Clinical Trial Results:
ILLUMINATE-B: An Open-Label Study to Evaluate the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Lumasiran in Infants and Young Children with Primary Hyperoxaluria Type 1
|
Summary
|
|
EudraCT number |
2018-004014-17 |
Trial protocol |
GB FR DE |
Global end of trial date |
26 Jul 2024
|
|
Results information
|
|
Results version number |
v1(current) |
This version publication date |
09 Feb 2025
|
First version publication date |
09 Feb 2025
|
Other versions |
|
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
|
|||
|
Trial identification
|
|||
Sponsor protocol code |
ALN-GO1-004
|
||
|
Additional study identifiers
|
|||
ISRCTN number |
- | ||
US NCT number |
NCT03905694 | ||
WHO universal trial number (UTN) |
- | ||
|
Sponsors
|
|||
Sponsor organisation name |
Alnylam Pharmaceuticals, Inc.
|
||
Sponsor organisation address |
300 Third Street, Cambridge, MA, United States, 02142
|
||
Public contact |
Clinical Trial Information Line, Alnylam Pharmaceuticals, Inc., +1 8772569526, clinicaltrials@alnylam.com
|
||
Scientific contact |
Clinical Trial Information Line, Alnylam Pharmaceuticals, Inc., +1 8772569526, clinicaltrials@alnylam.com
|
||
|
Paediatric regulatory details
|
|||
Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
|
||
EMA paediatric investigation plan number(s) |
EMEA-002079-PIP01-16 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
|
||
|
Results analysis stage
|
|||
Analysis stage |
Final
|
||
Date of interim/final analysis |
26 Jul 2024
|
||
Is this the analysis of the primary completion data? |
No
|
||
Global end of trial reached? |
Yes
|
||
Global end of trial date |
26 Jul 2024
|
||
Was the trial ended prematurely? |
No
|
||
|
General information about the trial
|
|||
Main objective of the trial |
The main objective of the trial is to evaluate the efficacy, safety, pharmacokinetics (PK), and pharmacodynamics (PD) of subcutaneous (SC) lumasiran in infants and young children with confirmed primary hyperoxaluria type 1 (PH1).
|
||
Protection of trial subjects |
The legal guardian(s) of each subject signed an informed consent form (ICF) before participating in the study and subjects may have provided assent as per the local and national requirements.
|
||
Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
22 Apr 2019
|
||
Long term follow-up planned |
No
|
||
Independent data monitoring committee (IDMC) involvement? |
Yes
|
||
|
Population of trial subjects
|
|||
Number of subjects enrolled per country |
|||
Country: Number of subjects enrolled |
France: 5
|
||
Country: Number of subjects enrolled |
Germany: 1
|
||
Country: Number of subjects enrolled |
Israel: 8
|
||
Country: Number of subjects enrolled |
United Kingdom: 2
|
||
Country: Number of subjects enrolled |
United States: 2
|
||
Worldwide total number of subjects |
18
|
||
EEA total number of subjects |
6
|
||
Number of subjects enrolled per age group |
|||
In utero |
0
|
||
Preterm newborn - gestational age < 37 wk |
0
|
||
Newborns (0-27 days) |
0
|
||
Infants and toddlers (28 days-23 months) |
4
|
||
Children (2-11 years) |
14
|
||
Adolescents (12-17 years) |
0
|
||
Adults (18-64 years) |
0
|
||
From 65 to 84 years |
0
|
||
85 years and over |
0
|
||
|
|||||||
|
Recruitment
|
|||||||
Recruitment details |
Subjects 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
|
|||||||
Screening details |
A total of 18 subjects with Primary hyperoxaluria type 1 (PH1) were enrolled and treated in this study. | ||||||
|
Period 1
|
|||||||
Period 1 title |
Primary Analysis Period
|
||||||
Is this the baseline period? |
Yes | ||||||
Allocation method |
Not applicable
|
||||||
Blinding used |
Not blinded | ||||||
|
Arms
|
|||||||
|
Arm title
|
Lumasiran | ||||||
Arm description |
