PH1, Primary Hyperoxaluria, RNAi Therapeutic, siRNA, AGT
Conditions
Keywords
Hyperoxaluria, Primary, Hyperoxaluria, Kidney Diseases, Urologic Diseases, Metabolism, Inborn Errors, Genetic Diseases, Inborn, Metabolic Diseases
Brief summary
The purpose of this study is to evaluate the long-term safety and tolerability of lumasiran in participants with Primary Hyperoxaluria Type 1.
Interventions
DRUGLumasiran
Multiple doses of lumasiran by SC injection
Sponsors
Alnylam Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Enrollment within 12 months of completion of Study ALN-GO1-001 * In the opinion of the investigator tolerated the study drug * If taking Vitamin B6 (pyridoxine), willing to remain on a stable regimen for the study duration * Women of child-bearing potential must have a negative pregnancy test, cannot be breast feeding, and must be willing to use a highly effective method of contraception * Willing to provide written informed consent and to comply with study requirements
Exclusion criteria
* Clinically significant health concerns (with the exception of PH1) * Clinically significant cardiovascular abnormality * Abnormal for AST/ALT and any other clinical safety laboratory result considered clinically significant * Requirement for chronic dialysis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With at Least One Adverse Event (AE) | Baseline (Day -1) up to 54 months | AE is any untoward medical occurrence in a participant 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 participants who received any amount of study drug. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in 24-hour Urinary Oxalate Corrected for Body Surface Area (BSA) at 54 Months | Baseline (Day -1) up to 54 months | Oxalate produced by the liver is the key toxic metabolite that drives disease pathology in participants with primary hyperoxaluria type 1 (PH1). The risk of disease complications increase continuously as oxalate levels increase. 24-hour urinary oxalate (millimole \[mmol\]/ 24 hour \[h\]/1.73 meters squared \[m\^2\]) corrected for BSA at each visit per participant was calculated as follows: \[Urine oxalate concentration (micromole per liter \[umol/L\])/1000 (umol/mmol)\]\*\[24hour urine volume (mL)/1000 (mL/L)\]\* \[24 hours/actual collection hours\]\*1.73/(BSA). Baseline was the derived baseline value from the lumasiran treated period of Study ALN-GO1-001. A negative change from baseline indicated a favorable outcome. PD analysis set included all participants who received any amount of study drug and who had at least 1 post-dose urine sample for PD. Overall number of participants analyzed are the number of participants with data available for analysis. |
| Change From Baseline in 24-hour Urinary Oxalate:Creatinine Ratio at 54 Months | Baseline (Day -1) up to 54 months | Baseline is the derived baseline value from the lumasiran treated period of Study ALN-GO1-001. A negative change from baseline indicates a favorable outcome. PD analysis set included all participants who received any amount of study drug and who had at least 1 post-dose urine sample for PD. |
| Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at 54 Months | Baseline (Day -1) up to 54 months | Baseline was defined as the last measurement prior to the first dose of lumasiran in the ALN-GO1-001 study. eGFR was calculated based on the Modification of Diet in Renal Disease (MDRD) formula for participants \>=18 years of age at enrollment and the Schwartz Bedside formula for participants \<18 years of age at enrollment. eGFR based on MDRD formula was calculated as follows: eGFR (mL/min/1.73 m\^2) = 175 × (serum creatinine {SCr} \[μmol/deciliter(dL)\]/88.4)-1.154 × (age)-0.203 × (0.742, if female), or × (1.212, if African American) and based on Schwartz formula: eGFR (mL/min/1.73m2) = (36.2 × height \[cm\])/ SCr (μmol /dL). Safety analysis set included all participants who received any amount of study drug. |
Countries
France, Germany, Israel, Netherlands, United Kingdom
Participant flow
Recruitment details
Participants took part in the study at 9 study centers in France, Germany, Israel, Netherlands and the United Kingdom from 04 April 2018 to 07 February 2023. A total of 20 participants previously treated in Study 001B (NCT02706886) were enrolled and treated in this study.
Pre-assignment details
The cumulative dose of lumasiran administered over 6 months was the same for both 1 mg/kg once monthly (QM) & 3 mg/kg once every 3 months (Q3M), these participants were pooled into one arm as recommended by the Safety Review Committee (SRC). As pre-specified in the SAP, participants who began treatment at 1 mg/kg QM, then transitioned to 3 mg/kg Q3M were to be summarized as a single group. All 3 participants who began treatment at 1 mg/kg QM transitioned to 3 mg/kg Q3M regimen by Month 6.
Participants by arm
| Arm | Count |
|---|---|
| Lumasiran (ALN-GO1): 1.0 mg/kg QM or 3.0 mg/kg Q3M Participants enrolling from study 001B, received lumasiran, SC injection, at a starting dose of 1.0 mg/kg QM or 3.0 mg/kg Q3M from Day 1 up to a maximum of Month 6. By Month 6, all participants were approved to change dose and/or dosing regimen to receive lumasiran, SC injection at a dose of 3.0 mg/kg, Q3M, up to Month 51 of the treatment period.
All 3 participants who began treatment at 1 mg/kg QM transitioned to 3 mg/kg Q3M regimen by Month 6. As the cumulative dose administered over 6 months was the same for both 1 mg/kg QM & 3 mg/kg Q3M, these participants were pooled into one arm as recommended by the SRC. | 13 |
| Lumasiran (ALN-GO1): 3.0 mg/kg QM Participants enrolling from study 001B, received lumasiran, SC injection, at a starting dose of 3.0 mg/kg, QM, from Day 1 up to a maximum of Month 21. By Month 21, all participants were approved to change dosing regimen to receive lumasiran, SC injection, at a dose of 3.0 mg/kg, Q3M, up to Month 51 of the treatment period. | 7 |
| Total | 20 |
Baseline characteristics
| Characteristic | Lumasiran (ALN-GO1): 3.0 mg/kg QM | Total | Lumasiran (ALN-GO1): 1.0 mg/kg QM or 3.0 mg/kg Q3M |
|---|---|---|---|
| Age, Continuous | 12.6 years STANDARD_DEVIATION 3.95 | 14.9 years STANDARD_DEVIATION 10.18 | 16.1 years STANDARD_DEVIATION 12.31 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants | 20 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants | 4 Participants | 2 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 5 Participants | 15 Participants | 10 Participants |
| Sex: Female, Male Female | 4 Participants | 13 Participants | 9 Participants |
| Sex: Female, Male Male | 3 Participants | 7 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 7 |
| other Total, other adverse events | 13 / 13 | 7 / 7 |
| serious Total, serious adverse events | 4 / 13 | 3 / 7 |
Outcome results
Primary
Number of Participants With at Least One Adverse Event (AE)
AE is any untoward medical occurrence in a participant 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 participants who received any amount of study drug.
Time frame: Baseline (Day -1) up to 54 months
Population: The cumulative dose of lumasiran administered over 6 months was the same for both 1 mg/kg QM \& 3 mg/kg Q3M, these participants were pooled into one arm as recommended by the SRC. As pre-specified in the SAP, participants who began treatment at 1 mg/kg QM, then transitioned to 3 mg/kg Q3M were to be summarized as a single group. All 3 participants who began treatment at 1 mg/kg QM transitioned to 3 mg/kg Q3M regimen by Month 6.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lumasiran (ALN-GO1): 1.0 mg/kg QM or 3.0 mg/kg Q3M | Number of Participants With at Least One Adverse Event (AE) | 13 Participants |
| Lumasiran (ALN-GO1): 3.0 mg/kg QM | Number of Participants With at Least One Adverse Event (AE) | 7 Participants |
Secondary
Change From Baseline in 24-hour Urinary Oxalate Corrected for Body Surface Area (BSA) at 54 Months
Oxalate produced by the liver is the key toxic metabolite that drives disease pathology in participants with primary hyperoxaluria type 1 (PH1). The risk of disease complications increase continuously as oxalate levels increase. 24-hour urinary oxalate (millimole \[mmol\]/ 24 hour \[h\]/1.73 meters squared \[m\^2\]) corrected for BSA at each visit per participant was calculated as follows: \[Urine oxalate concentration (micromole per liter \[umol/L\])/1000 (umol/mmol)\]\*\[24hour urine volume (mL)/1000 (mL/L)\]\* \[24 hours/actual collection hours\]\*1.73/(BSA). Baseline was the derived baseline value from the lumasiran treated period of Study ALN-GO1-001. A negative change from baseline indicated a favorable outcome. PD analysis set included all participants who received any amount of study drug and who had at least 1 post-dose urine sample for PD. Overall number of participants analyzed are the number of participants with data available for analysis.
