A Study to Evaluate Lumasiran in Patients With Advanced Primary Hyperoxaluria Type 1

Phase 3

Active, not recruiting

Conditions: Primary Hyperoxaluria
Primary Hyperoxaluria Type 1

Interventions: Drug: Lumasiran

Registration Number: NCT04152200

Lead Sponsor: Alnylam Pharmaceuticals

Brief Summary: The purpose of this study is to evaluate the efficacy, safety, pharmacokinetics (PK), and pharmacodynamics (PD) of lumasiran in patients with Advanced Primary Hyperoxaluria Type 1 (PH1).

Detailed Description: Not available

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 21

Inclusion Criteria

Has documented diagnosis of primary hyperoxaluria type 1 (PH1)
Estimated glomerular filtration rate (eGFR) ≤45 mL/min/1.73 m^2 for patients ≥12 months of age (<12 months of age, must have serum creatinine considered elevated for age)
Meets plasma oxalate level requirements
If taking Vitamin B6 (pyridoxine), must have been on stable regimen for at least 90 days
If on dialysis, may be on hemodialysis therapy only and must have been on a stable regimen for at least 4 weeks

Exclusion Criteria

Hemodialysis/peritoneal dialysis combination therapy or peritoneal dialysis alone
Diagnosis of conditions other than PH1 contributing to renal insufficiency
History of liver transplant
History of kidney transplant and currently receiving immunosuppressants

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Lumasiran	Lumasiran	All patients will receive open-label lumasiran.

Primary Outcome Measures

Name	Time	Method
Cohort A: Percent 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. For Cohort A, the baseline was defined as the mean of all plasma oxalate level values collected prior to the first dose of lumasiran.
Cohort B: Percent Change in Pre-dialysis 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. For Cohort B, the baseline is defined as the mean of the last four pre-dialysis plasma oxalate samples collected prior to the first dose of lumasiran. In Cohort B, only pre-dialysis samples are utilized.