Subjects weighing <10 kg received loading doses of lumasiran SC injection 6.0 mg/kg monthly (QM) for 3 months, followed by maintenance doses of 3.0 mg/kg QM during 6-month primary analysis period (PAP) & QM in 54-month extension period (EP). Subjects transitioning from <10 kg to ≥10 kg continued QM doses at 3.0 mg/kg until next visit coinciding with a dose for subjects weighing ≥10 kg. Thereafter, subjects followed Q3M dosing until end of study. Subjects weighing ≥10 to <20 kg received 6.0 mg/kg QM for 3 months, maintenance doses of 6.0 mg/kg at Months 3 & 6 in PAP & Q3M in EP. Subjects ≥20 kg received 3.0 mg/kg QM for 3 months, followed by maintenance doses of 3.0 mg/kg at Months 3 & 6 in PAP & Q3M in EP. Subjects with weight increases to a new dosing category (<10 kg to ≥10 kg/<20 kg to ≥20 kg) followed new regimen for rest of the study/until next dosing category threshold was reached; subjects did not revert to lower-weight dosing schedules if their weight subsequently decreased. | ||||||
Arm type |
Experimental | ||||||
Investigational medicinal product name |
Lumasiran
|
||||||
Investigational medicinal product code |
ALN-GO1
|
||||||
Other name |
|||||||
Pharmaceutical forms |
Solution for injection
|
||||||
Routes of administration |
Subcutaneous use
|
||||||
Dosage and administration details |
Subjects 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. Subjects transitioning from <10 kg to ≥10 kg continued QM doses at 3.0 mg/kg until next visit coinciding with a dose for subjects weighing ≥10 kg. Thereafter, subjects followed Q3M dosing until end of study. Subjects weighing ≥10 to <20 kg received 6.0 mg/kg QM for 3 months, then maintenance doses of 6.0 mg/kg Q3M. Subjects ≥20 kg received 3.0 mg/kg QM for 3 months, followed by maintenance doses of 3.0 mg/kg Q3M. Subjects with weight increases to a new dosing category (<10 kg to ≥10 kg/<20 kg to ≥20 kg) followed new regimen for rest of the study/until next dosing category threshold was reached; subjects did not revert to lower-weight dosing schedules if their weight subsequently decreased.
|
||||||
|
|||||||
|
Period 2
|
|||||||
Period 2 title |
Long-term Extension Period
|
||||||
Is this the baseline period? |
No | ||||||
Allocation method |
Not applicable
|
||||||
Blinding used |
Not blinded | ||||||
|
Arms
|
|||||||
|
Arm title
|
Lumasiran | ||||||
Arm description |
Subjects weighing <10 kg received loading doses of lumasiran SC injection 6.0 mg/kg monthly (QM) for 3 months, followed by maintenance doses of 3.0 mg/kg QM during 6-month primary analysis period (PAP) & QM in 54-month extension period (EP). Subjects transitioning from <10 kg to ≥10 kg continued QM doses at 3.0 mg/kg until next visit coinciding with a dose for subjects weighing ≥10 kg. Thereafter, subjects followed Q3M dosing until end of study. Subjects weighing ≥10 to <20 kg received 6.0 mg/kg QM for 3 months, maintenance doses of 6.0 mg/kg at Months 3 & 6 in PAP & Q3M in EP. Subjects ≥20 kg received 3.0 mg/kg QM for 3 months, followed by maintenance doses of 3.0 mg/kg at Months 3 & 6 in PAP & Q3M in EP. Subjects with weight increases to a new dosing category (<10 kg to ≥10 kg/<20 kg to ≥20 kg) followed new regimen for rest of the study/until next dosing category threshold was reached; subjects did not revert to lower-weight dosing schedules if their weight subsequently decreased. | ||||||
Arm type |
Experimental | ||||||
Investigational medicinal product name |
Lumasiran
|
||||||
Investigational medicinal product code |
ALN-GO1
|
||||||
Other name |
|||||||
Pharmaceutical forms |
Solution for injection
|
||||||
Routes of administration |
Subcutaneous use
|
||||||
Dosage and administration details |
Subjects 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. Subjects transitioning from <10 kg to ≥10 kg continued QM doses at 3.0 mg/kg until next visit coinciding with a dose for subjects weighing ≥10 kg. Thereafter, subjects followed Q3M dosing until end of study. Subjects weighing ≥10 to <20 kg received 6.0 mg/kg QM for 3 months, then maintenance doses of 6.0 mg/kg Q3M. Subjects ≥20 kg received 3.0 mg/kg QM for 3 months, followed by maintenance doses of 3.0 mg/kg Q3M. Subjects with weight increases to a new dosing category (<10 kg to ≥10 kg/<20 kg to ≥20 kg) followed new regimen for rest of the study/until next dosing category threshold was reached; subjects did not revert to lower-weight dosing schedules if their weight subsequently decreased.
