Primary Hyperoxaluria MedDRA version: 20.1 Level: PT Classification code 10020703 Term: Hyperoxaluria System Organ Class: 10038359 - Renal and urinary disorders
Conditions
Interventions
Product Name: Nedosiran
Product Code: DCR-PHXC
Pharmaceutical Form: Solution for injection
INN or Proposed INN: DCR-L1360
CAS Number: 2247026-22-6
Current Sponsor code: DCR-PHXC
Other descriptive name
Sponsors
Dicerna Pharmaceuticals Inc
Eligibility
Sex/Gender
All
Inclusion criteria
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 =65 years) yes F.1.3.1 Number of subjects for this age range
Exclusion criteria
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), antihepatitis 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 o
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To assess the efficacy of DCR-PHXC in reducing urinary oxalate burden in patients with PH (types 1 and 2);Secondary Objective: 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;Primary 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).;Timepoint(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 2.49% for the primary endpoint, in order to preserve an overall type I error at the 1-sided 2.5% level. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary 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;Timepoint(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. | — |
Countries
Australia, Canada, France, Germany, Israel, Italy, Japan, Lebanon, Netherlands, New Zealand, Poland, Romania, Spain, United Kingdom, United States
Contacts
Public ContactRalf Rosskamp
Dicerna Pharmaceuticals Inc
Outcome results
None listed