Secondary Outcome Measures

Name	Time	Method
Change in Quality of Life As Assessed by Pediatric Quality of Life Inventory (PedsQL) Total Score From Baseline to Month 6 in Patients >=2 to 18 Years of Age at Time of Informed Consent	Baseline to Month 6	Peds-QL is a modular approach to measuring quality of life (QOL) in healthy children and adolescents and those with acute and chronic health conditions. The PedsQL Generic Core Scales contain 23 items designed to measure core domains of health (physical, emotional, and social functioning) and role (school functioning). Scores are summarized as Total Scale Score, Physical Health Summary Score, and Psychosocial Health Summary Score. The Total Scale Score will be reported for this study. The PedsQL will be completed by patients (or caregivers, as appropriate) who are ≥2 to \<18 years of age at the time of consent. Total score range: 0 - 100, with higher scores indicating better health-related quality of life (HRQoL). Baseline is defined as last non-missing value collected prior to the first dose of lumasiran.
Cohort A: 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. Baseline is defined as the mean of all assessments prior to the first dose date/time of lumasiran.
Apparent Clearance (CL/F) of Lumasiran	Day 1; Month 6	CL/F is the rate at which lumasiran is eliminated from the body.
Maximum Plasma Concentration (Cmax) of Lumasiran	Day 1; Month 6	Cmax is the highest concentration of lumasiran in the plasma after a dose is given.
Percent Change in Plasma Oxalate Area Under the Curve From 0-24 Hours [AUC(0-24)] Between Dialysis Sessions From Baseline to Month 60	Baseline to Month 60
Percent Change in 24-hour Urinary Oxalate Excretion Corrected for Body Surface Area (BSA) From Baseline to Month 60	Baseline to Month 60
Absolute Change in Plasma Oxalate From Baseline to Month 6	Baseline to Month 6	Absolute change in plasma oxalate was estimated by an average absolute change from baseline across Months 3 through 6. A negative change from Baseline indicates a favorable outcome. For Cohort A, the baseline was defined as the mean of all plasma oxalate level values collected prior to the first dose of lumasiran; for Cohort B, the baseline was defined as the mean of the last 4 pre-dialysis plasma oxalate level values collected prior to the first dose of lumasiran. In Cohort B patients, the plasma oxalate baseline was similarly defined except that the values obtained from the plasma oxalate profile assessment visits only included the pre-dialysis sample collected per visit.
Cohort A: Absolute Change in 24-hour Urinary Oxalate Excretion Corrected for Body Surface Area (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. Baseline is defined as the median of all valid 24-hr urine assessments collected prior to the first dose date/time of lumasiran without any non-protocol-related sample issues.
Cohort A: Percent Change in Spot Urinary Oxalate:Creatinine Ratio From Baseline to Month 6	Baseline to Month 6	Percent change in spot urinary oxalate:creatinine ratio was estimated by an average percent change from baseline across Months 3 through 6. A negative change from Baseline indicates a favorable outcome. Baseline was defined as the mean of all assessments prior to the first dose date/time of lumasiran.
Absolute Change in Plasma Oxalate From Baseline to Month 60	Baseline to Month 60
Change in Quality of Life As Assessed by Pediatric Quality of Life Inventory (PedsQL) Total Score From Baseline to Month 60 in Patients >=2 to 18 Years of Age at Time of Informed Consent	Baseline to Month 60	Peds-QL is a modular approach to measuring quality of life (QOL) in healthy children and adolescents and those with acute and chronic health conditions. The PedsQL Generic Core Scales contain 23 items designed to measure core domains of health (physical, emotional, and social functioning) and role (school functioning). Scores are summarized as Total Scale Score, Physical Health Summary Score, and Psychosocial Health Summary Score. The Total Scale Score will be reported for this study. The PedsQL will be completed by patients (or caregivers, as appropriate) who are ≥2 to \<18 years of age at the time of consent. Total score range: 0 - 100, with higher scores indicating better health-related quality of life (HRQoL). Baseline is defined as last non-missing value collected prior to the first dose of lumasiran.
Cohort B: Percent Change in Plasma Oxalate Area Under the Curve From 0-24 Hours [AUC(0-24)] Between Dialysis Sessions From Baseline to Month 6	Baseline to Month 6	Percent change in plasma oxalate AUC(0-24) was estimated by an average percent change from baseline across Months 3 through 6. A negative change from Baseline indicates a favorable outcome. Baseline was defined as the mean value of all valid AUC (μmol/L/24h) profiles being computed prior to the first dose of lumasiran.
Cohort A: Absolute Change in Spot Urinary Oxalate:Creatinine Ratio From Baseline to Month 6	Baseline to Month 6	Absolute change in spot urinary oxalate:creatinine ratio was estimated by an average absolute change from baseline across Months 3 through 6. A negative change from Baseline indicates a favorable outcome. Baseline was defined as the mean of all assessments prior to the first dose date/time of lumasiran.
Change in Quality of Life As Assessed by Kidney Disease and Quality of Life (KDQOL) Scores From Baseline to Month 6 in Patients ≥18 Years of Age at Time of Informed Consent	Baseline to Month 6	The KDQOL questionnaire is used to assess 3 core domains of kidney disease including: burden, symptoms/problems, and effects of kidney disease on daily life. The KDQOL subscales (Burden of Kidney Disease, Effect of Kidney Disease on Daily Life, and Symptoms and Problems of Kidney Disease), and the accompanying Short Form-12 (SF-12) Physical Component Summary and Mental Component Summary will be assessed for this study. These will be completed by patients who are ≥18 years of age at the time of consent. Score range (per domain): 0 - 100; higher scores indicate better HRQoL. Baseline is defined as last non-missing value collected prior to the first dose of lumasiran.
Time to Maximum Plasma Concentration (Tmax) of Lumasiran	Day 1; Month 6	Tmax is the time it takes for lumasiran to reach the maximum concentration (Cmax) after administration.
Elimination Half-life (t½β) of Lumasiran	Day 1; Month 6	t½β is the time it takes for the concentration of the drug in the plasma to be reduced by 50%.
Area Under the Concentration-time Curve From 0 to 24 Hours [AUC(0-24)] for Lumasiran	Day 1; Month 6	AUC(0-24) is the area under the plasma concentration-time curve over the last 24-h dosing interval.
Apparent Volume of Distribution (V/F) of Lumasiran	Day 1; Month 6	V/F is the propensity of lumasiran to either remain in the plasma or redistribute to other tissues.
Percent Change in Spot Urinary Oxalate:Creatinine Ratio From Baseline to Month 60	Baseline to Month 60
Change in Frequency of Dialysis From Baseline to End of Study	Baseline to Month 60
Absolute Change in Spot Urinary Oxalate:Creatinine Ratio From Baseline to Month 60	Baseline to Month 60
Change in Nephrocalcinosis From Baseline to End of Study	Baseline to Month 60	Nephrocalcinosis will be assessed by renal ultrasound.
Change in Mode of Dialysis From Baseline to End of Study	Baseline to Month 60	Modes of dialysis are defined as hemodialysis and peritoneal dialysis.
Change in Frequency of Renal Stone Events From Baseline to End of Study	Baseline to Month 60
Change in Measures of Systemic Oxalosis From Baseline to End of Study	Baseline to Month 60	Systemic oxalosis will be assessed in cardiac, skeletal, ophthalmologic, and dermatologic systems.
Absolute Change in 24-hour Urinary Oxalate Excretion Corrected for Body Surface Area (BSA) From Baseline to Month 60	Baseline to Month 60
Change in Renal Function Assessed by Estimated Glomerular Filtration Rate (eGFR) From Baseline to End of Study	Baseline to Month 60
Change in Quality of Life As Assessed by Kidney Disease and Quality of Life (KDQOL) Scores From Baseline to Month 60 in Patients ≥18 Years of Age at Time of Informed Consent	Baseline to Month 60	The KDQOL questionnaire is used to assess 3 core domains of kidney disease including: burden, symptoms/problems, and effects of kidney disease on daily life. The KDQOL subscales (Burden of Kidney Disease, Effect of Kidney Disease on Daily Life, and Symptoms and Problems of Kidney Disease), and the accompanying Short Form-12 (SF-12) Physical Component Summary and Mental Component Summary will be assessed for this study. These will be completed by patients who are ≥18 years of age at the time of consent. Score range (per domain): 0 - 100; higher scores indicate better HRQoL. Baseline is defined as last non-missing value collected prior to the first dose of lumasiran.
Percent Change in Plasma Oxalate From Baseline to End of Study	Baseline to Month 60