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    Summary
    EudraCT Number:2019-001458-24
    Sponsor's Protocol Code Number:ALN-TTR02-011
    National Competent Authority:Czechia - SUKL
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-07-03
    Trial 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 ConcernedCzechia - SUKL
    A.2EudraCT number2019-001458-24
    A.3Full title of the trial
    APOLLO-B: A Phase 3, Randomized, Double-blind, Placebo-controlled Multicenter Study to Evaluate the Efficacy and Safety of Patisiran in Patients with Transthyretin Amyloidosis with Cardiomyopathy (ATTR Amyloidosis with Cardiomyopathy)
    APOLLO-B: Randomizované, dvojitě zaslepené, placebem kontrolované, multicentrické klinické hodnocení fáze 3 hodnotící účinnost a bezpečnost patisiranu u pacientů s transthyretinovou amyloidózou a kardiomyopatií (ATTR amyloidóza s kardiomyopatií)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to Evaluate Patisiran in Patients with Transthyretin Amyloidosis with Cardiomyopathy
    Klinické hodnocení patisiranu u pacientů s transthyretinovou amyloidózou a kardiomyopatií
    A.3.2Name or abbreviated title of the trial where available
    A study to Evaluate Patisiran in Patients with Transthyretin Amyloidosis with Cardiomyopathy
    Klinické hodnocení patisiranu u pacientů s transthyretinovou amyloidózou a kardiomyopatií
    A.4.1Sponsor's protocol code numberALN-TTR02-011
    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 SponsorAlnylam Pharmaceuticals, 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 supportAlnylam Pharmaceuticals, Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAlnylam Pharmaceuticals, Inc
    B.5.2Functional name of contact pointClinical Trials Information Line
    B.5.3 Address:
    B.5.3.1Street Address300 Third Street
    B.5.3.2Town/ cityCambridge
    B.5.3.3Post code02142
    B.5.3.4CountryUnited States
    B.5.4Telephone number+ 001877256 9526
    B.5.6E-mailclinicaltrials@alnylam.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 Onpattro
    D.2.1.1.2Name of the Marketing Authorisation holderAlnylam Netherlands B.V.
    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/3/11/857
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Concentrate 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 INNPATISIRAN
    D.3.9.1CAS number 1386913-72-9
    D.3.9.2Current sponsor codeALN-TTR02
    D.3.9.3Other descriptive namepatisiran
    D.3.9.4EV Substance CodeSUB189946
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.0
    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 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
    Transthyretin Amyloidosis with Cardiomyopathy (ATTR Amyloidosis with Cardiomyopathy)
    E.1.1.1Medical condition in easily understood language
    Transthyretin Amyloidosis with Cardiomyopathy (ATTR Amyloidosis with Cardiomyopathy)
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 27.0
    E.1.2Level PT
    E.1.2Classification code 10007509
    E.1.2Term Cardiac amyloidosis
    E.1.2System Organ Class 10007541 - Cardiac disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy of patisiran compared with placebo treatment on functional capacity (6-minute walk test [6-MWT]) in patients with ATTR amyloidosis with cardiomyopathy
    E.2.2Secondary objectives of the trial
    To evaluate the efficacy of patisiran compared
    with placebo treatment on:
    - Health status and health-related quality of life
    - Patient mortality and hospitalizations, and urgent heart failure (HF) visits
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Age 18 (or age of legal consent, whichever is older) to 85 years, inclusive.
    2. Documented diagnosis of ATTR amyloidosis with cardiomyopathy, classified as either hATTR amyloidosis with cardiomyopathy or wtATTR amyloidosis with cardiomyopathy:
    Hereditary ATTR amyloidosis with cardiomyopathy diagnosed based on meeting all of the following criteria:
    a. TTR pathogenic mutation consistent with hATTR.
    b. Evidence of cardiac involvement by echocardiography with an end-diastolic interventricular septal wall thickness >12 mm (based on central echocardiogram reading at screening).
    c. Amyloid deposits in cardiac or noncardiac tissue (eg, fat pad aspirate, salivary gland, median nerve connective sheath) confirmed by Congo Red (or equivalent) staining OR technetium (99mTc) scintigraphy (99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid [DPD-Tc], 99mTc-pyrophosphate [PYP-Tc], or 99mTc-hydroxymethylene
    diphosphonate (HMDP]) with Grade 2 or 3 cardiac uptake, if monoclonal gammopathy of undetermined significance (MGUS) has been excluded.
    d. If MGUS, confirm TTR protein in tissue with immunohistochemistry (IHC) or mass spectrometry.

    Wild-type ATTR amyloidosis with cardiomyopathy diagnosed based on meeting all of the following criteria:
    a. Absence of pathogenic TTR mutation.
    b. Evidence of cardiac involvement by echocardiography with an end-diastolic interventricular septal wall thickness >12mm (based on central
    echocardiogram reading at screening).
    c. Amyloid deposits in cardiac tissue with TTR precursor identification by IHC, mass spectrometry, OR technetium (99mTc) scintigraphy (99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid [DPD-Tc], 99mTc-pyrophosphate [PYP-Tc] or 99mTc-hydroxymethylene
    diphosphonate [HMDP]) with Grade 2 or 3 cardiac uptake, if MGUS has been excluded.
    d. If MGUS, confirm TTR protein in cardiac tissue with IHC or mass spectrometry

    3. Medical history of HF with at least 1 prior hospitalization for HF (not due to arrhythmia or a conduction system disturbance treated with a permanent pacemaker) OR clinical evidence of HF (with or without hospitalization) manifested by signs and symptoms of volume overload or elevated intracardiac pressures (eg, elevated jugular venous pressure, shortness of breath or signs of pulmonary congestion on x-ray or auscultation, peripheral edema) that currently requires treatment with a diuretic.

    4. Patient meets one of the following criteria:
    a. Tafamidis naïve; in addition to patients who have never taken tafamidis, those who have been on tafamidis for ≤30 days total and have not received any tafamidis in the 6 months prior to baseline will be considered tafamidis naïve and may qualify for the study.
    b. Currently on tafamidis (for ≥6 months) and has demonstrated disease progression, as determined by the Investigator. (At the time of study entry, tafamidis treatment must be on-label use of commercial tafamidis for the treatment of ATTR amyloidosis with cardiomyopathy at
    the approved dose in the country of use.)

    5. Patient is clinically stable, with no CV-related hospitalizations within 6 weeks prior to randomization, as assessed by the Investigator.
    6. Able to complete ≥150 m on the 6-MWT at screening.
    7. Screening NT-proBNP >300 ng/L and <8500 ng/L; in patients with permanent or persistent atrial fibrillation, screening NT-proBNP >600 ng/L and <8500 ng/L.
    8. Patient is able to understand and is willing and able to comply with the study requirements and to provide written informed consent; and patient agrees to sign the medical records release form for collection of vital status.
    E.4Principal exclusion criteria
    1. Has known primary amyloidosis (AL) or leptomeningeal amyloidosis.
    2. NYHA Class III AND ATTR amyloidosis disease Stage 3 (defined as both NT-proBNP >3000 ng/L and estimated glomerular filtration rate [eGFR] <45 ml/min/1.73 m2).[Gillmore 2018]
    3. NYHA Class IV at the Screening visit.
    4. Has a polyneuropathy disability (PND) Score IIIa, IIIb, or IV (requires cane or stick to walk, or is wheelchair bound) at the Screening visit.
    5. Has any of the following laboratory parameter assessments at screening:
    a. Aspartate transaminase (AST) or alanine transaminase (ALT) levels>2.0 × the upper limit of normal (ULN).
    b. Total bilirubin >2 × ULN.
    c. International normalized ratio (INR)>1.5 (unless patient is on anticoagulant therapy, in which case excluded if INR>3.5).
    6. Has eGFR <30 mL/min/1.73 m2 (using the modification of diet in renal disease [MDRD] formula).
    7. Has known human immunodeficiency virus infection; or evidence of current or chronic hepatitis C virus or hepatitis B virus infection.
    8. Tafamidis naïve patients (at baseline) for whom the Investigator actively plans or anticipates commencing treatment with tafamidis during the 12-month double-blind period, taking into consideration clinical status, patient preference and/or commercial availability of tafamidis.
    9. Is currently taking diflunisal; if previously on this agent, must have at least a 30-day wash-out prior to dosing (Day 1).
    10. Is currently taking doxycycline, ursodeoxycholic acid or tauroursodeoxycholic acid; if previously on any of these agents, must have completed a 30-day wash-out prior to dosing (Day 1).
    11. Received prior TTR-lowering treatment (including patisiran) or participated in a gene therapy trial for hATTR amyloidosis.
    12. Current or future participation in another investigational device or drug study, scheduled to occur during this study, or has received an investigational agent or device within 30 days (or 5 half-lives of the investigational drug, whichever is longer) prior to dosing (Day 1). In the case of investigational TTR stabilizer drugs, washout for 6 months prior to dosing (Day 1) is required; this does not apply to patients who are on tafamidis at baseline (per inclusion Criterion 4).
    13. Requires chronic treatment with non-dihydropyridine calcium channel blockers (eg, verapamil, diltiazem).
    14. Other non-TTR cardiomyopathy, hypertensive cardiomyopathy, cardiomyopathy due to valvular heart disease, or cardiomyopathy due to ischemic heart disease (eg, prior myocardial infarction with documented history of cardiac enzymes and electrocardiogram [ECG] changes).
    15. Has non-amyloid disease affecting exercise testing (eg, severe chronic obstructive pulmonary disease, severe arthritis, or peripheral vascular disease affecting ambulation).
    16. Recent or planned orthopedic procedure during the double-blind period (eg, lower extremity or back surgery) that could impact 6-MWT.
    17. Unstable congestive heart failure (CHF) (eg, no adjustment of diuretics at time of screening required to achieve optimal treatment of CHF).
    18. Had acute coronary syndrome or unstable angina within the past 3 months.
    19. Has history of sustained ventricular tachycardia or aborted ventricular fibrillation.
    20. Has history of atrioventricular nodal or sinoatrial nodal dysfunction for which a pacemaker is indicated but will not be placed.
    21. Has persistent elevation of systolic (>180 mmHg) and diastolic (>100 mmHg) blood pressure that is considered uncontrolled by physician.
    22. Has untreated hypo- or hyperthyroidism.
    23. Prior or planned heart, liver, or other organ transplant.
    24. Had a malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated.
    25. Has other medical conditions or comorbidities which, in the opinion of the Investigator, would interfere with study compliance or data interpretation; or, in the opinion of the Investigator, taking part in the
    study would jeopardize the safety of the patient.
    26. Has a history of severe hypersensitivity (eg. anaphylaxis) to any of the excipients in patisiran. Also see exclusion Criterion 11, which excludes all patients with prior TTR-lowering
    treatment including
    patisiran.
    27. Female patient is pregnant or breast-feeding.
    28. Has a known history of alcohol abuse within the past 2 years or daily heavy alcohol consumption (for females, more than 14 units of alcohol per week; for males, more than 21 units of alcohol per week [unit: 1 glass of wine [125 mL] = 1 measure of spirits = ½ pint of beer]);
    29. History of illicit drug abuse within the past 5 years that in the opinion of the Investigator would interfere with compliance with study procedures or follow-up visits.
    E.5 End points
    E.5.1Primary end point(s)
    Change from baseline at Month 12 in 6-MWT
    E.5.1.1Timepoint(s) of evaluation of this end point
    Double blind period: Month 12; this assessment will also be performed at
    Month 6 (Weeks 25-26) and Month 9 (Weeks 37-38)
    Open label extension period: Year 2 weeks 79-80, weeks 91-92, weeks
    106-107; Year 3 weeks 133-134, weeks 145-146, weeks 157-158; Year 4
    weeks 184-185, weeks 208-209.
    E.5.2Secondary end point(s)
    -Change from baseline at Month 12 in Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) score

    -Composite endpoint of all-cause mortality, frequency of cardiovascular (CV) events (CV hospitalizations and urgent HF visits) and change from
    baseline in 6-MWT over the 12-month double-blind period

    -Composite endpoint of all-cause mortality and frequency of all-cause hospitalizations and urgent HF visits over the 12-month double-blind
    period
    E.5.2.1Timepoint(s) of evaluation of this end point
    Double blind period: Month 12 (Weeks 52-53); this assessment will also be performed at Month 6 (Weeks 25-26) and Month 9 (Weeks 37-38). Open label extension period: Year 2 weeks 79-80, weeks 91-92, weeks 106-107; Year 3 weeks 133-134, weeks 145-146, weeks 157-158; Year 4 weeks 184-185, weeks 208-209.
    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 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 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 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 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 EEA29
    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
    Argentina
    Chile
    New Zealand
    Hong Kong
    Taiwan
    Australia
    Brazil
    Japan
    Korea, Republic of
    Mexico
    United Kingdom
    United States
    Belgium
    Czechia
    Denmark
    France
    Italy
    Netherlands
    Portugal
    Sweden
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years5
    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: 210
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 90
    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 state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 101
    F.4.2.2In the whole clinical trial 300
    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)
    none
    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 Decision2019-09-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-07-10
    P. End of Trial
    P.End of Trial StatusOngoing
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