|
||||||
|
|||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Baseline characteristics reporting groups
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Primary Analysis Period
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects weighing <10 kg received loading doses of lumasiran SC injection 6.0 mg/kg monthly (QM) for 3 months, followed by maintenance doses of 3.0 mg/kg QM during 6-month primary analysis period (PAP) & QM in 54-month extension period (EP). Subjects transitioning from <10 kg to ≥10 kg continued QM doses at 3.0 mg/kg until next visit coinciding with a dose for subjects weighing ≥10 kg. Thereafter, subjects followed Q3M dosing until end of study. Subjects weighing ≥10 to <20 kg received 6.0 mg/kg QM for 3 months, maintenance doses of 6.0 mg/kg at Months 3 & 6 in PAP & Q3M in EP. Subjects ≥20 kg received 3.0 mg/kg QM for 3 months, followed by maintenance doses of 3.0 mg/kg at Months 3 & 6 in PAP & Q3M in EP. Subjects with weight increases to a new dosing category (<10 kg to ≥10 kg/<20 kg to ≥20 kg) followed new regimen for rest of the study/until next dosing category threshold was reached; subjects did not revert to lower-weight dosing schedules if their weight subsequently decreased. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
|
End points reporting groups
|
|||
Reporting group title |
Lumasiran
|
||
Reporting group description |
Subjects weighing <10 kg received loading doses of lumasiran SC injection 6.0 mg/kg monthly (QM) for 3 months, followed by maintenance doses of 3.0 mg/kg QM during 6-month primary analysis period (PAP) & QM in 54-month extension period (EP). Subjects transitioning from <10 kg to ≥10 kg continued QM doses at 3.0 mg/kg until next visit coinciding with a dose for subjects weighing ≥10 kg. Thereafter, subjects followed Q3M dosing until end of study. Subjects weighing ≥10 to <20 kg received 6.0 mg/kg QM for 3 months, maintenance doses of 6.0 mg/kg at Months 3 & 6 in PAP & Q3M in EP. Subjects ≥20 kg received 3.0 mg/kg QM for 3 months, followed by maintenance doses of 3.0 mg/kg at Months 3 & 6 in PAP & Q3M in EP. Subjects with weight increases to a new dosing category (<10 kg to ≥10 kg/<20 kg to ≥20 kg) followed new regimen for rest of the study/until next dosing category threshold was reached; subjects did not revert to lower-weight dosing schedules if their weight subsequently decreased. | ||
Reporting group title |
Lumasiran
|
||
Reporting group description |
Subjects weighing <10 kg received loading doses of lumasiran SC injection 6.0 mg/kg monthly (QM) for 3 months, followed by maintenance doses of 3.0 mg/kg QM during 6-month primary analysis period (PAP) & QM in 54-month extension period (EP). Subjects transitioning from <10 kg to ≥10 kg continued QM doses at 3.0 mg/kg until next visit coinciding with a dose for subjects weighing ≥10 kg. Thereafter, subjects followed Q3M dosing until end of study. Subjects weighing ≥10 to <20 kg received 6.0 mg/kg QM for 3 months, maintenance doses of 6.0 mg/kg at Months 3 & 6 in PAP & Q3M in EP. Subjects ≥20 kg received 3.0 mg/kg QM for 3 months, followed by maintenance doses of 3.0 mg/kg at Months 3 & 6 in PAP & Q3M in EP. Subjects with weight increases to a new dosing category (<10 kg to ≥10 kg/<20 kg to ≥20 kg) followed new regimen for rest of the study/until next dosing category threshold was reached; subjects did not revert to lower-weight dosing schedules if their weight subsequently decreased. | ||
|
|||||||||
End point title |
Percentage Change in Spot Urinary Oxalate:Creatinine Ratio From Baseline to Month 6 [1] | ||||||||
End point description |
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. Efficacy analysis set included all subjects 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 3 through Month 6.
