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

• ClinicalTrials.gov Identifier: NCT02706886
• Recruitment Status: Completed
• First Posted: March 11, 2016
• Results First Posted: January 30, 2020
• Last Update Posted: January 30, 2020
• Sponsor: Alnylam Pharmaceuticals
• Information provided by (Responsible Party): Alnylam Pharmaceuticals

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Primary Hyperoxaluria Type 1 (PH1)	Drug: Lumasiran; Drug: Placebo	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 52 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Participant)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: March 8, 2016
• Actual Primary Completion Date: January 23, 2019
• Actual Study Completion Date: January 23, 2019

Arms and Interventions

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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: ALN-GO1

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Adverse Events (AEs) [ Time Frame: 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 :

1. Maximum Concentration (Cmax) of Lumasiran in Plasma [ 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 ]
   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.
2. Time to Cmax (Tmax) of Lumasiran in Plasma [ 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 ]
   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.
3. Area Under the Concentration-Time Curve From Time 0 to Time of Last Measurable Concentration (AUC0-last) of Lumasiran in Plasma [ 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 ]
   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.
4. Terminal Half-life (t1/2) of Lumasiran in Plasma [ 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 ]
   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.
5. Fraction Excreted in Urine in 24 Hours (Fe0-24) of Lumasiran [ 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 ]
   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.
6. Renal Clearance (CLR) of Lumasiran [ 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 ]
   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.
7. Baseline Plasma Glycolate Concentration [ Time Frame: 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.
8. Percentage Change From Baseline in Plasma Glycolate Concentration [ Time Frame: 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.
9. Baseline Spot Urine Glycolate:Creatinine Ratio in Part A [ Time Frame: Part A (SAD): Baseline ]
   The endpoint was only measured in Part A.
10. Percentage Change From Baseline in Spot Urine Glycolate:Creatinine Ratio in Part A [ Time Frame: Part A (SAD): Days 29 and 57 ]
    The endpoint was only measured in Part A.
11. Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B [ Time Frame: Part B (MAD): Baseline ]
    The endpoint was only measured in Part B.
12. Percentage Change From Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B [ Time Frame: Part B (MAD): 24 hour urine collections on Days 29, 57, 85, 113, 141, 169, 197 ]
    The endpoint was only measured in Part B.
13. Baseline 24 Hour Urine Glycolate:Creatinine Ratio in Part B - Initial 85 Days [ Time Frame: Part B (MAD): Baseline ]
    The endpoint was only measured during the initial 85 days in Part B.
14. Percentage Change From Baseline of 24 Hour Urine Glycolate:Creatinine Ratio in Part B - Initial 85 Days [ Time Frame: 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.
15. Baseline Creatinine Clearance Corrected for BSA in Part B [ Time Frame: Part B (MAD): Baseline ]
16. 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 ]

Eligibility Criteria

• Ages Eligible for Study: 6 Years to 64 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

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

Contacts and Locations

Locations

France

Clinical Trial Site

Bordeaux, France

Clinical Trial Site

Lyon, France

Clinical Trial Site

Paris, France

Germany

Clinical Trial Site

Bonn, Germany

Israel

Clinical Trial Site

Haifa, Israel

Clinical Trial Site

Jerusalem, Israel

Netherlands

Clinical Trial Site

Amsterdam, Netherlands

United Kingdom

Clinical Trial Site

Birmingham, United Kingdom

Clinical Trial Site

London, United Kingdom

Sponsors and Collaborators

Alnylam Pharmaceuticals

Investigators

• Study Director: Tracy McGregor, MD, MSCI; Alnylam Pharmaceuticals

  Study Documents (Full-Text)

Documents provided by Alnylam Pharmaceuticals:

Statistical Analysis Plan  [PDF] November 1, 2017

Study Protocol  [PDF] February 14, 2018

More Information

Additional Information:

For information about the drug ALN-GO1 and Primary Hyperoxaluria Type 1 (PH1), clink this link 

• Responsible Party: Alnylam Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02706886
• Other Study ID Numbers: ALN-GO1-001; 2015-004407-23 ( EudraCT Number )
• First Posted: March 11, 2016
• Results First Posted: January 30, 2020
• Last Update Posted: January 30, 2020
• Last Verified: January 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Alnylam Pharmaceuticals:

PH1; Primary Hyperoxaluria; RNAi therapeutic; siRNA; AGT

Additional relevant MeSH terms:

Hyperoxaluria, Primary; Hyperoxaluria; Kidney Diseases; Urologic Diseases; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases