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

Primary Purpose

Primary Hyperoxaluria Type 1 (PH1)

Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Lumasiran
Placebo
Sponsored by
Alnylam Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Primary Hyperoxaluria Type 1 (PH1) focused on measuring PH1, Primary Hyperoxaluria, RNAi therapeutic, siRNA, AGT

Eligibility Criteria

6 Years - 64 Years (Child, Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

  • Clinical Trial Site
  • Clinical Trial Site
  • Clinical Trial Site
  • Clinical Trial Site
  • Clinical Trial Site
  • Clinical Trial Site
  • Clinical Trial Site
  • Clinical Trial Site
  • Clinical Trial Site

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm 8

Arm 9

Arm Type

Placebo Comparator

Experimental

Experimental

Experimental

Experimental

Placebo Comparator

Experimental

Experimental

Experimental

Arm Label

Part A: SAD: Placebo

Part A: SAD: Lumasiran 0.3 mg/kg

Part A: SAD: Lumasiran 1.0 mg/kg

Part A: SAD: Lumasiran 3.0 mg/kg

Part A: SAD: Lumasiran 6.0 mg/kg

Part B: MAD: Placebo

Part B: MAD: Lumasiran 1.0 mg/kg qM

Part B: MAD: Lumasiran 3.0 mg/kg qM

Part B: MAD: Lumasiran 3.0 mg/kg q3M

Arm Description

A single dose of matching placebo will be administered subcutaneously (SC).

A single dose of 0.3 mg/kg lumasiran will be administered SC.

A single dose of 1.0 mg/kg lumasiran will be administered SC.

A single dose of 3.0 mg/kg lumasiran will be administered SC.

A single dose of 6.0 mg/kg lumasiran will be administered SC.

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.

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.

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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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 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.
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.
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.
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.
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.
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.
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.
Baseline Spot Urine Glycolate:Creatinine Ratio in Part A
The endpoint was only measured in Part A.
Percentage Change From Baseline in Spot Urine Glycolate:Creatinine Ratio in Part A
The endpoint was only measured in Part A.
Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B
The endpoint was only measured in Part B.
Percentage Change From Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B
The endpoint was only measured in Part B.
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.
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.
Baseline Creatinine Clearance Corrected for BSA in Part B
Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B

Full Information

First Posted
March 3, 2016
Last Updated
January 22, 2020
Sponsor
Alnylam Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT02706886
Brief Title
Study of Lumasiran in Healthy Adults and Patients With Primary Hyperoxaluria Type 1
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
Study Type
Interventional

2. Study Status

Record Verification Date
January 2020
Overall Recruitment Status
Completed
Study Start Date
March 8, 2016 (Actual)
Primary Completion Date
January 23, 2019 (Actual)
Study Completion Date
January 23, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Alnylam Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Primary Hyperoxaluria Type 1 (PH1)
Keywords
PH1, Primary Hyperoxaluria, RNAi therapeutic, siRNA, AGT

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
Participant
Allocation
Randomized
Enrollment
52 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Part A: SAD: Placebo
Arm Type
Placebo Comparator
Arm Description
A single dose of matching placebo will be administered subcutaneously (SC).
Arm Title
Part A: SAD: Lumasiran 0.3 mg/kg
Arm Type
Experimental
Arm Description
A single dose of 0.3 mg/kg lumasiran will be administered SC.
Arm Title
Part A: SAD: Lumasiran 1.0 mg/kg
Arm Type
Experimental
Arm Description
A single dose of 1.0 mg/kg lumasiran will be administered SC.
Arm Title
Part A: SAD: Lumasiran 3.0 mg/kg
Arm Type
Experimental
Arm Description
A single dose of 3.0 mg/kg lumasiran will be administered SC.
Arm Title
Part A: SAD: Lumasiran 6.0 mg/kg
Arm Type
Experimental
Arm Description
A single dose of 6.0 mg/kg lumasiran will be administered SC.
Arm Title
Part B: MAD: Placebo
Arm Type
Placebo Comparator
Arm Description
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.
Arm Title
Part B: MAD: Lumasiran 1.0 mg/kg qM
Arm Type
Experimental
Arm Description
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.
Arm Title
Part B: MAD: Lumasiran 3.0 mg/kg qM
Arm Type
Experimental
Arm Description
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.
Arm Title
Part B: MAD: Lumasiran 3.0 mg/kg q3M
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Lumasiran
Other Intervention Name(s)
ALN-GO1
Intervention Description
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).
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
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).
Primary Outcome Measure Information:
Title
Number of Participants With Adverse Events (AEs)
Description
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
Secondary Outcome Measure Information:
Title
Maximum Concentration (Cmax) of Lumasiran in Plasma
Description
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
Title
Time to Cmax (Tmax) of Lumasiran in Plasma
Description
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
Title
Area Under the Concentration-Time Curve From Time 0 to Time of Last Measurable Concentration (AUC0-last) of Lumasiran in Plasma
Description
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
Title
Terminal Half-life (t1/2) of Lumasiran in Plasma
Description
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
Title
Fraction Excreted in Urine in 24 Hours (Fe0-24) of Lumasiran
Description
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
Title
Renal Clearance (CLR) of Lumasiran
Description
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
Title
Baseline Plasma Glycolate Concentration
Description
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
Title
Percentage Change From Baseline in Plasma Glycolate Concentration
Description
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
Title
Baseline Spot Urine Glycolate:Creatinine Ratio in Part A
Description
The endpoint was only measured in Part A.
Time Frame
Part A (SAD): Baseline
Title
Percentage Change From Baseline in Spot Urine Glycolate:Creatinine Ratio in Part A
Description
The endpoint was only measured in Part A.
Time Frame
Part A (SAD): Days 29 and 57
Title
Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B
Description
The endpoint was only measured in Part B.
Time Frame
Part B (MAD): Baseline
Title
Percentage Change From Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B
Description
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
Title
Baseline 24 Hour Urine Glycolate:Creatinine Ratio in Part B - Initial 85 Days
Description
The endpoint was only measured during the initial 85 days in Part B.
Time Frame
Part B (MAD): Baseline
Title
Percentage Change From Baseline of 24 Hour Urine Glycolate:Creatinine Ratio in Part B - Initial 85 Days
Description
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
Title
Baseline Creatinine Clearance Corrected for BSA in Part B
Time Frame
Part B (MAD): Baseline
Title
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
6 Years
Maximum Age & Unit of Time
64 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Tracy McGregor, MD, MSCI
Organizational Affiliation
Alnylam Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Clinical Trial Site
City
Bordeaux
Country
France
Facility Name
Clinical Trial Site
City
Lyon
Country
France
Facility Name
Clinical Trial Site
City
Paris
Country
France
Facility Name
Clinical Trial Site
City
Bonn
Country
Germany
Facility Name
Clinical Trial Site
City
Haifa
Country
Israel
Facility Name
Clinical Trial Site
City
Jerusalem
Country
Israel
Facility Name
Clinical Trial Site
City
Amsterdam
Country
Netherlands
Facility Name
Clinical Trial Site
City
Birmingham
Country
United Kingdom
Facility Name
Clinical Trial Site
City
London
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
33985991
Citation
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.
Results Reference
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Study of Lumasiran in Healthy Adults and Patients With Primary Hyperoxaluria Type 1

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