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    Summary
    EudraCT Number:2020-000344-67
    Sponsor's Protocol Code Number:DCR-PHXC-104
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2020-05-14
    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 ConcernedUK - MHRA
    A.2EudraCT number2020-000344-67
    A.3Full title of the trial
    A Phase 1 Placebo-Controlled, Double-Blind, Multicenter Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a Single Dose of DCR-PHXC in Patients with Primary Hyperoxaluria Type 3
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Safety & Tolerability Study of DCR-PHXC in Patients with Primary Hyperoxaluria Type 3
    A.3.2Name or abbreviated title of the trial where available
    PHYOX4
    A.4.1Sponsor's protocol code numberDCR-PHXC-104
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/426/2019
    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 pointKerry Russell
    B.5.3 Address:
    B.5.3.1Street Address33 Hayden Ave.
    B.5.3.2Town/ cityLexington
    B.5.3.3Post codeMA 02421
    B.5.3.4CountryUnited States
    B.5.4Telephone number001617 621 8097
    B.5.6E-mailkrussell@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/3/18/2052
    D.3 Description of the IMP
    D.3.1Product nameDCR-PHXC
    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 INNnedosiran
    D.3.9.1CAS number 2247026-22-6
    D.3.9.2Current sponsor codeDCR-PHXC
    D.3.9.3Other descriptive nameDCR-L1360
    D.3.9.4EV Substance CodeSUB190536
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number170
    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
    Primary Hyperoxaluria Type 3
    E.1.1.1Medical condition in easily understood language
    Primary hyperoxaluria is where the liver overproduces oxalate. Therefore calcium-oxalate crystals form in the urinary system and lead to
    the formation of kidney stones and impaired kidney function.
    E.1.1.2Therapeutic area Diseases [C] - Nutritional and Metabolic Diseases [C18]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10020703
    E.1.2Term Hyperoxaluria
    E.1.2System Organ Class 10038359 - Renal and urinary 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 safety and tolerability of a single dose of DCR-PHXC in patients with PH3
    E.2.2Secondary objectives of the trial
    1. To characterize the plasma PK of a single dose of DCR-PHXC in patients with PH3
    2. To assess the efficacy of a single dose of DCR PHXC in reducing oxalate burden in patients with PH3
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Age
    1. At least 6 years of age at the time of signing the informed consent/assent
    Type of Participant and Disease Characteristics
    2. Documented diagnosis of PH3, confirmed by genotyping (historically available genotype information is acceptable for study eligibility)
    3. 24-hour Uox excretion ≥ 0.7 mmol (adjusted per 1.73 m2 BSA in participants < 18 years of age) in both collections performed in the screening period
    4. Less than 20% variation between the two 24-hour urinary creatinine measurements in the screening period. Individuals who do not achieve < 20% variation between the 2 screening values may undergo a second round of urine collection. An extra 7 calendar days may be added to the screening window for participants to complete a second round of urine collection. Should potential participants again fail to achieve the within-20% variation, they will be excluded from participation.
    5. Estimated GFR at screening ≥ 30 mL/min normalized to 1.73 m2 BSA, calculated using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) formula in participants aged ≥ 18 years (Levey & Stevens, 2010) or the multivariate formula by Schwartz in participants aged 6 to 17 years (Schwartz et al., 2012).
    6. History of at least one stone event within the last 12 months. Stone events are defined as any of the following:
    a. Renal stone requiring medical intervention, e.g., outpatient procedures such as lithotripsy, or hospitalization or inpatient surgical intervention for confirmed stone-related pain and/or complications
    b. Stone passage with or without hematuria
    c. Renal colic requiring medication
    7. Male or female
    Male participants:
    A male participant with a female 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.
    Female participants:
    A female participant is eligible to participate if she is not pregnant (see Section 10.4.1), not breastfeeding, and at least 1 of the following conditions applies:
    Not a woman of childbearing potential (WOCBP) as defined in Section 10.4.1
    OR
    A WOCBP who agrees to follow the contraceptive guidance in Section 10.4.2 for at least 12 weeks after the last dose of study intervention.
    Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
    8. Participant (and/or participant’s parent or legal guardian if participant is a minor [defined as patient < 18 years of age, or younger than the age of majority according to local regulations]) is capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
    a. Adolescents (12 to < 18 years of age, or older than 12 years but younger than the age of majority according to local regulations) must be able to provide written assent for participation.
    b. For children younger than 12 years of age, assent will be based on local regulations.
