Primary Hyperoxaluria Type 1 (PH1)
Conditions
Keywords
PH1, Primary hyperoxaluria, RNAi therapeutic, siRNA, AGT, Oxalate
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).
Interventions
DRUGPlacebo
Placebo by SC injection
DRUGLumasiran
Lumasiran by SC injection
Sponsors
Alnylam Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
6 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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 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. |
| 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. |
| 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. |
| 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. |
| 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 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. |
| 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Rate of Renal Stone Events | 12-Month Period prior to Informed Consent, 6-Month DB Period | A renal stone event is defined as a patient-reported event that includes ≥1 of the following: visit to healthcare provider because of a renal stone; medication for renal colic; stone passage; macroscopic hematuria due to a renal stone. Lower rates indicate a favorable outcome. |
| Change From Baseline in Nephrocalcinosis as Assessed by Renal Ultrasound | Baseline, Month 6 | Renal ultrasound data were used to grade medullary nephrocalcinosis findings (range: 0 to 3), where a higher grade indicates greater severity. Improving=if both sides improve, or one side improves and the other side has no change; No change=if both sides have no change; Worsening=if both sides worsen, or one side worsens and the other side has no change; Indeterminate=if one side improves and the other side worsens. |
Countries
France, Germany, Israel, Netherlands, Switzerland, United Arab Emirates, United Kingdom, United States
Participant flow
Recruitment details
Participants with PH1 were enrolled at sixteen sites in France, Germany, Israel, the Netherlands, Switzerland, the United Arab Emirates, the United Kingdom and the United States.
Pre-assignment details
Participants were treated with placebo or lumasiran during the 6-month Double-Blind (DB) Period. All participants received lumasiran during the 3-Month Blinded Treatment Extension Period and 51-Month Open-Label Extension Period.
Participants by arm
| Arm | Count |
|---|---|
| Placebo/Lumasiran Lumasiran-matching placebo was administered SC at Day 1 and Months 1, 2 and 3 during the 6-Month 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 OLE period. | 13 |
| 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. | 26 |
| Total | 39 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| 6-Month Double-Blind Period | Parent/Caregiver Withdrew Consent | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo/Lumasiran | Lumasiran/Lumasiran | Total |
|---|---|---|---|
| 24-hour Urinary Oxalate:Creatinine Ratio | 0.231 mmol/mmol STANDARD_DEVIATION 0.1306 | 0.209 mmol/mmol STANDARD_DEVIATION 0.1012 | 0.216 mmol/mmol STANDARD_DEVIATION 0.1106 |
| 24-Hour Urinary Oxalate Excretion Corrected for BSA | 1.79 mmol/24hr/1.73m^2 STANDARD_DEVIATION 0.68 | 1.83 mmol/24hr/1.73m^2 STANDARD_DEVIATION 0.6 | 1.82 mmol/24hr/1.73m^2 STANDARD_DEVIATION 0.62 |
| Age at Informed Consent | 17.0 years STANDARD_DEVIATION 15.19 | 18.7 years STANDARD_DEVIATION 11.52 | 18.1 years STANDARD_DEVIATION 12.68 |
| Age, Customized 12 to <18 Years | 1 Participants | 5 Participants | 6 Participants |
| Age, Customized 18 to <65 Years | 5 Participants | 12 Participants | 17 Participants |
| Age, Customized 6 to <12 Years | 7 Participants | 9 Participants | 16 Participants |
| Estimated Glomerular Filtration Rate (eGFR) | 78.834 mL/min/1.73m^2 STANDARD_DEVIATION 29.9841 | 82.967 mL/min/1.73m^2 STANDARD_DEVIATION 25.5499 | 81.589 mL/min/1.73m^2 STANDARD_DEVIATION 26.782 |
| Race/Ethnicity, Customized Asian | 3 Participants | 3 Participants | 6 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 13 Participants | 25 Participants | 38 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 9 Participants | 21 Participants | 30 Participants |
| Sex: Female, Male Female | 5 Participants | 8 Participants | 13 Participants |
| Sex: Female, Male Male | 8 Participants | 18 Participants | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 13 | 0 / 26 |
| other Total, other adverse events | 9 / 13 | 12 / 13 | 25 / 26 |
| serious Total, serious adverse events | 0 / 13 | 1 / 13 | 5 / 26 |
Outcome results
Primary
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.
