A Study of Intra-thrombus Plasmin (Human) In Acute Peripheral Arterial Occlusion

A Phase 2, Randomized, Open-label (With Blinded Plasminogen Activator and Placebo Control Groups) Study to Evaluate the Effects of Different Intra-thrombus Infusion Regimens of Plasmin (Human) Compared to Plasminogen Activator and Placebo In Patients With Acute Lower Extremity Native Artery or Bypass Graft Occlusion

The primary purpose of this Phase 2 study is to optimize Plasmin delivery by comparing different delivery regimens in patients with peripheral arterial occlusion. The study includes a blinded plasminogen activator treatment group and a blinded plasminogen activator placebo group. The study will also assess safety and tolerability of Plasmin at 150 and 250 mg doses.

Study Overview

• Status: Completed
• Conditions: Acute Peripheral Arterial Occlusion
• Intervention / Treatment: Biological: Plasmin; Biological: Plasminogen Activator; Other: Placebo

• Study Type: Interventional
• Enrollment (Actual): 174
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium, 1070
    • Erasme Hospital, Brussels
  • Edegem, Belgium
    • University hospital Antwerp
  • Leuven, Belgium
    • Chirurgie UZ Leuven
  • Limburg
    • Genk, Limburg, Belgium, 3600
      • Ziekenhuis Oost Limburg, Campus St. Jan
• Bulgaria
  • Sofia, Bulgaria, 1309
    • Clinic of Vascular Surgery and Angiology
  • Sofia, Bulgaria
    • Tokuda Hospital Sofia
• Czech Republic
  • Ostrava - Vitkovice, Czech Republic
    • Vascular Centre Vitkovicka Nemocnice
  • Prague, Czech Republic
    • Cevni Chirurgie, Nemocnice Na Homolce
  • Prague, Czech Republic
    • IKEM, Kardiologicka klinika
  • Prague, Czech Republic
    • University Hospital Kralovske Vinobrady
  • Usti nad Labem, Czech Republic
    • Chirurgicka klinika IPVZ
• Germany
  • Bonn, Germany
    • Universitätsklinikum Bonn, Radiologische Universitätsklinik
  • Dresden, Germany
    • Universitäts GefäßCentrum Uniklinikum Dresden
  • Leipzig, Germany
    • Klinik für Innere Medizin I - Angiologie / Kardiologie
• India
  • Gujarat, India
    • Life Care Institute of Medical Sciences and Research
  • Karnataka, India
    • Gokula Metropolis Clinical Research Centre, M. S. Ramaiah Hospital
• Peru
  • Lima, Peru
    • Hospital Nacional Edgardo Rebagliati Martins
  • Lima, Peru
    • Centro de Investigación y Atención Cardiovascular
  • Lima, Peru
    • Hospital Nacional Guillermo Almenara Irigoyen-EsSalud
  • Lima, Peru
    • Instituto Neuro Cardiovascular De Las Americas
• Poland
  • Bytom, Poland
    • Wojewodzki Szpital Specjalistyczny nr 4 w Bytomiu
  • Chrzanow, Poland
    • Malopolskie Centrum Sercowo-Naczyniowe PAKS American Heart of Poland Sp. z o.o
  • Gdansk, Poland
    • Uniwersyleckie Centrum Kliniczne
  • Poznan, Poland
    • Szpital Kliniczny Przemienienia Panskiego Uniwersytetu Medycznego Im. Karola Marcinkowskiego w Poznaniu
  • Poznan, Poland
    • Zaklad Opieki Zdrowonej Ministerstwa Spraw Wewnetrznych i Administracji w Poznaniu
  • Szczecin, Poland
    • Samodzielny Publiczny Szpital Kliniczny nr 2 PUM w Szczecinie
• Romania
  • Bucuresti, Romania
    • Institutul de Urgenta pentru Boli Cardiovasculare "Prof.Dr.C.C.Iliescu"
  • Cluj-Napoca, Romania
    • Institutul Inimii "Nicolae Stancioiu" Cluj-Napoca
  • Iasi, Romania
    • Inst.de Boli Cardiovasculare "Prof.I.M.Georgescu" Iasi
  • Targu Mures, Romania
    • Institutul de Boli Cardiovasculare si Transplant Mures
• Serbia
  • Beograd, Serbia, 11040
    • Institut za kardiovaskularne bolesti Dedinje
  • Beograd, Serbia
    • Klinicki Centar Srbije
  • Nis, Serbia
    • Klinički Centar Niš
  • Novi Sad, Serbia
    • Klinicki centar Vojvodine
• Slovakia
  • Bratislava, Slovakia, 83348
    • Oddelenie diagnostickej a intervencnej radiologie, The National Institute of Cardiovascular Diseases
  • Kosice, Slovakia
    • The Eastern Slovak Institute of Cardiovascular Diseases
• Spain
  • Alcorcon, Spain
    • Fundacion Hospital Alcorcon
• United States
  • New York
    • Buffalo, New York, United States, 14209
      • Kaleida Health System
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Unilateral limb ischemia - Society of Vascular Surgery Categories I and IIa
• Onset of symptoms less than or equal to 14 days
• Thrombosed infrainguinal bypass graft or native artery
• Diagnosis by arteriography of occlusive thrombus in graft or artery
• Ability to embed the infusion catheter into the thrombus
• Women of childbearing potential must use contraception and have a negative pregnancy test