    Other
    9. Affiliated with or is a beneficiary of a health insurance system (if applicable per national regulations)
    E.4Principal exclusion criteria
    Medical Conditions
    1. Prior renal or hepatic transplantation; or planned transplantation within the study period
    2. Currently receiving dialysis or anticipating requirement for dialysis during the study period
    3. Plasma oxalate > 30 µmol/L
    4. Documented evidence of clinical manifestations of systemic oxalosis (including pre-existing retinal, heart, or skin calcifications, or history of severe bone pain, pathological fractures, or bone deformations)
    5. Presence of any condition or comorbidities that would interfere with study compliance or data interpretation or potentially impact patient safety including, but not restricted to:
    a. Severe intercurrent illness
    b. Known causes of active liver disease/injury or transaminase elevation (e.g., alcoholic liver disease, nonalcoholic fatty liver disease/steatohepatitis)
    c. Physician concerns about intake of drugs of abuse or 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)
    d. history of serious mental illness that includes, but is not limited to, schizophrenia, bipolar disorder, or severe depression requiring hospitalization or pharmacological intervention
    e. clinically relevant history or presence of cardiovascular, respiratory, gastrointestinal, hematological, lymphatic, neurological, musculoskeletal, genitourinary, immunological diseases, including dermatological including rash, severe eczema or dermatitis, or connective tissue diseases or disorders
    Prior/Concomitant Therapy
    6. Use of an RNAi drug within the last 6 months
    7. History of one or more of the following reactions to an oligonucleotide-based therapy:
    a. Severe thrombocytopenia (platelet count ≤ 100,000/µL)
    b. Hepatotoxicity, defined as alanine transaminase (ALT) or aspartate transaminase (AST) > 3 times the upper limit of normal (ULN) and total bilirubin > 2 × ULN or international normalized ratio (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
    Prior/Concurrent Clinical Study Experience
    8. Participation in any clinical study in which they received an investigational medicinal product (IMP) within 4 months or 5 times the half-life of the drug (whichever is longer) before Screening
    Diagnostic Assessments
    9. Liver function test abnormalities: ALT and/or AST >1.5 × ULN for age and gender
    10. Positive screening for hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV) antibodies, or anti-human immunodeficiency virus (HIV) 1 and 2 antibodies. If participant has been tested in the past 3 months, medical record documentation of this testing can be used for screening.
    11. Positive anti-dsDNA test at Screening
    Other Exclusions
    12. Known hypersensitivity to DCR-PHXC or any of its ingredients
    13. Inability or unwillingness to comply with the specified study procedures, including the lifestyle considerations detailed in Section 5.3.
    E.5 End points
    E.5.1Primary end point(s)
    • Incidence and severity of treatment-emergent AEs, SAEs, and AESI
    • Changes from baseline in clinical laboratory test results, including hematology, serum chemistry, and urinalysis
    • Changes from baseline in vital signs measurements
    • Changes from baseline in 12-lead ECG findings
    • Incidence and nature of treatment-emergent clinically significant physical examination findings
    E.5.1.1Timepoint(s) of evaluation of this end point
    All the primary end points will be evaluated from baseline to end of study.
    E.5.2Secondary end point(s)
    1. Plasma PK parameters of DCR-PHXC and its metabolites, including Cmax, AUC(0-t), and AUC(0-inf), if estimable
    2. The proportion of participants achieving a > 30% decrease from baseline in 24-hour Uox on 2 consecutive visits
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Plasma PK parameters will be evaluated until Day 29.
    2. Decrease in 24-hour Uox will be evaluated from Baseline until End of 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 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) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    safety
    E.7.2Therapeutic exploratory (Phase II) No
    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 EEA4
    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
    France
    Germany
    Netherlands
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months9
    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: 4
    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) Yes
    F.1.1.5.1Number of subjects for this age range: 2
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 2
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 3
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 3
    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 7
    F.4.2.2In the whole clinical trial 10
    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)
    In order to provide continued patient access to DCR-PHXC and to expand the safety database for the product, a rollover long-term extension study, DCR-PHXC-301, is available for participants successfully completing this 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 Decision2020-06-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-08-07
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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