Primary Hyperoxaluria Type 1, Primary Hyperoxaluria
Conditions
Keywords
PH1, Primary Hyperoxaluria, Hyperoxaluria, RNAi Therapeutic, siRNA, AGT, Systemic Oxalosis
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).
Interventions
DRUGLumasiran
Lumasiran will be administered by subcutaneous (SC) injection.
Sponsors
Alnylam Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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 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 | — |
| 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. |
| Absolute Change in 24-hour Urinary Oxalate Excretion Corrected for Body Surface Area (BSA) 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 Spot Urinary Oxalate:Creatinine Ratio From Baseline to Month 60 | Baseline to Month 60 | — |
| Percent Change in Spot Urinary Oxalate:Creatinine Ratio 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. |
| 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. |
| 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 | — |
| Change in Nephrocalcinosis From Baseline to End of Study | Baseline to Month 60 | Nephrocalcinosis will be assessed by renal ultrasound. |
| Change in Frequency of Dialysis From Baseline to End of Study | Baseline to Month 60 | — |
| 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 Renal Function Assessed by Estimated Glomerular Filtration Rate (eGFR) From Baseline to End of Study | Baseline to Month 60 | — |
| Absolute Change in Plasma Oxalate From Baseline to Month 60 | Baseline to Month 60 | — |
| Apparent Clearance (CL/F) of Lumasiran | Day 1; Month 6 | CL/F is the rate at which lumasiran is eliminated from the body. |
Countries
Australia, Belgium, France, Israel, Italy, Jordan, Lebanon, Netherlands, Turkey (Türkiye), United Arab Emirates, United States
Participant flow
Recruitment details
Patients with advanced primary hyperoxaluria type 1 (PH1) were enrolled at thirteen sites in Australia, Belgium, France, Israel, Jordan, Lebanon, the Netherlands, Turkey, the United Arab Emirates and the United States.
Participants by arm
| Arm | Count |
|---|---|
| Cohort A: Lumasiran Patients not on dialysis received open-label lumasiran based on weight. Patients weighing \<10 kg received loading doses of lumasiran subcutaneous (SC) injection 6.0 mg/kg monthly for 3 months, followed by maintenance doses of lumasiran SC injection 3.0 mg/kg monthly during the 6-month primary analysis period and monthly during the 54-month extension period. Patients in maintenance dosing who transitioned from \<10 kg to ≥10 kg continued to receive monthly doses at 3.0 mg/kg until the next visit that coincided with a dose for patients weighing ≥10 kg. Thereafter, patients followed every-3-months dosing until the end of the study. Patients weighing ≥10 to \<20 kg received loading doses of lumasiran SC injection 6.0 mg/kg monthly for 3 months, followed by maintenance doses of lumasiran SC injection 6.0 mg/kg at Months 3 and 6 in the 6-month primary analysis period and every three months during the 54-month extension period. Patients weighing ≥20 kg received loading doses of lumasiran SC injection 3.0 mg/kg monthly for 3 months, followed by maintenance doses of lumasiran SC injection 3.0 mg/kg at Months 3 and 6 in the 6-month primary analysis period and every three months during the 54-month extension period. Patients with weight increases crossing the threshold for the next weight-based dosing category (\<10 kg to ≥10 kg or \<20 kg to ≥20 kg) followed the new dosing regimen for the remainder of the study or until the next dosing category threshold was reached. | 6 |
