Conditions: PH1 Primary Hyperoxaluria RNAi Therapeutic siRNA AGT
Keywords: Hyperoxaluria, Primary Hyperoxaluria Kidney Diseases Urologic Diseases Metabolism, Inborn Errors Genetic Diseases, Inborn Metabolic Diseases
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 20
Healthy volunteers: no

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.

Detailed description:

Arms:
arm 1: Participants enrolling from study 001B (NCT02706886), received lumasiran, subcutaneous (SC) injection, at a starting dose of 1.0 milligrams per kilograms (mg/kg) once monthly (QM) or 3.0 mg/kg once every 3 months \[Q3M\]) 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 Safety Review Committee (SRC). arm 2: 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.

Interventions: intervention 1: Lumasiran
Intervention descriptions: intervention 1: Multiple doses of lumasiran by SC injection

Protocol document:
Prot_000.pdf: 
 
 
Official Title:  
A Phase 2, Multicenter, Open-Label, Extension Study to Evaluate the Long-
Term Administration of ALN-GO1 in Patients With Primary Hyperoxaluria 
Type 1 
 
NCT Number:   
NCT03350451 
 
Document Date:   
Clinical Study Protocol, 04 May 2020 






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INVESTIGATOR’S AGREEMENT 
 
I have read the ALN-GO1-002 protocol and agree to conduct the study as outlined.  I agree to 
maintain the confidentiality of all information received or developed in connection with this 
protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 


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PROTOCOL SYNOPSIS 
Protocol Title 
A Phase 2, Multicenter, Open-Label, Extension Study to Evaluate the Long-Term 
Administration of ALN-GO1 in Patients with Primary Hyperoxaluria Type 1 
Product Name 
lumasiran (ALN-GO1) 
Indication 
Primary Hyperoxaluria Type 1 (PH1) 
Phase 
2 
Study center(s)   
Up to 15 clinical study centers, worldwide 
Objectives 
Primary 
• Evaluate the long-term safety of multiple doses of ALN-GO1 in patients with PH1 
Secondary 
• Evaluate the pharmacodynamic (PD) effect of ALN-GO1 on urinary oxalate 
excretion 
• Characterize the effect of ALN-GO1 on markers of renal function 
Exploratory Objectives 
• Characterize the pharmacokinetics (PK) of ALN-GO1 
• Evaluate the PD effect of ALN-GO1 on urinary glycolate excretion, plasma 
oxalate concentration, plasma glycolate concentration, and urine 
oxalate:creatinine ratio 
• Evaluate the incidence of anti-drug antibodies (ADA) 
Endpoints 
Primary 
• Incidence of adverse events (AEs) 
Secondary 
• Change in 24-hour urinary oxalate corrected for body surface area (BSA) over 
time 
• Change in 24-hour urinary oxalate:creatinine ratio over time  
• Change in estimated glomerular filtration rate (eGFR) over time 


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Exploratory 
• Describe the effects of ALN-GO1 on other safety parameters, including 
assessments of vital signs, electrocardiograms (ECGs), renal ultrasounds, clinical 
laboratory parameters, and physical examinations 
• Assess ALN-GO1 plasma PK parameters including maximum plasma 
concentration (Cmax), time to maximum plasma concentration (tmax), elimination 
half-life (t½β), area under the concentration-time curve (AUC), fraction of drug 
excreted in urine (Fe), apparent clearance (CL/F), and apparent volume of 
distribution (V/F) 
• Change from Baseline over the course of the study in the following PD 
parameters: 
− Urinary glycolate excretion 
− Plasma oxalate concentration 
− Plasma glycolate concentration 
− Spot urinary oxalate:creatinine ratio 
• Incidence of ADA 
Study Design 
This is a multicenter, open-label, extension study to evaluate the long-term safety, PK, and 
PD of subcutaneously administered ALN-GO1 in patients with PH1 who completed 
Study ALN-GO1-001.  
Consented eligible patients will enroll in this study and initially receive subcutaneous (SC) 
injections of ALN-GO1 at the same dose and regimen as they received in 
Study ALN-GO1-001.  Based on emerging data, the safety review committee (SRC) may 
authorize an alteration of dose and/or dose regimen to one that is no higher than the highest 
dose evaluated in either Part A or Part B of Study ALN-GO1-001.  If such an authorization 
occurs, dose and/or dose regimen alteration may occur for an individual patient or entire 
cohort.  This alteration may apply to subsequent doses for patients already enrolled and 
previously dosed in the study and/or to the initial dose and regimen for patients who have not 
yet been dosed in this study.  Patients will be assessed for safety at each study visit.  PD 
assessments will be completed quarterly over the first 12 months on study, and approximately 
every 6 months thereafter for the study duration.  PK assessments will be conducted during 
the first 12 months of the study. 
Patients may receive ALN-GO1 as long as they do not fulfill any of the study discontinuation 
criteria or until ALN-GO1 is commercially available in the patient’s territory or the 
ALN-GO1 development program is discontinued (whichever comes first). 
Number of Planned Patients 
Up to 20 patients are planned for enrollment in this study. 
Diagnosis and Main Eligibility Criteria 
Patients diagnosed with PH1, who completed Study ALN-GO1-001. 


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Investigational Product, Dose and Mode of Administration 
ALN-GO1 will be supplied as a sterile solution in water for subcutaneous (SC) injection.  
ALN-GO1 is a synthetic, double-stranded small interfering RNA (siRNA) oligonucleotide 
directed against hydroxyacid oxidase 1 (HAO1) mRNA that is covalently linked to a ligand 
containing 3 N-acetylgalactosamine (GalNAc) residues.  Patients will initially receive SC 
injections of ALN-GO1 at the same dose and regimen they received in Study ALN-GO1-001. 
Based on emerging data, the SRC can authorize an alteration of dose and/or dose regimen to 
one that is no higher than the highest dose evaluated in either Part A or Part B of Study 
ALN-GO1-001.  If such an authorization occurs, dose and/or dose regimen alteration may 
occur for an individual patient or entire cohort.  This alteration may apply to subsequent 
doses for patients already enrolled and previously dosed in the study and/or to the initial dose 
and regimen for patients who have not yet been dosed in this study. 
Reference Therapy, Dose and Mode of Administration 
Not applicable 
Duration of Treatment 
The estimated duration of treatment in this study is up to 54 months. 
Statistical Methods 
Sample size is not determined through a power calculation but based on the anticipated 
number of patients who complete Study ALN-GO1-001 and are eligible to enroll in this 
study. 
The safety analysis set will include all patients who received at least 1 dose of study drug.  
Patients with missing PD or PK data will be excluded from those analyses as appropriate. 
Incidence of AEs will be summarized by maximum severity and relationship to ALN-GO1.  
Incidence of serious adverse events (SAEs) and AEs leading to discontinuation will also be 
tabulated. By-patient listings will be provided for deaths, SAEs, and AEs leading to 
discontinuation. 
Descriptive statistics will be provided for clinical laboratory evaluations and vital signs data.  
Laboratory shift tables from baseline to worst values will be presented. Abnormal physical 
examination findings, ECG, and echo data will be presented in by-patient listings.  
Descriptive statistics will be provided for ECG interval data and presented as both actual 
values and changes from baseline relative to each on study evaluation and to the last 
evaluation on-study. 
Descriptive statistics (eg, mean and standard error of the mean) for observed levels of PD 
parameters and the relative change from baseline will be presented for each of the postdose 
follow-up time points. 
PK analyses will be conducted using non-compartmental methods.  PK parameters including 
Cmax, tmax, t½β, AUC, Fe, CL/F, and V/F will be estimated.  Other PK parameters may be 
calculated, if deemed necessary.  Anti-drug antibody results will be summarized 
descriptively.  A by-patient listing will also be provided. 






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Abbreviations:  ADA=anti-drug antibodies; AE=adverse event; BMI=body mass index; D=day; disc=discontinuation; ECG=electrocardiogram; Echo=echocardiogram; 
eGFR=estimated glomerular filtration rate; EOT=end of treatment; ET=early termination; F/U=follow-up; KDQOL=Kidney Disease Quality of Life Questionnaire; M=month; 
PD=pharmacodynamics; PedsQL=Pediatric Quality of Life Inventory; PK=pharmacokinetic; Q=every; QOL=quality of life; SC=subcutaneous. 
Notes: 
• 
Body weight must be obtained within 4 months prior to dosing.  
• 
Where feasible, when scheduled at the same time points, the assessments of vital signs and 12-lead ECGs should be performed first, before the physical examinations, 
blood sample collections, and urine collections. 
• 
Assessments should be performed predose, where applicable, and unless otherwise noted. 
• 
Grey shaded solid columns indicate the study day when the 24-hour urine collection for PD analysis should begin.  Patients may be admitted to the clinical study center 
to complete the 24-hour urine collections.  Assessments may be performed at the study center or at an offsite location (eg, patient’s home).  
• 
Visits and study drug dosing may be conducted offsite where applicable country and local regulations and infrastructure allow (at the discretion of the Investigator, based 
on safety and tolerability) provided the patient has tolerated ALN-GO1 administered in the clinic.  If a visit is conducted offsite, a body system assessment may be 
performed in lieu of a physical examination.  
• 
In situations where a study visit is unable to be completed (either at the site or offsite by a healthcare professional), the Investigator (or delegate) will verbally contact the 
patient within the study visit window to assess concomitant medications and adverse events. 
• 
Hatched columns indicate study visits to be conducted only for subjects who require monthly dosing. 
 
a Screening and Baseline visits may be combined, if possible. Assessments required prior to dosing during the screening or baseline visit in this protocol do not need to be repeated 
if performed in the ALN-GO1-001 protocol within the 30 days before the first dose with the exception of vital signs, ECGs, and physical examinations. 
b Patients who discontinue study drug early will be asked to return for their next scheduled visit to complete ET assessments and to complete safety follow-up visits once every 
3 months, per the safety follow-up schedule in this table, for up to 6 months after the last dose of lumasiran (Section 5.3.1). 
c Demographic data will be obtained from Study ALN-GO1-001. 
d Complete medical history will be obtained at screening and any changes will be updated on admission at the Baseline visit, if different from the Screening visit.  Events 
occurring after signing of the informed consent or assent (if applicable) form and before study drug administration will be captured as medical history. 
e During the Baseline visit and at EOT, height will be measured in triplicate for all patients; for all other study visits height will only be measured for patients <18 years of age.  
For patients <18 years of age, at each time point, height will be measured in centimeters, and in triplicate, to facilitate calculation of eGFR using the Schwartz Bedside formula.   
f Vital signs (blood pressure, heart rate, body temperature, and respiratory rate) will be measured in the supine or seated position after the patient has rested comfortably for 
approximately 10 minutes.  Body temperature can be measured using oral, tympanic, or axillary methods; the temperature measurement method should be consistently utilized 
for the study duration, if feasible.  At Baseline only, vital signs will be measured within 1 hour predose; and 30 minutes (±5 minutes) and 4 hours (±15 minutes) postdose. 
g Baseline visit 12-lead ECGs are triplicate and will be measured approximately 5 minutes apart.  Recordings will be obtained after the patient has rested comfortably in the supine 
position for approximately 10 minutes.  Patients should remain supine between ECGs.  ECGs should be obtained at visits to the clinical study center where indicated in the 
Schedule of Assessments prior to study drug administration (see Section 7.4.4). ECGs do not need to be conducted for interim doses.  After Month 12, ECGs will be performed 
at Months 24, 36, 48, and 54; all postbaseline ECGs will be measured in singlicate. 
h Echo should be performed at Baseline only if the most recent echo was performed ≥30 days before Day 1. Echo will be performed during the first 12 months only. 
i Pregnancy tests will be performed for women of childbearing potential only.  Pregnancy testing should be performed prior to each dose; results of the pregnancy test must be 
known before ALN-GO1 administration.  A serum pregnancy test will be performed at Baseline or after the onset of menarche if the patient was not of childbearing potential at 
Baseline, and urine pregnancy tests will be performed thereafter, and any time pregnancy is suspected.  Patients who become pregnant should inform the clinical study center as 
soon as a pregnancy is confirmed. 
j Clinical laboratory tests will be evaluated by a central laboratory. 
k Study drug will be administered via SC injection.  In patients whose disease progression requires a dialysis regimen, patients will continue on their current dosing regimen (see 
Section 6.2.2). 
l Blood and urine samples for PK analysis will be obtained at the time points listed in Table 5. 
m During the Baseline visit, the blood sample for PD analysis must be collected within 1 hour predose.  In patients who progress to requiring dialysis, when a dialysis session is on 
same day as scheduled visit, the blood sample for PD analysis must be collected predialysis.  


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n Single, 24-hour urine sample collections will be performed before dosing, as indicated.  For study visits through the Month 12 visit, urine collections should be completed within 
7 days before each study visit.  For study visits after the Month 12 visit (ie, Month 18 through the EOS) urine collections should be completed within 14 days before each study 
visit.  
o QOL questionnaires include the KDQOL-36 for adults (age ≥18 years at Screening), and the PedsQL (the generic and ESRD modules) for children (age <18 years at screening). 
p After Month 12, renal ultrasound will be performed at Months 24, 36, 48, and 54 (see Section 7.4.6). 
q Events occurring or continuing after the completion of follow-up of Study ALN-GO1-001 and before first study drug administration in ALN-GO1-002 will be captured as 
medical history.  Events that occur after first study drug administration, and baseline events that worsen after first study drug administration in ALN-GO1-002, must be recorded 
and reported as AEs.   
 


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TABLE OF CONTENTS 
SPONSOR PROTOCOL APPROVAL ...........................................................................................2 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
PROTOCOL SYNOPSIS ................................................................................................................4 
TABLE OF CONTENTS ...............................................................................................................11 
LIST OF TABLES .........................................................................................................................14 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................15 
1. 
INTRODUCTION ......................................................................................................17 
1.1. 
Disease Overview .......................................................................................................17 
1.2. 
ALN-GO1 ...................................................................................................................18 
1.3. 
Study Design Rationale ..............................................................................................18 
1.4. 
Dose Rationale ............................................................................................................18 
1.5. 
Benefit-Risk Assessment ............................................................................................18 
2. 
OBJECTIVES .............................................................................................................20 
2.1. 
Primary Objective .......................................................................................................20 
2.2. 
Secondary Objectives .................................................................................................20 
2.3. 
Exploratory Objectives ...............................................................................................20 
3. 
ENDPOINTS ..............................................................................................................20 
3.1. 
Primary Endpoint ........................................................................................................20 
3.2. 
Secondary Endpoints ..................................................................................................20 
3.3. 
Exploratory Endpoints ................................................................................................20 
4. 
INVESTIGATIONAL PLAN .....................................................................................21 
4.1. 
Summary of Study Design ..........................................................................................21 
4.2. 
Duration of Treatment ................................................................................................21 
4.2.1. 
Definition of the End of Study for an Individual Patient ............................................21 
4.3. 
Number of Patients .....................................................................................................21 
4.4. 
Method of Assigning Patients to Treatment Groups ..................................................22 
4.5. 
Blinding ......................................................................................................................22 
4.6. 
Safety Review Committee ..........................................................................................22 
5. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................22 
5.1. 
Inclusion Criteria ........................................................................................................22 
5.2. 
Exclusion Criteria .......................................................................................................22 


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5.3. 
Removal from Therapy or Assessment.......................................................................23 
5.3.1. 
Discontinuation of Study Drug ...................................................................................23 
5.3.2. 
Withdrawal From Study .............................................................................................24 
6. 
TREATMENTS ..........................................................................................................24 
6.1. 
Treatments Administered ............................................................................................24 
6.2. 
Investigational Study Drug .........................................................................................24 
6.2.1. 
Description ..................................................................................................................24 
6.2.2. 
Dose and Administration ............................................................................................24 
6.2.3. 
Dose Modifications .....................................................................................................25 
6.2.3.1. 
Liver Function Test Criteria for Withholding, Monitoring and Stopping 
Study Drug Dosing .....................................................................................................25 
6.2.4. 
Preparation, Handling, and Storage ............................................................................26 
6.2.5. 
Packaging and Labeling ..............................................................................................27 
6.2.6. 
Accountability .............................................................................................................27 
6.3. 
Concomitant Medications ...........................................................................................27 
6.4. 
Contraceptive Requirements .......................................................................................28 
6.5. 
Treatment Compliance ................................................................................................28 
7. 
STUDY ASSESSMENTS ..........................................................................................28 
7.1. 
Screening/Baseline Assessments ................................................................................29 
7.2. 
Pharmacodynamic and Renal Assessments ................................................................29 
7.2.1. 
Validity Criteria for 24-hour Urine Collections .........................................................30 
7.3. 
Pharmacokinetic Assessments ....................................................................................30 
7.4. 
Safety Assessments .....................................................................................................30 
7.4.1. 
Vital Signs ..................................................................................................................30 
7.4.2. 
Weight and Height ......................................................................................................31 
7.4.3. 
Physical Examination .................................................................................................31 
7.4.4. 
Electrocardiogram .......................................................................................................31 
7.4.5. 
Echocardiography .......................................................................................................32 
7.4.6. 
Renal Ultrasound ........................................................................................................32 
7.4.7. 
Clinical Laboratory Assessments ...............................................................................32 
7.4.7.1. 
Immunogenicity ..........................................................................................................33 
7.4.7.2. 
Pregnancy Testing ......................................................................................................33 
7.4.7.3. 
Additional Liver Function Assessments .....................................................................34 


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7.4.7.4. 
Maximum Blood Volume ...........................................................................................34 
7.4.8. 
Adverse Events ...........................................................................................................35 
7.4.8.1. 
Definitions ..................................................................................................................35 
7.4.8.2. 
Eliciting and Recording Adverse Events ....................................................................37 
7.4.8.3. 
Serious Adverse Events Require Immediate Reporting to Sponsor/Designee ...........37 
7.4.8.4. 
Sponsor Safety Reporting to Regulatory Authorities .................................................38 
7.4.8.5. 
Serious Adverse Event Notification to the Institutional Review 
Board/Independent Ethics Committee ........................................................................39 
7.4.8.6. 
Pregnancy Reporting ..................................................................................................39 
7.4.8.7. 
Overdose Reporting ....................................................................................................39 
7.4.9. 
COVID-19 Data Collection ........................................................................................39 
7.5. 
Other Assessments ......................................................................................................39 
7.5.1. 
Quality of Life (QOL) ................................................................................................39 
8. 
STATISTICS ..............................................................................................................40 
8.1. 
Determination of Sample Size ....................................................................................40 
8.2. 
Statistical Methodology ..............................................................................................40 
8.2.1. 
Populations to be Analyzed ........................................................................................40 
8.2.2. 
Examination of Subgroups .........................................................................................40 
8.2.3. 
Handling of Missing Data ...........................................................................................40 
8.2.4. 
Baseline Evaluations ...................................................................................................40 
8.2.5. 
Pharmacodynamic Analysis........................................................................................40 
8.2.6. 
Pharmacokinetic Analysis ..........................................................................................41 
8.2.7. 
Anti-drug Analyses .....................................................................................................41 
8.2.8. 
Safety Analyses ..........................................................................................................41 
8.2.9. 
Other Analyses ............................................................................................................41 
8.2.10. 
Interim Analysis ..........................................................................................................42 
9. 
STUDY ADMINISTRATION ...................................................................................42 
9.1. 
Ethical and Regulatory Considerations ......................................................................42 
9.1.1. 
Informed Consent .......................................................................................................42 
9.1.2. 
Ethical Review ............................................................................................................42 
9.1.3. 
Serious Breach of Protocol .........................................................................................43 
9.1.4. 
Study Documentation, Confidentiality, and Records Retention .................................43 
9.1.5. 
End of the Study .........................................................................................................44 


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9.1.6. 
Discontinuation of the Clinical Study.........................................................................44 
9.2. 
Data Quality Control and Quality Assurance .............................................................44 
9.2.1. 
Data Handling .............................................................................................................44 
9.2.2. 
Study Monitoring ........................................................................................................44 
9.2.3. 
Audits and Inspections ................................................................................................45 
9.3. 
Publication Policy .......................................................................................................45 
10. 
LIST OF REFERENCES ............................................................................................46 
11. 
APPENDICES ............................................................................................................47 
11.1. 
Pharmacokinetic Assessment Time Points .................................................................47 
11.2. 
Blood Volume Limits in Pediatric Patients ................................................................48 
 
LIST OF TABLES 
Table 1: 
Schedule of Assessments ..............................................................................................7 
Table 2: 
Monitoring and Dosing Rules for Asymptomatic Patients with Confirmed 
Isolated Elevations of ALT and/or AST >3× ULN, with No Alternative 
Cause Identified ..........................................................................................................26 
Table 3: 
Clinical Laboratory Assessments ...............................................................................32 
Table 4: 
Hepatic Assessments in Patients Who Experience Elevated Transaminases .............34 
Table 5 
Pharmacokinetic Time Points .....................................................................................47 
Table 6: 
Maximum Allowable Total Blood Volume Collection Chart ....................................48 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation 
Explanation 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
AGT 
Liver peroxisomal enzyme alanine-glyoxylate aminotransferase 
AGXT 
Alanine glyoxylate aminotransferase 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
BMI 
Body mass index 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
Cmax 
Maximum plasma concentration 
CL/F 
Apparent clearance 
COVID-19 
Coronavirus Disease 2019 
CRO 
Contract research organization 
eCRF 
Electronic case report form 
ECG 
Electrocardiogram 
Echo 
Echocardiography 
EDC 
Electronic data capture 
eGFR 
Estimated glomerular filtration rate 
EOS 
End of Study (visit) 
EOT 
End of Treatment (visit) 
ESRD 
End-stage renal disease 
Fe 
Fraction of drug excreted in urine 
FSH 
Follicle-stimulating hormone 
GalNAc 
N-acetyl galactosamine 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GO 
glycolate oxidase 
HAO1 
Hydroxyacid oxidase 1 
HCV 
Hepatitis C virus 


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Abbreviation 
Explanation 
HIV 
Human immunodeficiency virus 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ISRs 
Injection site reactions 
KDQOL 
Kidney Disease Quality of Life Questionnaire 
LFT 
Liver function test 
MDRD 
Modification of Diet in Renal Disease (formula) 
MedDRA 
Medical Dictionary for Regulatory Activities 
mRNA 
Messenger ribonucleic acid 
NHP 
Non-human primate 
PD 
Pharmacodynamics 
PedsQL 
Pediatric Quality of Life Inventory 
PH1 
Primary hyperoxaluria type 1 
PK 
Pharmacokinetics 
QOL 
Quality of life 
QTcB 
Bazett-corrected QT interval 
QTcF 
Fridericia corrected QT interval 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
siRNA 
Small interfering ribonucleic acid 
SOC 
System Organ Class 
SRC 
Safety Review Committee 
SUSARs 
Suspected unexpected serious adverse reactions 
t½β 
Elimination half-life 
tmax 
Time to maximum plasma concentration   
ULN 
Upper limit of normal 
V/F 
Apparent volume of distribution 
WOCBP 
Women of childbearing potential 


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1. 
INTRODUCTION 
1.1. 
Disease Overview  
Alnylam Pharmaceuticals is developing lumasiran (ALN-GO1), a synthetic, small interfering 
RNA (siRNA) therapeutic directed against hydroxyacid oxidase 1 (HAO1) messenger RNA 
(mRNA), which is covalently linked to a ligand containing 3 N-acetylgalactosamine residues.  
ALN-GO1 is currently in development for the treatment of primary hyperoxaluria type 1 (PH1). 
PH1 is a rare, autosomal recessive disease characterized by excessive production of oxalate and 
consequent hyperoxaluria.  Given the relative insolubility of oxalate, it crystallizes in the urinary 
tract, primarily as calcium oxalate.  This results in recurrent nephrolithiasis and/or 
nephrocalcinosis, with progressive renal disease leading to renal failure.[Cochat and Rumsby 
2013]  As renal function declines, calcium oxalate is deposited systemically, with consequent 
end organ damage.  This stage of the disease, called systemic oxalosis, arises when the 
glomerular filtration rate (GFR) has declined to below 30 to 45 mL/min per 1.73 m2.[Cochat and 
Rumsby 2013] 
PH1 is caused by mutations in both alleles of the alanine glyoxylate aminotransferase (AGXT) 
gene, which encodes the liver peroxisomal enzyme alanine-glyoxylate aminotransferase (AGT).  
Over 150 mutations in AGXT have been described.  There are broad genotype–phenotype 
associations, notably in the responsiveness of disease caused by some mutations, to treatment 
with pyridoxine (vitamin B6).  However, disease phenotype can be highly variable, including the 
responsiveness to vitamin B6 treatment, even within families.[Hopp 2015] 
Given the rarity and heterogeneity of PH1, many patients go undiagnosed for years after the 
initial clinical manifestations of the disease.  The incidence of PH1 is approximately 1 in 
120,000 live births, and the prevalence is 1 to 3 per million in North America and 
Europe.[Cochat and Rumsby 2013; Hopp 2015; Hoppe 2010]  The disease is more prevalent in 
areas where consanguineous marriages are common, especially in the Middle East and Northern 
Africa.[Al-Eisa 2004; Kamoun and Lakhoua 1996] 
PH1 is primarily a pediatric disease, with symptoms first appearing in approximately half 
(48.6%) of the patients in the Rare Kidney Stone Consortium Primary Hyperoxaluria Registry 
between birth and four years of age.  Approximately three-quarters of patients (74.7%) showed 
signs or symptoms before the age of 15 and 83.5% showed symptoms before 20 years of age.  In 
comparison, only 16.5% of patients first displayed symptoms after age 20.  Additionally, nearly 
one third (29.9%) of patients were diagnosed between birth and four years of age and two-thirds 
(66%) were diagnosed before 20 years of age.[Atlas 2007]  The majority of patients are, 
therefore, diagnosed as children, and consequently, are more likely to have some preservation of 
renal function at time of diagnosis.  
Most PH1 patients exhibit urinary oxalate excretion greater than 2-fold the upper limit of normal 
(ULN), although patients with severely compromised renal function may have lower excretion 
rates.  PH1 is definitively diagnosed by gene sequencing to detect pathological mutations in 
AGXT, or by evaluation of AGT enzymatic activity in liver tissue obtained by biopsy.  
Currently, there are no approved therapies for the treatment of PH1.  Disease management is 
based on supportive measures, including high fluid intake, potassium citrate (to increase urinary 
oxalate solubility), vitamin B6, and treatment of complications such as urinary tract stones and 


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infections.  Dietary modification plays a minor role in treatment since endogenous oxalate 
production far exceeds dietary intake.  Patients progressing to or presenting with end-stage renal 
disease (ESRD) require intense kidney dialysis.  However, dialysis, day and night, 6 days per 
week, may be inadequate to effectively offload accumulating oxalate.[Cochat 2012]  Combined 
liver/kidney transplantation offers potentially curative therapy, but with limited availability, the 
attendant medical risks, and intense use of health care resources.  Therefore, there is a high 
unmet medical need for additional treatments for patients with PH1.  The deterioration of renal 
function that occurs in PH1 disease indicates the importance of investigating potentially disease-
modifying interventions as early as possible after diagnosis. 
1.2. 
ALN-GO1 
ALN-GO1 (containing siRNA drug substance ALN-65585) is an investigational medicinal 
product that comprises a synthetic siRNA that specifically targets the mRNA of the hydroxyacid 
oxidase (HAO1) gene which encodes glycolate oxidase (GO).  The drug substance is conjugated 
to an N-Acetyl galactosamine ligand (GalNAc) to facilitate targeted delivery to the liver and 
formulated in Water for Injection. 
1.3. 
Study Design Rationale 
This is a Phase 2, multicenter, open-label, extension study to evaluate the long-term 
administration of ALN-GO1 in patients with PH1.  Within 12 months of completing 
Study ALN-GO1-001, patients may enroll in this study to receive open-label treatment with 
ALN-GO1 for approximately 4.5 years.  Safety and efficacy assessments will be performed 
periodically as outlined in the Schedule of Assessments (Table 1). 
1.4. 
Dose Rationale 
Patients will initially receive ALN-GO1 at the same dose and regimen they received in 
Study ALN-GO1-001.  Based on emerging data, the Safety Review Committee (SRC) can 
authorize an alteration of dose and/or dose regimen to one that is no higher than the highest dose 
evaluated in either Part A or Part B of Study ALN-GO1-001.  This alteration may apply to 
subsequent doses for patients already enrolled and previously dosed in the study and/or to the 
initial dose and regimen for patients who have not yet been dosed in this study. 
1.5. 
Benefit-Risk Assessment  
ALN-GO1 is designed to reduce hepatic production of oxalate.  The potential benefit of this 
treatment is the amelioration of the clinical course of PH1 in patients across the spectrum of 
disease, irrespective of age and disease stage.  While the clinical benefit of long-term treatment 
with ALN-GO1 is unknown at present, it is anticipated that long term suppression of urinary 
oxalate excretion with ALN-GO1 could provide meaningful benefit.  The potential risks of 
ALN-GO1 include pathway- and disease-specific risks, and non-specific, off-target risks.  
Reduction of GO is expected to lead to reduction in hepatic oxalate production at the expense of 
increased glycolate, an organic acid.  Therefore, study drug-induced increases in plasma and 
urine glycolate levels are anticipated in patients administered ALN-GO1.  Since elevated levels 
of this organic acid are expected to be readily buffered, and its high solubility is not expected to 
result in crystallization in the urinary tract, the potential risk of increased glycolate production is 


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considered low.  Importantly, no toxicity has been observed in non-human primate (NHP) 
pharmacology and toxicology studies, where profound suppression of hepatic GO, with 
associated increases in plasma glycolate levels, has been demonstrated.  In particular, 
maintenance of normal serum bicarbonate levels in these animals indicates that there is no 
evidence of acidosis.  Finally, a recent clinical case study described a child with an incidentally 
discovered homozygous defect in HAO1, the gene encoding GO.  The patient exhibited marked 
elevations of urine glycolate, but no associated metabolic abnormalities and normal renal and 
hepatic function.[Frishberg 2014] 
The potential for negative consequences of ALN-GO1 administration to patients with impaired 
renal function, including those with ESRD, is considered low.  ALN-GO1, in common with other 
Sponsor-developed RNA interference compounds, is conjugated to N-acetyl galactosamine 
(GalNAc) to enable rapid and specific uptake by hepatocytes via the asialoglycoprotein receptor.  
Clinically effective doses of ALN-GO1 are not expected to saturate this receptor-mediated 
uptake or to result in enhanced extra-hepatic uptake or significant extra-hepatic exposure via 
accumulation.  
Study assessments and visits have been reduced as much as possible to minimize the burden of 
the study on children without risking patient safety.  The potential benefit to children enrolled in 
this study includes possible reduction in oxalate production during the study period, which may 
have an ameliorating effect on the course of their disease.  In addition, experience in children 
with this disease under carefully controlled conditions will provide data that may enhance the 
future development of this therapeutic.  
Non-specific potential risks to patients include: embryofetal risk, injection site reactions (ISRs), 
and liver function test (LFT) abnormalities. 
No data are available on the use of ALN-GO1 in pregnancy or while breastfeeding; however, 
there is no implication of human teratogenicity based on class effects or genotoxic potential.  
Embryofetal risk is limited by requiring that women of childbearing potential (WOCBP) must 
have a negative pregnancy test, cannot be breast feeding, and must be willing to use a highly 
effective method of contraception as specified in the protocol.  No male contraception is 
considered to be required. 
ALN-GO1 is administered subcutaneously, and occurrence of ISRs will be carefully monitored.  
As ALN-GO1 is a hepatically-targeted therapeutic, and although nonclinical data suggest that 
there is a wide margin between the proposed clinical doses and any hepatic findings in 
toxicology studies, LFTs will be carefully monitored. 
During the course of this study, safety will be monitored by study Investigators, the Sponsor 
Medical Monitor, and a SRC. 
Overall, in this clinical study of ALN-GO1, the benefit-risk assessment is favorable in patients 
with PH1.  The suppression of urinary oxalate excretion with ALN-GO1 may provide a 
pharmacological benefit.   
The dose or dose regimen used in this study may be adjusted based on emerging data to enable 
an optimal pharmacodynamic (PD) effect that is well tolerated. 
A summary of the clinical and nonclinical data relevant to the investigational drug and its study 
in human subjects is provided in the Investigator’s Brochure. 


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2. 
OBJECTIVES 
2.1. 
Primary Objective 
• Evaluate the long-term safety of multiple doses of ALN-GO1 in patients with PH1 
2.2. 
Secondary Objectives 
• Evaluate the PD effect of ALN-GO1 on urinary oxalate excretion 
• Characterize the effect of ALN-GO1 on markers of renal function 
2.3. 
Exploratory Objectives 
• Characterize the pharmacokinetics (PK) of ALN-GO1 
• Evaluate the PD effect of ALN-GO1 on urinary glycolate excretion, plasma oxalate 
concentration, plasma glycolate concentration, and urine oxalate:creatinine ratio 
• Evaluate the incidence of anti-drug antibodies (ADA) 
3. 
ENDPOINTS 
3.1. 
Primary Endpoint 
• Incidence of adverse events (AEs)  
3.2. 
Secondary Endpoints 
• Change in 24-hour urinary oxalate corrected for body surface area (BSA) over time 
• Change in 24-hour urinary oxalate:creatinine ratio over time  
• Change in estimated glomerular filtration rate (eGFR) over time 
3.3. 
Exploratory Endpoints 
• Describe the effects of ALN-GO1 on other safety parameters, including assessments 
of vital signs, electrocardiograms (ECG), renal ultrasounds, clinical laboratory 
parameters, and physical examinations. 
• Assess ALN-GO1 plasma PK parameters including maximum plasma concentration 
(Cmax), time to maximum plasma concentration (tmax), elimination half-life (t½β), area 
under the concentration-time curve (AUC), fraction of drug excreted in urine (Fe), 
apparent clearance (CL/F), and apparent volume of distribution (V/F). 
• Change from Baseline over the course of the study in the following PD parameters: 
− Urinary glycolate excretion  
− Plasma oxalate concentration 
− Plasma glycolate concentration 


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− Spot urinary oxalate:creatinine ratio 
• Incidence of ADA 
4. 
INVESTIGATIONAL PLAN 
4.1. 
Summary of Study Design 
This is a multicenter, open-label extension study to evaluate the long-term safety, PK, and PD of 
subcutaneously administered ALN-GO1 in patients with PH1 who completed 
Study ALN-GO1-001.  
Consented eligible patients will enroll in this study and initially receive subcutaneous (SC) 
injections of ALN-GO1 at the same dose and regimen as they received in Study ALN-GO1-001.  
Based on emerging data, the SRC may authorize an alteration of dose and/or dose regimen to one 
that is no higher than the highest dose evaluated in either Part A or Part B of 
Study ALN-GO1-001.  If such an authorization occurs, dose and/or dose regimen alteration may 
occur for an individual patient or entire cohort.  This alteration may apply to subsequent doses 
for patients already enrolled and previously dosed in the study and/or to the initial dose and 
regimen for patients who have not yet been dosed in this study.  Patients will be assessed for 
safety at each study visit.   
PD assessments will be completed quarterly over the first 12 months on study, and 
approximately every 6 months thereafter for the study duration.  PK assessments will be 
conducted during the first 12 months on study (Table 1). 
Patients may receive ALN-GO1 as long as they do not fulfill any of the study discontinuation 
criteria (see Section 5.3.1) or until ALN-GO1 is commercially available in the patient’s territory 
or the ALN-GO1 development program is discontinued (whichever comes first). 
4.2. 
Duration of Treatment 
The estimated duration of treatment in this study is up to 54 months.  
4.2.1. 
Definition of the End of Study for an Individual Patient 
The End of Treatment (EOT) visit is defined as the visit when the final dose of ALN-GO1 is 
administered.  The End of Study (EOS) visit is defined as the visit 3 months after the EOT.  
Patients are considered to have completed the study when they have completed the EOS visit. 
Patients who discontinue treatment but remain on study for assessments are considered to have 
reached the end of the study upon completing 6 months of monitoring following the final dose of 
ALN-GO1. 
For patients who withdraw from the study, see Section 5.3.2. 
4.3. 
Number of Patients 
Up to 20 patients are planned for enrollment in this study. 


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4.4. 
Method of Assigning Patients to Treatment Groups 
Not applicable.  This is an open-label study. 
4.5. 
Blinding 
Not applicable.  This is an open-label study. 
4.6. 
Safety Review Committee 
An SRC will perform ongoing reviews of safety, tolerability, and available study data collected 
in this study with the primary purpose of protecting the safety of patients.  At a minimum, 
reviews will be conducted every 3 months.  
The SRC will be comprised of the Sponsor Medical Monitor, a Medical Monitor from the 
contract research organization (CRO), 3 Investigators from participating clinical study centers or 
their designees, and an independent pediatrician experienced in clinical investigation who is not 
a study investigator.  
The SRC is governed by a charter that was signed prior to enrollment of the first subject. 
5. 
SELECTION AND WITHDRAWAL OF PATIENTS 
5.1. 
Inclusion Criteria 
Each patient must meet all of the following inclusion criteria to be eligible for enrollment in the 
study: 
1. Enrollment within 12 months of completion of Study ALN-GO1-001 and in the opinion 
of the investigator, tolerated the study drug 
2. If taking vitamin B6 (pyridoxine), willing to remain on a stable regimen for the study 
duration 
3. 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 from 
14 days before first dose and throughout study participation until the completion of the 
follow-up period 
4. Willing and able to comply with the study requirements and to provide written informed 
consent and assent in the case of patients under the age of legal consent, per local and 
national requirements 
5.2. 
Exclusion Criteria 
Each patient must not meet any of the following exclusion criteria to be eligible for enrollment in 
the study: 
1. Any uncontrolled or serious disease, or any medical or surgical condition (with the 
exception of PH1) that may either interfere with participation in the clinical study, and/or 
put the patient significant risk (according to the Investigator’s judgment) if he/she 
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2. An underlying known disease or surgical or medical condition (with the exception of 
PH1) that in the opinion of the investigator might interfere with the interpretation of the 
clinical study results 
3. Requirement for chronic dialysis 
4. Triplicate 12-lead ECG with clinically significant abnormalities at Baseline visit, at the 
discretion of the investigator 
5. Echo assessment of abnormal left ventricular systolic function, defined as left ventricular 
ejection fraction <55% at Screening 
6. Abnormal for aspartate aminotransferase (AST)/alanine aminotransferase (ALT) and any 
other clinical safety laboratory result considered clinically significant and unacceptable 
by the Investigator at Baseline, at discretion of investigator 
7. Legal incapacity or limited legal capacity at Screening of patient, parent, or legal 
guardian 
5.3. 
Removal from Therapy or Assessment 
Patients or their legal guardian (in case patient has not reached the age of majority) are free to 
discontinue treatment or withdraw from the study at any time and for any reason, without penalty 
to their continuing medical care.  Any discontinuation of treatment or withdrawal from the study 
must be fully documented in the electronic case report form (eCRF), and should be followed up 
by the Investigator.  The Investigator may withdraw a patient at any time if this is considered to 
be in the patient’s best interest. 
Discontinuation of study drug and withdrawal from the study are described in Section 5.3.1 and 
Section 5.3.2, respectively. 
5.3.1. 
Discontinuation of Study Drug 
The Investigator or designee may discontinue dosing in a patient if the patient: 
• Is in violation of the protocol 
• Experiences a serious or intolerable AE 
• Becomes pregnant 
• Is found to be considerably noncompliant with the protocol requirements 
The Investigator will confer with the Sponsor or Medical Monitor before discontinuing dosing in 
the patient.  Patients who are pregnant will be discontinued from dosing immediately (see 
Section 7.4.8.6 for reporting and follow-up of pregnancy).  In general, patients who discontinue 
study drug dosing for any reason will be encouraged to complete the End of Treatment 
assessments and safety and PD follow up visits so that their experience is captured in the final 
analyses.  Patients who discontinue study drug but who remain on study may receive local 
standard of care treatment for their disease, as applicable. 


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5.3.2. 
Withdrawal From Study 
A patient/legal guardian may withdraw from the study at any time.  If a patient/legal guardian 
chooses to withdraw from the study, every effort should be made to conduct the End of 
Treatment assessments and safety and PD follow-up visits (see Table 1). 
When a patient withdraws from the study, the primary reason for discontinuation must be 
recorded in the appropriate section of the electronic case report form (eCRF) and all efforts will 
be made to complete and report the observations as thoroughly as possible.  If a patient 
withdraws due to a serious adverse event (SAE), the SAE should be followed as described in 
Section 7.4.8.  There will be no replacements of patients who withdraw from this study. 
6. 
TREATMENTS 
6.1. 
Treatments Administered 
Study drug supplied for this study must not be used for any purpose other than the present study 
and must not be administered to any person not enrolled in the study.  Study drug that has been 
dispensed to a patient and returned unused must not be re-dispensed to a different patient. 
6.2. 
Investigational Study Drug 
Detailed information describing the preparation, administration, and storage of ALN-GO1 is 
provided in the Pharmacy Manual. 
6.2.1. 
Description 
ALN-GO1 is a synthetic, double-stranded small interfering RNA oligonucleotide directed 
against HAO1 mRNA that is covalently linked to a ligand containing 3 N-acetylgalactosamine 
residues. 
6.2.2. 
Dose and Administration 
Initially, patients will receive SC injections of ALN-GO1 at the same dose and regimen as they 
received in Study ALN-GO1-001.  Based on emerging data, the SRC may authorize an alteration 
of dose and/or dose regimen to one that is no higher than the highest dose evaluated in either 
Part A or Part B of Study ALN-GO1-001.  If such an authorization occurs, dose and/or dose 
regimen alteration may occur for an individual patient or entire cohort.  This alteration may 
apply to subsequent doses for patients already enrolled and previously dosed in the study and/or 
to the initial dose and regimen for patients who have not yet been dosed in this study. 
Patients will be administered study drug by SC injection(s).  The body weight obtained within 
4 months before the study visit day or dosing day will be used for calculation of the ALN-GO1 
dose to be administered.  
Study drug will be administered under the supervision of the Investigator or designee.  Detailed 
instructions for study drug administration are found in the Pharmacy Manual. 
Dosing will be permitted at a location other than the study center (for example, the patient’s 
home) by a healthcare professional with the oversight of the Investigator at all time points, 


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provided the patient has tolerated ALN-GO1 administered in the clinic.  However, continued 
study drug administration at the study center should be considered for patients who have ongoing 
study drug-related AEs, worsening injection site reactions with repeat dosing, or for anyone in 
the opinion of the Investigator who would benefit from clinical observation following dosing.  
If the patient is unable to come to the study site, and a visit by a healthcare professional is not 
possible due to circumstances related to the COVID-19 pandemic, ALN-GO1 may be 
administered by the patient or the caregiver under the oversight of the Investigator, and 
following consultation with the Medical Monitor, as allowed by applicable country and local 
regulations.  In such cases, the patient or caregiver must receive appropriate training on 
ALN-GO1 administration prior to dosing.  This measure is intended to remain in effect only 
during periods of time when the COVID-19 pandemic impedes the ability of patients to travel to 
the study site and healthcare professionals to go to patients' homes for dosing. 
The sites of injection may be the abdomen, the upper arms, or thighs.  If a local reaction around 
the injection site occurs, photographs may be obtained. 
Patients whose disease progresses to requiring a dialysis regimen will continue on their planned 
dosing regimen.  The ALN-GO1 dose will be administered as soon as feasible following the end 
of dialysis, eg, within 2 hours of completing the dialysis session.  If a patient does not receive a 
dose of ALN-GO1 within the specified dosing window, the Investigator should contact the 
Medical Monitor.  After such consultation, the dose may be administered or considered missed 
and not administered. 
If a patient misses multiple doses of study drug, the Investigator, in consultation with the 
Medical Monitor, will discuss whether the patient will be able to continue on the study. 
Additional details can be found in the Pharmacy Manual.  In addition, instructions and 
procedures related to administration of ALN-GO1 by a patient or caregiver will be provided in 
the Patient/Caregiver Storage and Administration Instructions.  
6.2.3. 
Dose Modifications 
Dose modification is not permitted in this study, except as noted in Section 6.2.2. 
If a study drug-related AE occurs in a patient that the Investigator judges as presenting a 
potential risk to the patient for further dosing, the study drug dose may be held at the discretion 
of the Investigator and the Medical Monitor should be contacted. 
6.2.3.1. 
Liver Function Test Criteria for Withholding, Monitoring and Stopping Study 
Drug Dosing  
1. LFT results from the previous visit should be reviewed prior to dosing.   
2. For any ALT or AST elevation >3× ULN central laboratory results should be used to 
guide subsequent monitoring as detailed in Table 2.  
3. For any ALT or AST elevation >3× ULN:  
a. If local laboratory results are obtained, confirm using central laboratory, as soon as 
possible, ideally within 2 to 3 days, but no later than 7 days. 
b. If an alternative cause is found, provide appropriate care. 


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c. If an alternative cause is not found, perform assessments per Table 2 and Table 4. 
4. For any ALT or AST elevation >3× ULN without alternative cause that is accompanied 
by clinical symptoms consistent with liver injury (eg, nausea, right upper quadrant 
abdominal pain, jaundice) or elevated bilirubin to ≥2× ULN or INR ≥1.5, permanently 
discontinue dosing. 
5. For confirmed ALT or AST elevations >3× ULN without alternative cause and not 
accompanied by symptoms or elevated bilirubin ≥2× ULN or INR ≥1.5, see Table 2 
(below): 
Table 2: 
Monitoring and Dosing Rules for Asymptomatic Patients with Confirmed Isolated 
Elevations of ALT and/or AST >3× ULN, with No Alternative Cause Identified  
Transaminase Level 
Action 
>3× to 5× ULN 
• 
May continue dosing 
• 
Evaluate the initial elevation in LFT per the following assessments: 
• 
Table 4 (all assessments to be performed once) 
• 
Hematology, serum chemistry and LFT per Table 3  
• 
Coagulation (prothrombin time, partial thromboplastin time, 
international normalized ratio) 
• 
Monitor LFTs at least every two weeks 
• 
If elevation persists for ≥2 months, must discuss with the medical monitor 
before continuing dosing 
>5× to 8× ULN 
• 
Hold study drug dosing until recovery to ≤1.5× ULN or baseline; may 
resume dosing after discussion with the Medical Monitor 
• 
Evaluate the initial elevation in LFT per the following assessments 
• 
Table 4 (all assessments to be performed once) 
• 
Hematology, serum chemistry and LFT per Table 3 
• 
Coagulation (prothrombin time, partial thromboplastin time, 
international normalized ratio) 
• 
Monitor LFTs at least weekly until ALT and/or AST is declining on 
2 consecutive draws, then may decrease monitoring to biweekly 
• 
If ALT or AST rises to >5× ULN following resumption of dosing, 
permanently discontinue dosing 
>8× ULN 
Permanently discontinue dosing after confirmation of the transaminase value at 
the central laboratory. 
Abbreviations:  ALT=alanine transaminase; AST=aspartate transaminase; LFT=liver function test(s); ULN=upper 
limit of normal. 
Notes:  In addition to these criteria, other assessments or evaluations may be performed per Investigator discretion, 
as appropriate.   
6.2.4. 
Preparation, Handling, and Storage 
Staff at each clinical study center, or the healthcare professional performing administration at 
home, will be responsible for preparation of ALN-GO1 doses according to procedures detailed in 
the Pharmacy Manual.  In cases where ALN-GO1 is administered at home by a patient/caregiver, 


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dosing may be prepared and administered by the patient/caregiver according to procedures 
detailed in the Patient/Caregiver Storage and Administration Instructions.  No special procedures 
for the safe handling of study drug are required. 
Study drug will be stored upright and refrigerated at approximately 5±3°C.  
Instructions specific to unused study drug and additional storage will be provided in the 
Pharmacy Manual and the Patient/Caregiver Storage and Administration Instructions. 
A Sponsor representative or designee will be permitted, upon request, to audit the supplies, 
storage, dispensing procedures, and records. 
6.2.5. 
Packaging and Labeling 
All packaging, labeling, and production of study drug will be in compliance with current Good 
Manufacturing Practice specifications, as well as applicable local regulations.  Study drug labels 
and external packaging will include all appropriate information as per local labeling 
requirements.  Additional details will be available in the Pharmacy Manual. 
6.2.6. 
Accountability 
The Investigator or designee will maintain accurate records of receipt and the condition of the 
study drug supplied for this study, including dates of receipt.  In addition, accurate records will 
be kept of when and how much study drug is dispensed and administered to each patient in the 
study.  Any reasons for departure from the protocol dispensing regimen must also be recorded. 
At the completion of the study, there will be a final reconciliation of all study drugs.   
Further instructions about drug accountability are detailed in the Pharmacy Manual. 
6.3. 
Concomitant Medications 
Use of concomitant medications will be recorded on the patient’s eCRF as specified in the 
Schedule of Assessments (see Table 1).  This includes all prescription medications, herbal 
preparations, over the counter medications, vitamins, and minerals.  Any changes in medications 
during the study will also be recorded on the eCRF.   
Standard vitamins and topical medications are permitted.  However, topical steroids must not be 
applied anywhere near the injection site(s) unless medically indicated.  Any treatment for an 
injection site reaction must be prescribed by the investigator or his/her designee. 
Any concomitant medication that is required for the patient’s welfare may be administered by the 
Investigator.  However, it is the responsibility of the Investigator to ensure that details regarding 
the medication are recorded on the eCRF.  Concomitant medication will be coded using an 
internationally recognized and accepted coding dictionary. 
Patients may be treated for PH1 according to local standard of care.  Patients can continue their 
current standard of care regimen, including hyperhydration, crystallization inhibitors, and/or 
pyridoxine therapy during the study.  Standard of care treatment may be adjusted in accordance 
with clinical judgement.  


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6.4. 
Contraceptive Requirements 
Women of child-bearing potential must be willing to use a highly effective method of 
contraception 14 days before first dose and throughout study participation until the completion of 
the follow-up period.  Highly effective methods of birth control result in a low failure rate (ie, 
less than 1% per year).  Birth control methods which may be considered as highly effective 
include: 
• Established use of oral (except low-dose gestagens [eg, lynestrenol and 
norethisterone]), implantable, injectable, or transdermal hormonal methods of 
contraception 
• Placement of an intrauterine device  
• Placement of an intrauterine hormone-releasing system  
• Bilateral tubal occlusion 
• Surgical sterilization of male partner (with the appropriate post-vasectomy 
documentation of the absence of sperm in the ejaculate; for female patients on the 
study, the vasectomized male partner should be the sole partner for that patient); 
• True sexual abstinence, when in line with the preferred and usual lifestyle of the 
patient.  Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception.  Abstinent 
subjects have to agree to use one of the above-mentioned contraceptive methods, if 
they start sexual relationships during the study until the completion of the follow-up 
period. 
WOCBP includes any female patient who has experienced menarche and who is not 
postmenopausal or permanently sterilized (eg, bilateral tubal occlusion, hysterectomy, or 
bilateral salpingectomy).  Postmenopausal state is defined as no menses for 12 months without 
an alternative medical cause, confirmed by follicle stimulating hormone (FSH) level within the 
postmenopausal range. 
No male contraception is considered to be required.  However, use of contraception (condom) by 
males may be required in some countries, eg, France, in order to comply with local requirements 
as described in the corresponding patient informed consent forms. 
Compliance with contraception requirements will be assessed by the Investigator throughout the 
course of the study.  
6.5. 
Treatment Compliance 
Compliance with study drug administration will be verified by study staff.  
7. 
STUDY ASSESSMENTS 
The schedule of study assessments is provided in Table 1. 
Where applicable country and local regulations and infrastructure allow for home healthcare, 
healthcare may take place at a location other than the clinical trial site to perform study 


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assessments, which may include pregnancy testing (as applicable), collection of blood and urine 
samples, measurement of vital signs, height and body weight, body system assessment, and 
preparation and administration of study drug (at the discretion of the Investigator) at all 
timepoints as specified in the Schedule of Assessments. 
7.1. 
Screening/Baseline Assessments 
The Screening and Baseline (Day -1/ Day 1) visits may be combined, if possible.  The final visit 
in Study ALN-GO1-001 may be conducted with the Screening and Baseline visit in this 
protocol.  If the final visit in Study ALN-GO1-001 is within 30 days of Day 1, then assessments 
required by both protocols do not need to be duplicated.   
Patient demographic data will be obtained from Study ALN-GO1-001.  Complete medical 
history will be obtained at screening and any changes will be updated on admission at the 
Baseline visit, if different from the Screening visit.  Events occurring after signing of the 
informed consent or assent (if applicable) form and before study drug administration will be 
captured as medical history.  
7.2. 
Pharmacodynamic and Renal Assessments 
Urine and blood samples will be collected for assessment of PD parameters (oxalate and 
glycolate concentrations) at the time points in the Schedule of Assessments (Table 1).  See 
24-hour urine collection validity criteria in Section 7.2.1.   
Patients will have the option to bring the 24-hour urine collections to the clinical study center at 
specified visits, courier samples to the clinical study center or to the vendor performing analyses, 
or elect to have the 24-hour urine collected during an inpatient stay at the clinical study center 
for other assessments. 
Additionally, blood samples for measurement of eGFR will be obtained at the time points in the 
Schedule of Assessments (Table 1).  eGFR (mL/min/1.73m2) will be calculated to assess renal 
function during the study.  The calculation will be based on the Modification of Diet in Renal 
Disease (MDRD) formula for patients ≥18 years of age at Screening and the Schwartz Bedside 
Formula for patients <18 years of age at Screening.[Levey 2009; Schwartz 2009] 
Blood samples will be collected predose for plasma oxalate assessment in all patients, as 
specified in the Schedule of Assessments.  In patients who have disease has progressed to 
requiring dialysis, if dialysis session is on same day as scheduled visit, blood samples for 
assessment of plasma oxalate will be collected pre-dialysis.  In addition to plasma oxalate 
assessment, in patients on dialysis who are not anuric (ie, patients who are able to continue to 
produce urine ≥100 ml per day) 24-hour urinary oxalate excretion will continue to be assessed. 
Biologic samples for biomarker research and possible metabolic profiling can be retained on 
behalf of the Sponsor for a maximum of 15 years following the last patient’s last visit in the 
study. 
Details regarding the processing and aliquoting of samples for storage and PD analyses are 
provided in the Laboratory Manual. 


