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: In order to be eligible to participate in this study, an individual must meet all of the following criteria: Age 1. Participant must be 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 PH, confirmed by genotyping (historically available genotype information is acceptable for study eligibility) 3. Participant successfully completed a Dicerna Pharmaceuticals, Inc. study of DCR PHXC, or is the sibling of a participant who successfully completed a Dicerna Pharmaceuticals, Inc. study of DCR PHXC. a. For participants rolling over from a multidose study of DCR-PHXC, enrollment should occur within a window of 25 to 75 days from the last dose of study intervention. In order to minimize any gap in administration of DCR-PHXC, every effort should be made to enroll participants as soon as all assessments from the previous study have been completed. It should be noted if the participant was required to repeat the end-of-study (EOS) 24-hour Uox collection for violation of completeness criteria. b. Siblings must i. be younger than 18 years of age ii. meet all other eligibility criteria (including genotyping) iii. have two 24-hour Uox values = ?0.7 mmol (adjusted per 1.73 m2 BSA) at screening iv. have less than 20% variation between the two 24-hour urinary creatinine excretion values obtained 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. 4. 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). In Japan, the equation by Uemura et al. will be used for participants aged 6 to 17 years and the equation by Matsuo et al. will be used in participants aged = 18 years (Uemura et al., 2014; Matsuo et al., 2009). Note: For participants rolling over from a 6-month multidose study of DCR-PHXC, the eGFR value from either the Day 150 or Day 180 (EOS) visit may be used for screening. Sex 5. 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 one 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 6. Participant (and/or participant’s parent or legal guardian if participant is
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 3. 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) Prior/Concomitant Therapy 4. Use of an RNAi drug (other than DCR-PHXC) within the last 6 months 5. 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 × 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 6. Participants receiving pyridoxine (vitamin B6) 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 7. Participation in any clinical study in which they received an investigational medicinal product (IMP) other than DCR-PHXC within 4 months before Screening. a. For IMPs (other than DCR-PHXC) 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 8. Plasma oxalate > 30 µmol/L Note: For participants > 18 years of age rolling over from a 6-month multidose study of DCR-PHXC, the plasma oxalate value from either the Day 150 or Day 180 (EOS) visit may be used for screening. If the previous study is blinded at the time of entry in DCR PHXC-301, plasma oxalate values will be reviewed by the unblinded Medical Monitor. For participants = 18 years of age rolling over from a 6 month multidose study of DCR-PHXC, the plasma oxalate value from Screening in the previous study will be used. Other Exclusions 9. Known hypersensitivity to DCR PHXC or any of its ingredients 10. 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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the effect of DCR PHXC on estimated glomerular filtration rate (eGFR) ;Secondary Objective: Key Secondary: To evaluate the safety and tolerability of DCR PHXC when administered monthly to patients with PH Secondary: 1. To identify the proportion of participants with normalized or near-normalized 24-hour Uox 2. To assess the effect of DCR-PHXC on stone events in patients with PH 3. To assess the effect of DCR-PHXC on stone burden in patients with PH 4. To evaluate the incidence of chronic kidney disease (CKD) and end-stage renal disease (ESRD) in participants with PH 5. To evaluate the effect of DCR-PHXC on Quality of Life (QoL) assessments in patients with PH 6. To assess the efficacy of DCR PHXC in reducing Uox burden in patients with PH 7. To assess the long-term efficacy of DCR PHXC in reducing Uox burden in patients with PH Exploratory objectives: 1. To characterize the PK of DCR-PHXC in patients with PH ;Primary end point(s): The annual rate of decline in eGFR. ;Timepoint(s) of evaluation of this end point: Ongoing evaluation of all medical assessments and patient’s quality of life questionnaires. Continuous risk-benefit assessments will be conducted by the Sponsor and the Medical Monitor of the CRO. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Key Secondary: •The incidence and severity of treatment-emergent adverse events (TEAE) and serious adverse events (SAE) •Change from Baseline in 12-lead electrocardiogram (ECG), physical examination findings, vital signs, and clinical laboratory tests (hematology, chemistry, coagulation parameters, and urinalysis) Secondary: 1. The proportion of participants with a 24 hour Uox level (< 0.46 mmol/24 hours or = 0.46 - < 0.60 mmol/24 hours [adjusted per 1.73 m2 body surface area (BSA) in participants aged < 18 years]) at quarterly intervals throughout the study 2. Change from Baseline in the number of stone events over a 12-month period, annually in Year 1, Year 2, etc. 3. Change from Baseline in the stone burden at Year 1, Year 2, etc. 4. The number of participants with severe CKD (GFR = 15 29 mL/min) or ESRD (GFR <15 mL/min); adjusted per 1.73 m2 BSA in participants aged < 18 years 5. Change from Baseline in the Short Form (36) Health Survey (SF-36®), Wisconsin Stone Quality of Life Questionnaire (WISQOL), and EQ-5D-5L in adults; and in the Pediatric Quality of Life Inventory (PedsQL) in children 6. Area under the curve (AUC) of 24-hour Uox from Day 90 to Day 180, based on percent change from Baseline. This endpoint will only be assessed in participants randomized to placebo in a previous study of DCR-PHXC and pediatric siblings of participants who successfully completed a Dicerna study of DCR-PHXC 7. Percent change from Baseline in 24-hour Uox at 3-month intervals throughout the study. This endpoint will be assessed only after Month 6 in those participants randomized to placebo in a previous study of DCR PHXC and pediatric siblings of participants who successfully completed a Dicerna study of DCR-PHXC Exploratory: 1. Population and individual pharmacokinetic (PK) parameters for DCR PHXC, including clearance (CL) and volume of distribution (V) estimates along with secondary parameters of area under the curve (AUC), maximum observ | — |
Countries
Australia, Canada, France, Germany, Israel, Italy, Japan, Lebanon, Netherlands, New Zealand, Poland, Romania, Spain, United Kingdom, United States
Contacts
Public ContactKerry Russell
Dicerna Pharmaceuticals Inc
Outcome results
None listed