Primary Hyperoxaluria, Primary Hyperoxaluria Type 1 (PH1)
Conditions
Keywords
PH1, Primary Hyperoxaluria, Hyperoxaluria, RNAi Therapeutic, siRNA, AGT
Brief summary
The purpose of this study is to evaluate the efficacy, safety, pharmacokinetics (PK), and pharmacodynamics (PD) of lumasiran in infants and young children with confirmed 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
Age
0 Years to 5 Years
Healthy volunteers
No
Inclusion criteria
* Has genetic confirmation of primary hyperoxaluria type 1 (PH1) * Meets urinary oxalate excretion requirements * If taking Vitamin B6 (pyridoxine), must have been on stable regimen for at least 90 days
Exclusion criteria
* If \<12 months old at screening, has an abnormally high serum creatinine * If ≥12 months old at screening, has an estimated glomerular filtration rate (GFR) of ≤45 mL/min/1.73m\^2 * Clinical evidence of systemic oxalosis * History of kidney or liver transplant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change in Plasma Oxalate From Baseline to End of Study (Month 60) | From Baseline to Month 6 and Month 60 | The lower limit of quantification (LLOQ) was 5.55 micromoles per liter (μmol/L). A negative change from baseline indicates a favorable outcome. |
| Percentage of Time That Spot Urinary Oxalate: Creatinine Ratio is at or Below the Near-normalization Threshold (≤1.5 × Upper Limit of Normal (ULN) for Age) | Up to 60 months | Percentage of time that spot urinary oxalate: creatinine (UOx:Cr) ratio level is at or below ≤ 1.5xULN is calculated as (cumulative months at or below near normalization threshold divided by cumulative months of assessments)\*100. Cumulative months in near-normalization is defined as the summation across all intervals that met the near-normal threshold and cumulative months of valid assessments is defined as the summation across all valid post-baseline collections. ULN levels of spot urinary oxalate to creatinine ratio where urine oxalate levels were analyzed using enzymatic assay. The age-dependent reference ULN levels of spot urinary oxalate to creatinine ratio are as follows: 1-1.5 years=0.158; 1.5-2 years=0.138; 2-2.5 years=0.124; 2.5-3 years=0.116; 3-3.5 years=0.102; 3.5-4 years=0.094; 4-4.5 years=0.088; 4.5-5 years=0.082; 5-5.5 years=0.077; 5.5-6 years=0.073. |
| Absolute Change in Spot Urinary Oxalate: Creatinine Ratio From Baseline | From Baseline to Month 6 and Month 60 | The absolute change is represented as ratio of millimoles of urinary oxalate to millimoles of urinary creatinine. |
| Absolute Change in Plasma Oxalate From Baseline to End of Study (Month 60) | From Baseline to Month 6 and Month 60 | The LLOQ was 5.55 μmol/L. A negative change from Baseline indicates a favorable outcome. |
| Maximum Observed Plasma Concentration (Cmax) of Lumasiran | 2 hours, 4 hours, 8 hours, 12 hours, and 24 hours post-dose on Day 1, Month 6, Month 12, Month 18 and Month 24 | Cmax was the maximum plasma concentration post-dose within the pharmacokinetic (PK) sampling time frame. Higher Cmax generally indicates higher drug exposure. |
| Percentage of Participants With Spot Urinary Oxalate: Creatinine Ratio Levels ≤ the ULN for Age | Up to 60 months | The percentage of participants meeting the criteria (UOx:Cr ratio ≤ the ULN for age) at least at one post-baseline visit were reported for this outcome measure. The age-dependent reference ULN levels of spot urinary oxalate to creatinine ratio are as follows: 1-1.5 years=0.158; 1.5-2 years=0.138; 2-2.5 years=0.124; 2.5-3 years=0.116; 3-3.5 years=0.102; 3.5-4 years=0.094; 4-4.5 years=0.088; 4.5-5 years=0.082; 5-5.5 years=0.077; 5.5-6 years=0.073. |
