E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute Lower Limb Ischemia |
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E.1.1.1 | Medical condition in easily understood language |
Acute Lower Limb Ischemia |
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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 | 17.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10066920 |
E.1.2 | Term | Leg ischemia |
E.1.2 | System Organ Class | 100000004866 |
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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 efficacy of MST-188 in subjects receiving catheter-directed recombinant tissue plasminogen activator (rt-PA) for acute lower limb ischemia, and
- To evaluate whether MST-188 results in more rapid thrombolysis and tissue perfusion
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E.2.2 | Secondary objectives of the trial |
- To assess the clinically-meaningful benefit of therapy, tabulating outcomes such as duration of thrombolytic therapy, amputation-free survival, target limb re-interventions, and
- To assess the need for endovascular or open surgical re-interventions.
These objectives will be measured through up to 90 days of follow-up.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Written documentation of informed consent
2. Age ≥30 and <80 years
3. Symptoms consistent with acute ischemia in the target lower limb of ≤14 days’ duration and classified as Rutherford Category IIa or IIb
4. Subject is hospitalized or in the process of admission for the treatment of acute limb ischemia (ALI)
5. Angiographic confirmation of thrombotic lower limb arterial occlusion ≥10 cm in length
6. Planned recombinant tissue plasminogen activator (rt-PA) intra-arterial, catheter-directed thrombolytic therapy
7. Target lower limb transcutaneous oxygen tension (TcPO2) ≤40 mmHg
8. Ankle-brachial index (ABI) ≤0.60 in the target lower limb or, if vessels are incompressible as defined by ABI ≥1.40 then a toe-brachial index (TBI) ≤0.50
9. If sexually active, the subject agrees to use reliable contraception while participating in this study and for at least 30 days after discontinuation of blinded study drug infusion
10. If the subject is female and of child-bearing potential, must have negative pregnancy test (urine or serum)
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E.4 | Principal exclusion criteria |
1. Prosthetic bypass graft occlusion within 1 month of implantation or autogenous graft occlusion within 6 months of placement
2. Prior major amputation in the target limb
3. Inability to place a guidewire to the distal end of the occluding thrombus and position an infusion catheter into the thrombus
4. Thrombotic occlusion limited to the infrapopliteal arteries
5. Occlusion of all of the following tibial arteries on the baseline angiogram: anterior tibial, posterior tibial and peroneal
6. Thrombosis of or embolization deemed to be from a popliteal aneurysm by investigator
7. Motor loss with inability to dorsiflex the foot
8. Rhabdomyolysis and/or myoglobinuria
9. Embolization as the suspected cause of the arterial occlusion
10. Treatment with a thrombolytic agent within the last 48 hours
11. Subject has a known or suspected bleeding diathesis
12. Intracranial or spinal surgery or severe intracranial trauma within the last 3 months
13. History of hemorrhagic stroke, known intracranial neoplasm, aneurysm, or arteriovenous malformation
14. Thrombotic or embolic stroke within 6 months or transient ischemic attack within 3 months
15. Major surgery, intraocular surgery, organ biopsy, lumbar puncture, or puncture of an incompressible artery in the last 10 days
16. New York Heart Association Class IV congestive heart failure
17. Active gastrointestinal or other active organ bleeding
18. Uncontrolled arterial hypertension with systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg
19. Hemoglobin <8 g/dL
20. Subject’s international normalized ratio (INR) >1.7 and unable to be corrected prior to gaining arterial access
21. Subject has platelet count <75,000/mm3
22. Subject has hepatic dysfunction defined by alanine aminotransferase (ALT) >3-fold the institution’s upper limit of normal
23. Subject has a serum creatinine value >1.5 mg/dL or is on dialysis
24. Subject is pregnant or nursing
25. Current vascular graft infection
26. Subject is already hospitalized for any condition other than acute lower limb ischemia in the target limb
27. Subject is currently receiving another investigational drug or has received any investigational drug within 30 days prior to randomization
28. Any contraindications for receiving rt-PA, anticoagulants, or contrast media
29. Subject is otherwise not an appropriate study subject, in the Investigator's judgment
30. Subject has been previously randomized in the present trial or any prior MST-188 clinical trial
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Change in TcPO2
2. Change in TcPO2 as measured by area under the curve (AUC) for change in TcPO2
3. Volume of thrombus dissolved after start of MST-188 infusion as assessed by angiography
4. Change in ABI and TBI (or TBI only in subjects with incompressible vessels) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Baseline, 8 hours, 12 hours, and 24 hours
2. Baseline, 8 hours, 12 hours, and 24 hours
3. At approximately 8 hours and 24 hours
4. Baseline, 8 hours, 12 hours, and 24 hours |
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E.5.2 | Secondary end point(s) |
1. Time to reperfusion, measured from the start of MST-188 infusion to attainment of specific increases in TcPO2
2. Open surgery-free survival
3. Patency of the target vessel
4. Freedom from repeat thrombolysis of the target vessel
5. Freedom from major surgery in the target limb
6. Freedom from major amputation
7. All-cause mortality |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Attainment of specific increases in TcPO2
2. Over 30 days and 90 days
3. Over 30 days and 90 days
4. Over 90 days
5. Over 90 days
6. Over 90 days
7. Over 90 days |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
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) | 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 | Yes |
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 |
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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.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 13 |
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 | No |
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 |
Czech Republic |
Hungary |
Poland |
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 | 1 |
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 | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |