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    Summary
    EudraCT Number:2012-000083-24
    Sponsor's Protocol Code Number:0624-206
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2012-04-02
    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 ConcernedGermany - PEI
    A.2EudraCT number2012-000083-24
    A.3Full title of the trial
    A PHASE 2, RANDOMIZED, DOUBLE-BLIND, MULTICENTER, DOSERANGING, CROSSOVER STUDY TO EVALUATE THE SAFETY AND EFFICACY OF SUBCUTANEOUS ADMINISTRATION OF CINRYZE® (C1 ESTERASE INHIBITOR [HUMAN]) WITH RECOMBINANT HUMAN HYALURONIDASE (rHuPH20) FOR THE PREVENTION OF ANGIOEDEMA ATTACKS IN ADOLESCENTS AND ADULTS WITH HEREDITARY ANGIOEDEMA
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study of the Safety and Efficacy of Subcutaneous Administration of Cinryze with Recombinant Human Hyaluronidase for the Prevention of HAE Attacks
    A.4.1Sponsor's protocol code number0624-206
    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 SponsorViroPharma Incorporated
    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 supportViroPharma SPRL
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationViropharma SPRL
    B.5.2Functional name of contact pointDanielle Tierens
    B.5.3 Address:
    B.5.3.1Street AddressRue Montoyer 47
    B.5.3.2Town/ cityBrussels
    B.5.3.3Post code1000
    B.5.3.4CountryBelgium
    B.5.4Telephone number+32027470971
    B.5.5Fax number+32027062421
    B.5.6E-maildanielle.tierens@viropharma.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 CINRYZE
    D.2.1.1.2Name of the Marketing Authorisation holderViropharma SPRL
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Powder and solvent for solution for injection
    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.3.9.3Other descriptive nameCOMPLEMENT C1 ESTERASE INHIBITOR
    D.3.9.4EV Substance CodeSUB22696
    D.3.10 Strength
    D.3.10.1Concentration unit U unit(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    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) 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 Yes
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Angioedema.
    E.1.1.1Medical condition in easily understood language
    Symptoms or signs such as swelling or pain at any location.
    E.1.1.2Therapeutic area Body processes [G] - Genetic Phenomena [G05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10019860
    E.1.2Term Hereditary angioedema
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy of 1000 U and 2000 U doses of CINRYZE with
    rHuPH20 administered by SC injection to prevent angiodema attacks.
    To assess the safety and tolerability of CINRYZE with rHuPH20
    administered by SC injection.
    The following objectives applies to subjects who developed antibodies to
    rHuPH20 while participating in VIROPHARMA Study 0624-206 at German
    investigational sites.
    •To perform a longitudinal analysis of treatment-emergent anti-rHuPH20
    antibody titers after completion of dosing with rHuPH20.
    •To further characterize treatment-emergent anti-rHuPH20 binding
    antibodies (e.g., evaluation of binding to native PH20, reactivity with
    PH20 in an immunoblot, cross-reactivity with other human
    hyaluronidases) in applicable subjects.
    E.2.2Secondary objectives of the trial
    To determine the optimal dose of CINRYZE with rHuPH20 administered by SC injection for prevention of angioedema attacks based upon benefit-risk assessment.
    To further characterize the PK/PD of CINRYZE with rHuPH20 administered by SC injection.
    To assess the immunogenicity of CINRYZE with rHuPH20 following SC administration.
    To assess subject acceptance of SC administration of CINRYZE with rHuPH20 for prevention of angioedema attacks.
    To evaluate subject experience with self administration of SC CINRYZE with rHuPH20.
    To assess health status (quality of life) of this patient population.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Be ≥12 years of age.
    2. Have a confirmed diagnosis of HAE with a history of at least one of the following:
    • C1 INH antigen level below normal
    • Functional C1 INH level below normal
    3. If currently receiving prophylactic IV CINRYZE therapy (i.e., 1000 U every 3 or 4 days or up to 2000 U per week) or other C1 INH therapy, have:
    • during the 3 consecutive months prior to randomization, an angioedema attack rate of ≤1.0 moderate or severe attack per month (average).
    NOTE: if the duration of prophylactic therapy is <3 months, but at least 1 month, the subject should satisfy this attack rate (i.e., ≤1.0 moderate or severe attack per month [average]) for the timeframe that the subject has actually received prophylactic therapy.
    AND
    • during the 3 consecutive months prior to starting prophylactic therapy, a history of at least 2.0 moderate or severe angioedema attacks per month (average).
    NOTE: the attack rate may be estimated based on subject recall.
    4. If not on prophylactic C1 INH therapy, have a history of at least 2.0 moderate or severe angioedema attacks per month (average) during the 3 consecutive months prior to randomization.
    NOTE: the attack rate may be estimated based on subject recall.