| Percentage of Participants With Spot Urinary Oxalate: Creatinine Ratio Levels ≤ 1.5xULN for Age | Up to 60 months | The percentage of participants meeting the criteria (UOx:Cr ratio ≤ 1.5xULN for age) at least at one post-baseline visit were reported for this outcome measure. The age-dependent reference ULN levels of spot urinary oxalate to creatinine ratio are as follows: 1-1.5 years=0.158; 1.5-2 years=0.138; 2-2.5 years=0.124; 2.5-3 years=0.116; 3-3.5 years=0.102; 3.5-4 years=0.094; 4-4.5 years=0.088; 4.5-5 years=0.082; 5-5.5 years=0.077; 5.5-6 years=0.073. |
| Time to Maximum Observed Plasma Concentration (Tmax) of Lumasiran | 2 hours, 4 hours, 8 hours, 12 hours, and 24 hours post-dose on Day 1, Month 6, Month 12, Month 18 and Month 24 | Tmax was estimated by calculating the time required to reach the maximum plasma concentration (Cmax) after the drug administration. Lower Tmax generally indicates faster drug absorption from the administration site. |
| Percentage Change in Spot Urinary Oxalate: Creatinine Ratio in the Extension Period (Month 6 to End of Study [Month 60]) | From Month 6 to Month 60 | A negative change from baseline indicates a favorable outcome. |
| Area Under the Concentration-time Curve From 0 to 24 Hours (AUC0-24) of Lumasiran | 24 hours post-dose on Day 1, Month 6, Month 12, Month 18 and Month 24 | AUC0-24 was the total drug exposure calculated as the area under the plasma concentration-time curve from the time of dosing (t = 0) to 24 hours. |
| Area Under the Concentration-time Curve From 0 to Last Quantifiable Concentration (AUC0-last) of Lumasiran | 2 hours, 4 hours, 8 hours, 12 hours, and 24 hours post-dose on Day 1, Month 6, Month 12, Month 18 and Month 24 | AUC0-last was the total drug exposure calculated as the area under the plasma concentration-time curve from time 0 to the time of the last measurable (quantifiable) concentration (C\_last). |
| Area Under the Concentration-time Curve From 0 to Infinity (AUC0-infinity) of Lumasiran | 2 hours, 4 hours, 8 hours, 12 hours, and 24 hours post-dose on Day 1, Month 6, Month 12, Month 18 and Month 24 | AUC0-infinity was the total drug exposure estimated as the area under the plasma concentration-time curve from time 0 extrapolated to infinity. |
| Apparent Clearance (CL/F) of Lumasiran | 2 hours, 4 hours, 8 hours, 12 hours, and 24 hours post-dose on Day 1, Month 6, Month 12, Month 18 and Month 24 | Apparent clearance was calculated by dividing the area under the plasma concentration-time curve from zero infinity by the dose administered. A higher clearance generally indicates faster elimination from the body. |
| Apparent Volume of Distribution (V/F) of Lumasiran | 2 hours, 4 hours, 8 hours, 12 hours, and 24 hours post-dose on Day 1, Month 6, Month 12, Month 18 and Month 24 | Apparent Volume of Distribution generally indicates the extent of drug distribution in the body. |
| Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | From Baseline to Month 6 and Month 60 | eGFR \[in milliliters per minute per 1.73 meters square (mL/min/1.73m\^2)\] was calculated from serum creatinine (SCr) based on the Schwartz Bedside Formula for participants ≥12 months of age at the time of assessment. |
| Number of Participants With Adverse Events (AEs) | Up to 60 months | An Adverse Event (AE) is any untoward medical occurrence in a participant or clinical investigational participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. |
| Elimination Half-life (t1/2beta) of Lumasiran | 2 hours, 4 hours, 8 hours, 12 hours, and 24 hours post-dose on Day 1, Month 6, Month 12, Month 18 and Month 24 | Elimination half-life was estimated from the terminal phase of the plasma concentration-time profile post-dose. Shorter half-life generally indicates rapid drug elimination from the body. |
Countries
France, Germany, Israel, United Kingdom, United States
Participant flow
Recruitment details
Participants took part in the study at investigative sites in France, Germany, Israel, the United Kingdom, and the United States from 22 April 2019 to 26 July 2024.