Time frame: Baseline to Month 6
Population: FAS: All randomized participants who received any amount of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo/Lumasiran | Percent Change in 24-hour Urinary Oxalate Excretion Corrected for Body Surface Area (BSA) From Baseline to Month 6 | -11.8 percent change | Standard Error 3.8 |
| Lumasiran/Lumasiran | Percent Change in 24-hour Urinary Oxalate Excretion Corrected for Body Surface Area (BSA) From Baseline to Month 6 | -65.4 percent change | Standard Error 2.9 |
Comparison: The Mixed-Effect Model Repeated Measures (MMRM) includes fixed effects of treatment arms (lumasiran vs. placebo) and scheduled visits (months 3, 4, 5, and 6), baseline 24-hour urinary oxalate corrected for BSA as a continuous fixed covariate, and patient as a random effect. The variance-covariance matrix is assumed to be unstructured. Satterthwaite approximation is used to estimate denominator degrees of freedom.p-value: <0.000195% CI: [-62.314, -44.778]MMRM
Secondary
Absolute Change in 24-hour Urinary Oxalate Corrected for 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.
Time frame: Baseline to Month 6
Population: FAS: All randomized participants who received any amount of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo/Lumasiran | Absolute Change in 24-hour Urinary Oxalate Corrected for BSA From Baseline to Month 6 | -0.27 mmol/24hr/1.73m^2 | Standard Error 0.08 |
| Lumasiran/Lumasiran | Absolute Change in 24-hour Urinary Oxalate Corrected for BSA From Baseline to Month 6 | -1.24 mmol/24hr/1.73m^2 | Standard Error 0.06 |
Comparison: The MMRM includes fixed effects of treatment arms (lumasiran vs. placebo) and scheduled visits (months 3, 4, 5, and 6), baseline 24-hour urinary oxalate corrected for BSA as a continuous fixed covariate, and patient as a random effect. The variance-covariance matrix is assumed to be unstructured. Satterthwaite approximation is used to estimate denominator degrees of freedom.p-value: <0.000195% CI: [-1.177, -0.772]MMRM
Secondary
Absolute Change in 24-hour Urinary Oxalate:Creatinine Ratio From Baseline in the Extension Period
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.
Time frame: From Baseline to Month 54 and Month 60
Population: All Lumasiran Treated Set: All participants who received any amount of lumasiran including participants who took lumasiran during the 6-month double-blinded period and participants who initially took placebo during the 6-month double-blinded period and then switched to lumasiran during the extension period. Overall number analyzed is number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at the specified timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo/Lumasiran | Absolute Change in 24-hour Urinary Oxalate:Creatinine Ratio From Baseline in the Extension Period | At Month 54 | -0.145 mmol/mmol | Standard Deviation 0.1242 |
| Lumasiran/Lumasiran | Absolute Change in 24-hour Urinary Oxalate:Creatinine Ratio From Baseline in the Extension Period | At Month 54 | -0.127 mmol/mmol | Standard Deviation 0.1063 |
| Lumasiran/Lumasiran | Absolute Change in 24-hour Urinary Oxalate:Creatinine Ratio From Baseline in the Extension Period | At Month 60 | -0.138 mmol/mmol | Standard Deviation 0.1162 |
Secondary
Absolute Change in 24-hour Urinary Oxalate Excretion Corrected for BSA From Baseline in the Extension Period
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.
Time frame: From Baseline to Month 54 and Month 60
Population: All Lumasiran Treated Set: All participants who received any amount of lumasiran including participants who took lumasiran during the 6-month double-blinded period and participants who initially took placebo during the 6-month double-blinded period and then switched to lumasiran during the extension period. Overall number analyzed is number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at the specified timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo/Lumasiran | Absolute Change in 24-hour Urinary Oxalate Excretion Corrected for BSA From Baseline in the Extension Period | At Month 54 | -0.951 mmol/24hr/1.73m^2 | Standard Deviation 0.6148 |
| Lumasiran/Lumasiran | Absolute Change in 24-hour Urinary Oxalate Excretion Corrected for BSA From Baseline in the Extension Period | At Month 54 | -1.086 mmol/24hr/1.73m^2 | Standard Deviation 0.7678 |
| Lumasiran/Lumasiran | Absolute Change in 24-hour Urinary Oxalate Excretion Corrected for BSA From Baseline in the Extension Period | At Month 60 | -1.129 mmol/24hr/1.73m^2 | Standard Deviation 0.7581 |
Secondary
Absolute Change in Plasma Oxalate From 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.
Time frame: Baseline to Month 6
Population: Plasma Oxalate Analysis Set: all participants who received any amount of study drug and had baseline plasma oxalate level ≥1.5×LLOQ. LLOQ is 5.55 μmol/L.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo/Lumasiran | Absolute Change in Plasma Oxalate From Baseline to Month 6 | 1.3 μmol/L | Standard Error 1.1 |
| Lumasiran/Lumasiran | Absolute Change in Plasma Oxalate From Baseline to Month 6 | -7.5 μmol/L | Standard Error 0.8 |
Comparison: The MMRM includes fixed effects of treatment arms (lumasiran vs. placebo) and scheduled visits (months 3, 4, 5, and 6), baseline plasma oxalate as a continuous fixed covariate, and patient as a random effect. The variance-covariance matrix is assumed to be unstructured. Satterthwaite approximation is used to estimate denominator degrees of freedom.p-value: <0.000195% CI: [-11.45, -5.98]MMRM
Secondary
Change in Estimated Glomerular Filtration Rate (eGFR) From Baseline in the Extension Period
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.
Time frame: From Baseline to Month 54 and Month 60
Population: All Lumasiran Treated Set: All participants who received any amount of lumasiran including participants who took lumasiran during the 6-month double-blinded period and participants who initially took placebo during the 6-month double-blinded period and then switched to lumasiran during the extension period. Overall number analyzed is number of participants with data available for analysis. Number analysed is the number of participants with data available for analysis at the specified timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo/Lumasiran | Change in Estimated Glomerular Filtration Rate (eGFR) From Baseline in the Extension Period | At Month 54 | -12.860 mL/min/1.73m^2 | Standard Deviation 9.5386 |
| Lumasiran/Lumasiran | Change in Estimated Glomerular Filtration Rate (eGFR) From Baseline in the Extension Period | At Month 54 | -6.899 mL/min/1.73m^2 | Standard Deviation 12.9302 |
| Lumasiran/Lumasiran | Change in Estimated Glomerular Filtration Rate (eGFR) From Baseline in the Extension Period | At Month 60 | -2.892 mL/min/1.73m^2 | Standard Deviation 11.6544 |
Secondary
Change in Estimated Glomerular Filtration Rate (eGFR) From Baseline to Week 2 and 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.
Time frame: Baseline, Week 2, Months 1, 2, 3, 4, 5 and 6
Population: Participants from the FAS (all randomized participants who received any amount of study drug) for whom data are available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo/Lumasiran | Change in Estimated Glomerular Filtration Rate (eGFR) From Baseline to Week 2 and Months 1, 2, 3, 4, 5 and 6 | Month 2 | -5 mL/min/1.73m^2 | Standard Deviation 8 |
| Placebo/Lumasiran | Change in Estimated Glomerular Filtration Rate (eGFR) From Baseline to Week 2 and Months 1, 2, 3, 4, 5 and 6 | Month 4 | -4 mL/min/1.73m^2 | Standard Deviation 8 |
| Placebo/Lumasiran | Change in Estimated Glomerular Filtration Rate (eGFR) From Baseline to Week 2 and Months 1, 2, 3, 4, 5 and 6 | Month 1 | -6 mL/min/1.73m^2 | Standard Deviation 7 |
| Placebo/Lumasiran | Change in Estimated Glomerular Filtration Rate (eGFR) From Baseline to Week 2 and Months 1, 2, 3, 4, 5 and 6 | Month 5 | -4 mL/min/1.73m^2 | Standard Deviation 7 |
| Placebo/Lumasiran | Change in Estimated Glomerular Filtration Rate (eGFR) From Baseline to Week 2 and Months 1, 2, 3, 4, 5 and 6 | Month 3 | -3 mL/min/1.73m^2 | Standard Deviation 6 |
| Placebo/Lumasiran | Change in Estimated Glomerular Filtration Rate (eGFR) From Baseline to Week 2 and Months 1, 2, 3, 4, 5 and 6 | Month 6 | 0 mL/min/1.73m^2 | Standard Deviation 6 |
| Placebo/Lumasiran | Change in Estimated Glomerular Filtration Rate (eGFR) From Baseline to Week 2 and Months 1, 2, 3, 4, 5 and 6 | Week 2 | -5 mL/min/1.73m^2 | Standard Deviation 9 |
| Lumasiran/Lumasiran | Change in Estimated Glomerular Filtration Rate (eGFR) From Baseline to Week 2 and Months 1, 2, 3, 4, 5 and 6 | Month 6 | -3 mL/min/1.73m^2 | Standard Deviation 11 |