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7.2.1. 
Validity Criteria for 24-hour Urine Collections  
24-hour urine collections will be performed as specified in the Schedule of Assessments 
(Table 1).  Any or all of the 24-hour urine collections may be conducted supervised.  If 24-hour 
urine is not a supervised collection, patients may either bring 24-hour urine collections to the 
clinic or have it couriered to the designated laboratory.   
If collection does not meet the validity criteria specified below, a single repeat collection should 
be obtained within ±14 days of the visit day.  The dose does not need to be held if validity results 
are unknown prior to dosing. 
A 24-urine collection will be considered valid if each of the following criteria are met:  
• The collection is between 18-26 hours in duration between the initial discarded void 
and the last void or attempt to void.  
• No voids are missed between the start and end time of the collection as indicated by 
the patient's urine collection record.  
• The 24-hour creatinine content is at least 10 mg/kg as assessed by the central 
laboratory.  
A single repeat collection as specified above, does not need to be obtained within ±14 days for 
patients on dialysis. 
7.3. 
Pharmacokinetic Assessments 
Blood and urine samples will be collected for assessment of ALN-GO1 PK parameters and 
possible metabolite analysis at the time points in the Schedule of Assessments (Table 1).  A 
detailed schedule of time points for the collection of blood samples for PK analysis is in Table 5 
in Appendix 11.1. 
The concentration of ALN-GO1 will be determined using a validated assay.  Details regarding 
the processing, shipping, and analysis of the samples will be provided in the Laboratory Manual. 
7.4. 
Safety Assessments 
The assessment of safety during the course of the study will consist of the surveillance and 
recording of adverse events (AEs) including serious adverse events (SAEs), recording of 
concomitant medication and measurements of vital signs, weight and height, physical 
examination and ECG findings, and clinical laboratory tests.  Echocardiograms and renal 
ultrasounds will also be assessed. 
Safety will be monitored over the course of the study by an SRC as described in Section 4.6. 
7.4.1. 
Vital Signs 
Vital sign measurements include blood pressure, heart rate, body temperature, and respiratory 
rate.  Vital signs will be measured in the supine or seated position, after the patient has rested 
comfortably for approximately 10 minutes.  Blood pressure should be taken using the same arm.  
Body temperature in degrees Celsius will be obtained via oral, tympanic, or axillary methods.  
Heart rate will be counted for a full minute and recorded in beats per minute, and respiration rate 
will be counted for a full minute and recorded in breaths per minute. 


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Vital sign measurements will be performed as specified in the Schedule of Assessments 
(Table 1).  For the safety of the patient, additional vital sign assessments may be added at the 
discretion of the Investigator. 
7.4.2. 
Weight and Height 
During the Baseline visit and at EOT, height will be measured in centimeters in triplicate for all 
patients; for all other study visits height will only be measured for patients <18 years of age.  For 
patients <18 years of age, at each time point, height will be measured in centimeters, and in 
triplicate, to facilitate calculation of eGFR using the Schwartz Bedside formula. 
7.4.3. 
Physical Examination 
Full physical examinations will include the examination of the following:  general appearance, 
head, eyes, ears, nose and throat, chest/respiratory, heart/cardiovascular, gastrointestinal/liver, 
musculoskeletal/extremities, dermatological/skin, thyroid/neck, lymph nodes, and 
neurological/psychiatric.  
A symptom-directed physical examination will include only those organ systems necessary for 
the evaluation of changes in symptoms, or the onset of new symptoms, since the last visit. 
If a study visit occurs at a location other than the study center, a body system assessment may be 
performed in lieu of a physical examination.   
Physical examinations will be performed as specified in the Schedule of Assessments (Table 1).  
7.4.4. 
Electrocardiogram 
At Baseline, triplicate 12-lead ECGs will be measured 5 minutes apart.  Recordings will be 
obtained after the subject/patient has rested comfortably in the supine position for approximately 
10 minutes.  Patients should remain supine between ECGs.  ECGs should be obtained at visits to 
the clinical study center according to the Schedule of Assessments (see Table 1) prior to study 
drug administration.  At all post-baseline visits, ECGs will be measured in singlicate, and 
obtained predose.  ECGs do not need to be conducted for interim doses. 
Additional ECGs may be collected at the discretion of the Investigator.  The electrophysiological 
parameters assessed will include, but are not limited to, rhythm, ventricular rate, PR interval, 
QRS duration, QT interval, ST and T waves, Bazett-corrected QT interval (QTcB) and Fridericia 
corrected QT interval (QTcF).  
The Investigator or designee is responsible for reviewing the ECGs to assess whether the results 
have changed since the Baseline visit and to determine the clinical significance of the results.  
For any clinically significant changes from the Baseline visit (eg, ischemic ECG changes, 
wave/interval changes, or arrhythmia), the Investigator must contact the Medical Monitor to 
discuss continued participation of the subject/patient in the study. 
After Month 12, ECGs will be performed at Months 24, 36, 48, and 54 only.  During periods of 
time when the COVID-19 pandemic impedes the ability of patients to travel to the study site, 
ECGs may be completed up to 9 months after the intended time point.  


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7.4.5. 
Echocardiography 
Echo assessments will be performed as specified in the Schedule of Assessments (Table 1), and 
according to instructions provided in a study manual.  The Investigator or designee is responsible 
for reviewing the echos to assess whether the results have changed since the Baseline visit and to 
determine the clinical significance of the results.  For any clinically significant changes from the 
Baseline visit, the Investigator must contact the Medical Monitor. 
7.4.6. 
Renal Ultrasound 
Renal ultrasound will be performed according to instructions provided in a study manual.  The 
Investigator or designee is responsible for reviewing the renal ultrasound to assess whether the 
results have changed since the Baseline visit and to determine the clinical significance of the 
results.  For any clinically significant worsening from the Baseline visit, the Investigator must 
contact the Medical Monitor.   
After Month 12, renal ultrasound will be performed at Months 24, 36, 48, and 54 only.  During 
periods of time when the COVID-19 pandemic impedes the ability of patients to travel to the 
study site, renal ultrasounds may be completed up to 9 months after the intended time point. 
7.4.7. 
Clinical Laboratory Assessments 
The following clinical laboratory tests will be evaluated by a central laboratory.  Specific 
instructions for transaminase elevations are provided in Section 6.2.3.1.  For any other 
unexplained clinically relevant abnormal laboratory test occurring after study drug 
administration, the test should be repeated and followed up at the discretion of the Investigator, 
and in conjunction with the Medical Monitor if feasible, or as per SRC advice, until it has 
returned to the normal range or stabilized, and/or a diagnosis is made to adequately explain the 
abnormality.  Additional safety laboratory assessments as indicated by the clinical situation may 
be requested.  Clinical laboratory assessments are listed in Table 3 and will be assessed as 
specified in the Schedule of Assessments (Table 1).  While local laboratory results may be used 
for urgent clinical and dosing decisions, on the day of the clinic visit assessments, all laboratory 
assessments specified in the following table which are performed at the clinic should also be sent 
in parallel to the central laboratory, blood volumes permitting.  Central laboratory results (once 
available) should be used for subsequent clinical and dosing decisions in the case of discrepant 
local and central laboratory results of samples drawn on the same day.   
For any safety event or laboratory abnormality, additional laboratory assessments, imaging, and 
consultation may be performed for clinical evaluation and/or in consultation with the Medical 
Monitor, or as per SRC advice; results may be collected and included in the clinical database.  
Clinical laboratory assessments may be collected at the clinical site or at a location other than the 
clinical study center by a trained healthcare professional, where applicable country and local 
regulations and infrastructure and allow. 
Table 3: 
Clinical Laboratory Assessments 
Hematology 
Complete blood count with differential 
 
Serum Chemistry 


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Sodium 
Potassium 
BUN 
Phosphate 
Creatinine and eGFR (using the MDRD formula for 
adults (≥18 years of age) or the Bedside Schwartz 
formula for Children <18 years) 
Albumin 
Uric acid 
Calcium 
Total protein 
Carbon dioxide 
Glucose 
Chloride 
Liver Function Tests 
 
AST 
ALP 
ALT 
Bilirubin (total and direct) 
Urinalysis 
Visual inspection for appearance and color 
Bilirubin 
pH (dipstick) 
Nitrite 
Specific gravity 
RBCs 
Ketones 
Urobilinogen 
Albumin 
Leukocytes 
Glucose 
Microscopy (if clinically indicated) 
Protein 
    
Pregnancy Testing (WOCBP only) 
β-human chorionic gonadotropin 
Abbreviations:  ALP=alkaline phosphatase; ALT=alanine transaminase; AST=aspartate transaminase; BUN=blood 
urea nitrogen; eGFR=estimated glomerular filtration rate; MDRD=modification of diet in renal disease; 
WOCBP=women of child-bearing potential. 
7.4.7.1. 
Immunogenicity 
Blood samples will be collected to evaluate ADA.  Blood samples for ADA testing must be 
collected before study drug administration. 
Details regarding the processing, shipping, and analysis of the samples will be provided in the 
Laboratory Manual. 
7.4.7.2. 
Pregnancy Testing 
A pregnancy test will be performed for WOCBP only.  A serum pregnancy test will be 
performed at Baseline and urine pregnancy tests will be performed thereafter per the Schedule of 
Assessments (Table 1) and at any time pregnancy is suspected.  Pregnancy testing may be 
performed offsite by a patient/caregiver if the patient/caregiver will be administering the study 
drug.  The results of the pregnancy test must be known before study drug administration.  
Patients who are pregnant are not eligible for study participation.  Any woman with a positive 
pregnancy test during the study will be discontinued from study drug but will continue to be 


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followed for safety.  Patients determined to be pregnant while on study will be followed until the 
pregnancy outcome is known (see Section 7.4.8.6 for follow-up instructions). 
7.4.7.3. 
Additional Liver Function Assessments  
Additional laboratory assessments will be performed in patients who experience any LFT 
abnormalities as outlined in Section 6.2.3.1.  Following the occurrence of elevated liver 
transaminases or other LFT abnormalities per central laboratory without an alternative cause 
identified, all assessments in Table 4 will be performed one time, as well as hematology, serum 
chemistry, and LFT assessments from Table 3, and coagulation and other assessments or 
evaluations per Investigator discretion, as appropriate. 
Monitoring, including criteria for withholding the study drug, are described in Section 6.2.3.1. 
Table 4: 
Hepatic Assessments in Patients Who Experience Elevated Transaminases 
Extended Hepatic Panel 
Herpes Simplex Virus 1 and 2 antibody IgM, IgG 
Herpes Zoster Virus IgM, IgG 
HIV 1 and 2a 
HHV-6  
Cytomegalovirus antibodies, IgM, IgG 
HBs Ag, HBc antibody IgM and IgG 
Anti-nuclear antibodies 
Epstein-Barr Virus antibodies, IgM and IgG 
Anti-smooth muscle antibodies 
Anti-mitochondrial antibodies 
HCV antibody 
HAV antibody IgM 
HCV RNA PCR – qualitative and quantitative 
HEV antibody IgM 
Imaging 
Abdominal ultrasound with Doppler flow (or CT or MRI) including right upper quadrant 
Focused Medical and Travel History 
Use of any potentially hepatotoxic concomitant 
medications, including over the counter medications 
and herbal remedies 
Alcohol consumption  
Other potentially hepatotoxic agents including any 
work-related exposures 
Recent travels to areas where hepatitis A or E 
is endemic 
Abbreviations:  CT=computed tomography; HAV=hepatitis A virus; HBc=hepatitis B core; HBsAg=hepatitis B 
virus surface antigen; HCV=hepatitis C virus; HEV=hepatitis E virus; HHV-6=human herpesvirus 6; HIV=human 
immunodeficiency virus; IgG=immunoglobulin G antibody; IgM=immunoglobulin M antibody; MRI=magnetic 
resonance imagery; PCR=polymerase chain reaction; RNA=ribonucleic acid. 
Note: 
• 
All assessments will be measured in central laboratory.  The full panel of assessments should only be 
performed once; individual assessments may be repeated, as needed. 
a HIV testing will not be performed where prohibited by local regulations. 
7.4.7.4. 
Maximum Blood Volume 
The maximum blood volume, which will be collected from pediatric patients over the course of 
the study, will be based on age and weight and will not exceed those specified in Table 6 from 


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the Feinstein Institute for Medical Research Human Subject Protection Program Guidance 
Document (Section 11.2 in the Appendix).[Feinstein Institute 2013]  
7.4.8. 
Adverse Events 
7.4.8.1. 
Definitions 
Adverse Event 
According to the International Conference on Harmonization (ICH) E2A guideline Definitions 
and Standards for Expedited Reporting, and 21 CFR 312.32, IND Safety Reporting, an adverse 
event (AE) is any untoward medical occurrence in a patient or clinical investigational subject 
administered a medicinal product and which does not necessarily have a causal relationship with 
this treatment. 
Serious Adverse Event 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening (an event which places the patient at immediate risk of death from 
the event as it occurred.  It does not include an event that had it occurred in a more 
severe form might have caused death) 
• Requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly or birth defect 
• Is an important medical event that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient and may require 
intervention to prevent one of the other outcomes listed in the definition above (eg, 
events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias, convulsions, or the development of drug 
dependency or abuse). 
Adverse Event Severity 
Adverse events are to be graded according to the categories detailed below: 
Mild: 
Mild events are those which are easily tolerated with no disruption of normal 
daily activity. 
Moderate: 
Moderate events are those which cause sufficient discomfort to interfere with 
normal daily activities. 
Severe: 
Severe events are those which incapacitate and prevent usual activity. 
Changes in severity should be documented in the medical record to allow assessment of the 
duration of the event at each level of severity.  Adverse events characterized as intermittent 
require documentation of the start and stop of each incidence.  When changes in the severity of 
an AE occur more frequently than once a day, the maximum severity for the experience that day 


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should be noted.  If the severity category changes over a number of days, then those changes 
should be recorded separately (with distinct onset dates) 
AE severity and seriousness are assessed independently.  ‘Severity’ characterizes the intensity of 
an AE.  ‘Serious’ is a regulatory definition and serves as a guide to the Sponsor for defining 
regulatory reporting obligations (see definition for Serious Adverse Event). 
Relationship of the Adverse Event to Study Treatment 
The relationship of each AE to study treatment should be evaluated by the Investigator using the 
following criteria:  
Definitely related: 
A clinical event, including laboratory test abnormality, occurring in a plausible 
time relationship to the medication administration, and which cannot be 
explained by concurrent disease or other drugs or chemicals.  The response to 
withdrawal of the drug should be clinically plausible. 
Possibly related: 
A clinical event, including laboratory test abnormality, with a reasonable time 
sequence to the medication administration, but which could also be explained 
by concurrent disease or other drugs or chemicals.  Information on the drug 
withdrawal may be lacking or unclear. 
Unlikely related: 
A clinical event, including laboratory test abnormality, with little or no 
temporal relationship to medication administration, and which other drugs, 
chemicals, or underlying disease provide plausible explanations. 
Not related: 
A clinical event, including laboratory test abnormality that has no temporal 
relationship to the medication or has more likely alternative etiology. 
Adverse Events of Clinical Interest 
The following are considered to be AEs of clinical interest:  
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3× upper limit 
of normal (ULN ) 
• Severe or serious injection site reactions (ISRs); ISRs that are associated with a recall 
phenomenon (reaction at the site of a prior injection with subsequent injections), or 
those that lead to temporary dose interruption or permanent discontinuation of study 
drug.  
An ISR is defined as a local reaction at or near the site of injection. “At or near” the 
injection site includes reactions at the injection site, adjacent to the injection site, or a 
reaction which may shift slightly away from the injection site due to gravity (eg, as 
may occur with swelling or hematoma).  A systemic reaction which includes the 
injection site, eg, generalized urticaria, other distinct entities or conditions like 
lymphadenopathy that may be near the injection site is not considered an ISR.  
These AEs will be recorded both on a supplemental eCRF and on an Adverse Event of Clinical 
Interest form.  Refer to the eCRF completion guidelines for details. 


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7.4.8.2. 
Eliciting and Recording Adverse Events 
Eliciting Adverse Events 
The patient should be asked about medically relevant changes in his/her health since the last 
visit.  The patient should also be asked if he/she has been hospitalized, had any accidents, used 
any new medications, or changed concomitant medication routines (both prescription and 
over-the-counter).  In addition to patient observations, AEs will be documented from any 
clinically relevant laboratory findings, physical examination findings, electrocardiogram 
changes, or other findings that are relevant to patient safety. 
Recording Adverse Events 
The Investigator is responsible for recording non-serious AEs that are observed or reported by 
the patient after administration of the first dose of study drug regardless of their relationship to 
study drug through the end of study.  Non-serious AEs will be followed until the end of study.   
The Investigator is responsible for recording SAEs that are observed or reported by the patient 
after the time when the informed consent is signed regardless of their relationship to study drug 
through the end of study.  SAEs will be followed until satisfactory resolution, until baseline level 
is reached, or until the SAE is considered by the Investigator to be chronic or the patient is 
stable, as appropriate. 
All AEs must be recorded in the source records for the clinical study center and in the eCRF for 
the patient, whether or not they are considered to be drug-related.  Each AE must be described in 
detail:  onset time and date, description of event, severity, relationship to investigational drug, 
action taken, and outcome (including time and date of resolution, if applicable). 
For SAEs, record the event(s) in the eCRF.  If the electronic data capture (EDC) system is 
unavailable, complete the back-up SAE form. 
For AEs that are considered AEs of clinical interest, additional clinical information may be 
collected based upon the severity or nature of the event.  Refer to CRF completion guidelines for 
details on reporting events in the supplemental eCRF. 
For all ISRs, the Investigator, or delegate, should submit an Injection Site Reactions Signs or 
Symptoms eCRF, recording additional information (eg, descriptions, onset and resolution date, 
severity, treatment given, and event outcome). 
In some cases, where it is medically appropriate, further evaluation may include photographs, 
referral to a dermatologist, skin biopsy, or other laboratory testing.  If a biopsy was obtained, the 
Sponsor may request that the biopsy also be reviewed by a central dermatopathologist.  To better 
understand the safety profile of the study drug, additional analysis of biopsy tissue may be 
performed as permitted by local regulations.  Refer to the CRF completion guidelines for details 
on the form(s). 
7.4.8.3. 
Serious Adverse Events Require Immediate Reporting to Sponsor/Designee 
An assessment of the seriousness of each AE will be made by the Investigator.  Any AE and 
laboratory abnormality that meets the SAE criteria in Section 7.4.8.1 must be reported to the 
Sponsor or designee within 24 hours from the time that clinical study center staff first learns of 
the event.  All SAEs must be reported regardless of the relationship to study drug. 


