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    Summary
    EudraCT Number:2009-010191-19
    Sponsor's Protocol Code Number:ALS-002-2009
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2009-10-05
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2009-010191-19
    A.3Full title of the trial
    A randomized, double-blind, placebo-controlled phase IIIa study on bIAP, an anti-inflammatory moiety,
    in patients undergoing combined aortic valve replacement and coronary artery bypass grafting.
    A.3.2Name or abbreviated title of the trial where available
    APPIRED II
    A.4.1Sponsor's protocol code numberALS-002-2009
    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 SponsorAlloksys Life Sciences BV
    B.1.3.4CountryNetherlands
    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 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 No
    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 namebIAP
    D.3.2Product code EC 3.1.3.1
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPIntravenous bolus use (Noncurrent)
    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 typeProduct is derived from bovine intestinal mucosa
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection
    D.8.4Route of administration of the placeboIntravenous bolus use (Noncurrent)
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Patients undergoing invasive cardiac surgery with prolonged perfusion time. This often is associated with
    potentially life-threatening inflammatory complications due to ischemic periods during surgery both local
    (Damaged tissue release of nucleotide) and at sites distant from there (e.g. ischemia of the intestinal tract).
    Alkaline phosphatase detoxifies nucleotides and bacterial toxins and consequently reduces the overall
    inflammatory insult as demonstrated in the preceding APPIRED I study.
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 12.0
    E.1.2Level LLT
    E.1.2Classification code 10057944
    E.1.2Term Combined valvular disease
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The objective of this study is to determine the efficacy of bIAP as a prophylactic agent against inflammation-mediated complications from more invasive cardiac surgery, valvular surgery and CABG with cardiopulmonary-bypass time of longer than 1 hour.

    Primary study endpoint is the postulated reduction of the number of post-surgical SIRS cases in the bIAP-treated patient group as compared to the placebo-treated group. SIRS, in the sense of this study, is indicated by an increased TNF-α level of at least 10 pg/ml above the pre-surgical level, which is normally followed by an increase of IL-6 and IL-8.
    E.2.2Secondary objectives of the trial
    The incidence of new organ dysfunction within 14 days of surgery will be assessed, next to the duration of organ dysfunction, lengths of organ dysfunction-associated intensive care unit (ICU) and hospital stays, ventilation-assistance and renal failure-dialysis days, volume of blood and blood products infused within 24 hours of surgery, incidence of hospital readmission and 30-day all-cause mortality. Safety will be assessed by incidence and severity of adverse events, changes in physical examination, vital signs and changes in clinical laboratory measurements.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or non-pregnant, non-lactating female patients of any race in the ages of >18 years.
    2. Patients scheduled for combined aortic valve replacement and CABG surgery
    3. Patients who have given written informed consent prior to participation in the trial and who undertake to
    comply with the protocol.
    E.4Principal exclusion criteria
    1. Patients who are unwilling or unable to be fully evaluated for follow-up.
    2. Patients who have base AP levels at > 125 IU/L, or levels < 30 IU/L (ammediol, DEA (diethanolamine) units)
    3. Patients who show pre-operative infections or who are suspected of endocarditis or systemic infection.
    4. Patients who refuse to accept medically-indicated blood products.
    5. Patients who have evidence of significant hepatic disease, including history of clinical signs or laboratory values of total bilirubin > 34.2 µmol/L (> 2.0 mg/dL), ALT (>120) or AST (>135) corresponding to > 3X upper limit of normal.
    6. Patients who received investigational drugs in the 30 days prior to study drug administration, or are currently participating in a study during which the administration of investigational drugs within one month is anticipated.
    7. Patients who require pre-operative ventilatory support.
    8. Patients who have renal insufficiency (history of creatinine >177µmol/L or >2.0 mg/dL) or chronic renal failure requiring dialysis.
    9. Patients who are planned to receive leukocyte-depletion filtration as part of the bypass circuitry.
    10. Patients with severe neurological deficits.
    11. Patients who have a recent history of drug or alcohol abuse.
    12. Patients with a diagnosis of idiopathic thrombocytopenia.
    13. Patients with a history of cancer who have received chemotherapy or radiation therapy within the past 3 months. Patients receiving only adjuvant hormonal therapy are not excluded.
    14. Patients who are scheduled to receive "stress doses" of glucocorticoids (i.e., doses >2 mg/kg/day of methylprednisolone or equivalent) prior to, during or following surgery.
    15. Patients who are vegetarians or veganists or those patients that may be expected not to be tolerant for bovine proteins.
    16. Patients who are, in the opinion of the investigator, unsuitable for the study. A well-documented screening log should be present in the clinic.
    E.5 End points
    E.5.1Primary end point(s)
    Main study primary endpoint is the reduction of post-surgical SIRS in bIAP–treated patients as compared to placebo–treated patients,that is the reduction of incidences of fulminate SIRS responses, indicated by pro-Inflammatory cytokines. The pro-inflammatory cytokine (TNF-α, IL-6 and IL-8) levels will be measured
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    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 No
    E.8.1.4Double blind Yes
    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 Yes
    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.8.5The 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 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
    The expected mortality will be calculated within this study based on the individual EuroSCORE of the patients included. If at any time the 30-day mortality in the verum group exceeds the confidence interval, this will be reason to terminate the study.

    If any new safety risk regarding the study drugs came aware to the sponsor or the investigator this will be reason to assess the ongoing study.
    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 months6
    E.8.9.1In the Member State concerned days2
    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 days2
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2009-10-05. Yes
    F.3.3.2Women of child-bearing potential using contraception Yes
    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
    product has not been applied in these populations. Data on transplacental transmission are not known.
    Patients undergo valvular surgery combine with CABG and will give consent personally
    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 50
    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)
    not different from normal standard of care
    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 Decision2010-03-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2009-11-05
    P. End of Trial
    P.End of Trial StatusOngoing
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