| Lumasiran/Lumasiran | Change in Estimated Glomerular Filtration Rate (eGFR) From Baseline to Week 2 and Months 1, 2, 3, 4, 5 and 6 | Week 2 | -4 mL/min/1.73m^2 | Standard Deviation 9 |
| Lumasiran/Lumasiran | Change in Estimated Glomerular Filtration Rate (eGFR) From Baseline to Week 2 and Months 1, 2, 3, 4, 5 and 6 | Month 1 | -2 mL/min/1.73m^2 | Standard Deviation 12 |
| Lumasiran/Lumasiran | Change in Estimated Glomerular Filtration Rate (eGFR) From Baseline to Week 2 and Months 1, 2, 3, 4, 5 and 6 | Month 2 | -2 mL/min/1.73m^2 | Standard Deviation 15 |
| Lumasiran/Lumasiran | Change in Estimated Glomerular Filtration Rate (eGFR) From Baseline to Week 2 and Months 1, 2, 3, 4, 5 and 6 | Month 3 | 0 mL/min/1.73m^2 | Standard Deviation 11 |
| Lumasiran/Lumasiran | Change in Estimated Glomerular Filtration Rate (eGFR) From Baseline to Week 2 and Months 1, 2, 3, 4, 5 and 6 | Month 4 | -4 mL/min/1.73m^2 | Standard Deviation 10 |
| Lumasiran/Lumasiran | Change in Estimated Glomerular Filtration Rate (eGFR) From Baseline to Week 2 and Months 1, 2, 3, 4, 5 and 6 | Month 5 | -6 mL/min/1.73m^2 | Standard Deviation 13 |
Secondary
Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
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.
Time frame: 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).
Population: Per the SAP, long-term safety of lumasiran (in the extension period \[EP\]) was to be summarized by treatment sequence (placebo/lumasiran \& lumasiran/lumasiran) using the All Lumasiran Treated Set. In this set, data is presented during lumasiran treatment only. The lumasiran/lumasiran arm received lumasiran in both DB \& EP period hence, safety data is reported together for DB+EP period for this arm. Placebo/Lumasiran: first day of lumasiran dosing (Month 6) was considered baseline (Day 1) of EP.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo/Lumasiran | Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Adverse Event (AE) | 9 Participants |
| Placebo/Lumasiran | Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious Adverse Event (SAE) | 0 Participants |
| Lumasiran/Lumasiran | Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Adverse Event (AE) | 12 Participants |
| Lumasiran/Lumasiran | Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious Adverse Event (SAE) | 1 Participants |
| Lumasiran/Lumasiran | Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Adverse Event (AE) | 25 Participants |
| Lumasiran/Lumasiran | Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious Adverse Event (SAE) | 5 Participants |
Secondary
Percentage Change in 24-hour Urinary Oxalate Excretion Corrected by BSA From Baseline in the Extension Period
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.
Time frame: From Baseline to Month 54 and Month 60
Population: All Lumasiran Treated Set: All participants who received any amount of lumasiran including participants who took lumasiran during the 6-month double-blinded period and participants who initially took placebo during the 6-month double-blinded period and then switched to lumasiran during the extension period. Overall number analyzed is number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at the specified timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo/Lumasiran | Percentage Change in 24-hour Urinary Oxalate Excretion Corrected by BSA From Baseline in the Extension Period | At Month 54 | -55.57 percent change | Standard Deviation 11.903 |
| Lumasiran/Lumasiran | Percentage Change in 24-hour Urinary Oxalate Excretion Corrected by BSA From Baseline in the Extension Period | At Month 54 | -53.87 percent change | Standard Deviation 41.919 |
| Lumasiran/Lumasiran | Percentage Change in 24-hour Urinary Oxalate Excretion Corrected by BSA From Baseline in the Extension Period | At Month 60 | -53.98 percent change | Standard Deviation 28.476 |
Secondary
Percentage 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.
