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

A Phase 1/2, Single-Blind, Placebo-Controlled, Single and Multiple Ascending Dose Safety, Tolerability, Pharmacokinetic and Pharmacodynamics Study of Subcutaneously Administered ALN-GO1 in Healthy Adult Subjects, and Patients With Primary Hyperoxaluria Type 1

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 Overview

• Status: Completed
• Conditions: Primary Hyperoxaluria Type 1 (PH1)
• Intervention / Treatment: Drug: Placebo; Drug: Lumasiran

• Study Type: Interventional
• Enrollment (Actual): 52
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• France
  • Bordeaux, France
    • Clinical Trial Site
  • Lyon, France
    • Clinical Trial Site
  • Paris, France
    • Clinical Trial Site
• Germany
  • Bonn, Germany
    • Clinical Trial Site
• Israel
  • Haifa, Israel
    • Clinical Trial Site
  • Jerusalem, Israel
    • Clinical Trial Site
• Netherlands
  • Amsterdam, Netherlands
    • Clinical Trial Site
• United Kingdom
  • Birmingham, United Kingdom
    • Clinical Trial Site
  • London, United Kingdom
    • Clinical Trial Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 years to 62 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria for Parts A and B:

• Women of child bearing potential must have a negative pregnancy test, cannot be breastfeeding, and must be willing to use contraception.
• Willing to provide written informed consent and to comply with study requirements.

Additional Inclusion Criteria for Part B:

• Confirmation of PH1 disease
• Meet 24 hour urine oxalate excretion requirements
• Estimated glomerular filtration rate (GFR) of >45 mL/min/1.73m^2
• If taking Vitamin B6 (pyridoxine), must have been on stable regimen for at least 90 days

Exclusion Criteria for Parts A and B:

• Clinically significant health concerns (with the exception of PH1 for patients in Part B)
• Clinically significant electrocardiogram (ECG) abnormalities
• Abnormal for aspartate aminotransferase (AST)/alanine aminotransferase (ALT) and any other clinical safety laboratory result considered clinically significant
• Received an investigational agent within 3 months before the first dose of study drug or are in follow-up of another clinical study
• Known history of allergic reaction to an oligonucleotide or N-acetylgalactosamine (GalNAc)
• History of intolerance to subcutaneous injection

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

9

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Part A: SAD: Placebo; A single dose of matching placebo will be administered subcutaneously (SC).	Drug: Placebo; 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).
Experimental: Part A: SAD: Lumasiran 0.3 mg/kg; A single dose of 0.3 mg/kg lumasiran will be administered SC.	Drug: Lumasiran; 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).; Other Names: ALN-GO1
Experimental: Part A: SAD: Lumasiran 1.0 mg/kg; A single dose of 1.0 mg/kg lumasiran will be administered SC.	Drug: Lumasiran; 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).; Other Names: ALN-GO1
Experimental: Part A: SAD: Lumasiran 3.0 mg/kg; A single dose of 3.0 mg/kg lumasiran will be administered SC.	Drug: Lumasiran; 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).; Other Names: ALN-GO1
Experimental: Part A: SAD: Lumasiran 6.0 mg/kg; A single dose of 6.0 mg/kg lumasiran will be administered SC.	Drug: Lumasiran; 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).; Other Names: ALN-GO1
Placebo Comparator: Part B: MAD: 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.	Drug: Placebo; 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).
Experimental: Part B: MAD: Lumasiran 1.0 mg/kg qM; 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.	Drug: Lumasiran; 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).; Other Names: ALN-GO1
Experimental: Part B: MAD: Lumasiran 3.0 mg/kg qM; 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.	Drug: Lumasiran; 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).; Other Names: ALN-GO1
Experimental: Part B: MAD: Lumasiran 3.0 mg/kg q3M; 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.	Drug: Lumasiran; 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).; Other Names: ALN-GO1

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Part A (SAD): Up to 405 days; Part B (MAD): Up to 546 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	Part B (MAD): 24 hour urine collections on Days 29, 57 and 85
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

Collaborators and Investigators

• Sponsor: Alnylam Pharmaceuticals
• Investigators: Study Director: Tracy McGregor, MD, MSCI, Alnylam Pharmaceuticals

Publications and helpful links

General Publications

• Frishberg Y, Deschenes G, Groothoff JW, Hulton SA, Magen D, Harambat J, Van't Hoff WG, Lorch U, Milliner DS, Lieske JC, Haslett P, Garg PP, Vaishnaw AK, Talamudupula S, Lu J, Habtemariam BA, Erbe DV, McGregor TL, Cochat P; study collaborators. Phase 1/2 Study of Lumasiran for Treatment of Primary Hyperoxaluria Type 1: A Placebo-Controlled Randomized Clinical Trial. Clin J Am Soc Nephrol. 2021 Jul;16(7):1025-1036. doi: 10.2215/CJN.14730920. Epub 2021 May 13.

Study record dates

Study Major Dates

• Study Start (Actual): March 8, 2016
• Primary Completion (Actual): January 23, 2019
• Study Completion (Actual): January 23, 2019

Study Registration Dates

• First Submitted: March 3, 2016
• First Submitted That Met QC Criteria: March 8, 2016
• First Posted (Estimate): March 11, 2016

Study Record Updates

• Last Update Posted (Actual): January 30, 2020
• Last Update Submitted That Met QC Criteria: January 22, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Keywords: RNAi therapeutic; siRNA; PH1; Primary Hyperoxaluria; AGT
• Additional Relevant MeSH Terms: Metabolic Diseases; Kidney Diseases; Urologic Diseases; Genetic Diseases, Inborn; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Hyperoxaluria; Hyperoxaluria, Primary; Renal Agents; Lumasiran
• Other Study ID Numbers: ALN-GO1-001; 2015-004407-23 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No