|
||||||||
End point type |
Primary
|
||||||||
End point timeframe |
Baseline to Month 6
|
||||||||
| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Formal statistics were analyzed for this study using the mixed model for repeated measures (MMRM) model. As this is a single-arm study, statistical analysis data could not be presented. |
|||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Percentage Change in Spot Urinary Oxalate:Creatinine Ratio From Baseline in the Extension Period (Month 6 to End of Study [Month 60]) | ||||||||
End point description |
A negative change from Baseline indicates a favorable outcome. Efficacy analysis set included all subjects 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.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
From Month 6 to Month 60
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
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] | ||||||||
End point description |
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 was defined as summation across all intervals meeting near-normal threshold & cumulative months of valid assessments was summation across all valid post-baseline collections. ULN levels of spot UOx:Cr ratio where urine oxalate levels were analyzed by enzymatic assay. Age-dependent reference ULN levels of spot UOx:Cr ratio are: 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. Efficacy analysis set=all subjects who were treated with Lumasiran & had at least one spot UOx:Cr ratio value at baseline & at least one spot UOx:Cr ratio value from assessment(s) throughout the study duration.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Up to 60 months
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||||
End point title |
Absolute Change in Spot Urinary Oxalate: Creatinine Ratio From Baseline | ||||||||||||
End point description |
The absolute change is represented as the ratio of millimoles of urinary oxalate to millimoles of urinary creatinine. Efficacy analysis set included all subjects 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.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline to Month 6 and Month 60
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||
End point title |
Percentage of Subjects With Spot Urinary Oxalate: Creatinine Ratio Levels ≤ the ULN for Age | ||||||||
End point description |
The percentage of subjects meeting the criteria (UOx:Cr ratio ≤ the ULN for age) at least at one post-baseline visit were reported for this endpoint. 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. Efficacy analysis set included all subjects 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.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Up to 60 months
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Percentage of Subjects With Spot Urinary Oxalate: Creatinine Ratio Levels ≤ 1.5xULN for Age | ||||||||
End point description |
The percentage of subjects 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.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Up to 60 months
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||||
End point title |
Percentage Change in Plasma Oxalate From Baseline to End of Study (Month 60) | ||||||||||||
End point description |
The Lower Limit of Quantification (LLOQ) was 5.55 micromoles per liter (µmol/L) . A negative change from Baseline indicates a favorable outcome. Efficacy analysis set included all subjects 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.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline to Month 6 and Month 60
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Absolute Change in Plasma Oxalate From Baseline to End of Study (Month 60) | ||||||||||||
End point description |
The LLOQ was 5.55 μmol/L. A negative change from Baseline indicates a favorable outcome. Efficacy analysis set included all subjects 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.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline to Month 6 and Month 60
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||||
End point title |
Maximum Observed Plasma Concentration (Cmax) of Lumasiran | ||||||||||||||||||
End point description |
Cmax was the maximum plasma concentration post-dose within the pharmacokinetic (PK) sampling time frame. Higher Cmax generally indicates higher drug exposure. PK analysis set included all subjects 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 subjects with data available for analysis at specified timepoints.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
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
|
||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||||||||||
End point title |
Time to Maximum Observed Plasma Concentration (Tmax) of Lumasiran | ||||||||||||||||||
End point description |
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. PK analysis set included all subjects 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 subjects with data available for analysis at specified timepoints.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
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
|
||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||||||||||
End point title |
Elimination Half-life (t1/2beta) of Lumasiran | ||||||||||||||||||
End point description |
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. PK analysis set included all subjects 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 subjects with data available for analysis. Number analyzed is the number of subjects with data available for analysis at specified timepoints.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
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
|
||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||||||||||
End point title |
Area Under the Concentration-time Curve From 0 to 24 Hours (AUC0-24) of Lumasiran | ||||||||||||||||||
End point description |
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. PK analysis set included all subjects 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 subjects with data available for analysis. Number analyzed is the number of subjects with data available for analysis at specified timepoints.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
