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    The EU Clinical Trials Register currently displays   43845   clinical trials with a EudraCT protocol, of which   7282   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    Summary
    EudraCT Number:2004-002508-13
    Sponsor's Protocol Code Number:PADHIF00704
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2005-05-23
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - PEI
    A.2EudraCT number2004-002508-13
    A.3Full title of the trial
    A Phase 2, Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter, Dose-Selection Study of Ad2/Hypoxia Inducible Factor HIF-1alfa/VP16 in Patients with Intermittent Claudication.
    A.3.2Name or abbreviated title of the trial where available
    WALK
    A.4.1Sponsor's protocol code numberPADHIF00704
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberNA
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorGenzyme Europe BV
    B.1.3.4CountryNetherlands
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAd2/HIF-1α/VP16
    D.3.2Product code Ad2/HIF-1α/VP16
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPIntramuscular use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor codeAd2/ HIF-1α/VP16
    D.3.10 Strength
    D.3.10.1Concentration unit ml millilitre(s)
    D.3.10.3Concentration number1x10*9 / 1x10*10 to 1x10*11 vp/ml
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Information not present in EudraCT
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product Yes
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    D.3.11.10Medicinal product containing genetically modified organisms Yes
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection
    D.8.4Route of administration of the placeboIntramuscular use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Peripheral Arterial Disease (PAD): Intermittent Claudication (IC)
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10009241
    E.1.2Term Claudication intermittent
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    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).
    This is done by assessing:
    • the safety and tolerability of 3 doses of Ad2/HIF-1α/VP16 compared to Placebo-control in the treatment of severe intermittent claudication (IC)
    • the efficacy of 3 doses of Ad2/HIF-1α/VP16 compared to Placebo-control in the treatment of severe IC
    E.2.2Secondary objectives of the trial
    This study is being conducted to:
    •Provide a basis for optimal dose selection for Phase 3 studies
    •Provide a basis for patient population, safety and efficacy parameters, and sample size determinations for Phase 3 studies
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Male and females 40 to 80 years of age, inclusive.
    2.Clinical diagnosis of peripheral arterial disease (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.
    •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
    -the post-exercise ABI in the non-index limb is also reduced by greater than or equal to 20% (according to current protocol)or
    -a medically significant stenosis of a femeropopilteal or infrapopliteal artery is present, as documented via imaging study (such as MR, conventional angiography, duplex ultrasound, or CT)
    •If the ABI cannot be measured in either leg (due to noncompressable arteries), then a toe-brachial index (TBI) of ≤ 0.70 may be used in its place to confirm PAD.
    3.Symptoms of severe IC in at least 1 lower limb persisting for ≥ 6 months.
    4.Patients with a PWT of 1 to 12 minutes (inclusive) using the standard 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 (eg, 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 3 weeks of treatment administration.
    5.Patients have been considered for other potential treatment options including exercise rehabilitation, smoking cessation, and pharmacological therapy prior to enrollment.
    6.Claudication severity, concomitant medications for the treatment of coronary artery disease (CAD), PAD, and IC, smoking status and exercise habits should be clinically stable for 3 months prior to Screening.
    7.At Screening, patients will be required to be in compliance with the American Cancer Society (ACS) or other current national recommended guidelines for screening for malignancies of the colon, lung, breast, cervix, uterus (females only) and prostate (males only).
    8.Patients who are committed to following the protocol requirements as evidenced by written informed consent.
    E.4Principal exclusion criteria
    1.Patients with either current or any history of critical limb ischemia (CLI) (classified as Rutherford Category 4,5 or 6).
    2.Patients in whom arterial insufficiency in the lower extremity is the result of acute limb ischemia or an immunological or inflammatory non-atherosclerotic disorder and systemic sclerosis.
    3.A PAD-specific surgical revascularization procedure within 6 months of Enrollment or PAD-specific a percutaneous procedure within 3 months of Enrollment, or patients likely to require a PAD-specific revascularization procedure within 6 months after Enrollment.
    4.Patients with aortoiliac disease that limits inflow in either leg.
    5.Patients in whom walking impairment due to pain in the index leg is the result of nonatherosclerotic comorbid conditions.
    6.Conditions other than IC of significant severity that could confound peak walking time on the standardized exercise treadmill test causing premature or inconsistent termination of exercise (eg, angina pectoris, heart failure [New York Heart Association {NYHA} Classes III and IV], respiratory disease [eg, chronic obstructive pulmonary disease], orthopedic disease, neurological disorders, rheumatologic disorders [eg, severe degenerative joint diseases], dyspnea, fatigue, prior lower limb amputation, including amputations proximal to the metatarsal or phalangeal joints).
    7.Presence or history of cancer within 5 years or not current with American Cancer Society (ACS) (or other nationally recognized) cancer screening guidelines, except low grade and fully resolved nonmelanoma skin malignancy.
    8.Patients with a well defined clinical or genetic disorder predisposing to malignancy should be excluded (eg, von Hippel- Lindau, familial polyposis coli, BRCA1, BRCA2, etc).
    9.Patients with baseline funduscopic evidence of active proliferative diabetic retinopathy, preproliferative diabetic retinopathy, or wet age-related macular degeneration (AMD)
    AND/OR
    Patients with a history of treatment for active proliferative diabetic retinopathy or wet AMD within 5 years of study participation.
    10.Diabetes type 1 (juvenile onset).
    11.Poorly controlled type 2 diabetes (ie, HbA1C > 10%) at Screening.
    12.Active hepatitis defined as clinically significant increase in liver enzymes (ie, 3 times the upper limit of normal [ULN]) or other current infectious disease.
    13.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.
    14.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 (eg, serum creatinine ≥ 2.5 mg/dL), as judged by the investigator.
    15.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 and/or myocardial infarction within 4 weeks before Enrollment,
    •Coronary artery bypass grafting or percutaneous coronary intervention within 3 months before Enrollment,
    •Transient ischemic attack within 3 months before Enrollment,
    •Deep vein thrombosis within 3 months,
    •Severe chronic obstructive pulmonary disease (room air arterial PO2 < 60mmHg or PCO2 > 50mmHg, or abnormal pulmonary function tests (forced expiratory volume [FEV1] < 1.2 L/sec),
    •Thrombocytopenia,
    •Undergoing hemodialysis,
    •Patients with immunocompromised conditions, organ transplant recipients and/or need for immunosuppressive therapy,
    •Neurological dementia (ie, Alzheimer’s Disease),
    •Hemorrhagic stroke.
    16.Patients with a known allergy to the vehicle placebo control, or any other medications or imaging agents required for participation in this study.
    17.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.
    18.Fertile men and women who are not willing to use barrier-type contraception for at least 90days post treatment.
    19.Patients with a recent history of alcoholism or drug abuse; severe emotional, behavioral or psychiatric problems who may not be able to adequately comply with the requirements of the study.
    20.Patients receiving experimental medications or participating in another study using an experimental drug or experimental procedure within 30 days of enrollment into this study.
    21.Patients previously enrolled in a prior angiogenic gene therapy clinical study, unless patient was a known placebo patient.
    E.5 End points
    E.5.1Primary end point(s)
    The safety data collected for the Phase 2 therapeutic dose-selection study include:
    1.AEs and vital signs
    -Adverse vascular events
    2.Clinical laboratory parameters
    -Hematology, liver function tests, renal function test, blood chemistry (including EPO
    -PSA, occult blood in stool
    3.Selected cancer screening
    4.Antibody titels and neutralizing antibody titers
    5.Eye examinations
    6.Potential adenoviral vector circulation within the blood
    7.Potential adenoviral vector shedding

    The primary efficacy variable is:
    Change from Baseline to week 26 in PWT using a standardized exercise treadmill test
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Information not present in EudraCT
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA20
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    Last visit of the last subject after 2 years follow up.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Information not present in EudraCT
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 100
    F.4.2.2In the whole clinical trial 300
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    There is no further care or treatment after completion of the study and patients will be followed up under normal medical care.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2005-11-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2005-11-23
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2010-03-11
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