    5. Agree to avoid his/her known HAE triggers during the study to the best of his/her ability.
    6. Agree to adhere to the protocol-defined schedule of assessments and procedures.
    7. If female, be post-menopausal (cessation of menses greater than or equal to 1 year), surgically sterile, or following an acceptable nonhormonal method of birth control such as intrauterine device or barrier control for at least 1 complete menstrual cycle before the screening visit and agree to continue use through the 30-day post-treatment visit, or using hormonal birth control products for at least 3 months prior to the first dose of study drug in Treatment Period 1 and agree to continue use through the 30-day post-treatment visit.
    8. If male, be surgically sterile or agree to follow an acceptable method of birth control (e.g., barrier control) from the screening visit through 2 months after the last dose of study drug.
    9. If an adult (≥18 years of age), be informed of the nature of the study and provide written informed consent before any study-specific procedures are performed.
    OR
    If a child (<18 years of age), have a parent(s)/legal guardian who is informed of the nature of the study provide written informed consent for the child to participate in the study before any study-specific procedures are performed (with assent from the child when appropriate).
    Alternatively, certain sites/IRAs may permit adolescents who are <18 years of age to be informed of the nature of the study and provide written informed consent without consent from a parent(s)/legal guardian.

    To be elgible for the post treatment follow up, the subject must:
    1.Be informed of the nature of the study and provide written informed
    consent before any study-specific procedures are performed.
    2.Have anti-rHuPH20 binding antibody titers detected post-baseline at a
    titer > 1:20
    E.4Principal exclusion criteria
    1. Have received any C1 INH therapy or any blood products for treatment or prevention of an angioedema attack within 7 days prior to the first dose of study drug in Treatment Period 1.
    2. Be receiving prophylactic IV CINRYZE that exceeds the approved dosing regimen of 1000 U every 3 or 4 days (maximum weekly dose of 2000 U).
    3. Have had angioedema attack signs or symptoms within 2 days prior to the first dose of study drug in Treatment Period 1.
    4. Have received any androgen therapy (e.g., danazol, oxandrolone, stanozolol, testosterone) within 7 days prior to the first dose of study drug in Treatment Period 1.
    5. If female, have started taking or changed the dose of any hormonal contraceptive regimen or hormone replacement therapy (i.e., estrogen/progestin containing products) within 3 months prior to the first dose of study drug in Treatment Period 1.
    6. Have a history of hypercoagulability (abnormal blood clotting).
    7. Have a diagnosis of acquired angioedema or known to have C1 INH antibodies.
    8. Have a history of allergic reaction to C1 INH products, including CINRYZE (or any components of CINRYZE), or other blood products.
    9. Have a known allergy to hyaluronidase or any other ingredient in the study formulation.
    10. Be pregnant or breastfeeding.
    11. Have received an investigational study drug within 30 days prior to the first dose of study drug in Treatment Period 1.
    12. Have, as determined by the Investigator and/or the Sponsor's medical monitor, any surgical or medical condition that could interfere with the administration of study drug or interpretation of study results.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint is the number of angioedema attacks recorded during each treatment period, normalized for the number of days the subject participated in that period.
    E.5.1.1Timepoint(s) of evaluation of this end point
    End of the treatment period.
    E.5.2Secondary end point(s)
    •Cumulative Attack-Severity. This score is the sum of the maximum symptom severity recorded for each angioedema attack in a treatment period.
    • Cumulative Daily-Severity. This score is the sum of the severity scores recorded for every day of reported symptoms in a treatment period.
    • Time (measured in days from the first dose of study drug in a treatment period) to the first angioedema attack reported in that treatment period.
    • Effects of C1 INH and C4 levels on clinical outcome (frequency, severity or anatomic location of attack) during each treatment period.
    • Number of angioedema attacks requiring acute treatment during each treatment period.
    E.5.2.1Timepoint(s) of evaluation of this end point
    End of the treatment period.
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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 Yes
    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 Yes
    E.8.2.3.1Comparator description
    Different dose of the same product.
    E.8.2.4Number of treatment arms in the trial2
    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 Yes
    E.8.5.1Number of sites anticipated in the EEA11
    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 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
    Last visit last subject.
    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 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 months9
    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 Yes
    F.1.1Number of subjects for this age range: 1
    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) Yes
    F.1.1.6.1Number of subjects for this age range: 1
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 44
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 2
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 11
    F.4.2.2In the whole clinical trial 47
    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)
    A post-treatment visit will be performed at the investigative site 1 week after the last dose of study drug in Treatment Period 2 for followup safety assessments. Subjects must report to the investigational site for the 1-week post-treatment visit. In addition, subjects will have a blood sample for C1 INH and rHuPH20 antibody testing collected 30 days after the last dose of study drug.

    Subjects who developed antibody titers >1:20 to rHuPH20 will be offered to participate in a 1 year followup.
    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 Decision2012-08-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-07-31
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2014-09-04
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