Exclusion Criteria:

• Any medical or social condition that may interfere with study participation
• Women who are pregnant or lactating
• Hemorrhagic stroke history
• Thrombotic or embolic stroke or cerebrovascular events (including transient ischemic attack) within one year
• Intracranial or spinal neurosurgery, or severe intracranial trauma in the last 3 months
• Major surgery, organ biopsy, or major trauma within the past 10 days
• Lumbar puncture or non-compressible arterial puncture in the past 10 days
• Intraocular surgery within the past 10 days
• Active gastrointestinal or organ bleeding
• Uncontrolled arterial hypertension (systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg)
• Known intracranial neoplasm, aneurysm, or arteriovenous malformation
• Current bleeding diathesis
• Platelet count <75 x 10e9/L
• Active graft infection
• Occlusion occurred within one month of synthetic graft placement
• Occlusion occurred within 6 months of autologous graft placement
• A sequential composite graft with dual outflows to correct multiple occlusions
• Medically unable to tolerate an open vascular procedure
• Known prothrombotic state
• Hemoglobin <10.0 g/dL
• Impaired renal function or renal disease that constitutes a contraindication to contrast angiography, including creatinine >2.0 mg/dL
• Treatment with a full dose plasminogen activator (PA) within the last 48 hours
• Treatment with a glycoprotein IIb/IIIa class of platelet inhibitor within the past 5 days
• Treatment with oral anticoagulants, and with an international normalized ratio of >1.7

