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    The EU Clinical Trials Register currently displays   43865   clinical trials with a EudraCT protocol, of which   7286   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    Summary
    EudraCT Number:2012-002319-25
    Sponsor's Protocol Code Number:
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2012-10-16
    Trial results View 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 number2012-002319-25
    A.3Full title of the trial
    A pilot, phase IIb, randomised, multicentre trial of Argatroban in combination with recombinant tissue plasminogen activator for acute stroke
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A pilot study of Argatroban combined with TPA (alteplase) for the treatment of acute stroke.
    A.3.2Name or abbreviated title of the trial where available
    ARTSS-2
    A.4.1Sponsor's protocol code number
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01464788
    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 SponsorUniversity of Texas Health Science Center
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportNational Institutes for Health (NIH) U.S Dept of Health
    B.4.2CountryUnited States
    B.4.1Name of organisation providing supportFarb Fund University of Texas
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNewcastle University
    B.5.2Functional name of contact pointProf G Ford
    B.5.3 Address:
    B.5.3.1Street AddressClinical Research Facility 4th Floor Leazes Wing
    B.5.3.2Town/ cityRoyal Victoria Infirmary, Newcastle upon Tyne
    B.5.3.3Post codeNE1 4LP
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01912227744
    B.5.5Fax number01912820064
    B.5.6E-mailgary.ford@ncl.ac.uk
    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.2.1.1.1Trade name Exembol
    D.2.1.1.2Name of the Marketing Authorisation holderMitsubishi Pharma Europe Ltd
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 nameArgatroban
    D.3.2Product code n/a
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous drip use (Noncurrent)
    Intravenous bolus use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNArgatroban
    D.3.9.1CAS number 74863846
    D.3.9.4EV Substance CodeAS2
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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 No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Ischemic Stroke
    E.1.1.1Medical condition in easily understood language
    Stroke
    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
    To estimate overall treatment benefit (improvement in disability) among stroke patients treated with rt-PA (alteplase) who are randomised to also receive either low-dose Argatroban, high-dose Argatroban or neither.
    E.2.2Secondary objectives of the trial
    1) To help verify the safety (as measured by incidence of intracranial haemorrhage) of low-dose combination Argatroban and rt-PA (alteplase) and test the safety of high-dose combination treatment
    2) To assess rates of early recanalisation for use in assessing mechanisms of treatment effect and in predicting outcome of the drug combination.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Disabling Ischemic stroke symptoms with onset < 3 hours treated with IV rt-PA (alteplase) by local standards*.
    * or ≤ 4.5 hours according to local standard of care.
    2. Age ≥ 18.
    3. NIHSS ≥ 10* or any NIHSS with an intracranial clot should be demonstrated on neurovascular imaging (TCD or CTA) in any one of the following areas: distal ICA, MCA (M1 or M2), PCA (P1 or P2), distal vertebral or basilar artery.
    - TCD criteria: TIBI 0, 1, 2 or 3
    - CT-Angiogram: TIMI 0 or 1
    * NIHSS ≥ 10, demonstration of clot on neuroimaging is not necessary (i.e., enrollment can proceed with non-contrast head CT alone), but if performed, a clot must be demonstrated.
    4. For those patients who will undergo repeat CT-Angiogram at 2-3 hours, estimated glomerular filtration rate (eGFR) must be ≥ 60 mL/min/1.73m2.
    5. Females of childbearing potential must have a negative serum pregnancy test prior to the administration of trial medication.
    6. Signed (written) informed consent by the patient or the patient’s legal representative and/or guardian.
    E.4Principal exclusion criteria
    1. Patients whom the treating physician is planning (or could plan) to treat with intra-arterial thrombolysis or other endovascular procedures (i.e., mechanical clot retrieval) aimed at recanalisation.
    2. Evidence of intracranial haemorrhage (ICH) on baseline CT scan or diagnosis of a non-vascular cause of neurologic deficit.
    3. NIHSS Level of Consciousness score (1a) ≥ 2.
    4. Pre-existing disability with mRS ≥ 2.
    5. CT scan findings of hypoattenuation of the x-ray signal (hypodensity) involving ≥ 1/3 of the MCA territory.
    6. Any evidence of clinically significant bleeding, or known coagulopathy.
    7. INR >1.5.
    8. Patients with an elevated aPTT greater than the upper limit of normal
    9. Patients currently, or within the previous 24 hours, on an oral direct thrombin inhibitor.
    10. Heparin flush required for an IV line. Line flushes with saline only.
    11. Any history of intra-cranial haemorrhage, known arteriovenous-malformation or unsecured cerebral aneurysms.
    12. Significant bleeding episode within the 3 weeks before study enrollment.
    13. Major surgery or serious trauma in last 2 weeks.
    14. Patients who have had an arterial puncture at a non-compressible site, biopsy of parenchymal organ, or lumbar puncture within the last 2 weeks.
    15. Previous stroke, myocardial infarction (MI), post myocardial infarction pericarditis, intracranial surgery, or significant head trauma within 3 months.
    16. Uncontrolled hypertension (SBP > 185 mmHg or DBP >110 mmHg) that does not respond to intravenous anti-hypertensive agents.
    17. Surgical intervention (any reason) anticipated within the next 48 hours.
    18. Known history of clinically significant hepatic dysfunction or liver disease – including a current history of alcohol abuse.
    19. Abnormal blood glucose <50 mg/dL (2.7 mmol/L).
    20. History of primary or metastatic brain tumor.
    21. Current platelet count < 100,000/mm3.
    22. Life expectancy < 3 months.
    23.Patients who, in the judgment of the investigator, needs to be on concomitant (i.e., during the Argatroban infusion) anticoagulants other than Argatroban, including any form of heparin, UFH, LMWH, defibrinogenating agent, dextran, other direct thrombin inhibitors or thrombolytic agents, GPIIb/IIIa inhibitor or warfarin. [*Caveat: However, if in the judgment of the investigator a patient needs to be anticoagulated, but this can be deferred for 48 hours, then they could be included.]
    24. Currently participating or has participated in any investigational drug or device study within 30 days before the first dose of study medication.
    25. Known hypersensitivity to Argatroban or its agents.
    26. Additional exclusion criteria if patient presents between 3-4.5 hours:
    a) Age >80
    b) Currently taking oral anticoagulants (regardless of INR)
    c) A history of stroke and diabetes.
    d) NIHSS > 25.
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome measure is an excellent functional outcome measured by the percentage of patients with a 0 or 1 on the modified Rankin Scale (mRS) at day 90 as assessed by study personnel blinded to treatment.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Day 90
    E.5.2Secondary end point(s)
    1) Safety as measured by the incidence of:
    a) symptomatic intracranial haemorrhage
    b) parenchymal haemorrhage 2
    c) major systemic haemorrhage
    2) Rates and completeness of arterial recanalisation assessed at baseline and 2 - 3 hours by CT-angiogram (CTA)
    3) Neurological deficits improvement from baseline to 2 hours, 24 hours, end of Argatroban infusion, day 7/discharge and day 90 as measured by NIHSS
    4) Quality of Life - obtained by standard gamble, time-trade-off method and visual analogue scale (VAS)
    5) Cost and cost effectiveness analysis
    medical costs associated with each treatment
    incremetal cost effectiveness ratio (change in cost divided by quality of life gained)
    E.5.2.1Timepoint(s) of evaluation of this end point
    1) a)b)c) Within the first 7 days or discharge whichever occurs first.
    2) Between 2 and 3 hours of the tPA bolus time
    3) Baseline NIH Stroke scale will be tracked from pre-tPA to: 2 hours (±30 minutes); 24 hours (±4 hours); end of Argatroban infusion or 48 hours from tPA bolus (±4 hours) and day 7/discharge.
    4) day 7 or discharge (whichever comes first) and day 90(-/+ 10 days)
    5) Day 90 (-/+ 10 days)
    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 Yes
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind Yes
    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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    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.8.4.1Number of sites anticipated in Member State concerned6
    E.8.5The trial involves multiple Member States No
    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 States
    E.8.7Trial 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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days5
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days29
    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: 25
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 25
    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 state50
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 50
    F.4.2.2In the whole clinical trial 105
    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)
    Due to the stage of development there will be no continued provision of the intervention at the end of the study.
    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 Northumberland, Tyne and Wear CLRN
    G.4.3.4Network Country United Kingdom
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2012-11-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-07-24
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2015-07-01
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