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    Summary
    EudraCT Number:2020-003313-35
    Sponsor's Protocol Code Number:DCR-A1AT-201
    National Competent Authority:Portugal - INFARMED
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2021-04-09
    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 ConcernedPortugal - INFARMED
    A.2EudraCT number2020-003313-35
    A.3Full title of the trial
    A Phase 2, Randomized, Double-blind, Placebo-controlled Study Investigating Safety, Tolerability, Pharmacokinetics and
    Pharmacodynamics of Two Dose Levels of Belcesiran in Patients with Alpha-1 Antitrypsin Deficiency-Associated Liver Disease
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical study to evaluate safety, tolerability, Pharmacokinetics and Pharmacodynamis of Belcesiran in patients with PiZZ Alpha-1 Antitrypsin Deficiency - Associated Liver Disease
    A.4.1Sponsor's protocol code numberDCR-A1AT-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 SponsorDicerna 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 supportDicerna Pharmaceuticals, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationDicerna Pharmaceuticals, Inc.
    B.5.2Functional name of contact pointClinical Trials
    B.5.3 Address:
    B.5.3.1Street Address75 Hayden Avenue
    B.5.3.2Town/ cityLexington
    B.5.3.3Post codeMA 02421
    B.5.3.4CountryUnited States
    B.5.6E-mailclinicaltrials@dicerna.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/3/19/2235
    D.3 Description of the IMP
    D.3.1Product nameBelcesiran
    D.3.2Product code DCR-A1AT
    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 INNBelcesiran
    D.3.9.1CAS number 2375562-01-7
    D.3.9.2Current sponsor codeDCR-A1AT
    D.3.9.3Other descriptive nameSynthetic double-stranded siRNA oligonucleotide directed against SERPINA1 mRNA and containing four modified nucleosides which form a ligand cluster of four N-acetylgalactosamine residues
    D.3.9.4EV Substance CodeSUB199253
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number175
    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
    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
    PiZZAlpha-1 Antitrypsin Deficiency Associated Liver Disease
    E.1.1.1Medical condition in easily understood language
    PiZZ A1ATD-associated liver disease is a progressive Alpha1 Antitrypsin-Deficiency Associated Liver Disease condition resulting in liver fibrosis, cirrhosis, and hepatocellular carcinoma.
    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 23.1
    E.1.2Level LLT
    E.1.2Classification code 10001806
    E.1.2Term Alpha-1 anti-trypsin deficiency
    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
    1. To evaluate the safety and tolerability of multiple doses of belcesiran in patients with AATLD.
    2. To characterize the PD of belcesiran in patients with AATLD.
    E.2.2Secondary objectives of the trial
    Secondary Objectives:
    1. To characterize the PK of belcesiran in the plasma of patients with AATLD.
    2. To assess the effect of belcesiran on liver histology in patients with AATLD

    Exploratory Endpoints:
    1. To assess the effect of belcesiran on liver stiffness in patients with AATLD
    2. To assess the effect of belcesiran on liver fibrosis and/or inflammation in patients with AATLD
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Aged 18 to 75 years, inclusive, at the time of signing the ICF.
    2. Documented diagnosis of PiZZ-type AATD, confirmed by genotyping. Historical genotyping data may be used, if available.
    3. AATLD, with a liver fibrosis score categorized as F1, F2, F3, or F4 in
    the METAVIR scoring system, documented by liver biopsy during
    Screening.
    4. Post-bronchodilator FEV1 > 45% of predicted at Screening.
    5. Participants receiving augmentation therapy on a regular basis and
    intending to continue augmentation therapy during the study are eligible
    to participate.
    6. eGFR at Screening ¿ 60 mL/min normalized to 1.73 m2 BSA.
    7. Non-smokers (defined as having not smoked cigarettes daily for at
    least the preceding 12 months) with current non-smoking status
    confirmed by urine cotinine at Screening AND any previous smoking
    history prior to 12 months must be < 15 pack years, including use of
    e-cigarettes. Participants may be on nicotine replacement (patch or
    gum). A positive urine cotinine result due to nicotine replacement is
    acceptable for enrollment at the discretion of the Investigator.
    8. Male or female
    Male participants:
    A male participant with a partner of childbearing potential must agree to
    use contraception, as detailed in Section 10.4.2, during the treatment
    period and for at least 12 weeks after the last dose of study intervention
    and refrain from donating sperm during this period. Contraceptive use
    should be consistent with local regulations regarding the methods of
    contraception for those participating in clinical studies.
    Female participants:
    A female participant is eligible to participate if she is not pregnant (see
    Section 10.4.3) and not breastfeeding. WOCBP must be using a highly
    effective method of contraception, as defined in Section 10.4.2.
    9. Capable of giving signed informed consent, which includes compliance
    with the requirements (including consent to undergo paired liver
    biopsies) and restrictions listed in the ICF and in this protocol.
    E.4Principal exclusion criteria
    1. Any condition which, in the investigator's opinion might jeopardize
    participant's safety or compliance with the protocol.
    2. History of chronic liver disease other than non-alcoholic fatty liver
    disease from any cause other than PiZZ-type AATD. Diagnostic testing
    exclusions are defined in the Diagnostic Assessments section below.
    3. Child-Pugh Score B or C
    4. History of one single severe exacerbation of underlying lung disease
    in the year prior to randomization. A severe exacerbation is defined as
    an exacerbation that requires hospitalization or a visit to the emergency
    room.
    5. History of rapid decline in pulmonary function, as assessed by the
    Investigator.
    6. Known or suspected abuse of drugs in the opinion of the Investigator
    7. Known or suspected excessive consumption of alcohol ( ¿ 21 units of
    alcohol per week in men and ¿ 14 units of alcohol per week in women;
    where a "unit" of alcohol is equivalent to a 12-ounce beer, 4-ounce glass
    of wine, or 1 ounce shot of hard liquor as defined by the
    World Health Organization)
    8. Any of the following: myocardial infarction, stroke, classification of
    heart failure New York Heart Association (NYHA) Class IV,
    hospitalization for unstable angina pectoris or transient ischaemic attack
    within the past 90 days prior to the day of screening (V2A) and between
    screening and randomization
    9. History of malignancy, unless the malignancy (other than
    hepatocellular or lung cancer) has been in complete remission off
    chemotherapy and without additional medical or surgical
    interventions within the preceding 5 years, or unless the malignancy has
    been an adequately treated skin cancer (other than melanoma) or,
    superficial bladder tumor, or in situ cervical cancer in the preceding 1
    year.
    11. History of one or more of the following reactions to an oligonucleotide-based therapy:
    a. Severe thrombocytopenia (platelet count < 100,000/ mm^3)
    b. hepatotoxicity, defined as ALT or AST > 3 × ULN and total bilirubin > 2 × ULN or INR > 1.5
    c. severe flu-like symptoms leading to discontinuation of therapy
    d. localized skin reaction from the injection (graded severe) leading to discontinuation of therapy
    e. coagulopathy/clinically significant prolongation of clotting time
    12. Participation in any clinical study in which they received an IMP
    within 4 months (or 5 times the half-life, whichever is longer) before
    Screening
    13. AST and ALT > 5 × ULN at Screening. For individuals with any serum
    aminotransferase elevation > 2 × ULN, autoimmune
    hepatitis should be ruled out through the appropriate screening tests,
    which may include total IgG or gamma-globulin levels and/or serologic
    markers (i.e., antinuclear antibodies, anti-smooth-muscle antibodies at a
    titer of at least 1:40, anti-liver/kidney microsomal-1 antibodies, antiliver cytosol antibody [anti-LC 1], or antisoluble
    liver/liver pancreas [anti-SLA/LP] antibodies).
    14. ALP 2 × ULN at Screening
    15. Serum AFP value > 100 ng/mL at Screening. If AFP at screening is >
    ULN but < 100 ng/mL, the participant is still eligible if an appropriate
    hepatic imaging study reveals no lesions
    16. Positive screening for antimitochondrial antibodies (only required if
    primary biliary cirrhosis is suspected)
    17. Platelets < 100,000/mm 3 at Screening
    18. INR > 1.6 × ULN at Screening
    19. Positive screening for HBsAg, HCV antibodies, or HIV1 and 2
    antibodies. If a participant has been tested in the past 3 months, medical
    record documentation of this testing can be used for eligibility.
    E.5 End points
    E.5.1Primary end point(s)
    Cohorts 1 and 2:
    1. The incidence and nature of TEAEs, and the change from Baseline in
    PFTs, 12 -lead ECGs, physical examination findings, vital signs, and
    clinical laboratory tests
    2. Changes from baseline to weeks 24 (Cohort 1)/48 (Cohort 2) in
    serum AAT protein concentrations
    Cohort 3:
    1. Change from baseline to week 24 in serum Z-AAT protein levels
    2. Change from baseline to week 24 in liver Z-AAT protein levels
    E.5.1.1Timepoint(s) of evaluation of this end point
    1-2. Throughout the study
    E.5.2Secondary end point(s)
    Secondary End Points:
    1. PK profile of belcesiran
    2. Change from Baseline up until week 96 in liver fibrosis
    3. Change from Baseline up until week 96 in diastase-resistant PASpositive AAT globules

    Exploratory End Points:
    1. Change from Baseline up until week 96 in FibroScan® score
    2. Change from Baseline up until week 96 in ELF score
    3. Change from Baseline up until week 96 in CK-18
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary End Points:
    1-3. Throughout the study

    Exploratory End Points:
    1-3. Throughout the study
    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 trial3
    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 EEA16
    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
    New Zealand
    United States
    Austria
    France
    Sweden
    Netherlands
    Spain
    Germany
    Belgium
    Ireland
    Portugal
    United Kingdom
    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 years5
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months2
    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: 41
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 5
    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 37
    F.4.2.2In the whole clinical trial 46
    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 Decision2021-08-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-07-02
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2023-12-08
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