| Cohort B: Lumasiran Patients on dialysis received open-label lumasiran based on weight. Patients weighing \<10 kg received loading doses of lumasiran subcutaneous (SC) injection 6.0 mg/kg monthly for 3 months, followed by maintenance doses of lumasiran SC injection 3.0 mg/kg monthly during the 6-month primary analysis period and monthly during the 54-month extension period. Patients in maintenance dosing who transitioned from \<10 kg to ≥10 kg continued to receive monthly doses at 3.0 mg/kg until the next visit that coincided with a dose for patients weighing ≥10 kg. Thereafter, patients followed every-3-months dosing until the end of the study. Patients weighing ≥10 to \<20 kg received loading doses of lumasiran SC injection 6.0 mg/kg monthly for 3 months, followed by maintenance doses of lumasiran SC injection 6.0 mg/kg at Months 3 and 6 in the 6-month primary analysis period and every three months during the 54-month extension period. Patients weighing ≥20 kg received loading doses of lumasiran SC injection 3.0 mg/kg monthly for 3 months, followed by maintenance doses of lumasiran SC injection 3.0 mg/kg at Months 3 and 6 in the 6-month primary analysis period and every three months during the 54-month extension period. Patients with weight increases crossing the threshold for the next weight-based dosing category (\<10 kg to ≥10 kg or \<20 kg to ≥20 kg) followed the new dosing regimen for the remainder of the study or until the next dosing category threshold was reached. | 15 |
| Total | 21 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Long-term Extension Period | Entered Long-term Extension Period after completion of the Primary Analysis Period | 6 | 15 |
Baseline characteristics
| Characteristic | Cohort A: Lumasiran | Cohort B: Lumasiran | Total |
|---|---|---|---|
| Age, Continuous | 9.0 years | 6.0 years | 8.0 years |
| Plasma Oxalate | 64.73 μmol/L STANDARD_DEVIATION 41.3 | 108.35 μmol/L STANDARD_DEVIATION 29.53 | 95.89 μmol/L STANDARD_DEVIATION 38.01 |
| Race/Ethnicity, Customized Asian | 1 Participants | 3 Participants | 4 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 6 Participants | 14 Participants | 20 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 4 Participants | 12 Participants | 16 Participants |
| Sex: Female, Male Female | 3 Participants | 6 Participants | 9 Participants |
| Sex: Female, Male Male | 3 Participants | 9 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 15 |
| other Total, other adverse events | 5 / 6 | 13 / 15 |
| serious Total, serious adverse events | 1 / 6 | 8 / 15 |
Outcome results
Primary
Cohort A: Percent Change in Plasma Oxalate From 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.
Time frame: Baseline to Month 6
Population: Full Analysis Set (FAS): All patients who received any amount of lumasiran and had at least 1 evaluable plasma oxalate value (pre-dialysis in Cohort B) at baseline and at least 1 evaluable plasma oxalate value from assessment(s) at Month 3 through Month 6.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Cohort A: Lumasiran | Cohort A: Percent Change in Plasma Oxalate From Baseline to Month 6 | -33.33 percent change | Standard Error 17.63 |
Comparison: Restricted maximum likelihood (REML) based Mixed Model Repeated Measures (MMRM) was used to test against the null hypothesis of mean change from baseline outcome being equal to 0. The model includes scheduled visits and baseline plasma oxalate (μmol/L) as fixed effects and patient as a random factor. Autoregressive (1) was used to model the within-patient variability.95% CI: [-81.82, 15.16]Mixed model repeated measures (MMRM)
Primary
Cohort B: Percent Change in Pre-dialysis Plasma Oxalate From 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.
Time frame: Baseline to Month 6
Population: FAS: All patients who received any amount of lumasiran and had at least 1 evaluable plasma oxalate value (pre-dialysis in Cohort B) at baseline and at least 1 evaluable plasma oxalate value from assessment(s) at Month 3 through Month 6.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Cohort A: Lumasiran | Cohort B: Percent Change in Pre-dialysis Plasma Oxalate From Baseline to Month 6 | -42.43 percent change | Standard Error 3.95 |
Comparison: REML based Mixed Model Repeated Measures MMRM was used to test against the null hypothesis of mean change from baseline outcome being equal to 0. The model includes scheduled visits and baseline plasma oxalate (μmol/L) as fixed effects and patient as a random factor. Autoregressive (1) was used to model the within-patient variability.95% CI: [-50.71, -34.15]MMRM
Secondary
Absolute Change in 24-hour Urinary Oxalate Excretion Corrected for Body Surface Area (BSA) From Baseline to Month 60
Time frame: Baseline to Month 60
Secondary
Absolute Change in Plasma Oxalate From 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.