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

11

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Plasmin Open-label Treatment Group A; Open-label 150 mg Plasmin administered without initial proximal pulse; 5-hour infusion using 10 mL/hour infusion rate.	Biological: Plasmin; Plasmin prepared in 0.9% saline for injection; Other Names: Plasmin (Human)
Experimental: Plasmin Open-label Treatment Group B; Open-label 150 mg Plasmin administered with initial proximal pulse; 5-hour infusion using 15 mL/hour infusion rate	Biological: Plasmin; Plasmin prepared in 0.9% saline for injection; Other Names: Plasmin (Human)
Experimental: Plasmin Open-label Treatment Group C; Open-label 150 mg Plasmin administered with proximal pulse; 5 hour infusion using 30 mL/hour infusion rate.	Biological: Plasmin; Plasmin prepared in 0.9% saline for injection; Other Names: Plasmin (Human)
Experimental: Plasmin Open-label Treatment Group D; Open-label 150 mg Plasmin administered with proximal pulse; 2-hour infusion using 35 mL/hour infusion rate	Biological: Plasmin; Plasmin prepared in 0.9% saline for injection; Other Names: Plasmin (Human)
Active Comparator: Plasminogen Activator Blinded Group E; PA administered for five hours at a dose and volume according to the Investigator's clinical judgement/standard practice	Biological: Plasminogen Activator; Plasminogen activator used according to the Investigator's clinical judgment.; Other Names: tissue plasminogen activator (tPA); urokinase (UK)
Placebo Comparator: PA Placebo Blinded Treatment Arm F; PA placebo (normal saline for injection) administered for five hours at a dose and volume according to the Investigator's clinical judgement/standard practice for PA administration	Other: Placebo; Normal saline for injection at the same volume as the plasminogen activator.; Other Names: Normal saline
Experimental: Plasmin Open-label Treatment Group G; Open-label 150 mg Plasmin administered without pulsing; 5-hour infusion using 60 mL/hour infusion rate	Biological: Plasmin; Plasmin prepared in 0.9% saline for injection; Other Names: Plasmin (Human)
Experimental: Plasmin Open-label Treatment Group H; Open-label 150 mg Plasmin administered without pulsing; 2-hour infusion using 75 mL/hour infusion rate	Biological: Plasmin; Plasmin prepared in 0.9% saline for injection; Other Names: Plasmin (Human)
Experimental: Plasmin Open-label Treatment Group I; Open-label 150 mg Plasmin administered without pulsing; 5-hour infusion using 30 mL/hour infusion rate with balloon occlusion catheter	Biological: Plasmin; Plasmin prepared in 0.9% saline for injection; Other Names: Plasmin (Human)
Experimental: Plasmin Open-label Treatment Group J; Open-label 150 mg Plasmin administered without pulsing; 2-hour infusion using 35 mL/hour infusion rate with balloon occlusion catheter	Biological: Plasmin; Plasmin prepared in 0.9% saline for injection; Other Names: Plasmin (Human)
Experimental: Plasmin Open-label Treatment Group M; Open-label 250 mg Plasmin administered without pulsing; 5-hour infusion using 30 mL/hour infusion rate with balloon occlusion catheter	Biological: Plasmin; Plasmin prepared in 0.9% saline for injection; Other Names: Plasmin (Human)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Proportion of Subjects With >50% Thrombolysis	The proportion of subjects with >50% thrombolysis at the end of treatment compared to baseline by arteriography.	5 hours (Treatment Groups A, B, C, G, I, M) or 2 hours (Treatment Groups D, H, J)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	30 days

Collaborators and Investigators

• Sponsor: Grifols Therapeutics LLC
• Investigators: Study Director: Kecia Courtney, Grifols Therapeutics

Publications and helpful links

General Publications

• Comerota AJ, Davidovic L, Hanna K, Courtney KL, Shlansky-Goldberg RD. Phase 2, randomized, open-label study on catheter-directed thrombolysis with plasmin versus rtPA and placebo in acute peripheral arterial occlusion. J Drug Assess. 2019 Apr 9;8(1):43-54. doi: 10.1080/21556660.2019.1586402. eCollection 2019.

Study record dates

Study Major Dates

• Study Start: December 1, 2010
• Primary Completion (Actual): December 1, 2015
• Study Completion (Actual): January 1, 2016

Study Registration Dates

• First Submitted: October 13, 2010
• First Submitted That Met QC Criteria: October 14, 2010
• First Posted (Estimate): October 18, 2010

Study Record Updates

• Last Update Posted (Estimate): January 16, 2017
• Last Update Submitted That Met QC Criteria: November 28, 2016
• Last Verified: November 1, 2016

More Information

Terms related to this study

• Keywords: Acute Limb Ischemia
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Embolism and Thrombosis; Arterial Occlusive Diseases; Thrombosis; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Tissue Plasminogen Activator; Plasminogen; Fibrinolysin
• Other Study ID Numbers: T05018-2004; 2010-019760-36 (EudraCT Number)