad, 76307, Germany

Location

Universitätsklinikum Schleswig Holstein/Campus Luebeck

Lübeck, 23538, Germany

Location

Klinikum Grosshadern

Munich, 81377, Germany

Location

Universitätsklinikum Munster

Münster, 48149, Germany

Location

Belfast City Hospital

Belfast, BT9 7AB, United Kingdom

Location

Selly Oak Hospital

Birmingham, B29 6JD, United Kingdom

Location

Ninewells Hospital & Medical School

Dundee, DD1 9SY, United Kingdom

Location

Hull Royal Infirmary

Hull, HU3 2JZ, United Kingdom

Location

St. George's Hospital and Medical School

London, SW17 0QT, United Kingdom

Location

Ealing Hospital

Southall, Middlesex, UB1 3HW, United Kingdom

Location

Related Publications (1)

• Creager MA, Olin JW, Belch JJ, Moneta GL, Henry TD, Rajagopalan S, Annex BH, Hiatt WR. Effect of hypoxia-inducible factor-1alpha gene therapy on walking performance in patients with intermittent claudication. Circulation. 2011 Oct 18;124(16):1765-73. doi: 10.1161/CIRCULATIONAHA.110.009407. Epub 2011 Sep 26.

  PMID: 21947297 DERIVED

MeSH Terms

Conditions

Intermittent Claudication; Peripheral Vascular Diseases; Atherosclerosis; Peripheral Arterial Disease

Interventions

Hypoxia-Inducible Factor 1, alpha Subunit; Sodium Chloride

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Arteriosclerosis; Arterial Occlusive Diseases

Intervention Hierarchy (Ancestors)

Hypoxia-Inducible Factor 1; Basic Helix-Loop-Helix Transcription Factors; DNA-Binding Proteins; Proteins; Amino Acids, Peptides, and Proteins; Transcription Factors; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Study Officials

• Medical Monitor

  Genzyme, a Sanofi Company

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 30, 2005
• First Posted: July 8, 2005
• Study Start: February 1, 2005
• Primary Completion: September 1, 2008
• Study Completion: March 1, 2010
• Last Updated: April 3, 2015

Record last verified: 2015-03

Locations

GB (6); US (35); DE (6)