Pre-assignment details
A total of 18 participants with Primary hyperoxaluria type 1 (PH1) were enrolled and treated in this study.
Participants by arm
| Arm | Count |
|---|---|
| Lumasiran Participants weighing \<10 kg received loading doses of lumasiran SC injection 6.0 mg/kg QM for 3 months, followed by maintenance doses of 3.0 mg/kg QM during the 6-month PAP & QM during the 54-month EP. Participants who transitioned from \<10 kg to ≥10 kg continued monthly doses at 3.0 mg/kg until the next visit that coincided with a dose for participants weighing ≥10 kg. Thereafter, participants followed Q3M dosing until the end of the study.
Participants weighing ≥10 to \<20 kg received lumasiran 6.0 mg/kg QM for 3 months, then maintenance doses of 6.0 mg/kg at Months 3 & 6 in the 6-month PAP & Q3M during the 54-month EP.
Participants ≥20 kg received lumasiran 3.0 mg/kg QM for 3 months, followed by maintenance doses of 3.0 mg/kg Months 3 & 6 in the 6-month PAP & Q3M during the 54-month EP.
Participants with weight increases to a new dosing category (\<10 kg to ≥10 kg or \<20 kg to ≥20 kg) followed the new regimen for the rest of the study or until the next dosing category threshold was reached; participants did not switch back to lower-weight dosing schedules if their body weight subsequently decreased. | 18 |
| Total | 18 |
Baseline characteristics
| Characteristic | Lumasiran |
|---|---|
| Age, Continuous | 43.7 months STANDARD_DEVIATION 21.3 |
| Race/Ethnicity, Customized Hispanic or Latino | 2 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 16 Participants |
| Race/Ethnicity, Customized Other | 2 Participants |
| Race/Ethnicity, Customized White | 16 Participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 8 Participants |
| Spot Urinary Oxalate:Creatinine Ratio | 0.6306 mmol/mmol STANDARD_DEVIATION 0.42636 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 18 |
| other Total, other adverse events | 18 / 18 |
| serious Total, serious adverse events | 2 / 18 |
Outcome results
Primary
Percentage 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.
Time frame: Baseline to Month 6
Population: Efficacy Analysis Set: All participants who received any amount of lumasiran and had at least 1 valid spot urinary oxalate:creatinine ratio value at baseline and at least 1 valid spot urinary oxalate:creatinine ratio value from assessment(s) at Month 3 through Month 6.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lumasiran | Percentage Change in Spot Urinary Oxalate:Creatinine Ratio From Baseline to Month 6 | -71.97 percent change | Standard Error 2.706 |
Comparison: Mixed-effect Model Repeated Measures (MMRM) includes scheduled visits (months 3, 4, 5, and 6) and baseline spot urinary oxalate:creatine ratio as fixed effects. Autoregressive (1) was used to model the within-patient error.95% CI: [-77.52, -66.42]Mixed model for repeated measures (MMRM)
Secondary
Absolute Change in Plasma Oxalate From Baseline to End of Study (Month 60)
The LLOQ was 5.55 μmol/L. A negative change from Baseline indicates a favorable outcome.
Time frame: From Baseline to Month 6 and Month 60
Population: Efficacy analysis set included all participants who were treated with Lumasiran and had at least one spot urinary oxalate:creatinine ratio value at baseline and at least one spot urinary oxalate:creatinine ratio value from assessment(s) throughout the study duration.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lumasiran | Absolute Change in Plasma Oxalate From Baseline to End of Study (Month 60) | Month 6 | -5.03 µmol/L | Standard Error 1.294 |
| Lumasiran | Absolute Change in Plasma Oxalate From Baseline to End of Study (Month 60) | Month 60 | -5.03 µmol/L | Standard Error 1.859 |
Secondary
Absolute Change in Spot Urinary Oxalate: Creatinine Ratio From Baseline
The absolute change is represented as ratio of millimoles of urinary oxalate to millimoles of urinary creatinine.
