A Study to Evaluate Lumasiran in Children and Adults With Primary Hyperoxaluria Type 1

Phase 3

Completed

Conditions: Primary Hyperoxaluria Type 1 (PH1)

Interventions: Drug: Placebo
Drug: Lumasiran

Registration Number: NCT03681184

Lead Sponsor: Alnylam Pharmaceuticals

Brief Summary: The purpose of this study is to evaluate the efficacy and safety of lumasiran in children and adults with primary hyperoxaluria type 1 (PH1).

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 39

Inclusion Criteria

Willing to provide written informed consent or assent and to comply with study requirements
Confirmation of PH1 disease
Meet the 24 hour urine oxalate excretion requirements
If taking Vitamin B6 (pyridoxine), must have been on stable regimen for at least 90 days

Exclusion Criteria

Clinically significant health concerns (with the exception of PH1) or clinical evidence of extrarenal systemic oxalosis
Clinically significant abnormal laboratory results
Known active or evidence of HIV or hepatitis B or C infection
An estimated GFR of < 30 mL/min/1.73m^2 at screening
Received an investigational agent within 30 days or 5 half-lives before the first dose of study drug or are in follow-up of another clinical study
History of kidney or liver transplant
Known history of multiple drug allergies or allergic reaction to an oligonucleotide or GalNAc
History of intolerance to subcutaneous injection
Women who are pregnant, planning a pregnancy, or breast-feeding or those of child bearing potential and not willing to use contraception
History of alcohol abuse within the last 12 months, or unable or unwilling to limit alcohol consumption throughout the study

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Lumasiran/Lumasiran	Placebo	Lumasiran was administered SC, 3.0 mg/kg, at Day 1 and Months 1, 2 and 3 during the 6-Month DB Period, followed by lumasiran SC, 3.0 mg/kg at Month 6, and lumasiran-matching placebo SC at Months 7 and 8 during the 3-Month Blinded Treatment Extension Period, followed by lumasiran SC, 3.0 mg/kg, at Month 9 and then every three months during the 51-Month OLE period.
Placebo/Lumasiran	Placebo	Lumasiran-matching placebo (normal saline \[0.9% NaCl\]) was administered subcutaneously (SC) at Day 1 and Months 1, 2 and 3 during the 6-Month Double-blind (DB) Period, followed by lumasiran SC, 3.0 mg/kg, at Months 6, 7 and 8 during the 3-Month Blinded Treatment Extension Period, followed by lumasiran SC, 3.0 mg/kg, at Month 9 and then every three months during the 51-Month Open-label Extension (OLE) period.
Placebo/Lumasiran	Lumasiran	Lumasiran-matching placebo (normal saline \[0.9% NaCl\]) was administered subcutaneously (SC) at Day 1 and Months 1, 2 and 3 during the 6-Month Double-blind (DB) Period, followed by lumasiran SC, 3.0 mg/kg, at Months 6, 7 and 8 during the 3-Month Blinded Treatment Extension Period, followed by lumasiran SC, 3.0 mg/kg, at Month 9 and then every three months during the 51-Month Open-label Extension (OLE) period.
Lumasiran/Lumasiran	Lumasiran	Lumasiran was administered SC, 3.0 mg/kg, at Day 1 and Months 1, 2 and 3 during the 6-Month DB Period, followed by lumasiran SC, 3.0 mg/kg at Month 6, and lumasiran-matching placebo SC at Months 7 and 8 during the 3-Month Blinded Treatment Extension Period, followed by lumasiran SC, 3.0 mg/kg, at Month 9 and then every three months during the 51-Month OLE period.

Primary Outcome Measures

Name	Time	Method
Percent Change in 24-hour Urinary Oxalate Excretion Corrected for Body Surface Area (BSA) From Baseline to Month 6	Baseline to Month 6	Percent change in 24-hour urinary oxalate excretion corrected for BSA was estimated by an average percent change from baseline across Months 3 through 6. Only valid urine samples without any non-protocol-related issues were included in the analysis. A negative change from Baseline indicates a favorable outcome.