Time frame: Baseline to Month 6
Population: FAS: All patients who received any amount of lumasiran and had at least 1 evaluable plasma oxalate value (pre-dialysis in Cohort B) at baseline and at least 1 evaluable plasma oxalate value from assessment(s) at Month 3 through Month 6.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Cohort A: Lumasiran | Absolute Change in Plasma Oxalate From Baseline to Month 6 | -35.28 μmol/L | Standard Error 7.4 |
| Cohort B: Lumasiran | Absolute Change in Plasma Oxalate From Baseline to Month 6 | -48.33 μmol/L | Standard Error 3.63 |
Secondary
Absolute Change in Plasma Oxalate From Baseline to Month 60
Time frame: Baseline to Month 60
Secondary
Absolute Change in Spot Urinary Oxalate:Creatinine Ratio From Baseline to Month 60
Time frame: Baseline to Month 60
Secondary
Apparent Clearance (CL/F) of Lumasiran
CL/F is the rate at which lumasiran is eliminated from the body.
Time frame: Day 1; Month 6
Population: PK Analysis Set: All patients who received any amount of lumasiran, have at least 1 postdose blood sample for PK parameters, and have evaluable PK data at the given timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A: Lumasiran | Apparent Clearance (CL/F) of Lumasiran | Day 1 | 7.8440 Liters/hour (L/h) | Geometric Coefficient of Variation 105.5 |
| Cohort A: Lumasiran | Apparent Clearance (CL/F) of Lumasiran | Month 6 | 4.8496 Liters/hour (L/h) | Geometric Coefficient of Variation 112.8 |
| Cohort B: Lumasiran | Apparent Clearance (CL/F) of Lumasiran | Day 1 | 5.1003 Liters/hour (L/h) | Geometric Coefficient of Variation 77.7 |
| Cohort B: Lumasiran | Apparent Clearance (CL/F) of Lumasiran | Month 6 | 6.8556 Liters/hour (L/h) | Geometric Coefficient of Variation 44.8 |
| All Lumasiran | Apparent Clearance (CL/F) of Lumasiran | Day 1 | 5.7356 Liters/hour (L/h) | Geometric Coefficient of Variation 82.6 |
| All Lumasiran | Apparent Clearance (CL/F) of Lumasiran | Month 6 | 5.9104 Liters/hour (L/h) | Geometric Coefficient of Variation 70.1 |
Secondary
Apparent Volume of Distribution (V/F) of Lumasiran
V/F is the propensity of lumasiran to either remain in the plasma or redistribute to other tissues.
Time frame: Day 1; Month 6
Population: PK Analysis Set: All patients who received any amount of lumasiran, have at least 1 postdose blood sample for PK parameters, and have evaluable PK data at the given timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A: Lumasiran | Apparent Volume of Distribution (V/F) of Lumasiran | Day 1 | 77.5329 Liters (L) | Geometric Coefficient of Variation 91.1 |
| Cohort A: Lumasiran | Apparent Volume of Distribution (V/F) of Lumasiran | Month 6 | 41.7081 Liters (L) | Geometric Coefficient of Variation 229.3 |
| Cohort B: Lumasiran | Apparent Volume of Distribution (V/F) of Lumasiran | Day 1 | 25.7429 Liters (L) | Geometric Coefficient of Variation 196.4 |
| Cohort B: Lumasiran | Apparent Volume of Distribution (V/F) of Lumasiran | Month 6 | 36.8305 Liters (L) | Geometric Coefficient of Variation 166.9 |
| All Lumasiran | Apparent Volume of Distribution (V/F) of Lumasiran | Day 1 | 34.7734 Liters (L) | Geometric Coefficient of Variation 185.7 |
| All Lumasiran | Apparent Volume of Distribution (V/F) of Lumasiran | Month 6 | 38.8468 Liters (L) | Geometric Coefficient of Variation 161.3 |
Secondary
Area Under the Concentration-time Curve From 0 to 24 Hours [AUC(0-24)] for Lumasiran
AUC(0-24) is the area under the plasma concentration-time curve over the last 24-h dosing interval.
