Assessments and endpoints
PD, kidney stone, Nedosiran PD, ISRs
ADVERSE EVENT, SECONDARY, ADVERSE EVENT, INJECTION SITE REACTIONS, KIDNEY STONE, EVENTS
The primary objective of this study was to assess the safety and tolerability of nedosiran in patients with PH3. Safety was assessed via adverse event (AE) reporting, physical examinations, electrocardiograms, vital signs, and clinical laboratory tests conducted at screening and throughout the study. AEs were coded using the Medical Dictionary for Regulatory Activities (version 23.1 or higher). Key AE variables were the incidence and severity of any treatment-emergent AEs (until end of study; Day 85), serious AEs (until 30 days after last day of participation), and AEs of special interest (AESIs). Injection site reactions (ISRs) were considered AESIs and defined as signs or symptoms at the injection site, with a time to onset ≥ 4 h post-dose. ISRs were evaluated according to the Common Terminology Criteria for Adverse Events version 5.0.Prespecified secondary objectives were Uox excretion and nedosiran PK characterization. Nedosiran PD was assessed by measuring changes in 24-h Uox excretion at baseline (screening) and at Days 29, 43, 57, and 85 post-dose. The predefined PD responder definition was the proportion of participants achieving a > 30% decrease from baseline in 24-h Uox on two consecutive visits. To maintain the integrity of all analyses related to 24-h Uox measurement, on-treatment 24-h urinary creatinine excretion values were required to be within 20% of baseline, defined as the mean of the two screening values; collections that did not meet this criterion were repeated. Collections with a reported duration of < 22 h or > 26 h at screening or on treatment were considered invalid, and participants were asked to repeat them.We also explored 24-h Uox/creatinine ratio (calculated from 24-h urine samples); kidney stone events (12 months prior to screening and during study); levels of urinary creatinine, citrate, calcium, phosphate, and magnesium; and fluid intake (4- to 7-day period before each 24-h urine collection).Serial blood samples were collected pre-dose and at prespecified post-dose times for plasma nedosiran concentration measurements. Individual blood concentration–time data were used to calculate nedosiran PK parameters using non-compartmental analysis. The primary PK parameters were maximum measured plasma concentration (CAntibodies to nedosiran and anti–double-stranded DNA antibodies were measured at screening, at Days 1 and 85 post-dose, and at the visit for any participants prematurely discontinuing from the study.