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    Summary
    EudraCT Number:2016-000502-11
    Sponsor's Protocol Code Number:EKOS-12
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2016-10-17
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2016-000502-11
    A.3Full title of the trial
    Study of the Optimum Duration of Acoustic Pulse Thrombolysis (APT) Procedure in the Treatment of Acute Submassive Pulmonary Embolism (OPTALYSE PE).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of treatment of a blood clot located in the pulmonary artery(ies), to find the optimum duration of ultrasound and dose of a clot dissolving drug.
    A.3.2Name or abbreviated title of the trial where available
    EKOS and r-tPA thrombolysis in Pulmonary Embolism (OPTALYSE STUDY)
    A.4.1Sponsor's protocol code numberEKOS-12
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02396758
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorEKOS Corporation
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportEKOS Corporation
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationEKOS Corporation
    B.5.2Functional name of contact pointLynn Allen
    B.5.3 Address:
    B.5.3.1Street Address11911 North Creek Parkway S
    B.5.3.2Town/ cityBothell
    B.5.3.3Post codeWA 98011
    B.5.3.4CountryUnited States
    B.5.4Telephone number4254153100
    B.5.5Fax number4254153102
    B.5.6E-mailLynn.Allen@ekoscorp.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameActilyse, Activase, r-tPA
    D.3.4Pharmaceutical form Powder and solvent for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntraarterial use
    Intrapulmonary use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNALTEPLASE
    D.3.9.1CAS number 105857-23-6
    D.3.9.4EV Substance CodeAS1
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product Yes
    D.3.11.13.1Other medicinal product typer-tPA, manufactured using gene technology from ovarial cell cultures of the chinese hamster
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Submassive pulmonary embolism
    E.1.1.1Medical condition in easily understood language
    A blood clot located in one or both pulmonary arteries which interferes with blood flow through the heart and lungs, accompanied by dysfunction of the right lower heart chamber (right ventricle).
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The principle objective of this study is to determine the optimum dose of thrombolytic (the agent used to dissolve or break up blood clots) and the duration of ultrasound procedure (together defined as the APT Procedure) as a treatment for submassive pulmonary embolism.

    The drug will be delivered under local anaesthetic by passing an EKOS catheter through a vein in the groin to the location of the blood clot in the pulmonary artery. X-ray guidance is used. The EKOS catheter then delivers the drug and ultrasound over a period of hours. This study will explore a reduction in the amount of drug delivered and a reduction in treatment time compared to those used in previous studies.
    E.2.2Secondary objectives of the trial
    The secondary research objectives are:
    1 Treatment success of an APT procedure assessed by an Adjudication Committee blinded to the APT treatment group. Treatment success is defined in the Adjudication Committee Charter.

    2 Changes from baseline in measurements obtained from an echocardiogram (ultrasound image of the heart). These measurements will be recorded at 4 hours and 48 hours post procedure, then at 30 days, 90 days and 365 days after the end of the APT procedure.

    3 Change from baseline in thrombus burden by Miller Score as assessed by pulmonary angiogram (PAgram). This is a CT image of the pulmonary arteries - the vessels which carry blood from the heart to the lungs). The PA gram will be performed within 4 hours of the end of APT. However this can only be assessed for subjects for whom pre and post PA grams are available.

    4 Change from baseline in thrombus burden by modified Miller score as assessed by Computed Tomography Angiography CTA at 48 hours af
    E.2.3Trial contains a sub-study No
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    After the four treatment arms have been completed and results analysed, a fifth treatment arm may be tested The treatment and dose for the fifth treatment arm will be determined and will fall within the range of EKOS treatment duration from 2 to 6 hours and r-tPA for 1 to 2mg/hour/catheter (total r-tPA dose of 4 to 24mg. The sample size requirement will be assessed using available information at the time.