Time frame: From Baseline to Month 6 and Month 60
Population: Efficacy analysis set included all participants who were treated with Lumasiran and had at least one spot urinary oxalate:creatinine ratio value at baseline and at least one spot urinary oxalate:creatinine ratio value from assessment(s) throughout the study duration.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lumasiran | Absolute Change in Spot Urinary Oxalate: Creatinine Ratio From Baseline | Month 6 | -0.4880 mmol/mmol | Standard Error 0.09127 |
| Lumasiran | Absolute Change in Spot Urinary Oxalate: Creatinine Ratio From Baseline | Month 60 | -0.5179 mmol/mmol | Standard Error 0.09929 |
Secondary
Apparent Clearance (CL/F) of Lumasiran
Apparent clearance was calculated by dividing the area under the plasma concentration-time curve from zero infinity by the dose administered. A higher clearance generally indicates faster elimination from the body.
Time frame: 2 hours, 4 hours, 8 hours, 12 hours, and 24 hours post-dose on Day 1, Month 6, Month 12, Month 18 and Month 24
Population: PK analysis set included all participants who had received at least one full dose of Lumasiran and had at least one post-dose blood sample for PK parameters and had evaluable PK data. Overall number analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at specified timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Lumasiran | Apparent Clearance (CL/F) of Lumasiran | Day 1 | 8.62 liters per hour (L/h) | Geometric Coefficient of Variation 24 |
| Lumasiran | Apparent Clearance (CL/F) of Lumasiran | Month 6 | 10.2 liters per hour (L/h) | Geometric Coefficient of Variation 32.3 |
| Lumasiran | Apparent Clearance (CL/F) of Lumasiran | Month 12 | 7.06 liters per hour (L/h) | Geometric Coefficient of Variation 28.3 |
| Lumasiran | Apparent Clearance (CL/F) of Lumasiran | Month 18 | 6.87 liters per hour (L/h) | Geometric Coefficient of Variation 30.6 |
| Lumasiran | Apparent Clearance (CL/F) of Lumasiran | Month 24 | 8.22 liters per hour (L/h) | Geometric Coefficient of Variation 37.7 |
Secondary
Apparent Volume of Distribution (V/F) of Lumasiran
Apparent Volume of Distribution generally indicates the extent of drug distribution in the body.
Time frame: 2 hours, 4 hours, 8 hours, 12 hours, and 24 hours post-dose on Day 1, Month 6, Month 12, Month 18 and Month 24
Population: PK analysis set included all participants who had received at least one full dose of Lumasiran and had at least one post-dose blood sample for PK parameters and had evaluable PK data. Overall number analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at specified timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Lumasiran | Apparent Volume of Distribution (V/F) of Lumasiran | Day 1 | 57.2 Liters (L) | Geometric Coefficient of Variation 69.8 |
| Lumasiran | Apparent Volume of Distribution (V/F) of Lumasiran | Month 6 | 81 Liters (L) | Geometric Coefficient of Variation 71.1 |
| Lumasiran | Apparent Volume of Distribution (V/F) of Lumasiran | Month 12 | 36 Liters (L) | Geometric Coefficient of Variation 75.6 |
| Lumasiran | Apparent Volume of Distribution (V/F) of Lumasiran | Month 18 | 43.1 Liters (L) | Geometric Coefficient of Variation 107.1 |
| Lumasiran | Apparent Volume of Distribution (V/F) of Lumasiran | Month 24 | 57.6 Liters (L) | Geometric Coefficient of Variation 70.6 |
Secondary
Area Under the Concentration-time Curve From 0 to 24 Hours (AUC0-24) of Lumasiran
AUC0-24 was the total drug exposure calculated as the area under the plasma concentration-time curve from the time of dosing (t = 0) to 24 hours.
