Conditions: Primary Hyperoxaluria Type 1 (PH1)
Keywords: PH1 Primary hyperoxaluria RNAi therapeutic siRNA AGT Oxalate
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 39
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of lumasiran in children and adults with primary hyperoxaluria type 1 (PH1).

Detailed description:

Arms:
arm 1: Lumasiran-matching placebo (normal saline \[0.9% NaCl\]) was administered subcutaneously (SC) at Day 1 and Months 1, 2 and 3 during the 6-Month Double-blind (DB) Period, followed by lumasiran SC, 3.0 mg/kg, at Months 6, 7 and 8 during the 3-Month Blinded Treatment Extension Period, followed by lumasiran SC, 3.0 mg/kg, at Month 9 and then every three months during the 51-Month Open-label Extension (OLE) period. arm 2: Lumasiran was administered SC, 3.0 mg/kg, at Day 1 and Months 1, 2 and 3 during the 6-Month DB Period, followed by lumasiran SC, 3.0 mg/kg at Month 6, and lumasiran-matching placebo SC at Months 7 and 8 during the 3-Month Blinded Treatment Extension Period, followed by lumasiran SC, 3.0 mg/kg, at Month 9 and then every three months during the 51-Month OLE period.

Interventions: intervention 1: Placebo intervention 2: Lumasiran
Intervention descriptions: intervention 1: Placebo by SC injection intervention 2: Lumasiran by SC injection

Protocol document:
Prot_002.pdf: 
 
 
Official Title: ILLUMINATE-A: A Phase 3 Randomized, Double-blind, Placebo-Controlled Study with 
an Extended Dosing Period to Evaluate the Efficacy and Safety of Lumasiran in Children and 
Adults with Primary Hyperoxaluria Type 1 
 
NCT Number:   
NCT03681184 
 
Document Date:   
Protocol Amendment 3, 06 May 2020 
 






Clinical Study Protocol ALN-GO1-003 
lumasiran 
Amendment 3, 06 May 2020 
Alnylam Pharmaceuticals 
Confidential 
3 
INVESTIGATOR’S AGREEMENT 
I have read the ALN-GO1-003 protocol and agree to conduct the study in accordance with the 
protocol and all applicable regulations.  I agree to ensure that Financial Disclosure Statements 
will be completed by me (including, if applicable, my spouse [or legal partner] and dependent 
children), my subinvestigators (including, if applicable, their spouses [or legal partners] and 
dependent children) at the start of the study and for up to 1 year after the study is completed, if 
there are changes that affect my financial disclosure status.  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 






Clinical Study Protocol ALN-GO1-003 
lumasiran 
Amendment 3, 06 May 2020 
Alnylam Pharmaceuticals 
Confidential 
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month blinded treatment extension period and an open-label extension period of up to 51 months.  A 
schematic of the study design is shown in Figure 1. 
Number of Planned Patients 
The planned enrollment for this study is 30 patients. 
Diagnosis and Main Eligibility Criteria 
This study will include adults and children (≥6 years of age) with a documented diagnosis of PH1 based 
on urinary oxalate excretion ≥0.70 mmol/24h/1.73m2 and confirmed alanine glyoxylate aminotransferase 
(AGXT) mutations, and eGFR ≥30 mL/min/1.73m2 at screening. 
Study Drug, Dose, and Mode of Administration 
Lumasiran (ALN-GO1) is an investigational agent comprised of a synthetic, small interfering RNA 
(siRNA) (drug substance ALN-65585) covalently linked to a triantennary N-acetylgalactosamine 
(GalNAc) ligand, designed to target liver hydroxyacid oxidase 1 (HAO1) mRNA, blocking production of 
glycolate oxidase (GO) and hence reducing hepatic oxalate production. 
Lumasiran will be administered at a dose of 3.0 mg/kg as a subcutaneous (SC) injection.  See Figure 1 
for the dose schedule. 
Reference Treatment, Dose, and Mode of Administration 
The control drug for this study will be a placebo (sodium chloride 0.9% w/v for SC administration).  See 
Figure 1 for the dose schedule. 
Duration of Treatment and Study 
The duration of treatment with study drug is up to 5 years, including a 6-month double-blind treatment 
period followed by a 3-month blinded treatment extension period, and up to a 51-month open-label 
extension period. 
The estimated total time on study, inclusive of screening, for each patient is up to 62 months, including up 
to 2 months of screening followed by up to 60 months of treatment. 
Figure 1: 
Study Design 
 
Abbreviations:  q3M=once every 3 months; qM=once monthly; qMx3=once monthly for 3 consecutive months 
*  Patients randomized to lumasiran will also receive 2 qM doses of placebo during the 3-month blinded treatment 
extension period. 
















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• See Section 4.3.1 for instructions for patients who discontinue study drug. 
• 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, renal stone events, adverse events, and healthcare 
utilization. 
• Gray-shaded column indicates the visit where assessments span 2 days. 
Table 3: 
Pharmacokinetic and ECG Assessment Time Points: All Sites except East Asian Sites 
Study Month/ Study Day 
Sampling Time 
(hh:mm) 
Blood PK Sample 
ECG 
Screening 
Any time during visit 
 
Xa 
Month 0 
(Day 1) 
Predose  
X 
Xb 
04:00 (±1 hour) 
X 
Xb 
24:00 (±2 hours) 
X 
 
Month 3  
(Day 85± 4 days)  
Predose  
X 
Xa 
04:00 (±1 hour) 
X 
 
Month 6 (Day 169±7 days) 
Predose  
X 
Xb 
04:00 (±1 hour) 
X 
Xb 
24:00 (±2 hours) 
X 
 
Month 9 (Day 253±4 days) 
Predose  
X 
Xa 
04:00 (±1 hour) 
X 
 
Month 12 (Day 337±28 days) 
Predose 
X 
Xa 
04:00 (±1 hour) 
X 
 
24:00 (±2 hours) 
X 
 
Months 24, 36, 48, 60 (see Table 2) 
Predose 
 
Xa 
Abbreviations:  ECG=electrocardiogram; hh:mm=hour:minute;  PK=pharmacokinetics 
Notes:  
• 
Predose samples are collected on the day of dosing. 
• 
The hour (±range) indicate sample collection timing relative to dosing.  Precise PK sample times (hour and minute) are recorded.  See Section 7.2.7 for 
additional information on PK assessments. 


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• 
Patients should be supine for at least 10 minutes before each ECG is obtained. See Section 6.5.4 for additional information on ECG assessments. 
• 
Blood samples for PK assessment may be collected at 24 hours postdose as feasible during periods of time when the COVID-19 pandemic impedes the 
ability of patients to travel to the study site and the healthcare professionals to go to the patients’ homes.    
a For Screening, Month 3, Month 9, Month 12 and annual visits (Month 24, Month 36, Month 48, Month 60), singlicate ECGs are performed using a local ECG 
machine.  During periods of time when the COVID-19 pandemic impedes the ability of patients to travel to the study site, ECG assessments may be completed 
up to 7 months after the intended timepoint for visits at Month 12 and later. 
b For Month 0 (Day 1) and Month 6, triplicate ECGs are performed predose and postdose timepoints using a central machine and central reads.  Triplicate ECG 
readings occur approximately 5 minutes apart.   
Table 4: 
Pharmacokinetic and Electrocardiogram Assessment Time Points: East Asian Sites  
Study Month  
(Study Day) 
Sampling Time 
(hh:mm) 
Blood PK Sample 
ECG  
Screening 
Any time during visit 
 
Xa 
Month 0  
(Day 1) 
Predose  
X 
Xb 
00:30 (±10 min) 
X 
 
02:00 (±20 min) 
X 
 
04:00 (±20 min) 
X 
Xb 
06:00 (±20 min) 
X 
 
08:00 (±20 min) 
X 
 
24:00 (±2 hours) 
X 
Xb 
Month 3 
(Day 85±4 days) 
Predose 
X 
Xa 
04:00 (±1 hour) 
X 
 
Month 6 (Day 169±7 days) 
Predose  
X 
Xb 
00:30 (±10 min) 
X 
 
02:00 (±20 min) 
X 
 
04:00 (±20 min) 
X 
Xb 
06:00 (±20 min) 
X 
 


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Study Month  
(Study Day) 
Sampling Time 
(hh:mm) 
Blood PK Sample 
ECG  
08:00 (±20 min) 
X 
 
24:00 (±2 hours) 
X 
Xb 
Month 9 (Day 253±4 days) 
Predose  
X 
Xa 
04:00 (±1 hour) 
X 
 
Month 12 (Day 337)  
Predose  
X 
Xb 
 
00:30 (±10 min) 
X 
 
 
02:00 (±20 min) 
X 
 
 
04:00 (±1 hour) 
X 
Xb 
 
06:00 (±20 min) 
X 
 
 
08:00 (±20 min) 
X 
 
 
24:00 (±2 hours) 
X 
Xb 
Months 24, 36, 48, 60 (see Table 2) 
Predose 
 
Xa 
Abbreviations:  ECG=electrocardiogram; hh:mm=hour:minute; PK=pharmacokinetics 
Notes:  
• 
East Asian includes sites in China, Korea, Japan, Taiwan, and Hong Kong. 
• 
Predose samples are collected on the day of dosing. 
• 
The hour (±range) indicate sample collection timing relative to dosing.  Precise PK sample times (hour and minute) are recorded.  See Section 7.2.7 for 
additional information on PK assessments.  
• 
Patients should be supine for at least 10 minutes before each ECG is obtained. See Section 6.5.4 for additional information on ECG assessments. 
a For Screening, Month 3, Month 9, and annual visits (Month 24, Month 36, Month 48, Month 60), singlicate ECGs are performed using a local ECG machine.   
b For Month 0 (Day 1), Month 6, and Month 12 triplicate ECGs are performed predose and postdose timepoints using a central machine and central reads.  
Triplicate ECG readings occur approximately 5 minutes apart. 
 


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Table 5: 
Urine Pharmacokinetic Assessment Time Points: East Asian Sites  
Study Day 
Sampling Time 
(hh:mm)  
Pooled Urine  
PK Sample 
Month 0 
(Day 1) 
Predose 
X 
0-6 hours (±30 min) 
X 
6-12 hours (±30 min) 
X 
12-24 hours (±2 hours) 
X 
Month 6  
(Day 169 ±7 days) 
Predose 
X 
0-6 hours (±30 min) 
X 
6-12 hours (±30 min) 
X 
12-24 hours (±2 hours) 
X 
 
 
Month 12 (Day 337±7 days) 
Predose 
X 
0-6 hours (±30 min) 
X 
6-12 hours (±30 min) 
X 
12-24 hours (±2 hours) 
X 
Abbreviations:  hh:mm=hour:minute; PK=pharmacokinetics 
Notes:  
• 
East Asian includes sites in China, Korea, Japan, Taiwan, and Hong Kong.  
• 
The hour (±range) indicate sample collection timing relative to dosing.  Precise PK sample times (hour and minute) are 
recorded.  See Section 6.4.1 and Section 7.2.7 for additional information on PK assessments. 
• 
All predose samples are spot urine samples; postdose urine samples are pooled samples.


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TABLE OF CONTENTS 
SPONSOR PROTOCOL APPROVAL ...........................................................................................2 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
PROTOCOL SYNOPSIS ................................................................................................................4 
TABLE OF CONTENTS ...............................................................................................................18 
LIST OF TABLES .........................................................................................................................22 
LIST OF FIGURES .......................................................................................................................22 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................23 
1. 
INTRODUCTION ......................................................................................................26 
1.1. 
Disease Overview .......................................................................................................26 
1.2. 
Lumasiran (ALN-GO1) ..............................................................................................27 
1.2.1. 
Summary of Nonclinical Data with Lumasiran ..........................................................27 
1.2.2. 
Summary of Clinical Data with Lumasiran ................................................................28 
1.3. 
Study Design Rationale ..............................................................................................28 
1.4. 
Dose Rationale ............................................................................................................29 
1.5. 
Benefit-Risk Assessment ............................................................................................30 
2. 
OBJECTIVES AND ENDPOINTS ............................................................................31 
3. 
INVESTIGATIONAL PLAN .....................................................................................32 
3.1. 
Summary of Study Design ..........................................................................................32 
3.2. 
Duration of Treatment ................................................................................................34 
3.3. 
Duration of Study .......................................................................................................34 
3.3.1. 
Definition of End of Study for an Individual Patient .................................................34 
3.4. 
Number of Planned Patients .......................................................................................34 
3.5. 
Method of Assigning Patients to Treatment Groups ..................................................34 
3.6. 
Blinding ......................................................................................................................34 
3.6.1. 
Emergency Unblinding ...............................................................................................35 
3.7. 
Data Monitoring Committee .......................................................................................36 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................36 
4.1. 
Inclusion Criteria ........................................................................................................36 
4.2. 
Exclusion Criteria .......................................................................................................36 
4.3. 
Removal from Therapy or Assessment.......................................................................37 


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4.3.1. 
Discontinuation of Study Drug ...................................................................................38 
4.3.2. 
Stopping a Patient's Study Participation .....................................................................38 
4.3.3. 
Replacement of Study Patients ...................................................................................39 
4.3.4. 
Lost to Follow-Up.......................................................................................................39 
5. 
TREATMENTS AND OTHER REQUIREMENTS ..................................................40 
5.1. 
Treatments Administered ............................................................................................40 
5.2. 
Study Drug ..................................................................................................................40 
5.2.1. 
Description ..................................................................................................................40 
5.2.2. 
Dose and Administration ............................................................................................40 
5.2.3. 
Dose Modifications .....................................................................................................41 
5.2.3.1. 
LFT Criteria for Withholding, Monitoring and Stopping Study Drug Dosing...........41 
5.2.4. 
Preparation, Handling, and Storage ............................................................................43 
5.2.5. 
Packaging and Labeling ..............................................................................................44 
5.2.6. 
Accountability .............................................................................................................44 
5.3. 
Concomitant Medications ...........................................................................................44 
5.4. 
Treatment Compliance ................................................................................................45 
5.5. 
Other Requirements ....................................................................................................45 
5.5.1. 
Contraception ..............................................................................................................45 
5.5.2. 
Alcohol Restrictions ...................................................................................................46 
5.5.3. 
Dietary Restrictions ....................................................................................................46 
6. 
STUDY ASSESSMENTS ..........................................................................................46 
6.1. 
Screening Assessments ...............................................................................................46 
6.1.1. 
Retesting .....................................................................................................................47 
6.1.2. 
Rescreening .................................................................................................................47 
6.2. 
Efficacy Assessments .................................................................................................47 
6.3. 
Pharmacodynamic and Renal Assessments ................................................................47 
6.3.1. 
24-hour Urine Collections to determine Urinary Oxalate Excretion ..........................47 
6.3.1.1. 
Validity Criteria for 24-hour Urine Collections .........................................................49 
6.3.1.2. 
Urinary Oxalate:Creatinine Ratio ...............................................................................49 
6.3.2. 
Estimated Glomerular Filtration Rate .........................................................................49 
6.3.3. 
Renal Stone Events .....................................................................................................49 
6.3.4. 
Sample Analysis .........................................................................................................49 
6.4. 
Pharmacokinetic Assessments ....................................................................................50 


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6.4.1. 
Pharmacokinetic Assessments in Patients at East Asian Study Centers .....................50 
6.5. 
Safety Assessments .....................................................................................................50 
6.5.1. 
Vital Signs ..................................................................................................................50 
6.5.2. 
Weight and Height ......................................................................................................51 
6.5.3. 
Physical Examination .................................................................................................51 
6.5.4. 
Electrocardiogram .......................................................................................................51 
6.5.5. 
Renal Ultrasound ........................................................................................................51 
6.5.6. 
Clinical Laboratory Assessments ...............................................................................52 
6.5.6.1. 
Immunogenicity ..........................................................................................................53 
6.5.6.2. 
Pregnancy Testing ......................................................................................................54 
6.5.6.3. 
Additional Liver Function Assessments .....................................................................54 
6.5.6.4. 
Maximum Blood Volume ...........................................................................................55 
6.5.7. 
Adverse Events ...........................................................................................................56 
6.5.7.1. 
Definitions ..................................................................................................................56 
6.5.7.2. 
Eliciting and Recording Adverse Events ....................................................................57 
6.5.7.3. 
Reporting Adverse Events of Clinical Interest to Sponsor/Designee .........................58 
6.5.7.4. 
Serious Adverse Events Require Immediate Reporting to Sponsor/Designee ...........58 
6.5.7.5. 
Sponsor Safety Reporting to Regulatory Authorities .................................................59 
6.5.7.6. 
Serious Adverse Event Notification to the Institutional Review 
Board/Independent Ethics Committee ........................................................................59 
6.5.7.7. 
Pregnancy Reporting ..................................................................................................59 
6.5.7.8. 
Overdose Reporting ....................................................................................................59 
6.5.8. 
COVID-19 Data Collection ........................................................................................60 
6.6. 
Biomarkers, DNA Genotyping, and Biospecimen Repository ...................................60 
6.7. 
Quality of Life (QOL) ................................................................................................60 
6.8. 
Patient and Caregiver Experience Surveys .................................................................61 
6.9. 
Patient and Caregiver Impact Questionnaire ..............................................................61 
6.10. 
Healthcare Resource Utilization .................................................................................62 
7. 
STATISTICS ..............................................................................................................62 
7.1. 
Determination of Sample Size ....................................................................................62 
7.2. 
Statistical Methodology ..............................................................................................62 
7.2.1. 
Populations to be Analyzed ........................................................................................62 
7.2.2. 
Examination of Subgroups .........................................................................................63 


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7.2.3. 
Handling of Missing Data ...........................................................................................63 
7.2.4. 
Baseline Evaluations ...................................................................................................63 
7.2.5. 
Efficacy Analyses .......................................................................................................63 
7.2.5.1. 
Primary Endpoint ........................................................................................................63 
7.2.5.2. 
Secondary Endpoints ..................................................................................................64 
7.2.5.3. 
Exploratory Endpoints ................................................................................................64 
7.2.6. 
Pharmacodynamic Analysis........................................................................................64 
7.2.7. 
Pharmacokinetic Analysis ..........................................................................................64 
7.2.8. 
Safety Analyses ..........................................................................................................65 
7.2.9. 
Immunogenicity Analyses ..........................................................................................65 
7.2.10. 
Other Analyses ............................................................................................................65 
7.2.11. 
Interim Analysis ..........................................................................................................65 
7.2.12. 
Optional Additional Research .....................................................................................65 
8. 
STUDY ADMINISTRATION ...................................................................................65 
8.1. 
Ethical and Regulatory Considerations ......................................................................65 
8.1.1. 
Informed Consent .......................................................................................................66 
8.1.2. 
Ethical Review ............................................................................................................66 
8.1.3. 
Serious Breach of Protocol .........................................................................................67 
8.1.4. 
Study Documentation, Confidentiality, and Records Retention .................................67 
8.1.5. 
End of Study ...............................................................................................................67 
8.1.6. 
Termination of the Clinical Study or Site Closure .....................................................67 
8.2. 
Data Quality Control and Quality Assurance .............................................................68 
8.2.1. 
Data Handling .............................................................................................................68 
8.2.2. 
Study Monitoring ........................................................................................................68 
8.2.3. 
Audits and Inspections ................................................................................................68 
8.3. 
Publication Policy .......................................................................................................69 
9. 
LIST OF REFERENCES ............................................................................................70 
10. 
APPENDICES ............................................................................................................72 
10.1. 
Formulae for Estimated Glomerular Filtration Rate Calculation ...............................72 
10.2. 
Blood Volume Limits in Pediatric Patients ................................................................73 
 


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LIST OF TABLES 
Table 1: 
Schedule of Assessments – 6-Month Double-Blind Treatment Period and 
Blinded Treatment Extension (Screening through Month 9 Assessments) ..................7 
Table 2: 
Schedule of Assessments – Open Label Extension Period (After Month 9 
through Year 5) ...........................................................................................................11 
Table 3: 
Pharmacokinetic and ECG Assessment Time Points: All Sites except East 
Asian Sites ..................................................................................................................14 
Table 4: 
Pharmacokinetic and Electrocardiogram Assessment Time Points: East 
Asian Sites ..................................................................................................................15 
Table 5: 
Urine Pharmacokinetic Assessment Time Points: East Asian Sites ...........................17 
Table 6: 
Monitoring and Dosing Rules for Asymptomatic Patients with Confirmed 
Isolated Elevations of ALT and/or AST >3× ULN, with No Alternative 
Cause Identified ..........................................................................................................43 
Table 7: 
24-hour Urine Collection Procedure by Study Visit...................................................48 
Table 8: 
Clinical Laboratory Assessments ...............................................................................53 
Table 9: 
Hepatic Assessments in Patients Who Experience Elevated Transaminases .............55 
Table 10: Maximum Allowable Total Blood Volume Collection Chart ....................................73 
 
LIST OF FIGURES 
Figure 1: 
Study Design .................................................................................................................6 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation  
Definition 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AGT 
Alanine-glyoxylate aminotransferase 
AGXT 
Alanine glyoxylate aminotransferase gene 
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 
CFR 
Code of Federal Regulation 
CL/F 
Apparent clearance 
COVID-19 
Coronavirus disease 2019 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
EOS 
End of study 
EOT 
End of treatment 
ET 
Early termination 
EQ-5D 
Euro Quality of Life Health State Profile Questionnaire 
ESRD 
End-stage renal disease 
FAS 
Full analysis set 
GalNAc 
N-acetylgalactosamine 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GO 
Glycolate oxidase 
HAO1 
Hydroxyacid oxidase 1 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 


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Abbreviation  
Definition 
ICF 
Informed consent form  
ICH 
International Council on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IRS 
Interactive Response System 
ISR 
Injection site reactions 
KDQOL 
Kidney Disease Quality of Life Questionnaire 
LFT 
Liver function tests 
MAD 
Multiple-ascending dose 
MDRD 
Modification of diet in renal disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-effect model for repeated measures 
MNAR 
Missing not at random 
mRNA 
Messenger ribonucleic acid 
OLE 
Open-label extension 
PD 
Pharmacodynamic 
PedsQL 
Pediatric Quality of Life Inventory 
PH1 
Primary hyperoxaluria type 1 
PK 
Pharmacokinetic 
PMM 
Pattern mixture model 
PP 
Per protocol 
PT 
Preferred Term 
q3M 
Once every 3 months 
qM 
Once monthly  
qMx3 
Once monthly for 3 consecutive months 
SAD 
Single-ascending dose 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
siRNA 
Small interfering RNA 


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Abbreviation  
Definition 
SOC 
System Organ Class 
SUSAR 
Suspected unexpected serious adverse reaction 
t½β 
Elimination half-life 
tmax 
Time to maximum plasma concentration 
TMF 
Trial master file 
ULN 
Upper limit of normal 
V/F 
Apparent volume of distribution 
VAS 
Visual analog scale 
WOCBP 
Women of child-bearing potential 
WHO 
World Health Organization 
 


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1. 
INTRODUCTION 
1.1. 
Disease Overview 
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.[Cochat and Rumsby 2013]  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.[Cochat and Rumsby 2013]  This devastating condition, systemic oxalosis, arises when 
the estimated glomerular filtration rate (eGFR) has declined to below 30 to 45 mL/min/1.73 
m2.[Cochat and Rumsby 2013]  Without treatment, the disease progresses inexorably, and death 
from end-stage renal disease (ESRD) and/or complications of oxalosis is inevitable.[Cochat and 
Rumsby 2013; Harambat 2010; van der Hoeven 2012]   
Over 150 mutations in AGXT have been described.[Williams 2009]  While there are broad 
genotype–phenotype associations with the underlying causative defect, patients can present with 
very different symptoms, disease course, including timing of an individual’s eGFR decline, and 
treatment response.[Danpure 2014; Hoppe 1997]  Patients progress at various rates and an event 
that leads to acute or chronic worsening, such as an obstructive kidney stone or episode of 
dehydration, can occur at any time. 
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; Boualla 2015; Frishberg 2005; Kamoun and 
Lakhoua 1996] 
PH1 often presents as a pediatric disease, but many patients remain undiagnosed for years after 
the initial clinical manifestations of the disease.[Lieske 2005; Mandrile 2014; van Woerden 
2003]  A recently published analysis of 247 patients with PH1 from 206 pedigrees in the Rare 
Kidney Stone Consortium PH Registry demonstrated a median age of first symptoms at 5.2 years 
of age and a cumulative renal survival of 76%, 43%, and 12% at 20 years, 40 years, and 60 
years, respectively.[Hopp 2015]  Similarly, an analysis of 526 patients with PH1 published by 
the OxalEurope Consortium indicated a median age of disease symptom onset of 3.9 years and a 
median age of diagnosis of 8.1 years.  Overall, 43% of all patients diagnosed with PH1 had 
already progressed to ESRD at the time of diagnosis.[Mandrile 2014]  The deterioration of renal 
function highlights the importance of investigating potentially disease-modifying interventions 
as soon as possible after diagnosis. 


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There are no approved therapies for the treatment of PH1 and the current standard of care is 
burdensome to patients and their families.  Disease management is based on supportive 
measures, including high fluid intake and crystallization inhibitors to increase urinary oxalate 
solubility, and treatment of disease complications such as urinary tract stones and infections.  A 
minority of patients experience oxalate lowering with therapeutic doses of pyridoxine (vitamin 
B6).  Dietary modification plays a minor role in treatment since endogenous oxalate production 
far exceeds dietary intake.  Patients progressing to, or presenting with ESRD require intense 
kidney dialysis.  Dialysis is not viewed as an effective therapy for PH1, but rather serves as a 
bridge to a liver-kidney transplant or as an alternative to no therapy at all.  Dialysis is often 
inadequate to effectively offload accumulating oxalate, and systemic oxalosis with end organ 
damage may develop despite this burdensome treatment.  Dialysis regimens for PH1 are more 
involved than conventional dialysis, predisposing to increased risk of complications.  Combined 
liver/kidney transplantation offers potentially curative therapy; but is limited due to restricted 
availability, complications associated with the procedure, ethical considerations in resource-poor 
settings [Cochat and Rumsby 2013], and intense use of health care resources. 
PH1 can progress to be a serious, severely debilitating disease with significant morbidity and 
mortality and negatively impacts quality of life.  Limited and burdensome management options 
for PH1 outlined above highlight the serious unmet need for a safe and efficacious treatment for 
patients with this devastating disease. 
1.2. 
Lumasiran (ALN-GO1) 
Alnylam Pharmaceuticals, Inc. (the Sponsor) is developing lumasiran (ALN-GO1), an 
investigational agent comprised of a synthetic, small interfering RNA (siRNA) (drug substance 
ALN-65585) covalently linked to a triantennary N-acetylgalactosamine (GalNAc) ligand, 
designed to target liver hydroxyacid oxidase 1 (HAO1) mRNA, blocking production of glycolate 
oxidase (GO) and hence reducing hepatic oxalate production, which is the underlying cause of 
the morbidity and mortality associated with PH1. 
The proposed indication for lumasiran is the treatment of primary hyperoxaluria type 1 (PH1). 
1.2.1. 
Summary of Nonclinical Data with Lumasiran  
The pharmacology, safety pharmacology, pharmacokinetics, and toxicology of lumasiran were 
evaluated in a series of in vitro and in vivo nonclinical studies.  Lumasiran was 
pharmacologically active in rodents and cynomolgus monkeys (hereafter referred to as 
monkeys).  Subcutaneous (SC) administration of lumasiran demonstrated potent, dose-dependent 
pharmacologic activity resulting in reduced hepatic HAO1 mRNA levels with the expected 
increases in glycolate levels in wild-type and diseased animals and subsequent reductions in 
urinary oxalate in diseased animals. 
No lumasiran-related safety pharmacology findings were identified in Good Laboratory Practice 
(GLP)-compliant repeat dose toxicity studies in monkeys.  Lumasiran was well tolerated in both 
the rat and monkey repeat dose toxicology studies and did not result in any dose-limiting effects 
at the highest doses tested.  In vitro and in vivo genetic toxicity studies were all negative at 
(ICH) S2 (R1) limit doses.  Based on this class of drugs and the data to date, a favorable safety 
profile of lumasiran has been demonstrated and supports the use of lumasiran in the current 
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A summary of nonclinical studies is included in the current edition of the Investigator’s 
Brochure. 
1.2.2. 
Summary of Clinical Data with Lumasiran  
Lumasiran is being investigated in 2 ongoing clinical studies, Study ALN-GO1-001 and Study 
ALN-GO1-002.  
Study ALN-GO1-001 is a 2-part (single-ascending dose [SAD] and multiple-ascending dose 
[MAD]) study designed to evaluate the safety, tolerability, PK, and PD of lumasiran in healthy 
adult subjects and in adult and pediatric patients with PH1.  In the SAD part of the study (Part 
A), healthy adult subjects were randomized to receive one single blind dose of lumasiran (0.3-6.0 
mg/kg) or placebo (6:2).  In the MAD part of the study (Part B), patients ≥6 years of age with 
PH1 and eGFR>45 mL/min/1.73 m2 were randomized 3:1 to receive single blind doses of 
lumasiran or placebo at 1 mg/kg monthly for 3 doses, 3 mg/kg monthly for 3 doses or 3 mg/kg 
every 3 months for 2 doses.  Patients who initially received placebo transitioned to an open-label 
portion of the study to receive doses of lumasiran.  The primary objective is to evaluate the 
safety and tolerability of subcutaneously administered lumasiran.  Secondary and exploratory 
objectives of the study include the characterization of plasma and urine PK and the evaluation of 
the PD effect, including glycolate and oxalate levels.   
Study ALN-GO1-002 is a Phase 2 open-label extension study to evaluate the long-term safety, 
PK, and PD of lumasiran in patients with PH1 who have completed Study ALN-GO1-001.  
Available safety data indicate that lumasiran has an acceptable safety and tolerability profile 
across all dosing regimens evaluated.  Preliminary data from Study ALN-GO1-001 demonstrate 
a mean maximal reduction in 24-hour urinary oxalate of 64% (Cohorts 1-3) and achievement of 
normal to near-normal levels of urinary oxalate (<0.70 mmol/24h/1.73 m2) in patients dosed with 
lumasiran (range: 0.29 to 0.67 mmol/24h/1.73 m2).  Further information on the chemistry, 
pharmacology, efficacy, and safety of lumasiran is provided in the current edition of the 
Investigator’s Brochure. 
1.3. 
Study Design Rationale 
Lumasiran is proposed to reduce urinary oxalate production resulting in lower urinary oxalate 
excretion in patients with relatively intact renal function.  In preclinical models and in patients 
with PH1, SC administration of lumasiran demonstrated potent, dose-dependent pharmacologic 
activity resulting substantial reductions in urinary oxalate.[Liebow 2017]  
This is a multicenter, multinational, randomized, double-blind, placebo-controlled Phase 3 study 
designed to demonstrate the clinical efficacy and safety of lumasiran in patients with PH1.  The 
primary endpoint for the study is percent change in 24-hour urinary oxalate excretion from 
baseline to Month 6. 
Urinary oxalate excretion is the most sensitive and clinically relevant marker that directly relates 
to the PH1 disease pathophysiology in this population, and is used clinically for diagnosis and 
management of patients with PH1 who have preserved renal function.  Elevated urinary oxalate 
is the direct cause of kidney stones and renal failure in patients with PH1.  Lowered urinary 
oxalate excretion is expected to provide clinical benefit in patients with preserved renal function 
by directly targeting the cause of the disease: toxic urinary oxalate levels that lead to oxalate 


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crystallization in the kidneys and urinary tract.  Reduced urinary oxalate excretion therefore is 
expected to reduce kidney stone burden and potentially stabilize renal function. 
The primary endpoint will evaluate the effect of lumasiran versus placebo on urinary oxalate at 
Month 6.  After 6 months, patients originally assigned to lumasiran will continue to receive 
lumasiran, and patients originally assigned to placebo will receive lumasiran in a blinded 
extension period through Month 9 to preserve blinding.  Patients randomized to lumasiran will 
receive injections of placebo at Month 7 and Month 8 to maintain the blind. All patients will then 
be followed in an open-label period of up to 51 months to evaluate the long-term safety and 
efficacy of lumasiran.  Use of a placebo comparator and limiting the duration of placebo 
exposure to the 6-month double-blind period are appropriate based on the lack of approved 
therapies for patients with PH1 while allowing an estimation of the treatment effect and an 
understanding of the safety profile of lumasiran.  All patients will continue their current standard 
of care regimen, which may include hyperhydration, crystallization inhibitors, and/or pyridoxine 
therapy, for the first 12 months of the study, after which they can adjust per the 
recommendations of their treating physician.  Current disease management options are presented 
in Section 1.1. 
The study population will be comprised of children and adults with a documented diagnosis of 
PH1, elevated urinary oxalate, and GFR ≥30 mL/min/1.73m2.  Lumasiran is currently being 
investigated in a similar patient population (ie, patients with PH1 ≥6 years of age with relatively 
intact renal function) in Study ALN-GO1-001.  Enrolling pediatric patients in this study is 
acceptable given that PH1 presents as a pediatric disease with life-threatening consequences and 
hence there is a high unmet medical need in this population. 
1.4. 
Dose Rationale 
Data from study ALN-GO1-001 Parts A and B in healthy subjects and PH1 patients and 
associated PK/PD modeling were used to support dose selection for this study.  The proposed 
dosing regimen for this study is 3.0 mg/kg once monthly for 3 consecutive months (monthly for 
3 doses: loading dose phase) followed by 3.0 mg/kg once every 3 months (maintenance phase) 
starting 1 month after the last loading dose.  This regimen is expected to be well-tolerated and to 
optimize the proportion of patients with a rapid and sustained reduction in urinary oxalate.  
In patients with PH1, population PK/PD modeling demonstrated dose dependent oxalate 
reductions over the dose range (1.0 to 6.0 mg/kg continuous once monthly or once every 3 
months SC administrations), with diminishing additional effect predicted with higher doses 
consistent with an asymptotic rather than linear relationship.  For a given dose, the PK/PD model 
indicated that monthly administration leads to a more rapid decline in urinary oxalate levels 
relative to dosing every 3 months.  A combination of monthly dosing in a loading phase and then 
dosing every 3 months in a maintenance phase achieves the goals of rapid and consistent 
lowering of urinary oxalate to normal or near normal levels in PH1 patients.  Preclinical and 
clinical data indicate the renal pathway is a minor elimination route for lumasiran. Thus, renal 
impairment is not expected to influence systemic exposure, PD, and safety properties of 
lumasiran, and no dose adjustments are needed based on renal function.  Thus, a lumasiran 
dosing regimen of 3.0 mg/kg once monthly for 3 doses followed by 3.0 mg/kg once every 3 
months has been selected for this study in PH1 patients ≥6 years old with eGFR 
>30 mL/min/1.73 m2.   


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1.5. 
Benefit-Risk Assessment 
PH1 is a rare autosomal recessive disease characterized by excessive oxalate production by the 
liver leading to excessive urinary oxalate and varying types and degrees of renal disease, often 
progressing to end-stage renal disease. Systemic accumulation of calcium oxalate results in 
severe end-organ damage. Without treatment, the disease progresses, and patients die from end-
stage renal disease and/or complication of oxalosis.  
Lumasiran is designed to reduce hepatic production of oxalate. Based on the available data from 
nonclinical studies and the Phase 1 clinical study ALN-GO1-001, lumasiran, administered 
subcutaneously, demonstrated a potent, dose-dependent inhibition of glycolate oxidase resulting 
in increased plasma and urinary glycolate and decreased urinary oxalate.  Unlike oxalate, 
glycolate is highly soluble and readily excreted in the urine. Thus, by reducing the production of 
oxalate, it is possible that lumasiran may ameliorate the signs and symptoms of PH1 and alter the 
clinical course in patients across the spectrum of disease, irrespective of age and disease stage.  
In the Phase 1 clinical study, lumasiran has been well tolerated with an acceptable safety profile 
based on the available safety data. Most adverse events have been mild or moderate in severity. 
There have been no severe or serious adverse events related to study drug. Transient, mild 
injection site reactions (ISRs) have been observed but have not resulted in any treatment 
discontinuations or dose adjustments. No clinically significant laboratory or hematologic 
changes have been observed. 
Given the biological target of lumasiran, the available nonclinical and clinical data, and mode of 
administration, important potential risks for lumasiran are injection site reactions and liver 
function test abnormalities.  During the study, patients will be closely monitored, including 
evaluation of injection sites, laboratory monitoring for liver function test abnormalities, renal 
function, plasma and urine glycolate levels, and other standard hematology and blood 
chemistries. The study has specific inclusion and exclusion criteria to ensure that patients have 
adequate hepatic function and specific rules for dose withholding and stopping have been 
incorporated in the protocol for abnormalities in liver function tests. As the risk of embryofetal 
toxicity is currently unknown, women of childbearing potential participating in the study 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.   
An external, independent Data Monitoring Committee (DMC) will monitor and ensure the safety 
of trial participants (see Section 3.7).  
Based on the emerging efficacy and safety data from the ongoing clinical study (ALN-GO1-001) 
and nonclinical studies, the benefit-risk assessment is positive and supports the evaluation of 
lumasiran in a Phase 3 study in pediatric and adult patients with PH1.  
Detailed information about the known and expected benefits and risks of lumasiran may be 
found in the current edition of the Investigator’s Brochure. 






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baseline collections will be used to determine eligibility for the study, defined as urinary oxalate 
excretion of ≥0.70 mmol/24h/1.73m2.  
Consenting (and assenting, where applicable) patients who meet all eligibility criteria will be 
randomized 2:1 to receive their first dose of subcutaneously administered lumasiran or placebo 
on Day 1.  Treatment groups will be stratified at randomization by mean urinary oxalate 
excretion from the first 2 valid baseline collections (see Section 3.5). 
During the 6-month, placebo-controlled, double-blind treatment period, patients will receive 
loading doses of 3.0 mg/kg lumasiran or placebo administered monthly for 3 doses (at Day 1, 
Month 1, and Month 2) followed by the first maintenance dose of 3.0 mg/kg lumasiran or 
placebo administered at Month 3 and then once every 3 months.   
After the Month 6 visit assessments are completed (ie, end of the 6-month double-blind 
treatment period), patients from both treatment arms (lumasiran and placebo) will begin the 
3-month blinded treatment extension period, in which all patients will receive active drug.  To 
maintain the blind to treatment assignment, study drug will continue to be administered in a 
double-blind manner and at the same frequency as in the 6-month double-blind period.  In the 
3-month treatment extension period, patients will receive study drug according to initial 
treatment assignment as follows:  
• Patients who had been randomized to placebo will receive 3.0 mg/kg lumasiran 
monthly at Months 6, 7, and 8  
• Patients who had been randomized to lumasiran will be given 3.0 mg/kg lumasiran at 
Month 6 and placebo at Months 7 and 8 
• All patients will be given a maintenance dose of lumasiran at Month 9 and then once 
every 3 months thereafter 
Assessments of efficacy and safety will be conducted during visits to the clinical study center 
every 2 weeks for the first month of this part of the study and monthly thereafter through 
Month 9. 
Patients will receive their first open-label dose of lumasiran at Month 9 to begin their 
participation in the open-label extension (OLE) part of the study, in which they will be treated 
with lumasiran administered once every 3 months for up to 48 months; patients will receive their 
last dose of lumasiran at Month 57.  Patients entering the OLE period will undergo efficacy and 
safety assessments every 3 months through Month 24, and every 6 months until the end of study 
(EOS) visit at Month 60. 
24-hour urine collections will be performed for evaluation of oxalate excretion.  At the Month 6 
and Month 12 visits, patients will provide at least three 24-hour urine collections and ≥2 of these 
collections must be valid (see Section 6.3.1.1) prior to completion of the Month 6 and Month 12 
visit assessments.  Single 24-hour urine collections will be obtained for the study visits specified 
in the Schedules of Assessments.  Details on 24-hour urine collection procedures are included in 
Section 6.3.1.   
An external, independent DMC will monitor safety over the course of the study.  Details for the 
committee will be provided in DMC charter. 


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3.2. 
Duration of Treatment  
The duration of treatment with study drug is up to 5 years, including a 6-month double-blind 
treatment period followed by a 3-month blinded treatment extension period, and up to a 51-
month open-label extension period. 
3.3. 
Duration of Study 
The estimated total time on study, inclusive of screening, for each patient is up to 62 months, 
including up to 2 months of screening followed by up to 60 months of treatment (see 
Section 3.2). 
3.3.1. 
Definition of End of Study for an Individual Patient 
A patient is considered to have reached the end of the study if: 
• the patient has completed the end of study (EOS; Month 60) visit, or  
• the patient has completed the safety follow-up visits until PD recovery of 24-hour 
urinary oxalate is >70% of baseline, and plasma glycolate is <30% above baseline or 
≤ the ULN, or  
• the patient has completed 12 months of monitoring following the final lumasiran 
dose.  
3.4. 
Number of Planned Patients 
The planned enrollment for this study is 30 patients. 
3.5. 
Method of Assigning Patients to Treatment Groups 
Using the Interactive Response System (IRS), patients will be randomized 2:1 to the lumasiran 
or placebo arm.  Randomization will be stratified by mean baseline urinary oxalate level 
(>1.70 mmol/24h/1.73m2 versus ≤1.70 mmol/24h/1.73m2).  The mean urinary oxalate level for 
stratification will be calculated using the values obtained from the first 2 valid baseline 24-hour 
urine collections.  
Each patient will be uniquely identified in the study by a combination of the site number and 
patient identification number.  Upon signing the informed consent form (ICF), the patient will be 
assigned a patient identification number by the IRS.  The Investigator or his/her designee will 
contact the IRS to randomize the patient after confirming that the patient fulfills all the inclusion 
criteria and none of the exclusion criteria.  
3.6. 
Blinding 
All site personnel (with the exception of some site pharmacists) and patients (including their 
families or caregivers) will be blinded to study drug treatment assignment until the last patient 
completes the assessments at the Month 9 visit.  Site pharmacists may be unblinded to study drug 
treatment only where required by documented pharmacy procedure.  All Sponsor personnel with 
direct oversight of the conduct and management of the study (except for staff involved in 
randomization and study drug supply) will be blinded to study drug treatment until the 6-month 


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treatment period data is unblinded for the primary analysis.  Sponsor personnel who may have 
treatment assignment information will not have access to patient level data from the clinical trial 
databases.   
The independent DMC and an independent biostatistics group will have access to patient level 
treatment assignments.   
To maintain the blind to treatment assignment, during the 3-month blinded treatment extension 
period, study drug will continue to be administered in a double-blind manner and at the same 
frequency as in the 6-month double-blind period.  However, the study is designed so that all 
patients will receive active drug during the extension period according to initial treatment 
assignment as follows: 
• Patients randomized to placebo: 3.0 mg/kg lumasiran administered as monthly 
loading doses (Month 6, 7, and 8)  
• Patients randomized to lumasiran: 3.0 mg/kg lumasiran administered as a single 
maintenance dose at Month 6  
Therefore, all site personnel and patients will be aware that all patients will receive active drug 
administered at Month 6 even though all doses of study drug will be masked.   
The Sponsor and all site personnel will be blinded to central laboratory results of urinary and 
plasma oxalate and glycolate from after the time of the first dose until unblinding.  Results will 
not be reported to the Investigator from the first dose to until the last patient completes the 
assessments at the Month 9 visit.  In addition, Investigators and staff involved with this trial and 
all medical staff involved in the patient’s medical care should refrain from obtaining local 
oxalate or glycolate measurements until the sites and patients are unblinded, or until the patient 
ends the study, whichever is earlier.  If oxalate or glycolate is measured during the blinded 
period, all reasonable steps must be undertaken to avoid informing the patient and site personnel 
of the results until the sites and patients are unblinded. 
A list of all Alnylam personnel or personnel working on behalf of Alnylam who are unblinded to 
study data will be maintained in the trial master file (TMF).  Any unplanned unblinding 
occurring during the study period will be documented and reported in the clinical study report.  
Additional details are provided in a separate blinding plan. 
3.6.1. 
Emergency Unblinding 
If the treating physician determines that the clinical management of the patient requires 
knowledge of the study drug assignment, the Investigator may break the blind, as necessary.  If 
time permits, clinical study center personnel should contact the Medical Monitor before 
unblinding to discuss the need to unblind the patient, but must do so within 1 working day after 
the unblinding event.  Unblinding information should be limited to the fewest number of people 
on a need-to-know basis. A record of when the blind was broken, who was unblinded, who broke 
the blind, and why it was broken, will be maintained in the TMF.   
Refer to the IRS instructions for details on unblinding. 


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3.7. 
Data Monitoring Committee 
An external independent DMC will oversee the safety and overall conduct of this study. The 
DMC will operate under the rules of a charter that will be reviewed and approved at the 
organizational meeting of the DMC. Details are provided in the DMC Charter. 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS 
4.1. 
Inclusion Criteria 
Patients are eligible to be included in the study if all the following criteria apply: 
Age 
1. Age 6 years or older.   
Patient and Disease Characteristics 
2. Documentation or confirmation of PH1 as determined by genetic analysis prior to 
randomization. 
3. Mean 24-hour urinary oxalate excretion from the first 2 valid 24-hour urine collections is 
≥0.70 mmol/24h/1.73m2  
4. If taking pyridoxine (vitamin B6) for the treatment of PH1, must have been on stable 
regimen for at least 90 days before randomization, and willing to remain on this stable 
regimen for 12 months from first study drug administration. 
Informed Consent 
5. Patient is able to understand and is willing and able to comply with the study 
requirements and to provide written informed consent.  In the case of patients under the 
age of legal consent, the legal guardian(s) must provide informed consent and the patient 
should provide assent per local and national requirements.  
4.2. 
Exclusion Criteria 
Patients are excluded from the study if any of the following criteria apply: 
Disease-specific Conditions 
1. Medical history includes clinical evidence of extrarenal systemic oxalosis, as determined 
by the Investigator. 
Laboratory Assessments 
2. Has any of the following laboratory parameter assessments at screening:  
a. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2 × upper 
limit of normal (ULN)  
b. Total bilirubin >1.5 x ULN.  Patients with elevated total bilirubin that is secondary to 
documented Gilbert’s syndrome are eligible if the total bilirubin is <2 x ULN 
c. International normalized ratio (INR) >1.5 (patients on oral anticoagulant [eg, 
warfarin] with an INR <3.5 will be allowed) 


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3. Has known active human immunodeficiency virus (HIV) infection; or evidence of current 
or chronic hepatitis C virus (HCV) or hepatitis B virus (HBV) infection 
4. Estimated GFR of <30 mL/min/1.73m2 at screening (calculation will be based on the 
Modification of Diet in Renal Disease [MDRD] formula for patients ≥18 years of age and 
the Schwartz Bedside Formula for patients <18 years of age) See Section 10.1  
Prior/Concomitant Therapy 
5. Received an investigational agent within the last 30 days or 5 half-lives, whichever is 
longer, prior to the first dose of study drug, or are in follow-up of another clinical study 
prior to randomization  
Medical Conditions 
6. History of renal or liver transplant 
7. Has other medical conditions or comorbidities, which in the opinion of the Investigator, 
would interfere with study compliance or data interpretation 
8. History of multiple drug allergies or history of allergic reaction to an oligonucleotide or 
GalNAc. 
9. History of intolerance to subcutaneous (SC) injection(s) 
Contraception, Pregnancy, and Breastfeeding  
10. Is not willing to comply with the contraceptive requirements during the study period, as 
described in Section 5.5.1.  
11. Female patient is pregnant, planning a pregnancy, or breast-feeding. 
Alcohol Use 
12. Unwilling or unable to limit alcohol consumption throughout the course of the study. 
Alcohol intake of >2 units/day is excluded during the study (unit: 1 glass of wine 
[approximately 125 mL] = 1 measure of spirits [approximately 1 fluid ounce] = ½ pint of 
beer [approximately 284 mL] 
13. History of alcohol abuse, within the last 12 months before screening, in the opinion of the 
investigator. 
4.3. 
Removal from Therapy or Assessment 
Patients or their legal guardians are free to discontinue study drug and/or stop participation in the 
study at any time and for any reason, without penalty to their continuing medical care.  The 
Investigator or the Sponsor may stop a patient’s participation in the study at any time if this is 
considered to be in the patient’s best interest.  Any discontinuation of treatment or the stopping 
of the patient’s participation in the study must be fully documented in the electronic case report 
form (eCRF), and should be followed up by the Investigator.   
Discontinuation of study drug is described in Section 4.3.1, while the stopping of a patient’s 
participation in the study is detailed in Section 4.3.2. 


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4.3.1. 
Discontinuation of Study Drug 
The Investigator, or designee, may discontinue study drug in a patient, if the patient: 
• Is in significant violation of the protocol 
• Experiences a serious or intolerable AE 
• Is non-adherent to treatment regimen 
• Becomes pregnant 
• Is lost to follow-up 
• Has another reason (non-adverse event) 
• Or, the study is terminated by the Sponsor 
The Investigator will confer with the Sponsor or Medical Monitor before discontinuing dosing in 
the patient.   
Patients who are pregnant will be discontinued from study drug dosing immediately (see 
Section 6.5.7.7 for reporting and follow-up of pregnancy).  A positive urine pregnancy test 
should be subsequently confirmed by a serum pregnancy test prior to discontinuing the study 
drug. 
If a patient discontinues dosing due to an adverse event (AE), including serious adverse events 
(SAEs), the event should be followed as described in Section 6.5.7.  When a patient discontinues 
study drug dosing, the primary reason must be recorded in the appropriate section of the eCRF.  
Patients who discontinue study drug and remain on study may receive treatment consistent with 
local standard practice for their disease per Investigator judgment, as applicable.  
Patients who discontinue from study drug prior to completion of the Month 6 assessments will be 
encouraged to remain on study and complete monthly assessments (including 24-hour urine 
collections, but excluding PK assessments) through Month 6.  They will then be asked to 
complete safety follow-up visits once every 3 months per the safety follow-up schedule (see 
Table 2).  Patients who discontinue study drug after completion of the Month 6 assessments will 
be asked to return for their next scheduled visit to complete early termination (ET) assessments 
and complete safety follow-up visits once every 3 months thereafter per the safety follow-up 
schedule (see Table 2). 
While the study sites and patients remain blinded, the patient will be followed until 12 months 
after the last dose of lumasiran.  If the patient is still in follow-up at the time when sites and 
patients are unblinded, PD recovery should be evaluated to determine if the patient meets the PD 
recovery criteria (ie, 24-hour urinary oxalate is >70% of baseline, and plasma glycolate is <30% 
above baseline or ≤ the ULN) and is eligible to stop study follow-up. 
4.3.2. 
Stopping a Patient's Study Participation 
A patient or their legal guardian may stop participation in the study at any time.  Patients 
considering stopping their participation in the study during the blinded period of the study should 
be informed that they can discontinue study drug and complete their study assessments through 
the Month 6 visit and complete safety follow-up visits as described in Section 4.3.1, or 
alternatively may complete any minimal assessments for which the patient or their legal guardian 


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consents.  If a patient or their legal guardian chooses to discontinue study drug and stop 
participation in all follow-up prior to the completion of the Month 6 visit, every effort should be 
made to conduct the assessments scheduled to be performed at the Month 6 visit and the safety 
follow-up assessments (see Table 1).   
Patients or their legal guardians considering stopping participation in the study after the sites 
have been unblinded should be informed that they can discontinue study drug and complete 
safety follow-up visits as described in Section 4.3.1, or alternatively may complete any minimal 
assessments for which the patient or legal guardian consents.   
If a patient or their legal guardian still chooses to stop participation in the study, every effort 
should be made to conduct the ET assessments prior to stopping study participation (see 
Table 2). 
The patient may decide to withdraw consent, informing the study doctor at any time in writing or 
in any other form that may be locally required.  The Sponsor will continue to keep and use the 
patient’s study information (including any data resulting from the analysis of patient’s biological 
samples until the time of withdrawal) according to applicable law.  The process for the storage 
and, as applicable, further use of remaining samples will be followed per local requirements. 
The Investigator or Sponsor may stop the participation of a patient in the study at any time if this 
is considered to be in the patient’s best interest.  However, study integrity and interpretation is 
best maintained if all enrolled patients continue study assessments and follow-up even if study 
drug is discontinued. 
The primary reason that a patient’s study participation is stopped must be recorded in the 
appropriate section of the eCRF and all efforts will be made to complete and report the 
observations as thoroughly as possible.  If a patient’s study participation is stopped due to an 
adverse event (AE), including SAEs, the event should be followed as described in Section 6.5.7. 
Patients stopping participation in the study will be asked if they are willing to consent to either 
be contacted by telephone or to allow non-patient contact follow-up (eg, medical record review) 
up to 6 years after enrolling onto the study to document their overall health status. 
4.3.3. 
Replacement of Study Patients  
Patients who discontinue the study drug or stop participation in the study will not be replaced. 
4.3.4. 
Lost to Follow-Up 
A patient will be considered lost to follow-up if the patient repeatedly fails to return for 
scheduled visits and is unable to be contacted by the clinical study center.  The following actions 
must be taken if a patient misses a required study visit: 
• The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of maintaining the assigned visit 
schedule and ascertain if the patient wishes to and/or should continue in the study. 
• Before a patient is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the patient (where possible, 3 telephone calls and, if 
necessary,  a certified letter to the patient’s last known mailing address or local 


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equivalent methods). These contact attempts should be documented in the patient’s 
medical record. 
• Should the patient continue to be unreachable, the patient will be considered to have 
stopped participation in the study.  
5. 
TREATMENTS AND OTHER REQUIREMENTS 
5.1. 
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 and returned unused must not be re-dispensed. 
5.2. 
Study Drug 
Detailed information describing the preparation, administration, and storage of lumasiran and 
placebo is provided in the Pharmacy Manual. 
5.2.1. 
Description 
Lumasiran will be supplied as a sterile solution in water for SC injection.  See the Pharmacy 
Manual for further details of solution concentration and fill volume. 
The control drug for this study will be a placebo (sodium chloride 0.9% w/v for SC 
administration).  Placebo will be provided by the Sponsor; it will be packaged identically to 
lumasiran. 
5.2.2. 
Dose and Administration 
Study drug is administered based on total body weight.  Body weight collected within 4 months 
prior to the study drug dose or the predose weight collected on the study visit day or dosing day 
will be used for dose calculations. 
During the 6-month double-blind treatment period (Day 1 through Month 6 assessments), 
patients will be administered loading doses of 3.0 mg/kg lumasiran or an equivalent volume of 
placebo as an SC injection once monthly for 3 doses (administered at Day 1, Month 1, and 
Month 2 visits) followed by 1 maintenance dose of 3.0 mg/kg lumasiran or placebo administered 
at the Month 3 visit.  During the 3-month blinded treatment extension period (from dosing at 
Month 6 [following completion of all assessments] through Assessments at Month 9), patients 
randomized to placebo will be administered loading doses of 3.0 mg/kg as an SC injection once 
monthly for 3 doses (administered at Month 6, Month 7, and Month 8 visits).  Patients 
randomized to lumasiran will continue to receive a maintenance dose at the Month 6 visit.  
Patients randomized to lumasiran will receive doses of placebo administered at the Month 7 and 
Month 8 visits to keep all procedures same between the lumasiran and placebo arm patients and 
maintain the blind. 
In order to maintain the blind to treatment assignment, study drug will continue to be 
administered in the blinded treatment extension period in a double-blind fashion.  However, due 
to study design features, both patients and study site personnel will be aware that all patients will 


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receive active drug at Month 6.  Patients will receive their first open-label maintenance dose of 
lumasiran at Month 9.   
Study drug injections will be administered under the supervision of the Investigator.  The 
injection site may be marked and mapped for later observation.  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.  Detailed instructions for study drug administration are found in 
the Pharmacy Manual.   
From Month 12 through the end of the study, study drug administration may be conducted at a 
location other than the study center (eg, home) by a healthcare professional with the oversight of 
the Investigator, where applicable country and local regulations and infrastructure allow.  
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, lumasiran may be 
administered by the patient or 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 lumasiran 
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.   
If a patient does not receive a dose of study drug 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 the study (see also 
Section 4.3). 
Additional details can be found in the Pharmacy Manual.  In addition, instructions and 
procedures related to administration of lumasiran by a patient or caregiver will be provided in the 
Patient/Caregiver Storage and Administration Instructions. 
5.2.3. 
Dose Modifications 
Dose modifications are not permitted. 
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.   
5.2.3.1. 
LFT 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 6.  


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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. 
c. If an alternative cause is not found, perform assessments per Table 6 and Table 9. 
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 6 
(below): 


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Table 6: 
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 9 (all assessments to be performed once) 
• 
Hematology, serum chemistry, LFT per Table 8  
• 
Coagulation parameters (prothrombin time, partial thromboplastin 
time, international normalized ratio) 
• 
Monitor LFT at least every two weeks per Table 8. 
• 
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 9 (all assessments to be performed once) 
• 
Hematology, serum chemistry, LFT per Table 8  
• 
Coagulation parameters (prothrombin time, partial thromboplastin 
time, international normalized ratio) 
• 
Monitor LFT at least weekly per Table 8 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; INR=international normalized ratio; 
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. 
5.2.4. 
Preparation, Handling, and Storage 
Staff at each clinical study center and the healthcare professional will be responsible for 
preparation of lumasiran doses, according to procedures detailed in the Pharmacy Manual.  In 
cases where lumasiran is administered at home by a patient or caregiver, 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]. 
A Sponsor representative or designee will be permitted, upon request, to audit the supplies, 
storage, dispensing procedures, and records. 


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Instructions specific to unused study drug and additional storage will be provided in the 
Pharmacy Manual and the Patient/Caregiver Storage and Administration Instructions. 
5.2.5. 
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. 
5.2.6. 
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.  Used, 
partially used, and unused study drug will be returned to the Sponsor (or designee) or destroyed 
at the clinical study center according to applicable regulations. 
Further instructions about drug accountability will be detailed in the Pharmacy Manual. 
5.3. 
Concomitant Medications 
Use of concomitant medications will be recorded on the patient’s eCRF as specified in the 
Schedules of Assessments (see Table 1 and Table 2).  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 in the eCRF. 
If patients use NSAIDs intermittently or chronically, they must have been able to tolerate them 
with no previous side effects (eg, gastric distress or bleeding).   
Standard vitamins and topical medications are permitted.  However, topical steroids must not be 
applied anywhere near the injection site(s) unless medically indicated.  If taking pyridoxine 
(vitamin B6) for the treatment of PH1, patients must have been on stable regimen for at least 
90 days before randomization, and willing to remain on this stable regimen for 12 months from 
first study drug administration.  Patients should avoid high dose vitamin C preparations within 
4 days prior to oxalate assessments.   
For other permitted concomitant medications administered subcutaneously, do not administer in 
same injection site area as the study drug for 7 days after the last dose of study drug.  
Patients may be treated for PH1 according to local standard of care.  Patients should continue 
their current standard of care regimen, including hyperhydration, crystallization inhibitors, 
and/or pyridoxine therapy for the first 12 months of the study.  Standard of care treatment may 
be adjusted beginning at Month 12 in accordance with clinical judgement. 
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. 


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5.4. 
Treatment Compliance 
Compliance with study drug administration will be verified by study staff. 
5.5. 
Other Requirements 
5.5.1. 
Contraception 
Women of child-bearing potential must be willing to use acceptable methods of contraception 
from 14 days before first dose, throughout study participation, and for 90 days after last dose 
administration or until study completion.  Pediatric/adolescent female patients must initiate 
contraception at menarche or must discontinue study drug. 
Birth control methods which are considered acceptable include: 
• 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). 
• Established use of oral, implantable, injectable, or transdermal hormonal methods of 
contraception. Women of child-bearing potential who use hormonal contraceptives as 
a method of contraception must also use a barrier method (condom or occlusive cap 
[diaphragm or cervical/vault cap] in conjunction with spermicide [eg, foam, gel, film, 
cream, or suppository]).   
• If hormonal methods of contraception are medically contraindicated due to their 
underlying disease, a double-barrier method (combination of male condom with cap, 
diaphragm, or sponge, in conjunction with spermicide) is also considered an 
acceptable method of contraception. 
• 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 
patients must agree to use one of the above-mentioned contraceptive methods, if they 
start heterosexual relationships during the study and until study completion. 
Women of child-bearing potential include female patients who have experienced menarche (or 
begin menarche over the course of the study) and who are not postmenopausal or permanently 
sterilized (eg, bilateral tubal occlusion, hysterectomy, or bilateral salpingectomy).  A 
postmenopausal state is defined as the absence of menses for 12 months without an alternative 
medical cause, confirmed by follicle-stimulating hormone level within the postmenopausal 
range. 
For male patients, no contraception is required.  However, use by males of contraception 
(condom) may be required in some countries, e.g., France, in order to comply with local 
requirements as described in the corresponding patient informed consent forms.  


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Compliance with contraception requirements will be assessed on a regular basis by the 
Investigator throughout the course of the study. 
5.5.2. 
Alcohol Restrictions 
Patients will limit alcohol consumption throughout the course of the study.  Alcohol is limited to 
no more than 2 units per day (unit:  1 glass of wine [approximately 125 mL] = 1 measure of 
spirits [approximately 1 fluid ounce] = ½ pint of beer [approximately 284 mL]) for the duration 
of the study. 
5.5.3. 
Dietary Restrictions 
Patients should refrain from consumption of foods with high oxalate content, including, but not 
limited to, chocolate, rhubarb, spinach, and beet root, for 1 week prior to assessments of urinary 
and plasma oxalate.  
6. 
STUDY ASSESSMENTS 
The schedules of study assessments is provided in Table 1, Table 2, Table 3, and Table 4.   
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 (urine or serum), clinical laboratory 
assessments, urine collections, DNA testing, symptom-directed physical examination / body 
system assessment, vital signs, body weight, height, PK and PD blood collection, blood 
collection for vitamin B6 levels, ADA and exploratory analyses (blood and urine) assessments, 
at all timepoints as specified in the Schedule of Assessments. 
6.1. 
Screening Assessments 
An informed consent form (ICF) or assent form in the case of patients under the age of legal 
consent that has been approved by the appropriate Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC) must be signed by the patient (or legal guardian if under the age of legal 
consent) before the Screening procedures are initiated.  All patients (or their legal guardians if 
under the age of legal consent) will be given a copy of the signed and dated ICF and/or assent 
form.  In the case when a patient reaches the legal age of consent during the study, the 
investigator must obtain the patient's informed consent prior to performing any further study 
interventions and/or procedures involving that patient (see Section 8.1.1). 
Patients will be screened to ensure that they meet all the inclusion criteria and none of the 
exclusion criteria (see Section 4.1 and Section 4.2).   
Patient demographic data and medical history/disease history will be obtained.  Any changes to 
medical history occurring between the screening assessment and Day 1 will be updated prior to 
study drug administration. 
A blood sample for PH1/AGXT mutation analysis will be collected for patients who do not have 
documented PH1 genetic analysis to confirm eligibility.  


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During the screening period, at least 3 separate 24-hour urine collections will be completed to 
assess urinary oxalate excretion.  Patients are strongly encouraged to complete these collections 
during supervised visits unless they are already familiar with the collection procedures.  At least 
2 of these collections need to be confirmed to be valid collections (see Section 6.3.1.1) prior to 
receiving study drug on Day 1.  The mean urinary oxalate excretion from the first 2 valid 
baseline collections will be used to determine eligibility for the study (see Section 4.1) and 
randomization stratification. 
6.1.1. 
Retesting  
If in the Investigator’s judgement, the screening laboratory abnormalities are likely to be 
transient, then laboratory tests, excluding urinary oxalate, may be repeated.  The investigator’s 
rationale is to be documented.  Laboratory values can be retested once during Screening as long 
as the patient can be evaluated for eligibility and randomized within the allowed Screening 
period. 
6.1.2. 
Rescreening 
A patient who does not meet all study eligibility criteria may be allowed to return for rescreening 
if appropriate in the opinion of the investigator and after consultation with the Medical Monitor.  
A patient will be re-consented and assent obtained (if applicable) if rescreening occurs outside of 
the 60-day screening window.  In this case, all screening procedures must be repeated.  
6.2. 
Efficacy Assessments 
The efficacy of lumasiran will be assessed by evaluating the percent change in 24-hour urinary 
oxalate excretion determined from 24-hour urine sample collections described in Section 6.3.1. 
6.3. 
Pharmacodynamic and Renal Assessments 
Urine and blood samples will be collected for assessment of PD parameters (plasma and urinary 
oxalate and glycolate concentrations) and renal parameters at the time points specified in the 
Schedules of Assessments (Table 1 and Table 2).  All blood and urine samples will be collected 
prior to dosing, if applicable.  
Where local regulations allow and infrastructure is in place, home nursing may be used to collect 
urine samples or for repeat blood sample collection, if necessary.  
6.3.1. 
24-hour Urine Collections to determine Urinary Oxalate Excretion 
Urinary oxalate excretion will be determined from 24-hour urine sample collections to be 
completed at the time points specified in the Schedules of Assessment (Table 1 and Table 2) to 
assess urinary oxalate excretion.  Urinary oxalate concentrations will be analyzed centrally using 
a validated assay.  The duration of collection and volume of urine in the collection will be 
recorded in the eCRF.  An aliquot of the 24-hour urine collection will also be used to determine 
urinary creatinine content to determine if the 24-hour urine collections need to be repeated (see 
Section 6.3.1.1).  
Single void collections for random urine sample for PD analysis should be collected as a first 
morning void when possible.  


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Table 7 shows the 24-hour urine collection procedure by study visit. 
Table 7: 
24-hour Urine Collection Procedure by Study Visit 
Study Visit and Urine 
Collection Window 
Number of 
Collections 
to Schedule 
Validity 
Requirement 
Prior to Dosing 
(see Sec 6.3.1.1) 
Option for 
Catheterized 
Collection?  
Notes 
Screening 
(within 60-day period) 
3 
2 valid 
collections prior 
to dosing 
No 
Supervised collections are 
encouraged unless patient 
already familiar with collection 
procedure. If any collections are 
invalid, the remaining 
collections for screening must be 
supervised.  
Month 6 and Month 12 
(within 14 days prior to 
dosing) 
3 
2 valid 
collections prior 
to dosing 
Yes 
If a patient has had ≥2 prior 
invalid collections, all 3 
collections must be supervised.  
At least 2 valid collections must 
be obtained prior to dosing. If 
any collections for the timepoint 
are invalid, the remaining 
collections for the timepoint 
must be supervised. 
Interim Monthly Visits 
with Dosing 
(Months 1-3 and Months 7-9 
[within 7 days prior to 
dosing]) 
1 
No 
Yes 
If invalid collection is obtained 
for the timepoint, single repeat 
collection must be supervised.  
Repeat collection, if necessary, 
is to be completed within 
±7 days of dosing. 
Interim Monthly Visits 
Without Dosing 
(Month 4 and Month 5 
[within 7 days prior to visit]) 
1 
No 
Yes 
If invalid collection is obtained 
for the timepoint, single repeat 
collection must be supervised. 
Repeat collection, if necessary, 
is to be completed within 
±7 days of the visit. 
Visits after Month 12 
(within 14 days prior to visit) 
1 
No 
Yes 
If collection is invalid for the 
timepoint, single repeat 
collection must be obtained 
within ±14 days of the visit. 
Dose should not be held if 
validity results unknown prior to 
dosing. 
Safety Follow-up Visits 
(within ±7 days of visit) 
1 
No 
Yes 
Repeat collections are optional. 
Abbreviations: Sec=section 
Notes: 
• 
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.  
• 
Optional catheterized collections are permitted at any visit after initial study drug administration at the 
discretion of the Investigator with agreement of patient and/or legal guardian, if applicable.  


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6.3.1.1. 
Validity Criteria for 24-hour Urine Collections 
A urine collection will be considered valid if each of the following criteria are met: 
• The collection is between 22-26 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 diary. 
• The 24-hour creatinine content is at least 10 mg/kg as assessed by the central 
laboratory. 
6.3.1.2. 
Urinary Oxalate:Creatinine Ratio 
Urine oxalate:creatinine ratios will be calculated from the oxalate and creatinine levels measured 
in the 24-hour urine collections to assess the PD effect of lumasiran on urinary oxalate:creatinine 
ratio.  Urinary oxalate:creatinine ratios from random spot urine collections will also be 
measured. 
6.3.2. 
Estimated Glomerular Filtration Rate 
Blood samples for the assessment of eGFR will be obtained at the time points specified in the 
Schedules of Assessment (Table 1 and Table 2).  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 and the Schwartz Bedside 
Formula for patients <18 years of age at screening (Appendix 10.1).[Levey 2009; Schwartz 
2009]  
6.3.3. 
Renal Stone Events 
A renal stone event is defined as an event which includes at least one of the following: 
• Visit to healthcare provider (eg, outpatient clinic, urgent care, emergency department, 
procedure) because of a renal stone 
• Medication for renal colic  
• Stone passage 
• Macroscopic hematuria due to a renal stone 
All relevant clinical information pertaining to the event should be obtained, including laboratory 
values, medical records, discharge summaries, and medical test results.   
Since renal stone events are recorded as an efficacy assessment for lumasiran, these will not be 
treated as AEs or SAEs.  However, if a patient experiences other AEs or SAEs during a renal 
stone event, they should be reported (see Section 6.5.7.1). 
6.3.4. 
Sample Analysis 
All PD assessments will be analyzed centrally.  Details on the blinding of study results are 
provided in Section 3.6.  


Cli nic al St u d y Pr ot oc ol A L N -G O 1 -0 0 3  
l u m asir a n 
A me n d me nt  3, 0 6  M a y  2 0 2 0  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
5 0  
Details re gar di n g t h e pr ocessi n g a n d ali q u oti n g of sa m ples f or st ora ge a n d a nal ys es will be 
pr o vi de d i n t he La b orat or y M a n ual.  
6. 4.  
P h ar m ac o ki netic Assess me nts  
Bl o o d sa m ples will be c ollecte d f or t he assess me nt of l u masira n P K para m eters  i ncl u di n g 
meta b olites (as necessar y)  at t he ti me p oi nts i n dicate d i n t he Sc he d ules of Assess me nts ( Ta ble  1  
Ta ble  2 ).  A d etaile d sc h e d ule of ti me p oi nts f or t he c ollecti o n of bl o o d sa m ples f or P K a nal ysis 
is i n Ta ble  3  a n d Ta ble  4  (f or patie nts at E ast Asia n St u d y C e nters; see Secti o n  6. 4. 1 ). 
T he c o nce ntrati o n of l u m asira n i n bl o o d sa m ples will be deter mi ne d usi n g a vali date d ass a y.  
Details re gar di n g s a m ple v ol u mes t o be  c ollecte d, a n d t he pr ocessi n g, s hi p pi n g, a n d a nal ysis of 
t he sa m ples will be pr o vi de d i n t he La b orat or y Ma n ual. 
6. 4. 1.  
P h ar m a c o ki netic Assess me nts i n P atie nts at  E ast Asi a n St u d y  Ce nters  
I n p atie nts w h o are i n e nr olle d at East Asia n sites, w hic h i ncl u de sites i n C hi na, K orea, J a pa n, 
Tai wa n, a n d H o n g K o n g, bl o o d a n d uri ne sa m ples f or P K a nal ysis will be c ollecte d at t he ti me 
p oi nts i n dicate d i n Ta ble  4  a n d Ta ble  5 . 
Plas ma P K para meters s u c h as C ma x , tma x , t½ β, A U C, C L/ F, a n d V/ F will be calc ulate d f or t he 
l u masira n plas ma c o nce ntrati o n pr ofiles.  I n a d diti o n, uri ne P K para m eters will be calc ulate d 
usi n g p o ole d uri ne s a m ples c ollecte d o v er 2 4  h o urs fr o m patie nts at East Asia n st u d y ce nters 
acc or di n g t o t he s c he d ule pr o vi de d i n Ta ble  5 . 
6. 5.  
S afet y Assess me nts  
T he assess me nt of s afet y d uri n g t he st u d y will c o nsist of t he s ur veilla nce a n d rec or di n g of A Es  
i ncl u di n g seri o us a d v erse e ve nts ( S A Es), rec or di n g of c o nc o mita nt me dicati o n a n d 
meas ure me nts of vital si g ns,  w ei g ht a n d hei g ht, p h ysical e x a mi nati o n, a n d electr ocar di o gra m 
(E C G ) fi n di n gs a n d la b orat or y t ests. 
Safet y will be m o nit ore d o ver t he c o urse of t he st u d y b y a  D M C  as descri be d i n  Secti o n  3. 7 . 
6. 5. 1.  
Vit al Si g ns  
Vital si g ns will be meas ure d as s pe cifie d i n t he Sc he d ules of Assess me nts ( Ta ble  1  a n d T a ble  2 ) 
a n d i ncl u de bl o o d press ure, heart rate, b o d y t e m perat ure, a n d res pir at or y rat e.  Vital si g ns will be 
me as ure d pre d ose, w h e n a p plic a ble.  O n Da y  1 a n d M o nt h 6 o nl y, vital si g ns will als o be 
meas ure d 3 0  ±  1 0  mi n utes p ost d ose.  W he n vital si g ns a n d bl o o d sa m ple c ollecti o n occ ur at t he 
sa me ti me, vital si g ns s h o ul d be perf or m e d bef ore bl o o d sa m ples are dra w n, w here p ossi ble. 
Vital si g ns s h o ul d be me as ure d i n t he seate d or s u pi ne p ositi o n, after t he patie nt has reste d 
c o mf orta bl y f or 1 0 mi n ut es.  Bl o o d pr ess ure s h o ul d be ta ke n usi n g t he sa m e ar m.  B o d y 
te m perat ur e i n de grees Celsi us will be o btai ne d via oral, t y m p a nic, or a xillar y met h o ds.  Heart 
rate will be c o u nte d f or a f ull mi n ute a n d rec or de d i n beats per mi n ute, a n d res pirati o n rat e will 
be c o u nte d f or a f ull mi n ute a n d rec or de d i n br eat hs per mi n ute.  
A d diti o nal vital si g n assess me nts, as me di call y i n dicate d, ma y be a d de d at t he discr eti o n of t he 
I n v esti gat or, or as p er D M C a d vice. 
Vital si g ns res ults will be rec or de d i n t he e C R F.  


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6.5.2. 
Weight and Height 
Height will be measured in centimeters.  For patients <18 years of age at the study visit, height 
will be measured in triplicate.  Body weight will be measured in kilograms.  Height and body 
weight measurements will be collected as specified in the Schedules of Assessments (Table 1 
and Table 2) and will be recorded in the eCRF.  Body weight collected within 4 months prior to 
the study drug dose or the predose weight collected on the study visit day or dosing day will be 
used for dose calculations.   
6.5.3. 
Physical Examination 
Full and symptom-directed physical examinations will be conducted according to the Schedules 
of Assessments (Table 1 and Table 2); if a physical examination is scheduled for a dosing visit, it 
should be conducted prior to dosing.  Full physical examinations will include the examination of 
the following:  general appearance; head, eyes, ears, nose and throat; respiratory, cardiovascular, 
gastrointestinal, musculoskeletal, and dermatological systems; thyroid; lymph nodes; and 
neurological status.  If a visit is conducted offsite (eg, home), a body system assessment may be 
performed in lieu of a physical examination. 
Symptom-directed physical examinations will be guided by evaluation of changes in symptoms, 
or the onset of new symptoms, since the last visit. 
Physical examination notes regarding any observed abnormalities will be recorded in the eCRF. 
6.5.4. 
Electrocardiogram 
12-lead ECGs will be obtained, as specified in the Schedules of Assessments (Table 1 and 
Table 2).  Specific timepoints and details regarding the method of ECG acquisition 
(local/singlicate or central/triplicate) are provided in Table 3 and Table 4.  Patients should be 
supine for at least 10 minutes before each ECG is obtained.   Triplicate 12-lead ECGs will have 
readings approximately 5 minutes apart and will be centrally read. 
When ECG and blood sample collection occur at the same time, ECGs should be performed 
before blood samples are drawn, when possible.  
The Investigator or qualified designee will review all ECGs to assess whether the results have 
changed since the Baseline visit and to determine the clinical significance of the results.  These 
assessments will be recorded in the eCRF.  Additional ECGs may be collected at the discretion 
of the Investigator, or as per DMC advice.  Recordings will be archived according to the Study 
Manual. 
During periods of time when the COVID-19 pandemic impedes the ability of patients to travel to 
the study site, ECG assessments may be completed up to 7 months after the intended timepoint 
for visits at Month 12 and later. 
6.5.5. 
Renal Ultrasound 
Renal ultrasounds will be obtained as specified in the Schedules of Assessments (Table 1 and 
Table 2).  Renal ultrasound will be performed according to instructions provided in the Study 
Manual in a standardized manner.  Renal ultrasounds will be reviewed centrally and those 
obtained at Screening and Month 6 will be read in a blinded manner.  


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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 7 months after the intended timepoint 
for visits at Month 12 and later. 
6.5.6. 
Clinical Laboratory Assessments 
The following clinical laboratory tests will be evaluated by a central laboratory.  Specific 
instructions for transaminase elevations are provided in Section 5.2.3.1.  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, 
or as per DMC advice, until it has returned to the normal range or stabilized, and/or a diagnosis 
is made to adequately explain the abnormality.  Additional safety laboratories and assessments as 
indicated by the clinical situation may be requested.  Clinical laboratory assessments are listed in 
Table 8 and will be assessed as specified in the Schedule of Assessments (Table 1 and Table 2). 
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 Table 8 which are performed 
at the clinic should also be sent in parallel to the central laboratory.  Central laboratory results 
(once available) should be used for subsequent clinical and dosing decisions in the case of 
discrepant local and central laboratory results on 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; results may be collected and should be 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. 


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Table 8: 
Clinical Laboratory Assessments 
Hematology 
Complete blood count with differential 
 
Serum Chemistry 
Sodium 
Potassium 
BUN 
Phosphate 
Creatinine and eGFR (using the MDRD formula for 
adults [≥18 years of age at screening] or the Bedside 
Schwartz formula for children <18 years at 
screening) 
Albumin 
Uric acid 
Calcium 
Total protein 
Carbon dioxide 
Glucose 
Chloride 
Pyridoxine (vitamin B6)a 
 
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 
 
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; 
PH1=primary hyperoxaluria type 1; RBC=red blood cell  
a Pyridoxine (vitamin B6) is required through Month 18 and only for patients receiving vitamin B6 for the treatment 
of PH1.  On days when a blood sample for pyridoxine will be collected, patients should be instructed not to take 
vitamin B6 within 6 hours prior to blood sample collection.  
6.5.6.1. 
Immunogenicity 
Blood samples will be collected to evaluate antidrug antibodies.  Blood samples for antidrug 
antibody testing must be collected before study drug administration as specified in the Schedules 
of Assessments (Table 1 and Table 2).  A blood sample to evaluate antidrug antibodies will be 
collected at the Early Termination (ET) visit, if applicable. 
Details regarding the processing, shipping, and analysis of the samples will be provided in the 
Laboratory Manual. 


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6.5.6.2. 
Pregnancy Testing 
A pregnancy test will be performed for women of child-bearing potential, and for 
pediatric/adolescent females upon initiation of menarche.  A serum pregnancy test will be 
performed at Screening or upon initiation of menarche, if applicable, and urine pregnancy tests 
will be performed thereafter per the Schedule of Assessments and any time pregnancy is 
suspected.  More frequent pregnancy testing may be performed where required per local 
requirements.  The results of the pregnancy test must be known before study drug administration.  
Patients who are pregnant at Screening are not eligible for study participation.  Any woman with 
a positive urine pregnancy test, subsequently confirmed by a positive serum pregnancy test, 
during the study will be discontinued from study drug, but will continue to be followed for 
safety.  Patients determined to be pregnant while on study will be followed at least until the 
pregnancy outcome is known (see Section 6.5.7.7 for follow-up instructions).   
Pregnancy testing may be performed offsite by a patient/caregiver if the patient/caregiver will be 
administering study drug.   
6.5.6.3. 
Additional Liver Function Assessments  
Additional laboratory assessments will be performed in patients who experience any LFT 
abnormalities as outlined in Section 5.2.3.1.  Following the occurrence of elevated liver 
transaminases or other LFT abnormalities per central laboratory, all assessments in Table 9 will 
be performed one time, as well as hematology, serum chemistry, LFTs from Table 8, and 
coagulation parameters, and other assessments or evaluations per Investigator discretion, as 
appropriate.   
Monitoring, including criteria for withholding the study drug, are described in Section 5.2.3.1. 


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Table 9: 
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. 
6.5.6.4. 
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 10 from 
the Feinstein Institute for Medical Research Human Subject Protection Program Guidance 
Document (Section 10.2 in the Appendix).[Feinstein Institute 2013]  Collections per the SOA do 
not exceed the maximum 24-hour or 30-day volume limits for a 15 kg child who is not at an East 
Asian site.  At East Asian sites, if a patient weighs less than 30 kg, then PK blood samples 
should be limited to 1 ml at each time point and the blood samples for exploratory analyses 
should not be drawn. 


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6.5.7. 
Adverse Events 
6.5.7.1. 
Definitions 
Adverse Event  
According to the International Council on Harmonisation (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. 
Renal stone events (as defined in Section 6.3.3) are recorded for efficacy assessment of 
lumasiran.  These events will not be treated as AEs or SAEs.  Other AEs or SAEs occurring 
during a renal stone event are reported. 
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 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).  Reactions with onset and resolution within 


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4 hours of the injection (eg, transient pain/burning at injection site) do not meet the 
study definition of ISRs, unless immediate treatment is required.  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.  
For information on recording and reporting of AEs of clinical interest, see Section 6.5.7.2 and 
Section 6.5.7.3 , respectively. 
Adverse Event Severity 
Adverse events are to be graded according to the categories detailed below: 
Mild: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
Moderate: 
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age appropriate instrumental activities of daily living (eg, preparing 
meals, shopping for groceries or clothes, using the telephone, managing 
money). 
Severe: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care activities of daily living (ie, bathing, dressing and 
undressing, feeding self, using the toilet, taking medications, and not 
bedridden); OR life-threatening consequences; urgent intervention 
indicated; OR death related to an adverse event. 
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 
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 SAE). 
Relationship of the Adverse Event to Study Drug  
The relationship of each AE to study drug should be evaluated by the Investigator by a “yes” or 
“no” response to the question: “Is there a reasonable possibility that the event may have been 
caused by the study drug?” A “yes” response indicates that the event is considered as related to 
the study drug. 
6.5.7.2. 
Eliciting and Recording Adverse Events 
Eliciting Adverse Events 
The patient and legal guardian, if applicable, should be asked about medically relevant changes 
in the patient’s health since the last visit.  The patient and legal guardian, if applicable, should 
also be asked if the patient has been hospitalized, had any accidents, used any new medications, 


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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, ECG 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 study drug, action 
taken, and outcome (including time and date of resolution, if applicable). 
For SAEs, record the event(s) in both the eCRF and the SAE form. 
6.5.7.3. 
Reporting Adverse Events of Clinical Interest to Sponsor/Designee 
For AEs that are considered AEs of clinical interest (Section 6.5.7.1), the Sponsor or its designee 
should be notified within 24 hours using a supplemental AEs of Clinical Interest eCRF.  
Additional clinical and laboratory information may be collected.  Refer to CRF completion 
guidelines for details on reporting events in the supplemental AEs of Clinical Interest eCRF.   
For all ISRs, the Investigator, or delegate, should submit a supplemental ISR eCRF, recording 
additional information (eg, descriptions, onset and resolution date, severity, treatment given, 
event outcome). 
6.5.7.4. 
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 6.5.7.1 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. 
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 


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To report the SAE, complete the 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 Manual. 
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. 
6.5.7.5. 
Sponsor Safety Reporting to Regulatory Authorities 
The Sponsor or its representative will 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. 
6.5.7.6. 
Serious Adverse Event Notification to the Institutional Review 
Board/Independent Ethics Committee 
Suspected unexpected serious adverse reactions (SUSARs) will be reported to the IRB/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. 
6.5.7.7. 
Pregnancy Reporting 
If a female patient becomes pregnant during the study through study completion, 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, 
the possible effects on the fetus, and be counseled to not breastfeed for 90 days after the last dose 
of study drug. 
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 6.5.7.4. 
6.5.7.8. 
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.  The investigator will decide whether a dose is to be considered an overdose, in 
consultation with the Sponsor.  In the event of an overdose, the actual dose administered must be 
recorded in the eCRF. 


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All reports of overdose (with or without an AE) must be reported within 24 hours to the Sponsor 
or designee. 
6.5.8. 
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. 
6.6. 
Biomarkers, DNA Genotyping, and Biospecimen Repository 
Alnylam’s RNAi therapeutics platform permits the highly specific targeting of investigational 
therapies based on genetic sequence.  It is possible that variations in the target genetic sequence 
will result in variations in drug effect. 
More generally, genetic variations may account for the well-described heterogeneous 
manifestations of disease in patients with PH1, as well as their responses to treatment. 
To permit exploratory investigations and the application of novel approaches to bioanalyses that 
may further elucidate the outcomes of this study, or potentially advance understanding of the 
safety, mechanism of action, and/or efficacy of lumasiran, a set of biological specimens will be 
collected at the timepoints indicated in the Schedule of Assessments (Table 1). 
These specimens will be securely stored in a central biorepository for up to 10 years following 
the completion of this clinical study (ie, last patient last visit), or as per local regulations.  After 
10 years have elapsed, samples will be destroyed. 
Where allowed per local regulations, ethics committee (IRB/EC) approval, and patient consent 
(and assent, where applicable), the samples will be collected as part of this study.  Potential 
exploratory investigations may include DNA, RNA or biochemical metabolite assessments as 
they relate to disease progression, efficacy or safety.  
Details regarding the collection, processing, storage, and shipping of the samples will be 
provided in the Laboratory Manual. 
Exploratory analysis of these biospecimens will be performed by Alnylam Pharmaceuticals or its 
designees. 
When biobanking is permitted by local regulation, patients/subjects will be advised during the 
informed consent process of these biobanking details and the potential for exploratory 
investigation of their samples. 
6.7. 
Quality of Life (QOL) 
QOL questionnaires will be used to evaluate overall health status and quality of life at the 
timepoints listed in Table 1 and Table 2.  During periods of time when the COVID-19 pandemic 
impedes the ability of patients to travel to the study site, the KDQOL, PedsQL, and the EQ-5D 
questionnaires can be completed up to 4 months after the intended time point.   
The age of the patient at screening will determine which age-specific questionnaires will be 
utilized for the duration of the study.   
QOL assessments include the following: 


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• KDQOL, specifically the KDQOL-36 for patients ≥18 years of age at screening, and 
the PedsQL, including the generic and ESRD modules (parent and/or self-report 
versions) [Salido-Guadarrama 2014] for patients <18 years of age at screening.  
• EQ-5D: a standardized instrument consisting of a questionnaire and a visual analog 
scale pertaining to 5 dimensions.  Scoring of the questionnaire is based on degrees of 
disability.  Scoring of the visual analog scale is based on a visual scale ranging from 0 
(worst imaginable health state) to 100 (best imaginable health state).  Higher scores 
indicate better health status.  The EQ-5D-5L questionnaire will be utilized in patients 
≥18 years of age at screening, and the EQ-5D-Y questionnaire will be utilized in 
patients <18 years of age at screening, where available.[Herdman 2011] 
6.8. 
Patient and Caregiver Experience Surveys 
The patient and caregiver experience surveys assess patients’ experience living with PH1, 
including their experience with PH1 treatments, as well as the effect of PH1 on patients’ 
caregivers.  These surveys will be completed at the time points specified in the Schedules of 
Assessment (Table 1 and Table 2) and each take approximately 10 minutes to complete.  During 
periods of time when the COVID-19 pandemic impedes the ability of patients to travel to the 
study site, the patient and caregiver experience surveys can be completed up to 4 months after 
the intended time point. 
For the Patient Experience Survey, patients ≥13 years of age at screening will complete the 
survey themselves if they are able.  If the patient is unable to complete the Patient Experience 
Survey alone, their caregiver or site staff may complete the survey for the patient.  If the patient 
is <13 years of age at screening, a caregiver will complete the Patient Experience Survey on 
behalf of the patient for as long as the patient remains under the legal age of consent. 
Additionally, for patients under legal age of consent at the time of screening, their caregiver will 
also be asked to complete the Caregiver Experience Survey. For patients who reach the legal age 
of consent per local regulations during the study, caregivers will be encouraged to continue 
completing the survey, but are not required to do so.   
6.9. 
Patient and Caregiver Impact Questionnaire 
The patient and caregiver impact questionnaire will be used to assess impacts of PH1 on the 
patients’ lives, including their need to relocate/travel to receive treatment, the number and type 
of healthcare providers they use, and their ability to work and/or go to school.  The questionnaire 
will also assess the impact on caregivers’ employment.  This questionnaire will be completed at 
the time points specified in the Schedules of Assessment (Table 1 and Table 2) and takes 
approximately 10 to 12 minutes to complete.  During periods of time when the COVID-19 
pandemic impedes the ability of patients to travel to the study site, the patient and caregiver 
impact questionnaires can be completed up to 4 months after the intended time point.  
Patients ≥13 years of age at screening will complete the questionnaire themselves if they are 
able.  If the patient is unable to complete the survey alone, their caregiver or site staff may 
complete the survey on the patient’s behalf.  If the patient is <13 years of age at screening, a 
caregiver will complete the questionnaire on behalf of the patient.  For patients who reach the 
legal age of consent per local regulations during the study, and whose caregivers had previously 


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completed the Patient Impact Questionnaire on their behalf, caregivers will be encouraged to 
continue completing the questionnaire, but are not required to do so. 
6.10. 
Healthcare Resource Utilization 
Healthcare resource utilization will be assessed using patient-reported information related to 
hospitalizations, urgent healthcare visits, procedures and surgeries.   
7. 
STATISTICS 
A Statistical Analysis Plan (SAP) will be finalized prior to database lock.  The plan will detail 
the implementation of the statistical analyses in accordance with the principle features stated in 
the protocol. 
7.1. 
Determination of Sample Size 
The planned enrollment for the study is 30 patients.  
Patients will be randomized 2:1 to receive lumasiran or placebo, respectively. Assuming the 
mean percent reduction from baseline to Month 6 in 24-hour urinary oxalate corrected for body 
surface area (BSA) is 17% in the placebo arm and the standard deviation in both arms is 25%, 
24 patients will provide 90% power to detect a treatment difference of 37% at a 2-sided 5% 
significance level (ie, 54% reduction in the lumasiran arm).  To account for potential drop-outs, 
30 patients are planned to be enrolled in the study. 
7.2. 
Statistical Methodology 
The statistical and analytical plans presented below are brief summaries of planned analyses.  
More complete plans will be detailed in the statistical analysis plan (SAP).  Changes to the 
methods described in the final SAP will be described and justified as needed in the clinical study 
report.  For information on study endpoints, see Section 2. 
Additional data summaries to help understand any impact of COVID-19 on efficacy and safety 
assessments will be outlined in the SAP.  
7.2.1. 
Populations to be Analyzed 
The populations (analysis sets) are defined as follows: 
• Full Analysis Set (FAS):  All randomized patients who received any amount of study 
drug.  Patients will be analyzed according to the treatment to which they were 
randomized.   
• Per-protocol (PP) Set: All randomized patients who received any amount of study 
drug, had baseline and at least one post-baseline 24-hour urinary oxalate, and did not 
experience any major protocol deviations that may impact the efficacy results within 
the 6-month double-blinded period. Patients will be analyzed according to the 
randomized treatment arms. 
• Safety Analysis Set:  All patients who received any amount a of study drug. Patients 
will be analyzed according to the treatment actually received. 


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• PK Analysis Set:  All patients who received at any amount of study drug and have at 
least 1 PK concentration measurement. 
• All Lumasiran Treated Set: All patients who received any amount of lumasiran 
including patients who took lumasiran during the 6-month double-blinded period and 
patients who initially took placebo during the 6-month double-blinded period and 
then switched to lumasiran during the extension period. 
The primary population used to evaluate efficacy will be the Full Analysis Set for the primary 
endpoint and secondary endpoints during the double-blind period.  Safety during the double-
blind period will be analyzed using the Safety Analysis Set.  The PK Analysis Set will be used to 
evaluate the PK endpoints.  The All Lumasiran Treated Set will be used to summarize the long-
term efficacy and safety of lumasiran. 
7.2.2. 
Examination of Subgroups 
Subgroup analyses may be conducted for selected endpoints.  Detailed methodology will be 
provided in the SAP. 
7.2.3. 
Handling of Missing Data 
Every effort will be made to minimize the amount of missing data in the study, particularly for 
the 24-hour urinary oxalate assessments.  Details will be provided in the SAP. 
7.2.4. 
Baseline Evaluations 
Demographics and other disease-specific baseline characteristics will be summarized 
descriptively by treatment arm and overall for the FAS and Safety Analysis Set. 
7.2.5. 
Efficacy Analyses 
7.2.5.1. 
Primary Endpoint 
The primary endpoint is to compare the percent change from baseline to Month 6 in 24-hour 
urinary oxalate corrected for BSA between the treatment groups in the Full Analysis Set.  The 
analysis will be performed using a mixed-effect model for repeated measures (MMRM) 
approach.  The outcome variable is percent change from baseline in urinary oxalate corrected for 
BSA.  The model includes baseline value as covariate and fixed effect terms including treatment 
arm and visit (Months 3, 4, 5, 6).  The treatment estimates from this model will represent an 
average percent change from baseline of 24-hour urinary oxalate excretion across months 3 
through 6 at which the treatment effect is expected to have reached steady state.  Furthermore, 
given the variability of 24-hour urinary oxalate, averaging the values across these visits will 
yield stable treatment estimates. 
Baseline and Month 6 urinary oxalate values are planned to be collected in triplicate (minimum 
requirement of duplicate) and the calculated median of valid collections during each time period 
(visit) will be used in the analysis. BSA will be calculated using the Mosteller formula. 
Sensitivity analyses will be conducted to assess the robustness of the estimates and will be 
detailed in the SAP. 


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A patient is considered to have completed the primary outcome measure at the time of 
completion of the Month 6 assessments. 
7.2.5.2. 
Secondary Endpoints 
To control the overall type I error, these secondary endpoints will be tested in the following 
hierarchical order: 
• Absolute change in 24-hour urinary oxalate corrected for BSA from baseline to Month 6 
• Change in 24-hour urinary oxalate:creatinine ratio (value/ULN) from baseline to Month 6 
• Proportion of patients with 24-hour urinary oxalate level at or below 1.5 x ULN at Month 6 
• Proportion of patients with 24-hour urinary oxalate level at or below ULN at Month 6 
• Percent change in plasma oxalate from baseline to Month 6 
• Absolute change in plasma oxalate from baseline to Month 6 
Continuous endpoints will be analyzed using an MMRM approach similar to the one described 
for the primary endpoint.  Binary endpoints will be analyzed using the Cochran-Mantel-Haenszel 
test stratified by baseline urinary oxalate. The odds ratio and the differences in proportions with 
corresponding 95% confidence will also be summarized. 
Secondary endpoints assessed beyond Month 6 will be summarized descriptively. Change in 
eGFR over time will also be summarized descriptively. 
7.2.5.3. 
Exploratory Endpoints 
Details will be described in the SAP. 
7.2.6. 
Pharmacodynamic Analysis 
Analysis of the PD parameters are specified in Section 7.2.5.2.  Any PD parameters not already 
prespecified for testing will be summarized descriptively. 
7.2.7. 
Pharmacokinetic Analysis 
Population pharmacokinetic analysis will be performed to describe the plasma concentration 
profiles of lumasiran. The impact of relevant patient covariates such as age, weight, race, gender, 
hepatic impairment, and renal impairment on the PK of lumasiran will be assessed using 
population PK approach. 
For patients enrolled in East Asian centers with 24-hour PK collection, pharmacokinetic analyses 
of plasma and urine will be conducted using noncompartmental methods.  Plasma 
pharmacokinetic parameters including, but will not be limited to:  maximum plasma 
concentration (Cmax), time to maximum plasma concentration (tmax), elimination half-life (t½β), 
area under the concentration-time curve (AUC), apparent clearance (CL/F), and apparent volume 
of distribution (V/F) will be determine using noncompartmental approach.  Other parameters 
may be calculated, if deemed necessary.  In addition, relevant urine PK parameters will be 
calculated using 24-hour urine PK profiles.  


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7.2.8. 
Safety Analyses 
The primary parameter is the frequency and seriousness of AEs.  Safety parameters also include 
vital signs, ECGs, clinical laboratory assessments and physical exams.  The extent of exposure 
will also be summarized.  The primary summaries of the safety of lumasiran versus placebo will 
be based on safety parameters within the 6-month double-blind treatment period, using the 
Safety Analysis Set.  Additional safety analyses will also be performed for the extension periods. 
Prior and concomitant medications will be coded using the World Health Organization (WHO) 
Drug Dictionary.  Results will be tabulated by Anatomical Therapeutic Chemical (ATC) 
Classification System and Preferred Term (PT).  
Adverse events will be coded by the Medical Dictionary for Regulatory Activities (MedDRA).  
AEs, SAEs, related AEs, and AEs leading to discontinuation will be summarized by System 
Organ Class (SOC) and PT for each treatment arm.  By-patient listings will be provided for 
deaths, SAEs, and events leading to discontinuation of treatment. 
Descriptive statistics will be provided for clinical laboratory data, ECG, and vital signs data.  
Laboratory shift tables from baseline to worst values will be presented. 
Other safety summaries will be presented as appropriate.  Further details will be specified in the 
SAP. 
7.2.9. 
Immunogenicity Analyses 
ADA results will be summarized descriptively. 
7.2.10. 
Other Analyses 
Other exploratory analyses will be detailed in the SAP.   
7.2.11. 
Interim Analysis 
No interim analysis is planned. 
7.2.12. 
Optional Additional Research 
Optional additional research may be conducted in the future on the biological samples and/or 
data collected during the study in accordance with the strict terms of the informed consent form 
(see Section 4.3.2). 
8. 
STUDY ADMINISTRATION 
8.1. 
Ethical and Regulatory Considerations 
This study will be conducted in accordance with the protocol, all applicable regulatory 
requirements, and the current 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. 


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8.1.1. 
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 tests or procedures that are not part of routine care.  
When a patient under the age of legal consent who has been enrolled in the study reaches the 
legal age of consent, the investigator must obtain the patient's informed consent prior to 
performing any further research interventions and/or procedures involving that patient. 
The Investigator must maintain the original, signed ICF (assent form, if applicable).  A copy of 
the signed ICF (assent form, 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. 
8.1.2. 
Ethical Review 
The study protocol, including the ICF (and assent form, if applicable), 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 patient 
materials 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. 
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 6.5.6.4.  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, IRBs, or IECs 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 study drug.  The Sponsor or 
designee will provide this information to the Investigator. 


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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 randomized under the 
amended protocol, and patients/legal guardian must be re-consented to the most current version 
of the ICF (and assent form, as applicable). 
8.1.3. 
Serious Breach of Protocol 
Investigators must notify the medical monitor within 24 hours of becoming aware of a 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. 
8.1.4. 
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 as locally required, 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 added to the document.  Documents not for submission to the Sponsor 
(eg, signed ICFs) 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. 
To comply 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. 
8.1.5. 
End of Study 
The end of study is defined as the last patient last visit. 
8.1.6. 
Termination of the Clinical Study or Site Closure 
The Sponsor, or designee, reserves the right to terminate the study or a clinical study site at any 
time.  Conditions that may warrant this action may include, but are not limited to: 
• The discovery of an unexpected, serious, or unacceptable risk to patients participating 
in the study 


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• Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of participants by the Investigator 
• The decision on the part of the Sponsor to suspend or discontinue treatment with the 
study drug 
Should the study be terminated, and/or the site 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. 
8.2. 
Data Quality Control and Quality Assurance 
8.2.1. 
Data Handling 
Study data must be recorded on CRFs (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 site 
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. 
8.2.2. 
Study Monitoring 
The Monitor, as a representative of the Sponsor, has an obligation to closely follow the study 
conduct at the site.  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, site standard operating 
procedures and training records, and other records relative to study conduct. 
8.2.3. 
Audits and Inspections 
Periodically, the Sponsor or its authorized representatives audit clinical investigative sites 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 site to perform audits or inspections, including source 


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data verification.  The Investigator should contact the Sponsor, or its designee, immediately if 
contacted by a regulatory agency, an IEC or an IRB about an inspection. 
8.3. 
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 
publication (eg, manuscript, abstracts, oral/slide presentations, book chapters) based on this 
study, must be provided and confirmed received at the Sponsor at least 30 days before its 
submission.  The Clinical Trial Agreement among the institution, Investigator, and Alnylam will 
detail the procedures for Alnylam’s review of publications. 
Authorship of any publications resulting from this study will be determined on the basis of the 
Uniform Requirement for Manuscripts Submitted to Biomedical Journals (International 
Committee of Medical Journal Editors). 
 


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9. 
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. 
Boualla L, Tajir M, Oulahiane N, Lyahyai J, Laarabi FZ, Chafai Elalaoui S, et al. AGXT Gene 
Mutations and Prevalence of Primary Hyperoxaluria Type 1 in Moroccan Population. Genet Test 
Mol Biomarkers. 2015 Sep 18. 
Cochat P,Rumsby G. Primary hyperoxaluria. N Engl J Med. 2013 Aug 15;369(7):649-58. 
Danpure CJ. Primary Hyperoxaluria. In: Beaudet AL, editor. The Online Metabolic and 
Molecular Bases of Inherited Disease. New York, NY: The McGraw-Hill Companies, Inc.; 2014. 
Feinstein Institute. The Feinstein Institute for Medical Research.  Human Subject Protection 
Program Guidance Document:  Maximum Blood Draw Limits. 2013. 
Frishberg Y, Rinat C, Shalata A, Khatib I, Feinstein S, Becker-Cohen R, et al. Intra-familial 
clinical heterogeneity: absence of genotype-phenotype correlation in primary hyperoxaluria type 
1 in Israel. Am J Nephrol. 2005 May-Jun;25(3):269-75. 
Harambat J, Fargue S, Acquaviva C, Gagnadoux MF, Janssen F, Liutkus A, et al. Genotype-
phenotype correlation in primary hyperoxaluria type 1: the p.Gly170Arg AGXT mutation is 
associated with a better outcome. Kidney Int. 2010 Mar;77(5):443-9. 
Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, et al. Development and 
preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011 
Dec;20(10):1727-36. 
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. 
Hoppe B, Danpure CJ, Rumsby G, Fryer P, Jennings PR, Blau N, et al. A vertical 
(pseudodominant) pattern of inheritance in the autosomal recessive disease primary 
hyperoxaluria type 1: lack of relationship between genotype, enzymic phenotype, and disease 
severity. Am J Kidney Dis. 1997 Jan;29(1):36-44. 
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. 
Liebow A, Li X, Racie T, Hettinger J, Bettencourt BR, Najafian N, et al. An Investigational 
RNAi Therapeutic Targeting Glycolate Oxidase Reduces Oxalate Production in Models of 
Primary Hyperoxaluria. J Am Soc Nephrol. 2017 Feb;28(2):494-503. 
Lieske JC, Monico CG, Holmes WS, Bergstralh EJ, Slezak JM, Rohlinger AL, et al. 
International registry for primary hyperoxaluria. Am J Nephrol. 2005 May-Jun;25(3):290-6. 


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Mandrile G, van Woerden CS, Berchialla P, Beck BB, Acquaviva Bourdain C, Hulton SA, et al. 
Data from a large European study indicate that the outcome of primary hyperoxaluria type 1 
correlates with the AGXT mutation type. Kidney Int. 2014 Dec;86(6):1197-204. 
Salido-Guadarrama I, Romero-Cordoba S, Peralta-Zaragoza O, Hidalgo-Miranda A,Rodriguez-
Dorantes M. MicroRNAs transported by exosomes in body fluids as mediators of intercellular 
communication in cancer. Onco Targets Ther. 2014;7:1327-38. 
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. 
van der Hoeven SM, van Woerden CS,Groothoff JW. Primary hyperoxaluria type 1, a too often 
missed diagnosis and potentially treatable cause of end-stage renal disease in adults: results of 
the Dutch cohort. Nephrol Dial Transplant. 2012 Oct;27(10):3855-62. 
van Woerden CS, Groothoff JW, Wanders RJ, Davin JC,Wijburg FA. Primary hyperoxaluria 
type 1 in The Netherlands: prevalence and outcome. Nephrol Dial Transplant. 2003 
Feb;18(2):273-9. 
Williams EL, Acquaviva C, Amoroso A, Chevalier F, Coulter-Mackie M, Monico CG, et al. 
Primary hyperoxaluria type 1: update and additional mutation analysis of the AGXT gene. Hum 
Mutat. 2009 Jun;30(6):910-7. 
 


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10. 
APPENDICES 
10.1. 
Formulae for Estimated Glomerular Filtration Rate Calculation 
Estimated glomerular filtration rate (eGFR; in mL/min/1.73m2) will be calculated from serum 
creatinine (SCr) based on the Modification of Diet in Renal Disease formula for patients 
≥18 years of age and the Schwartz Bedside Formula for patients <18 years of age. 
 
Modification of Diet in Renal Disease Formula [Levey 2009] 
• Conventional units 
− eGFR (mL/min/1.73m2) = 175 × (SCr [mg/dL])-1.154 × (age)-0.203 × (0.742, if 
female), or × (1.212, if African American) 
• SI units 
− eGFR (mL/min/1.73m2) = 175 × (SCr [μmol/L]/88.4)-1.154 × (age)-0.203 × (0.742, if 
female), or × (1.212, if African American) 
 
Schwartz Bedside Formula [Schwartz 2009] 
• Conventional units 
− eGFR (mL/min/1.73 m2) = (0.413 × height [cm])/SCr (mg/dL) 
• SI units 
− eGFR (mL/min/1.73 m2) = (36.2 × height [cm])/SCr (µmol/L) 
 
 


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10.2. 
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 10, which 
was adapted from the Feinstein Institute for Medical Research Human Subject Protection 
Program Guidance Document. 
Table 10: 
Maximum Allowable Total Blood Volume Collection Chart 
Body 
Weight  
Body 
Weight  
Total blood 
volume  
Maximum allowable 
volume in a 24 hour 
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]  
 


Clinical Study Protocol ALN-GO1-003 
ALN-GO1 (lumasiran) 
Amendment 3 Summary of Changes, 06 May 2020 
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Confidential 
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ALN-GO1-003 PROTOCOL AMENDMENT 3  
SUMMARY OF CHANGES DATED 06 MAY 2020 
ILLUMINATE-A: A Phase 3 Randomized, Double-Blind, Placebo Controlled Study with 
an Extended Dosing Period to Evaluate the Efficacy and Safety of Lumasiran in Children 
and Adults 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 2020] and the United States Food and Drug 
Administration [FDA 2020] on the conduct of clinical trials during the COVID-19 pandemic.  
The USMs are summarized in Section 1.1 and described in greater detail in Section 2.   
This protocol amendment also incorporates the 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 will not be implemented until appropriate Health Authority and Ethics 
Committee (EC) and/or Institutional Review Board (IRB) approval, if applicable.  These changes 
are summarized in Section 1.2 and described in greater detail in Section 2. 
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.  
• Lumasiran dosing outside the study center (expanded use of offsite administration) 
Following appropriate training on lumasiran 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.   
• Study visits  
Except for assessments with other specified timing requirements, study assessments can 
be performed within the expanded window of ±28 days (previously ±14 days).  The 
expanded window for study visits is to ensure patient safety and to the extent possible, 
maintain study integrity amid travel and other restrictions related to the COVID-19 
pandemic. 


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• Kidney Disease Quality of Life Questionnaire (KDQOL), Pediatric Quality of Life 
Inventory (PedsQL), Euro Quality of Life Health State Profile Questionnaire 
(EQ-5D), the Patient/Caregiver Experience surveys, and Patient/Caregiver 
questionnaires.   
The KDQOL, PedsQL, and EQ-5D questionnaires, the patient and caregiver experience 
surveys, and the patient and caregiver impact questionnaires may be completed up to 
4 months after the intended time point. 
• Renal ultrasound and electrocardiogram (ECG) assessments 
Renal ultrasound and ECG assessments may be completed up to 7 months after the 
intended timepoint for visits at Month 12 and later 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.  
• Physical examination 
If a visit is conducted offsite (eg, home), a body system assessment may be performed in 
lieu of a physical examination. 
• Assessments required to be performed in the clinic (offsite assessments) 
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 (urine or serum), 
clinical laboratory assessments, urine collections, DNA testing, a body system 
assessment, vital signs, body weight, height, PK and PD blood collection, blood 
collection for vitamin B6 levels, ADA and exploratory analyses (blood and urine) 
assessments, at all timepoints as specified in the Schedule of Assessments. 
• Assessment of adverse events (AEs), concomitant medications, renal stone events, 
and healthcare utilization (remote contact permitted)  
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, concomitant medication use, renal stone 
events, and healthcare utilization, to ensure timely collection of patient data. 
• Pharmacokinetic assessments  
Blood samples for PK assessment should continue to be collected at 4 hours postdose as 
specified in the Schedule of Assessments.  Blood samples for PK assessment at 24 hours 
postdose are to be collected only if feasible 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. 
• Impact of COVID-19 (collection of information)  


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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 
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 
Additional changes to study conduct (outlined below) will not be implemented until appropriate 
HA and EC/IRB approval.  The removal of the requirement for measurement of coagulation 
parameters as part of routine surveillance laboratory assessments, and also for following serial 
coagulation parameters in the case of asymptomatic patients with confirmed isolated elevations 
of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >3× upper limit of 
normal (ULN), with no alternative cause identified.  Removing these requirements mitigates 
patient burden regarding the volume of blood to be collected, which is particularly important for 
pediatric patients given the greater limits placed on blood volume collections.  No safety signal 
pertaining to coagulation has been identified to date in any clinical study conducted with 
lumasiran.  This amendment will also: 
• Remove the collection of blood samples to assess pyridoxine (Vitamin B6) levels after 
Month 18 and after discontinuation of pyridoxine therapy.  After a patient discontinues 
pyridoxine therapy, measurement of pyridoxine is no longer medically indicated to verify 
medication compliance.  
A detailed summary of changes is provided in Table 2 of Section 2.  The following changes are 
not detailed:  administrative changes, changes associated with administrative letters (between 
Amendments 2 and 3), and corrections to typographical errors, punctuation, grammar, 
abbreviations, and formatting. 


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2. 
PROTOCOL AMENDMENT 3 DETAILED SUMMARY OF CHANGES 
The primary section(s) of the protocol affected by the changes in Protocol Amendment 3 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 lumasiran dosing by the patient or caregiver and provide additional 
instructions on self-administration, and preparation, handling, and storage of the study drug. 
The primary change occurs in Section 5.2.2, Dose and Administration 
Revised text:  Study drug injections will be administered under the supervision of the Investigator or healthcare professional.  The 
injection site may be marked and mapped for later observation.  The sites preferred site of injection may be is the abdomen, Optional 
additional sites are the upper arms, or and thighs.  If a local reaction around the injection site occurs, photographs may be obtained.  
Detailed instructions for study drug administration are found in the Pharmacy Manual.   
From Month 1215 through the end of the study, study drug administration may be conducted at a location other than the study center 
(eg, home) by a home healthcare professional with the oversight of the Investigator, where applicable country and local regulations 
and infrastructure allow after consultation with the medical monitor.  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, lumasiran 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 lumasiran 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 the patient’s home for dosing.   
Additional details can be found in the Pharmacy Manual.  In addition, instructions and procedures related to administration of 
lumasiran by a patient or caregiver will be provided in the Patient/Caregiver Storage and Administration Instructions. 
Sections also reflecting this change:   
• Table 1 and Table 2, Schedules of Assessment 
• Section 3.1, Summary of Study Design 


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• Section 5.2.4, Preparation, Handling, and Storage 
• Section 5.4, Treatment Compliance 
• Section 6.5.6.2, Pregnancy Testing 
Purpose:  Allow additional offsite assessments. 
The primary change occurs in Section 6, 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 
(urine or serum), clinical laboratory assessments, urine collections, DNA testing, symptom directed physical examination / body 
system assessment, vital signs, body weight, height, PK and PD blood collection, blood collection for vitamin B6 levels, ADA 
and exploratory analyses (blood and urine) assessments, at all timepoints as specified in the Schedule of Assessments. Study 
assessments for pregnancy test (urine or serum), clinical lab assessments, urine collection, and DNA testing may be conducted at a 
location other than the study center by a home healthcare professional, where applicable country and local regulations and 
infrastructure allow. 
Sections also reflecting this change:   
• Section 6.5.3, Physical Examination 
Purpose:  Expand the study visit window. 
The primary change occurs in Table 2, Schedule of Assessments; Schedule of Assessments – Open Label Extension Period (After 
Month 9 through Year 5). 
Revised text:  In Table 2, the visit window was changed to ±28 days (previously ±14 days) for all visits. 
Section also reflecting this change:   
• Table 3, Pharmacokinetic and ECG Assessment Time Points: All Sites except East Asian Sites, Footnote Notes 
Purpose:  Expand study assessment windows for ECGs and renal ultrasound. 
The primary change occurs in Section 6.5.4, Electrocardiogram 
Revised text: During periods of time when the COVID-19 pandemic impedes the ability of patients to travel to the study site, 
ECG assessments may be completed up to 7 months after the intended timepoint for visits at Month 12 and later. 
Sections also reflecting this change:   


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• Table 3, Pharmacokinetic and ECG Assessment Time Points: All Sites except East Asian Sites, Footnote Notes 
• Section 6.5.5, Renal Ultrasound 
Purpose:  Expand the window for completion of QOL questionnaires, patient and caregiver experience surveys and patient and 
caregiver impact questionnaires.  
The primary change occurs in Section 6.7, Quality of Life (QOL) Questionnaires 
Revised text:  During periods of time when the COVID-19 pandemic impedes the ability of patients to travel to the study site, 
the KDQOL, PedsQL, and the EQ-5D questionnaires can be completed up to 4 months after the intended time point. 
Sections also reflecting this change: 
• Section 6.8, Patient and Caregiver Experience Survey 
• Section 6.9, Patient and Caregiver Impact Questionnaire 
Purpose:  Reduce required blood sample collection timepoints for PK assessments. 
The primary change occurs in Table 3, Pharmacokinetic and ECG Assessment Time Points: All Sites except East Asian Sites, 
Footnote Notes. 
Revised text:  Blood samples for PK assessment may be collected at 24 hours postdose as feasible during periods of time when 
the COVID-19 pandemic impedes the ability of patients to travel to the study site and the healthcare professionals to go to the 
patients’ homes. 
Purpose:  Allow continual assessments of AEs, concomitant medication use, renal stone events, and healthcare utilization via remote 
contact. 
The primary change occurs in Table 1 and Table 2, Schedules of Assessments  
Revised text: In situations where a study visit is unable to be completed (either at the study 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, renal stone events, adverse events, and healthcare utilization. 
Purpose:  To clarify lost to follow-up if a patient misses a required study visit. 
The primary change occurs in Section 4.3.4, Lost to Follow-Up 
Revised text:  A patient will be considered lost to follow-up if the patient repeatedly fails to return for scheduled visits and is unable to 
be contacted by the clinical study center.  The following actions must be taken if a patient misses fails to return to the clinical for a 
required study visit. 


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Purpose:  Collect information related to the impact of the COVID-19 pandemic on patient participation in the study. 
The primary change occurs in Section 6.5.8, COVID-19 Data Collection 
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 also reflecting this change:   
• Section 7.2, Statistical Methodology 
Purpose:  Revise and update informed consent instructions 
The primary change occurs in Section 8.1.1, Informed Consent 
Revised 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 8.1.2, Ethical Review 
Revised text:  In addition, the IRB or IEC must approve all patient materials 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 the requirement for measurement of pyridoxine after Month 18. 
The primary change occurs in Section 5.3, Concomitant Medications 
Revised text: Patients should continue their current standard of care regimen, including hyperhydration, crystallization inhibitors, 
and/or pyridoxine therapy for the first 12 months of the study.  Standard of care treatment may be adjusted beginning at Month 12 in 
accordance with clinical judgement.  If pyridoxine therapy is discontinued, pyridoxine levels should be assessed for at least the next 2 
study visits. 
Sections also reflecting this change:  
• Table 2, Schedule of Assessments 
• Table 8, Clinical Laboratory Assessments, Footnotes 
Purpose:  Removes the requirement for measurement of coagulation parameters as part of routine surveillance laboratory 
assessments.  
The primary change occurs in Section 6.5.6 Table 8, Clinical Laboratory Assessments 
Revised text:  Coagulation:  Prothrombin time, Partial thromboplastin time, International normalized ratio. 
Section also reflecting this change:  
• Table 6, Monitoring and Dosing Rules for Asymptomatic Patients with Confirmed Isolated Elevations of ALT and/or AST 
>3× ULN, with No Alternative Cause Identified 
Purpose:  Expand the window for obtaining body weight to 4 months (from 3 months) before dosing to calculate the study drug dose. 
The primary change occurs in Section 5.2.2, Dose and Administration 
Revised text: Body weight collected within 3 4 months prior to the study drug dose or the predose weight collected on the study visit 
day or dosing day will be used for dose calculations. 
Section also reflecting this change:  
• Section 6.5.2, Weight and Height 


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3. 
REFERENCES 
Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) Pandemic, 
(20/03/2020; updated 27/03/2020; updated 28/04/2020). 
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
10/guidanceclinicaltrials_covid19_en.pdf 
FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic: 
Guidance for Industry, Investigators, and Institutional Review Boards (03/2020; updated 
16/04/2020). https://www.fda.gov/regulatory-information/search-fda-guidance-documents/fda-
guidance-conduct-clinical-trials-medical-products-during-covid-19-pandemic 
 


Clinical Study Protocol ALN-GO1-003 
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Amendment 2 Summary of Changes, 19 March 2019  
 
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Confidential 
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ALN-GO1-003 PROTOCOL AMENDMENT 2  
SUMMARY OF CHANGES DATED 19 MARCH 2019 
 
ILLUMINATE-A:  A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study 
with an Extended Dosing Period to Evaluate the Efficacy and Safety of Lumasiran in 
Children and Adults with Primary Hyperoxaluria Type 1 
 
Rationale for Protocol Amendment 
The primary purpose for this protocol amendment is to broaden the patient population by 
allowing enrollment of patients with a glomerular filtration rate ≥30 mL/min/1.73 m2 and to 
align clinical objectives and endpoints across the Phase 3 program.  A summary of the changes is 
outlined below. 
The following inclusion criterion has been modified: 
 Specify (to 2 decimals) the mean 24-hour urinary oxalate excretion as ≥0.70 
mmol/24h/1.73m2. 
The following exclusion criterion has been modified: 
 Change the exclusion threshold for the glomerular filtration rate from 
≤45 mL/min/1.73 m2 to <30 mL/min/1.73 m2. 
In addition, the following changes have been implemented for this study: 
 Clarify that the Month 12 visit spans 2 days in the Schedule of Assessments for the 
Open Label Extension Period (Table 2). 
 Clarify that a predose PK sample is taken on the day of dosing in the PK assessment 
tables (Table 3 and Table 4). 
 Add a rationale for the dosing regimen in patients with eGFR ≥30 mL/min/1.73 m2. 
 Update the secondary and exploratory objectives and endpoints, including changing 
the evaluation of the long-term effects of lumasiran and plasma oxalate levels from 
exploratory to secondary objectives and endpoints.   
 Update the blinding rules to accommodate site pharmacies with established policies 
that do not support masking the study drug during transfer from vial to syringe. 
 Clarify that additional liver function tests are performed when no alternative cause is 
identified. 
 Add that male patients may be required to use contraception (condom) in some 
countries, such as France, to comply with local requirements. 
 Clarify that specific study assessments may be conducted at a location other than the 
study center by a home healthcare professional. 


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 Add that patients may be rescreened per investigator judgment and after consultation 
with the Medical Monitor. 
 Specify that pregnancy tests may be performed more frequently as per local 
requirements. 
 Clarify that if the relationship between an AE and the study drug is at least reasonably 
possible, it is considered “related” to the study drug. 
 Update the description of the quality of life questionnaires. 
 Update the description of the analysis populations, how missing data are handled, and 
descriptions of the primary and secondary endpoints and analyses. 
 Update the description of the pharmacodynamic analysis. 
 Stipulate discontinuation criteria for the termination of the clinical trial or a clinical 
study site. 
 Remove that an Institution or Investigator must wait 18 months to submit a 
publication once the primary manuscript has been published since the number of 
months varies per local requirements and this information is specified in the clinical 
trial agreement. 
A detailed summary of changes is provided in Table 1.  Corrections to typographical errors, 
punctuation, grammar, abbreviations, and formatting (including administrative changes between 
protocol amendment 1 and protocol amendment 2) are not detailed. 
 


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Table 1: 
Protocol Amendment 2 Detailed Summary of Changes 
The primary section(s) of the protocol affected by the changes in Protocol Amendment 2 are indicated.  Deleted text is indicated by 
strikeout; added text is indicated by bold font. 
Purpose: Clarify that the Month 12 visit spans 2 days. 
The change occurs in Table 2, Schedule of Assessments – Open Label Extension Period (After Month 9 through Year 5) (bullet in “Notes”) 
Added: 
 
Gray-shaded column indicates the visit where assessments span 2 days. 
Purpose: Clarify that a predose PK sample is taken on the day of dosing. 
The change occurs in Table 3, Pharmacokinetic and Electrocardiogram Assessment Time Points: All Sites except East Asian Sites (bullet in 
“Notes”) 
Added:  
 
Predose samples are collected on the day of dosing. 
Sections also containing this change:  
 
Table 4, Pharmacokinetic and Electrocardiogram Assessment Time Points: East Asian Sites 
Purpose: Add a rationale for the dosing regimen in patients with eGFR ≥30 mL/min/1.73 m2. 
The primary change occurs in 1.4, Dose Rationale 
Added: 
In patients with PH1, population PK/PD modeling demonstrated dose dependent oxalate reductions over the dose range (1.0 to 
6.0 mg/kg continuous once monthly or once every 3 months SC administrations), with diminishing additional effect predicted 
with higher doses consistent with an asymptotic rather than linear relationship.  For a given dose, the PK/PD model indicated 
that monthly administration leads to a more rapid decline in urinary oxalate levels relative to dosing every 3 months.  A 
combination of monthly dosing in a loading phase and then dosing every 3 months in a maintenance phase achieves the goals 
of rapid and consistent lowering of urinary oxalate to normal or near normal levels in PH1 patients. Preclinical and clinical 
data indicate the renal pathway is a minor elimination route for lumasiran. Thus, renal impairment is not expected to 
influence systemic exposure, PD, and safety properties of lumasiran, and no dose adjustments are needed based on 
renal function. Thus, a lumasiran dosing regimen of 3.0 mg/kg once monthly for 3 doses followed by 3.0 mg/kg once every 3 
months has been selected for this study in PH1 patients ≥6 years old with eGFR>45 ≥30 mL/min/1.73 m2.  








Clinical Study Protocol ALN-GO1-003 
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 
Section 3.1, Summary of Study Design 
 
Section 3.5, Method of Assigning Patients to Treatment Groups 
Purpose: Update the threshold for the glomerular filtration rate to <30 mL/min/1.73 m2 in the exclusion criteria; elsewhere state that patients 
included in this study have eGFR ≥30 mL/min/1.73m2. 
The primary change occurs in Section 4.2, Exclusion Criteria #4 
Now reads: 
Estimated GFR of ≤45 <30 mL/min/1.73m2 at screening (calculation will be based on the Modification of Diet in Renal 
Disease [MDRD] formula for patients ≥18 years of age and the Schwartz Bedside Formula for patients <18 years of age). 
Sections containing this change:  
 
Synopsis 
 
Section1.3, Study Design Rationale  
 
Section 1.4, Dose Rationale 
Purpose: Delete paragraph to accommodate those site pharmacies whose established policy does not support masking the syringe prior to 
transfer of the study drug from vial to syringe 
The change occurs in 5.2.2, Dose and Administration 
Deleted text: 
To maintain the blind, the syringes will be masked prior to study drug withdrawal from the masked vial. A pharmacist, or 
other qualified healthcare professional, will withdraw study drug from the masked vial into the masked syringe.  A full 
description of the blinding procedure is included in the Pharmacy Manual. 
Purpose: Clarify that additional liver function tests are performed when no alternative cause is identified. 
The change occurs in 5.2.3.1, LFT Criteria for Withholding, Monitoring and Stopping Study Drug Dosing (#3) 
Now reads: 
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. 


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c. b. If an alternative cause is found, provide appropriate care. 
b. c. If an alternative cause is not found, perform assessments per Table 6 and Table 9. 
Purpose: Add that male patients may be required to use contraception (condom) in some countries, such as France, to comply with local 
requirements. 
The change occurs in Section 5.5.1, Contraception 
Now reads: 
For male patients, no contraception is required.  However, contraception use by men should be consistent use by males of 
contraception (condom) may be required in some countries, eg, France, in order to comply with local regulations 
requirements as described in the corresponding patient informed consent forms.  
Purpose: Clarify that specific study assessments may be conducted at a location other than the study center by a home healthcare professional. 
The primary change occurs in 6, Study Assessments 
Now reads: 
The schedules of study assessments is provided in Table 1, Table 2, Table 3, and Table 4.  Study assessments for pregnancy 
test (urine or serum), clinical lab assessments, urine collection, and DNA testing may be conducted at a location other 
than the study center by a home healthcare professional, where applicable country and local regulations and 
infrastructure allow. 
Purpose: Add that patients may be rescreened per investigator judgment and after consultation with the Medical Monitor. 
The primary change occurs in 6.1.2, Rescreening 
Now reads: 
A patient who does not meet all study eligibility criteria due to a transient condition observed at Screening (eg, prohibited 
medications that were subsequently discontinued) will may be allowed to return for rescreening if appropriate in the 
opinion of the investigator and after consultation with the Medical Monitor.  A patient will be re-consented and assent 
obtained (if applicable) if rescreening occurs outside of the 60-day screening window.  In this case, all screening procedures 
must be repeated.  
Purpose: Specify that pregnancy tests may be performed more frequently per local requirements. 


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The primary change occurs in 6.5.6.2, Pregnancy Testing 
Section now 
reads: 
A serum pregnancy test will be performed at Screening or upon initiation of menarche, if applicable, and urine pregnancy tests 
will be performed thereafter per the Schedules of Assessments and any time pregnancy is suspected.  More frequent 
pregnancy testing may be performed where required per local regulations requirements.   
Sections also containing this change:  
 
Table 1, Schedule of Assessments – 6-Month Double-Blind Treatment Period and Blinded Treatment Extension (Screening through 
Month 9 Assessments) 
 
Table 2, Schedule of Assessments – Open Label Extension Period (After Month 9 through Year 5) 
Purpose: Clarify that if the relationship between an AE and the study drug is at least reasonably possible, it is considered “related” to the 
study drug. 
The change occurs in Section 6.5.7.1 Definitions, Relationship of the Adverse Event to Study Drug 
Now reads: 
The relationship of each AE to study drug should be evaluated by the Investigator by a “yes” or “no” response to the question: 
“Is there a reasonable possibility that the event may have been caused by the study drug?” A “yes” response indicates that 
the event is considered as related to the study drug. 
Purpose: Update the description of the quality of life questionnaire. 
The change occurs in 6.7, Quality of Life 
Now reads: 
QOL assessments include the following: 
 
Kidney disease Quality of Life Questionnaire (KDQOL), specifically the KDQOL SF1.3 and KDQOL-36 for patients 
≥18 years of age at screening, and the Pediatric Quality of Life Inventory (PedsQL), including the generic and ESRD 
modules (parent and/or self-report versions) [20] for patients <18 years of age at screening. 
 
EQ-5D, a standardized instrument consisting of a questionnaire and a visual analog scale pertaining to 5 dimensions 
(mobility, self-care, usual activities, pain/discomfort, and anxiety/depression).  Scoring of the questionnaire is based on 
3 degrees of disability (severe, moderate, or none).  Scoring of the visual analog scale is based on a visual scale ranging 
from 0 (worst imaginable health state) to 100 (best imaginable health state).  Higher scores indicate better health status.  


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The EQ-5D-5L value set questionnaire will be utilized in patients ≥18 years of age at screening, and the 5Y EQ-5D-Y 
questionnaire value set will be utilized in patients <18 years of age at screening, where available.[21] 
Purpose: Update the description of the analysis populations. 
The change occurs in 7.2.1, Populations to be Analyzed 
Now reads: 
 
Per-protocol (PP) Set: All randomized patients who received any amount of study drug, had baseline and at least one 
post-baseline 24-hour urinary oxalate, and did not experience any major protocol deviations that may impact the efficacy 
results within the 6-month double-blinded period.  Patients will be analyzed according to the randomized treatment 
actually recived arms. 
 
All Lumasiran Treated Set: All patients who received any amount of lumasiran including patients who took 
lumasiran during the 6-month double-blinded period and patients who initially took placebo during the 6-month 
double-blinded period and then switched to lumasiran during the extension period. 
The primary population used to evaluate efficacy will be the Full Analysis Set. The for the primary endpoint will also be 
analyzed for the Per protocol Set and secondary endpoints during the double-blind period.  Safety during the double-
blind period will be analyzed using the Safety Analysis Set.  The PK Aanalysis Set will be used to evaluate the PK 
endpoints.  The All Lumasiran Treated Set will be conducted in the PK Analysis Set used to summarize the long-term 
efficacy and safety of lumasiran. 
Purpose: Update how missing data are handled. 
The change occurs in 7.2.3, Handling of Missing Data 
Deleted text: 
To assess the impact of missing data under more conservative assumptions, a pattern mixture model (PMM) based on missing 
not at random (MNAR) assumptions will be performed as a sensitivity analysis.  
Purpose: Update the description of the primary endpoint. 
The change occurs in 7.2.5.1, Primary Endpoint 
Now reads: 
The primary endpoint is to compare the percent change from baseline to Month 6 in 24-hour urinary oxalate corrected for 
BSA between the treatment groups in the Full Analysis Set.  The analysis will be performed using a mixed-effect model for 


Clinical Study Protocol ALN-GO1-003 
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repeated measures (MMRM) approach.  The outcome variable is percent change from baseline in urinary oxalate corrected for 
BSA.  The model includes baseline value as covariate and fixed effect terms including treatment arm and visit (Months 1, 2, 3, 
4, 5, 6).  The treatment estimates from this model will represent an average percent change from baseline of 24-hour 
urinary oxalate excretion across months 3 through 6 at which the treatment effect is expected to have reached steady 
state.  Furthermore, given the variability of 24-hour urinary oxalate, averaging the values across these visits will yield 
stable treatment estimates. 
Baseline and Month 6 urinary oxalate values are planned to be collected in triplicate (minimum requirement of duplicate) and 
the calculated mean median of valid collections during each time period (visit) will be used in the analysis. BSA will be 
calculated using the Mosteller formula. 
Purpose: Update the description of the secondary endpoint analyses. 
The primary change occurs in 7.2.5.2, Secondary Endpoints 
Now reads: 
To control the overall type I error, these secondary endpoints will be tested in the following hierarchical order: 
• 
Absolute change in 24-hour urinary oxalate corrected for BSA from baseline to Month 6 
• 
Change in 24-hour urinary oxalate:creatinine ratio (value/ULN) from baseline to Month 6 
• 
Proportion of patients with 24-hour urinary oxalate level at or below 1.5xULN [ULN=0.46 mmol/24h/1.73m2] at Month 6 
• 
Proportion of patients with 24-hour urinary oxalate level at or below ULN [ULN=0.46 mmol/24h/1.73m2] at Month 6 
• 
Percent change in plasma oxalate from baseline to Month 6 
• 
Absolute change in plasma oxalate from baseline to Month 6 
Continuous endpoints will be analyzed using an MMRM approach similar to the one described for the primary endpoint.  For 
bBinary endpoints, will be analyzed using the Cochran-Mantel-Haenszel test stratified by baseline urinary oxalate.  The 
odds ratio and the differences in proportions with corresponding 95% confidence will also be summarized. 
Change in eGFR from baseline to Month Secondary endpoints assessed beyond Month 6 will be summarized descriptively. 
Change in eGFR over time will also be summarized descriptively. 
Purpose: Update the description of the pharmacodynamic analysis. 


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The change occurs in 7.2.6, Pharmacodynamic Analysis 
Now reads: 
Urinary oxalate and glycolate excretion, urinary oxalate: creatinine ratio, and plasma levels of oxalate and glycolate 
will be summarized over time descriptively by treatment arm. Analysis of the PD parameters are specified in 
Section 7.2.5.2. Any PD parameters not already prespecified for testing will be summarized descriptively. 
Purpose: Stipulate discontinuation criteria for the termination of the clinical trial or a clinical study site. 
The change occurs in Section 8.1.6, Termination of the Clinical Study or Site Closure 
Now reads: 
The Sponsor, or designee, reserves the right to terminate the study for or a clinical or administrative reasonsstudy site at any 
time.  If the site does Conditions that may warrant this action may include, but are not recruit at a reasonable rate, or if 
there is insufficient adherence limited to: 
 
The discovery of an unexpected, serious, or unacceptable risk to patients participating in the study 
 
Failure of the Investigator to comply with the protocol, the requirements, the study may be closed at that site. of the 
IRB/IEC or local health authorities, the Sponsor's procedures, or GCP guidelines 
 
Inadequate recruitment of participants by the Investigator 
 
The decision on the part of the Sponsor to suspend or discontinue treatment with the study drug 
Should the study be terminated, and/or the site 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, IRB/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. 
Purpose: Remove that an Institution or Investigator must wait 18 months to submit a publication once the primary manuscript has been 
published since the number of months varies per local requirements and this information is specified in the clinical trial agreement.  
The change occurs in Section 8.3, Publication Policy 
Deleted text: 
A separate publication by Institution or Investigator may not be submitted for publication until after this primary manuscript is 
published, or following the period of 18 months after completion of the study at all centers. 


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Purpose: Correct typographical errors, punctuation, grammar, abbreviations, and formatting. 
These changes are not listed individually. 
 


Clinical Study Protocol ALN-GO1-003 
ALN-GO1 (lumasiran) 
Amendment 1 Summary of Changes, 23 July 2018 
 
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ALN-GO1-003 PROTOCOL AMENDMENT 1  
SUMMARY OF CHANGES DATED 23 July 2018 
 
ILLUMINATE-A:  A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study with 
an Extended Dosing Period to Evaluate the Efficacy and Safety of Lumasiran in Children 
and Adults with Primary Hyperoxaluria Type 1 
 
Rationale for Protocol Amendment 
The primary purpose for this protocol amendment is to provide additional clarification about the 
patient caregiver surveys specific to patients under the legal age of consent, and to make 
corrections to the Open Label Extension Period Schedule of Assessments, which was missing the 
Month 27 visit in Year 2 (Study Day 757 ±14 days).  In addition, the visit schedule for the 
12-lead electrocardiogram and renal ultrasound assessments through Year 5 in the Open Label 
Extension Period was corrected from annually to Month 36 and Month 48. 
In the clinical laboratory assessments table, a correction was made to remove the 
immunogenicity (antidrug antibodies) assessment from the table, which was erroneously 
included in the original table. 
Also, the nomenclature used in the protocol title was updated. 
A detailed summary of changes is provided in Table 1.  Corrections to typographical errors, 
punctuation, grammar, abbreviations, and formatting (including administrative changes between 
the original protocol and amendment 1) are not detailed. 
 


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Amendment 1 Summary of Changes, 23 July 2018 
 
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Table 1: 
Protocol Amendment 1 Detailed Summary of Changes 
The primary section(s) of the protocol affected by the changes in Protocol Amendment 1 are indicated.  The corresponding text has 
been revised throughout the protocol.  Deleted text is indicated by strikeout; added text is indicated by bold font. 
Purpose:  Updated nomenclature used in the protocol title 
The primary change occurs in the title page 
Revised title: 
ILLUMINATE A003:  A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study with an Extended Dosing Period 
to Evaluate the Efficacy and Safety of Lumasiran in Children and Adults with Primary Hyperoxaluria Type 1 
Section(s) also containing this change:   
 
Synopsis  
Purpose:  Added Month 27 visit to the Open Label Extension Period Schedule of Assessments, and corrected scheduled visits for 12-lead ECG and 
renal ultrasound assessments from annually to Month 36 and Month 48. 
The primary change occurs in Table 2:  Schedule of Assessments – Open Label Extension Period (After Month 9 through Year 5) 
Purpose:  Updated patient and caregiver experience survey information 
The primary change occurs in Section 6.8, Patient and Caregiver Experience Surveys 


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Amendment 1 Summary of Changes, 23 July 2018 
 
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Revised text: 
The patient and caregiver experience surveys assesses patients’ experience living with PH1, including their experience 
with PH1 treatments, as well as the effect of PH1 on patients’ caregivers.  Theseis surveys will be completed at the time 
points specified in the Schedules of Assessment (Table 1 and Table 2) and each takes approximately 10 minutes to 
complete.  
For the Patient Experience Survey, patient portion of the experience survey, patients ≥138 years of age at screening will 
complete the survey themselves if they are able.  If the patient is unable to complete the Patient Experience Survey 
survey alone, their caregiver or site staff may complete the survey for the patient.  If the patient is <138 years of age at 
screening, a caregiver will complete the Patient Experience Survey on behalf of the patient for as long as the patient 
remains under the legal age of consentthe patient section of the survey on behalf of the patient for as long as the patient 
remains <18 years of age.   For patients who reach the legal age of consent per local regulations 18 years of age during the 
study, caregivers will be encouraged to continue completing the patient section of the survey,  but are not required to do 
so.  Additionally, for patients under legal age of consent at the time of screening, their caregiver will also be asked 
to complete the Caregiver Experience Survey. For patients who reach the legal age of consent per local regulations 
during the study, caregivers will be encouraged to continue completing the survey, but are not required to do so.   
For the Caregiver Experience Survey, caregivers will be asked to complete the survey at all time points 
Section(s) also containing this change:  
 
Section 6.9, Patient and Caregiver Impact Questionnaire 


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Amendment 1 Summary of Changes, 23 July 2018 
 
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Purpose:  Updated patient and caregiver impact questionnaire details 
The primary change occurs in Section 6.9, Patient and Caregiver Impact Questionnaire 
Added text: 
The patient and caregiver impact questionnaire will be used to assess impacts of PH1 on the patients’ lives, including their 
need to relocate/travel to receive treatment, the number and type of healthcare providers they use, and their ability to work 
and/or go to school.  The questionnaire will also assess the impact on caregivers’ employment.  This survey 
questionnaire will be completed at the time points specified in the Schedules of Assessment (Table 1 and Table 2) and 
takes approximately 10-12 minutes to complete.  
Patients ≥138 years of age at screening will complete the questionnaire  themselves if they are able.  If the patient is 
unable to complete the survey alone, their caregiver or site staff may complete the survey on the patient’s behalf.  If the 
patient is <138 years of age at screening, a caregiver will complete the patient section of the questionnaire on behalf of the 
patient for as long as the patient remains <18 years of age.  For patients who reach the legal age of consent per local 
regulations 18 years of age during the study, and whose caregivers had previously completed the Patient Impact 
Questionnaire  on their behalf, caregivers will be encouraged to continue completing the questionnaire, but are not 
required to do so 
Section(s) also containing this change:  
 
Section 6.8, Patient and Caregiver Experience Surveys 
Purpose:  Correct typographical errors, punctuation, grammar, abbreviations, and formatting 
These changes are not listed individually. 
 

SAP_001.pdf: 
 
 
Official Title: ILLUMINATE-A: A Phase 3 Randomized, Double-blind, Placebo-Controlled 
Study with an Extended Dosing Period to Evaluate the Efficacy and Safety of 
Lumasiran in Children and Adults with Primary Hyperoxaluria Type 1 
 
NCT Number:   
NCT03681184 
 
Document Date:   
Statistical Analysis Plan Version 2.0, 21 November 2019 


Statistical Analysis Plan, Protocol ALN-GO1-003 
ALN-GO1 (lumasiran) 
21 November 2019, Version 2.0 SAP 
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Confidential 
1 
STATISTICAL ANALYSIS PLAN 
 
ILLUMINATE-A: A Phase 3 Randomized, Double-blind, Placebo-Controlled 
Study with an Extended Dosing Period to Evaluate the Efficacy and Safety of 
Lumasiran in Children and Adults with Primary Hyperoxaluria Type 1 
 
Protocol Number: 
Protocol Version and Date: 
ALN-GO1-003 
Protocol Amendment 2: 19 March 2019 
Protocol Amendment 1: 23 July 2018 
Original Protocol: 09 July 2018 
 
Investigational Drug: 
ALN-GO1 (lumasiran) 
Phase: 
Phase 3 
Sponsor: 
Alnylam Pharmaceuticals, Inc. 
300 Third Street 
Cambridge, MA  02142 USA 
Tel: +1 (617) 551-8200 
Fax: +1 (617) 551-8101 
Sponsor Contact: 
 
 
 
Analysis Plan Version and 
Date: 
Version 2.0: November 21, 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. 


Statistical Analysis Plan, Protocol ALN-GO1-003 
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21 November 2019, Version 2.0 SAP 
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APPROVAL SIGNATURE PAGE 
ILLUMINATE-A: A Phase 3 Randomized, Double-blind, Placebo-Controlled 
Study with an Extended Dosing Period to Evaluate the Efficacy and Safety of 
Lumasiran in Children and Adults with Primary Hyperoxaluria Type 1 
 
Protocol Number: 
ALN-GO1-003  
Analysis Plan Version and 
Date: November 21, 2019 
Version 2.0 
 
This Statistical Analysis Plan has been authored by: 
 
 
 
Alnylam Pharmaceuticals, Inc. 
 
 
This Statistical Analysis Plan has been approved and signed electronically on the final page by the 
following: 
 
 
 
Alnylam Pharmaceuticals, Inc 
 
 
  
Alnylam Pharmaceuticals, Inc. 


Statistical Analysis Plan, Protocol ALN-GO1-003 
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TABLE OF CONTENTS 
APPROVAL SIGNATURE PAGE .................................................................................................2 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF TABLES ...........................................................................................................................5 
LIST OF FIGURES .........................................................................................................................5 
ABBREVIATIONS .........................................................................................................................6 
1. 
INTRODUCTION ........................................................................................................8 
2. 
STUDY OVERVIEW ...................................................................................................8 
2.1. 
Synopsis of Study Design .............................................................................................8 
2.2. 
Randomization Methodology .......................................................................................9 
2.3. 
Blinding ........................................................................................................................9 
2.4. 
Study Procedures ........................................................................................................10 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................10 
3.1. 
Objectives ...................................................................................................................10 
3.1.1. 
Primary Objective .......................................................................................................10 
3.1.2. 
Secondary Objectives .................................................................................................10 
3.1.3. 
Exploratory Objectives ...............................................................................................10 
3.1.4. 
Safety Objective ..........................................................................................................11 
3.2. 
Endpoints ....................................................................................................................11 
3.2.1. 
Primary Endpoint ........................................................................................................11 
3.2.2. 
Secondary Endpoints ..................................................................................................11 
3.2.3. 
Exploratory Endpoints ................................................................................................11 
3.2.4. 
Safety Endpoints .........................................................................................................12 
4. 
PATIENT POPULATION ..........................................................................................12 
4.1. 
Patient Definitions ......................................................................................................12 
4.2. 
Protocol Deviations ....................................................................................................12 
5. 
GENERAL STATISTICAL METHODS ...................................................................14 
5.1. 
Sample Size Justification ............................................................................................14 
5.2. 
General Methods .........................................................................................................14 
5.3. 
Computing Environment ............................................................................................15 
5.4. 
Baseline Definitions ....................................................................................................16 
5.5. 
Randomization Stratification Factors .........................................................................16 


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5.6. 
Multiple Comparisons/Multiplicity ............................................................................16 
5.7. 
Missing Data ...............................................................................................................17 
5.8. 
Visit Windows ............................................................................................................17 
5.9. 
Interim Analysis ..........................................................................................................18 
5.10. 
Analysis for Primary Endpoint and Database lock .....................................................18 
6. 
STUDY ANALYSES .................................................................................................19 
6.1. 
Patient Disposition ......................................................................................................19 
6.2. 
Demographics and Baseline characteristics ................................................................19 
6.3. 
Medical History ..........................................................................................................20 
6.4. 
Prior and Concomitant Medications ...........................................................................20 
6.5. 
Dosing and Extent of Exposure ..................................................................................20 
7. 
STATISTICAL ANALYSIS ......................................................................................21 
7.1. 
Primary Endpoint ........................................................................................................21 
7.1.1. 
Sensitivity Analysis ....................................................................................................22 
7.2. 
Secondary Endpoints ..................................................................................................22 
7.3. 
Subgroup Analysis ......................................................................................................24 
7.4. 
Exploratory Analysis ..................................................................................................25 
7.5. 
Pharmacodynamic Analysis........................................................................................27 
7.6. 
Pharmacokinetic Analysis ..........................................................................................27 
7.7. 
Safety Analyses ..........................................................................................................27 
7.7.1. 
Adverse Events ...........................................................................................................27 
7.7.2. 
Clinical Laboratory Data ............................................................................................29 
7.7.3. 
Vital Signs ..................................................................................................................30 
7.7.4. 
Physical Examinations ................................................................................................30 
7.7.5. 
Electrocardiogram .......................................................................................................31 
7.8. 
Anti-Drug Antibody ....................................................................................................31 
8. 
CHANGES TO PLANNED ANALYSES..................................................................32 
9. 
REFERENCES ...........................................................................................................34 
APPENDIX A. UPPER LIMIT OF NORMAL FOR 24-HOUR URINARY 
OXALATE CORRECTED FOR BSA .......................................................................35 


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LIST OF TABLES 
Table 1: 
Analyses of the Primary Endpoint ..............................................................................22 
Table 2: 
Analysis of Secondary Endpoints to Month 6^...........................................................23 
Table 3: 
QOL instruments by Age at Screening (<18 years old vs. ≥ 18 years old) ................26 
LIST OF FIGURES 
Figure 1: 
Study Design .................................................................................................................9 


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ABBREVIATIONS 
Abbreviation 
Definition 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AGT 
alanine-glyoxylate aminotransferase 
AGXT 
alanine glyoxylate aminotransferase gene 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical Classification System 
AUC 
Area under the concentration-time curve 
BMI 
Body mass index 
BSA 
Body surface area 
Cmax
Maximum plasma concentration 
CSR 
Clinical study report 
DB 
Double-blind  
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
EOS 
End of study 
EOT 
End of treatment 
ET 
Early termination 
EQ-5D 
Euro Quality of Life Health State Profile Questionnaire 
ESRD 
End-stage renal disease 
FAS 
Full analysis set 
GO 
Glycolate oxidase 
IRS 
Interactive response system 
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 


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Abbreviation 
Definition 
PD 
Pharmacodynamic  
PT 
Preferred term 
PK 
Pharmacokinetics 
PedsQL 
Pediatric Quality of Life 
PH1 
Primary hyperoxaluria type 1 
QoL 
Quality of life 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
SMQ 
Standardized MedDRA Queries 
VAS 
Visual analog system 
ULN 
Upper Limit of Normal 


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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.[Cochat 2013]  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.[Cochat 2013]  This 
devastating condition, systemic oxalosis, arises when the estimated glomerular filtration rate 
(eGFR) has declined to below 30 to 45 mL/min/1.73 m2.[Cochat 2013] 
The ILLUMINATE-A Study (ALN-GO1-003) is a Phase 3 study designed to evaluate the 
efficacy and safety of SC-administered lumasiran in patients with PH1. This statistical analysis 
plan (SAP) has been developed based on the protocol of the ILLUMINATE-A study 
(Amendment 2 dated 19 March 2019).  
The analysis methods described in the protocol may be updated in this statistical analysis plan 
(SAP). Any change to the data analysis methods described in the protocol, as well as the 
justification for the change, will be described in this SAP (Section 8) and the clinical study report 
(CSR). Additional exploratory analyses of the data may be conducted when deemed appropriate. 
2. 
STUDY OVERVIEW 
2.1. 
Synopsis of Study Design 
The ILLUMINATE-A Study (ALN-GO1-003) is a multicenter, multinational Phase 3 study 
designed to evaluate the efficacy and safety of lumasiran in approximately 30 patients with PH1; 
the study is comprised of a 2:1 randomized, double-blind, placebo-controlled period of 6 months, 
followed by an 3-month blinded treatment extension period and an open label extension period 
of up to 51 months to evaluate the long-term safety and efficacy of lumasiran.  
The study design schema is presented in Figure 1.  


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Figure 1: 
Study Design 
 
*To maintain the blind to treatment assignment, study drug will be administered in the same manner and at the same 
frequency as in the 6-month double-blind period. Patients randomized to lumasiran will also receive 2 qM doses of 
placebo during the 3-month blinded treatment extension.  
2.2. 
Randomization Methodology 
Patients will be randomized 2:1 to receive either lumasiran or placebo in a double-blind manner. 
Treatment will be stratified at randomization based upon mean 24-hour urinary oxalate level 
from the first 2 valid samples collected during screening (≤1.70 mmol/24hr/1.73m2 vs. > 1.70 
mmol/24hr/1.73m2).  
2.3. 
Blinding 
Treatment assignments will be maintained by the interactive response system (IRS). Any 
unplanned unblinding occurring during the 6-month double-blind placebo-controlled treatment 
period will be documented and reported in the CSR. 
Alnylam and all sponsor personnel (except for staff involved in study drug supply, eTMF and 
study drug supply) will also be blinded to treatment assignments and laboratory results until the 
interim database lock for the primary analysis of the 6-month double-blind treatment period. 
Investigators and all site personnel will be blinded to treatment assignments and laboratory 
results that could potentially unblind them (e.g., 24-hour urinary oxalate, 24-hour urinary 
glycolate, plasma oxalate, plasma glycolate, spot urinary oxalate, spot urinary glycolate, renal 
ultrasound, pharmacokinetics (PK), antidrug antibody (ADA) until the last patient completes the 
assessments at the Month 9 visit.  
Details regarding the blinding aspects during the study are outlined in a Randomization and 
Blinding Plan for ALN-GO1-003. The plan defines blinded data sources, identifies roles and 
responsibilities of study team members at Alnylam (or external) with their access (if any) to 
blinded data sources and addresses actions to be taken if a potentially unblinding event occurs 
prior to the interim database lock for the primary analysis of the 6-month double-blind treatment 
period in order to preserve the integrity of this study. 


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An independent, external data monitoring committee (DMC) and an independent, external 
biostatistics group supporting the DMC will have access to subject level data treatment 
assignments and blinded data sources throughout the study.   
To identify irregular and potentially erroneous results of PK a pharmacodynamic (PD) data from 
blinded data sources prior to unblinding, a clinical pharmacologist independent of the study team 
reviews the listings of such data with dummy subject ID (i.e., no link to other clinical data) and 
communicates the findings to unblinded personnel at a clinical research organization for issue 
resolution. 
2.4. 
Study Procedures 
The schedule of assessments is described in the study protocol (Table 1 and Table 2). Testing on 
PD samples for the study endpoints is performed at 
 using validated PD assay.  
3. 
OBJECTIVES AND ENDPOINTS 
3.1. 
Objectives 
3.1.1. 
Primary Objective 
• To evaluate the effect of lumasiran on the percent reduction in urinary oxalate 
excretion 
3.1.2. 
Secondary Objectives 
• To characterize the effect of lumasiran on absolute levels of urinary oxalate 
excretion, urinary oxalate: creatinine ratios, and plasma oxalate 
• To evaluate the long-term effect of lumasiran 
• To evaluate the effect of lumasiran on renal function 
3.1.3. 
Exploratory Objectives 
• To evaluate quality of life (QoL) 
• To evaluate the change in nephrocalcinosis and renal stones 
• To evaluate additional pharmacodynamic (PD) parameters of plasma glycolate, 
urinary glycolate and urinary oxalate in spot urine collections 
• To characterize the Pharmacokinetics (PK) of lumasiran 
• To assess for antidrug antibodies (ADA) against lumasiran 
• To evaluate the effects of lumasiran on patient and caregiver resource use 
• To describe the patient experiences on lumasiran in PH1 Patients and the 
experiences of caregivers for these patients 


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3.1.4. 
Safety Objective  
• To evaluate the safety and tolerability of lumasiran in patients with PH1 
3.2. 
Endpoints 
3.2.1. 
Primary Endpoint 
Percent change in 24-hour urinary oxalate excretion from baseline through Month 6 corrected for 
body surface area (BSA). 
3.2.2. 
Secondary Endpoints 
• Absolute change in 24-hour urinary oxalate corrected for body surface area (BSA) 
from baseline to Month 6  
• Percent change in 24-hour urinary oxalate: creatinine ratio from baseline to Month 6  
• Percent change in plasma oxalate from baseline to Month 6 
• Proportion of patients with 24-hour urinary oxalate level at or below 1.5xULN at 
Month 6 
• Proportion of patients with 24-hour urinary oxalate level at or below ULN at Month 
6 
• Absolute change in plasma oxalate from baseline to Month 6 
• Change in in estimated glomerular filtration rate (eGFR) from baseline to Month 6  
• Change from baseline (percent and absolute) 24-hour urinary oxalate excretion, 
percentage of time that 24-hour urinary oxalate is ≤1.5 × ULN, 24-hour urinary 
oxalate: creatinine ratios and eGFR in the extension periods 
3.2.3. 
Exploratory Endpoints 
• Change in Kidney Disease Quality of Life Questionnaire (KDQOL) for patients ≥18 
years of age at screening, and the Pediatric Quality of Life Inventory (PedsQL) [the 
generic and ESRD modules]) for patients <18 years of age at screening 
• Change in Euro Quality of Life Health State Profile Questionnaire (EQ-5D) and EQ-
5D Visual Analog Scale (VAS) 
• Change in rate of renal stone events 
• Change in nephrocalcinosis as assessed by renal ultrasound 
• Change in urinary and plasma glycolate 
• Change in urinary oxalate: creatinine ratios as assessed in random spot urine 
collections 
• PK profile of lumasiran 
• Frequency of ADA 


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• Change in patient resource use (e.g., work/school attendance, visits to 
doctor/hospital) 
• Change in patient experiences as evaluated by a patient and caregiver experience 
survey  
3.2.4. 
Safety Endpoints 
The primary safety parameter is frequency and seriousness of adverse events (AEs) during the 
double-blind treatment period and in the extension periods.  
Other safety parameters also include vital signs (including height and weight), 12-lead ECGs, 
clinical laboratory assessments, and physical exams. Renal stone events are defined in the 
protocol efficacy assessments and will not be included in any safety summaries of AEs and/or 
SAEs.  
4. 
PATIENT POPULATION 
4.1. 
Patient Definitions 
The populations (analysis sets) are defined as follows:  
• Full Analysis Set (FAS): All randomized patients who received any amount of 
study drug. Patients will be analyzed according to the treatment to which they were 
randomized. 
• Safety Analysis Set: All patients who received any amount of study drug. Patients 
will be analyzed according to the treatment actually received. 
• PK Analysis Set: All patients who received any amount of study drug and have at 
least 1 PK concentration measurement. 
• All Lumasiran Treated Set: All patients who received any amount of lumasiran, 
including patients who took lumasiran during the 6-month double-blind period and 
patients who initially took placebo during the 6-month double-blind period and then 
switched to lumasiran during the extension period. 
• Plasma Oxalate Analysis Set: All patients who received any amount of study drug 
and have a baseline plasma oxalate level ≥ 1.5*LLOQ 
The primary population used to evaluate efficacy will be the Full Analysis Set (FAS) for the 
primary and secondary endpoints during the 6-month double-blind period. Safety during the 
double-blind period will be analyzed using the Safety Analysis Set. The PK Set will be used to 
evaluate the PK endpoints. The All Lumasiran Treated Set will be used to summarize the long-
term efficacy and safety of lumasiran. The Plasma Oxalate Analysis Set will be used to evaluate 
the endpoints for the change from baseline in plasma oxalate. 
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 


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and/or reliability of the trial 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. Major protocol deviations 
will be reviewed and approved by Alnylam prior to the interim database lock for the primary 
analysis of the 6-month double-blind treatment period and unblinding of treatment assessment 
for all patients. All protocol deviations will be presented in a listing. 
The Sponsor or designee will be responsible for producing the final protocol deviations file. This 
file will include at a minimum each protocol deviation and whether or not this deviation is 
classified as a major protocol deviation. This file will be finalized prior to the primary treatment 
phase database lock and study unblinding. 
Protocol deviations will be summarized in the clinical study report. 


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5. 
GENERAL STATISTICAL METHODS 
5.1. 
Sample Size Justification 
The planned total enrollment for the study is approximately 30 patients. 
Twenty-four patients will yield 90% power to detect a treatment difference of 37% at a 2-sided 
5% significance level assuming the mean percent reduction from baseline to Month 6 in 24-hour 
urinary oxalate corrected for BSA is 17% with a standard deviation (SD) of 25% in the placebo 
arm, and a mean percent reduction from baseline to Month 6 in 24-hour urinary oxalate corrected 
for BSA of 54% with SD of 25% in the lumasiran arm. 
5.2. 
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 database plus one additional decimal. 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 
ages<18 years old), 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 any repeated collections 
at a visit, then the median will represent the value at that visit. For biomarker and/or lab data, if 
any value is recorded as <lower limit of quantification (LLOQ) then the assigned value used for 
calculations of summary statistics will be assigned a value of the 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.  
Tables and figures will primarily summarize data during the double-blind period and during 
lumasiran treatment. These time periods are defined directly below. In addition, there will be a 
subset of tables and figures for efficacy endpoints which will also summarize by protocol defined 
study visit across the entire study for patients in the FAS set.  
During the Double-Blind (DB) Period: defined as the time period prior to the first study drug 
dose date/time in the extension period (e.g. date/time of lumasiran dose at month 6).  
Tables and figures will be presented by treatment arm (lumasiran or placebo). For safety 
summaries (i.e. AEs, Labs, ECGs, VS, etc.), all assessments up to the date/time of the first dose 
in the extension period (i.e. date/time of lumasiran at month 6) or, for patients not dosed in the 
extension period, all assessments collected within 84 days of the last dose of study drug will be 
included. For efficacy summaries, all data up to and including the month 6 visit will be 
presented.  
Extension Period: defined as the period starting on/after the first date/time of lumasiran at 
month 6 (i.e. start of the 3-month blinded treatment extension period).     


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During Lumasiran treatment: defined as the time period during which patients receive 
lumasiran (i.e. on or after the first date/time of lumasiran until 84 days after the last dose of 
lumasiran). Baseline and study days will be relative to the first dose of lumasiran and will be re-
derived for patients initially randomized to placebo (Section 5.4 and Section 5.8).    
Summary tables and figures will be presented by treatment sequence (lumasiran/lumasiran, 
placebo/lumasiran and all lumasiran treated). Both safety and efficacy summaries will include all 
assessments during lumasiran treatment (i.e. any assessment collected on or after the first dose 
until 84 days after the last dose of lumasiran).  
Per-patient listings will include all data collected during the entire study. The listings will be 
sorted by randomized arm. Within patient, there will be a variable to indicate the period of the 
data collection.  
Day 1 will be defined as the day of the first dose of study drug (lumasiran or placebo). Day is 
relative to 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 assessment date is before the date of the first dose of study drug, then study day will be 
calculated as:  
Study Day = Date of assessment – date of first dose of study drug  
For patients who were randomized to placebo but later received lumasiran, these patients will 
have additional variables displayed in listings to reflect the data collected relative to the first 
dose of lumasiran. At a minimum, all listings will include two sets of definitions for the 
following variables:   
• Baseline: relative to first randomized dose of placebo and relative to first dose of 
lumasiran (Section 5.4).  
• Study Day: relative to first randomized dose of placebo and relative to first dose of 
lumasiran.  
• Visit:  based upon actual study visits and visits re-aligned relative to first dose of 
lumasiran (Section 5.8). 
Formal statistical hypothesis testing will be performed on the primary and secondary efficacy 
endpoints evaluated during the DB period (except eGFR as this endpoint is not expected to 
change within six months). Testing will be conducted at the nominal 2-sided 0.05 level of 
significance. Secondary endpoints will be tested in a prespecified hierarchy (Section 5.6). 
Summary statistics will be presented, as well as 2-sided 95% confidence intervals on selected 
parameters, as described in the sections below.  
All data recorded on the CRF will be displayed in data listings. 
5.3. 
Computing Environment 
All statistical analyses will be performed using validated SAS statistical software Version 9.4 (or 
later), unless otherwise noted.  


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5.4. 
Baseline Definitions 
Baseline definitions applied to double-blind (DB) period:  
For 24-hour urine PD parameters, baseline will be defined as the median of all valid 24-hour 
urine PD parameters collected prior to the first dose date/time of study drug (lumasiran or 
placebo). Baseline for other PD parameters will use the mean of all measurements collected prior 
to the first dose date/time of study drug (lumasiran or placebo). 
For other parameters, baseline is defined as the last non-missing value prior to the first dose 
date/time of the study drug (lumasiran or placebo), unless otherwise specified. The baseline 
value for any measurements with multiple values at a visit (e.g. ECGs, height and weight for 
patients <18 years old) will be defined as the mean of the latest values collected prior to the first 
dose date/time of study drug. 
Baseline definitions applied to During Lumasiran Treatment:  
For patients randomized to lumasiran, baseline as defined above for the double-blind period will 
be used.  
For patients randomized to placebo who took at least one dose of lumasiran in the extension 
period, baseline for all parameters [except for 24-hour urine PD parameters] will be defined as 
above but the date of the first dose date/time of study drug will be the first date/time of lumasiran 
dose. For 24-hour urine PD parameters, the baseline will be defined as the median of all valid 
assessments at month 6. If the subject does not have two valid 24-hour urine PD assessments at 
month 6, then the baseline will be calculated based on the latest three valid 24-hour urine PD 
collections prior to the first dose date/time of lumasiran.  
5.5. 
Randomization Stratification Factors  
The mean 24-hour urinary oxalate excretion (≤1.70 mmol/24h/1.73m2 or >1.70 
mmol/24h/1.73m2) from the first 2 valid 24-hour urine collections during screening will be the 
stratification factor. The stratification factor will be recorded in both the IRS (Interactive 
Response System) and the clinical database.  
The central laboratory for the 24-hour urinary oxalate measurements used for randomization 
during screening was transitioned from 
 (i.e., Clinical Assay) to 
 
(i.e., Validated PD assay). As a result, the first 5 subjects were stratified using the results based 
on the Clinical Assay 
 and the remaining patients were stratified 
using the results based on the Validated PD Assay 
. 
The planned statistical methods will adjust for baseline 24-hour urinary oxalate (refer to 
Section 5.4  and Section 7.1) and may not match the stratification factors as recorded in IRS.  
Any discrepancies will be summarized. 
5.6. 
Multiple Comparisons/Multiplicity 
The family-wise Type I error control for the primary and secondary endpoints will be achieved 
by the gatekeeping testing strategy. Once the primary hypothesis testing is statistically 
significant at a 2-sided 0.05 significance level, the secondary endpoints will be tested in the 
following hierarchical order.  


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1. Absolute change in 24-hour urinary oxalate corrected for BSA from baseline to Month 6  
2. Percent change in 24-hour urinary oxalate: creatinine ratio from baseline to Month 6 
3. Percent change in plasma oxalate from baseline to Month 6 
4. Proportion of patients with 24-hour urinary oxalate levels at or below 1.5xULN at 
Month 6 
5. Proportion of patients with 24-hour urinary oxalate levels at or below ULN at Month 6 
6. Absolute change in plasma oxalate from baseline to Month 6 
Only if the comparison is significant at a 2-sided 0.05 significance level will the next endpoint in 
the hierarchy be formally tested; if a given comparison is not significant at a 2-sided 0.05 
significance level, the subsequent tests will be performed, and the results will be summarized, 
but statistical significance will not be inferred.  
5.7. 
Missing Data  
Patients who discontinue the study prior to Month 6 will be encouraged to remain on study and 
complete their remaining clinical visits (excluding PK assessments) through the visit at Month 6 
and only safety follow-up visits afterwards. All data collected regardless of whether it was 
collected before or after treatment discontinuation will be used for analysis. However, it is 
possible that data will remain missing. 
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. 
5.8. 
Visit Windows 
For table and figure summaries of the DB period, all data will be tabulated and analyzed per the 
evaluation visit as recorded on the electronic case report forms (eCRF) even if the assessment is 
outside of window.  
For table and figure summaries of the during lumasiran treatment, the data collected at study 
visits during the extension period will be re-mapped for the patients randomized to placebo to 
reflect the visit relative to the first dose of lumasiran (e.g. Month 7 re-mapped to Month 1), 
Month 8 re-mapped to Month 2, etc.).  
Unless otherwise specified, data collected at an unscheduled visit will be included in by patient 
listings and/or spaghetti plot figures, but no assignment of the scheduled visit will be made for 
the purposes of summary tabulations. However, unscheduled study visits will be used in the 
calculation of baseline values and for the any categorical shift tables (e.g. shift from baseline to 
worst post-baseline value). 


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5.9. 
Interim Analysis 
There will not be an interim analysis prior to the primary analysis of the 6-month double blind 
period which will occur when the last patient completes the 6-month visit. There may be interim 
analyses conducted after the 6-month double-blind period to support regulatory and/or 
publications requests. 
5.10. 
Analysis for Primary Endpoint and Database lock  
As this study will be ongoing at the time of the primary analysis, the study database will have an 
interim database lock occur (i.e. data in EDC will be frozen and external data such as laboratory 
data will be QA’d and cleaned) when the last patient completes the 6-month visit to conduct the 
primary analysis of the double-blind period. Additional details regarding the interim database 
lock are located in the study Data Management Plan. The study will then be unblinded and all 
data entered as of the date of the primary treatment phase database lock will included in the 
summary of the Clinical Study Report (CSR).  
After the study is completed (i.e. all patients complete the long-term open-label extension period 
and/or required safety follow-up visit(s)), the database will be hard locked, and all data will be 
summarized in the updated CSR.  


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6. 
STUDY ANALYSES 
6.1. 
Patient Disposition 
Number and percentage of patients will be tabulated for the following categories: 
• Screen Failures 
• Enrolled (signed informed consent and met eligibility) 
• Randomized 
• Treated  
• Full Analysis Set (FAS) 
• Safety Analysis Set  
• PK Analysis Set 
• All Lumasiran Treated Set 
• Plasma Oxalate Analysis Set 
Summaries of the number and percentage of patients who discontinued treatment, withdrew from 
study, and primary reasons for either discontinuation of treatment and/or withdrawal from study 
will be presented. Additionally, the number of patients who completed the month 6 visit will also 
be displayed. A patient is defined as having completed the month 6 visit if the patient has at least 
one valid 24-hour urinary oxalate corrected for BSA at that visit. 
The number and percent of patients enrolled by country and site will be summarized by 
randomized arm and overall. The number and percent of patients in each randomization stratum 
recorded in IRS vs. clinical database will also be summarized by randomized treatment arm and 
overall. 
Data listings of those patients who withdrew and/or discontinued treatment including the 
associated reasons will also be presented. A separate listing of screening failure patients with the 
associated reason for screen failures will be generated. 
6.2. 
Demographics and Baseline characteristics 
Descriptive statistics of demographic characteristics including but not limited to: age (years), age 
category (6 to <12, 12to <18, ≥18 to <65 and ≥65), gender, race, ethnicity, region, height, 
weight, BSA, and body mass index (BMI) will be presented. For patients <18 years at screening, 
modified z-scores for height, weight and body mass index will also be summarized.  
Additional disease baseline characteristics including but not limited to: 24-hour urinary oxalate 
excretion corrected for BSA (mmol/24hours/1.73m2), 24-hour urinary oxalate: creatinine ratio, 
eGFR (mL/min/1.73m2), plasma glycolate (µmol/L), plasma oxalate (µmol/L), and total number 
of patients reported with vitamin B6 use prior to study entry will be summarized using 
descriptive statistics.   
A tabular summary of historical disease characteristic information such as: age at diagnosis, time 
from diagnosis to first dose date (months), time from first symptoms to first dose date (months), 


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time from diagnosis to first symptoms (months), number of siblings with PH1, reported history 
of disease events (e.g. pyelonephritis, renal stones, kidney stones, urinary tract infection), and 
genotype will also be presented.  
6.3. 
Medical History 
A complete medical and surgical history will be collected during screening. The medical and 
surgical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA; 
Version 21.1 or higher). 
Medical and surgical history will be summarized for the Safety Analysis Sets by system organ 
class, high level term and preferred term. 
6.4. 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the World Health Organization (WHO) 
Drug Dictionary (September 2018 or later). Prior medications are defined as medications that 
were taken prior to and stopped before the first dose of treatment (lumasiran or placebo). 
Concomitant medications are defined as medications which were taken prior to and were 
ongoing while on study drug or medication(s) taken on or after the first dose date of the study 
drug. 
Tabular summary of the number and percentage of subjects taking concomitant medications will 
be summarized by anatomic therapeutic class (ATC) and preferred term. Data will be presented 
for the Safety Analysis Sets. A separate tabular summary of Prior Vitamin B6 and Concomitant 
Vitamin B6 use will be summarized by ATC and preferred term. 
One subject/patient listing for prior medication/concomitant medications and a separate listing 
for prior and concomitant vitamin B6 medications will be generated. 
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 dosing per subject, cumulative number of 
doses received, duration of drug exposure (months), cumulative drug exposure time (months), 
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.  The exposure 
during the DB period will be right censored; that is, the date of the last exposure will not be later 
than the first date of dosing in the Extension period.  
Dose interruptions and compliance are not taken into account. 


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7. 
STATISTICAL ANALYSIS 
7.1. 
Primary Endpoint 
The primary endpoint of this study is the percent change from baseline to Month 6 in 24-hour 
urinary oxalate corrected for body surface area (BSA). The primary comparison between the 
randomized arms is based on the percent changes at months 3, 4,5, and 6 from baseline.  The 
analysis will be conducted using the Full Analysis Set.  
24-hour urinary oxalate (mmol/24hrs/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. 
Only valid 24-hour urinary oxalate values will be included in the analysis (note: valid is defined 
as: creatinine ≥10.0 mg/kg, duration of collection 22 to 26 hours, no missing voids and the 
sample was not collected within 14 days after the most recent dialysis session, if applicable).  
The primary analysis will be performed using a restricted maximum likelihood (REML) based 
Mixed-Effect Model Repeated Measures (MMRM) approach. The outcome variable is percent 
change from baseline in 24-hour urinary oxalate corrected for BSA (mmol/24hr/1.73m2) at 
months 3, 4, 5, and 6. Analysis will include fixed effects of treatment arm (lumasiran vs. 
placebo) and scheduled visits (months 3, 4, 5 and 6), as well as continuous, fixed covariate of 
baseline 24-hour urinary oxalate corrected for BSA (mmol/24hr/1.73m2) level and patient as a 
random factor. The treatment estimates from this model will represent an average percent change 
from baseline of 24-hour urinary oxalate excretion across months 3 through 6 at which the 
treatment effect is expected to have reached steady state. Furthermore, given the variability of 
24-hour urinary oxalate, averaging the values across these visits will yield stable treatment 
estimates. An unstructured covariance structure matrix will be used to model the within-patient 
error. If the fit of the unstructured covariance structure matrix fails to converge, then the 
following covariance structures will be assessed: autoregressive (1), compound symmetry, and 
Toeplitz and the structure selected will be based upon the best fit chosen by Akaike Information 
Criteria (AIC). The Satterthwaite approximation will be used to estimate denominator degrees of 
freedom. At each visit, least square (LS) means with corresponding standard errors (SEM) and 
95% confidence intervals (CI) will be displayed by treatment arm. The primary comparison is 
the LS mean treatment difference (lumasiran – placebo) in percent change from baseline of 24-
hour urinary oxalate excretion from months 3 to 6.  This LS mean difference will be presented 
along with corresponding standard errors (SEMs), 95% CIs and p-value from the model. 
Descriptive statistics will also be generated by treatment arm at each scheduled visit. LS Mean 
(+/- SEM) figures of percent reduction by treatment arm will be plotted as well as individual 
spaghetti plots. A table of the mean maximum percent reduction during the 6-months for each 
treatment arm will also be generated. It should also be noted that the primary measure (i.e., 24-
hour urinary oxalate corrected for BSA), as well as other PD markers, is based on validated PD 
assay 
.  


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7.1.1. 
Sensitivity Analysis   
Sensitivity analysis will be conducted to evaluate the sensitivity to the estimated treatment effect 
by the assumption of lumasiran reaching steady state of the treatment effect at month 3 and 
maintained through month 6.  
• Sensitivity analysis 1 estimates the treatment effect of the primary endpoint without 
assuming   equal treatment effect from month 3 through month 6. The analysis adds 
the interaction of visit and treatment to the primary MMRM model, when month 3 
through month 6 data are used.  
• Sensitivity analysis 2, similar to sensitivity analysis 1, estimates the treatment effect 
of the primary endpoint without assuming equal treatment effect from month 3 
through month 6, but including all post-baseline data (including percent change 
from baseline at months 1 and 2)). 
Table 1: 
Analyses of the Primary Endpoint   
Analysis 
Analysis Set 
Statistical model 
Data1 
Primary analysis 
Full Analysis 
Set 
MMRM 
(subject, baseline, treatment, 
visit) 
M3, M4, M5, 
M6 
Sensitivity Analysis 
1 
Full Analysis 
Set 
MMRM 
(subject, baseline, treatment, visit, 
treatment*visit) 
M3, M4, M5, 
M6 
Sensitivity Analysis 
2 
Full Analysis 
Set 
MMRM 
(subject, baseline, treatment, visit, 
treatment*visit) 
M1, M2, M3, 
M4, M5, M6 
1Percent change from baseline in 24-hour urinary oxalate corrected for BSA at each month (M) to be used in the 
model. 
7.2. 
Secondary Endpoints 
For secondary endpoints assessed to Month 6, the analysis will compare randomized arms 
(lumasiran vs. placebo) using the Full Analysis Set.  During the Double-Blind Period, data will 
be collected during Screening, Day 1 and Months 1, 2, 3, 4, 5 and 6 with the exception of eGFR 
which is also collected at Week 2. To control for type I error, the primary and selected secondary 
endpoints will be tested in a hierarchical order as described in Section 5.6. 
Absolute change from baseline in 24-hour urinary oxalate corrected for BSA will be analyzed 
using an MMRM model as specified for the primary endpoint. The percent change in 24-hour 
urinary oxalate: creatinine ratio, the percent change and the absolute change in plasma oxalate 
from baseline to Month 6 will also be analyzed using a similar MMRM model to the primary 
endpoint with the exception being that the baseline variable will be the baseline value of the 
corresponding endpoint.  
For the two plasma oxalate related endpoints, a separate enriched analysis set of patients (i.e., 
Plasma Oxalate Analysis set) will be used. The plasma oxalate analysis set is defined as those 
patients who received any amount of study drug and have a baseline plasma oxalate level ≥ 
1.5*LLOQ.  The LLOQ of the plasma oxalate assay is 5.55 µmol/L.
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possible to quantify plasma oxalate levels below LLOQ using the assay, patients with baseline 
plasma oxalate levels near the LLOQ (i.e. <1.5*LLOQ) are excluded from the analysis to ensure 
that meaningful reductions in plasma oxalate can be evaluated for the study population.   
For binary endpoints, i.e., the proportion of patients with 24-hour urinary oxalate ≤1.5 ULN and 
≤ ULN at Month 6 the number and associated percent of patients who met each threshold at 
Month 6 will be presented by treatment arm. Refer to Appendix A for the value of ULN. Binary 
endpoints will be analyzed using a Cochran-Mantel-Haenszel (CMH) test stratified by baseline 
urinary oxalate (≤1.70 mmol/24hr/1.73m2 vs. >1.70 mmol/24hr/1.73m2). The odds ratio with the 
corresponding 95% confidence interval and associated p-value will be presented. In addition, the 
differences in proportion of responders and corresponding 95% confidence interval using the 
Newcombe method based on the Wilson score will also be presented. 
For continuous endpoints (including eGFR), descriptive statistics will be generated by treatment 
arm. LS Mean (+/- standard error) by treatment arm will be plotted for continuous PD endpoints. 
Spaghetti plots will also be generated for all continuous endpoints. 
Table 2: 
Analysis of Secondary Endpoints to Month 6^ 
Endpoints 
Statistical 
Method 
Analysis Population 
Absolute change in 24-hour urinary oxalate to Month 
6 
MMRM 
Full Analysis Set 
Percent change in 24-hour urinary oxalate:creatinine 
ratio to Month 6 
MMRM 
Full Analysis Set 
Percent change in plasma oxalate from baseline to 
Month 6 
MMRM 
Plasma Oxalate Analysis Set 
Proportion of Patients with 24-hour urinary oxalate 
≤1.5xULN at Month 6 
CMH 
Full Analysis Set 
Proportion of Patients with 24-hour urinary oxalate 
≤ULN at Month 6 
CMH 
Full Analysis Set 
Absolute change in plasma oxalate from baseline to 
Month 6 
MMRM 
Plasma Oxalate Analysis Set 
^eGFR will be summarized descriptively (i.e. no formal testing) because this endpoint is not expected to change 
during the 6 months.  
The following secondary endpoints which are assessed beyond Month 6 will be summarized to 
demonstrate long-term durability of lumasiran using the All Lumasiran Treated Set. 
Descriptive statistics of percent change in 24-hour urinary oxalate at and after 6 months of 
lumasiran will be presented by treatment sequence (lumasiran/lumasiran, placebo/lumasiran) and 
the all treated arm (pooling treatment arms). A Wilcoxon-signed rank test (2-sided) will be 
conducted to test the null hypothesis of no change from baseline at selected timepoints (Months 
6, 12, 18, 30, 36, 42 and 54).  Additionally, the mean percent change from baseline with 
associated 95% (CIs) confidence intervals at each selected timepoint will also be presented. 
Supportive figures of mean (+/-standard error) percent change will be generated. 


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Descriptive statistics of percent change in 24-hour urinary oxalate will also be generated at visits 
during the entire study using the FAS set. Supportive figure of mean (+/- standard error) percent 
change will also be generated. An analysis of the percentage of time that 24-hour urinary oxalate 
level is at or below the near-normalization threshold will be summarized. A patient is considered 
to have met the threshold if the 24-hour urinary oxalate level is ≤1.5xULN at a post-baseline 
visit.  
For each patient, the percentage of time that 24-hour urinary oxalate level is at or below the near 
normalization threshold (ie, ≤1.5xULN) will be calculated as follows:  
𝑐𝑢𝑚𝑢𝑙𝑎𝑡𝑖𝑣𝑒 𝑚𝑜𝑛𝑡ℎ𝑠 𝑎𝑡 𝑜𝑟 𝑏𝑒𝑙𝑜𝑤 𝑛𝑒𝑎𝑟 𝑛𝑜𝑟𝑚𝑎𝑙𝑖𝑧𝑎𝑡𝑖𝑜𝑛 𝑡ℎ𝑟𝑒𝑠ℎ𝑜𝑙𝑑
𝑐𝑢𝑚𝑢𝑙𝑎𝑡𝑖𝑣𝑒 𝑚𝑜𝑛𝑡ℎ𝑠 𝑜𝑓 𝑣𝑎𝑙𝑖𝑑 𝑎𝑠𝑠𝑒𝑠𝑠𝑚𝑒𝑛𝑡𝑠
 × 100 
where cumulative months at or below the near normalization will be defined as the summation 
across all intervals that met the threshold and cumulative months of valid assessments will be 
defined as the summation across all valid post-baseline collections.  
Given that the sample collection varies during the study (e.g. monthly up until M9, every 3 
months until M24, every 6 months until Month 60), the calculation will take into account the 
following considerations:  
• Time will be restricted to a maximum of 36 months on lumasiran (that is, up to 
protocol defined month 36 visit for lumasiran/lumasiran arm or up to protocol 
defined month 42 visit for placebo/lumasiran arm) or premature treatment 
discontinuation, whichever occurs first.  
• A linear interpolation method will be used for 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 the threshold (among the subset of 
patients who had at least one post-baseline value which met threshold) will be presented for each 
treatment sequence arm and the all treated arm.  In addition, the number of patients and 
associated percentage of patients in each category (e.g. <25%, ≥25% to <50%, ≥50% to <75%, 
≥75% to 100%) will also be presented.   
Descriptive statistics of eGFR at and after 6 months of lumasiran will be presented. Shift tables 
of eGFR categories from baseline to post-baseline visits and an overall worst post-baseline will 
also be generated. 
7.3. 
Subgroup Analysis 
Subgroup analyses will be conducted to assess the consistency of the treatment effect during the 
double-blind period for the primary endpoint within the following subgroups:  
• Age (6-11, 12 to 17 vs. ≥18 years at screening) 
• Gender (Male vs. Female) 
• Race (White vs. Non-White) 
• Baseline 24-hour urinary oxalate corrected for BSA (≤1.70 mmol/24h/1.73m2 vs. 
(>1.70 mmol/24h/1.73m2)   


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• Baseline eGFR (≤60 vs. >60)  
• History of renal stones (Yes vs. No)  
• Baseline vitamin B6 use (Yes vs. No) 
• Region 1 (North America [including US and Canada] vs. Other (outside of North 
America)).  
• Region 2 (Europe vs. Other (outside of Europe))   
Other subgroups may be examined, if deemed appropriate.  
Subgroup analyses will be performed for the primary endpoint of percent change in 24-hour 
urinary oxalate corrected for BSA to Month 6 using the FAS population. A forest plot will be 
generated to illustrate the estimated treatment effect along with the associated 95% confidence 
interval. If the number of patients in a subgroup for either arm is less than 5 patients, then only 
descriptive statistics will be generated.  
The subgroup analyses may be performed for secondary endpoints.  
7.4. 
Exploratory Analysis 
Exploratory endpoints will compare lumasiran versus placebo during the DB period using the 
Full Analysis Set. These endpoints will also be summarized during the long-term efficacy of 
lumasiran by treatment sequence arms (lumasiran/lumasiran, placebo/lumasiran) and all treated 
arm (pooling treatment sequence arms) using the All Lumasiran Treated Set.  
For changes in PD parameters (urinary oxalate: creatinine ratios as assessed in random spots, 
plasma glycolate, 24-hour urinary glycolate: creatinine ratio, and urinary glycolate: creatinine 
ratios as assessed in random spots), descriptive statistics will be presented by visit. 
To understand the treatment effect of lumasiran on kidney function, changes over time in renal 
stone events (as per section 6.3.3. in the protocol) and nephrocalcinosis will be explored.  
To evaluate changes in renal stones, protocol defined events will be collected continuously 
during the study (i.e. renal stone event defined as at least one of the following: visit to heath care 
provider because of a renal stone, medication for renal colic, stone passage and macroscopic 
hematuria due to a renal stone).  The total number of patients with a renal stone event, total 
number of renal stone events, total person-days at risk and rate of renal stone events during the 
respective period (i.e. DB period or during lumasiran treatment) will be presented. The rate will 
be calculated as total number of renal stone events divided by total person-days at risk during the 
respective period.  
To evaluate changes in nephrocalcinosis, a renal ultrasound will be performed at baseline and at 
Months 6, 12, 24, 36 48 and 60. The renal ultrasound will also measure the number of kidney 
stones, the size of the kidney stones, report the location of kidney stones and grade the 
nephrocalcinosis (range: 0 to 3) where a higher grade indicates greater severity. Changes in the 
grade of nephrocalcinosis for each kidney (right or left) will be categorized into 3 groups (‘no 
change’, ‘improving’, and ‘worsening’).  At each post-baseline visit, the number and associated 
percentage of patients in the following 4 categories of the overall change (i.e., accounting for 


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both kidneys),‘no change’, ‘improving’, ‘worsening’, and ‘indeterminate (one kidney improving 
and one worsening’,. will be presented. Descriptive statistics will also be generated. 
To explore changes in Quality of Life (QoL), patient resource use and patient experience (or 
caregiver experience) questionnaires will be collected at baseline and every 6 months during the 
course of the study. 
Changes in patient resource use and/or patient experience (or caregiver experience) will be 
summarized descriptively. 
The QoL instrument will be based upon the age of the patient at screening and the instrument 
will be used consistently throughout the study.  Table 3 outlines the QOL instruments to be 
collected based upon age at screening.  
Table 3: 
QOL instruments by Age at Screening (<18 years old vs. ≥ 18 years old) 
Age at 
Screening 
QOL 
Instruments 
Domains/Subscales 
Notes 
≥18 years 
old 
EQ-5D-5L 
5 domains (5 ordinal levels per domain): mobility, self-
care, usual activities, pain/discomfort and 
anxiety/depression 
1 scale: Visual Analogue Scale Score 
1 summary score: Index Score (representing health 
state utility for an average individual with the same 
combination of per-domain responses as the trial 
participant in question) 
VAS is a 
common 
variable in 
both 
instruments 
 
 
 <18 years 
old  
EQ-5D-Y 
5 domains (3 ordinal levels): mobility, looking after 
myself, doing usual activities, pain/discomfort and 
feeling worried/sad/unhappy 
1 scale: Visual Analogue Scale Score 
≥18 years 
old 
KDQOL-36 
 
5 subscales: SF-12 Physical Component Summary 
Score, SF-12 Mental Component Summary Score, 
Symptoms/Problems, Effects of Kidney Disease and 
Burden of Kidney Disease 
 
 
No common 
variables 
<18 years 
old 
PedsQL 
4 domains: Physical Functioning, Emotional 
Functioning, Social Functioning and School 
Functioning 
3 summary scores (total score, physical health summary 
score and psychosocial health summary score) 
<18 years 
old 
PedsQL ESRD 
7 domains: General Fatigue, About My Kidney 
Disease, Treatment Problems, Family and Peer 
Interaction, Worry, Perceived Physical Appearance, 
and Communication 
1 summary score: Total Score 
As shown in Table 3, the EQ-5D will be collected to measure general health status in both 
pediatrics and adult patients with PH1.  The VAS and Index Score will range from 0 to 100 
where lower values represent a worse quality of life.  


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During the double-blind period, the change from baseline to month 6 in VAS (pooling: EQ-5D-
5L and EQ-5D-Y) will be summarized by randomized treatment arm (lumasiran or placebo),  
For the EQ-5D instrument, categorical summaries of the percentage of patients reporting ordinal 
responses for each of the 5 domains will be presented. Descriptive statistics of actual and change 
in VAS and Index score (applies to only EQ-5D-5L) will also be generated.   
In addition, KDQOL-36 will be collected for adult patients to assess kidney disease specific 
measures and PedsQL will be collected for pediatric patients to further assess quality of life. In 
both instruments, values range from 0 to 100 and lower scores indicate a worse self-reported 
QoL. Descriptive statistics will be generated for each instrument. 
7.5. 
Pharmacodynamic Analysis 
Analyses of secondary endpoints relating to 24-hour urinary oxalate corrected for BSA and 24-
hour urinary oxalate: creatinine levels are described in Section 7.2 and Section 7.3.  Analyses of 
exploratory PD endpoints (urinary oxalate: creatinine ratios as assessed in random spots, plasma 
glycolate, 24-hour urinary glycolate: creatinine ratio, and urinary glycolate: creatinine ratios as 
assessed in random spots) are described in Section 7.4.  
7.6. 
Pharmacokinetic Analysis 
Pharmacokinetic analyses will be conducted using noncompartmental methods. PK parameters 
will be calculated using a validated version of Phoenix® WinNonlin. 
Population PK analysis is planned for all patients in the study and will be described in a separate 
population PK analysis plan. 
7.7. 
Safety Analyses 
Primary safety analyses will compare lumasiran versus placebo during the DB period using the 
Safety Analysis Set. Long-term safety analyses of lumasiran will be summarized by treatment 
sequence (lumasiran/lumasiran, placebo/lumasiran, all treated arm) using the All Lumasiran 
Treated Set.  
The safety analyses will be based upon treatment received (i.e. if a patient receives at least one 
dose of lumasiran, then he/she will be included in the lumasiran arm).  
The primary safety parameter is treatment emergent Adverse Event (AEs) which will be defined 
as an AE that occurs or worsens on or after the first dose date/time of study drug though 84 days 
after the last dose of study drug. In addition, any AE that worsened in intensity or was 
subsequently considered related to study drug will be considered treatment emergent.  Other 
safety parameters will include vital signs, ECGs, clinical laboratory assessments and physical 
exams.  
7.7.1. 
Adverse Events 
AEs will be classified using the Medical Dictionary for Regulatory Activities (MedDRA Version 
21.1 or later) and displayed in tables using System Organ Class (SOC) and Preferred Terms 
(PT). All treatment emergent AEs hereafter will be referred to as AEs in this document.  


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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 System Organ Class (SOC) and Preferred Term (PT) displaying the number of 
patients (percentage) and total events will be produced for the following tables:  
• All AEs 
• Severe AEs 
• AEs by Maximum Severity 
• AE related to treatment 
• AEs related to treatment by Maximum Severity 
• All SAEs 
• SAEs related to treatment 
• AEs leading to treatment discontinuation 
• AEs leading to treatment interruption 
• AEs leading to withdrawal  
Tabulations by PT in decreasing order in frequency within the lumasiran arm will be generated 
for the following tables:  
• All AEs 
• All SAEs 
• AEs related to treatment 
• SAEs related to treatment 
There will also be an All AE table generated displaying rates of adverse events adjusted for 
exposure-time during the respective period. 


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AE and SAE tables will be generated for each of the following subgroups: Age, Gender, Race, 
and eGFR categories.   
Patients who report multiple occurrences of the same AE (preferred term) will be classified 
according to the most severe occurrence or most related.  
Separate listings will be provided for deaths, SAEs, and AEs leading to discontinuation of study 
drug, withdrawal of study drug and/or dose interruption. By-subject AE listings will be provided.  
Additional summaries of other Standardised MedDRA Queries (SMQs) or adverse event 
grouping may be summarized such as but not limited to the following:    
Injection Site Reactions [ISRs]: AEs mapping to the High-Level Term (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 doses (any dose split into multiple injections will be considered 1 dose in 
summary), total number of doses with ISRs, and the signs and symptoms reported due to 
ISRs. If there are multiple ISRs that occur in between two consecutive injections, then 
these events will be considered as 1 ISR and considered related to the earlier injection. 
Hepatic AEs, including AEs of LFT abnormalities: These AEs are mapped to the 
Standardized MedDRA Query (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. 
7.7.2. 
Clinical Laboratory Data 
Clinical laboratory parameters will be expressed in Standard International (SI) units. Laboratory 
data collected and recorded below lower limit of quantification (LLQ) will be set to the lower 
limit of detection for calculation of summary statistics. Summaries will only include data from 
central laboratory. eGFR will not be reported in this section, as this is summarized in the efficacy 
section. For any local collections of LFTs, these will be included in a separate data listing.  Key 
laboratory parameters will be graded according to NCI CTCAE v5.0. 
Summaries for each lab parameter (hematology, chemistry, liver function tests, coagulation and 
urinalysis), which are continuous variables, will 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 ULN or below ULN).    
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 H when the value is higher than 
the upper limit of the reference ranges and with L when the value is lower than the lower limit of 
the reference ranges.  


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For hematology and chemistry labs, summary tables of potentially clinically significant 
abnormalities will also be provided.  
All laboratory data will be presented in data listings. Separate listings will be included for those 
laboratory data collected from local labs such as LFTs. 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>3xULN, AST>3xULN and total bilirubin >2x ULN at any 
visit.  
A tabular summary for LFTs will be generated to summarize the number and associated 
percentage of patient in each of the categories at any post-baseline visit:  
• ALT>1 & ≤3, ALT>3 & ≤5, ALT>5 & ≤10, ALT>10 & ≤20, ALT>20xULN 
• AST>1 & ≤3, AST>3&≤5, AST>5& ≤10, AST>10 & ≤20, AST>20xULN 
• ALT or AST>1 & ≤3, ALT or AST>3 & ≤5, ALT or AST>5 & ≤10, ALT or 
AST>10 & ≤20, AST or ALT>20xULN 
• WNL, ALP>1.5xULN 
• Total Bilirubin>1.5& ≤2, Total Bilirubin>2&≤3, Total Bilirubin>3& ≤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. 
For selected labs (e.g. ALT/ULN and AST/ULN), a table and figure of the values across the 
entire study will be generated by treatment sequence arms.  
7.7.3. 
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 old at screening, the modified z-score will be calculated for height, 
weight and body mass index (BMI) according to the CDC growth chart. A summary table of 
descriptive statistics of z-scores by visits and treatment arm will be summarized. A tabular 
summary of the proportion of patients with z-scores at various cut-points (e.g. ≥+/- 2 SD) will 
also be summarized as well.   
A separate listing of vital sign data will be generated. Per patient plots of z-scores over time for 
those patients <18 years old at screening will also be generated.  
7.7.4. 
Physical Examinations 
During the study, full physical examinations and abbreviated physical examinations will be 
conducted throughout the study. If any abnormalities are observed during these physical exams, 
then this will be recorded on the adverse event form.  


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A separate listing per patient will be generated to display the date and time of the physical exam.  
7.7.5. 
Electrocardiogram   
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
. 
The number and percentage of patients with normal, abnormal, and clinically significant 
abnormal results at baseline and each timepoint 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 -60 ms and > 60 ms) over all post-treatment evaluations will be summarized. 
A listing of all ECG data will be provided. 
7.8. 
Anti-Drug Antibody  
The number and associated percentage of patients who are ADA positive at baseline and at any 
post-baseline visit will be summarized by treatment group. A listing of patients with positive 
ADA assay results will be provided as well as a listing of all ADA results.  


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8. 
CHANGES TO PLANNED ANALYSES 
Below is a summary of changes in the Statistical Analysis Plan (SAP) version 2.0 which differ 
from SAP version 1.0 with corresponding rationale of why the change had been made.  
Summary of Changes 
Rationale 
List and order of secondary endpoints are 
modified (Section 3.2 and Section 5.6).  
The change to the list of secondary endpoints is 
made to align with protocol amendment 2. 
Additionally, additional results from ALN-GO1-
001 was evaluated to change the order of secondary 
endpoints to mitigate the risk 
Changes to sensitivity analysis to primary 
endpoint (Section 7.1):   
• 
Replace the initially planned sensitivity 
analysis with 2 sensitivity analyses to 
evaluate the assumption of steady state 
from month 3 to month 6 
• 
Remove per-protocol analysis 
The initially planned sensitivity analysis evaluates 
an endpoint of percent change from baseline at 
Month 6, which differs from the primary endpoint. 
Furthermore, this analysis is covered by the newly 
added sensitivity analysis.  
New sensitivity analyses are added to evaluate the 
sensitivity to the estimated treatment effect of the 
primary analysis by the assumption of lumasiran 
reaching steady state of the treatment effect at 
Month 3 and maintained through Month 6. 
Per-protocol analysis, though it helps address a 
question related non-compliance, does not provide 
additional evidence to efficacy.  
Secondary endpoint (Section 3.2)  
Percent change in 24-hour urinary oxalate: 
creatinine ratio (value/ULN) from baseline to 
Month 6 
The endpoint is modified because the 24h urinary 
oxalate: creatinine ratio upper limit of normal for 
ages 6 years and older is being extrapolated from 
the healthy adult population assessed with the 
validated PD assay 
. This extrapolation is 
supported by published data that suggest oxalate: 
creatinine in children 6 and above is similar to 
adults.  
ULN value for 24-hour urinary oxalate corrected 
by BSA is defined in Appendix   
 The ULN for the 
assay has been determined 
based on 100 samples from healthy normal 
volunteers. Refer to Biomarker white paper for 
details. The initial ULN value quoted is ULN for 
Clinical Diagnostic Assay from 
 
hence is not applicable and removed.   
Plasma Oxalate Analysis Set is added for the 
analysis of plasma oxalate endpoints 
The LLOQ of the plasma oxalate assay is 5.55 
µmol/L. Due to the inability of quantify oxalate 
level below LLOQ by the assay, patients with 
baseline plasma oxalate level measured near at 
LLOQ are excluded from the analysis to ensure the 
meaningful reduction can be evaluated for the study 
population.  
Add SAE and AE subgroup analyses for the 
double blinded period 
These safety analysis by Age, Race, Gender, 
Region, eGFR are aligned with ISS 


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Summary of Changes 
Rationale 
Other edits throughout  
To improve clarity 


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9. 
REFERENCES 
Cochat P,Rumsby G. Primary hyperoxaluria. N Engl J Med. 2013 Aug 15;369(7):649-58. 
 
 
 
 


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APPENDIX A. 
UPPER LIMIT OF NORMAL FOR 24-HOUR URINARY 
OXALATE CORRECTED FOR BSA 
To establish accurate and reproducible reference ranges of oxalate and glycolate levels in urine 
and plasma of healthy subjects, human urine and plasma samples from healthy male and female 
subjects were procured from BioIVT (formerly Bioreclamation IVT, Westbury, NY, USA), a 
commercial provider of biological samples. Of these samples, 24-hour urine samples were 
available from 100 healthy adults. Samples were processed and analyzed for oxalate using 
Quantitative PD Assay validated at 
. 
The ULN, based on these samples, for 24-hour urinary oxalate corrected for BSA is estimated to 
be 0.514 mmol/24hr/1.73m2. Details for sample collection and analysis and statistical method for 
ULN determination will be available from the white paper for Urinary and Plasma Levels in 
Healthy Subjects.