E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute Lower Extremity Native Artery or Bypass Graft Occlusion |
|
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 8.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10043628 |
E.1.2 | Term | Thrombosis NOS |
|
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 |
Stage 1:The primary objective is to evaluate the safety of Plasmin (Human) in escalating doses to patients with thrombosed infrainguinal native arteries or by-pass grafts. Selection of the 2 appropriate doses for Stage 2 will be based upon safety and arteriographic evidence of thrombolysis. Stage 2:The primary objective is to evaluate the safety and efficacy of 2 dosages of Plasmin in a blinded and randomized fashion in order to select the dose(s) for evaluation in Phase III trials. Arteriographic evidence of thrombolysis will be used as the efficacy variable for the selection of the appropriate dose(s) for Phase III.
|
|
E.2.2 | Secondary objectives of the trial |
Secondary efficacy objectives are to 1) evaluate the avoidance of open surgical procedures at Day 30 ± 3 after Plasmin treatment; 2) assess physiologic reperfusion (Ankle-Brachial Index, [ABI] increase of ≥ 0.15) at the end of Plasmin infusion, after intervention procedures, and at Days 1-2, 7 ± 1, 30 ± 3, and 3) assess graft patency by ultrasound at Day 7 ± 1 and Day 30 ± 3. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Age ≥ 18 years. 2. 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. 3. Unilateral limb ischemia: symptomatic, SVS acute ischemic categories I and IIa. 4. Onset of symptoms less or equal to 14 days. 5. Thrombosed (non-embolic) infrainguinal graft (synthetic, autologous, or single outflow composite) or infrainguinal native artery.For native arteries, only occlusions of ≥ 10 cm in length are eligible. 6. Diagnosis of occlusive thrombus in the graft or artery by arteriography after Informed Consent is obtained. 7. Ability to traverse the thrombus with a guidewire. 8. Signed Informed Consent prior to study entry. |
|
E.4 | Principal exclusion criteria |
1. Clinical evidence of significant disease that may interfere with the patient successfully completing the trial. 2. Women who are pregnant or lactating, or first 10 days post-partum. 3. Any medical or social condition which the investigator feels wil prohibit the subject from completing the trial 4. Cardiopulmonary resuscitation in the last 10 days. 5. Previous systemic or anaphylactoid allergy to contrast agent, streptokinase, or blood products. 6. Previous hemorrhagic stroke at any time. 7. Thrombotic or embolic stroke or cerebrovascular events (including transient ischemic attack (TIA)) within one year. 8. Intracranial or spinal neuro-surgery or severe intracranial trauma in the last 3 months. 9. Major surgery, organ biopsy, or major trauma within the last 10 days. 10. Lumbar puncture or non-compressible arterial puncture in the last 10 days. 11. Intra-ocular surgery within the last 10 days. 12. Active gastrointestinal or organ bleeding. Minor bleeding such as normal menses, cystitis, or minor hemorrhoidal bleeding are not exclusions. 13. Uncontrolled arterial hypertension, defined as a systolic blood pressure > 180 mmHg or diastolic blood pressure > 110 mmHg. 14. Known intracranial neoplasm, aneurysm, or arterio-venous malformation. 15. Current bleeding diathesis. 16. Platelet count < 75 x 10 exp 9 P/L. 17. Graft infection. 18. Occlusion of a new synthetic or autologous graft within 6 months of placement. A sequential composite graft with dual outflows to correct multiple occlusions is also ineligible. 19. Medically unable to tolerate open vascular procedure. 20. Known prothombotic state, e.g. anti-cardiolipin antibody, HIV-associated peripheral vascular disease. 21. Known contraindication to heparin (e.g. history of heparin-induced thrombocytopenia.) 22. Hemoglobin < 10.0 g/dL (low hemoglobin at screening in the absence of active bleeding may corrected by transfusion). 23. Impaired renal function or renal disease that constitutes a contraindication to contrast angiography., including a screen/baseline creatinine of >2.0 mg/dL or subjects on renal dialysis
24. Previous treatment with Plasmin. 25. 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™), UK (Abbokinase®)) within the last 48 hours. 26.Treatment with a glycoprotein IIb/IIIa class of platelet inhibitor within the past 5 days, for example, abciximab (ReoPro®), eptifibatide (Integrilin®) or tirofiban (Aggrastat®). 27.Treatment with warfarin (Coumadin®) and with an INR of >1.7 (elevated INR at screening may be corrected prior to study enrollment.) 28. Participation in another clinical trial within 30 days prior to entry (imaging studies without investigative treatment are permitted), or concomitant participation in another trial or study. 29. Mentally challenged adult subjects who cannot give independent informed consent. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint will be based on the arteriogram results from the central reading facility review. • Thrombolysis at the end of treatment (arteriogram #3) will be compared to baseline (arteriogram #1) evaluated using a scale of <50%, 50-75%, 76-90% and >90%. |
|
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 | Yes |
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 | Yes |
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) | Yes |
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 | Yes |
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 | Yes |
E.8.1.7.1 | Other trial design description |
combined Phase I and Phase II study |
|
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
|
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 26 |
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 |
|
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
| |
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 7 |
E.8.9.2 | In all countries concerned by the trial days | 0 |