Time frame: 24 hours post-dose on Day 1, Month 6, Month 12, Month 18 and Month 24
Population: PK analysis set included all participants who had received at least one full dose of Lumasiran and had at least one post-dose blood sample for PK parameters and had evaluable PK data. Overall number analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at specified timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Lumasiran | Area Under the Concentration-time Curve From 0 to 24 Hours (AUC0-24) of Lumasiran | Day 1 | 8050 hours*nanograms per milliliter (h*ng/mL) | Geometric Coefficient of Variation 37.7 |
| Lumasiran | Area Under the Concentration-time Curve From 0 to 24 Hours (AUC0-24) of Lumasiran | Month 6 | 8450 hours*nanograms per milliliter (h*ng/mL) | Geometric Coefficient of Variation 41.1 |
| Lumasiran | Area Under the Concentration-time Curve From 0 to 24 Hours (AUC0-24) of Lumasiran | Month 12 | 10800 hours*nanograms per milliliter (h*ng/mL) | Geometric Coefficient of Variation 39.3 |
| Lumasiran | Area Under the Concentration-time Curve From 0 to 24 Hours (AUC0-24) of Lumasiran | Month 18 | 8420 hours*nanograms per milliliter (h*ng/mL) | Geometric Coefficient of Variation 57.2 |
| Lumasiran | Area Under the Concentration-time Curve From 0 to 24 Hours (AUC0-24) of Lumasiran | Month 24 | 7420 hours*nanograms per milliliter (h*ng/mL) | Geometric Coefficient of Variation 61.6 |
Secondary
Area Under the Concentration-time Curve From 0 to Infinity (AUC0-infinity) of Lumasiran
AUC0-infinity was the total drug exposure estimated as the area under the plasma concentration-time curve from time 0 extrapolated to infinity.
Time frame: 2 hours, 4 hours, 8 hours, 12 hours, and 24 hours post-dose on Day 1, Month 6, Month 12, Month 18 and Month 24
Population: PK analysis set included all participants who had received at least one full dose of Lumasiran and had at least one post-dose blood sample for PK parameters and had evaluable PK data. Overall number analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at specified timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Lumasiran | Area Under the Concentration-time Curve From 0 to Infinity (AUC0-infinity) of Lumasiran | Day 1 | 9180 h*ng/mL | Geometric Coefficient of Variation 31.7 |
| Lumasiran | Area Under the Concentration-time Curve From 0 to Infinity (AUC0-infinity) of Lumasiran | Month 6 | 8840 h*ng/mL | Geometric Coefficient of Variation 40.9 |
| Lumasiran | Area Under the Concentration-time Curve From 0 to Infinity (AUC0-infinity) of Lumasiran | Month 12 | 11900 h*ng/mL | Geometric Coefficient of Variation 29.2 |
| Lumasiran | Area Under the Concentration-time Curve From 0 to Infinity (AUC0-infinity) of Lumasiran | Month 18 | 11600 h*ng/mL | Geometric Coefficient of Variation 48.6 |
| Lumasiran | Area Under the Concentration-time Curve From 0 to Infinity (AUC0-infinity) of Lumasiran | Month 24 | 9610 h*ng/mL | Geometric Coefficient of Variation 48.8 |
Secondary
Area Under the Concentration-time Curve From 0 to Last Quantifiable Concentration (AUC0-last) of Lumasiran
AUC0-last was the total drug exposure calculated as the area under the plasma concentration-time curve from time 0 to the time of the last measurable (quantifiable) concentration (C\_last).
Time frame: 2 hours, 4 hours, 8 hours, 12 hours, and 24 hours post-dose on Day 1, Month 6, Month 12, Month 18 and Month 24
Population: PK analysis set included all participants who had received at least one full dose of Lumasiran and had at least one post-dose blood sample for PK parameters and had evaluable PK data. Number analyzed is the number of participants with data available for analysis at specified timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Lumasiran | Area Under the Concentration-time Curve From 0 to Last Quantifiable Concentration (AUC0-last) of Lumasiran | Day 1 | 7870 h*ng/mL | Geometric Coefficient of Variation 33.4 |
| Lumasiran | Area Under the Concentration-time Curve From 0 to Last Quantifiable Concentration (AUC0-last) of Lumasiran | Month 6 | 6620 h*ng/mL | Geometric Coefficient of Variation 95.5 |
| Lumasiran | Area Under the Concentration-time Curve From 0 to Last Quantifiable Concentration (AUC0-last) of Lumasiran | Month 12 | 8480 h*ng/mL | Geometric Coefficient of Variation 76.1 |
| Lumasiran | Area Under the Concentration-time Curve From 0 to Last Quantifiable Concentration (AUC0-last) of Lumasiran | Month 18 | 5770 h*ng/mL | Geometric Coefficient of Variation 155 |
| Lumasiran | Area Under the Concentration-time Curve From 0 to Last Quantifiable Concentration (AUC0-last) of Lumasiran | Month 24 | 7100 h*ng/mL | Geometric Coefficient of Variation 80 |
Secondary
Change From Baseline in Estimated Glomerular Filtration Rate (eGFR)
eGFR \[in milliliters per minute per 1.73 meters square (mL/min/1.73m\^2)\] was calculated from serum creatinine (SCr) based on the Schwartz Bedside Formula for participants ≥12 months of age at the time of assessment.
Time frame: From Baseline to Month 6 and Month 60
Population: Efficacy analysis set included all participants who were treated with Lumasiran and had at least one spot urinary oxalate:creatinine ratio value at baseline and at least one spot urinary oxalate:creatinine ratio value from assessment(s) throughout the study duration. Overall number analyzed is the number of participants with data available for analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lumasiran | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Month 6 | -0.263 mL/min/1.73m^2 | Standard Error 3.8461 |
| Lumasiran | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Month 60 | -4.525 mL/min/1.73m^2 | Standard Error 4.8873 |
Secondary
Elimination Half-life (t1/2beta) of Lumasiran
Elimination half-life was estimated from the terminal phase of the plasma concentration-time profile post-dose. Shorter half-life generally indicates rapid drug elimination from the body.
Time frame: 2 hours, 4 hours, 8 hours, 12 hours, and 24 hours post-dose on Day 1, Month 6, Month 12, Month 18 and Month 24
Population: PK analysis set included all participants who had received at least one full dose of Lumasiran and had at least one post-dose blood sample for PK parameters and had evaluable PK data. Overall number analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at specified timepoints.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Lumasiran | Elimination Half-life (t1/2beta) of Lumasiran | Day 1 | 5.46 hours (h) |
| Lumasiran | Elimination Half-life (t1/2beta) of Lumasiran | Month 6 | 5.96 hours (h) |
| Lumasiran | Elimination Half-life (t1/2beta) of Lumasiran | Month 12 | 3.52 hours (h) |
| Lumasiran | Elimination Half-life (t1/2beta) of Lumasiran | Month 18 | 3.74 hours (h) |
| Lumasiran | Elimination Half-life (t1/2beta) of Lumasiran | Month 24 | 4.99 hours (h) |
Secondary
Maximum Observed Plasma Concentration (Cmax) of Lumasiran
Cmax was the maximum plasma concentration post-dose within the pharmacokinetic (PK) sampling time frame. Higher Cmax generally indicates higher drug exposure.
Time frame: 2 hours, 4 hours, 8 hours, 12 hours, and 24 hours post-dose on Day 1, Month 6, Month 12, Month 18 and Month 24
Population: PK analysis set included all participants who had received at least one full dose of Lumasiran and had at least one post-dose blood sample for PK parameters and had evaluable PK data. Number analyzed is the number of participants with data available for analysis at specified timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Lumasiran | Maximum Observed Plasma Concentration (Cmax) of Lumasiran | Day 1 | 886 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 58.9 |
| Lumasiran | Maximum Observed Plasma Concentration (Cmax) of Lumasiran | Month 6 | 869 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 84 |
| Lumasiran | Maximum Observed Plasma Concentration (Cmax) of Lumasiran | Month 12 | 1180 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 83.5 |
| Lumasiran | Maximum Observed Plasma Concentration (Cmax) of Lumasiran | Month 18 | 878 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 94 |
| Lumasiran | Maximum Observed Plasma Concentration (Cmax) of Lumasiran | Month 24 | 790 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 91.9 |
Secondary
Number of Participants With Adverse Events (AEs)
An Adverse Event (AE) is any untoward medical occurrence in a participant or clinical investigational participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment.
Time frame: Up to 60 months
Population: Safety analysis set included all participants who had received at least one dose of Lumasiran.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lumasiran | Number of Participants With Adverse Events (AEs) | 18 Participants |
Secondary
Percentage Change in Plasma Oxalate From Baseline to End of Study (Month 60)
The lower limit of quantification (LLOQ) was 5.55 micromoles per liter (μmol/L). A negative change from baseline indicates a favorable outcome.
Time frame: From Baseline to Month 6 and Month 60
Population: Efficacy analysis set included all participants who were treated with Lumasiran and had at least one spot urinary oxalate:creatinine ratio value at baseline and at least one spot urinary oxalate:creatinine ratio value from assessment(s) throughout the study duration.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lumasiran | Percentage Change in Plasma Oxalate From Baseline to End of Study (Month 60) | Month 6 | -32.06 percent change | Standard Error 6.711 |
| Lumasiran | Percentage Change in Plasma Oxalate From Baseline to End of Study (Month 60) | Month 60 | -24.78 percent change | Standard Error 12.814 |
Secondary
Percentage Change in Spot Urinary Oxalate: Creatinine Ratio in the Extension Period (Month 6 to End of Study [Month 60])
A negative change from baseline indicates a favorable outcome.
Time frame: From Month 6 to Month 60
Population: Efficacy analysis set included all participants who were treated with Lumasiran and had at least one spot urinary oxalate:creatinine ratio value at baseline and at least one spot urinary oxalate:creatinine ratio value from assessment(s) at Month 6 through Month 60.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lumasiran | Percentage Change in Spot Urinary Oxalate: Creatinine Ratio in the Extension Period (Month 6 to End of Study [Month 60]) | -74.48 percent change | Standard Error 4.246 |
Secondary
Percentage of Participants With Spot Urinary Oxalate: Creatinine Ratio Levels ≤ 1.5xULN for Age
The percentage of participants meeting the criteria (UOx:Cr ratio ≤ 1.5xULN for age) at least at one post-baseline visit were reported for this outcome measure. The age-dependent reference ULN levels of spot urinary oxalate to creatinine ratio are as follows: 1-1.5 years=0.158; 1.5-2 years=0.138; 2-2.5 years=0.124; 2.5-3 years=0.116; 3-3.5 years=0.102; 3.5-4 years=0.094; 4-4.5 years=0.088; 4.5-5 years=0.082; 5-5.5 years=0.077; 5.5-6 years=0.073.
Time frame: Up to 60 months
Population: Efficacy analysis set included all participants who were treated with Lumasiran and had at least one spot urinary oxalate:creatinine ratio value at baseline and at least one spot urinary oxalate:creatinine ratio value from assessment(s) throughout the study duration.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lumasiran | Percentage of Participants With Spot Urinary Oxalate: Creatinine Ratio Levels ≤ 1.5xULN for Age | 100 percentage of participants |
Secondary
Percentage of Participants With Spot Urinary Oxalate: Creatinine Ratio Levels ≤ the ULN for Age
The percentage of participants meeting the criteria (UOx:Cr ratio ≤ the ULN for age) at least at one post-baseline visit were reported for this outcome measure. The age-dependent reference ULN levels of spot urinary oxalate to creatinine ratio are as follows: 1-1.5 years=0.158; 1.5-2 years=0.138; 2-2.5 years=0.124; 2.5-3 years=0.116; 3-3.5 years=0.102; 3.5-4 years=0.094; 4-4.5 years=0.088; 4.5-5 years=0.082; 5-5.5 years=0.077; 5.5-6 years=0.073.
Time frame: Up to 60 months
Population: Efficacy analysis set included all participants who were treated with Lumasiran and had at least one spot urinary oxalate:creatinine ratio value at baseline and at least one spot urinary oxalate:creatinine ratio value from assessment(s) throughout the study duration.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lumasiran | Percentage of Participants With Spot Urinary Oxalate: Creatinine Ratio Levels ≤ the ULN for Age | 100 percentage of participants |
Secondary
Percentage of Time That Spot Urinary Oxalate: Creatinine Ratio is at or Below the Near-normalization Threshold (≤1.5 × Upper Limit of Normal (ULN) for Age)
Percentage of time that spot urinary oxalate: creatinine (UOx:Cr) ratio level is at or below ≤ 1.5xULN is calculated as (cumulative months at or below near normalization threshold divided by cumulative months of assessments)\*100. Cumulative months in near-normalization is defined as the summation across all intervals that met the near-normal threshold and cumulative months of valid assessments is defined as the summation across all valid post-baseline collections. ULN levels of spot urinary oxalate to creatinine ratio where urine oxalate levels were analyzed using enzymatic assay. The age-dependent reference ULN levels of spot urinary oxalate to creatinine ratio are as follows: 1-1.5 years=0.158; 1.5-2 years=0.138; 2-2.5 years=0.124; 2.5-3 years=0.116; 3-3.5 years=0.102; 3.5-4 years=0.094; 4-4.5 years=0.088; 4.5-5 years=0.082; 5-5.5 years=0.077; 5.5-6 years=0.073.
Time frame: Up to 60 months
Population: Efficacy analysis set included all participants who were treated with Lumasiran and had at least one spot urinary oxalate:creatinine ratio value at baseline and at least one spot urinary oxalate:creatinine ratio value from assessment(s) throughout the study duration.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lumasiran | Percentage of Time That Spot Urinary Oxalate: Creatinine Ratio is at or Below the Near-normalization Threshold (≤1.5 × Upper Limit of Normal (ULN) for Age) | 68.95 percentage of time |
Secondary
Time to Maximum Observed Plasma Concentration (Tmax) of Lumasiran
Tmax was estimated by calculating the time required to reach the maximum plasma concentration (Cmax) after the drug administration. Lower Tmax generally indicates faster drug absorption from the administration site.
Time frame: 2 hours, 4 hours, 8 hours, 12 hours, and 24 hours post-dose on Day 1, Month 6, Month 12, Month 18 and Month 24
Population: PK analysis set included all participants who had received at least one full dose of Lumasiran and had at least one post-dose blood sample for PK parameters and had evaluable PK data. Number analyzed is the number of participants with data available for analysis at specified timepoints.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Lumasiran | Time to Maximum Observed Plasma Concentration (Tmax) of Lumasiran | Day 1 | 3.74 hours (h) |
| Lumasiran | Time to Maximum Observed Plasma Concentration (Tmax) of Lumasiran | Month 6 | 4 hours (h) |
| Lumasiran | Time to Maximum Observed Plasma Concentration (Tmax) of Lumasiran | Month 12 | 4 hours (h) |
| Lumasiran | Time to Maximum Observed Plasma Concentration (Tmax) of Lumasiran | Month 18 | 3.64 hours (h) |
| Lumasiran | Time to Maximum Observed Plasma Concentration (Tmax) of Lumasiran | Month 24 | 3.73 hours (h) |