| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Peripheral Arterial Disease (PAD) with no or poor Chronic Critical Limb Ischemia (CLI) |
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| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To evaluate the safety and tolerability of a single administration of Ad2/HIF-1alfa/VP16 by direct intramuscular (IM) injection in the treatment of patients with no or poor option chronic Critical Limb Ischemia (CLI)
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| E.2.2 | Secondary objectives of the trial |
This study is being conducted to:
-assess the efficacy of Ad2/HIF-1alfa/VP16 (Ad/HIF) in improving the clinical status of patients with CLI, based on the resolution of rest-pain, partial or complete healing of non healing ulcers, and incidence of treatment failure
-provide a basis for patient population, efficacy and safety parameters and sample size calculations for future clinical trials |
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
1)Males or females between 40 and 85 years of age, inclusive.
2)Clinical diagnosis of peripheral artery disease (PAD), secondary to atherosclerosis, with signs and symptoms of chronic CLI (ie, rest-pain and/or non-healing ulcers) defined as Rutherford Class 4 or 5 in the limb chosen for treatment (the index limb).
3)The diagnosis of CLI must be confirmed by angiographic evidence (digital subtraction angiography [DSA], at a minimum) of infra inguinal disease in the index limb (eg, the superficial femoral artery, the profunda (deep femoral artery), the popliteal artery, or the infra-popliteal vessels), which is not considered suitable for revascularization.
4)Must have hemodynamic evidence of CLI in the index limb based on 1 of the following criteria:
a)Resting Ankle-Brachial Index (ABI) of ≤ 0.50 or resting ankle pressure ≤ 70 mmHg or a Toe pressure ≤ 50 mmHg OR
b)For patients with a resting ABI and ankle pressure or toe pressure in the index limb that is unreliable or unattainable, there must be documentation of
i)a clinical diagnosis of RC4 or RC5 CLI AND
ii)angiographic evidence of multilevel above-knee (eg, superficial or profound) and below knee (eg, tibial) occlusive disease in association with hemodynamic measures consistent with CLI (ie, a forefoot TCPO2 of ≤ 25 mmHg OR no toe waveform)
5)Must have no or currently very poor options for revascularization for reasons including, but not necessarily limited to, any of the following:
a)Significant co-morbidities that would prevent the patient from tolerating the procedure
b)No suitable target artery to bypass
c)Without suitable autologous conduit material or graft
d)Unsuccessful revascularization procedure
6)Must have clinically relevant inflow at various levels in the index limb (either native, or via bypass) identified by the following:
•no hemodynamically significant suprainguinal stenosis AND
•no hemodynamically significant stenosis in the iliac artery AND
•a patent common femoral artery and patent profunda (deep femoral artery) in the case of an occluded superficial femoral artery (in continuity with the common femoral artery), or a patent superficial femoral artery in the case of an occluded profunda (deep femoral artery; in continuity with the common femoral artery)
7)The index limb is the limb affected with CLI and must meet the following additional requirements:
a)In the case of RC5 patients with more than 1 ulcer on the index limb, 1 ulcer should be chosen as the target ulcer. The target ulcer in the index limb should be ≤ 7 cm in diameter at screening (after debridement) and be of ischemic origin.
b)The target ulcer must be the largest accessible and amenable to measurement by planimetry, eg, located on a flat surface (Note: Circumferential ulcers and ischemic cracks between the toes or on the heel may not be chosen as the target ulcer.)
c)The target ulcer and/or rest-pain in the index limb must have been present for a minimum of 2 weeks before screening without either evidence of improvement in response to conventional therapies or deterioration (ie, an increase or decrease in diameter ≥ 1 cm between screening and the day of scheduled study treatment).
8)Medical care for atherosclerotic disease in general, including specific optimization of risk, as well as pain and ulcer medical management (recommended guidelines are provided in Study Operations Manual [SOM]), should be established at least 2 weeks before screening
9)Patients who are committed to following the protocol requirements as evidenced by written informed consent
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| E.4 | Principal exclusion criteria |
1)Patients with advanced, chronic CLI (RC6) in the index limb, characterized by necrotic or gangrenous toes, or osteomyelitis, that threatens the functional foot and/or limb.
2)Presence of bilateral CLI, ie, patients with Rutherford class 4, 5, or 6 in the contralateral limb or a history of CLI in the contralateral limb with some exceptions
3)Presence of any ischemic ulcer that a)is > 7 cm in diameter b)is transdermal (ie, exposes tendon or bone) c)shows signs of non-treatable infection, either within the ulcer or at its margins d)had signs of a treatable infection that was treated with systemic antibiotics that was not finished within 2 weeks prior to treatment
4)Presence of ulcers of non-ischemic origin
5)Previous amputations to the index limb proximal to the transmetatarsal level of the foot such that the foot is no longer functional
6)Patients who have already seriously considered undergoing an imminent amputation to overcome severe rest pain or ulceration.