Secondary Outcome Measures

Name	Time	Method
Percent Change in 24-hour Urinary Oxalate:Creatinine Ratio From Baseline to Month 6	Baseline to Month 6	Percent change in 24-hour urinary oxalate:creatine ratio was estimated by an average percent change from baseline across Months 3 through 6. A negative change from Baseline indicates a favorable outcome.
Percentage Change in Plasma Oxalate From Baseline to Month 6	Baseline to Month 6	Percent change in plasma oxalate (umol/L) was estimated by an average percent change from baseline across Months 3 through 6. A negative change from Baseline indicates a favorable outcome.
Percentage Change in 24-hour Urinary Oxalate Excretion Corrected by BSA From Baseline in the Extension Period	From Baseline to Month 54 and Month 60	Percent change in 24-hour urinary oxalate excretion corrected for BSA was estimated by an average percent change from baseline in the extension periods. Only valid urine samples without any non-protocol-related issues were included in the analysis. A negative change from Baseline indicates a favorable outcome.
Absolute Change in 24-hour Urinary Oxalate Corrected for BSA From Baseline to Month 6	Baseline to Month 6	Absolute change in 24-hour urinary oxalate excretion corrected for BSA was estimated by an average absolute change from baseline across Months 3 through 6. Only valid urine samples without any non-protocol-related issues were included in the analysis. A negative change from Baseline indicates a favorable outcome.
Percentage of Participants With 24-hour Urinary Oxalate Level Corrected for BSA at or Below 1.5 x ULN at Month 6	Month 6	The upper limit of normal (ULN) = 0.514 mmol/24hr/1.73m\^2 for 24-hour urinary oxalate excretion corrected for BSA.
Percentage of Participants With 24-hour Urinary Oxalate Level Corrected for BSA at or Below ULN at Month 6	Month 6	The upper limit of normal (ULN) = 0.514 mmol/24hr/1.73m\^2 for 24-hour urinary oxalate excretion corrected for BSA.
Absolute Change in Plasma Oxalate From Baseline to Month 6	Baseline to Month 6	Absolute change in plasma oxalate (umol/L) was estimated by an average percent change from baseline across Months 3 through 6. A negative change from Baseline indicates a favorable outcome.
Change in Estimated Glomerular Filtration Rate (eGFR) From Baseline to Week 2 and Months 1, 2, 3, 4, 5 and 6	Baseline, Week 2, Months 1, 2, 3, 4, 5 and 6	eGFR is calculated from serum creatinine based on the Modification of Diet in Renal Disease formula for patients ≥18 years of age and the Schwartz Bedside Formula for patients \>1 year to \<18 years of age at screening. Change from baseline to Month 6 is reported.
Absolute Change in 24-hour Urinary Oxalate Excretion Corrected for BSA From Baseline in the Extension Period	From Baseline to Month 54 and Month 60	Absolute change in 24-hour urinary oxalate excretion corrected for BSA was estimated by an average absolute change from baseline in the extension periods. Only valid urine samples without any non-protocol-related issues were included in the analysis. A negative change from Baseline indicates a favorable outcome.
Percentage of Time That 24-hour Urinary Oxalate is at or Below 1.5 × ULN During Lumasiran Treatment	Up to Month 60	The upper limit of normal (ULN) = 0.514 mmol/24hr/1.73m\^2 for 24-hour urinary oxalate excretion corrected for BSA.
Absolute Change in 24-hour Urinary Oxalate:Creatinine Ratio From Baseline in the Extension Period	From Baseline to Month 54 and Month 60	Absolute change in 24-hour urinary oxalate:creatinine ratio was estimated by an average absolute change from baseline to the end of the OLE period at Month 54 and Month 60. A negative change from Baseline indicates a favorable outcome.
Change in Estimated Glomerular Filtration Rate (eGFR) From Baseline in the Extension Period	From Baseline to Month 54 and Month 60	eGFR is calculated from serum creatinine based on the Modification of Diet in Renal Disease formula for patients ≥18 years of age and the Schwartz Bedside Formula for patients \>1 year to \<18 years of age at screening.
Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)	DB Period (Placebo): From first dose of study drug (Day 1) up to Month 6; Placebo/Lumasiran: From first dose of lumasiran (Month 6) up to end of study (Month 60); Lumasiran/Lumasiran: From first dose of lumasiran (Day 1) up to end of study (Month 60).	An AE is any untoward medical occurrence in a clinical investigational participant administered a medicinal product \& which does not necessarily have a causal relationship with this treatment. SAE is any untoward medical occurrence that at any dose results in death, is life-threatening, requires in-patient hospitalization/prolongation of existing hospitalization, results in persistent/significant disability or incapacity, is a congenital anomaly or birth defect, is an important medical event that may not be immediately life-threatening/result in death/hospitalization but may jeopardize the participant \& may require intervention to prevent one of the other outcomes listed above. All Lumasiran Treated Set: All participants who received any amount of lumasiran including participants who took lumasiran during 6-month double-blinded period \& participants who initially took placebo during the 6-month double-blinded period and then switched to lumasiran during the extension period.