24 hours post-dose on Day 1, Month 6, Month 12, Month 18 and Month 24
|
||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||||||||||
End point title |
Area Under the Concentration-time Curve From 0 to Last Quantifiable Concentration (AUC0-last) of Lumasiran | ||||||||||||||||||
End point description |
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). PK analysis set included all subjects 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 subjects with data available for analysis at specified timepoints.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
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
|
||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||||||||||
End point title |
Area Under the Concentration-time Curve From 0 to infinity (AUC0-infinity) of Lumasiran | ||||||||||||||||||
End point description |
AUC0-infinity was the total drug exposure estimated as the area under the plasma concentration-time curve from time 0 extrapolated to infinity. PK analysis set included all subjects 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 subjects with data available for analysis. Number analyzed is the number of subjects with data available for analysis at specified timepoints.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
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
|
||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||||||||||
End point title |
Apparent Clearance (CL/F) of Lumasiran | ||||||||||||||||||
End point description |
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. PK analysis set included all subjects 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 subjects with data available for analysis. Number analyzed is the number of subjects with data available for analysis at specified timepoints.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
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
|
||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||||||||||
End point title |
Apparent Volume of Distribution (V/F) of Lumasiran | ||||||||||||||||||
End point description |
Apparent Volume of Distribution generally indicates the extent of drug distribution in the body. PK analysis set included all subjects 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 subjects with data available for analysis. Number analyzed is the number of subjects with data available for analysis at specified timepoints.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
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
|
||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||||
End point title |
Change from Baseline in Estimated Glomerular Filtration Rate (eGFR) | ||||||||||||
End point description |
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 subjects ≥12 months of age at the time of assessment. Efficacy analysis set included all subjects 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 subjects with data available for analysis.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline to Month 6 and Month 60
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||
End point title |
Number of Subjects With Adverse Events (AEs) | ||||||
End point description |
An Adverse Event (AE) is any untoward medical occurrence in a subject or clinical investigational subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment. Safety analysis set included all subjects who had received at least one dose of Lumasiran.
|
||||||
End point type |
Secondary
|
||||||
End point timeframe |
Up to 60 months
|
||||||
|
|||||||
| No statistical analyses for this end point | |||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Up to 60 months
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
Safety analysis set included all subjects who had received at least one dose of Lumasiran.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
25.0
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Lumasiran
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects weighing <10 kg received loading doses of lumasiran SC injection 6.0 mg/kg monthly (QM) for 3 months, followed by maintenance doses of 3.0 mg/kg QM during 6-month primary analysis period (PAP) & QM in 54-month extension period (EP). Subjects transitioning from <10 kg to ≥10 kg continued QM doses at 3.0 mg/kg until next visit coinciding with a dose for subjects weighing ≥10 kg. Thereafter, subjects followed Q3M dosing until end of study. Subjects weighing ≥10 to <20 kg received 6.0 mg/kg QM for 3 months, maintenance doses of 6.0 mg/kg at Months 3 & 6 in PAP & Q3M in EP. Subjects ≥20 kg received 3.0 mg/kg QM for 3 months, followed by maintenance doses of 3.0 mg/kg at Months 3 & 6 in PAP & Q3M in EP. Subjects with weight increases to a new dosing category (<10 kg to ≥10 kg/<20 kg to ≥20 kg) followed new regimen for rest of the study/until next dosing category threshold was reached; subjects did not revert to lower-weight dosing schedules if their weight subsequently decreased. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
09 Aug 2019 |
The following amendments were made to the Protocol: 1. An additional endpoint for the evaluation of the effects of lumasiran on additional measures of urinary oxalate was added. 2. Evaluation of lumasiran on plasma oxalate levels was changed from exploratory to secondary objectives and endpoints. 3. Updated the study sample size from 8 subjects to 20. 4. Updated the analysis population definitions. 5. Description of the efficacy analysis methods was included. |
||
04 May 2020 |
The following amendments were made to the Protocol: 1. Study visit windows were expanded. 2. Allowed flexibility for scope of physical examination; pregnancy testing when offsite visits occur. 3. Revised and updated informed consent instructions. 4. Revised and updated ethical review instructions. 5. Allowed continuous assessments (collected throughout the study) to be assessed via remote contact. |
||
Interruptions (globally) |
|||
| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
