Study of Lumasiran in Healthy Adults and Patients With Primary Hyperoxaluria Type 1

Phase 1

Completed

Conditions: Primary Hyperoxaluria Type 1 (PH1)

Interventions: Drug: Placebo
Drug: Lumasiran

Registration Number: NCT02706886

Lead Sponsor: Alnylam Pharmaceuticals

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 52

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Part B: MAD: Placebo	Placebo	Participants with primary hyperoxaluria type 1 (PH1) will be treated with placebo matching one of the lumasiran dosages in the lumasiran arms (one placebo participant for each lumasiran arm). At Day 85 these placebo treated participants will cross over to their respective Part B lumasiran arms in the Part B: MAD Study Day 85-End of Study Period and will then be treated with lumasiran. The estimated total time on study was up to 546 days.
Part A: SAD: Lumasiran 3.0 mg/kg	Lumasiran	A single dose of 3.0 mg/kg lumasiran will be administered SC.
Part A: SAD: Lumasiran 6.0 mg/kg	Lumasiran	A single dose of 6.0 mg/kg lumasiran will be administered SC.
Part B: MAD: Lumasiran 1.0 mg/kg qM	Lumasiran	Participants with PH1 will be treated with 1.0 mg/kg lumasiran SC once monthly (qM) on Days 1, 29 and 57. The estimated total time on study is up to 546 days. One participant from the Part B: MAD: Placebo arm will cross over to this lumasiran arm at Day 85. For this participant treatment with lumasiran starts at Day 85.
Part A: SAD: Placebo	Placebo	A single dose of matching placebo will be administered subcutaneously (SC).
Part A: SAD: Lumasiran 0.3 mg/kg	Lumasiran	A single dose of 0.3 mg/kg lumasiran will be administered SC.
Part A: SAD: Lumasiran 1.0 mg/kg	Lumasiran	A single dose of 1.0 mg/kg lumasiran will be administered SC.
Part B: MAD: Lumasiran 3.0 mg/kg qM	Lumasiran	Participants with PH1 will be treated with 3.0 mg/kg lumasiran SC qM on Days 1, 29 and 57. The estimated total time on study is up to 546 days. One participant from the Part B: MAD: Placebo arm will cross over to this lumasiran arm at Day 85. For this participant treatment with lumasiran starts at Day 85.
Part B: MAD: Lumasiran 3.0 mg/kg q3M	Lumasiran	Participants with PH1 will be treated with 3.0 mg/kg lumasiran SC once every three months (q3M) on Days 1 and 85. The estimated total time on study is up to 546 days. One participant from the Part B: MAD: Placebo arm will cross over to this lumasiran arm at Day 85. For this participant treatment with lumasiran starts at Day 85.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Adverse Events (AEs)	Part A (SAD): Up to 405 days; Part B (MAD): Up to 546 days	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.

Secondary Outcome Measures

Name	Time	Method
Maximum Concentration (Cmax) of Lumasiran in Plasma	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	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 to Cmax (Tmax) of Lumasiran in Plasma	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	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.
Area Under the Concentration-Time Curve From Time 0 to Time of Last Measurable Concentration (AUC0-last) of Lumasiran in Plasma	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	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.
Terminal Half-life (t1/2) of Lumasiran in Plasma	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	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.
Fraction Excreted in Urine in 24 Hours (Fe0-24) of Lumasiran	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	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.
Renal Clearance (CLR) of Lumasiran	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	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.
Baseline Plasma Glycolate Concentration	Part A (SAD): Baseline, Part B (MAD): Baseline	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.
Percentage Change From Baseline in Plasma Glycolate Concentration	Part A (SAD): Days 15, 29, 57 and 85; Part B (MAD): Days 15, 29, 57, 85	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.
Baseline Spot Urine Glycolate:Creatinine Ratio in Part A	Part A (SAD): Baseline	The endpoint was only measured in Part A.
Percentage Change From Baseline in Spot Urine Glycolate:Creatinine Ratio in Part A	Part A (SAD): Days 29 and 57	The endpoint was only measured in Part A.
Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B	Part B (MAD): Baseline	The endpoint was only measured in Part B.
Percentage Change From Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B	Part B (MAD): 24 hour urine collections on Days 29, 57, 85, 113, 141, 169, 197	The endpoint was only measured in Part B.
Baseline 24 Hour Urine Glycolate:Creatinine Ratio in Part B - Initial 85 Days	Part B (MAD): Baseline	The endpoint was only measured during the initial 85 days in Part B.
Percentage Change From Baseline of 24 Hour Urine Glycolate:Creatinine Ratio in Part B - Initial 85 Days	Part B (MAD): 24 hour urine collections on Days 29, 57 and 85	The endpoint was only measured during the initial 85 days in Part B.
Baseline Creatinine Clearance Corrected for BSA in Part B	Part B (MAD): Baseline
Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B	Part B (MAD): Days 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337, 365, 393, 421, 449