Time frame: Day 1; Month 6
Population: PK Analysis Set: All patients who received any amount of lumasiran, have at least 1 postdose blood sample for PK parameters, and have evaluable PK data at the given timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A: Lumasiran | Area Under the Concentration-time Curve From 0 to 24 Hours [AUC(0-24)] for Lumasiran | Day 1 | 13156.8031 h*ng/mL | Geometric Coefficient of Variation 64.6 |
| Cohort A: Lumasiran | Area Under the Concentration-time Curve From 0 to 24 Hours [AUC(0-24)] for Lumasiran | Month 6 | 11417.0267 h*ng/mL | Geometric Coefficient of Variation 33.5 |
| Cohort B: Lumasiran | Area Under the Concentration-time Curve From 0 to 24 Hours [AUC(0-24)] for Lumasiran | Day 1 | 13170.3716 h*ng/mL | Geometric Coefficient of Variation 35.6 |
| Cohort B: Lumasiran | Area Under the Concentration-time Curve From 0 to 24 Hours [AUC(0-24)] for Lumasiran | Month 6 | 20647.6317 h*ng/mL | Geometric Coefficient of Variation 61.6 |
| All Lumasiran | Area Under the Concentration-time Curve From 0 to 24 Hours [AUC(0-24)] for Lumasiran | Day 1 | 13164.1075 h*ng/mL | Geometric Coefficient of Variation 47.7 |
| All Lumasiran | Area Under the Concentration-time Curve From 0 to 24 Hours [AUC(0-24)] for Lumasiran | Month 6 | 14856.4905 h*ng/mL | Geometric Coefficient of Variation 55.9 |
Secondary
Change in Frequency of Dialysis From Baseline to End of Study
Time frame: Baseline to Month 60
Secondary
Change in Frequency of Renal Stone Events From Baseline to End of Study
Time frame: Baseline to Month 60
Secondary
Change in Measures of Systemic Oxalosis From Baseline to End of Study
Systemic oxalosis will be assessed in cardiac, skeletal, ophthalmologic, and dermatologic systems.
Time frame: Baseline to Month 60
Secondary
Change in Mode of Dialysis From Baseline to End of Study
Modes of dialysis are defined as hemodialysis and peritoneal dialysis.
Time frame: Baseline to Month 60
Secondary
Change in Nephrocalcinosis From Baseline to End of Study
Nephrocalcinosis will be assessed by renal ultrasound.
Time frame: Baseline to Month 60
Secondary
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
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 frame: Baseline to Month 60
Secondary
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
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 frame: Baseline to Month 6
Population: Participants from the FAS who were ≥18 years of age at the time of consent.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A: 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 | SF-12 Mental Component Score | -3.88 score on a scale | Standard Deviation 4.45 |
| Cohort A: 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 | Effects of Kidney Disease | -15.63 score on a scale | Standard Deviation 22.1 |
| Cohort A: 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 | Symptoms/Problems of Kidney Disease | -13.64 score on a scale | Standard Deviation 6.43 |
| Cohort A: 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 | Burden of Kidney Disease | -3.13 score on a scale | Standard Deviation 4.42 |
| Cohort A: 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 | SF-12 Physical Component Score | -1.56 score on a scale | Standard Deviation 1.19 |
| Cohort B: 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 | Burden of Kidney Disease | -4.69 score on a scale | Standard Deviation 16.44 |
| Cohort B: 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 | SF-12 Physical Component Score | -2.06 score on a scale | Standard Deviation 6.59 |
| Cohort B: 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 | SF-12 Mental Component Score | 1.58 score on a scale | Standard Deviation 9.61 |
| Cohort B: 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 | Symptoms/Problems of Kidney Disease | -5.73 score on a scale | Standard Deviation 7.49 |
| Cohort B: 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 | Effects of Kidney Disease | -10.16 score on a scale | Standard Deviation 14.96 |
Secondary
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
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.
Time frame: Baseline to Month 60
Secondary
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
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.
Time frame: Baseline to Month 6
Population: Participants from the FAS who were ≥2 to \<18 years of age at the time of consent with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort A: Lumasiran | 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 | -23.91 score on a scale | Standard Deviation 9.22 |
| Cohort B: Lumasiran | 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 | 0.10 score on a scale | Standard Deviation 8.52 |
Secondary
Change in Renal Function Assessed by Estimated Glomerular Filtration Rate (eGFR) From Baseline to End of Study
Time frame: Baseline to Month 60
Secondary
Cohort A: Absolute Change in 24-hour Urinary Oxalate Excretion Corrected for Body Surface Area (BSA) From 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.
Time frame: Baseline to Month 6
Population: FAS: All patients who received any amount of lumasiran (with data available for analysis) and had at least 1 evaluable plasma oxalate value (pre-dialysis in Cohort B) at baseline and at least 1 evaluable plasma oxalate value from assessment(s) at Month 3 through Month 6. No analyses were performed for patients in Cohort B that were anuric (ie, patients able to continue to produce urine ≥100 mL per day).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Cohort A: Lumasiran | Cohort A: Absolute Change in 24-hour Urinary Oxalate Excretion Corrected for Body Surface Area (BSA) From Baseline to Month 6 | -0.533 mmol/24hr/1.73m^2 | Standard Error 0.111 |
Secondary
Cohort A: Absolute Change in Spot Urinary Oxalate:Creatinine Ratio From 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.
Time frame: Baseline to Month 6
Population: FAS: All patients who received any amount of lumasiran and had at least 1 evaluable plasma oxalate value (pre-dialysis in Cohort B) at baseline and at least 1 evaluable plasma oxalate value from assessment(s) at Month 3 through Month 6.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Cohort A: Lumasiran | Cohort A: Absolute Change in Spot Urinary Oxalate:Creatinine Ratio From Baseline to Month 6 | -0.1879 ratio | Standard Error 0.016 |
Secondary
Cohort A: Percent Change in 24-hour Urinary Oxalate Excretion Corrected for Body Surface Area (BSA) From 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.
Time frame: Baseline to Month 6
Population: FAS: All patients who received any amount of lumasiran (with data available for analysis) and had at least 1 evaluable plasma oxalate value (pre-dialysis in Cohort B) at baseline and at least 1 evaluable plasma oxalate value from assessment(s) at Month 3 through Month 6. No analyses were performed for patients in Cohort B that were anuric (ie, patients able to continue to produce urine ≥100 mL per day).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Cohort A: Lumasiran | Cohort A: Percent Change in 24-hour Urinary Oxalate Excretion Corrected for Body Surface Area (BSA) From Baseline to Month 6 | -10.557 percent change | Standard Error 6.811 |
Secondary
Cohort A: Percent Change in Spot Urinary Oxalate:Creatinine Ratio From 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.
Time frame: Baseline to Month 6
Population: FAS: All patients who received any amount of lumasiran and had at least 1 evaluable plasma oxalate value (pre-dialysis in Cohort B) at baseline and at least 1 evaluable plasma oxalate value from assessment(s) at Month 3 through Month 6.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Cohort A: Lumasiran | Cohort A: Percent Change in Spot Urinary Oxalate:Creatinine Ratio From Baseline to Month 6 | -39.5136 percent change | Standard Error 9.4294 |
Secondary
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
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.
Time frame: Baseline to Month 6
Population: FAS: All patients who received any amount of lumasiran and had at least 1 evaluable plasma oxalate value (pre-dialysis in Cohort B) at baseline and at least 1 evaluable plasma oxalate value from assessment(s) at Month 3 through Month 6.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Cohort A: 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 | -41.4 percent change | Standard Error 4.4 |
Secondary
Elimination Half-life (t½β) of Lumasiran
t½β is the time it takes for the concentration of the drug in the plasma to be reduced by 50%.
