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    Summary
    EudraCT Number:2014-001213-12
    Sponsor's Protocol Code Number:HGT-FIR-096
    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:2014-07-29
    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 number2014-001213-12
    A.3Full title of the trial
    A Phase III, Randomized, Double-Blind, Placebo-Controlled, Multicenter Clinical Study Evaluating the Safety and Efficacy of Icatibant as a Treatment for Angiotensin-Converting Enzyme Inhibitor (ACE-I)-Induced Angioedema in Adults
    A.4.1Sponsor's protocol code numberHGT-FIR-096
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation PlanP/282/2012
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorShire Orphan Therapies, Inc.
    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 supportShire HGT, Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationShire Human Genetic Therapies Inc.
    B.5.2Functional name of contact pointEric Haltom
    B.5.3 Address:
    B.5.3.1Street Address300 Shire Way
    B.5.3.2Town/ cityLexington
    B.5.3.3Post codeMA 02421
    B.5.3.4CountryUnited States
    B.5.4Telephone number0017814829101
    B.5.6E-mailehaltom@shire.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.2.1.1.1Trade name Firazyr (icatibant) 30 mg solution for injection in pre filled syringe
    D.2.1.1.2Name of the Marketing Authorisation holderShire Orphan Therapies GmbH
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/03/133
    D.3 Description of the IMP
    D.3.1Product nameFirazyr (icatibant) 30 mg solution for injection in pre filled syringe
    D.3.4Pharmaceutical form Solution for injection in pre-filled syringe
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNIcatibant
    D.3.9.1CAS number 138614-30-9
    D.3.9.3Other descriptive nameICATIBANT ACETATE
    D.3.9.4EV Substance CodeSUB29718
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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
    D.8.3Pharmaceutical form of the placeboSolution for injection in pre-filled syringe
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    ACE-I-induced angioedema
    E.1.1.1Medical condition in easily understood language
    This is a rare medical condition where the
    body has local swellings in various body parts including the hands, feet,
    face and airway, (throat) caused by treatment with anti-hypertensive drugs.
    E.1.1.2Therapeutic area Body processes [G] - Circulatory and Respiratory Physiological Phenomena [G09]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    E.1.2Level PT
    E.1.2Classification code 10002424
    E.1.2Term Angioedema
    E.1.2System Organ Class 10040785 - Skin and subcutaneous tissue disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Primary Efficacy Objective:
    To compare the efficacy of icatibant with placebo in the treatment of angiotensinconverting enzyme inhibitor (ACE-I)-induced angioedema based on the Time to Meeting Discharge Criteria (TMDC) endpoint.

    Primary Safety Objective:
    To assess the safety and tolerability of icatibant treatment in patients experiencing an attack of ACE-I-induced angioedema.

    E.2.2Secondary objectives of the trial
    Key Secondary Efficacy Objective:
    To compare the efficacy of icatibant with placebo in the treatment of ACE-I-induced angioedema based on the Time to Onset of Symptom Relief (TOSR) endpoint.

