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    Summary
    EudraCT Number:2005-004055-35
    Sponsor's Protocol Code Number:Bay a 0128/12002
    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:2006-01-13
    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 number2005-004055-35
    A.3Full title of the trial
    A multi-center, randomized, double blind, placebo controlled study to investigate the efficacy and safety of Aprotinin on transfusion requirements in patients with bladder cancer undergoing radical or total cystectomy
    A.4.1Sponsor's protocol code numberBay a 0128/12002
    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 SponsorBayer HealthCare AG
    B.1.3.4CountryGermany
    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 Yes
    D.2.1.1.1Trade name Trasylol
    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 nameTrasylol
    D.3.2Product code Bay a 0128
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAprotinin
    D.3.9.3Other descriptive nameserine protease inhibitor
    D.3.10 Strength
    D.3.10.1Concentration unit IU/ml international unit(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10000
    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 Yes
    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 No
    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 infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Radical or total cystectomy on patients with bladder cancer
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 8.1
    E.1.2Level HLT
    E.1.2Classification code 10057191
    E.1.2Term Transfusion related complications
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Main objective: The objective of this study is to evaluate the safety and efficacy of aprotinin as compared to placebo, in reducing the need for subsequent blood transfusion in subjects with bladder cancer undergoing to radical or total cystectomy. The undermentioned procedures are allowed and belong to radical and total cystectomy:
    1. total cystectomy
    2. radical cystectomy procedures = cystectomy plus removal of adjacent tissues: cystoprostatectomy, removal of bladder and anterior vaginal wall, cystectomy plus ovariectomy and or hysterectomy
    3. urinary tract reconstructive procedures: incontinent cutaneous diversion (eg ileal conduit, etc), continent cutaneous diversion (eg Indiana pouch, etc), orthotopic diversion (eg neobladder)
    E.2.2Secondary objectives of the trial
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Subjects (men or non-pregnant women) 18 years of age and older.
    Subjects requiring elective radical or total cystectomy for bladder cancer.
    Documented, signed, dated informed consent obtained prior to any study specific procedures being performed.
    E.4Principal exclusion criteria
    • Subjects with previous exposure to aprotinin in the last 6 months (if the subject has undergone cardiac surgery in the last 6 months, all attempts should be made to ascertain if aprotinin was administered during surgery; if no records are available, or if the subject received aprotinin, the subject should be excluded)
    • Subjects with known or suspected allergy to aprotinin
    • Subjects undergoing laparoscopic resection.
    • Patients with symptoms indicative for sepsis or local urinary tract infections that make the patient inelegible for total or radical cystectomy
    • Subjects with a creatinine clearance less than 30 mL/min as calculated by the Cockcroft-Gault formula.
    • Subjects with a history of bleeding diathesis or known coagulation factor deficiency
    • Subjects with failure of a major organ system or any active significant medical illness that in the opinion of the Investigator is likely to affect the subject’s ability to complete the study or precludes the subject’s participation in the study
    • Subjects who refuse to receive allogenic blood products for religious or other reasons
    • Subjects whose preoperative RBC volume is so low that blood will have to be given peri-operatively (Hct or Hgb values <24% or <8 g/dL, respectively)
    • Subjects with a history of Deep Vein Thrombosis or Pulmonary Embolism
    • Women who are pregnant, breastfeeding or women of childbearing potential in whom the possibility of pregnancy cannot be excluded by a negative serum pregnancy test at screening.
    • Women of childbearing potential who are not using a reliable method of contraception. Methods of contraception that are considered reliable are intrauterine devices (IUDs), birth control pills, hormonal implants/patches, and barrier contraception when used with spermicidal products. The "Rhythm" method is not considered a reliable method of contraception.
    • Planned use of other antifibrinolytic agents (e.g., aminocaproic acid (Amicar®) or tranexamic acid (Cyklokapron®)
    • Subjects on chronic anticoagulant treatment with Vitamin K antagonists where it cannot be discontinued for the surgical procedure
    • Subjects on an investigational drug (i.e. not marketed) in the 30 days prior to screening or during the trial before the 6 week follow-up visit. Subjects involved in trials of marketed cancer therapy medications (including those approved for another indication) or combination with radiotherapy are allowed.
