Primary Hyperoxaluria MedDRA version: 20.1 Level: PT Classification code 10020703 Term: Hyperoxaluria System Organ Class: 10038359 - Renal and urinary disorders
Conditions
Sponsors
Dicerna Pharmaceuticals Inc
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Estimated glomerular filtration rate (eGFR) at Screening = 30 mL/min normalized to 1.73 m2 body surface area (BSA). 2. Documented diagnosis of PH1, PH2, or PH3 confirmed by genotyping (historically available genotype information is acceptable for study eligibility) 3. Average spot Uox-to-creatinine ratio at Screening above 2 times the 95th percentile for age based on Matos et al, 1999: > 0.44 mol/mol in participants 0.34 mol/mol in participants from 6 months to 0.26 mol/mol in participants 12 months to 0.20 mol/mol in participants from 2 to 0.16 mol/mol in participants from 3 to 0.14 mol/mol in participants from 5 to 0.12 mol/mol in participants from 7 to 11 years 4. Estimated glomerular filtration rate (eGFR) at Screening = 30 mL/min normalized to 1.73 m2 body surface area (BSA). For infants aged less than 12 months, serum creatinine below the 97.5th percentile of a healthy population (Boer et al., 2010) 5. Participants must have been on a stable treatment regimen for PH for 3 months prior to Day 1 and parent(s)/legal guardian should be willing to ensure participant remains on the same stable treatment regimen during the study. Dose adjustments for interval weight gain are acceptable. 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 10.5.2, 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 10.5.1), not breastfeeding, and at least 1 of the following conditions applies: Not a woman of childbearing potential (WOCBP) as defined in Section 10.5.1 OR A WOCBP who agrees to follow the contraceptive guidance in Section 10.5.2 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 and Assent: 7. Participant's parent or legal guardian is capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol. a.For children younger than 12 years of age, assent will be based on local regulation. If assent is required, participant must be able to provide written assent for participation. Other 8. A legal guardian or primary caregiver must be available to help the study-site personnel ensure follow up; accompany the participant to the study site on each assessment day according to the SoA (e.g., able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures); consistently and consecutively be available to provide information on the participant using the rating scales during the scheduled study visits; accurately and reliably dispense study intervention as directed. 9. Affiliated with or is a beneficiary of a health insurance system (if applicable per national regulations) Are the trial subjects under 18? yes Number of subjects for this age range: 25 F.1.2 Adults (18-64 years) no F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 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 (Pox) > 30 µmol/L at Screening 4.Documented evidence of clinical manifestations of severe systemic oxalosis (including preexisting 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 participant’s 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 [NAFLD/NASH]) c.History of serious mental illness that includes, but is not limited to, schizophrenia, bipolar disorder, or severe depression requiring hospitalization or pharmacological intervention d.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 6.Use of an RNAi drug within the last 6 months 7.History of 1 or more of the following reactions to an oligonucleotidebased therapy: a.Severe thrombocytopenia (platelet count = 100,000/µL) b.Hepatotoxicity, defined as ALT or AST > 3 times the upper 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 8.Participation in any clinical study in which they received an IMP within 4 months or 5 times the half-life of the drug (whichever is longer) 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 9.Liver function test (LFT) abnormalities: ALT and/or AST > 1.5 × ULN for age and gender 10.Known hypersensitivity to nedosiran, or any of its ingredients 11.Participants who are suitable for, and have access to, another approved PH1 treatment 12.Inability or unwillingness to comply with the specified study procedures, including the lifestyle considerations detailed in Section 5.3.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To assess the efficacy of nedosiran in neonates, infants, and children with PH and relatively intact renal function based upon eGFR and serum creatinine;Secondary Objective: 1. To characterize the safety of nedosiran in neonates, infants, and children with PH and relatively intact renal function based upon eGFR and serum creatinine 2. To characterize the PK of nedosiran in neonates, infants, and children with PH and relatively intact renal function based upon eGFR and serum creatinine 3. To assess the efficacy of nedosiran in neonates, infants, and children with PH and relatively intact renal function based upon eGFR and serum creatinine 4. To evaluate the effect of nedosiran on eGFR in neonates, infants, and children with PH and relatively intact renal function based upon eGFR and serum creatinine;Primary end point(s): Percent and absolute change from Baseline to Month 6 in spot urinary oxalate-to-creatinine ratio in PH1, PH2, or PH3 participant subgroups ;Timepoint(s) of evaluation of this end point: The percent and absolute change in average spot urinary oxalate-tocreatinine ratio from Baseline to Day 180 will be summarized | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. The incidence and nature of TEAEs and SAEs Change from Baseline in 12-lead ECG, physical examination findings, vital sign assessments, and clinical laboratory tests 2. Plasma PK parameters for nedosiran and/or its metabolites, including Cmax, AUCt and AUC8 (if estimable) 3. Percentage of participants with spot urinary oxalate-to-creatinine ratio = the ULN or = 1.5 x ULN at any time point through Month 6 in PH1, PH2, or PH3 participant subgroups 4. Change from Baseline in eGFR at Month 6 (only in participants = 12 Months of age at Screening) in PH1, PH2, or PH3 participant subgroups;Timepoint(s) of evaluation of this end point: 1. Descriptive statistics will be provided for absolute values and changes from baseline in physical examination findings, vital sign measurements, ECGs, and clinical laboratory results at each timepoint 2. Pharmacokinetic analyses will be described in the SAP finalized before database lock. The population PK analysis will be presented separately from the main CSR 3. The percentage of participants with spot urinary oxalate-to-creatinine ratio = the ULN and = 1.5 x ULN at any time point through Month 6 will be summarized. 4. The percent change from baseline in eGFR at Month 6 (only in participants = 12 Months of age at Screening) will be summarized. | — |
Countries
Canada, Germany, Italy, Japan, Lebanon, Poland, Spain, Turkey, United Kingdom, United States
Contacts
Public ContactCatherine Sullivan
Dicerna Pharmaceuticals Inc
Outcome results
None listed