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

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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:
Information provided by (Responsible Party):
Alnylam Pharmaceuticals

Tracking Information
First Submitted Date  ICMJE March 3, 2016
First Posted Date  ICMJE March 11, 2016
Results First Submitted Date  ICMJE January 22, 2020
Results First Posted Date  ICMJE January 30, 2020
Last Update Posted Date January 30, 2020
Actual Study Start Date  ICMJE March 8, 2016
Actual Primary Completion Date January 23, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 22, 2020)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: March 8, 2016)
The safety of ALN-GO1 evaluated by the proportion of subjects experiencing adverse events (AEs) [ Time Frame: Part A (SAD phase): Up to 181 days; Part B (MAD phase): Up to 321 days ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 22, 2020)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Baseline Spot Urine Glycolate:Creatinine Ratio in Part A [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ 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.
  • 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.
  • 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.
  • 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 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: March 8, 2016)
  • Profile of pharmacokinetics (PK) of ALN-GO1 [ Time Frame: Part A (SAD phase): Up to 2 days; Part B (MAD phase): Up to 141 days ]
    Cmax
  • Profile of pharmacokinetics (PK) of ALN-GO1 [ Time Frame: Part A (SAD phase): Up to 2 days; Part B (MAD phase): Up to 141 days ]
    tmax
  • Profile of pharmacokinetics (PK) of ALN-GO1 [ Time Frame: Part A (SAD phase): Up to 2 days; Part B (MAD phase): Up to 141 days ]
    AUC
  • Profile of pharmacokinetics (PK) of ALN-GO1 [ Time Frame: Part A (SAD phase): Up to 2 days; Part B (MAD phase): Up to 141 days ]
  • The effect of ALN-GO1 on plasma glycolate concentration [ Time Frame: Part A (SAD phase): Up to 181 days; Part B (MAD phase): Up to 321 days ]
  • The effect of ALN-GO1 on urinary glycolate excretion [ Time Frame: Part B (MAD phase): Up to 321 days ]
  • The effect of ALN-GO1 on urinary oxalate excretion [ Time Frame: Part B (MAD phase): Up to 321 days ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of Lumasiran in Healthy Adults and Patients With Primary Hyperoxaluria Type 1
Official Title  ICMJE 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
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 Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
Condition  ICMJE Primary Hyperoxaluria Type 1 (PH1)
Intervention  ICMJE
  • 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
  • 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).
Study Arms  ICMJE
  • Placebo Comparator: Part A: SAD: Placebo
    A single dose of matching placebo will be administered subcutaneously (SC).
    Intervention: Drug: Placebo
  • Experimental: Part A: SAD: Lumasiran 0.3 mg/kg
    A single dose of 0.3 mg/kg lumasiran will be administered SC.
    Intervention: Drug: Lumasiran
  • Experimental: Part A: SAD: Lumasiran 1.0 mg/kg
    A single dose of 1.0 mg/kg lumasiran will be administered SC.
    Intervention: Drug: Lumasiran
  • Experimental: Part A: SAD: Lumasiran 3.0 mg/kg
    A single dose of 3.0 mg/kg lumasiran will be administered SC.
    Intervention: Drug: Lumasiran
  • Experimental: Part A: SAD: Lumasiran 6.0 mg/kg
    A single dose of 6.0 mg/kg lumasiran will be administered SC.
    Intervention: Drug: Lumasiran
  • 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.
    Intervention: Drug: Placebo
  • 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.
    Intervention: Drug: Lumasiran
  • 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.
    Intervention: Drug: Lumasiran
  • 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.
    Intervention: Drug: Lumasiran
Publications * Frishberg Y, Deschênes 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 10, 2018)
52
Original Estimated Enrollment  ICMJE
 (submitted: March 8, 2016)
60
Actual Study Completion Date  ICMJE January 23, 2019
Actual Primary Completion Date January 23, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 6 Years to 64 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE France,   Germany,   Israel,   Netherlands,   United Kingdom
Removed Location Countries Jordan,   United States
 
Administrative Information
NCT Number  ICMJE NCT02706886
Other Study ID Numbers  ICMJE ALN-GO1-001
2015-004407-23 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Alnylam Pharmaceuticals
Study Sponsor  ICMJE Alnylam Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Tracy McGregor, MD, MSCI Alnylam Pharmaceuticals
PRS Account Alnylam Pharmaceuticals
Verification Date January 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP