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    Summary
    EudraCT Number:2015-004318-14
    Sponsor's Protocol Code Number:NEOD001-201
    National Competent Authority:Austria - BASG
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-08-22
    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 ConcernedAustria - BASG
    A.2EudraCT number2015-004318-14
    A.3Full title of the trial
    A Phase 2b, Randomized, Double-blind, Placebo-controlled Study of NEOD001 in Previously Treated Subjects with Light Chain (AL) Amyloidosis who have Persistent Cardiac Dysfunction
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to evaluate whether NEOD001 is safe and effective in subjects with light chain AL amyloidosis affecting the heart.
    A.4.1Sponsor's protocol code numberNEOD001-201
    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 SponsorProthena Therapeutics Limited
    B.1.3.4CountryIreland
    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 supportProthena Therapeutics Limited
    B.4.2CountryIreland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationProthena Biosciences Inc
    B.5.2Functional name of contact pointJay Soto
    B.5.3 Address:
    B.5.3.1Street Address331 Oyster Point Boulevard
    B.5.3.2Town/ citySouth San Francisco, California
    B.5.3.3Post code94080
    B.5.3.4CountryUnited States
    B.5.4Telephone number+16506152131
    B.5.5Fax number+16508378560
    B.5.6E-mailjay.soto@prothena.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/3/13/1100
    D.3 Description of the IMP
    D.3.1Product nameNEOD001
    D.3.4Pharmaceutical form Powder for solution for infusion
    D.3.4.1Specific paediatric formulation No
    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 INNN/A
    D.3.9.1CAS number N/A
    D.3.9.2Current sponsor codeNEOD001
    D.3.9.3Other descriptive nameHumanized IgG1, kappa anti-serum amyloid A and anti-AL amyloid antibody
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(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 No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    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 drip use (Noncurrent)
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Light chain (AL) amyloidosis involves a hematologic disorder caused by clonal plasma cells that produce misfolded immunoglobulin light chains. Overproduction of misfolded light chains results in both soluble, aggregated forms of light chains and insoluble,fibrillar deposits of abnormal AL protein (amyloid),in the tissues and organs. This can cause a range of symptoms and organ dysfunction including cardiac,renal,and hepatic dysfunction,gastrointestinal involvement and neuropathy and macroglossia
    E.1.1.1Medical condition in easily understood language
    Light chain (AL) amyloidosis is a blood disorder, which causes progressive organ damage as a result of the misfolding of proteins. This disease can produce a range of symptoms and organ dysfunction
    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 PT
    E.1.2Classification code 10036673
    E.1.2Term Primary amyloidosis
    E.1.2System Organ Class 10021428 - Immune system disorders
    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 and safety of NEOD001 versus placebo in subjects with AL amyloidosis who have persistent cardiac dysfunction.
    E.2.2Secondary objectives of the trial
    •Change from baseline to 12 months of treatment in the Physical
    Component Score (PCS) of the Short Form-36 Version 2 (SF-36v2)
    •Change from baseline to 12 months of treatment in the 6MWT distance
    (meters)
    •NT-Pro BNP Slope over 12 months of treatment
    •Renal evaluable subjects: renal best response from baseline through
    12 months of treatment
    •Peripheral neuropathy evaluable subjects: change from baseline to 12
    months of treatment in NIS-LL total score
    •Hepatic evaluable subjects: hepatic best response from baseline
    through 12 months of treatment
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Age ≥18 years

    2. Confirmed diagnosis of systemic AL amyloidosis by the following:
    o Histochemical diagnosis of amyloidosis determined by polarizing light microscopy of green birefringent material in Congo red-stained tissue specimens OR characteristic electron microscopy appearance
    AND
    o Confirmatory electron microscopy OR immunohistochemistry OR mass spectrometry of AL amyloidosis

    3. If the subject meets any of the following criteria, confirm diagnosis of AL amyloidosis by mass spectrometry OR immunoelectron microscopy of amyloid material in tissue biopsy:
    o Is black or African American
    o Is over 75 years of age (at time of diagnosis) with concurrent monoclonal gammopathy
    o Has a history of familial amyloidosis and has concurrent monoclonal gammopathy
    OR
    o If the subject meets any of the above 3 conditions and has echocardiographic evidence of amyloidosis, biopsy-proven amyloidosis with a monoclonal gammopathy and no tissue is available for mass spectrometry or immunoelectron microscopy, the subject must have gene sequencing consistent with transthyretin (TTR) wild type (e.g., no TTR mutation present) AND must score 0 in technetium-99m-3,3-diphosphono-1,2 propanodicarboxylic acid (99mTc DPD; Rapezzi et al, 2011), hydroxymethylenediphosphonate (99mTc HMDP; Galat et al, 2015), or pyrophosphate (99mTc PYP; Bokhari et al, 2013) scintigraphy

    4. Cardiac involvement as defined by BOTH of the following:
    o Past documented or presently noted clinical signs and symptoms supportive of a diagnosis of heart failure in the setting of a confirmed diagnosis of AL amyloidosis in the absence of an alternative explanation for heart failure
    o Either an endomyocardial biopsy demonstrating AL amyloidosis OR an echocardiogram demonstrating a mean left ventricular wall thickness at diastole >12 mm in the absence of other causes (e.g., severe hypertension, aortic stenosis), which would adequately explain the degree of wall thickening

    5. NT-proBNP ≥650 pg/mL and ≤5000 pg/mL (i.e., ≥76.7 pmol/L and ≤590 pmol/L)

    6. Received at least one prior systemic chemotherapeutic regimen, which may include stem cell transplant, for AL amyloidosis

    7. Achieved at least a partial hematologic response to a first-line therapy resulting in a stable hematologic condition not currently requiring additional active treatment against the plasma cell dyscrasia component of their AL disease

    8. Adequate bone marrow reserve, hepatic and renal function, as demonstrated by:
    o Absolute neutrophil count (ANC) ≥1.0 × 109/L
    o Platelet count ≥75 × 109/L
    o Hemoglobin ≥9 g/dL
    o Total bilirubin ≤2 × upper limit of normal (ULN)
    o Aspartate aminotransferase (AST) ≤3 × ULN
    o Alanine aminotransferase (ALT) ≤3 × ULN
    o Alkaline phosphatase (ALP) ≤5 × ULN (except for subjects with hepatomegaly and isozymes specific to liver, rather than bone)
    o Estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 as estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation

    9. Systolic blood pressure 90-180 mmHg

    10. Distance walked during each of the two Screening 6-minute walk tests (6MWTs) is >100 meters and <600 meters

    11. Women of childbearing potential (WOCBP) must have 2 negative pregnancy tests during Screening, the second within 24 hours prior to the first administration of study drug and must agree to use highly effective physician-approved contraception from Screening to 90 days following the last study drug administration

    12. Male subjects must be surgically sterile or must agree to use highly effective physician-approved contraception from Screening to 90 days following the last study drug administration

    13. Ability to understand and willingness to sign an informed consent form prior to initiation of any study procedures
    E.4Principal exclusion criteria
    Subjects must not meet any of the following criteria:

    1. Diagnosis of non-AL amyloidosis

    2. Meets the International Myeloma Working Group (IMWG) definition of Multiple Myeloma

    3. Symptomatic orthostatic hypotension that in the medical judgment of the Investigator would interfere with subject's ability to safely receive treatment or complete study assessments

    4. Myocardial infarction, uncontrolled angina, uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia, within 6 months prior to the Month 1-Day 1 Visit

    5. Severe valvular stenosis (e.g. aortic or mitral stenosis with a valve area <1.0 cm2) or severe congenital heart disease

    6. ECG evidence of acute ischemia or active conduction system abnormalities with the exception of any of the following:
    o First degree atrioventricular (AV) block
    o Second degree AV block Type 1 (Mobitz Type 1/Wenckebach type)
    o Right or left bundle branch block
    o Atrial fibrillation with a controlled ventricular rate (uncontrolled [i.e., >110 bpm] ventricular rate is not allowed [determined by an average of three beats in Lead II or 3 representative beats if Lead II is not representative of the overall ECG])

    7. Has not recovered (i.e., equivalent to a Common Terminology Criteria for Adverse Events [CTCAE] ≥Grade 2) from the clinically significant toxic effects of prior anticancer therapy. Exception: subjects with prior bortezomib treatment may have CTCAE Grade 2 neuropathy.

    8. Received any of the following within the specified time frame prior to the Month 1-Day 1 Visit:
    o Oral or intravenous antibiotics, antifungals, or antivirals within 1 week, with the exception of prophylactic oral agents. Note: In the event that a subject requires the chronic use of antivirals, Medical Monitor permission is required for entry into the study.
    o Hematopoietic growth factors, transfusions of blood or blood products within 1 week
    o Chemotherapy, radiotherapy, or other plasma cell directed therapy within 6 months
    o ASCT within 12 months
    o Major surgery within 4 weeks
    o Planned major surgery or organ transplant during the study
    o Any other investigational agent within 4 weeks
    o Prior treatment with NEOD001, 11-1F4, anti-serum amyloid P (SAP) antibody (exception: allowed as part of established diagnostic procedures such as SAP scintigraphy), or other investigational treatment directed at amyloid
    o Doxycycline within 6 weeks

    9. Active malignancy with the exception of any of the following:
    o Adequately treated basal cell carcinoma, squamous cell carcinoma, or in situ cervical cancer
    o Adequately treated Stage I cancer from which the subject is currently in remission and has been in remission for ≥2 years
    o Low-risk prostate cancer with Gleason score <7 and prostate-specific antigen <10 mg/mL
    o Any other cancer from which the subject has been disease-free for ≥2 years

    10. History of Grade ≥3 infusion-related adverse events (AEs) or hypersensitivity to another monoclonal antibody

    11. History of severe allergy to any of the components of NEOD001 such as histidine/L-histidine hydrochloride monohydrate, trehalose dehydrate, or polysorbate 20

    12. Currently known uncontrolled bacterial, viral, fungal, HIV, hepatitis B, or hepatitis C infection

    13. Women who are breastfeeding

    14. Any condition which could interfere with, or the treatment for which might interfere with, the conduct of the study or which would, in the opinion of the Investigator, unacceptably increase the subject’s risk by participating in the study

    15. Unable or unwilling to adhere to the study-specified procedures and restrictions

    16. Subject is under legal custodianship

    17. Waldenström's macroglobulinemia and/or immunoglobulin M (IgM) monoclonal gammopathy
    E.5 End points
    E.5.1Primary end point(s)
    NT-proBNP best response
    E.5.1.1Timepoint(s) of evaluation of this end point
    NT-proBNP best response from baseline through 12 months of treatment
    E.5.2Secondary end point(s)
    - SF-36v2
    - 6MWT
    - NT-ProBNP Slope
    - Renal best response
    - Peripheral neuropathy score
    - Hepatic Best Response
    E.5.2.1Timepoint(s) of evaluation of this end point
    •Change from baseline to 12 months of treatment in the Physical Component Score (PCS) of the Short Form-36 Version 2 (SF-36v2)
    •Change from baseline to 12 months of treatment in the 6MWT distance (meters)
    •NT-Pro BNP Slope over 12 months of treatment
    •Renal evaluable subjects: renal best response from baseline through 12 months of treatment
    •Peripheral neuropathy evaluable subjects: change from baseline to 12 months of treatment in NIS-LL total score
    •Hepatic evaluable subjects: hepatic best response from baseline through 12 months of treatment
    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 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) 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 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.8.5The 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 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
    Austria
    France
    Germany
    Greece
    Israel
    Italy
    Spain
    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
    LVLS

    The study will end when the last subject completes 12 months of study treatment and the 30-day safety follow-up period (i.e., EOS Visit). Subjects who complete the study and meet the eligibility criteria will be considered for entry into a separate open-label extension study, during which subjects will receive active treatment and may receive concurrent chemotherapy.
    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 months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months0
    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: 65
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 65
    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 state2
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 55
    F.4.2.2In the whole clinical trial 129
    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)
    After completing the Month 12 Visit, a subject may be considered for entry into an open-label extension study, during which subjects may receive concurrent chemotherapy. The open-label extension study will be submitted as a separate protocol at a time prior to initiation.
    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 Decision2016-07-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-06-07
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-03-05
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