Conditions: Primary Hyperoxaluria Primary Hyperoxaluria Type 1 (PH1)
Keywords: PH1 Primary Hyperoxaluria Hyperoxaluria RNAi Therapeutic siRNA AGT
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 18
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy, safety, pharmacokinetics (PK), and pharmacodynamics (PD) of lumasiran in infants and young children with confirmed primary hyperoxaluria type 1 (PH1).

Detailed description:

Arms:
arm 1: Lumasiran will be administered by subcutaneous (SC) injection.

Interventions: intervention 1: Lumasiran
Intervention descriptions: intervention 1: Lumasiran will be administered by subcutaneous (SC) injection.

Protocol document:
SAP_002.pdf: 
Statistical Analysis Plan, Protocol ALN-GO1-004 
ALN-GO1 (lumasiran) 
3 August 2020, Version 3.0 SAP Amendment 2 
Alnylam Pharmaceuticals 
Confidential 
1 
STATISTICAL ANALYSIS PLAN 
 
ILLUMINATE-B: AN OPEN-LABEL STUDY TO EVALUATE THE 
EFFICACY, SAFETY, PHARMACOKINETICS, AND 
PHARMACODYNAMICS OF LUMASIRAN IN INFANTS AND YOUNG 
CHILDREN WITH PRIMARY HYPEROXALURIA TYPE 1 
 
Protocol Number: 
Protocol Version and Date: 
ALN-GO1-004 
Amendment 2: 04 May 2020 
Amendment 1: 09 August 2019 
Original: 08 November 2018 
Investigational Drug: 
ALN-GO1 (Lumasiran) 
Phase: 
Phase 3 
Sponsor: 
Alnylam Pharmaceuticals, Inc. 
300 Third Street 
Cambridge, MA  02142 USA 
Tel: 
 
Fax: 
 
Sponsor Representative: 
 
 
Analysis Plan Version and 
Date: 
Amendment 2: Version 3.0: 3 Aug 2020 
Amendment 1: Version 2.0: 12 Nov 2019 
Original: Version 1.0: 20 May 2019 
 
Confidentiality Statement 
The concepts and information contained in this document or generated during the study are 
considered proprietary and may not be disclosed in whole or in part without expressed written 
authorization of Alnylam Pharmaceuticals, Inc. 
 


Statistical Analysis Plan, Protocol ALN-GO1-004 
ALN-GO1 (lumasiran) 
3 August 2020, Version 3.0 SAP Amendment 2 
Alnylam Pharmaceuticals 
Confidential 
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APPROVAL SIGNATURE PAGE 
 
ILLUMINATE-B: An Open-Label Study to Evaluate the Efficacy, Safety, 
Pharmacokinetics, and Pharmacodynamics of Lumasiran in Infants and Young 
Children with Primary Hyperoxaluria Type 1 
 
Protocol Number: 
ALN-GO1-004  
Analysis Plan Version and 
Date: 
Version 3.0/3 Aug 2020 
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-GO1-004 
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3 August 2020, Version 3.0 SAP Amendment 2 
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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 ...................................................................................................9 
2.1. 
Synopsis of Study Design .............................................................................................9 
2.2. 
Randomization Methodology .......................................................................................9 
2.3. 
Blinding ........................................................................................................................9 
2.4. 
Data Monitoring Committee .......................................................................................10 
2.5. 
Study Procedures ........................................................................................................10 
3. 
ENDPOINTS ..............................................................................................................11 
3.1. 
Primary Endpoint ........................................................................................................11 
3.2. 
Secondary Endpoints ..................................................................................................11 
3.3. 
Exploratory Endpoints ................................................................................................11 
3.4. 
Safety Endpoint ..........................................................................................................11 
4. 
PATIENT POPULATION ..........................................................................................12 
4.1. 
Patient Definitions ......................................................................................................12 
4.2. 
Protocol Deviations ....................................................................................................12 
5. 
GENERAL STATISTICAL METHODS ...................................................................13 
5.1. 
Sample Size Justification ............................................................................................13 
5.2. 
General Methods .........................................................................................................13 
5.3. 
Computing Environment ............................................................................................14 
5.4. 
Baseline Definitions ....................................................................................................14 
5.5. 
Missing Data ...............................................................................................................14 
5.6. 
Visit Windows ............................................................................................................15 
5.7. 
Interim Analysis ..........................................................................................................15 
5.8. 
Analysis for Primary Endpoint ...................................................................................15 
6. 
STUDY ANALYSES .................................................................................................16 
6.1. 
Patient Disposition ......................................................................................................16 


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6.2. 
Demographics and Baseline characteristics ................................................................16 
6.3. 
Medical History ..........................................................................................................16 
6.4. 
Prior and Concomitant Medications ...........................................................................17 
7. 
STATISTICAL ANALYSIS ......................................................................................18 
7.1. 
Primary Endpoint ........................................................................................................18 
7.1.1. 
Sensitivity Analysis ....................................................................................................19 
7.1.2. 
Analyses of 24-Hour Urinary Oxalate Excretion .......................................................19 
7.2. 
Subgroup Analysis ......................................................................................................19 
7.3. 
Secondary Endpoints ..................................................................................................20 
7.4. 
Exploratory Efficacy Analysis ....................................................................................21 
7.5. 
Pharmacodynamic Analysis........................................................................................22 
7.6. 
Pharmacokinetic Analysis ..........................................................................................22 
7.7. 
Safety Analyses ..........................................................................................................22 
7.7.1. 
Adverse Events ...........................................................................................................23 
7.7.2. 
Dosing and Extent of Exposure ..................................................................................24 
7.7.3. 
Clinical Laboratory Data ............................................................................................24 
7.7.4. 
Vital Signs ..................................................................................................................25 
7.7.5. 
Physical Examinations ................................................................................................26 
7.7.6. 
Electrocardiogram .......................................................................................................26 
7.8. 
Anti-Drug Antibody ....................................................................................................26 
7.9. 
COVID-19 Pandemic Impact Analyses ......................................................................26 
7.9.1 
General impact ............................................................................................................26 
7.9.2 
Impact on Efficacy ......................................................................................................27 
7.9.3 
Impact on Adverse Events ..........................................................................................27 
7.9.4 
Other Impacts ..............................................................................................................27 
8. 
CHANGES TO PLANNED ANALYSES..................................................................28 
9. 
REFERENCES ...........................................................................................................29 
10. 
APPENDICES ............................................................................................................30 
10.1. 
Urinary Oxalate calculation ........................................................................................30 
10.1.1. 
Spot Urinary Oxalate:Creatinine Ratio .......................................................................30 
10.1.2. 
24-Hour Urinary Oxalate Corrected for BSA .............................................................30 
10.2. 
Spot Urinary UOx:Cr Ratio Given Natural Growth ...................................................30 
10.2.1. 
Natural decline of spot urinary UOx:Cr ratio in healthy pediatric population ...........30 


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10.2.2. 
Effect of Age on Spot urinary UOx:Cr ratio in pediatric PH1 patients ......................31 
10.3. 
Urinary Excretion Correlation Between Spot and 24-Hour Values ...........................31 
10.4. 
Normal Range Analysis ..............................................................................................35 
10.5. 
Medical History Adjustment .......................................................................................35 
10.6. 
Category of Vineland Adaptive Behavior Scale .........................................................35 
10.7. 
COVID-19 Pandemic Phase Start Dates by Country .................................................36 
 
LIST OF TABLES 
Table 1: 
Loading Maintenance Doses of Lumasiran for Different Body Weight 
Categories .....................................................................................................................9 
Table 2: 
Percent Reduction from Baseline over Time of Spot Urinary Oxalate: 
Creatinine Ratios Vs 24-Hour Urinary Oxalate Excretion in Study 001B .................32 
Table 3: 
Observed Percent Coefficient of Variation from Spot Urinary Oxalate: 
Creatinine Ratios vs 24-Hour Urinary Oxalate Excretion ..........................................34 
Table 4: 
Adaptive Level of Vineland Composite Scores ..........................................................35 
Table 5: 
COVID-19 Pandemic Phase Start Dates by Country .................................................36 
 
LIST OF FIGURES 
Figure 1: 
Spot urinary UOx:Cr ratio (mmol/mmol) in children with PH1 based on 
[Lieske 2005] Data .....................................................................................................31 
Figure 2: 
Scatterplot of Spot Urinary Oxalate:Creatinine Ratios vs 24-hour Urinary 
Oxalate Excretion in Study 001B ...............................................................................32 
Figure 3: 
Scatterplot of Percent Change from Baseline in Spot Urinary Oxalate: 
Creatinine Ratios vs 24-hour Urinary Oxalate Excretion in Study 001B ...................33 
Figure 4: 
Percent Coefficient of Variation Comparison of Spot Urinary Oxalate: 
Creatinine and 24-Hour Urinary Oxalate Excretion ...................................................34 
 


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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 
CDC 
Center for disease control and prevention  
CI 
Confidence interval 
Cmax 
Maximum plasma concentration 
CFR 
Code of Federal Regulation 
CL/F 
Apparent clearance 
CSR 
Clinical study report 
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 
ESRD 
End-stage renal disease 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GO 
Glycolate oxidase 
ICF 
Informed consent form 
LFT 
Liver function test 
LLOQ 
Lower limit of quantitation 
LLN 
Lower limit of normal 


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Abbreviation 
Definition 
LOD 
Limit of detection 
MedDRA 
Medical dictionary for regulatory activities 
UOx:Cr 
Oxalate:creatinine 
PT 
Preferred term 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SOC 
System Organ Class 
SMQ 
Standardized MedDRA query 
ULN 
Upper limit of normal 
WHO 
World Health Organization 
WNL 
Within Normal Limit 


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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 and Rumsby 2013]  As renal function declines, 
elimination of oxalate is further reduced, such that oxalate levels in plasma rise and calcium 
oxalate subsequently accumulates in bone, vasculature, skin, retina, heart, and nervous system, 
resulting in severe end-organ damage. This devastating condition, systemic oxalosis, arises when 
the estimated glomerular filtration rate (eGFR) has declined to below 30 to 45 mL/min/1.73 m2.  
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]  
The ILLUMINATE-B Study (ALN-GO1-004) is an open-label phase 3 study designed to 
evaluate the efficacy and safety of subcutaneously administered lumasiran in infants and young 
children (<6 years of age) with PH1 and relatively preserved renal function. This statistical 
analysis plan (SAP) has been developed based on the Amendment 2 protocol of the 
ILLUMINATE-B study (dated 04 May 2020).  
The analysis methods described in the protocol may be updated in this SAP. Any change to the 
data analysis methods described in the protocol, as well as the justification for the change, will 
be described in the SAP (Section 8) and clinical study report (CSR). Additional exploratory 
analyses of the data may be conducted when deemed appropriate. 


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2. 
STUDY OVERVIEW 
2.1. 
Synopsis of Study Design 
The ILLUMINATE-B Study (ALN-GO1-004) is a multicenter, multinational, open-label, single 
arm phase 3 study designed to evaluate the efficacy and safety of lumasiran in infants and young 
children (<6 years of age) with PH1 and relatively preserved renal function. 
This study consists of 2 periods: a 6-month primary analysis period followed by a long-term 
extension period.  During the 6-month primary analysis period, patients will undergo efficacy 
and safety assessments every 2 weeks for the first month and monthly thereafter.  During the 
long-term extension period of up to 54 months, dosing will continue as listed in Table 1, with 
visits to the study site for evaluations occurring at least every 3 months and every 6 months for 
patients whose weight ≥ 10 kg after Month 24 visit.  
Lumasiran will be administered as a subcutaneous (SC) injection with weight-based dosing for 
three body weight categories as listed in Table 1. 
Table 1: 
Loading Maintenance Doses of Lumasiran for Different Body Weight 
Categories 
Weight 
Loading Dose 
(Day 1, Month 1, Month 2) 
Maintenance Dose 
(Month 3 and Beyond) 
0 to <10 kg 
6.0 mg/kg monthly for 3 months 
3.0 mg/kg monthly 
≥10 to <20 kg 
6.0 mg/kg monthly for 3 months 
6.0 mg/kg every 3 months 
≥20 kg 
3.0 mg/kg monthly for 3 months 
3.0 mg/kg every 3 months 
For all patients, the dose will be based on body weight measurement obtained within 7 days prior 
to dosing. 
Patients with weight increases that cross the threshold for the next weight-based dosing category 
(between 0 and less than 10kg (0-<10 kg) to greater or equal to 10kg and less than 20kg (≥10-
<20 kg) to greater or equal to 20kg (≥20 kg)) will follow the new dosing regimen for the 
remainder of the study or until the next dosing category threshold is reached (i.e., patients will 
not switch back to the lower-weight dosing schedule if their body weight subsequently 
decreases).   
Patients in maintenance dosing who transition from 0-<10 kg to ≥10-<20 kg will continue to 
receive monthly doses at 3.0 mg/kg until the next visit that coincides with the Schedule of 
Assessments for patients weighing ≥10-<20 kg.  Thereafter, patients will follow every-3-months 
dosing until the end of the study. 
2.2. 
Randomization Methodology 
Not applicable 
2.3. 
Blinding 
Not applicable 


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2.4. 
Data Monitoring Committee 
An independent Data Monitoring Committee (DMC) will oversee the safety and overall conduct 
of this study, providing input to the Sponsor.  The DMC will operate under the rules of a charter 
that will be reviewed and approved by the DMC.  Details are provided in the DMC Charter. 
2.5. 
Study Procedures 
The schedule of assessments is described in the study protocol (Table 1 and Table 2). 