    The details for the fifth arm are included in the protocol for the study being reviewed.
    E.3Principal inclusion criteria
    1. Male or female ≥ 18 years of age and ≤ 75 years of age
    2. Computed tomography angiography (CTA) evidence of proximal pulmonary embolism (PE) (filling defect in at least one main or lobar pulmonary artery)
    3. PE symptom duration ≤14 days
    4. Submassive PE: RV/LV diameter ≥ 0.9 from CTA and haemodynamically stable
    5. Treatment must be started within 48 hours of diagnosis of PE by CTA
    6. Signed Informed consent obtained from subject or Legally Authorized Representative
    E.4Principal exclusion criteria
    1. Stroke or transient ischemic attack (TIA), head trauma, or other active intracranial or intraspinal disease within one year
    2. Recent (within one month) active bleeding from a major organ
    3. Major surgery within seven days of screening for study enrollment
    4. Clinician deems the subject high-risk for catastrophic bleeding
    5. History of heparin-induced thrombocytopaenia (HIT)
    6. Catheter-based pharmacomechanical treatment for PE within 3 days of study enrollment
    7. Systolic blood pressure (SBP) less than 90 mm Hg and/or use of vasopressors
    8. Cardiac arrest (including pulseless electrical activity and asystole) requiring active cardiopulmonary resuscitation (CPR)
    9. Evidence of irreversible neurological compromise
    10. Life expectancy < one year
    11. Use of thrombolytics or glycoprotein IIb/IIIa antagonists within 3 days prior to APT procedure
    12. Out-of-Range haematological parameter laboratory values: Haematocrit < 30%, Platelets < 100 thousand/μL, INR > 3,
    13. Creatinine outside the normal range for the treating institution
    14. Subject is pregnant (positive pregnancy test; women of childbearing capacity must be tested) or breast feeding
    15. Active cancer (metastatic, progressive, or treated within the last 6 months). Exception: subjects with non-melanoma primary skin cancers are eligible to participate in the study
    16. Known allergy, hypersensitivity, or thrombocytopaenia from heparin, r-tPA, or iodinated contrast except for mild-moderate contrast allergies for which steroid pre-medication can be used
    E.5 End points
    E.5.1Primary end point(s)
    EFFICACY
    The primary efficacy endpoint is the change in the ratio of the measurement of the RV/LV as measured by computed tomographic angiography (CTA) from baseline to 48 ± 6 hours after the start of the APT.

    SAFETY
    The primary safety outcome is frequency of major bleeding within 72 hours after initiating the APT Procedure. Evaluation of clinically overt bleeding will depend upon the suspected bleeding site and clinician’s judgment. Major bleeding events will be defined according to the International Society on Thrombosis and Haemostasis (ISTH) criteria for major bleeding
    1. Fatal bleeding and/or
    2. Symptomatic bleeding in a critical area or organ (intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome) and/or
    3. Bleeding causing a fall in hemoglobin level of 20 g/L or more, or leading to transfusion of two or more units of whole blood or red blood cells
    Major bleeding events will be categorized as in-hospital and/or taking place within 72 hours or at time of hospital discharge (whichever is earlier) of start of the APT Procedure.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary efficacy endpoint is the change in the ratio of the measurement of the RV/LV as measured by computed tomographic angiography (CTA) from baseline to 48 ± 6 hours after the start of the APT.

    The primary safety outcome is frequency of major bleeding within 72 hours after initiating the APT Procedure.
    E.5.2Secondary end point(s)
    1. Treatment success of an APT Procedure group assessed by an Adjudication Committee blinded to APT Procedure treatment group. Treatment success is defined in the Adjudication Committee Charter.
    2. Change from baseline in echocardiographic parameters including RV/LV ratio, Tricuspid Annular Plane Systolic Excursion (TAPSE), estimated Right Ventricular Systolic Pressure (RVSP), and collapse of the inferior vena cava (IVC) with respiration within 4 hours and 48 hours and at 30 days, 90 days and 365 days after the end of the APT Procedure.
    3. Change from baseline in thrombus burden by Miller score as assessed by pulmonary arteriography (PAgram) within 4 hours after the end of the APT Procedure for subjects for whom pre and post PAgrams are available.
    4. Change from baseline in thrombus burden by modified Miller score as assessed by CTA at 48 hrs. after the start of the APT Procedure.
    5. 6 minute walk (6MW) distance with BORG score and requirement for oxygen therapy
    Quality of life (QOL) as measured by the Patient Reported Outcomes Measurement Information System Physical Function (PROMIS PF-6) and Pulmonary Embolism Quality of Life (PEmb-QOL) at all post-hospitalization subject visits and phone contacts.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Change from baseline in echocardiographic parameters within 4 hours and 48 hours and at 30 days, 90 days and 365 days after the end of the APT Procedure.

    Change from baseline in thrombus burden by Miller score as assessed by pulmonary arteriography (PAgram) within 4 hours after the end of the APT Procedure for subjects for whom pre and post PAgrams are available.

    Change from baseline in thrombus burden by modified Miller score as assessed by CTA at 48 hrs. after the start of the APT Procedure.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States No
    E.8.5.1Number of sites anticipated in the EEA1
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee No
    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
    Last Subject Last Visit
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days28
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months11
    E.8.9.2In all countries concerned by the trial days31
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 0
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 0
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 10
    F.4.2.2In the whole clinical trial 150
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    The intervention (APT Procedure) will be administered in an emergency setting for a planned maximum duration of 6 hours...
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation South West Peninsula
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-05-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-07-21
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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