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The initial report should include at least the following information: 
• Patient’s study number 
• Description and date of onset of the event 
• Criterion for serious 
• Preliminary assignment of relationship to study drug, and 
• Investigator/site information 
To report the SAE, complete the eCRF.  If the EDC system is unavailable, complete the back-up 
SAE form.  Within 24 hours of receipt of follow-up information, the Investigator must update the 
SAE form.  SAEs must be reported using the contact information provided in the Study Binder. 
Appropriate remedial measures should be taken by the Investigator using his/her best medical 
judgment to treat the SAE.  These measures and the patient’s response to these measures should 
be recorded.  All SAEs, regardless of relationship to study drug, will be followed by the 
Investigator until satisfactory resolution or the Investigator deems the SAE to be chronic or 
stable.  Clinical, laboratory, and diagnostic measures should be employed by the Investigator as 
needed to adequately determine the etiology of the event. 
7.4.8.4. 
Sponsor Safety Reporting to Regulatory Authorities 
The Sponsor or its representative is required to report certain study events in an expedited 
manner to the Food and Drug Administration, the European Medicines Agency’s EudraVigilance 
electronic system according to Directive 2001/20/EC, and to all country Regulatory Authorities 
where the study is being conducted, according to local applicable regulations. 
The following describes the safety reporting timeline requirements for suspected unexpected 
serious adverse reactions (SUSARs) and other reportable events: 
Immediately and within 7 calendar days 
• Any suspected adverse reaction that is associated with the use of the study drug, 
unexpected, and fatal or life threatening.  Follow-up information must be reported in 
the following 8 days. 
Immediately and within 15 calendar days 
• Any suspected adverse reaction that is associated with the use of the study drug, 
unexpected, and serious, but not fatal or life threatening, and there is evidence to 
suggest a causal relationship between the study drug and the reaction. 
• Any finding from tests in laboratory animals that suggest a significant risk for human 
patients including reports of mutagenicity, teratogenicity, or carcinogenicity. 
• Any event in connection with the conduct of the study or the development of the 
study drug that may affect the safety of the study patients. 
In addition, periodic safety reporting to regulatory authorities will be performed by the Sponsor 
or its representative according to national and local regulations. 


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7.4.8.5. 
Serious Adverse Event Notification to the Institutional Review 
Board/Independent Ethics Committee 
SUSARs will be reported to the Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) per their institutional policy by the Investigator or Sponsor (or Sponsor 
designee) according to country requirements.  Copies of each report and documentation of 
IRB/IEC notification and acknowledgement of receipt will be kept in the Investigator’s study 
file. 
7.4.8.6. 
Pregnancy Reporting 
If a female patient becomes pregnant during the course of this study, the Investigator must report 
the pregnancy to the Sponsor or designee within 24 hours of being notified of the pregnancy.  
Details of the pregnancy will be recorded on the pregnancy reporting form.  The patient should 
receive any necessary counseling regarding the risks of continuing the pregnancy and the 
possible effects on the fetus. 
The pregnancy should be followed by the Investigator until completion.  At the completion of the 
pregnancy, the Investigator will document the outcome of the pregnancy.  If the outcome of the 
pregnancy results in a postpartum complication, spontaneous abortion, stillbirth, neonatal death, 
or congenital anomaly, then the Investigator should follow the procedures for reporting an SAE 
as outlined in Section 7.4.8.3.   
7.4.8.7. 
Overdose Reporting 
An overdose is defined as any dose administered to or taken by a patient (accidentally or 
intentionally) that exceeds the highest daily dose, or is at a higher frequency, than included in the 
protocol.  It is up to the investigator to decide whether a dose is to be considered an overdose, in 
consultation with the Sponsor.  Overdose must be recorded in the eCRF. 
All reports of overdose (with or without an AE) must be reported within 24 hours to the Sponsor 
or designee. 
7.4.9. 
COVID-19 Data Collection 
Information on the coronavirus disease 2019 (COVID-19) infection status of the patient, if 
known, and other information on the impact of the COVID-19 pandemic on the patient's 
participation in the study will be collected.  
7.5. 
Other Assessments 
7.5.1. 
Quality of Life (QOL) 
QOL will be assessed using the KDQOL, specifically the KDQOL-36[Rand Health Care 2000] 
for patients ≥18 years of age at Screening, and the PedsQL, including the generic and ESRD 
modules (parent and/or self-report versions)[Goldstein 2008; Varni 1999] for patients <18 years 
of age at Screening.  After Month 12, QOL questionnaires will not be collected (see the Schedule 
of Assessments, Table 1). 


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8. 
STATISTICS 
A detailed Statistical Analysis Plan (SAP) will be written after finalizing the protocol and before 
database lock.  The plan will detail the implementation of all the statistical analyses in 
accordance with the principal features stated in the protocol. 
8.1. 
Determination of Sample Size 
Sample size is not determined through a power calculation but based on the number of patients 
who complete Study ALN-GO1-001 and are eligible to enroll in this study. 
8.2. 
Statistical Methodology 
The statistical and analytical plans presented below summarize the more complete plans to be 
detailed in the SAP.  The SAP will be finalized before database lock.  Any changes to the 
methods described in the final SAP will be described and justified as needed in the clinical study 
report.  Additional data summaries to help understand any impact of COVID-19 on safety and 
efficacy assessments will be outlined in the SAP. 
8.2.1. 
Populations to be Analyzed 
The safety analysis set will include all patients who received at least 1 dose of study drug.  
Patients with missing PD or PK data will be excluded from the PK/PD analyses as appropriate. 
8.2.2. 
Examination of Subgroups 
Subgroup analyses may be conducted for selected endpoints.  Detailed methodology will be 
provided in the SAP. 
8.2.3. 
Handling of Missing Data 
Unrecorded values will be treated as missing.  The appropriateness of the method(s) described 
for handling missing data may be reassessed and documented in the SAP prior to database lock.  
Depending on the extent of missing values, further investigation may be made into the sensitivity 
of the analysis results to the method(s) specified. 
8.2.4. 
Baseline Evaluations 
Demographics and other baseline characteristics will be summarized.  Descriptive statistics for 
age, race, ethnicity, gender, height, body weight, and BMI will be provided. 
8.2.5. 
Pharmacodynamic Analysis 
PD analysis will be based on the change from baseline over the course of the study in the 
following PD parameters: 
• eGFR  
• 24-hour urinary oxalate corrected for BSA 
• Urinary glycolate excretion  
• Plasma oxalate concentration 


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• Plasma glycolate concentration 
• 24-hour and spot urinary oxalate:creatinine ratio 
The PD parameters will be summarized using descriptive statistics for actual results and relative 
to baseline for each follow-up time points. 
For the parameter eGFR, the change from baseline over the course of the study will be 
summarized using descriptive statistics for actual results and relative to baseline for each 
follow-up time points. 
8.2.6. 
Pharmacokinetic Analysis 
Pharmacokinetic analyses will be conducted using noncompartmental methods.   
Pharmacokinetic parameters include, but will not be limited to:  Cmax, tmax, t½β, AUC, Fe, CL/F, 
and V/F.  Other parameters may be calculated, if deemed necessary.  
8.2.7. 
Anti-drug Analyses 
Anti-drug antibody results will be summarized descriptively.  A by-patient data listing will also 
be provided. 
8.2.8. 
Safety Analyses 
Extent of exposure will be summarized.  Adverse events will be summarized by the Medical 
Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC) and Preferred Term.  
Prior and concomitant medications will be classified using an internationally recognized and 
accepted coding dictionary. 
Incidence of AEs (those events that started after exposure to study drug or worsened in severity 
after dosing) will be presented.  Incidence of AEs will also be presented by maximum severity 
and relationship to study medication.  The incidence of SAEs and AEs leading to discontinuation 
of treatment will also be tabulated.  By-patient listings will be provided for deaths, SAEs, and 
events leading to discontinuation of treatment.  Additional tabular summaries of AEs may be 
presented by other grouping including, but not limited to high level term (HLT), high level group 
term (HLGT), or standardized MedDRA query (SMQ).  
Descriptive statistics will be provided for clinical laboratory data and vital signs data, presented 
as both actual values and changes from baseline relative to each on-study evaluation and to the 
last evaluation on study.  Laboratory shift tables from baseline to worst values will be presented.  
Abnormal physical examination findings, renal ultrasound, ECG, and echo data will be presented 
in by-patient listings. 
Descriptive statistics will be provided for electrocardiogram interval data and presented as both 
actual values and changes from baseline relative to each on-study evaluation and to the last 
evaluation on study.  Details of any abnormalities will be included in patient listings. 
8.2.9. 
Other Analyses 
QOL questionnaires are not required after Month 12.  No change from baseline analyses are 
planned for the QOL questionnaires; listings will be provided.  


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8.2.10. 
Interim Analysis 
There is no formal interim analysis planned for this open-label study.  Interim data examinations 
may be performed and will generally be descriptive in nature.  Interim data from the study may 
be presented at scientific meetings. 
9. 
STUDY ADMINISTRATION 
9.1. 
Ethical and Regulatory Considerations 
This study will be conducted in accordance with the protocol, all applicable regulatory 
requirements, and the guidelines of Good Clinical Practice (GCP).  Compliance with GCP 
provides public assurance that the rights, safety, and well-being of study patients are protected 
consistent with the principles that have their origin in the Declaration of Helsinki. 
9.1.1. 
Informed Consent 
The Investigator will ensure that the patient/legal guardian is given full and adequate oral and 
written information about the nature, purpose, possible risk and benefit of the study.  
Patients/Legal guardians must also be notified that they are free to discontinue from the study at 
any time.  The patient/legal guardian should be given the opportunity to ask questions and 
allowed time to consider the information provided.  In the case of patients under the age of legal 
consent, legal guardian(s) must provide informed consent and the patient should provide assent 
per local regulations and institutional standards. 
The patient’s/legal guardian's signed and dated informed consent (or assent, if applicable) must 
be obtained before conducting any study procedures. 
The Investigator must maintain the original, signed Informed Consent Form or Assent Form (if 
applicable).  A copy of the signed Informed Consent Form (or assent, if applicable) must be 
given to the patient/legal guardian. 
The Investigator will inform the patient/legal guardian if new information becomes available that 
may be relevant to the patient’s/legal guardian’s willingness to continue participation in the 
study.  Communication of this information should be documented. 
9.1.2. 
Ethical Review 
The final study protocol, including the final version of the Informed Consent Form, must be 
approved or given a favorable opinion in writing by an IRB or IEC, as appropriate.  The 
Investigator must submit written approval before he or she can enroll any patient into the study. 
The Investigator is responsible for informing the IRB or IEC of any amendment to the protocol 
in accordance with local requirements.  In addition, the IRB or IEC must approve all advertising 
used to recruit patients for the study (except those that support the need to remove an apparent 
immediate hazard to the patient).  The protocol must be reapproved by the IRB or IEC upon 
receipt of amendments and annually, as local regulations require. 


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Initial IRB approval of the protocol, and all materials approved by the IRB for this study 
including the patient consent form (and assent form, as applicable per institutional standards) and 
recruitment materials must be maintained by the Investigator and made available for inspection. 
The Investigator will submit reports of SAEs as outlined in Section 7.4.8.  In addition, the 
Investigator agrees to submit progress reports to the IRB or IEC per their local reporting 
requirements, or at least annually and at the conclusion of the study.  The reports will be made 
available to the Sponsor or designee. 
Any communications from regulatory agencies in regard to inspections, other studies that impact 
this protocol or the qualifications of study personnel should be promptly reported to the Sponsor 
or its designee. 
The Investigator is also responsible for providing the IRB with reports of any reportable serious 
adverse drug reactions from any other study conducted with the investigational drug.  The 
Sponsor or designee will provide this information to the Investigator. 
Major changes in this research activity, except those to remove an apparent immediate hazard to 
the patient, must be reviewed and approved by the Sponsor and the IRB or IEC that approved the 
study.  Amendments to the protocol must be submitted in writing to the Investigator’s IRB or 
IEC and the Regulatory Authority for approval before patients are enrolled under the amended 
protocol. 
9.1.3. 
Serious Breach of Protocol 
Investigators must notify the Medical Monitor within 24 hours of becoming aware of a potential 
serious breach of the protocol.  A serious breach is a breach that is likely to affect to a significant 
degree the safety and rights of a study participant or the reliability and robustness of the data 
generated in the clinical trial. 
9.1.4. 
Study Documentation, Confidentiality, and Records Retention 
All documentation relating to the study should be retained for 2 years after the last approval in an 
ICH territory, or the period of time required by applicable local law, whichever is longer.  If it 
becomes necessary for the Sponsor, the Sponsor’s designee, applicable IRB/IEC, or applicable 
regulatory authorities to review or audit any documentation relating to the study, the Investigator 
must permit direct access to all source documents/data.  Records will not be destroyed without 
informing the Sponsor in writing and giving the Sponsor the opportunity to store the records for 
a longer period of time at the Sponsor’s expense.   
The Investigator must ensure that the patients’ confidentiality will be maintained.  On the eCRFs 
or other documents submitted to the Sponsor or designees, patients should not be identified by 
their names, but by the assigned patient number or code.  If patient names are included on copies 
of documents submitted to the Sponsor or designees, the names will be obliterated, and the 
assigned patient number or code added to the document.  Documents not for submission to the 
Sponsor (eg, signed informed consent forms) should be maintained by the Investigator in strict 
confidence. 
The Investigator must treat all of the information related to the study and the compiled data as 
confidential, whose use is for the purpose of conducting the study.  The Sponsor must approve 
any transfer of information not directly involved in the study. 


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In compliance with local and/or regional regulations, this clinical study may be registered, and 
study results may be posted on public registries, such as ClinicalTrials.gov. 
9.1.5. 
End of the Study 
The end of the study is defined as the last patient last visit. 
9.1.6. 
Discontinuation of the Clinical Study 
The Sponsor reserves the right to discontinue the study for clinical or administrative reasons at 
any time.  If the clinical study center does not recruit at a reasonable rate, the study may be 
discontinued at that clinical study center.  Should the study be terminated and/or the clinical 
study center closed for whatever reason, all documentation and study drug pertaining to the study 
must be returned to the Sponsor or its representative, and the Investigators, IEC/IRB and 
Regulatory Authorities will be promptly informed of the termination and the reason for the 
decision.  The Investigator should promptly inform the patients and assure appropriate therapy 
and follow-up.  Patients should then be withdrawn from the study.   
9.2. 
Data Quality Control and Quality Assurance  
9.2.1. 
Data Handling 
Study data must be recorded on case report forms (paper and/or electronic) provided by the 
Sponsor or designee on behalf of the Sponsor.  Case report forms must be completed only by 
persons designated by the Investigator.  If eCRFs are used, study data must be entered by trained 
clinical study center personnel with access to a valid and secure eCRF system.  All data entered 
into the eCRF must also be available in the source documents.  Corrections on paper CRFs must 
be made so as to not obliterate the original data and must be initialed and dated by the person 
who made the correction. 
9.2.2. 
Study Monitoring 
The clinical monitor, as a representative of the Sponsor, has an obligation to closely follow the 
study conduct at the clinical study center.  The monitor will visit the Investigator and clinical 
study center periodically and will maintain frequent telephone and written contact.  The monitor 
will maintain current personal knowledge of the study through observation, review of study 
records and source documentation, and discussion of the conduct of the study with the 
Investigator and staff. 
The monitor will review source documents, systems and CRFs to ensure overall quality and 
completeness of the data and to confirm study procedures are complied with the requirements in 
the study protocol accurately.  The Sponsor, or its designee, will be allowed to conduct site visits 
to the investigation facilities for the purpose of monitoring any aspect of the study.  The 
Investigator agrees to allow the monitor to inspect the drug storage area, study drug stocks, drug 
accountability records, patient charts and study source documents, and other records relative to 
study conduct. 


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9.2.3. 
Audits and Inspections 
Periodically, the Sponsor or its authorized representatives audit clinical investigative clinical 
study centers as an independent review of core trial processes and documents to determine 
whether these activities were conducted, and data were recorded, analyzed, and accurately 
reported according to the protocol, GCP guidelines of the ICH, and any applicable regulatory 
requirements.  A regulatory authority, an IEC or an IRB may visit the clinical study center to 
perform audits or inspections, including source data verification.  The Investigator should contact 
the Sponsor, or its designee, immediately if contacted by a regulatory agency about an 
inspection. 
9.3. 
Publication Policy 
It is intended that after completion of the study, the data are to be submitted for publication in a 
scientific journal and/or for reporting at a scientific meeting.  A copy of any proposed manuscript 
must be provided and confirmed received at the Sponsor at least 30 days before its submission, 
and according to any additional publication details in the Investigator Agreement. 


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10. 
LIST OF REFERENCES 
Al-Eisa AA, Samhan M,Naseef M. End-stage renal disease in Kuwaiti children: an 8-year 
experience. Transplant Proc. 2004 Jul-Aug;36(6):1788-91. 
Atlas SA. The renin-angiotensin aldosterone system: pathophysiological role and pharmacologic 
inhibition. J Manag Care Pharm. 2007 Oct;13(8 Suppl B):9-20. 
Cochat P, et al. Primary hyperoxaluria Type 1: indications for screening and guidance for 
diagnosis and treatment. Nephrol Dial Transplant. 2012;27(5):1729-36. 
Cochat P,Rumsby G. Primary hyperoxaluria. N Engl J Med. 2013 Aug 15;369(7):649-58. 
Feinstein Institute. The Feinstein Institute for Medical Research.  Human Subject Protection 
Program Guidance Document:  Maximum Blood Draw Limits. 2013. 
Frishberg Y, Zeharia A, Lyakhovetsky R, Bargal R,Belostotsky R. Mutations in HAO1 encoding 
glycolate oxidase cause isolated glycolic aciduria. J Med Genet. 2014 Aug;51(8):526-9. 
Goldstein SL, Graham N, Warady BA, Seikaly M, McDonald R, Burwinkle TM, et al. 
Measuring health-related quality of life in children with ESRD: performance of the generic and 
ESRD-specific instrument of the Pediatric Quality of Life Inventory (PedsQL). Am J Kidney 
Dis. 2008 Feb;51(2):285-97. 
Hopp K, Cogal AG, Bergstralh EJ, Seide BM, Olson JB, Meek AM, et al. Phenotype-Genotype 
Correlations and Estimated Carrier Frequencies of Primary Hyperoxaluria. J Am Soc Nephrol. 
2015 Feb 2. 
Hoppe B. Evidence of true genotype-phenotype correlation in primary hyperoxaluria type 1. 
Kidney Int. 2010 Mar;77(5):383-5. 
Kamoun A,Lakhoua R. End-stage renal disease of the Tunisian child: epidemiology, etiologies, 
and outcome. Pediatr Nephrol. 1996 Aug;10(4):479-82. 
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, 3rd, Feldman HI, et al. A new 
equation to estimate glomerular filtration rate. Ann Intern Med. 2009 May 5;150(9):604-12. 
Rand Health Care. Kidney Disease and Quality of Life™ (KDQOL™-36) English Version 1.  
2000; 8]. Available from: 
https://www.rand.org/content/dam/rand/www/external/health/surveys_tools/kdqol/kdqol36.pdf. 
Schwartz GJ, Munoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, et al. New equations to 
estimate GFR in children with CKD. J Am Soc Nephrol. 2009 Mar;20(3):629-37. 
Varni JW, Seid M,Rode CA. The PedsQL: measurement model for the pediatric quality of life 
inventory. Med Care. 1999 Feb;37(2):126-39. 
 


