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    Summary
    EudraCT Number:2016-004087-19
    Sponsor's Protocol Code Number:EFC15110
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2018-03-27
    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 - BfArM
    A.2EudraCT number2016-004087-19
    A.3Full title of the trial
    ATLAS-PPX: an open-label, multinational, switching study to describe the efficacy and safety of fitusiran prophylaxis in patients with hemophilia A and B previously receiving factor or bypassing agent prophylaxis.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study of fitusiran in hemophilia A and B patients previously receiving factor or bypassing agent prophylaxis
    A.3.2Name or abbreviated title of the trial where available
    ATLAS-PPX
    A.4.1Sponsor's protocol code numberEFC15110
    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 SponsorGenzyme Corporation
    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 supportGenzyme Corporation
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPPD Global
    B.5.2Functional name of contact pointProject Management
    B.5.3 Address:
    B.5.3.1Street Address929 North Front Street
    B.5.3.2Town/ cityWilmington
    B.5.3.3Post code28401
    B.5.3.4CountryUnited States
    B.5.6E-mailDorota.Jusza@ppdi.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 No
    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/3/14/1297; EU/3/14/1298
    D.3 Description of the IMP
    D.3.1Product namefitusiran
    D.3.2Product code SAR439774
    D.3.4Pharmaceutical form 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.3.8INN - Proposed INNfitusiran
    D.3.9.1CAS number 1609016-97-8
    D.3.9.2Current sponsor codeSAR439774
    D.3.9.4EV Substance CodeSUB130859
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Hemophilia A or Hemophilia B
    E.1.1.1Medical condition in easily understood language
    Hemophilia is an inherited bleeding disorder in which the blood does not clot normally and can result in internal bleeding into the muscles and joints.
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10060613
    E.1.2Term Hemophilia A (Factor VIII)
    E.1.2System Organ Class 100000004850
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10060614
    E.1.2Term Hemophilia B (Factor IX)
    E.1.2System Organ Class 100000004850
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To characterize the frequency of bleeding episodes while receiving fitusiran treatment, relative to the frequency of bleeding episodes while receiving factor or bypassing agent prophylaxis.
    E.2.2Secondary objectives of the trial
    To characterize the following while receiving fitusiran treatment, relative to receiving factor or BPA prophylaxis:
     the frequency of spontaneous bleeding episodes
     the frequency of joint bleeding episodes
     health related quality of life (HRQOL) in patients ≥17 years of age
    To characterize the frequency of bleeding episodes during the onset period in patients receiving fitusiran
    To characterize the safety and tolerability of fitusiran
    To characterize the annualized weight-adjusted consumption of factor/BPA while receiving fitusiran treatment, relative to receiving factor or BPA prophylaxis
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Males ≥12 years of age.

    Severe hemophilia A or B as evidenced by:
    a . A central laboratory measurement or documented medical record evidence of FVIII <1% or FIX level ≤2% at Screening.

    A minimum of 2 bleeding episodes requiring BPA treatment within the last 6 months prior to Screening for patients with inhibitory antibodies to factor VIII or factor IX (Cohort A). A minimum of 1 bleeding episode requiring factor treatment within the last 12 months prior to Screening for patients without inhibitory antibodies to factor VIII or factor IX (Cohort B).

    Must meet either the definition of inhibitor or non-inhibitor patient as below:

    Inhibitor:
    Use of BPAs for prophylaxis and for any bleeding episodes for at least the last 6 months prior to Screening, and meet one of the following Nijmegen-modified Bethesda assay results criteria:
    - Inhibitor titer of ≥0.6 BU/mL at Screening, or
    - Inhibitor titer of <0.6 BU/mL at Screening with medical record evidence of 2 consecutive titers ≥0.6 BU/mL, or
    - Inhibitor titer of <0.6 BU/mL at Screening with medical record evidence of anamnestic response

    The subgroup of patients in Cohort A patients must additionally meet the following criteria to be eligible to start treatment with fitusiran directly after the screening period:
    - Hemophilia B with inhibitory antibody to Factor IX as defined above
    - Not responding adequately to BPA treatment (historical ABR ≥20) prior to enrollment
    - In the opinion of the Investigator, with approval of Sponsor Medical Monitor, 6-month BPA prophylaxis period should be omitted.


    Non-inhibitor:
    Use of factor concentrates for prophylaxis and for any bleeding episodes for at least the last 6 months prior to Screening, and meet each of the following criterion:
    Nijmegen-modified Bethesda assay inhibitor titer of <0.6 BU/mL at Screening and
    No use of bypassing agents to treat bleeding episodes for at least the last 6 months prior to Screening and
    No history of immune tolerance induction therapy within the past 3 years prior to Screening.

    Prescribed prophylactic treatment (documented in the medical or pharmacy records) of hemophilia with factor concentrates or BPAs for at least 6 months prior to Screening; the regimen must be consistent with the approved prescribing information for the product or local recommendations, allowing for adjustment to individual patient response, and designed to decrease spontaneous bleeding.
    6. Adherent to the prescribed prophylactic therapy for at least 6 months prior to Screening per Investigator assessment.
    7. Willing and able to comply with the study requirements and to provide written informed consent and assent in the case of patients under the age of legal consent, per local and national requirements.
    E.4Principal exclusion criteria
    1. Known co-existing bleeding disorders other than hemophilia A or B, ie, Von Willebrand’s disease, additional factor deficiencies, or platelet disorders.
    2. Current participation in immune tolerance induction therapy (ITI).
    3. AT activity <60% at Screening, as determined by central laboratory measurement
    4. Presence of clinically significant liver disease, or as indicated by any of the conditions below:
    a. INR >1.2;
    b. ALT and/or AST >1.5× upper limit of normal reference range (ULN);
    c. Total bilirubin >ULN (>1.5 ULN in patients with Gilbert’s Syndrome);
    d. History of portal hypertension, esophageal varices, or hepatic encephalopathy;
    e. Presence of ascites by physical exam.
    5. Hepatitis C virus antibody positive, except patients with a history of HCV infection who meet both conditions a. and b.:
    a. Completed curative treatment at least 12 weeks prior to enrollment and attained sustained virologic response as documented by a negative HCV RNA at screening, or they have spontaneously cleared infection as documented by negative HCV RNA at Screening.
    b. No evidence of cirrhosis according to one of the following assessments:
     FibroScan <12.5 kPa (where available), or
     FibroTest score <0.75 and APRI <2 (if FibroScan unavailable)
    6. Presence of acute hepatitis, ie, hepatitis A, hepatitis E.
    7. Presence of acute or chronic hepatitis B infection (IgM anti-HBc antibody positive or HBsAg positive).
    8. Platelet count ≤100,000/μL.
    9. Presence of acute infection at Screening.
    10. Known to be HIV positive with CD4 count <200 cells/μL.
    11. Estimated glomerular filtration rate ≤45 mL/min/1.73m2 (using the Modification of Diet in Renal Disease [MDRD] formula).
    12. Co-existing thrombophilic disorder, as determined by presence of any of the below as identified at central laboratory (or via historical results, where available):
    a. FV Leiden mutation (homozygous or heterozygous)
    b. Protein S deficiency
    c. Protein C deficiency
    d. Prothrombin mutation (G20210A; homozygous and heterozygous)
    13. History of antiphospholipid antibody syndrome.
    14. History of arterial or venous thromboembolism, atrial fibrillation, significant valvular disease, myocardial infarction, angina, transient ischemic attack, or stroke. Patients who have experienced thrombosis associated with indwelling venous access may be enrolled.
    15. Had a malignancy within 2 years, except for basal or squamous cell carcinoma of the skin that has been successfully treated.
    16. Any condition (eg, medical concern), which in the opinion of the Investigator, would make the patient unsuitable for dosing on Day 1 or which could interfere with the study compliance, the patient’s safety and/or the patient’s participation in the completion of the
    treatment period of the study. This includes significant active and poorly controlled (unstable) cardiovascular, neurologic, gastrointestinal, endocrine, renal or psychiatric disorders unrelated to hemophilia identified by key laboratory abnormalities or medical history.
    17. At Screening, anticipated need of surgery during the study or planned surgery scheduled to occur during the study.
    18. Completion of a surgical procedure within 14 days prior to Screening, or currently receiving additional factor concentrate or BPA infusion for postoperative hemostasis.
    19. History of multiple drug allergies or history of allergic reaction to an oligonucleotide or GalNAc.
    20. Inadequate venous access, as determined by the Investigator, to allow the blood draws required by the study protocol.
    21. History of intolerance to SC injection(s).
    22. Current or future participation in another clinical study, scheduled to occur during this study, involving an investigational product other than fitusiran or an investigational device; in order to participate in this study, patient must discontinue the investigational product or investigational device at least 30 days (or 5× the investigational product halflife, whichever is longer) prior to dosing (Day 1).
    23. Current or prior participation in a gene therapy trial.
    24. History of alcohol abuse within the 12 months before Screening. Alcohol abuse is defined as regular weekly intake of more than 14 units (unit: 1 glass of wine [approximately 125 mL] = 1 measure of spirits [approximately 1 fluid ounce] = ½ pint of beer [approximately 284 mL]).
    E.5 End points
    E.5.1Primary end point(s)
    Annualized Bleeding Rate (ABR) in the fitusiran efficacy period and the factor or BPA prophylaxis period
    E.5.1.1Timepoint(s) of evaluation of this end point
    Through 13 months
    E.5.2Secondary end point(s)
    Annualized spontaneous bleeding rate in the fitusiran efficacy period and the factor or BPA prophylaxis period

    Annualized joint bleeding rate in the fitusiran efficacy period and the factor or BPA prophylaxis period

    Change in Haem-A-QOL physical health score and total score in the fitusiran treatment period and the factor or BPA prophylaxis period

    ABR in the fitusiran onset period

    ABR in fitusiran treatment period

    Annualized weight-adjusted consumption of factor/BPA
    E.5.2.1Timepoint(s) of evaluation of this end point
    Through 13 months
    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 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 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 Yes
    E.8.1.7.1Other trial design description
    switching study
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.3.1Comparator description
    Rescue therapy per Standard of Care
    E.8.2.4Number of treatment arms in the trial1
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA20
    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
    Australia
    Canada
    China
    Denmark
    France
    Germany
    Hungary
    Ireland
    Israel
    Italy
    Japan
    Korea, Republic of
    Malaysia
    Portugal
    Russian Federation
    Spain
    Taiwan
    Turkey
    Ukraine
    United Kingdom
    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
    Last Patient Last Visit (LPLV)
    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 months10
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months10
    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: 7
    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) Yes
    F.1.1.6.1Number of subjects for this age range: 7
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 50
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 13
    F.2 Gender
    F.2.1Female No
    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 No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Subject must provide written informed consent and assent in the case of patients under the age of legal consent.
    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 44
    F.4.2.2In the whole clinical trial 70
    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)
    Consistent with pre-study treatment.
    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 Decision2018-06-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-11-27
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2022-03-25
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