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3. 
ENDPOINTS 
3.1. 
Primary Endpoint 
• Percent change in urinary oxalate excretion from baseline to Month 6 
− The primary endpoint is measured by the percent change from baseline in spot 
urinary oxalate:creatinine (UOx:Cr) ratios (mmol/mmol) from Month 3 to Month 
6, averaged over these time points. Other measures for urinary oxalate excretion 
include 24-hour urinary oxalate corrected by BSA and 24-hour urinary UOx:Cr 
ratio, when available. 
3.2. 
Secondary Endpoints 
Extension Phase 
• Percent change in urinary oxalate excretion from baseline  
• Percentage of time that spot urinary UOx:Cr ratio is at or below the near-
normalization threshold (≤1.5 × ULN for age) 
Duration of Study 
• Absolute change in urinary oxalate excretion from baseline 
• Change (percent and absolute) in plasma oxalate concentration from baseline 
• Proportion of patients with urinary oxalate excretion ≤ the upper limit of normal 
(ULN) for age and ≤ 1.5 x ULN for age 
• Plasma PK parameters of lumasiran  
• Change in estimated glomerular filtration rate (eGFR) from baseline 
3.3. 
Exploratory Endpoints 
• Change from baseline in nephrocalcinosis as assessed by renal ultrasound  
• Change in frequency of renal stone events 
• Change in urinary glycolate and plasma glycolate 
• Change in growth parameters (z-scores) from baseline over time 
• Changes in developmental milestones over time 
• Changes in patient and/or caregiver experience as evaluated by a patient/caregiver 
survey 
• Frequency and titer of ADA 
3.4. 
Safety Endpoint 
• Frequency of adverse events (AEs) 


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4. 
PATIENT POPULATION 
4.1. 
Patient Definitions 
The populations (analysis sets) are defined as follows:  
• Safety Analysis Set: All patients who received any amount of lumasiran during study. 
• Efficacy Analysis Set: All patients who received any amount of lumasiran and have at 
least one valid spot urinary UOx:Cr ratio value at baseline and at least one valid spot 
urinary UOx:Cr ratio value from assessment(s) at Month 3 through Month 6. 
• Primary Interim Efficacy Analysis Set: Among first 16 enrolled patients, all patients 
who received any amount of lumasiran and have at least one valid spot urinary 
UOx:Cr ratio value at baseline and at least one valid spot urinary UOx:Cr ratio value 
from assessment(s) at Month 3 through Month 6 
• PK Analysis Set: All patients who received one full dose of lumasiran and have at 
least one postdose blood sample for PK parameters and have evaluable PK data. 
The Safety Analysis Set will be used for safety analyses and sensitivity analysis of efficacy.  The 
Efficacy Analysis Set will be used to evaluate efficacy endpoints. The PK Analysis Sets will be 
used to conduct PK analyses of plasma lumasiran concentrations.  
The primary analysis period is defined as the time period from the date/time of the first 
lumasiran dose administration until either the date/time of lumasiran dose administration at 
Month 6 or the date of the Month 6 visit (Day 169) for patients who discontinued treatment 
prematurely. Primary analysis will be conducted using all data collected in the Primary Analysis 
Period.  All data up to the dosing at the Month 6 visit will be included in the Primary Analysis 
Period.  
The extension period starts after the date/time of lumasiran dose administration at Month 6 until 
the end of the study.  Analysis of Extension Phase will focus on long-term efficacy of lumasiran. 
Duration of Study is defined as the time period from on or after the first date/time of lumasiran 
dose until the end of the study.  Analyses of Duration of Study will summarize secondary 
endpoints using data collected during the entire study period.   These analyses focus on long-
term efficacy and safety effects of lumasiran during both the primary analysis period and the 
extension period. 
4.2. 
Protocol Deviations 
Protocol deviations will be classified into major or minor deviations by medical review. A major 
deviation is defined as a deviation that may significantly impact the completeness, accuracy 
and/or reliability of 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 an interim or full database lock. All protocol 
deviations will be presented in a listing. 
 Major protocol deviations will be summarized in the CSR. 


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5. 
GENERAL STATISTICAL METHODS 
5.1. 
Sample Size Justification 
The planned enrollment for this study is 20 patients, including at least 1 patient <12 months of 
age with weight <10 kg at consent. Patients who discontinue lumasiran or stop participation in 
the study prior to Month 6 may be replaced.   
The sample size was determined based on feasibility considerations, not power calculations.  
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 the database plus one additional decimal. The 
standard deviation and standard error will be presented to the level of precision collected in the 
database plus 2 additional decimals.  For any assessments with repeated collections at a given 
study visit (e.g. height) the mean will represent the value at that visit unless otherwise noted. For 
biomarker and/or lab data, if any value is recorded as <lower limit of quantitation (LLOQ) then 
the value used for calculations will be assigned a value of LLOQ. 
Categorical and ordinal data will be described using the patient count and percentages in each 
category. When count data are presented, the percentage will not be presented when the count is 
zero.  
Summary tables and figures for each study period will include all data collected during the 
corresponding period as defined in Section 4.1.  
The per-patient listings will include all data collected during each study period.  For per-patient 
listings of the duration of study, there will be a variable to indicate the period of the data 
collection (Primary Analysis Period or Extension Period).  
Day 1 will be defined as the day of the first dose of lumasiran. Study day is calculated relative to 
the first dose date of lumasiran for all patients:   
If the assessment date is after the date of first lumasiran dose, then the study day will be 
calculated as: 
Study Day = Date of assessment – date of first dose of lumasiran + 1, 
If the assessment date is before the date of the first dose of lumasiran, then the study day will be 
calculated as:  
Study Day = Date of assessment – date of first dose of lumasiran  
At a minimum, all listings will include the following variables:   
• Baseline: relative to first dose of lumasiran (Section 5.4).  
• Study Day: relative to first dose of lumasiran.  
• Visit labels:  visits based upon actual study visits (Section 5.6). 


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Summary statistics will be presented, as well as 2-sided 95% confidence interval (CI)s for 
primary/secondary endpoints or 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.  
5.4. 
Baseline Definitions 
For spot urinary UOx:Cr ratio, baseline is defined as the mean of all spot urinary UOx:Cr ratio 
values collected prior to the first dose date/time of lumasiran. Baseline for all 24-hour urine 
parameters (i.e. 24-hour urinary oxalate corrected for BSA, etc) is defined as the median of all 
measurements collected prior to the first dose date/time of lumasiran. For all other PD 
parameters (i.e., plasma oxalate, etc.), baseline will use the mean of all measurements collected 
prior to the first dose date/time of lumasiran. 
For other parameters, baseline is defined as the last non-missing value prior to the first dose 
date/time of lumasiran, unless otherwise specified. If multiple values are collected at a single 
visit (e.g. height, etc.), the mean of the values collected at the same visit will be used. 
5.5. 
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. 
For safety analyses, no date will be assigned to any AEs with fully missing dates and only 
partially missing dates will be imputed. 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 the first dose of lumasiran.  
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. 
For partial dates of renal stone events (start and stop dates): the first day/month will be imputed 
for start date, and the last day/month will be imputed for stop date. It is not expected that renal 
stone dates will be completely missing. 
Due to blood sample volume limitations related to patient age/size, missing data in blood sample 
tests are expected. For blood test parameters where fewer than 4 patients have available baseline 
values, no summary statistics will be provided, only by-patient listing will be provided. 


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5.6. 
Visit Windows 
For tabular and graphical summaries, 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.  
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 if prior to first dosing and for any categorical shift tables (e.g. shift 
from baseline to worst post-baseline value).  
5.7. 
Interim Analysis 
A primary interim analysis is planned when the first 16 enrolled patients complete Month 6 
assessment or discontinue treatment (if applicable).  The number of patients for the primary 
interim analysis is chosen due to the enrollment pattern and the need for evaluation of benefit 
risk in this population for regulatory submissions. It should be noted that this will also provide 
information on twice the number of patients originally planned to be enrolled in this study. No 
multiplicity adjustment is necessary, since no formal study hypothesis is being tested for this 
study.  
Further interim analyses may be conducted for lumasiran regulatory submission purposes and/or 
publication requests.  
5.8. 
Analysis for Primary Endpoint   
As this study will be ongoing at the time of the primary analysis, there will be an interim 
database lock when the last patient completes all Month 6 visit assessments. All data available as 
of the date of data cut for the interim database lock will be included in the interim CSR 
corresponding to the primary analysis period.  
After the study is completed (i.e. all patients complete the long-term extension period and/or 
required safety follow-up visit(s)), the database will be locked, and all data will be summarized 
in the final CSR.  


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6. 
STUDY ANALYSES 
6.1. 
Patient Disposition 
Number and percentage of patients will be tabulated for the following categories:  
• Enrolled (signed informed consent and met eligibility) 
• Safety Analysis Set 
• Efficacy Analysis Set 
• Primary Interim Efficacy Analysis Set 
• PK Analysis Set 
Summaries of the number and percentage of patients who discontinued treatment and/or 
withdrew from the study will be presented, along with the primary reasons for discontinuation of 
treatment and/or withdrawal from the study. 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 spot urinary UOx:Cr ratio result for the Month 6 visit.  
The number and percentage of patients enrolled by region will be summarized.  
Data listings of those patients who withdrew and/or discontinued treatment including the 
associated reasons will also be presented.  
The numbers of patients in each dose group will be summarized for the duration of study. 
Disposition will be summarized throughout the study. 
6.2. 
Demographics and Baseline characteristics 
Descriptive statistics of demographic characteristics including but not limited to : age (months, 2 
decimals), weight (kg), weight category (0-<10kg, 10-<20kg, ≥20kg), gender, race, ethnicity, 
region, height (cm), and body mass index (BMI) will be presented. The modified z-score for all 
patients will be calculated and summarized for height, weight and body mass index (BMI) 
according to the Centers for Disease Control and Prevention (CDC) growth chart.[CDC National 
Center for Health Statistics 2019] 
Additional baseline disease characteristics will be summarized using descriptive statistics. These 
include but are not limited to: spot urinary UOx:Cr ratio (mmol/mmol), plasma oxalate (umol/L), 
24-hour oxalate excretion corrected for BSA (mmol/24hours/1.73m2), 24-hour urinary UOx:Cr 
ratio (mmol/mmol), eGFR (ml/min/1.73m2),  spot urinary glycolate:creatinine ratio 
(mmol/mmol), plasma glycolate (umol/L), number of episodes with stone events in the past 12 
months, and total number of patients reporting pyridoxine (vitamin B6) use prior to study entry. 
The collecting schedules are specified in the Schedules of Assessment in protocol. 
6.3. 
Medical History 
A complete medical and surgical history will be collected at the screening visit. The medical and 
surgical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA 
Version 21.1 or later).  


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Medical and surgical history will be summarized for the Safety Analysis Sets by system organ 
class, high level term and preferred term.  
A tabular summary of historical PH1 disease characteristic information will be generated and 
include information on disease characteristics such as: time from diagnosis to first dose date 
(months), time from first symptoms to first dose date (months), time from first symptoms to 
diagnosis (months), number of siblings with PH1, reported history of disease events (e.g. 
pyelonephritis, renal stones, urinary tract infection). Reported medical history event rates may be 
adjusted based on age category, see Section 10.5. 
Separate by-patient listings will be generated.  
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 the first dose of the study medication. Concomitant medications are defined 
as medications which were taken prior to and were ongoing while on lumasiran or medication(s) 
taken on or after the first dose date of lumasiran.  
A tabular summary of the number and percentage of patients taking concomitant medications 
will be generated by anatomic therapeutic class (ATC) and preferred term. Data will be 
presented for the Safety Analysis Set.  
By-patient listings will be generated separately for prior medications, concomitant medications 
and pyridoxine (vitamin B6). 
Medications (Prior and Concomitant) will be summarized for the Safety Analysis Set.  


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7. 
STATISTICAL ANALYSIS 
7.1. 
Primary Endpoint 
The primary endpoint of this study is percent change in urinary oxalate excretion from baseline 
to the average of Month 3 to Month 6, which is measured by the primary outcome variable – 
percent change from baseline in spot urinary UOx:Cr ratio (mmol/mmol). The analysis will be 
conducted using the Efficacy Analysis Set.  
Spot urinary UOx:Cr ratio is calculated from single-void urine collections. For all patients, 
triplicate single-void samples will be collected within 7 days prior to dosing, as specified in the 
Schedules of Assessment in the protocol. The mean value of these triplicate samples will be used 
as the baseline and postdose values in the analysis to account for the variability of the measure.  
Despite historical data in healthy volunteers suggesting a natural decline in spot urinary UOx:Cr 
ratio in pediatrics, especially for children younger than 7 years old (Section 10.2.1 ), the effect of 
age on spot urinary UOx:Cr ratio in PH1 children is less clear (Section 10.2.2 ). Based on 
published data [Lieske 2005] at the time of writing of this SAP, it is considered that the 
potentially age-related decline in spot urinary UOx:Cr ratio level in children with PH1 is 
minimal, comparing with the anticipated treatment effect of lumasiran.    
The primary analysis of the primary outcome variable will be performed using a restricted 
maximum likelihood (REML) based Mixed-effect Model Repeated Measures (MMRM) 
approach. Analysis will include fixed effects of scheduled visits and baseline spot urinary 
UOx:Cr ratio value (mmol/mmol), including patient as a random factor. An autoregressive (1) 
covariance structure will be used to model the within-patient error given the small sample size 
for this study. The primary estimate is the LS mean of the primary variable averaged over Month 
3 to Month 6. This least square (LS) mean will be presented along with corresponding standard 
errors (SEMs), 95% confidence intervals (CI) and p-value from the model (i.e., testing against 
the null hypothesis of mean of primary outcome being equal to 0).  
If the fit of the autoregressive (1) covariance structure matrix fails to converge, the primary 
estimate will be calculated as the LS mean of the primary outcome variable average across 
scheduled visits of Month 3 to Month 6 (based on available measures), according to analysis of 
covariance (ANCOVA) model with covariate of baseline spot urinary UOx:Cr ratio value 
(mmol/mmol). This LS mean will be presented along with corresponding SEMs, 95% CI and p-
value from the model.     
Descriptive statistics will also be generated at each scheduled visit. Mean (+/- SEM) figures of 
percent reduction will be plotted as well as individual spaghetti plots and listings. A table of the 
mean maximum percent reduction during the 6-months will also be generated.  
Missing data on 24-hour urinary oxalate corrected for BSA are expected in the pediatric patients 
to be enrolled in this study. Existing correlation analysis based on PH1 patients older than 6 
years old of 24-hour urinary oxalate corrected for BSA and spot urinary UOx:Cr ratio is included 
in Section 10.3. 
Primary Interim Analysis 
A similar analysis will be performed for the primary interim efficacy analysis set, i.e., among the 
first 16 enrolled patients, those who received any amount of lumasiran and have at least one 


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valid spot urinary UOx:Cr ratio value at baseline and at least one valid spot urinary UOx:Cr ratio 
value from assessment(s) from Month 3 through Month 6. 
7.1.1. 
Sensitivity Analysis  
Sensitivity analyses include: 
• Percent change from baseline in spot urinary UOx:Cr ratio by visits in Efficacy 
Analysis Set 
• Percent change from baseline in spot urinary UOx:Cr ratio from Month 3 to Month 6 
in Safety Analysis Set 
• Percent change from baseline in ULNRatio (ratio of measured spot urinary UOx:Cr to 
ULN) from Month 3 to Month 6 in Efficacy Analysis Set 
Percent change from baseline in spot urinary UOx:Cr ratio by visits in Efficacy Analysis Set will 
be analyzed using MMRM, LS means with corresponding SEM and 95% CIs will be displayed. 
Percent change from baseline in spot urinary UOx:Cr ratio in Safety Analysis Sets will be 
analyzed using MMRM including all scheduled visits. LS mean with corresponding SEM and 
95% CIs will be displayed. 
To further adjust for any potentially confounding effect of natural maturation, the analysis of the 
ratio of spot urinary UOx:Cr ratio to the reference value (age-matched ULN established from the 
ULNs published in [Matos 1999]) that is established for healthy children of varying age will also 
be performed.  Percent change from baseline in ULN Ratio from Month 3 to Month 6 in Efficacy 
Analysis Set will be analyzed using MMRM, and LS means with corresponding SEM and 95% 
CIs will be displayed. A sensitivity analysis will be conducted with the 
 (Bayesian) ULN 
(See SAP Addendum Version 1.0) 
7.1.2. 
Analyses of 24-Hour Urinary Oxalate Excretion   
24-hour urinary oxalate analysis will be conducted to assess the robustness of the primary 
outcome. Only valid 24-hour urinary oxalate values (see Section 6.2.1.1 of the protocol) will be 
considered for analysis for patients in Efficacy Analysis Set. The correlation between spot urine 
and 24-hour collection urine values maybe investigated. The analyses for 24-hour urinary oxalate 
corrected for BSA and 24-hour urinary UOx:Cr ratio will be carried out with data as observed. 
Percent change from baseline of 24h urinary oxalate corrected for BSA and 24h UOx:Cr ratio 
through Month 6 will be summarized.  
7.2. 
Subgroup Analysis 
Subgroup analyses will include analyses of the primary endpoint by age groups and weight-
based dosing groups defined according to the baseline values: 
Age group: 0-<1 year, 1-<6 years; 
Weight-based dosing category: 0-<10 kg, ≥10-<20 kg, and ≥20 kg. 
For primary analysis period, weight-based dosing category will be determined by initial dose 
level; for extension phase, dosing category may be analyzed both by initial dose level and by the 
dose level received for the longest duration. 


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Other subgroups may be examined, if deemed appropriate.  
Subgroup analysis will be conducted for primary analysis of spot urinary UOx:Cr ratio in 
Efficacy Analysis Set to further understand the treatment effects. Descriptive statistics will be 
reported for the subgroups. 
The subgroup analyses may be performed for secondary endpoints in Section 7.3.  
7.3. 
Secondary Endpoints 
For efficacy secondary endpoints, the Efficacy Analysis Set will be used; for PK secondary 
endpoints, the PK Analysis Set will be used.  
Secondary endpoints in this study are as follows:  
Extension Period (Month 6 to End of Study) 
Percent change in spot urinary UOx:Cr ratio from baseline for all post-Month 6 visits will be 
summarized descriptively using the Efficacy Analysis Set. The analyses for 24-hour urinary 
oxalate corrected for BSA and 24-hour urinary UOx:Cr ratio will be carried out using Extension 
Period data as well. 
Duration of Study (Baseline to End of Study) 
Absolute changes in spot urinary UOx:Cr ratio and percent and absolute change in plasma 
oxalate from baseline using Efficacy Analysis Set will be performed similarly to primary 
analysis. In addition, percent and absolute change in plasma oxalate from baseline will also be 
analyzed using only patients in the Efficacy Analysis Set whose baseline plasma oxalate ≥ 
1.5*LLOQ.  LS means by postdose visits with corresponding SEM and 95% CIs will be 
displayed for the primary analysis period. 
For continuous endpoints (including eGFR), descriptive statistics will be generated at each 
scheduled visit. Mean (+/- SEM) figures of actual values and changes from baseline will be 
plotted as well as individual spaghetti plots and listings. For binary endpoints, the number and 
associated percent of patients who met each threshold (e.g. <=ULN or <=1.5x ULN) at visits will 
be presented.  
To demonstrate durability of the effect of lumasiran, for binary endpoints, (e.g. proportion of 
patients with spot urinary UOx:Cr ratio level <= ULN or <= 1.5 x ULN), tabular summaries of 
the number and percent of patients who met the threshold at post-baseline visits will be 
presented.  
An analysis of the percentage of time that spot urinary UOx:Cr ratio is at or below the near-
normalization threshold for the duration of study will be summarized. A patient is considered to 
have met the threshold if the spot urinary UOx:Cr ratio is ≤1.5xULN at a post-baseline visit.  
For each patient, the percentage of time that spot urinary UOx:Cr ratio is at or below the near-
normalization threshold of ≤1.5xULN will be calculated as follows: 
𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑎𝑎𝑎𝑎 𝑜𝑜𝑜𝑜 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑡𝑡ℎ𝑟𝑟𝑟𝑟𝑟𝑟ℎ𝑜𝑜𝑜𝑜𝑜𝑜
𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑜𝑜𝑜𝑜 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎
 × 100 


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where cumulative months in near-normalization will be defined as the summation across all 
intervals that met the near-normal 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, the calculation of percentage of time 
will include the following considerations:  
• Time will include all follow-up assessments until study end or premature treatment 
discontinuation, whichever occurs first.  
• A linear interpolation method will be used to determine the bookend dates at which 
the patient crossed into the normal threshold and crossed out of the normal 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 that met threshold) will be presented.  In 
addition, the number of patients and associated percentage of patients in each category (e.g. 
<25%, ≥25% to <50%, ≥50% to <75%, ≥75% of time at or below the threshold) will also be 
presented.   
Descriptive statistics of eGFR at and after 6 months of lumasiran will be presented using the 
Efficacy Analysis Set and Safety Analysis Set. Shift tables of eGFR categories from baseline to 
post-baseline visits and an overall worst post-baseline will also be generated 
To demonstrate durability of the treatment effect of lumasiran, additional secondary endpoints 
may be assessed. 
7.4. 
Exploratory Efficacy Analysis 
Efficacy exploratory endpoints will be analyzed using the Efficacy Analysis Set generally.  
To evaluate the changes in nephrocalcinosis, a renal ultrasound will be performed at baseline and 
6, 12, 24, 36, 48 and 60 months. The ultrasound will measure the grade of medullary 
nephrocalcinosis (range: 0 to 3) where a higher grade indicates greater severity.  
Changes in the grade of medullary nephrocalcinosis will be categorized in 3 groups (‘no change’, 
‘worsening’ or ‘improving’). Shifts in the grade of nephrocalcinosis from baseline to each post-
baseline visit will be summarized. The distribution of patients by extent of change in 
nephrocalcinosis grade (i.e., number of grades by which nephrocalcinosis improved or worsened) 
from baseline to each post-baseline visit will also be summarized. 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 
both kidneys), ‘no change’, ‘improving’, ‘worsening’, and ‘indeterminate (one kidney improving 
and one worsening)’ will be presented. Descriptive statistics will also be generated. 
To evaluate the changes in renal stone events, these events will be captured at baseline (i.e. 
historical information) and throughout the study. A renal stone event is defined as an event 
which includes 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.  
Total number of patients with a renal stone event, total number of renal stone events and rate of 
renal stone events during each study period will be calculated. The rate is calculated as total 


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number of renal stone events divided by total number of on-study days of patients during the 
respective period. And 95% confidence intervals will be presented.  
Changes in other PD markers (such as spot urinary and plasma glycolate) will be explored. 
Descriptive statistics of actual, absolute change and percent change in levels of these markers 
will be generated at baseline and each post-baseline visit (as applicable).  
Change in growth parameters (z-scores) from baseline over time and changes in developmental 
milestones over time will be summarized descriptively. The achievement of developmental 
milestones over time is assessed using Vineland Adaptive Behavior Scales. Composite scores for 
developmental milestones are collected and summarized using Vineland Adaptive Behavior 
Scales, second version (Vineland-II). Vineland-II consists of 5 domains each with subdomains. 
The adaptive levels associated with the domain and subdomain composite scores will be 
categorized and shift tables will be generated, details in Section 10.5. Vineland-II scores of each 
domain, subdomain, and the adaptive levels will also be presented in by-patient listing.  
Changes in healthcare resource use will be listed and  patient experience, and caregiver 
experience will be summarized descriptively, details in Section 10.6.  
Analysis of ADA is included in Section 7.8. 
7.5. 
Pharmacodynamic Analysis  
Analyses of pharmacodynamic (PD) endpoints based on urinary excretion and blood samples 
(i.e., spot urinary UOx:Cr ratio, 24hr urinary oxalate corrected for BSA, plasma oxalate, etc.) are 
included in primary/secondary/exploratory endpoints and described in Section 7.1 to Section 7.4. 
All PD analysis will be based on Efficacy Analysis Set. 
7.6. 
Pharmacokinetic Analysis 
Pharmacokinetic analyses will be conducted using noncompartmental methods. PK parameters 
will be calculated using a validated version of Phoenix® WinNonlin. All PK analysis will be 
based on PK Analysis Set. 
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 analysis is a descriptive summary of frequency of AEs using the Safety Analysis 
Set. The primary safety parameter is treatment emergent Adverse Events (AEs). A treatment 
emergent AE will be defined as an AE that occurs or worsens on or after the first dose date/time 
of lumasiran through 84 days after the last dose of lumasiran. 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. 
Safety analysis will be conducted both at Month 6 interim analysis and end of study. AE analysis 
may be generated for potential interim analyses if applicable. 


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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.  
An overview table of AEs will be generated. The overview table will include the number and 
percentage of patients in 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 
• AEs 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 study withdrawal  
Tabulations by PT in decreasing order of frequency within the Safety Analysis Set will be 
generated for the following tables:  
• All AEs 
• All SAEs 


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• AEs related to treatment 
• SAEs related to treatment 
There will also be an All AE table generated displaying rates of AEs adjusted for exposure-time 
during the respective period.  
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, dose interruption, or withdrawal from study. By-patient AE listings will be provided.  
Additional summaries of injection site reactions (ISRs) and AEs mapping to the Drug related 
hepatic disorders Standardized MedDRA Query (SMQ) will be generated as described below.  In 
addition, other SMQs or AE groupings may be evaluated. 
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. In addition, a table of the number of patients with at least 1 ISR, 
total number of injections, total number of injections complicated by ISRs and corresponding % 
of injections complicated by ISR with the most common signs and symptoms reported due to 
ISRs will be generated. 
Hepatic AEs, including Liver Function Test (LFT) abnormalities: Analysis of hepatic AEs 
will include AEs mapping to the SMQ Drug-related hepatic disorders – comprehensive search 
(includes all narrow and broad terms). Frequency (percentages) of hepatic AEs will be 
summarized by SOC and PT.  A separate listing will be generated of all patients reporting these 
events. 
7.7.2. 
Dosing and Extent of Exposure  
Summaries of exposure will include the following characteristics such as, but not limited to: the 
total number of doses received per patient, mean number of doses per patient, cumulative 
number of doses received, duration of drug exposure (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 primary analysis 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. 
7.7.3. 
Clinical Laboratory Data 
Clinical laboratory parameters will be expressed in Standard International (SI) units. Laboratory 
data collected and recorded as below the lower limit of quantitation (LLOQ) will be set to the 
LLOQ for calculation of summary statistics. Key laboratory parameters will be graded according 
to NCI CTCAE v5.0.  


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Clinical laboratory data by visit in summary tables will use data from central laboratory.  
eDISH plots and the summary tables and listings for abnormality for clinical laboratory data will 
be analyzed in two ways; one using only central laboratory data and one using both central and 
local laboratory data by the following rules;  
• Central laboratory data at both scheduled and unscheduled visits will be used.  
• If central laboratory data at a visit is missing, local laboratory data will be used.  
• If a patient has both local and central laboratory data at the same visit, the central data 
will be used.  
Shift tables will be generated to summarize shifts from baseline category to the worst post-
baseline category with directionality specified (e.g. hyper and hypo).    
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.  
For hematology and chemistry labs, summary tables of potentially clinically significant 
abnormalities may also be provided.  
• All laboratory data will be presented in data listings. The listing of the clinical 
laboratory data will display both local and central laboratory data. Out of range 
laboratory results will be identified in listings.   
LFTs: A listing will be generated for all patients with abnormal liver function tests as defined by 
alanine aminotransferase (ALT)>3xULN, aspartate aminotransferase (AST)>3xULN or total 
bilirubin >2x ULN at any visit.  
A tabular summary for LFTs will be generated to summarize the number and associated 
percentage of patients in each of the categories at any post-baseline visit:  
• ALT: Within normal limit (WNL), 1<ALT≤3, 3<ALT≤5, 5<ALT≤10, 10<ALT≤20, 
ALT>20xULN 
• AST: WNL, 1<AST≤3, 3<AST≤5, 5<AST≤10, 10<AST≤20, AST>20xULN 
• ALT or AST: WNL, 1<ALT or AST≤3, 3<ALT or AST≤5, 5<ALT or AST≤10, 
10<ALT or AST≤20, ALT or AST>20xULN 
• ALP: WNL, 1<ALP≤1.5xULN, ALP>1.5xULN 
• Total Bilirubin: WNL, 1<Total Bilirubin ≤1.5, 1.5<Total Bilirubin ≤2, 2<Total 
Bilirubin≤3, 3<Total Bilirubin≤5 and Total Bilirubin>5x ULN 
eDISH plots of peak bilirubin at any time versus peak ALT or AST at any time will also be 
presented. 
7.7.4. 
Vital Signs 
A summary table of potentially clinically significant shifts in vital signs may be generated. 


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A summary table of descriptive statistics of modified z-scores of patient height, weight, and BMI 
by visits will be generated. A tabular summary of the proportion of patients with z-scores at 
various cut-points (i.e. ≥+/- 2 SD) will also be generated.   
A by-patient listing of vital sign data will be generated. Per patient plots of z-scores over time 
may also be generated.  
7.7.5. 
Physical Examinations 
Full physical examinations and symptom-directed physical examinations will be conducted 
throughout the study. Clinically significant abnormalities observed during the physical 
examination are recorded on the medical history or AE eCRF as appropriate.  
A separate listing per patient will be generated to display the date and time of the physical exam.  
7.7.6. 
Electrocardiogram   
Rhythm from single Electrocardiogram (ECG) parameter will be collected. The number and 
percentage of patients with normal, abnormal, clinically significant abnormal results, and 
specified abnormalities at baseline and each timepoint will be summarized.  
A listing of all ECG data will be provided. 
7.8. 
Anti-Drug Antibody  
The number, titer and associated percentage of patients who are ADA positive at baseline and 
also, at any post-baseline visit will be summarized. A listing of AEs for patients with ADA 
positivity will be provided.  
A listing of all ADA data will be provided.  
7.9. 
COVID-19 Pandemic Impact Analyses 
Additional data were collected to characterize the impact of the COVID-19 pandemic on general 
study conduct, disposition, and quality of life, and subsequently, additional analyses and 
summaries will be provided in acknowledgement of multiple regulatory guidances (FDA 
Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic: 
Guidance for Industry, Investigators, and Institutional Review Boards, US Food and Drug 
Administration, 2020; Guidance on the Management of Clinical Trials during the COVID-19 
(Coronavirus) Pandemic, European Medicines Agency, 2020; Points to consider on implications 
of Coronavirus disease (COVID-19) on methodological aspects of ongoing clinical trials, 
European Medicines Agency, 2020; Statistical Considerations for Clinical Trials During the 
COVID-19 Public Health Emergency, US Food and Drug Administration, 2020). 
 
7.9.1 General impact 
Patients who discontinue treatment or stop study participation due to COVID-19 pandemic will 
be included in patient disposition summaries. Impact on study participation due to COVID-19 
pandemic, including visit completion, visit location changes, and study drug dosing and location 
changes, will be summarized overall on the patient level, and overall and by visit on the event 
level. 


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7.9.2 Impact on Efficacy 
COVID-19 pandemic impacted efficacy analyses are not carried out for the primary analysis 
since efficacy assessments (e.g., blood and urine samples for PD, renal ultrasound data) missed 
due to COVID-19 pandemic are minimal. 
However, the final analyses will include COVID-19 pandemic impacted efficacy analyses. The 
analyses will evaluate the impact of changes in the visit windows for the efficacy assessments 
made in the protocol amendment 2 (dated 04 May 2020) due to COVID-19 pandemic.  Missing 
efficacy data due to the COVID-19 pandemic will be summarized. 
7.9.3 Impact on Adverse Events 
Events will be considered during the COVID-19 pandemic if the event occurs on or after first 
confirmed case of COVID-19 based on the country where the study site is located, described in 
Appendix 10.7. 
An overall summary of AEs mapping to a COVID-19 custom query will include the number and 
percentage of patients, as well as events and event rates, with any AE, any AE related to study 
drug, any severe AE, any severe AE related to study drug, any SAE, any SAE related to study 
drug, any AE leading to treatment discontinuation, any study drug related AE leading to 
treatment discontinuation, any AE leading to study withdrawal, any study drug related AE 
leading to study withdrawal, and any deaths. AEs mapping to the COVID-19 custom query will 
be summarized by high level term and preferred term. Due to the evolving nature of 
COVID-19-related MedDRA terminology, the COVID-19 custom query will be based on the 
latest information available at the specified analysis timepoints. 
An overall summary of AEs by COVID-19 pandemic phase (i.e., pre-, during, and post) will 
include the number and percentage of patients, as well as events and event rates, with any AE 
and any SAE. 
7.9.4 Other Impacts 
Treatment duration will also be summarized by pandemic phase. Protocol deviation due to 
COVID-19 pandemic will be summarized and will be indicated in the listing of protocol 
deviation. Adverse event, study drug exposure, and efficacy listings will include identification of 
assessments occurring during the pandemic. For patients reporting an AE mapped to the 
COVID-19 custom query, AEs and prior and concomitant medications will also be presented in 
separate data listings. Additionally, patient profiles will be provided. 
 


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8. 
CHANGES TO PLANNED ANALYSES 
Summary of Changes from SAP V2.0 
Rationale 
Section 7.9 and Appendix 10.7are added  
To add the analysis plan for COVID-19 pandemic 
impact  
Remove the imputation for analyses of 24-Hour 
Urinary Oxalate Excretion in Section 7.1.2 
24-hour urine data are only available from few 
patients. Imputation planned initially will not lead  
meaningful results and thus will not be carried out 
The definition of PK Analysis Set is changed in 
Section 4.1 
PK Analysis Set is defined using all patients who 
received “one full” dose rather than “any amount” dose 
of lumasiran to account patients with adequate study 
drug exposure 
Add additional analysis for changes in plasma 
oxalate for patients whose baseline POx ≥ 
1.5xLLOQ in Section 7.3 
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, additional analysis is 
added so that meaningful reduction can be quantified 
Change clinical laboratory data source and 
detailed analysis plan in Section 7.7.3 
To align with the change in Protocol Amendment 2.0, 
the data handling for both central and local clinical 
laboratory data is added 
Various editorial changes 
To improve clarity 


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9. 
REFERENCES 
Clinical Growth Charts [database on the Internet]. CDC. 2019 [cited 12 Nov 2019]. Available 
from: https://www.cdc.gov/growthcharts/clinical_charts.htm. 
Cochat P,Rumsby G. Primary hyperoxaluria. N Engl J Med. 2013 Aug 15;369(7):649-58. 
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. 
Leumann EP, Dietl A,Matasovic A. Urinary oxalate and glycolate excretion in healthy infants 
and children. Pediatr Nephrol. 1990 Sep;4(5):493-7. 
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. 
Matos V, Van Melle G, Werner D, Bardy D,Guignard JP. Urinary oxalate and urate to creatinine 
ratios in a healthy pediatric population. Am J Kidney Dis. 1999 Aug;34(2):e1. 
Morgenstern BZ, Milliner DS, Murphy ME, Simmons PS, Moyer TP, Wilson DM, et al. Urinary 
oxalate and glycolate excretion patterns in the first year of life: a longitudinal study. J Pediatr. 
1993 Aug;123(2):248-51. 
Reusz GS, Dobos M, Byrd D, Sallay P, Miltenyi M,Tulassay T. Urinary calcium and oxalate 
excretion in children. Pediatr Nephrol. 1995 Feb;9(1):39-44. 
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. 


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10. 
APPENDICES 
10.1. 
Urinary Oxalate calculation  
10.1.1. 
Spot Urinary Oxalate:Creatinine Ratio 
Spot urinary UOx:Cr ratio is calculated using single urine void with spot urinary oxalate 
normalized by creatinine concentration to account for differences in urinary dilution. The unit of 
spot urinary UOx:Cr ratio is mmol/mmol.  
10.1.2. 
24-Hour Urinary Oxalate Corrected for BSA 
24-hour urinary oxalate (mmol/24hrs/1.73m2) corrected for BSA at each visit per patient is 
calculated as follows:  
Urinary oxalate concentration (umol/L)/1000 (umol/mmol)*24hr urinary volume (mL)/1000 
(mL/L)*24 hours/actual collection hours*1.73/(BSA) 
where BSA is calculated using the Mosteller formula: 
BSA=square root (mean height (cm)*weight (kg)/3600) at the visit. 
Only valid 24-hour urinary oxalate values will be considered for analysis. (note: valid is defined 
as: creatinine ≥5 mg/kg, duration of collection 18 to 26 hours, no missing voids and the sample 
was not collected within 14 days after the most recent dialysis session, if applicable). 
10.2. 
Spot Urinary UOx:Cr Ratio Given Natural Growth 
10.2.1. 
Natural decline of spot urinary UOx:Cr ratio in healthy pediatric population  
Cross sectional studies, where the spot urinary UOx:Cr ratios were compared across broad age 
ranges (e.g., 1 - 6 months, 6 – 12 months, 1 – 2 years), showed that in young children over the 
age range of 0 to about 8 years, the urinary UOx:Cr ratio declines with increasing age.  Data 
from healthy children ages 1 month to 17 years old (N=386) showed a decline in the 95th 
percentile of the spot urinary UOx:Cr ratio.[Matos 1999]. The decline in the UOx:Cr ratio 
appears to plateau after 7 years of age.[Matos 1999] A similar publication using data from 188 
children from birth to 16 years old showed that the mean (and 5 – 95th percentiles) of the UOx:Cr 
ratio declined with increasing age, with no further decline observed in children ages 9 and 
above.[Leumann 1990]  
On the other hand, longitudinal data based on 30 healthy infants where intensive random urine 
samples were collected starting from day 2 of birth with additional samples collected on weeks 2, 
8, 16, 24 and 36 show that the mean UOx:Cr ratio stays stable over a period of 8 months (day 2 
to week 36).[Morgenstern 1993] These findings are consistent with the results of another cross-
sectional study where the mean (5 – 95th percentile) of UOx:Cr ratios stayed stable from birth up 
to 1 year of age.[Reusz 1995] Relative to other cross-sectional studies, Reusz compared UOx:Cr 
ratios using age categories with narrow age ranges.[Reusz 1995]  


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10.2.2. 
Effect of Age on Spot urinary UOx:Cr ratio in pediatric PH1 patients 
There is limited longitudinal data of spot urinary UOx:Cr ratio in pediatric PH1 patients. Lieske 
reported spot urinary UOx:Cr ratio from 35 PH1 patients across ages from international registry 
of primary hyperoxaluria.[Lieske 2005]  Of these patients, 15 children are under 7 years old, 
with 2 less than 2 years old.  
To check whether similar decline is observed in PH1 patients as in selected studies involving 
unaffected children, single values of individual patient spot UOx:Cr (plotted in Figure 1) were 
read from Lieske’s paper using Digitize (R package). Lieske’s data are shown in Figure 1 along 
with the reference curves for Lower limit of normal (LLN) and ULN identified by Matos’ 
publication. All patients except for one patient under 1 year old had spot urinary UOx:Cr  ratios 
above the Matos ULN. 
 
Figure 1: 
Spot urinary UOx:Cr ratio (mmol/mmol) in children with PH1 based on 
[Lieske 2005] Data 
 
 
10.3. 
Urinary Excretion Correlation Between Spot and 24-Hour Values 
The correlation between percent reduction from baseline in spot urinary UOx:Cr ratio and 24-hour 
urinary oxalate excretion relative to baseline was evaluated based on ALN-GO1-001 data collected 
on August 18, 2018. Four patients were excluded due to a laboratory processing issue leading to 
potentially erroneous results in the UOx:Cr ratios from spot samples. A total of 156 paired samples 
from 16 patients are included in the analysis. The correlation between time-matched UOx:Cr ratios 
from spot urinary samples and oxalate excretion from 24-hour urinary collections was strong, with 
a Pearson correlation coefficient of 0.86 (95% CI: [0.82, 0.90]). 


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Table 2: 
Percent Reduction from Baseline over Time of Spot Urinary Oxalate: 
Creatinine Ratios Vs 24-Hour Urinary Oxalate Excretion in Study 001B 
Study Day 
 
24-hour Collections 
Urinary Oxalate Excretion 
Spot Urinary Oxalate:Creatinine 
Ratio 
 
N 
Mean % Reduction (SEM) 
Mean % Reduction (SEM) 
Day 29 
14 
49.8 (5.2) 
51.9 (6.8) 
Day 57 
15 
63.3 (4.2) 
59.3 (5.7) 
Day 85 
13 
63.2 (4.4) 
60.9 (6.7) 
Day 113 
13 
70.8 (4.1) 
60.0 (6.0) 
Day 141 
13 
70.9 (3.0) 
63.9 (6.6) 
Day 169 
11 
63.3 (5.0) 
70.2 (4.0) 
The observed mean percent reduction and standard error are similar in both urinary sample types 
(Table 2).  The data also show sustained reduction over time in both urinary sample types. 
 
Figure 2: 
Scatterplot of Spot Urinary Oxalate:Creatinine Ratios vs 24-hour Urinary 
Oxalate Excretion in Study 001B 
 
Time-matched paired samples are plotted from 20 patients enrolled in Part B, ALN-GO1-001 demonstrating a linear 
relationship. Regression: spot ratio = -0.004 + 0.083*24-hour urinary oxalate; R2=0.774. 
 
Spot Urine Oxalate/Creatinine Ratio
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35
24-hour Urine Oxalate Content Corrected for BSA (mmol/24hr/1.73m**2)
0.0
0.5
1.0
1.5
2.0
2.5
3.0


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Figure 3: 
Scatterplot of Percent Change from Baseline in Spot Urinary Oxalate: 
Creatinine Ratios vs 24-hour Urinary Oxalate Excretion in Study 001B 
 
Time-matched paired samples are plotted from 16 patients enrolled in Part B, ALN-GO1-001 demonstrating a linear 
relationship. Regression: spot ratio = -4.625 + 0.885*24-hour urinary oxalate; R2=0.656. 
 


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Figure 4: 
Percent Coefficient of Variation Comparison of Spot Urinary Oxalate: 
Creatinine and 24-Hour Urinary Oxalate Excretion 
 
For each patient, the percent coefficient of variation was calculated using (standard deviation / mean)*100%. A 
histogram of the results is presented for spot urinary (blue) and 24-hour urinary excretion (red). The fitted curves 
represent the normal distribution for each of the sample types. 
Table 3: 
Observed Percent Coefficient of Variation from Spot Urinary Oxalate: 
Creatinine Ratios vs 24-Hour Urinary Oxalate Excretion 
Urinary Sample 
N 
Mean 
95% CL 
Mean 
Std Dev Min 
Max 
Spot Ox/Cr ratio CV (%) 
20 
55.5 
[38.06, 72.96] 
37.29 
13.2 
143.5 
24hr oxalate CV (%) 
20 
52.6 
[40.47, 64.75] 
25.93 
16.8 
101.2 
CV Difference (%) 
20 
2.9 
[-7.07, 12.87] 
4.76 
-43.1 
50.0 
The population mean %CV is presented for both sample types.  In addition, the mean of the differences between 
spot urinary samples and 24-hour collections is also presented.  
Histograms depicting the coefficients of variation for spot urinary and 24-hour urinary samples are 
plotted, the mean and standard deviation for these coefficients of variation are similar (Figure 4 
and Table 3). The correlation between the spot urinary UOx:Cr ratios and 24-hour urinary oxalate 
excretion coefficients of variation was strong, with a Pearson correlation coefficient of 0.83 [0.62, 
0.93]. The difference between the coefficients of variation was 2.9% [-7.1%, 12.9%]. Therefore, 
the analysis of the data suggests that the correlation of variation for spot urinary samples is similar 
to that observed for 24-hour urinary samples.  This supports the previous findings that the 
variations between the urinary sample types are minimal. 


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10.4. 
Normal Range Analysis  
Normalization rate will be based on normal range analysis of PD parameters (i.e. spot urinary 
UOx:Cr ratio, 24-hour oxalate corrected BSA, etc.) from 
 healthy volunteer data. ULNs will 
be defined in the separate normal range report that will be finalized before database lock.  
10.5. 
Medical History Adjustment 
Baseline disease history within the preceding year is required at enrollment. For infants less than 
one year old, reported values may need to be adjusted to represent a medically meaningful 
baseline value. Below is an example of the adjustment criteria to be used in such situations, for 
the outcome of renal stone events: 
1. Patients less than 6 months old, baseline records will be presented in by-patient 
listings, however will not be used in summary tables 
2. Patients (≥0.5 and <1 year old): Annualized rate will be calculated from reported 
data;i.e. if a patient of 8 months old has had 2 renal stone events prior to screening, 
his/her renal stone event rate at baseline will be 2/(8/12) = 3 events per year 
3. Patients (≥1 year old): records at screening for the preceding year will be used to 
calculate baseline annual stone event rate without justification 
10.6. 
Category of Vineland Adaptive Behavior Scale 
Vineland adaptive behavior composite scores are collected and summarized using Vineland-II. 
The adaptive level of the composite scores can be categorized from “Low” to “High” in Table 4. 
Table 4: 
Adaptive Level of Vineland Composite Scores 
Adaptive Level 
v-Scale 
Standard Score 
Low 
1 to 9 
20 to 70 
Moderately Low 
10 to 12 
71 to 85 
Adequate 
13 to 17 
86 to 114 
Moderately High 
18 to 20 
115 to 129 
High 
21 to 24 
130 to 160 


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10.7. 
COVID-19 Pandemic Phase Start Dates by Country 
Table 5 is as reported by the World Health Organization. 
Table 5: 
COVID-19 Pandemic Phase Start Dates by Country 
Country 
Date of 1st Confirmed Case 
France 
2020-01-24 
Germany 
2020-01-28 
Israel 
2020-02-27 
United Kingdom 
2020-01-31 
United States 
2020-01-20 
 
 
 

Prot_000.pdf: 
Clinical Study Protocol ALN-GO1-004  
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CLINICAL STUDY PROTOCOL 
ALN-GO1-004 
 
Protocol Title: 
ILLUMINATE-B: An Open-Label Study to 
Evaluate the Efficacy, Safety, Pharmacokinetics, 
and Pharmacodynamics of Lumasiran in Infants 
and Young Children with Primary Hyperoxaluria 
Type 1 
Short Title: 
A Study to Evaluate Lumasiran in Infants and 
Young Children with Primary Hyperoxaluria 
Type 1 (ILLUMINATE-B) 
Study Drug: 
Lumasiran (ALN-GO1)  
EudraCT Number: 
2018-004014-17 
IND Number: 
128941 
Protocol Date: 
 
Original protocol, 08 November 2018 
Amendment 1.0, 09 August 2019 
Amendment 2, 04 May 2020 
Sponsor: 
Alnylam Pharmaceuticals, Inc. 
300 Third Street 
Cambridge, MA  02142 USA 
 
Sponsor Contact:   
 
 
 
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. 
 


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SPONSOR PROTOCOL APPROVAL 
 
I have read this protocol and I approve the design of this study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alnylam Pharmaceuticals, Inc. 
 
 
 
 
 
 
 
 
Date 


Clinical Study Protocol ALN-GO1-004  
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INVESTIGATOR’S AGREEMENT 
 
I have read the ALN-GO1-004 protocol and agree to conduct the study in accordance with the 
protocol and all applicable regulations.  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-GO1-004  
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PROTOCOL SYNOPSIS 
Protocol Title 
ILLUMINATE-B: An Open-Label Study to Evaluate the Efficacy, Safety, Pharmacokinetics, and 
Pharmacodynamics of Lumasiran in Infants and Young Children with Primary Hyperoxaluria Type 1 
Short Title 
A Study to Evaluate Lumasiran in Infants and Young Children with Primary Hyperoxaluria Type 1 
(ILLUMINATE-B) 
Study Drug 
Lumasiran (ALN-GO1) 
Phase 
Phase 3 
Study Center(s) 
The study will be conducted at approximately 9 clinical study centers in 5 countries. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
• 
Evaluate the effect of lumasiran on urinary 
oxalate excretion 
• Percent change in urinary oxalate excretion 
from baseline to Month 6 
Secondary 
 
Extension Phase 
(Month 6 to End of Study) 
• Evaluate the long-term effects of lumasiran 
on urinary oxalate 
Extension Phase 
(Month 6 to End of Study) 
• Percent change in urinary oxalate excretion 
from baseline 
• Percentage of time that spot urinary 
oxalate:creatinine ratio is at or below the 
near-normalization threshold (≤1.5 × ULN) 
Duration of Study 
• Evaluate the effects of lumasiran on 
additional measures of urinary oxalate 
 
 
 
• Evaluate the effects of lumasiran on plasma 
oxalate 
• Characterize the pharmacokinetics (PK) of 
lumasiran 
• Evaluate the effect of lumasiran on renal 
function 
Duration of Study 
• Absolute change in urinary oxalate excretion 
from baseline  
• Proportion of patients with urinary oxalate 
excretion ≤ the upper limit of normal (ULN) 
and ≤1.5 x ULN  
• Change (percent and absolute) in plasma 
oxalate from baseline 
• Plasma PK parameters of lumasiran  
• Change from baseline in estimated 
glomerular filtration rate (eGFR) 
Exploratory 
 
• Evaluate effect of lumasiran on 
nephrocalcinosis 
• Change from baseline in nephrocalcinosis as 
assessed by renal ultrasound  


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Objectives 
Endpoints 
• Evaluate the effect of lumasiran on the 
occurrence of renal stones 
• Evaluate the additional pharmacodynamic 
(PD) parameters of urinary glycolate and 
plasma glycolate 
• Evaluate growth parameters  
• Evaluate developmental milestones 
• Evaluate experiences of primary 
hyperoxaluria type 1 (PH1) patients and/or 
caregivers during treatment with lumasiran 
• Assess for antidrug antibodies (ADA) against 
lumasiran 
• Change in frequency of renal stone events 
• Change in urinary glycolate and plasma 
glycolate 
• Change in growth parameters (z-scores) from 
baseline over time 
• Changes in developmental milestones over 
time 
• Changes in patient and/or caregiver 
experience as evaluated by a 
patient/caregiver survey 
• Frequency of ADA 
Safety 
 
• To evaluate the safety and tolerability of 
lumasiran 
• Frequency of adverse events (AEs) 
Study Design 
This is a multicenter, multinational, open-label study designed to evaluate the efficacy, safety, PK, and 
PD of lumasiran in infants and young children (<6 years of age) with a documented diagnosis of PH1, as 
determined by genetic analysis, and relatively preserved renal function. 
To be included in the study, patients must reach an estimated gestational age of 37 weeks old (equivalent 
to full-term infant) but be less than 6 years old.  The urinary oxalate:creatinine ratio of at least 2 out of 3 
single-void collections during screening must be above the upper limit of normal (ULN) for age.  If the 
patient is ≥12 months old, eGFR must be >45 mL/min/1.73 m2 based on the Schwartz Bedside Formula.  
If the patient is <12 months old, then serum creatinine must be at or below the ULN for age. 
If the patient is taking therapeutic vitamin B6 (pyridoxine), the patient must have been on a stable 
regimen for at least 90 days before screening and must remain on this stable regimen until at least the 
Month 6 visit.  Dose adjustments for interval weight gain are acceptable. 
Patients will be screened from Day -60 to Day -1 to determine eligibility.  Patients who meet all eligibility 
criteria will be administered open-label lumasiran as a subcutaneous (SC) injection, utilizing weight-
based dosing, with dose adjustments for interval weight gain.  Patients will receive 3 loading doses (on 
Day 1, Month 1, and Month 2).  Starting at Month 3, patients will receive lumasiran either once monthly 
(patients weighing <10 kg) or once every 3 months (patients weighing ≥10 kg) at the maintenance dose. 
Efficacy, safety, tolerability, pharmacokinetics, and pharmacodynamics, and patient and caregiver 
experience and burden will be assessed.  Safety assessments will include collection of AEs, clinical 
laboratory tests, vital sign assessments, electrocardiograms (ECGs), physical examinations, and 
concomitant medications. 
This study will consist of 2 periods: a 6-month primary analysis period followed by a long-term extension 
period.  During the 6-month primary analysis period, patients will undergo efficacy and safety 
assessments every 2 weeks for the first month and monthly thereafter.  During the long-term extension 
period of up to 54 months, dosing will continue, and visits will occur at least every-3-months. 


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Number of Planned Patients 
The planned enrollment for this study is 20 patients, including at least 1 patient <12 months of age with 
weight <10 kg at consent.  Patients who discontinue study drug or stop participation in the study prior to 
Month 6 may be replaced, and the analysis of data collection prior to discontinuation is addressed in the 
statistical analysis plan. 
Diagnosis and Main Eligibility Criteria 
This study will include infants and young children (<6 years of age) with a documented diagnosis of PH1 
based on urinary oxalate excretion above the upper limit of normal (ULN) for age and confirmed alanine-
glyoxylate aminotransferase (AGXT) mutations, with relatively preserved renal function at screening 
(eGFR >45 mL/min/1.73 m2 based on Schwartz Bedside Formula). 
Study Drug, Dose, and Mode of Administration  
Lumasiran 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, decreasing production of glycolate 
oxidase (GO) and hence reducing hepatic oxalate production. 
Lumasiran will be administered as a subcutaneous (SC) injection with weight-based dosing, with dose 
adjustments for interval weight gain, as follows:  
Weight 
Loading Dose 
(Day 1, Month 1, Month 2) 
Maintenance Dose 
(Month 3 and Beyond) 
<10 kg 
6.0 mg/kg monthly for 3 months 
3.0 mg/kg monthly 
≥10 to <20 kg 
6.0 mg/kg monthly for 3 months 
6.0 mg/kg every 3 months 
≥20 kg 
3.0 mg/kg monthly for 3 months 
3.0 mg/kg every 3 months 
For patients who weigh <20 kg, the dose will be based on a weight obtained within 7 days prior to dosing.  
During periods of time when the COVID-19 pandemic impedes the ability of these patients to travel to 
the study site or healthcare professionals to go to patients' homes, a weight from up to 6 weeks prior to the 
planned monthly dose or up to 4 months prior to the planned quarterly dose may be used to calculate the 
amount of lumasiran to be administered. 
For patients who weigh ≥20 kg, the dose may be based on a weight obtained up to 4 months prior to the 
planned quarterly dose. 
Patients with weight increases crossing the threshold for the next weight-based dosing category (<10 kg 
to ≥10 kg or <20 kg to ≥20 kg) will follow the new dosing regimen for the remainder of the study or until 
the next dosing category threshold is reached (ie, patients will not switch back to the lower-weight dosing 
schedule if their body weight subsequently decreases).   
Patients in maintenance dosing who transition from <10 kg to ≥10 kg will continue to receive monthly 
doses at 3.0 mg/kg until the next visit that coincides with the Schedule of Assessments for patients 
weighing ≥10 kg.  Thereafter, patients will follow every-3-months dosing until the end of the study. 
Reference Treatment, Dose, and Mode of Administration 
Not applicable. 
Duration of Treatment and Study 
The duration of treatment with lumasiran is up to 60 months (a month is defined as 28 days).  The 


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estimated total time on study for each patient is up to 62 months, including up to 2 months of screening 
followed by up to 60 months of treatment. 
Statistical Methods 
The sample size was determined based on feasibility considerations, not power calculations.  
The Safety Analysis Set will include all patients who received at least 1 dose of study drug.  The Efficacy 
Analysis Set will include all patients who received any amount of lumasiran and have at least one valid 
spot urinary oxalate:creatinine ratio value at baseline and at least one valid spot urinary oxalate:creatinine 
ratio value from assessment(s) at Month 3 to Month 6.  The PK Analysis Set will include all patients who 
received any amount of study drug and have at least 1 postdose blood sample for PK parameters. 
The Safety Analysis Set will be used for safety analyses and sensitivity analysis of efficacy.  The Efficacy 
Analysis Set will be used to evaluate efficacy endpoints.  


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Table 1: 
Schedule of Assessments –Primary Analysis Period (Screening through Month 6): All Patients 
After Month 6, patients with weight <10 kg follow Table 2. Patients with weight ≥10 kg follow Table 4. 
Study Period 
Study Visit 
Screening 
6-Month Primary Analysis Period 
Baseline Wk 2 
M1 
M2 
M3 
M4 
M5 
M6 
Study Day  
(±Visit Window) 
Notes 
-60 to -1 
1 
 
15 
(±3) 
29 
(±14) 
57 
(±14) 
85 
(±14) 
113 
(±14) 
141 
(±14) 
169 
(±14) 
Informed consent 
Section 8.1.1 
X 
 
 
 
 
 
 
 
 
Demographics 
Section 6.1 
X 
 
 
 
 
 
 
 
 
Medical history 
Changes occurring between screening and 
Day 1 are to be updated prior to dosing. 
Section 6.1 
X 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
Section 4. 
X 
 
 
 
 
 
 
 
 
Full physical examination 
Section 6.5.3 
X 
 
 
 
 
 
 
 
X 
Abbreviated physical 
examination 
Section 6.5.3 
 
X 
X 
X 
X 
X 
X 
X 
 
Height/length 
Centimeters. Section 6.5.2 
X 
X 
 
X 
X 
X 
X 
X 
X 
Body weight 
Kilograms. 
Section 5.2.2; Section 6.5.2  
X 
X 
 
X 
X 
X 
X 
X 
X 
Vital signs 
Predose on dosing days.  On Day 1 (only), 
also measured 30 ± 10 minutes postdose. 
Section 6.5.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
Local 12-lead, singlicate, predose ECGs. 
Section 6.5.4 
X 
X 
 
 
 
X 
 
 
X 
DNA sample for PH1/AGXT 
mutation analysis 
Only for patients without documented PH1 
genetic analysis. 
X 
 
 
 
 
 
 
 
 
Exploratory DNA sample 
(optional) 
Where allowed per local regulations. 
Section 6.6 
X 
 
 
 
 
 
 
 
Clinical laboratory 
assessments 
Serum creatinine and LFTs are repeated if 
not collected <30 days before Day 1 
(Section 5.2.3.1); Section 6.1; Section 6.5.5 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Table 1: 
Schedule of Assessments –Primary Analysis Period (Screening through Month 6): All Patients 
After Month 6, patients with weight <10 kg follow Table 2. Patients with weight ≥10 kg follow Table 4. 
Study Period 
Study Visit 
Screening 
6-Month Primary Analysis Period 
Baseline Wk 2 
M1 
M2 
M3 
M4 
M5 
M6 
Study Day  
(±Visit Window) 
Notes 
-60 to -1 
1 
 
15 
(±3) 
29 
(±14) 
57 
(±14) 
85 
(±14) 
113 
(±14) 
141 
(±14) 
169 
(±14) 
Study drug dosing in 
patients <10 kg 
Dosing must be at least 21 days apart. 
Section 5.2.2; Table 7 
 
X 
 
X 
X 
X 
X 
X 
X 
Study drug dosing in 
patients ≥10 kg 
 
X 
 
X 
X 
X 
 
 
X 
Blood samples for PK 
analyses 
See Table 5 for blood collection timepoints. 
 
X 
 
 
 
 
 
 
X 
Blood samples for PD 
analyses 
Collected predose, when applicable. 
Section 6.3. 
X 
X 
 
X 
X 
X 
X 
X 
X 
24-hour urine collections for 
PD analyses 
At Screening and Month 6, three collections 
are performed predose. For patients unable to 
comply, a single catheterized 24- hour 
collection may be performed. Section 6.2 
X 
 
 
 
 
 
 
 
X 
Single-void urine 
collections for PD analysis 
(3 collections)  
Following screening, 3 single-void 
collections are collected within 7 days 
predose (first morning voids are preferred). 
Section 6.2 
X 
 
 
X 
X 
X 
X 
X 
X 
Blood sample for 
pyridoxine (vitamin B6) 
levels 
Only in patients receiving therapeutic 
pyridoxine. Do not collect within 6 hours of 
pyridoxine dose. Section 5.3 
X 
X 
 
 
 
X 
 
 
X 
Renal stone events 
Renal stone events are not considered AEs or 
SAEs. Section 6.3.3 
Continuous 
Renal ultrasound 
Performed as per procedure manual. 
Section 6.3.4 
X 
 
 
 
 
 
 
 
X 
Developmental assessment 
Vineland Adaptive Behavior Scale. 
Section 6.7 
X 
 
 
 
 
 
 
 
X 
Patient/caregiver experience 
and impact questionnaire 
Section 6.8 
X 
 
 
 
 
 
 
 
X 
ADA sample 
Collect predose. Section 6.5.5.1 
X 
 
X 
 
X 
 
 
X 


Clinical Study Protocol ALN-GO1-004  
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Alnylam Pharmaceuticals 
Confidential 
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Table 1: 
Schedule of Assessments –Primary Analysis Period (Screening through Month 6): All Patients 
After Month 6, patients with weight <10 kg follow Table 2. Patients with weight ≥10 kg follow Table 4. 
Study Period 
Study Visit 
Screening 
6-Month Primary Analysis Period 
Baseline Wk 2 
M1 
M2 
M3 
M4 
M5 
M6 
Study Day  
(±Visit Window) 
Notes 
-60 to -1 
1 
 
15 
(±3) 
29 
(±14) 
57 
(±14) 
85 
(±14) 
113 
(±14) 
141 
(±14) 
169 
(±14) 
Blood and urine samples for 
exploratory analyses 
Single-void urine and blood sample collected 
predose or prior to visit. Section 6.6 
X 
X 
 
X 
 
X 
 
 
X 
Review/record AEs 
SAEs are collected in the Screening period. 
Starting on Day 1, all AEs (ie, including 
SAEs) are collected. Section 6.5.6.2 
Continuous 
Prior and concomitant 
medications 
Section 5.3 
Continuous 
Abbreviations:  ADA=antidrug antibody; AE=adverse event; AGXT=alanine-glyoxylate aminotransferase gene; DNA=deoxyribonucleic acid; 
ECG=electrocardiogram; LFTs=liver function tests; M=Month; PD=pharmacodynamic; PH1=primary hyperoxaluria type 1; PK=pharmacokinetic; SAE=serious 
adverse event; Wk=Week 
Note: 
• One month is defined as 28 days. 
• Assessments are to be performed prior to dosing, where applicable. When scheduled at the same time points and where feasible, the assessments of vital 
signs and 12-lead ECGs should be performed before physical examinations and blood sample collections. 
• Visits and study drug dosing may be conducted offsite where applicable country and local regulations and infrastructure allow (at the discretion of the 
Investigator, based on safety and tolerability), provided the patient has tolerated a dose of lumasiran administered in the clinic.  If a visit is conducted offsite, 
a body system assessment may be performed in lieu of a physical examination. 
• In situations where a study visit is unable to be completed (either at the site or offsite by a healthcare professional), the Investigator (or delegate) will 
verbally contact the patient within the study visit window to assess concomitant medications, renal stone events, adverse events, and healthcare utilization. 
• Patients who discontinue from study drug prior to completion of the Month 6 assessments should be encouraged to remain on the study and complete 
assessments (including 24-hour urine collections but excluding PK assessments) through Month 6. They will also be asked to complete safety follow-up 
visits once every 3 months, per the safety follow-up schedule (see Table 3 or Table 4), for up to 12 months after the last dose of lumasiran, or until PD 
recovery (Section 3.3.1) (whichever is earlier). See Section 4.3.1 for instructions for patients who discontinue study drug. 
 


Clinical Study Protocol ALN-GO1-004  
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Table 2: Schedule of Assessments – Long-term Extension Period (Month 7 to Month 35): Patient Weight <10 kg 
Patients whose weight increases to ≥10 kg continue monthly dosing until the next visit that coincides with Table 4 and 
then patients will follow Table 4 until the end of the study. Patients with weight <10 kg follow Table 3 after Month 35. 
Study Visit 
 
M7; 
M8 
M9 
M10; 
M11 M12 M13; 
M14 
M15 M16; 
M17 M18 M19; 
M20 M21 M22; 
M23 M24 M25; 
M26 M27 M28; 
M29 M30 M31; 
M32 M33 M34; 
M35 
Study Day  
(±Visit Window) 
Note 
197, 
225 
(±14) 
253 
(±14) 
281, 
309 
(±14) 
337 
(±14) 
365, 
393 
(±14) 
421 
(±14) 
449, 
477 
(±14) 
505 
(±14) 
533, 
561 
(±14) 
589 
(±14) 
617, 
645 
(±14) 
673 
(±14) 
701, 
729 
(±14) 
757 
(±14) 
785, 
813 
(±14) 
841 
(±14) 
869, 
897 
(±14) 
925 
(±14) 
953, 
981 
(±14) 
Full physical 
examination 
Section 6.5.3 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Abbreviated 
physical 
examination 
Section 6.5.3 
X 
X 
X 
 
X 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Height/length 
Centimeters. 
Section 6.5.2 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Body weight 
Kilograms. 
Section 5.2.2; 
Section 6.5.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
Section 6.5.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
Local 12-lead, singlicate, 
predose ECGs. 
Section 6.5.4 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Clinical laboratory 
assessments 
Section 5.2.3.1; 
Section 6.5.5  
X 
X 
X 
X 
X 
X 
X 
X 
LFT 
only 
X 
LFT 
only 
X 
LFT 
only 
X 
LFT 
only 
X 
LFT 
only 
X 
LFT 
only 
Study drug dosing 
Dosing must be at least 
21 days apart. 
Section 5.2.2; Table 7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood samples for 
PK analyses 
See Table 5 for blood 
collection timepoints. 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
Blood samples for 
PD analyses 
Section 6.3 
X  
(Opt) 
X 
X  
(Opt) 
X 
X  
(Opt) 
X 
X  
(Opt) 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
24-hour urine 
collection for PD 
analyses 
(1 collection)  
Section 6.2 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Single-void urine 
collections 
(3 collections) 
Collected within 7 days 
predose (first morning 
voids preferred). 
Section 6.2 
X 
(Opt) 
X 
X 
(Opt) 
X 
X  
(Opt) 
X 
X 
(Opt) 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 


Clinical Study Protocol ALN-GO1-004  
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Amendment 2, 04 May 2020 
 
Alnylam Pharmaceuticals 
Confidential 
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Table 2: Schedule of Assessments – Long-term Extension Period (Month 7 to Month 35): Patient Weight <10 kg 
Patients whose weight increases to ≥10 kg continue monthly dosing until the next visit that coincides with Table 4 and 
then patients will follow Table 4 until the end of the study. Patients with weight <10 kg follow Table 3 after Month 35. 
Study Visit 
 
M7; 
M8 
M9 
M10; 
M11 M12 M13; 
M14 
M15 M16; 
M17 M18 M19; 
M20 M21 M22; 
M23 M24 M25; 
M26 M27 M28; 
M29 M30 M31; 
M32 M33 M34; 
M35 
Study Day  
(±Visit Window) 
Note 
197, 
225 
(±14) 
253 
(±14) 
281, 
309 
(±14) 
337 
(±14) 
365, 
393 
(±14) 
421 
(±14) 
449, 
477 
(±14) 
505 
(±14) 
533, 
561 
(±14) 
589 
(±14) 
617, 
645 
(±14) 
673 
(±14) 
701, 
729 
(±14) 
757 
(±14) 
785, 
813 
(±14) 
841 
(±14) 
869, 
897 
(±14) 
925 
(±14) 
953, 
981 
(±14) 
Blood sample for 
pyridoxine (vitamin 
B6) levels 
Only in patients receiving 
pyridoxine. Sample is 
collected >6 hrs. after 
pyridoxine dose. 
Section 5.3 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Renal stone events 
Renal stone events are 
not AEs or SAEs. 
Section 6.3.3 
Continuous 
Renal ultrasound 
Performed as per 
procedure manual. 
Section 6.3.4 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Developmental 
assessment 
Vineland Adaptive 
Behavior Scale. 
Section 6.7 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Patient/caregiver 
experience and 
impact 
questionnaire 
Section 6.8 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
ADA sample 
Collect predose. 
Section 6.5.5.1 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Blood and urine 
samples for 
exploratory analyses 
Single-void urine and 
blood sample collected 
predose or prior to visit. 
Section 6.6 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Review/ record AEs Section 6.5.6.2 
Continuous 
Prior and 
concomitant 
medications 
Section 5.3 
Continuous 
Abbreviations: ADA=antidrug antibody; AE=adverse event; ECG=electrocardiogram; ET=early termination; hrs=hours; M=month; Opt=optional; PD=pharmacodynamic; 
PK=pharmacokinetic; Pts=patients; SAE=serious adverse event 
Notes: 
• One month is defined as 28 days. 


Clinical Study Protocol ALN-GO1-004  
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Amendment 2, 04 May 2020 
 
Alnylam Pharmaceuticals 
Confidential 
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• Assessments are to be performed prior to dosing, where applicable. When scheduled at the same time points and where feasible, the assessments of vital signs and 12-lead ECGs 
should be performed before physical examinations and blood sample collections. 
• Visits and study drug dosing may be conducted offsite where applicable country and local regulations and infrastructure allow (at the discretion of the Investigator, based on 
safety and tolerability), provided the patient has tolerated a dose of lumasiran administered in the clinic.  If a visit is conducted offsite, a body system assessment may be 
performed in lieu of a physical examination. 
• In situations where a study visit is unable to be completed (either at the site or offsite by a healthcare professional), the Investigator (or delegate) will verbally contact the patient 
within the study visit window to assess concomitant medications, renal stone events, adverse events, and healthcare utilization. 
• Patients who discontinue study drug after Month 6 will be asked to return for their next scheduled visit to complete ET assessments and to complete safety follow-up visits once 
every 3 months, per the safety follow-up schedule (see Table 3 or Table 4), for up to 12 months after the last dose of lumasiran, or until PD recovery (Section 3.3.1) (whichever 
is earlier).  See Section 4.3.1 for instructions for patients who discontinue study drug. 
Table 3: Schedule of Assessments – Long-term Extension Period (Month 36 to End of Study): Patient Weight <10 kg 
Patients whose weight increases to ≥10 kg continue monthly dosing until the next visit that coincides with Table 4. 
Patients will then follow Table 4 until the end of the study. 
Study Period 
 
Long-term Extension Period 
EOT EOS/ 
ET 
Safety 
Follow-up 
(Pts who DC 
treatment) 
Study Visit 
 
M36 M37; 
M38 M39 M40;
M41 M42 M43; 
M44 M45 M46; 
M47 M48 M49;
M50 M51 M52; 
M53 M54 M55;
M56 
M57 
M60 
Study Day  
(±Visit Window) 
Notes 
1009 
(±14) 
1037, 
1065 
(±14) 
1093 
(±14) 
1121, 
1149 
(±14) 
1177 
(±14) 
1205, 
1233 
(±14) 
1261 
(±14) 
1289, 
1317 
(±14) 
1345 
(±14) 
1373, 
1401 
(±14) 
1429 
(±14) 
1457, 
1485 
(±14) 
1513 
(±14) 
1541, 
1569 
(±14) 
1597 
(±14) 
1681 
(±14) 
Every 84 
days (±14) 
Full physical 
examination 
Section 6.5.3 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
Abbreviated physical 
examination 
Section 6.5.3 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
Height/length 
Centimeters. Section 6.5.2 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Body weight 
Kilograms. 
Section 5.2.2; Section 6.5.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
Section 6.5.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
Local 12-lead, singlicate, 
predose ECGs. Section 6.5.4 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Clinical laboratory 
assessments 
Section 5.2.3.1; Section 6.5.5 
X 
LFT 
only 
X 
LFT 
only 
X 
LFT 
only 
X 
LFT 
only 
X 
LFT 
only 
X 
LFT 
only 
X 
LFT 
only 
X 
X 
X 
Study drug dosing 
Dosing must be at least 21 
days apart. Section 5.2.2; 
Table 7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Blood samples for 
PD analyses 
Section 6.3 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 


