Clinical trial NCT02706886: 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
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Primary Hyperoxaluria Type 1 (PH1)
Keywords: PH1
Primary Hyperoxaluria
RNAi therapeutic
siRNA
AGT
Lead sponsor: Alnylam Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2016-03-11
Enrollment: 52
Sex: ALL
Minimum age (years): 6
Maximum age (years): 64
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Number of Participants With Adverse Events (AEs)
timeFrame: Part A (SAD): Up to 405 days; Part B (MAD): Up to 546 days
Secondary outcomes:
measure: Maximum Concentration (Cmax) of Lumasiran in Plasma
timeFrame: 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
measure: Time to Cmax (Tmax) of Lumasiran in Plasma
timeFrame: 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
measure: Area Under the Concentration-Time Curve From Time 0 to Time of Last Measurable Concentration (AUC0-last) of Lumasiran in Plasma
timeFrame: 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
measure: Terminal Half-life (t1/2) of Lumasiran in Plasma
timeFrame: 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
measure: Fraction Excreted in Urine in 24 Hours (Fe0-24) of Lumasiran
timeFrame: 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
measure: Renal Clearance (CLR) of Lumasiran
timeFrame: 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
measure: Baseline Plasma Glycolate Concentration
timeFrame: Part A (SAD): Baseline, Part B (MAD): Baseline
measure: Percentage Change From Baseline in Plasma Glycolate Concentration
timeFrame: Part A (SAD): Days 15, 29, 57 and 85; Part B (MAD): Days 15, 29, 57, 85
measure: Baseline Spot Urine Glycolate:Creatinine Ratio in Part A
timeFrame: Part A (SAD): Baseline
measure: Percentage Change From Baseline in Spot Urine Glycolate:Creatinine Ratio in Part A
timeFrame: Part A (SAD): Days 29 and 57
measure: Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B
timeFrame: Part B (MAD): Baseline
measure: Percentage Change From Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B
timeFrame: Part B (MAD): 24 hour urine collections on Days 29, 57, 85, 113, 141, 169, 197
measure: Baseline 24 Hour Urine Glycolate:Creatinine Ratio in Part B - Initial 85 Days
timeFrame: Part B (MAD): Baseline
measure: Percentage Change From Baseline of 24 Hour Urine Glycolate:Creatinine Ratio in Part B - Initial 85 Days
timeFrame: Part B (MAD): 24 hour urine collections on Days 29, 57 and 85
measure: Baseline Creatinine Clearance Corrected for BSA in Part B
timeFrame: Part B (MAD): Baseline
measure: Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B
timeFrame: Part B (MAD): Days 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337, 365, 393, 421, 449
Other outcomes:
Locations:
city: Bordeaux
country: France
facility: Clinical Trial Site
city: Lyon
country: France
facility: Clinical Trial Site
city: Paris
country: France
facility: Clinical Trial Site
city: Bonn
country: Germany
facility: Clinical Trial Site
city: Haifa
country: Israel
facility: Clinical Trial Site
city: Jerusalem
country: Israel
facility: Clinical Trial Site
city: Amsterdam
country: Netherlands
facility: Clinical Trial Site
city: Birmingham
country: United Kingdom
facility: Clinical Trial Site
city: London
country: United Kingdom
facility: Clinical Trial Site
Study officials:
affiliation: Alnylam Pharmaceuticals
name: Tracy McGregor, MD, MSCI
role: STUDY_DIRECTOR
References:
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.