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    Summary
    EudraCT Number:2007-003635-23
    Sponsor's Protocol Code Number:XIG-AP 1
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2009-09-14
    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 number2007-003635-23
    A.3Full title of the trial
    A PRELIMINARY EVALUATION OF THE SAFETY PROFILE OF TWENTY-FOUR HOUR INFUSION OF HUMAN RECOMBINANT ACTIVATED PROTEIN C (XIGRIS) EARLY IN SEVERE ACUTE PANCREATITIS.
    A.3.2Name or abbreviated title of the trial where available
    XIG-AP 1
    A.4.1Sponsor's protocol code numberXIG-AP 1
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorCentral Manchester and Manchester Children's Hospitals NHS Trust
    B.1.3.4CountryUnited Kingdom
    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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 Xigris
    D.2.1.1.2Name of the Marketing Authorisation holderEli Lilly & Company Ltd
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    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 nameXigris
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPIntravenous use
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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 typerecombinant
    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
    Severe acute pancreatitis in man (with an APACHE II score of ≥ 15) appears to carry a considerably higher risk of death when compared to general critical care patients with similar APACHE II scores. Current concepts of the pathophysiology of pancreatic necrosis suggest that disease progression is related to early activation of microvascular thrombotic pathways thus a theoretical case can be made for the use of activated protein C, early in the disease course of this illness
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10033647
    E.1.2Term Pancreatitis acute
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of this study is to undertake a preliminary evaluation of the role of human recombinant activated protein C administered early in the disease course of human severe acute pancreatitis. The principal end-points are assessment of safety of treatment and assessment of effect of intervention on markers of the coagulation and inflammatory response.

    E.2.2Secondary objectives of the trial
    Interim analysis may indicate the feasibility or otherwise of a preliminary health economic analysis. Given that clinical experience with the use of xigris in severe acute pancreatitis is extremely limited, the proposed study will provided valuable baseline information that will help in two key areas: defining the nature of the acute pancreatitis population who may benefit from treatment with xigris and assessing the risk-benefit balance of intervention with xigris.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Acute pancreatitis – defined as acute abdominal pain with a threefold
    elevation of serum amylase or a twofold elevation of serum lipase.
    2. Severe disease – defined as an APACHE II score of ≥ 15 on admission to hospital together with a logistic organ dysfunction score of ≥ 2 within the first 24 hours of admission to hospital.
    3. Early disease – defined as being within 72 hours of onset of severe pain.
    4. No clinical evidence of haemorrhage
    5. Patients with no prior history of bleeding duodenal ulcer, haemorrhagic stroke or other haemorrhagic diathesis.
    6. Patients not taking warfarin or other anticoagulant medication.
    7. Patients without evidence of end-stage renal disease
    8. Patients who are not pregnant or lactating.
    9. Over 18 years of age.
    10. No surgery or endoscopic retrograde cholangiopancreatography (ERCP) within the previous 30 days.
    11. Patients able to give informed consent (or complying with current United Kingdom criteria for consent in critical care unit trials).
    E.4Principal exclusion criteria
    1. Inability to give consent.
    2. Non-severe acute pancreatitis – defined as an APACHE II score of < 15 on admission to hospital.
    3. Later presentation: in excess of 72 hours after onset of severe pain.
    4. Clinical evidence of haemorrhage.
    5. Patients with a prior history of bleeding duodenal ulcer, haemorrhagic stroke or other haemorrhagic diathesis.
    6. Patients taking warfarin or other anticoagulant medication. Thrombocytopenia, coagulopathy.
    7. Patients with evidence of end-stage renal disease. Patients with liver disease.
    8. Under 18 years of age.
    9. Surgery or ERCP within the previous 30 days.
    10. Patients who may be pregnant or lactating.
    E.5 End points
    E.5.1Primary end point(s)
    Primary endpoints
    The primary objective of this study is to undertake a preliminary evaluation of the role of human recombinant activated protein C administered early in the disease course of human severe acute pancreatitis. The principal end-points are assessment of safety of treatment and assessment of effect of intervention on specific markers of coagulation, in particular the Protein C response.

    Primary endpoint - clinical adverse event assessment
    1. All bleeding events
    2. Serious bleeding events. These are defined as per the PROWESS trial criteria as follows: any intracranial haemorrhage, any life-threatening bleed, any bleeding event requiring the administration of ≥ 3 units of packed red blood cells per day for 2 consecutive days or any bleeding event assessed as a serious adverse event.
    3. Thrombotic events – Any events observed (and recorded by the patients’ clinicians) will be noted.
    Any serious adverse events will be reported to the Eli Lilly pharmaco-vigilance division within 24 hours together with a causality assessment.


    Primary endpoint – Coagulation & Inflammatory Biomarkers

    Based on preliminary information discussed during the course of a meeting held during the 20th annual congress of the European Society of Intensive Care Medicine it appears that levels of protein C may be an important indicator of response to treatment with activated protein C (21) and that further, protein C levels may be indicators of consumptive coagulopathy in severe acute pancreatitis.
    In this study, protein C levels will be measured at baseline (prior to commencement of infusion) and at 24 hours upon completion of the Xigris infusion.
    Further measurements of protein C will be undertaken at 48 hours, 72 hours, 1 week and day 10.
    A baseline haematological profile (including full blood count and haematocrit) and clotting profile including PT, APTT and bleeding time will be recorded at baseline, after infusion and daily during the first week (in keeping with good clinical practice).
    Baseline evidence of pancreatic haemorrhage will be assessed by intravenous contrast-enhanced computed tomography prior to commencement of infusion. CT will be repeated 48 hours after completion of infusion.
    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 No
    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 Yes
    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 No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    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 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 concerned4
    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 No
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    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
    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 months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    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 Yes
    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 Yes
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Majority of patients with severe acute pancreatitis retain the ability to give informed consent, a minority will be critically ill who may benefit from the treatment and thus be recruited to the study.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state30
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2008-08-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2008-04-03
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2011-10-19
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