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    Summary
    EudraCT Number:2018-003098-91
    Sponsor's Protocol Code Number:DCR-PHXC-201
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2018-12-18
    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 ConcernedGermany - BfArM
    A.2EudraCT number2018-003098-91
    A.3Full title of the trial
    A Phase 2 Placebo-Controlled, Double-Blind, Multicenter Study to Evaluate the Efficacy, Safety, and Tolerability of DCR-PHXC Solution for Injection (subcutaneous use) in Patients with Primary Hyperoxaluria
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study for patients with Primary Hyperoxaluria to evaluate the efficacy, safety and tolerability of DCR-PHXC
    A.3.2Name or abbreviated title of the trial where available
    PHYOX 2
    A.4.1Sponsor's protocol code numberDCR-PHXC-201
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03847909
    A.5.3WHO Universal Trial Reference Number (UTRN)U1111-1224-6881
    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 pointKerry Russell
    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.5.4Telephone number001607-621-8097 0393
    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 nameNedosiran
    D.3.2Product code DCR-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 INNDCR-L1360
    D.3.9.2Current sponsor codeDCR-PHXC
    D.3.9.3Other descriptive nameNedosiran
    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
    E.1.1.1Medical condition in easily understood language
    Primary hyperoxaluria is where the liver overproduces oxalate. As a result 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 assess the efficacy of DCR PHXC in reducing urinary oxalate burden in patients with PH (types 1 and 2)
    E.2.2Secondary objectives of the trial
    Key Secondary
    To assess the efficacy of DCR PHXC in reducing urinary oxalate burden over time in patients with PH
    Secondary
    1. To evaluate the effect of DCR PHXC on stone burden in patients with PH
    2. To evaluate the effect of DCR-PHXC on plasma oxalate in patients with PH
    3. To evaluate the effect of DCR PHXC on eGFR
    4. To assess the safety of DCR PHXC in patients with PH
    5. To characterize the PK of DCR PHXC in patients with PH
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    In order to be eligible to participate in this study, an individual must meet all of the following 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 PH1 or PH2, 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. At least 12 participants must have at least one 24 hour Uox excretion ≥ 1.6 mmol (adjusted per 1.73 m2 BSA in participants aged < 18 years).
    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 equation in participants aged ≥ 18 years (Levey & Stevens, 2010) or the 2012 multivariate equation by Schwartz in participants aged 6 to 17 years (Schwartz et al., 2012).
    Sex
    6. 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 during the treatment period and 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.

    Informed Consent/Assent
    7. 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.
    E.4Principal exclusion criteria
    An individual who meets any of the following criteria will be excluded from participation in this study:

    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 RNA interference (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 aminotransferase (ALT) or aspartate aminotransferase (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
    8. Participants receiving pyridoxine must have been at a stable dose for at least 4 weeks prior to Day 1 and must be willing to remain on the same stable dose throughout the study.

    Prior/Concurrent Clinical Study Experience
    9. Participation in any clinical study in which they received an investigational medicinal product (IMP) within 4 months before Screening
    a. For IMPs with the potential to reduce urine and/or plasma oxalate concentrations, these concentrations must have returned to historical baseline levels prior to Screening

    Diagnostic assessments
    10. Liver function test abnormalities: ALT and/or AST >1.5 × ULN for age and gender
    11. 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. Viral serology testing not required in participants < 18 years of age.
    12. Positive urine drug screen (to include at minimum: amphetamines, barbiturates, cocaine, opiates, and benzodiazepines). Investigator discretion is allowed. Urine drug screening is not required in participants ≤ 12 years of age.

    Other Exclusions
    13. Known hypersensitivity to DCR PHXC, or any of its ingredients
    14. Inability or unwillingness to comply with the specified study procedures, including collection of 24-hour urine samples, and the lifestyle considerations detailed in Section 5.3
    E.5 End points
    E.5.1Primary end point(s)
    The proportion of participants with a reduction from baseline in 24-hour Uox of at least 70%, based on an AUC and/or reaching normalization or near-normalization of 24-hour Uox on at least 2 consecutive visits, starting from Day 90. Normalization of Uox is defined as < 0.46 mmol/24 hours; near-normalization is defined as ≥ 0.46 to < 0.60 mmol/24 hours (values adjusted per 1.73 m2 BSA in participants aged < 18 years).
    E.5.1.1Timepoint(s) of evaluation of this end point
    An interim analysis may be conducted upon completion of two-thirds of the participants for the purpose of re-evaluation of sample size. The interim unblinded analysis will be performed by an independent statistician other than the person responsible for the primary analysis of this study and treatment codes will be revealed to that party only.
    E.5.2Secondary end point(s)
    Key Secondary:
    AUC from Day 90 to Day 180, based on percent change from Baseline in 24-hour Uox
    Secondary:
    1. Percent change in the summed surface area and number of kidney stones identified via kidney ultrasound from Baseline to Day 180
    2. Percent change in plasma oxalate from Baseline to Day 180 (for adults only)
    3. Rate of change in eGFR from Baseline to Day 180
    4. AE and SAE; change from Baseline in 12 lead ECG, physical examination findings, vital signs, and clinical laboratory tests
    5. Population and individual PK parameters for DCR PHXC and its metabolites
    E.5.2.1Timepoint(s) of evaluation of this end point
    An interim analysis may be conducted upon completion of two-thirds of the participants for the purpose of re-evaluation of sample size. The interim unblinded analysis will be performed by an independent
    statistician other than the person responsible for the primary analysis of this study and treatment codes will be revealed to that party only. A
    minimal fraction of alpha (0.0001) will be spent at the interim analysis, as the trial will not be stopped early for efficacy or futility based on the results from the interim analysis. The final analysis will use alpha of
    0.0249 for the primary endpoint, in order to preserve an overall type I error at the 1-sided 0.025 level.
    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) 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 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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA30
    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
    Israel
    Japan
    Lebanon
    New Zealand
    United States
    France
    Germany
    Italy
    Netherlands
    Poland
    Romania
    Spain
    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
    The end of the study is defined as completion of the last visit or procedure shown in the SoA in the trial globally.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months6
    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: 12
    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: 6
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 6
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 22
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 2
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    children 6 <=18
    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 23
    F.4.2.2In the whole clinical trial 36
    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 roll-over long-term extension study is planned (DCR PHXC-301). Participants may be screened for entry into the roll-over study when all DCR PHXC-201 study assessments have been completed. Participants not eligible or not electing to roll over into study DCR PHXC-301 will be followed monthly until Uox returns to ≥ 80% of baseline.
    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 Decision2019-09-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-10-22
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2021-06-21
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