A Study to Evaluate DCR-PHXC in Children and Adults With Primary Hyperoxaluria Type 1 and Primary Hyperoxaluria Type 2

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy and safety of DCR-PHXC in Children and Adults with Primary Hyperoxaluria Type 1 (PH1) and Primary Hyperoxaluria Type 2 (PH2)

Official Title
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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

Conditions
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Primary Hyperoxaluria Type 1 (PH1), Primary Hyperoxaluria Type 2 (PH2), Kidney Diseases, Urologic Diseases, Genetic Disease

Intervention / Treatment
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* Drug: DCR-PHXC
* Drug: Sterile Normal Saline (0.9% NaCl)


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Capable and willing to provide written informed consent or assent Documented diagnosis of PH1 or PH2, confirmed by genotyping Must meet the 24 hour urine oxalate excretion requirements Less than 20% variation between the two 24-hour urinary creatinine excretion values derived from the two 24-hour urine collections in the screening period Estimated GFR at screening ≥ 30 mL/min normalized to 1.73 m2 BSA Key Exclusion Criteria: Renal or hepatic transplantation (prior or planned within the study period) Currently on dialysis or anticipated requirement for dialysis during the study period Plasma oxalate >30 µmol/L 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) Use of an RNA interference (RNAi) drug within the last 6 months Participation in any clinical study in which you received an investigational medicinal product (IMP) within 4 months before Screening Liver function test (LFT) abnormalities: Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >1.5 times upper limit of normal (ULN) for age and gender Inability or unwillingness to comply with study procedures

Ages Eligible for Study
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Minimum Age: 6 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DCR-PHXC<br>Intervention, drug, DCR-PHXC | Drug: DCR-PHXC<br>* Multiple fixed doses of DCR-PHXC by subcutaneous (SC) injection<br>* Other names: nedosiran;|
| Placebo Comparator: Placebo - Sterile Normal Saline (0.9% NaCl)<br>Placebo, sterile normal saline (0.9% NaCl) for subcutaneous (SC) injection | Drug: Sterile Normal Saline (0.9% NaCl)<br>* Sterile Normal Saline (0.9% NaCl) for subcutaneous (SC) injection, administered at same injection volume as DCR-PHXC, to serve as placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the curve (AUC) of percent change from baseline in 24-hour urinary oxalate excretion between Day 90 and Day 180 | Four measurements of percent change from baseline in 24-hour urinary oxalate are combined to determine a single AUC value | 3 months (Last 3 months of the 6 month treatment period) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 two consecutive study visits commencing at Day 90 and ending at Day 180 |  | 3 months (Last 3 months of the 6 month treatment period) | 
| Percent change in the summed surface area and number of kidney stones identified via kidney ultrasound from baseline to Day 180 |  | 6 months | 
| Percent change from baseline to Day 180 in plasma oxalate (for adults only) | Four measurements of percent change from baseline in plasma oxalate are combined to determine a single AUC value | 6 months | 
| Rate of change in eGFR from baseline to Day 180 |  | 6 months | 
| AE and SAE throughout the study |  | 6 months | 
| Change from baseline in 12-lead ECG | Standard 12-lead ECGs will be performed in the supine position after the subject has rested comfortably for 10 minutes. The parameters assessed will be rhythm, ventricular rate, PR interval, QRS duration, QT interval, and corrected QT interval (QTcF, Fridericia correction). The Investigator or designee is responsible for reviewing the ECG(s) to assess whether the results are within normal limits and to determine the clinical significance of the results. Standardized ECG acquisition equipment will be provided to all clinical trial sites at the start of the trial, to ensure parity across all sites. | 6 months | 
| The incidence and severity of treatment-emergent adverse events (TEAE) and SAEs associated with abnormal physical examination findings | A full physical examination will include a complete review of body systems: eyes, ears, nose, and throat, chest/respiratory, heart/cardiovascular, gastrointestinal/liver, musculoskeletal/extremities, dermatological/skin, thyroid/neck, lymph nodes, and neurological. A full physical exam is done at Screening, Day 180 and if a participant ends the study early. A brief physical examination will minimally include chest/respiratory, heart/cardiovascular, dermatological/skin, and gastrointestinal/liver. A brief physical examination will be performed may be performed at the Investigator's discretion at all other visits. | 6 months | 
| The incidence and severity of treatment-emergent adverse events (TEAE) and SAEs associated with abnormal vital signs | Vital signs include blood pressure, pulse/heart rate, oral body temperature, and respiratory rate. Parameters will be measured in the supine position, using an automated instrument or manually, after the participant has rested comfortably for 10 minutes. In the pediatric population, an age-appropriate cuff size should be used for blood pressure measurements. Temperature will be obtained in degrees Celsius (°C), pulse rate will be counted for a full minute and recorded in beats per minute, and respirations will be counted for a full minute and recorded in breaths per minute. | 6 months | 
| The incidence and severity of treatment-emergent adverse events (TEAE) and SAEs related to abnormal clinical laboratory tests (hematology, chemistry, coagulation parameters, and urinalysis) | To evaluate the safety and tolerability of DCR PHXC when administered monthly to patients with primary hyperoxaluria (PH) via the change from baseline and incidence of abnormal clinical laboratory tests. | 6 months | 
| To characterize the PK of DCR-PHXC in PH patients | Maximum observed plasma concentration (Cmax) | 6 months | 
| To characterize the PK of DCR-PHXC in PH patients | Area under the plasma concentration versus time curve (AUC) | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PH1, PH2, Primary Hyperoxaluria, RNAi, RNAi therapeutic, GalNAc, LDHA gene, LDH, siRNA