E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
acute peripheral arterial occlusion |
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E.1.1.1 | Medical condition in easily understood language |
Clots in the large arteries of the lower leg |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10057525 |
E.1.2 | Term | Peripheral artery occlusion |
E.1.2 | System Organ Class | 100000004866 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Evaluation of the safety and tolerability of different methods of administering Plasmin through analysis of major and minor bleeding events, deaths, AEs, SAEs, and abnormal laboratory values. |
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E.2.2 | Secondary objectives of the trial |
1. Avoidance of major surgical revascularization, mechanical device thrombectomy, major amputation (ankle and above), and CDT with a PA in the affected extremity from end of treatment to Day 30.
2. Ankle brachial index (ABI) improvement of ≥0.15 at the end of treatment and/or at post intervention time point (if performed).
3. Assessment of blood flow in treated native artery or graft by ultrasound at the end of treatment or post-intervention and Day 30.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Unilateral limb ischemia: symptomatic, SVS acute ischemic Categories I and IIa
2. Onset of symptoms ≤ 14 days
3. Thrombosed (non-embolic) infrainguinal graft (synthetic, autologous, or single outflow composite) or infrainguinal native artery. For native arteries, occlusions of ≥ 10 cm in length are eligible.
4.Diagnosis of occlusive thrombus
a.Diagnosis of occlusive thrombus in the graft or artery by arteriography after informed consent is obtained
b.Baseline Arteriogram must show a popliteal artery that is open and filling with contrast within which to place the BOC balloon (only for groups I, J and M)
5. Ability to access the thrombus with the infusion catheter and successfully embed the infusion segment of the infusion catheter.
6. Subject must be able to give written informed consent prior to study entry
7. Age ≥ 18 years
8. Women of childbearing potential must use adequate contraception for the duration of the study and must have a negative pregnancy test prior to study entry |
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E.4 | Principal exclusion criteria |
1. Any medical or social condition that may interfere with the subject successfully completing the study
2. Women who are pregnant or lactating, or first 10 days post-partum
Past Medical History
3. Definitive flow on duplex ultrasound through the occluded segment at baseline
4. Cardiopulmonary resuscitation in the last year
5. Previous systemic or anaphylactoid allergy to contrast agent, streptokinase, or blood products (subjects allergic to shellfish or iodine are permitted to enter the study).
6. Ineligible for thrombolytic treatment for any reason
Specific exclusions include: a. History of hemorrhagic stroke, b. Thrombotic or embolic stroke or cerebrovascular events (including transient ischemic attack [TIA]) within the past year, c. Intracranial or spinal neuro-surgery or severe intracranial trauma in the past 3 months, d. Major surgery, organ biopsy, or major trauma within the past 10 days, e. Lumbar puncture or non-compressible arterial puncture in the past 10 days, f. Intra-ocular surgery within the past 10 days, g. Active gastrointestinal or organ bleeding. Minor bleeding such as normal menses, cystitis, or minor hemorrhoidal bleeding are not exclusions, h. Uncontrolled arterial hypertension, defined as a systolic blood pressure >180 millimeters of mercury (mmHg) or diastolic blood pressure >110 mmHg. The subject will be eligible if the hypertension is controlled at the time of study enrollment., i. Known intracranial neoplasm, aneurysm, or arterio-venous malformation, j. Current bleeding diathesis, k. Platelet count <75 x 109/L, l. Subtherapeutic levels of unfractionated heparin anticoagulation as indicated by partial thromboplastin time (aPTT) <50 seconds or activated clotting time (ACT) <300 seconds (subtherapeutic anticoagulation level may be corrected by administration of additional heparin). Testing (aPTT or ACT) may be repeated prior to randomization.
7. Active graft infection
8. Occlusion occurred within one month of synthetic graft placement.
9. Occlusion occurred within 6 months of autologous graft placement
10. A sequential composite graft with dual outflows to correct multiple occlusions
11. Deemed by the Investigator to be medically unable to tolerate open vascular procedure
12. Known prothrombotic state, e.g., anti-cardiolipin antibody, human immunodeficiency virus (HIV)-associated peripheral vascular disease
13. Known contraindication to heparin (e.g., history of heparin-induced thrombocytopenia)
14. Hemoglobin <10.0 g/dL (low hemoglobin at screening in the absence of active bleeding may be corrected by transfusion). Hemoglobin testing can be repeated.
15. Impaired renal function or renal disease that constitutes a contraindication to contrast arteriography, including a screen/baseline creatinine of >2.0 mg/dL. Creatinine may be repeated following hydration for prerenal azotemia.
16. Active cancer except non-malignant tumors or basal cell carcinoma
17. Previous treatment with Plasmin
18. Treatment with full dose plasminogen activator (e.g., streptokinase (e.g., Streptase®, Kabikinase®), anistreplase (Eminase®), alteplase (e.g., Activase®), reteplase (e.g., Retavase®), tenecteplase (TNKase™), urokinase (UK, [Abbokinase®]) within the last 48 hours
19. Treatment with a glycoprotein IIb/IIIa class of platelet inhibitor within 5 days prior to study entry or at any time during the study, e.g., abciximab (ReoPro®), eptifibatide (Integrilin®) or tirofiban (Aggrastat®)
20. Treatment with oral anticoagulants (e.g., warfarin, acenocumarol), and with an international normalized ratio (INR) of >1.7 (elevated INR at screening may be corrected prior to study enrollment). INR testing can be repeated.
21. Participation in another clinical study within 30 days prior to entry (imaging
studies without investigative treatment are permitted), or concomitant
participation in another study.
22. Mentally challenged adult subjects who cannot give independent written informed consent.
23. Weight <62.5 kg (only for groups K, L and M) |
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E.5 End points |
E.5.1 | Primary end point(s) |
The proportion of subjects with >50% thrombolysis at the end of treatment compared to baseline by arteriography |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
The incidence of major and minor bleeding events, deaths, adverse events, serious adverse events, and abnormal laboratory values as a measure of safety and tolerability |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
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 | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Open Plasmin (Human) treatment groups, blinded comparator groups |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 13 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 65 |
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 |
Belgium |
Bulgaria |
Romania |
Slovakia |
Brazil |
Czech Republic |
Germany |
Hungary |
India |
Spain |
Sri Lanka |
Peru |
Poland |
Russian Federation |
Ukraine |
United States |
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E.8.7 | Trial 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
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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 | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |