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    Summary
    EudraCT Number:2020-003313-35
    Sponsor's Protocol Code Number:DCR-A1AT-201
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-03-19
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2020-003313-35
    A.3Full title of the trial
    A Phase 2a, Randomized, Double-blind, Placebo controlled, Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Study of Belcesiran in Patients with PiZZ Alpha-1 Antitrypsin Deficiency
    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.
    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 number185
    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 fibrosis, steatosis, and inflammation in patients with AATLD.

    Exploratory Endpoints:
    1. To assess the effect of belcesiran on total, soluble, or insoluble Z-AAT protein on paired liver biopsies from patients with AATLD.
    2. To assess the effect of belcesiran on liver stiffness in patients with AATLD.
    3. To assess the effect of belcesiran on liver fibrosis and/ or inflammation in patients with AATLD.
    4. To develop a comprehensive liver disease activity score in patients with AATLD.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Aged 18 to 70 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 fibrosis score categorized as F2, F3, or F4 in the METAVIR scoring scale, documented by liver biopsy.
    4. Consent to undergo paired liver biopsies, one at Screening and one at either 24 (± 2) weeks or 48 (± 2) weeks after of the first dose of the study intervention
    5. Pre- and Post-bronchodilator FEV1 > 60% of predicted at Screening
    6. Postbronchodilator DLCO ≥ 50% of predicted at Screening
    7. Serum AAT protein concentration > 10 mg/dL at the first assessment during Screening
    8. eGFR at Screening ≥ 60 mL/min normalized to 1.73 m^2 BSA
    9. Smoking cessation for at least 3 months prior to Screening
    10. Body mass index (BMI) within the range of 18 to 35 kg/m^2 (inclusive)
    11. Male or female:
    - Male: A male participant with a partner of childbearing potential must agree to use contraception, as detailed in Section 10.4.2 of the Protocol, 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: A female participant is eligible to participate if she is not pregnant, not breastfeeding, and not a WOCBP, as defined in Section 10.4.1. of the Protocol
    12. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
    E.4Principal exclusion criteria
    1. Presence of any condition or comorbidities that would interfere with study compliance or data interpretation or potentially affect patient safety including, but not restricted to:
    a. severe intercurrent illness
    b. physician concerns about intake of drugs of abuse, alcohol use disorder, excessive alcohol intake, or history of excessive alcohol intake in the 2 years prior to enrollment (defined as ≥ 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)
    c. clinically relevant history or presence of uncontrolled cardiovascular, respiratory, gastrointestinal, hematological, lymphatic, neurological, musculoskeletal, genitourinary, immunological diseases, and dermatological (including rash, severe eczema, or dermatitis) or connective tissue diseases or disorders. Diagnostic testing exclusions are defined in the Diagnostic Assessments section below
    2. History of chronic liver disease from any cause other than PiZZ-type AATD, including hepatitis B, hepatitis C, primary biliary cirrhosis, primary sclerosing cholangitis, cholestatic liver disease, and autoimmune liver diseases. Diagnostic testing exclusions are defined in the Diagnostic Assessments section below.
    3. Child-Pugh Score B or C
    4. History of acute exacerbations of underlying lung disease in the 3 months prior to Screening, defined as increased dyspnea, sputum volume, and sputum purulence. Individuals meeting this criterion may be re-screened after 2 months
    5. History of intolerance to SC injection(s) or significant abdominal scarring that could potentially hinder study intervention administration or evaluation of local tolerability
    6. AAT augmentation therapy in the 6 months prior to Screening
    7. Routine use of acetaminophen/paracetamol Note. Occasional use of 1000mg/day is acceptable
    8. Use of systemically acting steroids in the month prior to Screening and throughout the study period. Occasional use is acceptable if needed for patient safety, e.g., in the case of an exacerbation of underlying pre-existing conditions.
    9. Routine use of NSAIDs, or use within 3 days of dosing
    10. Use of an RNAi drug at any time
    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 before Screening
    13. AST and ALT > 5 × ULN at Screening Note: 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 (antinuclear antibodies, anti-smooth-muscle antibodies at a titer of at least 1:40, anti-liver/kidney microsomal-1 antibodies, anti-liver cytosol antibody [anti-LC 1], or anti-soluble liver/liver pancreas [anti-SLA/LP] antibodies).
    14. ALP 2 × ULN at Screening
    15. Serum alpha fetoprotein (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. HbA1c > 8% at Screening
    18. Fasting triglycerides > 400 mg/dL or total cholesterol > 400 mg/dL at Screening
    19. Platelets < 50,000/mm^3 at Screening
    20. White blood cells < 2000/mm^3 at Screening
    21. Neutrophils < 1000/mm^3 at Screening
    22. INR > 1.6 × ULN at Screening
    23. Hypertension:
    - Systolic BP > 150 mmHg and diastolic BP > 90 mmHg after 5 minutes rest in sitting position at Screening. Repeat measures are allowed.
    24. Positive screening for HBsAg, HCV antibodies, or HIV-1 and -2 antibodies. If a participant has been tested in the past 3 months, medical record documentation of this testing can be used for screening. Note: NOTE: In participants with previous treatment for hepatitis C with direct-acting HCV medication and seropositivity for HCV, or in participants with prior infection and spontaneous resolution, HCV RNA must be undetectable (at least two negative HCV RNA tests at least 12 weeks apart), and the HCV infection must have been resolved or cured > 3 years prior to enrollment.
    25. Positive urine drug screen (to include at a minimum: amphetamines, barbiturates, cocaine, opiates, and benzodiazepines), at the discretion of the Investigator
    26-27. Please refer to Protocol.
    E.5 End points
    E.5.1Primary end point(s)
    1. The incidence and nature of AEs, and the change from Baseline in PFTs, 12-lead ECGs, physical examination findings, vital signs, and clinical laboratory tests
    2. Changes in serum AAT protein concentrations over time
    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. Plasma PK parameters of belcesiran
    2. Changes from Baseline in liver histology as determined by METAVIR and Ishak scores, steatosis scores and Sirius Red staining

    Exploratory End Points:
    1. Changes from Baseline in number and area of diastase resistant PAS-positive AAT globules, and in measurements of soluble, insoluble, and total Z-AAT
    2. Changes from Baseline in MRE and FibroScan® scores
    3. Changes from Baseline in blood-based biomarkers of liver disease
    4. Changes from Baseline in multiple surrogate markers of liver disease
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary End Points:
    1-2. Throughout the study

    Exploratory End Points:
    1-4. 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 No
    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 EEA14
    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
    Belgium
    Germany
    Ireland
    Netherlands
    Portugal
    Spain
    Sweden
    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 years3
    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 years3
    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: 49
    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 state3
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 37
    F.4.2.2In the whole clinical trial 54
    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)
    Participants who complete this study may be given the opportunity to enroll in a planned long-term extension study.
    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 Decision2021-03-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-08-09
    P. End of Trial
    P.End of Trial StatusOngoing
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