7)Arterial insufficiency in the lower extremity resulting from a nonatherosclerotic disorder including, but not limited to, thromboangiitis obliterans [Buerger’s Disease]) and advanced scleroderma (CREST syndrome)
8)Neuropathic pain, peripheral neuropathy, or diabetic neuropathy sufficiently severe to confound the assessment of rest-pain
9)Considered a suitable candidate to undergo lower extremity arterial surgery or lumbar sympathectomy, or neural stimulation within 6 months after screening
10)Successful treatment using a revascularization procedure of the index limb in the 3 months prior to screening
11)Patients with symptoms of rest-pain who underwent lumbar sympathectomy or started neural stimulation therapy in the 3 months prior to screening without a clinical benefit
12)Patients with a successfully-treated episode of acute arterial occlusion in the index limb less than 2 months before screening
13)Cancer or a history of cancer within the past 5 years, or who do not fulfill recommended screening guidelines for colorectal, lung, prostate, breast, cervical and uterine cancers presented in Appendix I of this protocol, with the exception of low grade and fully resolved nonmelanoma skin malignancy
14)A well-defined clinical or genetic disorder predisposing to malignancy (eg, Von Hippel-Lindau, familial polyposis coli, BRCA1, BRCA2, etc)
15)Funduscopic evidence of active, proliferative diabetic retinopathy that is beeing treated or needs to be treated, or for which a final treatment session was given less than 6 months prior to screening, or wet age-related macular degeneration (AMD) that is beeing treated or needs to be treated
16)Poorly-controlled diabetes (ie, HbA1C > 12% at screening)
17)Active hepatitis (defined as a clinically significant increase in liver enzymes [ie, 3 times the ULN]) or other current, ongoing infectious diseases
18)Patients with symptoms of respiratory infection within 2 weeks of study drug administration and/or who have been on systemic or oral antibiotics for active infection within 4 weeks of study drug administration
19)Clinically significant abnormal hematology (eg, WBC of > 14,000), renal, hepatic, or other laboratory parameters that could be the result of an underlying malignancy or systemic infection, as judged by the investigator
20)Patients with
•a heart transplant;
•CAGB or percutaneous coronary intervention (PCI) within 3 months;
•concurrent CHR (NYHA Class 3 or 4);
•life threatening ventricular arrhythmias without protection
•any acute coronary syndrome in the past 4 weeks;
•hemorrhagic or otherwise debilitating stroke;
•TIA within the last 1 month;
•thrombocytopenia;
•receiving immunosuppressive therapy;
•undergoing hemodialysis;
•deep vein thrombosis (DVT) within 3 months; or
•any active disease, who may not be healthy enough to successfully complete all protocol requirements
21)A known allergy to any of the components used in the investigational product solutions, or any other medications
22)Fertile women who are pregnant or nursing.
23)Fertile men and women who are not willing to use barrier-type contraception for at least 90 days post treatment.
24)A recent history of alcoholism or drug abuse, or severe emotional, behavioral or psychiatric problems, or neurological dementia/Alzheimer’s disease
25)Receiving experimental medications or participating in another study using an experimental drug or procedure within 30 days of enrollment into this study
26)Previous enrollment in a prior angiogenic gene therapy clinical study, unless the patient was a known placebo patient
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint will be a primary composite efficacy endpoint, defined as follows:
the study patient is alive, with the index limb (ie, without a major amputation) and has at least partial healing of the target ulcer (ie, at least 30%) and/or total resolution of rest-pain at Week 52.
The safety of study treatment with Ad2/HIF-1alfa/VP16 or placebo will be based on:
-treatment-emergent AEs and SAEs,
-adverse vascular events (AVEs),
-clinical laboratory evaluations (hematology, liver function tests, renal function tests, blood chemistry, and urinalysis),
-selected cancer screening tests,
-physical examinations including vital signs,
-retinal eye examinations,
-12 lead electrocardiogram,
-Ad2 and neutralizing antibody titers,
-consumption of analgesics. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Information not present in EudraCT |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Information not present in EudraCT |
| E.6.7 | Pharmacodynamic | Information not present in EudraCT |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Information not present in EudraCT |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Information not present in EudraCT |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Information not present in EudraCT |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Information not present in EudraCT |
| E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | 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.8.5 | The trial involves multiple Member States | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
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