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11. 
APPENDICES 
11.1. 
Pharmacokinetic Assessment Time Points 
Table 5 contains a detailed schedule for the collection of blood and pooled urine samples for PK 
analysis. 
Table 5 
Pharmacokinetic Time Points 
Study Visit 
Time Point 
(hh:mm) 
PK Blood 
Pooled Urine Collection 
Baseline 
(Day 1) 
Predose (within 60 
minutes before dosing) 
X 
 
00:00 (dose) 
 
X 
(00:00-04:00) 
02:00 (±10 min) 
X 
04:00 (±10 min) 
 
04:01 (±10 min) 
 
X 
(04:01-08:00) 
08:00 (±15 min) 
X 
08:01 (±15 min) 
 
X 
(08:01-24:00) 
24:00 (±30 min) 
X 
Month 6 
(Day 169) 
 
Predose (within 60 
minutes before dosing) 
X 
 
00:00 (dose) 
 
X 
(00:00-04:00) 
02:00 (±10 min) 
X 
04:00 (±10 min) 
 
04:01 (±10 min) 
 
X 
(04:01-08:00) 
08:00 (±15 min) 
X 
Month 12 
(Day 337) 
 
Predose (within 60 
minutes before dosing) 
X 
 
00:00 (dose) 
 
X 
(00:00-04:00) 
02:00 (±10 min) 
X 
04:00 (±10 min) 
 
04:01 (±10 min) 
 
X 
(04:01-08:00) 
08:00 (±15 min) 
X 
 
 
 
 


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11.2. 
Blood Volume Limits in Pediatric Patients 
The maximum blood volume, which will be collected from pediatric patients over the course of 
the study, will be based on age and weight and will not exceed those specified in Table 6, which 
was adapted from the Human Subject Protection Program Guidance Document. 
Table 6: 
Maximum Allowable Total Blood Volume Collection Chart 
Body 
Weight  
Body 
Weight  
Total blood 
volume  
Maximum allowable volume 
in a 24-hour period 
Total volume collected 
in a 30-day period 
2.5% of 
total blood 
volume 
3% of  
total blood 
volume  
5% of 
total blood 
volume  
10% of 
total blood 
volume  
(kg) 
(lbs) 
(mL) 
(mL) 
(mL) 
(mL) 
(mL) 
1 
2.2 
100 
2.5 
3 
5 
10 
2 
4.4 
200 
5 
6 
10 
20 
3 
6.6 
240 
6 
7.2 
12 
24 
4 
8.8 
320 
8 
9.6 
16 
32 
5 
11 
400 
10 
12 
20 
40 
6 
13.2 
480 
12 
14.4 
24 
48 
7 
15.4 
560 
14 
16.8 
28 
56 
8 
17.6 
640 
16 
19.2 
32 
64 
9 
19.8 
720 
18 
21.6 
36 
72 
10 
22 
800 
20 
24 
40 
80 
11-15 
24-33 
880-1200 
22-30 
26.4-36 
44-60 
88-120 
16-20 
35-44 
1280-1600 
32-40 
38.4-48 
64-80 
128-160 
21-25 
46-55 
1680-2000 
42-50 
50.4-60 
64-100 
168-200 
26-30 
57-66 
2080-2400 
52-60 
62.4-72 
104-120 
208-240 
31-35 
68-77 
2480-2800 
62-70 
74 4-84 
124-140 
248-280 
36-40 
79-88 
2880-3200 
72-80 
86.4-96 
144-160 
288-320 
41-45 
90-99 
3280-3600 
82-90 
98.4-108 
164-180 
328-360 
46-50 
101-110 
3680-4000 
92-100 
110 4-120 
184-200 
368-400 
51-55 
112-121 
4080-4400 
102-110 
122.4-132 
204-220 
408-440 
56-60 
123-132 
4480-4800 
112-120 
134.4-144 
224-240 
448-480 
61-65 
134-143 
4880-5200 
122-130 
146 4-156 
244-260 
488-520 
66-70 
145-154 
5280-5600 
132-140 
158.4-168 
264-280 
528-560 
71-75 
156-165 
5680-6000 
142-150 
170.4-180 
284-300 
568-600 
76-80 
167-176 
6080-6400 
152-160 
182.4-192 
304-360 
608-640 
81-85 
178-187 
6480-6800 
162-170 
194.4-204 
324-340 
648-680 
86-90 
189-198 
6880-7200 
172-180 
206.4-216 
344-360 
688-720 
91-95 
200-209 
7280-7600 
182-190 
218.4-228 
364-380 
728-760 
96-100 
211-220 
7680-8000 
192-200 
230 4-240 
384-400 
768-800 
Adapted from http://www.feinsteininstitute.org/wp-content/uploads/2013/02/Maximum-Blood-Draw-
Limits.pdf.[Feinstein Institute 2013]  
 


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ALN-GO1-002 PROTOCOL AMENDMENT 2  
SUMMARY OF CHANGES DATED 04 MAY 2020 
A Phase 2, Multicenter, Open-Label, Extension Study to Evaluate the Long-Term 
Administration of ALN-GO1 in Patients with Primary Hyperoxaluria Type 1 
1. 
RATIONALE FOR PROTOCOL AMENDMENT 
The primary purpose of this protocol amendment is to incorporate Urgent Safety Measures 
(USMs) that were communicated to investigators in a Dear Investigator Letter, dated 
02 April 2020, to assure the safety of study participants while minimizing risks to study integrity 
amid the coronavirus 2019 (COVID-19) pandemic.  These changes are in line with guidance 
from both the European Medicines Agency (EMA) and the United States Food and Drug 
Administration (FDA) on the conduct of clinical trials during the COVID-19 pandemic.[EMA 
2020; FDA 2020]  The USMs are summarized in Section 1.1.  
This protocol amendment also incorporates changes that are not related to USMs.  After ongoing 
review and assessment of the safety data from studies conducted with lumasiran, modifications 
are designed to enhance patient safety and reduce patient burden regarding blood sampling.  
These changes are summarized in Section 1.2 and will not be implemented until appropriate 
Health Authority and Ethics Committee (EC) and/or Institutional Review Board (IRB) approval. 
1.1. 
Notification of Urgent Safety Measures Due to the Impact of the 
COVID-19 Pandemic 
The USM modifications and new procedures are outlined below, and a detailed summary of the 
USMs is provided in Table 1.  These measures were to be adopted immediately by the 
Investigator site as specified in the Dear Investigator Letter.  
• ALN-GO1 dosing outside the study center  
Following appropriate training on ALN-GO1 administration, dosing will be permitted at 
a location other than the study center (eg, at home) by the patient/caregiver at all time 
points under the oversight of the Investigator and following consultation with the Medical 
Monitor.  This measure is intended to remain in effect only during periods of time when 
the COVID-19 pandemic impedes the ability of patients to travel to the study site and 
healthcare professionals to go to patients' homes for dosing. 
In order to assure uniform and comprehensive training and to assure compliance with the 
dosing instructions, the sponsor has prepared both Investigator and caregiver-facing 
written materials.  
• Assessment of adverse events and concomitant medications 
In situations where a study visit is unable to be completed (either at the site or offsite by a 
healthcare professional), the Investigator (or delegate) will verbally contact the patient 
within the study visit window to assess AEs and concomitant medication use. 
• Study visits  


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Except for assessments with other specified timing requirements, study assessments and 
dosing can be performed within the expanded window of 28 days (was ±7 days at 
Month 12 and ±14 days thereafter). 
• Renal ultrasound and electrocardiogram assessments  
After Month 12, renal ultrasound and ECG assessments may be completed up to 
9 months after the intended time point to ensure patient safety, and to the extent possible, 
maintain study integrity amid travel and other restrictions related to the COVID-19 
pandemic.   
This expansion of the ECG assessment window is supported by results of a clinical 
corrected QT interval (QTc) assessment and nonclinical cardiac safety assessment of 
lumasiran, which demonstrated that lumasiran does not have QTc prolongation 
properties. 
• Assessments required to be performed in clinic  
Where applicable country and local regulations and infrastructure allow for home 
healthcare, healthcare may take place at a location other than the clinical trial site to 
perform study assessments, which may include pregnancy testing (as applicable), 
collection of blood and urine samples, measurement of vital signs, height and body 
weight, body system assessment, and preparation and administration of study drug (at the 
discretion of the Investigator) at all timepoints as specified in the Schedule of 
Assessments. 
• Full physical examination 
If a visit is conducted offsite (eg, home), a body system assessment can be performed in 
lieu of a physical examination.  
• Impact of COVID-19 (collection of information)  
Information related to the impact of the COVID-19 pandemic on patient participation in 
the study will be collected for each patient.  Additional information regarding collection 
of this information, including completion of a new case report form specific to 
COVID-19, will be provided separately.   
This change is implemented to enable analysis of the impact of the COVID-19 global 
pandemic on clinical trial data. 
• Updates to study administration 
Text was updated to provide clarification of Investigator responsibilities regarding 
communication of new study information to patients and IRB/IECs. 
1.2. 
Changes Not Related to Urgent Safety Measures 
The quality of life (QOL) questionnaire assessment data will not be summarized for this study as 
no predose data are available from Study ALN-GO1-001 Part B (Study 001B) to determine 
change from baseline.  Additional changes to study conduct (outlined below) will not be 
implemented until appropriate HA and EC/IRB approval. 


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• Remove QOL as an exploratory objective and endpoint.  The KDQOL for adults 
≥18 years of age, and the PedsQL; the generic and the end-stage renal disease 
[ESRD] modules for children <18 years of age will not be collected after Month 12.  
QOL data will be listed only but not summarized.  These assessments were not 
performed before the first lumasiran dose in Study 001B; therefore, change from 
baseline cannot be assessed.  
• Clarify coagulation studies assessed in patients with elevated liver enzymes. 
• Patients who discontinue pyridoxine (Vitamin B6) therapy during the study will not 
be required to provide additional blood samples for assessment of pyridoxine levels. 
• Clarify assessment time points: performed predose only (ECGs), and at Months 24, 
36, 48, and 54 after Month 12 (ECGs and renal ultrasound). 
A detailed summary of changes is provided in Table 2.  The following changes are not detailed:  
administrative changes, changes associated with administrative letters (between Amendments 1 
and 2), and corrections to typographical errors, punctuation, grammar, abbreviations, and 
formatting. 


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2. 
PROTOCOL AMENDMENT 2 DETAILED SUMMARY OF CHANGES 
The primary section(s) of the protocol affected by the changes in Protocol Amendment 2 are indicated.  The corresponding text has 
been revised throughout the protocol.  Deleted text is indicated by strikeout; added text is indicated by bold font. 
Table 1: 
Urgent Safety Measures COVID-19-related Changes to be Adopted Immediately 
Purpose:  Expand the use of offsite administration to include ALN-GO1 dosing by the caregiver and provide additional instructions 
on self administration, and preparation, handling, and storage of the study drug. 
The primary change occurs in Section 6.2.2, Dose and Administration 
Revised text:  Study drug will be administered under the supervision of the Investigator or designee.  Dosing will be permitted at a 
location other than the study center (eg, the patient’s home) by a healthcare professional with oversight of the Investigator at 
all time points, provided the patient has tolerated ALN-GO1 administered in the clinic. 
If the patient is unable to come to the study site, and a visit by a healthcare professional is not possible due to circumstances 
related to the COVID-19 pandemic, ALN-GO1 may be administered by the patient or the caregiver under the oversight of the 
Investigator, and following consultation with the Medical Monitor, as allowed by applicable country and local regulations.  In 
such cases, the patient or caregiver must receive appropriate training on ALN-GO1 administration prior to dosing.  
Administration by a patient or caregiver is intended to remain in effect only during periods of time when the COVID-19 
pandemic impedes the ability of patients to travel to the study site and healthcare professionals to go to the patients’ homes for 
dosing.   
In addition, instructions and procedures related to administration of ALN-GO1 by a patient or caregiver will be provided in 
the Patient/Caregiver Storage and Administration Instructions.  
Section(s) also reflecting this change:   
• Section 6.2.4, Preparation, Handling, Storage 
Purpose:  Allow additional offsite assessments 
The primary change occurs in Section 7, Study Assessments. 
Revised text:  Where applicable country and local regulations and infrastructure allow for home healthcare, healthcare may 
take place at a location other than the clinical trial site to perform study assessments, which may include pregnancy testing (as 
applicable), collection of blood and urine samples, measurement of vital signs, height and body weight, body system assessment, 


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and preparation and administration of study drug (at the discretion of the Investigator) at all timepoints as specified in the Schedule 
of Assessments.  
Section(s) also reflecting this change:   
• Section 7.4.3, Physical Examination 
• Section 7.4.7.2, Pregnancy Testing 
Purpose:  Expand the study visit window. 
The primary change occurs in Table 1, Schedule of Assessments. 
Revised text:  The study site visit window was changed from ±14 days to ±28 days through the end of the study. 
Purpose:  Expand the window for body weight measurement. 
The primary change occurs in notes for Table 1, Schedule of Assessments. 
Revised text:  Body weight must be obtained within 4 months prior to dosing. 
Section(s) also reflecting this change: 
• Section 6.2.2, Dose and Administration 
Purpose:  Expand study assessment windows for ECGs and renal ultrasound.  
The primary change occurs in Section 7.4.4, Electrocardiogram 
Revised (added) text:  During periods of time when the COVID-19 pandemic impedes the ability of patients to travel to the 
study site, ECGs may be completed up to 9 months after the intended timepoint. 
Section(s) also reflecting this change:   
• Section 7.4.6, Renal Ultrasound 
Purpose:  Allow continual assessments of AEs and concomitant medications via remote contact. 
The primary change occurs in Table 1, Schedule of Assessments (notes) 
Revised (added) text:  • 
In situations where a study visit is unable to be completed (either at the site or offsite by a healthcare 
professional), the Investigator (or delegate) will verbally contact the patient within the study visit window to assess 
concomitant medications and adverse events.  
Purpose:  Collect information related to the impact of the COVID-19 pandemic on patient participation in the study. 
The primary change occurs in Section 7.4.9, COVID-19 Data Collection 


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Revised text:  Information on the coronavirus disease 2019 (COVID-19) infection status of the patient, if known, and other 
information on the impact of the COVID-19 pandemic on the patient's participation in the study will be collected. 
Section(s) also reflecting this change:   
• Section 8.2, Statistical Methodology 
Purpose:  Revise and update informed consent instructions.  
The primary change occurs in Section 9.1.1, Informed Consent 
Revised (added) text:  The Investigator will inform the patient/legal guardian if new information becomes available that may be 
relevant to the patient’s/legal guardian’s willingness to continue participation in the study.  Communication of this 
information should be documented. 
Purpose:  Revise and update ethical review instructions. 
The primary change occurs in Section 9.1.2, Ethical Review 
Revised (added) text:  In addition, the IRB or IEC must approve all advertising used to recruit patients for the study (except those that 
support the need to remove an apparent immediate hazard to the patient). 
 
 


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Table 2: 
Changes Not Related to Urgent Safety Measures to be Implemented After Health Authority and Ethics 
Committee(EC)/Institutional Review Board (IRB) Approval, where applicable 
Purpose:  Remove QOL as an exploratory study objective and stop collection of the QOL (KDQOL and PedsQL) questionnaires after 
Month 12. 
The primary change occurs in Section 2.3, Exploratory Objectives 
• Characterize quality of life 
Sections also reflecting this change: 
• Section 3.3, Exploratory Endpoints 
• Section 7.5.1, Quality of Life 
• Section 8.2.9, Other Analyses 
• Synopsis, Exploratory Objectives; Exploratory Endpoints 
• Table 1, Schedule of Assessments 
Purpose:  To clarify coagulation parameters. 
The primary change occurs in Section 6.2.3, Table 2, Monitoring and Dosing Rules for Asymptomatic Patients with Confirmed 
Isolated Elevations of ALT and/or AST >3 x ULN, with no Alternative Cause 
Revised text:  • 
Hematology, serum chemistry, and LFT, and coagulation per Table 3  
• 
Coagulation (prothrombin time, partial thromboplastin time, international normalized ratio) 
Section(s) also reflecting this change: 
• Section 7.4.7.3, Additional Liver Function Assessments 
Purpose:  Remove the requirement for measurement of pyridoxine after discontinuation of pyridoxine therapy. 
The primary change occurs in Section 6.3, Concomitant Medications. 
Revised (deleted) text:  If pyridoxine therapy is discontinued, pyridoxine levels should be assessed for at least the next 2 study visits.  
Section(s) also reflecting this change:  
• Table 1, Schedule of Assessments 
Purpose:  Clarify the timing of 12-lead ECGs and renal ultrasounds.  


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The primary change occurs in Table 1, Schedule of Assessments 
Revised text:  After Month 12, ECGs and renal ultrasounds will be performed at X (Q12M) Months 24, 36, 48, and 54 only.  
Section(s) also reflecting this change:  
• Section 7.4.4, Electrocardiogram (remove the 2 to 4 hours after dosing timepoint) 
Purpose:  Clarify that vital signs will be measured in the supine or seated position. 
The primary change occurs in Section 7.4.1, Vital Signs 
Revised text:  Vital signs will be measured in the supine or seated position, after the patient has rested comfortably for approximately 
10 minutes. 


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3. 
REFERENCES 
EMA (Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) 
Pandemic, Version 1.0 (20/03/2020). https://www.ema.europa.eu/en/news/guidance-sponsors-
how-manage-clinical-trials-during-covid-19-pandemic) 
US FDA (FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 
Pandemic: Guidance for Industry, Investigators, and Institutional Review Boards. (27 March 
2020) https://www.fda.gov/regulatory-information/search-fda-guidance-documents/fda-
guidance-conduct-clinical-trials-medical-products-during-covid-19-pandemic).   
 

SAP_001.pdf: 
 
 
Official Title:  
A Phase 2, Multicenter, Open-Label, Extension Study to Evaluate the Long-
Term Administration of ALN-GO1 in Patients With Primary Hyperoxaluria 
Type 1 
 
NCT Number:   
NCT03350451 
 
Document Date:   
Statistical Analysis Plan, 23 May 2019 


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STATISTICAL ANALYSIS PLAN 
 
A Phase 2 Multicenter, Open-Label, Extension Study to Evaluate the Long-
Term Administration of ALN-GO1 in Patients with Primary Hyperoxaluria 
Type I 
 
Protocol Number: 
Protocol Version and Date: 
ALN-GO1-002 
Original Protocol, 30 March 2017 
Investigational Drug: 
Lumasiran (ALN-GO1) 
Phase: 
Phase 2 
Sponsor: 
Alnylam Pharmaceuticals, Inc. 
300 Third Street 
Cambridge, MA  02142 USA 
Tel: +1 (617) 551-8200 
Fax: +1 (617) 551-8101 
Sponsor Representative: 
 
 
Analysis Plan Version and 
Date: 
Version 1.0, 23 May 2019 
 
Confidentiality Statement 
The concepts and information contained in this document or generated during the study are 
considered proprietary and may not be disclosed in whole or in part without expressed written 
authorization of Alnylam Pharmaceuticals, Inc.
PI


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APPROVAL SIGNATURE PAGE 
 
A Phase 2 Multicenter, Open-Label, Extension Study to Evaluate the Long-Term 
Administration of ALN-GO1 in Patients with Primary Hyperoxaluria Type I 
 
Protocol Number: 
ALN-GO1-002 
Analysis Plan Version and 
Date: 
Version 1.0, 23 May 2019 
This Statistical Analysis Plan has been authored by:  
 
 
 
Alnylam Pharmaceuticals, Inc. 
 
The Statistical Analysis Plan has been approved and signed electronically on the final page by the 
following:  
 
 
 
Alnylam Pharmaceuticals, Inc 
 
 
 
 
Alnylam Pharmaceuticals, Inc. 
 
PI
PI
PI


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TABLE OF CONTENTS 
1. 
Introduction ...................................................................................................................... 6 
2. 
Study Overview ................................................................................................................ 7 
2.1. 
Synopsis of Study Design ...................................................................................... 7 
2.2. 
Study Procedures ................................................................................................... 7 
3. 
Objectives and Endpoints................................................................................................ 8 
3.1. 
Objectives .............................................................................................................. 8 
3.1.1. 
Primary Objective ................................................................................... 8 
3.1.2. 
Secondary Objectives ............................................................................. 8 
3.1.3. 
Exploratory Objectives ........................................................................... 8 
3.2. 
Endpoints ............................................................................................................... 9 
3.2.1. 
Primary Endpoint .................................................................................... 9 
3.2.2. 
Secondary Endpoints .............................................................................. 9 
3.2.3. 
Exploratory Endpoints ............................................................................ 9 
4. 
Patient Population .......................................................................................................... 10 
4.1. 
Patient Definitions ............................................................................................... 10 
4.2. 
Protocol Deviations .............................................................................................. 10 
5. 
General Statistical Methods .......................................................................................... 11 
5.1. 
General Methods .................................................................................................. 11 
5.2. 
Computing Environment ...................................................................................... 11 
5.3. 
Baseline Definitions ............................................................................................. 11 
5.4. 
Dose Groups......................................................................................................... 11 
5.5. 
Missing Data ........................................................................................................ 12 
5.6. 
Visit Windows ..................................................................................................... 12 
5.7. 
Interim Analysis ................................................................................................... 12 
6. 
Study analyses ................................................................................................................ 13 
6.1. 
Patient Disposition ............................................................................................... 13 
6.2. 
Demographics and Baseline characteristics ......................................................... 13 
6.3. 
Medical History ................................................................................................... 13 
6.4. 
Concomitant Medications .................................................................................... 13 
6.5. 
Dosing and Extent of Exposure ........................................................................... 14 
7. 
Statistical Analysis ......................................................................................................... 15 
7.1. 
Primary Endpoint ................................................................................................. 15 
7.1.1. 
Evaluate the incidence of Adverse Events (AEs) ................................. 15 


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7.2. 
Secondary Endpoints ........................................................................................... 16 
7.2.1. 
Evaluate the pharmacodynamic effect of lumasiran on 
urinary oxalate excretion ...................................................................... 16 
7.2.2. 
Change in estimated glomerular filtration rate (eGFR) and 
measured creatinine clearance over time .............................................. 17 
7.3. 
Exploratory Endpoints ......................................................................................... 18 
7.3.1. 
Other Safety Parameters ....................................................................... 18 
7.3.2. 
Characterize the Pharmacokinetics of lumasiran .................................. 20 
7.3.3. 
Evaluate the Pharmacodynamic Effect of lumasiran ............................ 20 
7.3.4. 
Characterize Quality of Life (QOL) ..................................................... 21 
7.3.5. 
Incidence of ADA ................................................................................. 21 
8. 
Changes to Planned Analyses ....................................................................................... 22 
9. 
References ....................................................................................................................... 23 
 


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 ABBREVIATIONS 
Abbreviation 
Definition 
ADA 
Anti-drug antibody 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical Classification System 
AUC 
Area under the concentration-time curve 
BSA 
Body surface area 
Cmax 
Maximum plasma concentration 
CSR 
Clinical study report 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
EOT 
End of treatment 
EQ-5D 
Euro Quality of Life Health State Profile Questionnaire 
ESRD 
End-stage renal disease 
GO 
Glycolate oxidase 
HLT 
high level term 
ISR 
Injection site reactions 
KDQOL 
Kidney Disease Quality of Life Questionnaire  
LLOQ  
Lower Limit of Quantification  
MedDRA 
Medical Dictionary for Regulatory Activities  
MMRM 
Mixed-effect repeated measures  
MNAR 
Missing not at random 
PD 
Pharmacodynamic(s) 
PedsQL 
Pediatric Quality of Life 
PH1 
Primary hyperoxaluria type 1 
PK 
Pharmacokinetic(s) 
PT 
Preferred term 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
SRC 
Safety Review Committee 


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1. 
INTRODUCTION 
Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disease characterized by 
excessive oxalate production by the liver and consequent hyperoxaluria.  PH1 is caused by 
mutations in the alanine glyoxylate aminotransferase (AGXT) gene, which encodes the liver 
peroxisomal enzyme alanine-glyoxylate aminotransferase (AGT).  As a consequence of AGT 
deficiency, glyoxylate accumulates and is oxidized to oxalate in the hepatocyte and ultimately 
transported to the kidneys for excretion.  Oxalate, in the form of its calcium salt, is excreted 
almost entirely by the kidney.  Due to its insolubility, calcium oxalate can crystallize readily in 
the urinary tract.  In PH1, excess urinary oxalate results in recurrent nephrolithiasis and/or 
nephrocalcinosis, which can lead to pain, infections, progressive kidney disease and failure, 
along with reduced quality of life.[1]  As renal function declines, elimination of oxalate is 
further reduced, such that calcium oxalate accumulates in bone, vasculature, skin, retina, heart, 
and nervous system, resulting in severe end-organ damage.  This devastating condition, 
systemic oxalosis, arises when the estimated glomerular filtration rate (eGFR) has declined 
below 30 to 45 mL/min/1.73 m2.   
The analysis methods described in the protocol may be updated in this statistical analysis plan 
(SAP).  Any changes to the data analysis methods described in the protocol, including 
justification for the changes, are described in Section 8 and in the clinical study report (CSR).  
Additional exploratory analyses of the data may be conducted when deemed appropriate. 


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2. 
STUDY OVERVIEW 
2.1. 
Synopsis of Study Design 
Study ALN-GO1-002 is an open-label, extension study designed to evaluate the long-term 
safety, pharmacokinetic (PK) and pharmacodynamics (PD) of subcutaneously administered 
lumasiran in patients with PH1 who completed the parent study (ALN-GO1-001).  The number 
of patients may include up to 20 PH1 patients from Part B of Study ALN-GO1-001.  
Eligible patients either receive the same dose and/or dose regimens of ALN-GO1 (hereinafter 
referred to as lumasiran) as administered in the parent study (1.0 mg/kg once monthly, 3.0 
mg/kg once monthly or 3.0 mg/kg once every 3 months) or may change dose regimens at any 
time.  Any change in dose regimen for a patient may occur due to emerging data and with the 
approval from the Safety Review Committee (SRC).    
2.2. 
Study Procedures 
The schedule of assessments is described in the study protocol (Table 1 and Table 2). 


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3. 
OBJECTIVES AND ENDPOINTS 
3.1. 
Objectives 
3.1.1. 
Primary Objective 
 Evaluate the long-term safety of multiple doses of lumasiran in patients with PH1 
3.1.2. 
Secondary Objectives 
 Evaluate the PD effect of lumasiran on urinary oxalate excretion 
 Characterize the effect of lumasiran on markers of renal function 
3.1.3. 
Exploratory Objectives 
 Characterize the PK of lumasiran 
 Evaluate the PD effect of lumasiran on urinary glycolate, plasma oxalate concentration, 
plasma glycolate concentration and urine oxalate:creatinine ratio 
 Characterize the quality of life 
 Evaluate the incidence of anti-drug antibodies (ADA) 
 
 


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3.2. 
Endpoints 
3.2.1. 
Primary Endpoint 
 Incidence of adverse events (AEs) 
3.2.2. 
Secondary Endpoints 
 Change in urinary oxalate excretion over time 
 Change in eGFR and measured creatinine clearance (mCrCl) over time  
3.2.3. 
Exploratory Endpoints 
 Describe the effect of lumasiran on other safety parameters, including assessments of 
vital signs, electrocardiograms (ECG), renal ultrasounds, clinical laboratory parameters, 
and physical examinations 
 Assess lumasiran plasma PK parameters including maximum plasma concentration 
(Cmax), time to maximum plasma concentration (tmax), elimination half-life, area under 
the curve, fraction of dose excreted in urine, apparent clearance and apparent volume of 
distribution. 
 Change from baseline over the course of the study in the following PD parameters: 
urinary glycolate excretion, plasma oxalate concentration, plasma glycolate 
concentration and urine oxalate:creatinine ratio  
 Quality of life as assessed by Kidney Disease Quality of Life Questionnaire (KDQOL) 
for adults (≥18 years of age) and the PedsQOL (the generic and ESRD modules) for 
children (<18 years of age) 
 Incidence of ADA 


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4. 
PATIENT POPULATION 
4.1. 
Patient Definitions 
The populations (analysis sets) are defined as follows:  
 Safety Analysis Set: All patients who receive any amount of study drug.  
 PD Analysis Set: All patients who receive any amount of study drug and who have at 
least 1 post-dose urine sample for PD.  
 PK Analysis Set: All patients who receive any amount of study drug and who have at 
least 1 post-dose PK concentration measurement. 
The Safety Analysis Set will be used to analyze safety and clinical activity data.  The PK and 
PD Analysis Sets will be used to conduct PK and PD analyses, respectively.  
4.2. 
Protocol Deviations 
Protocol deviations will be classified into major or minor deviations by medical review.  A 
major deviation is defined as a deviation that may significantly impact the completeness, 
accuracy and/or reliability of study data; that may significantly affect a patient’s rights, safety 
and well-being (ICH E3 R1 Structure and Contents of Clinical Study Reports Guidance for 
Industry, 2013).  Deviations not classified as major will be assigned as minor.  
Protocol deviations will be summarized in the CSR. 


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5. 
GENERAL STATISTICAL METHODS 
5.1. 
General Methods 
Continuous data will be described using descriptive statistics such as the number of observations 
(n), mean, standard deviation, standard error, median, quartiles, minimum, and maximum.  For 
the summary statistics of all numerical variables unless otherwise specified, minimum and 
maximum will be displayed to the same level of precision as reported.  Median and mean will 
be presented to the level of precision collected in the database plus 1 additional decimal.  The 
standard deviation and standard error will be presented to the level of precision collected in the 
database plus 2 additional decimals. 
For assessments with repeated collections at a given study visit (e.g., ECG parameters, height 
for patients <18 years of age), the mean will represent the value at the visit for all parameters 
except for 24-hour urine PD parameters.  For 24-hour urine PD parameters, if there are repeated 
collections at a particular visit then the median will represent the value at that visit.  For 
biomarker and/or laboratory data, if any value is recorded as less than the lower limit of 
quantification (LLOQ) then the value used for calculations will be assigned a value of LLOQ. 
Categorical and ordinal data will be described using the patient count and percentages in each 
category.  When count data are presented, the percentage will not be presented when the count 
is zero.  
Study Day 1 will be defined as the day of the first dose of lumasiran in this study.  Study day 
will be calculated relative to the first dose date of study drug for all patients:   
If the assessment date is after the date of first study drug dose, then the study day will be 
calculated as: 
Study Day = Date of assessment – date of first dose of study drug + 1, 
If the assessment date is before the date of the first dose of study drug, then the study day will 
be calculated as:  
Study Day = Date of assessment – date of first dose of study drug  
5.2. 
Computing Environment 
All statistical analyses will be performed using validated SAS statistical software Version 9.4 
(or later), unless otherwise noted.  
5.3. 
Baseline Definitions 
Baseline will be defined as the derived baseline value in Study ALN-GO1-001 (refer to SAP 
ALN-GO1-001, Version 2.0; dated August 13, 2018).  For data not collected in the parent study 
(e.g. KDQOL-36, PedsQOL, Renal Ultrasounds), the baseline value will be defined as the latest 
collection prior to the first dose of lumasiran in this study.  
5.4. 
Dose Groups 
All tables and figures will be presented by the initial dose regimens in this study, unless 
otherwise specified:  


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 1 mg/kg once monthly  
 3 mg/kg once every 3 months  
 Pooling of 1 mg/kg once monthly or 3 mg/kg once every 3 months 
 3 mg/kg once monthly 
 Total  
5.5. 
Missing Data  
For continuous and categorical variables, data will not be imputed unless otherwise specified.  
For safety analyses, any AEs with fully missing dates or partially missing dates, no date will be 
assigned.  An AE will be considered treatment-emergent unless it can be unequivocally 
determined (from the partial onset date and/or a partial or complete stop date) that the event 
occurred prior to first dose of study drug.  
For medications with partial start or stop dates, the first day/month will be imputed for start 
date, and the last day/month will be imputed for stop date.  For medications with a completely 
missing start date, the medications will be considered as started prior to the first dose of study 
drug in this study; medications will be classified as prior or both prior and concomitant 
depending on the medication stop dates.  If any medications have a completely missing stop 
date, then the medication will be assumed as ongoing. 
5.6. 
Visit Windows 
Data will be tabulated and analyzed per the visit as recorded on the electronic case report forms 
(eCRF) with the exception of visits prior to the first dose in this study [Note: Protocol states any 
assessments performed in the parent study within 30 days before the first dose in Study 002 do 
not need to be recollected (except for vital signs and physical examination)]. For any data that 
did not need to be recollected prior to the first dose in this study, the data at the latest visit from 
the parent study will be used for analysis.  
Data at unscheduled visits will be included in by-patient listings and figures, but no assignment 
to a scheduled visit will be made for the purposes of by-visit summary tabulations. However, 
unscheduled visits will be considered for any categorical summaries (e.g., shifts from baseline 
to worst post-baseline value).  For patients who discontinue study treatment, the time window 
for monitoring AEs and collecting PD assessments will be up to 84 days after the last dose.  
5.7. 
Interim Analysis 
Interim analyses will be performed to support regulatory activities and publications.  These 
analyses will be descriptive in nature and will not involve any formal hypothesis testing.  
For interim analyses, as this study will be ongoing, a cut-off approach will be implemented to 
ensure data quality.  The interim analysis will include data entered on or prior to a pre-specified 
cutoff date.  For assessments with start or end dates (e.g., exposure, AEs, medical history, etc), 
the start date will be compared to the prespecified cutoff date to determine whether the 
assessment is included in the analysis.  


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6. 
STUDY ANALYSES 
6.1. 
Patient Disposition 
Number and percentage of patients will be tabulated for the following categories:  
 Enrolled (signed informed consent and met eligibility) 
 Safety Analysis Set  
 PD Analysis Set 
 PK Analysis Set 
Summaries of the number and percentage of patients who discontinued treatment based upon the 
primary reason for discontinuation (e.g., AE, death, lost to follow-up, etc) will be presented.  
Summaries of the number and percent of patients who withdrew from the study prematurely and 
the associated reasons for withdrawal will be presented.  Per patient data listings will be 
presented displaying the primary reason that the patient discontinued treatment and/or went off 
study.  
6.2. 
Demographics and Baseline characteristics 
Baseline characteristics will be based upon the derived baseline in Study ALN-GO1-001 (refer 
to ALN-GO1-001 SAP; dated August 13, 2018).  These characteristics include but are not 
limited to age, gender, race, ethnicity, body weight, body height as well as baseline 24-hour 
urinary oxalate excretion corrected for body surface area (BSA), 24-urinary oxalate: creatinine 
ratio and eGFR. For a subset of baseline parameters (e.g. Quality of Life, renal ultrasounds, 
etc..), the baseline will be based upon the first dose of lumasiran in this study.  
6.3. 
Medical History 
Data recorded in medical history in this study and in the parent study (ALN-GO1-001) will be 
summarized by Medical Dictionary for Regulatory Activities (MedDRA) system organ class 
(SOC), high level term (HLT) and preferred term (PT).  A patient will only contribute once to 
the count for a given condition (overall, by SOC, by HLT, by PT).  Medical history and 
pregnancy test results will also be presented in data listings.  
6.4. 
 Concomitant Medications 
Concomitant medications are defined as medications which were taken after the first dose date 
of the study drug in this study and any medication that started prior to the first dose in this study 
and was ongoing on or after the date of the first dose of study drug in this study.    
Tabular summary of the number and percentage of patients taking concomitant medications will 
be summarized by anatomic therapeutic class (ATC) and PT.  Data will be presented for the 
Safety Analysis Set.  A separate tabular summary of concomitant vitamin B6 use will be 
summarized by ATC and PT.  
By-patient listings will be generated separately for concomitant medications and vitamin B6 
medications. 


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6.5. 
Dosing and Extent of Exposure 
Summaries of exposure will include the following categories such as, but not limited to: total 
number of doses received per patient, mean number of doses per patient, cumulative number of 
doses received per study group, duration of drug exposure (months) per study group, cumulative 
drug exposure time (months) per study group, the total dose administered (mg) and total volume 
administered (mL). 
Definition of drug exposure (days) will be defined as the minimum of [Exposure time= (date of 
last exposure – date of first dose +1)] where date of last exposure will represent either the date 
of the last dose administered dose +84, analysis cut-off date or end of study date.   
Dose interruptions and compliance are not taken into account. 
A separate per-patient exposure listing will be generated to display the initial dosing regimen in 
the parent study (ALN-GO1-001), the initial dosing regimen in this study and changes to the 
dose and/or regimen during this study. 


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7. 
STATISTICAL ANALYSIS 
7.1. 
Primary Endpoint 
7.1.1. 
Evaluate the incidence of Adverse Events (AEs) 
The primary safety parameter is the assessment of treatment-emergent AEs which will be 
defined as an AE that occurs or worsens on or after the first lumasiran dose date/time of this 
study though 84 days after the last dose of study drug.  In addition, any AE that worsens in 
intensity or was subsequently considered related to study drug will be considered 
treatment-emergent.  All analyses of AEs will be performed on the Safety Analysis Set.  
For summaries of AEs, there will be 3 sets of summaries: all AEs, AEs classified as renal stone 
events and AEs excluding those classified as renal stone events. A medical review of all AEs 
will be conducted to identify renal stone events.  
AEs will be coded using the MedDRA coding system (version 21.0 or later) and displayed in 
tables and data listings by SOC and PT.  Patients who report multiple occurrences of the same 
PT will be classified according to the most related or most severe category.  Patients with a 
missing relationship to study drug will be classified as the most related category.  Drug related 
AEs include events considered definitely related or possibly related to study drug by the 
investigator or events with missing relationship.  
An overview table of AEs will be tabulated.  The overview table will include the number and 
percentage of patients in following categories such as, but not limited to:  
 At least 1 AE 
 At least 1 drug related AE  
 At least 1 severe AE 
 At least 1 drug related severe AE  
 At least 1 serious adverse event (SAE) 
 At least 1 drug related SAE  
 At least 1 AE leading to treatment discontinuation 
 At least 1 drug related AE leading to treatment discontinuation  
 At least 1 AE leading to study withdrawal 
 At least 1 drug related AE leading to study withdrawal 
 Death 
Tabulations by SOC and PT displaying the number of patients (percentage) and total events will 
be produced for the following tables:  
 All AEs 
 Serious AEs 
 AEs by maximum severity 


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 AEs related to treatment 
 AEs and SAEs related to treatment by maximum severity  
There will also be an all AE table generated displaying rates of AEs adjusted for exposure-time.  
Separate listings will be provided for deaths, SAEs, and AEs leading to discontinuation of study 
drug, dose interruption, or study withdrawal.  By-patient AE listings will be provided.  
A subset of key AE outputs will also be generated to compare study groups of patients initially 
dosed with 3 mg/kg once monthly versus 3 mg/kg once every 3 months of lumasiran.  
Tabulations of the AE data will be adjusted for exposure-time.  
Summaries of other Standardised MedDRA Queries (SMQs) or AE groupings may be 
summarized such as but not limited to the following:    
Injection Site Reactions [ISRs]: AEs mapping to the HLT=” Injection Site Reactions” 
using MedDRA dictionary will be included in the summary.  Frequency (percentages) of 
ISRs by HLT and PT will be generated.  A separate listing will be generated to display all 
patients who reported ISRs.  
A table will also be generated to display the number of patients with at least 1 ISR, total 
number of injections, total number of injections complicated by ISRs and corresponding % 
of injections complicated by ISR with the most common signs and symptoms reported due 
to ISRs.  If there are multiple ISRs that occur in between 2 consecutive injections, then these 
events will be considered as 1 ISR and considered related to the preceding injection. 
Hepatic AEs, including AEs of liver function test (LFT) abnormalities: AEs mapping to 
the SMQ drug-related hepatic disorders - comprehensive search (includes all narrow and 
broad terms).  Frequency (percentages) of drug-related hepatic disorders will be summarized 
by SOC and PT.  A separate listing will be generated of all patients reporting these events. 
7.2. 
Secondary Endpoints 
7.2.1. 
Evaluate the pharmacodynamic effect of lumasiran on urinary oxalate excretion 
The analysis of 24-hour urinary oxalate excretion corrected for BSA will be based upon the 
results that meet the validity criteria (i.e., creatinine excretion ≥10 mg/kg, duration of collection 
18 to 26 hours, no missing voids and the sample was not collected within 14 days after the most 
recent dialysis session, if applicable). The analysis will be generated separately based upon data  
from laboratories using a clinical diagnostic PD assay or quantitative PD assay. 
Correlations between the assays will be performed comparing oxalate values, 24-hour urinary 
oxalate corrected for BSA, change and percentage change of 24-hour urinary oxalate corrected 
for BSA. Per-patient spaghetti plots may also be generated to compare the results over time.  
 
 
 
 


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24-hour urinary oxalate (mmol/24h/1.73m2) corrected for BSA at each visit per patient is 
calculated as follows:  
[Urine oxalate concentration (umol/L)/1000 (umol/mmol)]*[24hr urine volume (mL)/1000 
(mL/L)]* [24 hours/actual collection hours]*1.73/(BSA) 
 where BSA=square root (mean height (cm)*weight (kg)/3600) at the visit. 
Data will be summarized descriptively at baseline and at each post-baseline visit.  Tabular 
summaries will include actual value, change from baseline and percent change from baseline at 
each scheduled visit.  Per-patient figures and mean (+/-SEM) plots over time of the actual 
values, change from baseline and percent change from baseline will be generated.  A table of the 
maximum percent reduction per patient will also be generated.  
An analysis of the percentage of time at or below 1.5 x ULN will also be summarized. For each 
patient, the percentage of time will be calculated as follows: 
  
Percentage of time at or below 1.5x ULN = cumulative months at or below 1.5 x ULN *100  
                                                                                    cumulative  months of valid assessments 
where cumulative months at or below 1.5x ULN will be defined as the summation across all 
intervals that met the threshold of at or below 1.5x ULN and cumulative months of valid 
assessments will be defined as the summation across all valid post-baseline collections.  In order 
to quantify the months at or below 1.5x ULN, a linear interpolation method will be used to 
determine the bookend dates at which the patient crossed into the threshold and crossed out of 
the threshold.  
Descriptive statistics of percentage of time at or below 1.5x ULN (among the subset of patients 
who had at least 1 post-baseline value that was at or below 1.5x ULN) will be presented.  In 
addition, the number of patients and associated percentage of patients in each category (e.g., 
<25%, 25 to <50%, 50 to <75%, and ≥75%) will also be presented.   
The analysis of the percentage of time will also be calculated using the threshold of at or below 
ULN.  
 
7.2.2. 
Change in estimated glomerular filtration rate (eGFR) and measured creatinine 
clearance over time 
Analyses of eGFR and measured creatinine clearance over time will be performed on the Safety 
Analysis Set.  
The eGFR (mL/min/1.73m2) will be calculated from serum creatinine (SCr) based on the 
Modification of Diet in Renal Disease (MDRD) formula for patients ≥18 years of age at 
enrollment and the Schwartz Bedside Formula for subjects <18 years of age at enrollment in the 
parent study.  
MDRD Formula 
 eGFR (mL/min/1.73m2) = 175 × (SCr [µmol/dL]/88.4)-1.154 × (age)-0.203 × (0.742, if female), 
or × (1.212, if African American) 
Schwartz Bedside Formula 


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 eGFR (mL/min/1.73m2) = (36.2 × height [cm])/ SCr (µmol /dL) 
The eGFR (mL/min/1.73 m2) will be categorized into the following categories: ≥90, 60 to <90, 
30 to <60, 15 to <30, and <15.  A shift table of baseline to worst post-baseline eGFR (i.e., 
category with the lowest value) will be presented.  Additionally, the eGFR will also be 
summarized descriptively at each scheduled visit.  The descriptive statistics will include actual 
value, change from baseline and percent change from baseline at each scheduled visit.  Per-
patient plots and mean (+/- SEM) plots over time of the actual values, change from baseline and 
percent change from baseline will be generated. Additionally, slope of change of eGFR over 
time is will be estimated by a linear mixed effect model, if appropriate.  
Analysis of measured creatinine clearance will be performed on the PD Analysis Set.  The 
analysis will include only valid values (note: valid is defined as: creatinine ≥10 mg/kg, duration 
of collection 18 to 26 hours, no missing voids, and the sample was not collected within 14 days 
after the most recent dialysis session, if applicable). 
Measured urine creatinine clearance at each visit per patient will be calculated as: 
Urine Creatinine concentration (mg/dL)*24-hour urine volume (mL)/ plasma creatinine 
 
(mg/dL)*total minutes of collection time*1.73/BSA 
where BSA=square root (mean height (cm)*weight (kg)/3600) at that visit. 
Tabular summaries will include actual value, change from baseline and percent change from 
baseline at each scheduled visit. 
Per-patient figures and mean (+/-SEM) plots over time of the actual values, change from 
baseline and percent change from baseline will be generated.  
7.3. 
Exploratory Endpoints 
7.3.1. 
Other Safety Parameters 
Additional safety parameters include clinical laboratory parameters (hematology, serum 
chemistry, LFTs, urinalysis, and coagulations), vital signs, 12-lead ECGs, renal ultrasounds and 
physical examinations.  All additional safety parameters will be analyzed using the Safety 
Analysis Set.  
Clinical Laboratory Parameters:  Clinical laboratory parameters will be expressed in SI units. 
Laboratory data collected and recorded below the LLOQ will be set to the lower limit of 
quantification for the calculation of summary statistics.  Summaries will only include data from 
the central laboratory (except eGFR as this is summarized in efficacy).  Key laboratory 
parameters will be graded according to NCI CTCAE v5.0. 
Laboratory parameters (hematology, chemistry, liver function tests, coagulation and urinalysis), 
which are continuous variables, will each have a tabular summary of descriptive statistics at 
each scheduled visit.  Descriptive statistics include actual value, change from baseline and 
percent change from baseline at each scheduled visit.  
Shift tables will be generated to summarize shifts from baseline categories to the worst post-
baseline categories with directionality specified for any labs which could be reported in either 
direction (e.g. above threshold or below threshold).  


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Clinical laboratory tests with normal ranges will be classified as Low, Normal, and High.  For 
these tests, abnormal values will be flagged in the listings with grade appended (e.g. H1 will 
represent that the lab reported met the threshold of high range with grade 1).  
For hematology and chemistry laboratory assessments, summary tables of potentially clinically 
significant abnormalities will also be provided.  
All laboratory data will be presented in data listings.  Out of range laboratory results will be 
identified in listings.   
Liver Function Tests (LFTs): A listing will be generated for all patients with abnormal liver 
function tests as defined by ALT >3 × ULN, AST >3 × ULN or  total bilirubin >2 × ULN at any 
visit.  
A tabular summary for LFTs will be generated to summarize the number and associated 
percentage of patients in each of the categories at any post-baseline visit:  
 ALT >1 and ≤3, ALT >3 and ≤5, ALT >5 and ≤10, ALT >10 and ≤20, ALT >20 × ULN 
 AST >1 and ≤3, AST >3 and ≤5, AST >5 and ≤10, AST >10 and ≤20, AST >20 × ULN 
 ALT or AST >1 and ≤3, ALT or AST >3 and ≤5, ALT or AST >5 and ≤10, ALT or AST 
>10 and ≤20, AST or ALT >20 × ULN 
 WNL, ALP >1.5 × ULN 
 Total bilirubin >1.5and ≤2, total bilirubin >2 and ≤3, total bilirubin >3 and ≤5 and total 
bilirubin >5 
eDISH plots of peak total bilirubin at any time versus peak ALT or AST at any time will also be 
presented. 
Vital Signs: Descriptive statistics for each vital sign (e.g. systolic blood pressure, diastolic 
blood pressure, pulse rate, body temperature, respiratory rate, height, weight, body mass index) 
will be summarized at scheduled visits. Summaries will include actual values and changes from 
baseline. A summary table of potentially clinically significant shifts in vital signs will also be 
generated separately for pediatric patients (<18 years old) and adult patients.  
For any patient <18 years of age at screening, the modified z-score will be calculated for height, 
weight and body mass index (BMI) according to the CDC growth chart f.  Descriptive statistics 
of z-scores by visit and treatment arm will be summarized.  A tabular summary of the 
proportion of patients with z-scores at various cut-points (e.g., above and  below 2 SD) will also 
be summarized.   
A separate listing of vital sign data will be generated.  Per patient plots of z-scores over time for 
those patients <18 years of age at screening in Study 001 will also be generated.  
12-lead ECGs: Electrocardiogram (ECG) parameters include rhythm, ventricular rate, PR 
interval, QRS duration, QT interval, and QTc interval. Corrected QT interval (QTc), if not 
collected, will be calculated using the Fridericia’s correction formula.  
Fridericia’s cube-root corrected QT: QTcF (ms) = QT (ms)  3
60
)
(bpm
HR
. 


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The number and percentage of patients with normal, abnormal, and clinically significant 
abnormal results at baseline and each time point will be summarized.  
For electrocardiogram parameters, these will be summarized using descriptive statistics for 
actual values and for changes from baseline by scheduled time of evaluation.  
Baseline, post baseline maximum QTcF and post baseline maximum change from baseline in 
QTcF during the study will be summarized with descriptive statistics. The incidence of notable 
ECG changes from baseline in maximum absolute QTcF, intervals (≤450, > 450, > 480, and 
>500 ms) over all post-treatment evaluations, as well as in QTcF, maximum changes from 
baseline (≤30 ms, >30 to 60 ms and > 60 ms) over all post-treatment evaluations will be 
summarized.   
A listing of all ECG data will be provided. 
Physical Examinations: During the study, full physical examinations and symptom directed 
physical examinations will be conducted.  If any abnormalities are observed during these 
physical examinations or worsened from baseline, then this will be recorded on the AE form.  
A separate listing per patient will be generated to display the dates and times of the physical 
examination.  
Renal Ultrasounds:  During the study, renal ultrasounds will be collected at baseline, Month 12 
and Month 24.  The number and percentage of patients at baseline with findings of normal, 
abnormal, not clinically significant, clinically significant will be summarized.  In addition, the 
number and percentage of patients in categories to indicate if a significant change from baseline 
has been documented will also be summarized at each post-baseline visit.  Listings will also be 
generated.  
7.3.2. 
Characterize the Pharmacokinetics of lumasiran 
PK analyses will be conducted using noncompartmental methods using data with intensive 
plasma and urine PK samples.  PK parameters will be calculated using a validated version of 
Phoenix® WinNonlin. 
Population PK analysis of plasma data  is planned for all patients in the study and will be 
described in a separate population PK analysis plan. 
7.3.3. 
Evaluate the Pharmacodynamic Effect of lumasiran  
Analysis of PD parameters (e.g. 24-hour urine oxalate: creatinine ratio, plasma oxalate, urinary 
glycolate concentrations, plasma glycolate concentrations) will be performed on the PD 
Analysis Set.  The analysis will be performed based upon data from clinical diagnostic PD assay 
and quantitative PD assay. For all 24-hour urine parameters with the exception of 24-hour 
oxalate:creatinine ratio, only valid values will be used in the analysis (note: valid is defined as: 
creatinine ≥10 mg/kg, duration of collection 18 to 26 hours, no missing voids and the sample 
was not collected within 14 days after the most recent dialysis session, if applicable). 
Data will be summarized descriptively (n, mean, SD, SEM, median, quartiles, minimum and 
maximum) at baseline at each post-baseline scheduled visits.  Tabular summaries of actual 
value, change from baseline and percent change from baseline will be generated at each 


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scheduled visit.  Plots of the mean (+/-SEM) of actual values and percent change will also be 
generated.  Per-patient plots of actual values over time will be generated.  
For urine oxalate: creatinine ratio and plasma oxalate, the maximum mean reduction from 
baseline over time will be summarized descriptively.  
7.3.4. 
Characterize Quality of Life (QOL) 
Data from the QoL instruments will be collected to assess kidney disease specific measures. 
Analyses of these instruments will be performed on the Safety Analysis Set. The instrument 
used is based upon the age of the patient at screening; for each patient, the instrument selected 
based on age at screening will be used consistently throughout the study.  Table 1 outlines the 
QOL instruments to be used based upon age at screening.  
Table 1: 
QOL Instruments by Age at Screening in Study 002 (<18 years vs ≥18 years) 
Age at 
Screening 
QOL 
Instruments 
Domains/Subscales 
Notes 
≥18 years of 
age 
KDQOL-36 
 
5 subscales: SF-12 Physical Component Score, SF-12 Mental 
Component Score, Symptoms/Problems, Effects of Kidney Disease 
and Burden of Kidney Disease 
 
 
No 
common 
variables. 
<18 years of 
age 
PedsQL and 
ESRD model 
PedsQOL: 4 multi-dimensional scales: Physical Functioning, 
Emotional Functioning, Social Functioning and School Functioning 
3 summary scores (total score, physical health summary score and 
psychosocial health summary score). 
ESRD:7 domains:  General Fatigue, About My Kidney Disease, 
Treatment Problems, Family and Peer Interaction, Worry, Perceived 
Physical Appearance, and Communication. 
Total Score 
For each instrument, descriptive statistics will be generated at baseline and each post-baseline 
scheduled visit.  For the PedsQL, both parent and/or child may complete the questionnaire.  
Summary statistics at each visit for each subscale/score will summarize responses separately 
based upon the parent and child responses.  
7.3.5. 
Incidence of ADA 
The number and associated percentage of patients who are ADA positive at baseline and at any 
post-baseline visit will be summarized.  A listing of patients with ADA positivity with their 
associated titer value AEs will also be provided.  
 


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8. 
CHANGES TO PLANNED ANALYSES 


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9. 
REFERENCES 
1. 
Cochat, P. and G. Rumsby, Primary hyperoxaluria. N Engl J Med, 2013. 369(7): p. 649-58. 
 


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