Time frame: Day 1; Month 6
Population: PK Analysis Set: All patients who received any amount of lumasiran, have at least 1 postdose blood sample for PK parameters, and have evaluable PK data at the given timepoint.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort A: Lumasiran | Elimination Half-life (t½β) of Lumasiran | Day 1 | 9.0246 hours |
| Cohort A: Lumasiran | Elimination Half-life (t½β) of Lumasiran | Month 6 | 8.1069 hours |
| Cohort B: Lumasiran | Elimination Half-life (t½β) of Lumasiran | Day 1 | 3.6670 hours |
| Cohort B: Lumasiran | Elimination Half-life (t½β) of Lumasiran | Month 6 | 4.5131 hours |
| All Lumasiran | Elimination Half-life (t½β) of Lumasiran | Day 1 | 3.8302 hours |
| All Lumasiran | Elimination Half-life (t½β) of Lumasiran | Month 6 | 5.7484 hours |
Secondary
Maximum Plasma Concentration (Cmax) of Lumasiran
Cmax is the highest concentration of lumasiran in the plasma after a dose is given.
Time frame: Day 1; Month 6
Population: Pharmacokinetic (PK) Analysis Set: All patients who received any amount of lumasiran, have at least 1 postdose blood sample for PK parameters, and have evaluable PK data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A: Lumasiran | Maximum Plasma Concentration (Cmax) of Lumasiran | Day 1 | 1019.9 ng/mL | Geometric Coefficient of Variation 61.6 |
| Cohort A: Lumasiran | Maximum Plasma Concentration (Cmax) of Lumasiran | Month 6 | 1038.2 ng/mL | Geometric Coefficient of Variation 36.9 |
| Cohort B: Lumasiran | Maximum Plasma Concentration (Cmax) of Lumasiran | Day 1 | 1820.5 ng/mL | Geometric Coefficient of Variation 113.2 |
| Cohort B: Lumasiran | Maximum Plasma Concentration (Cmax) of Lumasiran | Month 6 | 1289.3 ng/mL | Geometric Coefficient of Variation 106 |
| All Lumasiran | Maximum Plasma Concentration (Cmax) of Lumasiran | Day 1 | 1542.8 ng/mL | Geometric Coefficient of Variation 103.7 |
| All Lumasiran | Maximum Plasma Concentration (Cmax) of Lumasiran | Month 6 | 1211.9 ng/mL | Geometric Coefficient of Variation 87.6 |
Secondary
Percent Change in 24-hour Urinary Oxalate Excretion Corrected for Body Surface Area (BSA) From Baseline to Month 60
Time frame: Baseline to Month 60
Secondary
Percent Change in Plasma Oxalate Area Under the Curve From 0-24 Hours [AUC(0-24)] Between Dialysis Sessions From Baseline to Month 60
Time frame: Baseline to Month 60
Secondary
Percent Change in Plasma Oxalate From Baseline to End of Study
Time frame: Baseline to Month 60
Secondary
Percent Change in Spot Urinary Oxalate:Creatinine Ratio From Baseline to Month 60
Time frame: Baseline to Month 60
Secondary
Time to Maximum Plasma Concentration (Tmax) of Lumasiran
Tmax is the time it takes for lumasiran to reach the maximum concentration (Cmax) after administration.
Time frame: Day 1; Month 6
Population: PK Analysis Set: All patients who received any amount of lumasiran, have at least 1 postdose blood sample for PK parameters, and have evaluable PK data.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort A: Lumasiran | Time to Maximum Plasma Concentration (Tmax) of Lumasiran | Day 1 | 3.8083 hours |
| Cohort A: Lumasiran | Time to Maximum Plasma Concentration (Tmax) of Lumasiran | Month 6 | 3.9083 hours |
| Cohort B: Lumasiran | Time to Maximum Plasma Concentration (Tmax) of Lumasiran | Day 1 | 4.0000 hours |
| Cohort B: Lumasiran | Time to Maximum Plasma Concentration (Tmax) of Lumasiran | Month 6 | 4.0167 hours |
| All Lumasiran | Time to Maximum Plasma Concentration (Tmax) of Lumasiran | Day 1 | 4.0000 hours |
| All Lumasiran | Time to Maximum Plasma Concentration (Tmax) of Lumasiran | Month 6 | 4.0000 hours |