Time frame: Baseline (Day -1) up to 54 months
Population: The cumulative dose of lumasiran administered over 6 months was the same for both 1 mg/kg QM \& 3 mg/kg Q3M, these participants were pooled into one arm as recommended by the SRC. As pre-specified in the SAP, participants who began treatment at 1 mg/kg QM, then transitioned to 3 mg/kg Q3M were to be summarized as a single group. All 3 participants who began treatment at 1 mg/kg QM transitioned to 3 mg/kg Q3M regimen by Month 6.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lumasiran (ALN-GO1): 1.0 mg/kg QM or 3.0 mg/kg Q3M | Change From Baseline in 24-hour Urinary Oxalate Corrected for Body Surface Area (BSA) at 54 Months | -1.425 mmol/24hr/1.73m^2 | Standard Error 0.2188 |
| Lumasiran (ALN-GO1): 3.0 mg/kg QM | Change From Baseline in 24-hour Urinary Oxalate Corrected for Body Surface Area (BSA) at 54 Months | -2.126 mmol/24hr/1.73m^2 | Standard Error 0.5528 |
Secondary
Change From Baseline in 24-hour Urinary Oxalate:Creatinine Ratio at 54 Months
Baseline is the derived baseline value from the lumasiran treated period of Study ALN-GO1-001. A negative change from baseline indicates a favorable outcome. PD analysis set included all participants who received any amount of study drug and who had at least 1 post-dose urine sample for PD.
Time frame: Baseline (Day -1) up to 54 months
Population: The cumulative dose of lumasiran administered over 6 months was the same for both 1 mg/kg QM \& 3 mg/kg Q3M, these participants were pooled into one arm as recommended by the SRC. As pre-specified in the SAP, participants who began treatment at 1 mg/kg QM, then transitioned to 3 mg/kg Q3M were to be summarized as a single group. All 3 participants who began treatment at 1 mg/kg QM transitioned to 3 mg/kg Q3M regimen by Month 6.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lumasiran (ALN-GO1): 1.0 mg/kg QM or 3.0 mg/kg Q3M | Change From Baseline in 24-hour Urinary Oxalate:Creatinine Ratio at 54 Months | -0.2175 mmol/mmol | Standard Deviation 0.0388 |
| Lumasiran (ALN-GO1): 3.0 mg/kg QM | Change From Baseline in 24-hour Urinary Oxalate:Creatinine Ratio at 54 Months | -0.2480 mmol/mmol | Standard Deviation 0.04047 |
Secondary
Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at 54 Months
Baseline was defined as the last measurement prior to the first dose of lumasiran in the ALN-GO1-001 study. eGFR was calculated based on the Modification of Diet in Renal Disease (MDRD) formula for participants \>=18 years of age at enrollment and the Schwartz Bedside formula for participants \<18 years of age at enrollment. eGFR based on MDRD formula was calculated as follows: eGFR (mL/min/1.73 m\^2) = 175 × (serum creatinine {SCr} \[μmol/deciliter(dL)\]/88.4)-1.154 × (age)-0.203 × (0.742, if female), or × (1.212, if African American) and based on Schwartz formula: eGFR (mL/min/1.73m2) = (36.2 × height \[cm\])/ SCr (μmol /dL). Safety analysis set included all participants who received any amount of study drug.
Time frame: Baseline (Day -1) up to 54 months
Population: The cumulative dose of lumasiran administered over 6 months was the same for both 1 mg/kg QM \& 3 mg/kg Q3M, these participants were pooled into one arm as recommended by the SRC. As pre-specified in the SAP, participants who began treatment at 1 mg/kg QM, then transitioned to 3 mg/kg Q3M were to be summarized as a single group. All 3 participants who began treatment at 1 mg/kg QM transitioned to 3 mg/kg Q3M regimen by Month 6.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lumasiran (ALN-GO1): 1.0 mg/kg QM or 3.0 mg/kg Q3M | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at 54 Months | 0.674 mL/min/1.73m^2 | Standard Error 3.797 |
| Lumasiran (ALN-GO1): 3.0 mg/kg QM | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at 54 Months | -12.026 mL/min/1.73m^2 | Standard Error 3.6369 |