Time frame: Baseline to Month 6
Population: Plasma Oxalate Analysis Set: all participants who received any amount of study drug and had baseline plasma oxalate level ≥1.5×lower limit of quantitation (LLOQ). LLOQ is 5.55 μmol/L.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo/Lumasiran | Percentage Change in Plasma Oxalate From Baseline to Month 6 | -0.3 percent change | Standard Error 4.3 |
| Lumasiran/Lumasiran | Percentage Change in Plasma Oxalate From Baseline to Month 6 | -39.8 percent change | Standard Error 2.9 |
Comparison: The MMRM includes fixed effects of treatment arms (lumasiran vs. placebo) and scheduled visits (months 3, 4, 5, and 6), baseline plasma oxalate as a continuous fixed covariate, and patient as a random effect. The variance-covariance matrix is assumed to be unstructured. Satterthwaite approximation is used to estimate denominator degrees of freedom.p-value: <0.000195% CI: [-50.1, -28.87]MMRM
Secondary
Percentage of Participants With 24-hour Urinary Oxalate Level Corrected for BSA at or Below 1.5 x ULN at Month 6
The upper limit of normal (ULN) = 0.514 mmol/24hr/1.73m\^2 for 24-hour urinary oxalate excretion corrected for BSA.
Time frame: Month 6
Population: Participants from the FAS (all randomized participants who received any amount of study drug) for whom data are available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo/Lumasiran | Percentage of Participants With 24-hour Urinary Oxalate Level Corrected for BSA at or Below 1.5 x ULN at Month 6 | 0 percentage of participants |
| Lumasiran/Lumasiran | Percentage of Participants With 24-hour Urinary Oxalate Level Corrected for BSA at or Below 1.5 x ULN at Month 6 | 84.0 percentage of participants |
Comparison: The proportion of participants (lumasiran vs. placebo) with 24-hour urinary oxalate ≤1.5 x ULN at Month 6 is analyzed using the Cochran-Mantel-Haenszel test, stratified by baseline 24-hour urinary oxalate corrected for BSA (≤1.70 mmol/24hr/1.73m\^2 vs. \>1.70 mmol/24hr/1.73m\^2). The difference in proportion (lumasiran vs. placebo) and the corresponding 95% confidence interval are calculated using the Newcombe method, based on the Wilson score.p-value: <0.000195% CI: [0.55, 0.94]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With 24-hour Urinary Oxalate Level Corrected for BSA at or Below ULN at Month 6
The upper limit of normal (ULN) = 0.514 mmol/24hr/1.73m\^2 for 24-hour urinary oxalate excretion corrected for BSA.
Time frame: Month 6
Population: Participants from the FAS (all randomized participants who received any amount of study drug) for whom data are available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo/Lumasiran | Percentage of Participants With 24-hour Urinary Oxalate Level Corrected for BSA at or Below ULN at Month 6 | 0 percentage of participants |
| Lumasiran/Lumasiran | Percentage of Participants With 24-hour Urinary Oxalate Level Corrected for BSA at or Below ULN at Month 6 | 52.0 percentage of participants |
Comparison: The proportion of participants (lumasiran vs. placebo) with 24-hour urinary oxalate ≤ULN at Month 6 is analyzed using the Cochran-Mantel-Haenszel test, stratified by baseline 24-hour urinary oxalate corrected for BSA (≤1.70 mmol/24hr/1.73m\^2 vs. \>1.70 mmol/24hr/1.73m\^2). The difference in proportion (lumasiran vs. placebo) and the corresponding 95% confidence interval are calculated using the Newcombe method, based on the Wilson score.p-value: 0.00195% CI: [0.23, 0.7]Cochran-Mantel-Haenszel
Secondary
Percentage of Time That 24-hour Urinary Oxalate is at or Below 1.5 × ULN During Lumasiran Treatment
The upper limit of normal (ULN) = 0.514 mmol/24hr/1.73m\^2 for 24-hour urinary oxalate excretion corrected for BSA.
Time frame: Up to Month 60
Population: All Lumasiran Treated Set: All participants who received any amount of lumasiran including participants who took lumasiran during the 6-month double-blinded period and participants who initially took placebo during the 6-month double-blinded period and then switched to lumasiran during the extension period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo/Lumasiran | Percentage of Time That 24-hour Urinary Oxalate is at or Below 1.5 × ULN During Lumasiran Treatment | 89.44 percentage of time |
| Lumasiran/Lumasiran | Percentage of Time That 24-hour Urinary Oxalate is at or Below 1.5 × ULN During Lumasiran Treatment | 89.23 percentage of time |
Secondary
Percent Change in 24-hour Urinary Oxalate:Creatinine Ratio From 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.
Time frame: Baseline to Month 6
Population: FAS: All randomized participants who received any amount of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo/Lumasiran | Percent Change in 24-hour Urinary Oxalate:Creatinine Ratio From Baseline to Month 6 | -10.8 percent change | Standard Error 5.4 |
| Lumasiran/Lumasiran | Percent Change in 24-hour Urinary Oxalate:Creatinine Ratio From Baseline to Month 6 | -62.5 percent change | Standard Error 4 |
Comparison: The MMRM includes fixed effects of treatment arms (lumasiran vs. placebo) and scheduled visits (months 3, 4, 5, and 6), baseline 24-hour urinary oxalate:creatinine ratio as a continuous fixed covariate, and patient as a random effect. The variance-covariance matrix is assumed to be unstructured. Satterthwaite approximation is used to estimate denominator degrees of freedom.p-value: <0.000195% CI: [-64.2653, -39.2784]MMRM
Other Pre-specified
Change From Baseline in Nephrocalcinosis as Assessed by Renal Ultrasound
Renal ultrasound data were used to grade medullary nephrocalcinosis findings (range: 0 to 3), where a higher grade indicates greater severity. Improving=if both sides improve, or one side improves and the other side has no change; No change=if both sides have no change; Worsening=if both sides worsen, or one side worsens and the other side has no change; Indeterminate=if one side improves and the other side worsens.
Time frame: Baseline, Month 6
Population: Participants from the FAS (all randomized participants who received any amount of study drug) with both Baseline and Month 6 renal ultrasounds.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo/Lumasiran | Change From Baseline in Nephrocalcinosis as Assessed by Renal Ultrasound | Improving | 0 Participants |
| Placebo/Lumasiran | Change From Baseline in Nephrocalcinosis as Assessed by Renal Ultrasound | No Change | 11 Participants |
| Placebo/Lumasiran | Change From Baseline in Nephrocalcinosis as Assessed by Renal Ultrasound | Worsening | 1 Participants |
| Placebo/Lumasiran | Change From Baseline in Nephrocalcinosis as Assessed by Renal Ultrasound | Indeterminate | 0 Participants |
| Lumasiran/Lumasiran | Change From Baseline in Nephrocalcinosis as Assessed by Renal Ultrasound | Indeterminate | 0 Participants |
| Lumasiran/Lumasiran | Change From Baseline in Nephrocalcinosis as Assessed by Renal Ultrasound | Improving | 3 Participants |
| Lumasiran/Lumasiran | Change From Baseline in Nephrocalcinosis as Assessed by Renal Ultrasound | Worsening | 0 Participants |
| Lumasiran/Lumasiran | Change From Baseline in Nephrocalcinosis as Assessed by Renal Ultrasound | No Change | 19 Participants |
Other Pre-specified
Rate of Renal Stone Events
A renal stone event is defined as a patient-reported event that includes ≥1 of the following: visit to healthcare provider because of a renal stone; medication for renal colic; stone passage; macroscopic hematuria due to a renal stone. Lower rates indicate a favorable outcome.
Time frame: 12-Month Period prior to Informed Consent, 6-Month DB Period
Population: FAS: All randomized participants who received any amount of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo/Lumasiran | Rate of Renal Stone Events | 12-Month Period prior to Informed Consent | 0.54 events per person-year |
| Placebo/Lumasiran | Rate of Renal Stone Events | 6-Month DB Period | 0.66 events per person-year |
| Lumasiran/Lumasiran | Rate of Renal Stone Events | 12-Month Period prior to Informed Consent | 3.19 events per person-year |
| Lumasiran/Lumasiran | Rate of Renal Stone Events | 6-Month DB Period | 1.09 events per person-year |