    E.5 End points
    E.5.1Primary end point(s)
    The objective of this study is to evaluate the safety and efficacy of aprotinin as compared to placebo, in reducing the need for subsequent blood transfusion in subjects with bladder cancer undergoing to radical or total cystectomy. The primary criterion for efficacy is the percent of patients requiring a blood transfusion anytime in the intra-operative or post-operative period (up to the earlier of Day 7 or discharge). The primary analysis will be based on all patients undergoing protocol defined surgery that are valid for analysis of intent to treat.

    Secondary end points:
    The number of units of blood or packed red cells transfused. There will be an analysis for the combination of autologous and allogenic transfusion and for allogenic alone.
    The number of units of blood or packed red cells transfused per patient requiring transfusion.
    The intraoperative blood loss determined as follow: a) by surgeon estimate b) summing weight of the blood in gauze and other materials and the suction drainage volume.
    The drainage volume (in milliliters) from the operative site in the first 8 hours post-operatively, and daily total drainage until removal of drains.
    Transfusion of platelets, colloids, plasma and number of patients requiring these products
    The change from preoperative hemoglobin concentration to postoperative hemoglobin concentration (obtained in the morning of postoperative Day 3, or, if transfused earlier, prior to transfusion)
    Surgeon’s assessment of the degree to which bleeding obscures his/her view of the surgical field, relative to past, similar procedures.
    Changes in blood markers related to inflammation and blood coagulation
    Time to discontinuing of mechanical ventilation
    Changes in FEV1
    Changes in the patients’ health related quality of life (HRQoL) (at baseline and 62 weeks post surgery) using the Functional Assessment Cancer Therapy for patients with Bladder cancer (FACT-Bl) questionnaire.
    In addition, exploratory analyses might be performed to determine the influence of factors known to affect blood loss (i.e., ASA/NSAID use, EPO use, concomitant medication use for DVT prophylaxis, and type of anesthesia) on the estimate of treatment effect. Also, changes in plasma urokinase plasminogen activator (uPA) will be exploratory.
    Health Economics and Outcomes variables will include:
    Prior to the surgery: Preoperative blood donation.
    In the intra-operative and postoperative period (up to discharge): Duration of surgery; Duration of Intensive Care Unit (ICU) stay post operation, Duration of recovery room stay post operation; Anti-infective medications, prophylactic and/or treatment for postoperative infection (wound infection and other infections); Length of hospital stay (from the date of surgery to the date of discharge); Cost of hospital stay (total cost and all itemized costs including cost of blood transfusion, autologous or allogenic-blood products, administration, and equipment; cost data will only be collected from applicable sites).
    A follow-up questionnaire will be administered to study subjects to collect the following information within the post discharge period: Number of office visit(s), Number of emergency room visit(s), Number and duration of hospitalization(s), Whether patient had an infection.
    The analyses of cost data will be outlined in the statistical analysis plan (SAP) before unblinding of the study. The Health Economics outcome results will be an addendum to the MRR.

    Overall survival up to 2 years
    An exploratory analysis of the overall survival will be performed based on data collected during the 2 year follow-up (by phone call every 3 months). Sub-analysis of survival data and the other secondary endpoints based on type of cancer and high plasma uPA at baseline will be performed. This data analysis will be performed after database lock for the primary and secondary analyses that will be closed after the 6 ± 2 week follow up visit. The survival data will not form part of the final MRR but will be included as an addendum to this document.
    A blood sample will be drawn to measure baseline aprotinin antibodies. This results will only be used to develop an assay that may be able to identify patients who have increased risk for developing hypersensitivity reaction to Trasylol. This assay is early in its development and it has not been nor will be used clinically to identify those individual risks.
    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 Yes
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans Information not present in EudraCT
    E.7.1.2Bioequivalence study Information not present in EudraCT
    E.7.1.3Other Information not present in EudraCT
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 Yes
    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 No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA17
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    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 duration of the study is approximately 36 months from the first
    subject being screened, including a two-year long term follow up.
    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 months3
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    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 Yes
    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 state60
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 142
    F.4.2.2In the whole clinical trial 284
    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)
    Long term survival follow up with 3 month interval phone calls by the investigators
    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 Decision2006-02-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2006-01-20
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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