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: DCR-PHXC
Pharmaceutical Form: Solution for injection
INN or Proposed INN: DCR-L1360
Current Sponsor code: DCR-PHXC
Concent
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. a. For participants rolling over from Study DCR-PHXC-101, a minimum 12 weeks must have elapsed from dosing in DCR-PHXC-101 and 24-hour Uox excretion must have returned to =80% of study DCR-PHXC-101 baseline. 4. Estimated GFR at screening = 30 mL/min normalized to 1.73 m2 BSA calculated using the Modification of Diet in Renal Disease (MDRD) formula in participants aged > 16 years, or the formula by Schwartz in participants aged 6 to 16 years (Levey et al., 1999; Schwartz et al., 2009; National Kidney Foundation, 2002). 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 a minor [defined as patient =65 years) yes F.1.3.1 Number of subjects for this age range 2
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. Documented evidence of clinical manifestations of systemic oxalosis 4. Presence of any condition or comorbidities that would interfere with study compliance or data interpretation or potentially impact study participant 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. 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, 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 5. Routine or chronic use of more than 3 grams of acetaminophen/paracetamol daily 6. Use of an RNAi drug (other than DCR-PHXC) 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 × 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 (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 9. Participation in any clinical study in which they received an investigational medicinal product (investigational medicinal product [IMP]; other than DCR-PHXC) 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the safety and tolerability of DCR-PHXC when administered monthly to patients with PH; Secondary Objective: 1.To identify the proportion of participants with normalized or near-normalized Uox 2.To identify the change in relative risk of participants with PH for end-stage renal disease (ESRD) 3.To assess the effect of DCR-PHXC on stone events in patients with PH 4.To assess the effect of DCR-PHXC on stone burden in patients with PH 5.To evaluate the incidence of ESRD in participants with PH 6.To evaluate the effect of DCR-PHXC on Quality of Life (QoL) assessments in patients with PH. 7.To evaluate the effect on DCR-PHXC on estimated glomerular filtration rate (eGFR) Exploratory objectives: 1.To assess the efficacy of DCR-PHXC in reducing Uox burden in patients with PH 2.To evaluate the long-term pharmacoeconomics of PH 3.To characterize the PK of DCR-PHXC in patients with PH ;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. ; Primary end point(s): •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
| Measure | Time frame |
|---|---|
| Secondary end point(s): 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 BSA in participants aged < 18 years]) on at least 2 consecutive visits, beginning with Day 90 (for participants rolling over from DCR-PHXC-101) or Month 3 (participants rolling over from repeat-dose studies of DCR PHXC) 2.Change from Baseline in the proportion of participants with 24-hour urinary oxalate excretion (Uox) levels in each of 4 quartile ranges (<1.1 mmol, 1.1 to <1.6 mmol, 1.6 to < 2.4 mmol, and = 2.4 mmol/24 hours [values adjusted per 1.73 m2 body surface area (BSA) in participants aged < 18 years]) 3.Change from Baseline in the number of stone events over a 12-month period, annually in Year 1, Year 2, etc. 4.Change from Baseline in the stone burden observed over a 12-month period, annually in Year 1, Year 2, etc. 5.The number of participants with ESRD, defined as eGFR < 30 mL/min 6.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 7.Annual change in eGFR Exploratory: 1.TWS area under the curve (AUC) of 24-hour Uox from Day 1 to Day 180, based on percent change from Baseline 2.Change in Quality Adjusted Life Years (QALY) 3.Population and individual pharmacokinetic (PK) parameters for DCR-PHXC, including clearance (CL) and volume of distribution (V) estimates along with secondary parameters of AUC, maximum observed concentration (Cmax), minimum observed concentration (Cmin), time to maximum concentration (Tmax), and terminal elimination half-life (t1/2) ;Timepoint(s) of evaluation of this end point: Ongoing evaluation of all medical assessments and patient’s quality | — |
Countries
Australia, Canada, France, Germany, Israel, Italy, Netherlands, New Zealand, Poland, Romania, Spain, United Kingdom, United States
Contacts
Public ContactRalf Rosskamp
Dicerna Pharmaceuticals Inc
Outcome results
None listed