The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single-ascending doses (SAD) and multiple-ascending doses (MAD) of lumasiran in healthy adult volunteers and subjects with primary hyperoxaluria type 1 (PH1). In Part A, single ascending dose (SAD) part, healthy adults were dosed with lumasiran or placebo once. In Part B, multiple ascending doses (MAD) part, patients with primary hyperoxaluria type 1 (PH1) were dosed with lumasiran or placebo. All patients that initially received placebo received lumasiran after completing placebo dosing.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
52
Lumasiran will be administered SC once in Part A. In Part B lumasiran will be administered SC qM (Days 1, 29 and 57) or q3M (Days 1 and 85).
Matching placebo (sterile saline: 0.9% sodium chloride \[NaCl\]) will be administered SC once in Part A. In Part B matching placebo will be administered SC qM (Days 1, 29 and 57) or q3M (Days 1 and 85).
Clinical Trial Site
Bordeaux, France
Clinical Trial Site
Lyon, France
Clinical Trial Site
Paris, France
Clinical Trial Site
Bonn, Germany
Clinical Trial Site
Haifa, Israel
Clinical Trial Site
Jerusalem, Israel
Clinical Trial Site
Amsterdam, Netherlands
Clinical Trial Site
Birmingham, United Kingdom
Clinical Trial Site
London, United Kingdom
Number of Participants With Adverse Events (AEs)
An AE is any untoward medical occurrence in a clinical investigational subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment.
Time frame: Part A (SAD): Up to 405 days; Part B (MAD): Up to 546 days
Maximum Concentration (Cmax) of Lumasiran in Plasma
Samples for Part A were collected only on Day 1; Part B on Days 1 and 57 for qM and on Days 1 and 85 for q3M arm groups.
Time frame: Part A (SAD): Day 1: predose, 30 minutes (min), 1 hour (h), 2 h, 4 h, 6 h, 8 h and 24 h; Part B (MAD): Days 1 and 57 for qM dosing and Days 1 and 85 for q3M dosing: predose, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h and 48 h
Time to Cmax (Tmax) of Lumasiran in Plasma
Samples for Part A were collected only on Day 1; Part B on Days 1 and 57 for qM and on Days 1 and 85 for q3M arm groups.
Time frame: Part A (SAD): Day 1: predose, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h; Part B (MAD): Days 1 and 57 for qM dosing and Days 1 and 85 for q3M dosing: predose, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h and 48 h
Area Under the Concentration-Time Curve From Time 0 to Time of Last Measurable Concentration (AUC0-last) of Lumasiran in Plasma
Samples for Part A were collected only on Day 1; Part B on Days 1 and 57 for qM and on Days 1 and 85 for q3M arm groups.
Time frame: Part A (SAD): Day 1: predose, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h; Part B (MAD): Days 1 and 57 for qM dosing and Days 1 and 85 for q3M dosing: predose, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h and 48 h
Terminal Half-life (t1/2) of Lumasiran in Plasma
Samples for Part A were collected only on Day 1; Part B on Days 1 and 57 for qM and on Days 1 and 85 for q3M arm groups.
Time frame: Part A (SAD): Day 1: predose, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h; Part B (MAD): Days 1 and 57 for qM dosing and Days 1 and 85 for q3M dosing: predose, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h and 48 h
Fraction Excreted in Urine in 24 Hours (Fe0-24) of Lumasiran
Samples for Part A were collected only on Day 1; Part B on Days 1 and 57 for qM and on Days 1 and 85 for q3M arm groups.
Time frame: Part A (SAD): Day 1: pooled urine 0-4 h, 4-8 h and 8-24 h; Part B (MAD): Part B (MAD phase): Days 1 and 57 for qM dosing and Days 1 and 85 for q3M dosing: pooled urine 0-4 h, 4-8 h, 8-12 h and 12-24 h
Renal Clearance (CLR) of Lumasiran
Samples for Part A were collected only on Day 1; Part B on Days 1 and 57 for qM and on Days 1 and 85 for q3M arm groups.
Time frame: Part A (SAD): Day 1: pooled urine 0-4 h, 4-8 h and 8-24 h; Part B (MAD): Part B (MAD phase): Days 1 and 57 for qM dosing and Days 1 and 85 for q3M dosing: pooled urine 0-4 h, 4-8 h, 8-12 h and 12-24 h
Baseline Plasma Glycolate Concentration
The pharmacodynamic (PD) outcome measure of plasma glycolate concentration could only be calculated for Part A. Due to an issue with the plasma glycolate assay at the testing laboratory the data for Part B could not be calculated.
Time frame: Part A (SAD): Baseline, Part B (MAD): Baseline
Percentage Change From Baseline in Plasma Glycolate Concentration
The PD outcome measure of plasma glycolate concentration could only be calculated for Part A. Due to an issue with the plasma glycolate assay at the testing laboratory the data for Part B could not be calculated.
Time frame: Part A (SAD): Days 15, 29, 57 and 85; Part B (MAD): Days 15, 29, 57, 85
Baseline Spot Urine Glycolate:Creatinine Ratio in Part A
The endpoint was only measured in Part A.
Time frame: Part A (SAD): Baseline
Percentage Change From Baseline in Spot Urine Glycolate:Creatinine Ratio in Part A
The endpoint was only measured in Part A.
Time frame: Part A (SAD): Days 29 and 57
Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B
The endpoint was only measured in Part B.
Time frame: Part B (MAD): Baseline
Percentage Change From Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B
The endpoint was only measured in Part B.
Time frame: Part B (MAD): 24 hour urine collections on Days 29, 57, 85, 113, 141, 169, 197
Baseline 24 Hour Urine Glycolate:Creatinine Ratio in Part B - Initial 85 Days
The endpoint was only measured during the initial 85 days in Part B.
Time frame: Part B (MAD): Baseline
Percentage Change From Baseline of 24 Hour Urine Glycolate:Creatinine Ratio in Part B - Initial 85 Days
The endpoint was only measured during the initial 85 days in Part B.
Time frame: Part B (MAD): 24 hour urine collections on Days 29, 57 and 85
Baseline Creatinine Clearance Corrected for BSA in Part B
Time frame: Part B (MAD): Baseline
Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B
Time frame: Part B (MAD): Days 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337, 365, 393, 421, 449
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