    Pharmacokinetic Objective:
    To characterize the pharmacokinetic (PK) properties of icatibant and its major metabolites (M1 and M2 [amino acids 1-5 and amino acids 7-10, respectively]) in patients with ACEI-induced angioedema.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female, 18 years of age or older.
    2. Patient is currently being treated with an ACE inhibitor.
    3. Patient presenting with an ACE inhibitor-induced angioedema attack of the head and/or neck region within 12 hours of onset (must be sufficiently less than 12 hours to allow study drug to be given with 12 hours of onset).
    4. Angioedema must be considered at least moderate in severity for at least one of the four primary efficacy angioedema-associated upper airway symptoms (difficulty breathing, difficulty swallowing, voice changes, tongue swelling).
    5. Patient must have voluntarily signed an Institutional Review Board/Independent Ethics Committee-approved informed consent form after all relevant aspects of the study have been explained and discussed with the patient.
    6. Females must have a negative urine pregnancy test prior to administration of the study medication, with the exception of those females who have had a total hysterectomy or bilateral oophorectomy, or who are 2 years post-menopausal.
    E.4Principal exclusion criteria
    1. Patient has a diagnosis of angioedema of other etiology (eg, hereditary or acquired angioedema, allergic angioedema [eg, food, insect bite or sting, evident clinical response to antihistamines and/or corticosteroids], anaphylaxis, trauma, abscess or
    infection or associated disease, local inflammation, local tumor, post-operative or post-radiogenic edema, salivary gland disorders, other [non-ACE inhibitor] druginduced angioedema).
    2. Patients with a family history of recurrent angioedema.
    3. Patients who have had a previous episode(s) of angioedema while not on ACE inhibitor therapy.
    4. Patients with acute urticaria (itchy, erythematous wheals).
    5. Patients who have an intervention to support the airway (eg, intubation, tracheotomy, cricothyrotomy) due to the current attack of angioedema.
    6. Patient has any of the following vascular conditions that, in the judgment of the investigator, would be a contraindication to participation in the study.
     Unstable angina pectoris or acute myocardial ischemia.
     Hypertensive urgency or emergency (diastolic blood pressure [DBP] >120 mm Hg or systolic blood pressure [SBP] >180 mm Hg).
     Within 1 month of a stroke or transient ischemic attack.
     New York Heart Association (NYHA) heart failure Class IV.
    7. Patient has a serious or acute condition or illness that, in the judgment of the investigator, would interfere with evaluating the safety and/or efficacy assessments of the study.
    8. Patient is pregnant or breast feeding.
    9. Patient has participated in another investigational study in the past 30 days.
    10. Patient is unable to understand the nature, scope, and possible consequences of the protocol, or is unlikely or unable to comply with the protocol assessments, or is unlikely to complete the study for any reason.
    11. Patients who are not suitable for the study in the opinion of the investigator.
    E.5 End points
    E.5.1Primary end point(s)
    Primary efficacy endpoint:
    Investigators will assess the severity of the following angioedema-associated upper airway symptoms: difficulty breathing, difficulty swallowing, voice changes, and tongue swelling. The assessment will be based on a 5-point severity scale from 0 (absent) to 4 (very severe).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Screening, 0.5 hr, every hour up to 8 hrs.
    During a stay longer than 8 hours in the emergency department or hospital, airway symptom assessments by the investigator will continue and be perfiormed every 2 hours from >8 to 24 hours and every 3 hours from >24 hours, until Time to Meeting Discharge Criteria (TMDC) endpoint has been met and the patient can be discharged.
    E.5.2Secondary end point(s)
    Safety Assessments:
    The following safety assessments will be performed at the specified time points:
     Physical examinations at baseline and at 8 hours after study drug administration. If the patient remains in the ED or hospital longer than 8 hours, an additional physical examination will be performed at discharge.
     Vital signs including blood pressure at baseline and at 0.5, 1, 2, 4, 6 and 8 hours after study drug administration. If the patient remains in the ED or hospital longer than 8 hours, vital signs will be performed at 3-hour intervals and at discharge.
     ECG at baseline and at 0.75 and 8 hours after study drug administration.
     Serum chemistry and hematology blood tests, and urinalysis at baseline and at 8 hours after study drug administration.
     Injection site reaction assessments at 0.5, 2, 4, and 8 hours after study drug
    administration.
    E.5.2.1Timepoint(s) of evaluation of this end point
    See above
    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 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) 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.8.2.4Number of treatment arms in the trial2
    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 Yes
    E.8.5.1Number of sites anticipated in the EEA4
    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 Yes
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Canada
    Israel
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    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.1.2.1Number of subjects for this age range: 118
    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 No
    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 2014-07-29. 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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 10
    F.4.2.2In the whole clinical trial 118
    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 applicable. ACE inhibitors use is in principle stopped after occurence of ACE-I-induced angioedema.
    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 Decision2014-09-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-08-13
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2015-08-22
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