Clinical Study Protocol ALN-GO1-004  
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Amendment 2, 04 May 2020 
 
Alnylam Pharmaceuticals 
Confidential 
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Table 3: Schedule of Assessments – Long-term Extension Period (Month 36 to End of Study): Patient Weight <10 kg 
Patients whose weight increases to ≥10 kg continue monthly dosing until the next visit that coincides with Table 4. 
Patients will then follow Table 4 until the end of the study. 
Study Period 
 
Long-term Extension Period 
EOT EOS/ 
ET 
Safety 
Follow-up 
(Pts who DC 
treatment) 
Study Visit 
 
M36 M37; 
M38 M39 M40;
M41 M42 M43; 
M44 M45 M46; 
M47 M48 M49;
M50 M51 M52; 
M53 M54 M55;
M56 
M57 
M60 
Study Day  
(±Visit Window) 
Notes 
1009 
(±14) 
1037, 
1065 
(±14) 
1093 
(±14) 
1121, 
1149 
(±14) 
1177 
(±14) 
1205, 
1233 
(±14) 
1261 
(±14) 
1289, 
1317 
(±14) 
1345 
(±14) 
1373, 
1401 
(±14) 
1429 
(±14) 
1457, 
1485 
(±14) 
1513 
(±14) 
1541, 
1569 
(±14) 
1597 
(±14) 
1681 
(±14) 
Every 84 
days (±14) 
24-hour urine 
collection for PD 
analyses 
(1 collection)  
Section 6.2 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
Single-void urine 
collections 
(3 collections) 
 
Collected within 7 days 
predose (first morning voids 
preferred). Section 6.2 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
Single-void urine 
collections 
(1 collection) 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
Renal stone events 
Renal stone events are not 
AEs or SAEs. Section 6.3.3 
Continuous 
Renal ultrasound 
Performed as per procedure 
manual. Section 6.3.4 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Developmental 
assessment 
Vineland Adaptive Behavior 
Scale. Section 6.7 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
Patient/caregiver 
experience and 
impact questionnaire 
Section 6.8 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
ADA sample 
Collect predose. 
Section 6.5.5.1 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
Blood and urine 
samples for 
exploratory analyses 
Single-void urine and blood 
sample collected predose or 
prior to visit. Section 6.6 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Review/ 
record AEs 
Section 6.5.6.2 
Continuous 


Clinical Study Protocol ALN-GO1-004  
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Amendment 2, 04 May 2020 
 
Alnylam Pharmaceuticals 
Confidential 
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Table 3: Schedule of Assessments – Long-term Extension Period (Month 36 to End of Study): Patient Weight <10 kg 
Patients whose weight increases to ≥10 kg continue monthly dosing until the next visit that coincides with Table 4. 
Patients will then follow Table 4 until the end of the study. 
Study Period 
 
Long-term Extension Period 
EOT EOS/ 
ET 
Safety 
Follow-up 
(Pts who DC 
treatment) 
Study Visit 
 
M36 M37; 
M38 M39 M40;
M41 M42 M43; 
M44 M45 M46; 
M47 M48 M49;
M50 M51 M52; 
M53 M54 M55;
M56 
M57 
M60 
Study Day  
(±Visit Window) 
Notes 
1009 
(±14) 
1037, 
1065 
(±14) 
1093 
(±14) 
1121, 
1149 
(±14) 
1177 
(±14) 
1205, 
1233 
(±14) 
1261 
(±14) 
1289, 
1317 
(±14) 
1345 
(±14) 
1373, 
1401 
(±14) 
1429 
(±14) 
1457, 
1485 
(±14) 
1513 
(±14) 
1541, 
1569 
(±14) 
1597 
(±14) 
1681 
(±14) 
Every 84 
days (±14) 
Prior and 
concomitant 
medications 
Section 5.3 
Continuous 
Abbreviations: ADA=antidrug antibody; AE=adverse event; DC=discontinue; ECG=electrocardiogram; EOS=end of study; EOT=end of treatment; ET=early termination; 
hrs=hours; M=month; PD=pharmacodynamic; PK=pharmacokinetic; Pts=patients; SAE=serious adverse event 
Notes: 
• One month is defined as 28 days. 
• Assessments are to be performed prior to dosing, where applicable. When scheduled at the same time points and where feasible, the assessments of vital signs and 12-lead ECGs 
should be performed before physical examinations and blood sample collections. 
• Visits and study drug dosing may be conducted offsite where applicable country and local regulations and infrastructure allow (at the discretion of the Investigator, based on 
safety and tolerability), provided the patient has tolerated a dose of lumasiran administered in the clinic.  If a visit is conducted offsite, a body system assessment may be 
performed in lieu of a physical examination. 
• In situations where a study visit is unable to be completed (either at the site or offsite by a healthcare professional), the Investigator (or delegate) will verbally contact the patient 
within the study visit window to assess concomitant medications, renal stone events, adverse events, and healthcare utilization. 
• Patients who discontinue study drug early will be asked to return for their next scheduled visit to complete ET assessments and to complete safety follow-up visits once every 3 
months, per the safety follow-up schedule in this table, for up to 12 months after the last dose of lumasiran, or until PD recovery (Section 3.3.1) (whichever is earlier).  See 
Section 4.3.1 for instructions for patients who discontinue study drug. 
 


Clinical Study Protocol ALN-GO1-004  
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Amendment 2, 04 May 2020 
 
Alnylam Pharmaceuticals 
Confidential 
16 
Table 4: Schedule of Assessments – Long-term Extension Period (Month 9 to End of Study): Patient Weight ≥10 kg 
Patients following Table 2 or Table 3 whose weight increases to ≥10 kg continue monthly dosing until the next visit that coincides with this 
table.  Patients will then follow this table until the end of the study. 
Study Period 
 
Long-term Extension Period 
EOT EOS/ 
ET 
Safety 
Follow-up 
(Pts who DC 
treatment) 
Study Visit 
 
M9 
M12 M15 M18 M21 M24 M27 M30 M33 M36 M39 M42 M45 M48 M51 
M54 
M57 M60 
Study Day  
(±Visit Window) 
Notes 
253 
(±28) 
337 
(±28) 
421 
(±28) 
505 
(±28) 
589 
(±28) 
673 
(±28) 
757 
(±28) 
841 
(±28) 
925 
(±28) 
1009 
(±28) 
1093 
(±28) 
1177 
(±28) 
1261 
(±28) 
1345 
(±28) 
1429 
(±28) 
1513 
(±28) 
1597 
(±28) 
1681 
(±28) 
Every 84 
days (±28) 
Full physical 
examination 
Section 6.5.3 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Abbreviated 
physical 
examination 
Section 6.5.3 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Height/length 
Centimeters. 
Section 6.5.2 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Body weight 
Kilograms. 
Section 6.5.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
Section 6.5.1 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
12-lead ECG 
Local 12-lead, 
singlicate, 
predose ECGs. 
Section 6.5.4 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Clinical laboratory 
assessments 
Section 5.2.3.1; 
Section 6.5.5 
X 
X 
X 
X 
X 
X 
LFT 
only 
X 
LFT 
only 
X 
LFT 
only 
X 
LFT 
only 
X 
LFT 
only 
X 
LFT 
only 
X 
X 
Pregnancy testing  
Females of child-
bearing potential 
only. 
Section 6.5.5.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study drug dosing 
Dosing must be at 
least 21 days 
apart. 
Section 5.2.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Blood samples for 
PK analyses 
See Table 5 for 
timepoints. 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood samples for 
PD analyses 
Section 6.3 
X 
X 
X 
X 
X 
X 
X 
(opt) 
X 
X 
(opt) 
X 
X 
(opt) 
X 
X 
(opt) 
X 
X 
(opt) 
X 
X 
(opt) 
X 
X 


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Table 4: Schedule of Assessments – Long-term Extension Period (Month 9 to End of Study): Patient Weight ≥10 kg 
Patients following Table 2 or Table 3 whose weight increases to ≥10 kg continue monthly dosing until the next visit that coincides with this 
table.  Patients will then follow this table until the end of the study. 
Study Period 
 
Long-term Extension Period 
EOT EOS/ 
ET 
Safety 
Follow-up 
(Pts who DC 
treatment) 
Study Visit 
 
M9 
M12 M15 M18 M21 M24 M27 M30 M33 M36 M39 M42 M45 M48 M51 
M54 
M57 M60 
Study Day  
(±Visit Window) 
Notes 
253 
(±28) 
337 
(±28) 
421 
(±28) 
505 
(±28) 
589 
(±28) 
673 
(±28) 
757 
(±28) 
841 
(±28) 
925 
(±28) 
1009 
(±28) 
1093 
(±28) 
1177 
(±28) 
1261 
(±28) 
1345 
(±28) 
1429 
(±28) 
1513 
(±28) 
1597 
(±28) 
1681 
(±28) 
Every 84 
days (±28) 
24-hour urine 
collection for PD 
analyses 
(1 collection)  
Section 6.2 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Single-void urine 
collections 
(3 collections) 
 
Collected within 
7 days predose 
(first morning 
voids preferred). 
Section 6.2 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
X 
Single-void urine 
collection 
(1 collection) 
 
 
 
 
 
 
X 
 
X 
 
X 
X 
X 
 
X 
X 
X 
 
 
Renal stone events Renal stone 
events are not 
AEs or SAEs. 
Section 6.3.3 
Continuous 
Renal ultrasound 
Performed as per 
procedure 
manual. 
Section 6.3.4 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Developmental 
assessment 
Vineland 
Adaptive 
Behavior Scale. 
Section 6.7 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Patient/ caregiver 
experience and 
impact 
questionnaire 
Section 6.8 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
ADA sample 
Collect predose. 
Section 6.5.5.1 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 


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Table 4: Schedule of Assessments – Long-term Extension Period (Month 9 to End of Study): Patient Weight ≥10 kg 
Patients following Table 2 or Table 3 whose weight increases to ≥10 kg continue monthly dosing until the next visit that coincides with this 
table.  Patients will then follow this table until the end of the study. 
Study Period 
 
Long-term Extension Period 
EOT EOS/ 
ET 
Safety 
Follow-up 
(Pts who DC 
treatment) 
Study Visit 
 
M9 
M12 M15 M18 M21 M24 M27 M30 M33 M36 M39 M42 M45 M48 M51 
M54 
M57 M60 
Study Day  
(±Visit Window) 
Notes 
253 
(±28) 
337 
(±28) 
421 
(±28) 
505 
(±28) 
589 
(±28) 
673 
(±28) 
757 
(±28) 
841 
(±28) 
925 
(±28) 
1009 
(±28) 
1093 
(±28) 
1177 
(±28) 
1261 
(±28) 
1345 
(±28) 
1429 
(±28) 
1513 
(±28) 
1597 
(±28) 
1681 
(±28) 
Every 84 
days (±28) 
Blood and urine 
samples for 
exploratory 
analyses 
Single-void urine 
and blood sample 
collected predose 
or prior to visit. 
Section 6.6 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Review/ 
record AEs 
Section 6.5.6.2 
Continuous 
Prior and 
concomitant 
medications 
Section 5.3 
Continuous 
Abbreviations: ADA=antidrug antibody; AE=adverse event; DC=discontinue; ECG=electrocardiogram; EOS=end of study; EOT=end of treatment; ET=early termination; 
hrs=hours; M=month; PD=pharmacodynamic; PK=pharmacokinetic; Pts=patients; SAE=serious adverse event 
Notes: 
• One month is defined as 28 days. 
• Assessments are to be performed prior to dosing, where applicable. When scheduled at the same time points and where feasible, the assessments of vital signs and 12-lead 
ECGs should be performed before physical examinations and blood sample collections. 
• Visits and study drug dosing may be conducted offsite where applicable country and local regulations and infrastructure allow (at the discretion of the Investigator, based on 
safety and tolerability), provided the patient has tolerated a dose of lumasiran administered in the clinic.  If a visit is conducted offsite, a body system assessment may be 
performed in lieu of a physical examination. 
• In situations where a study visit is unable to be completed (either at the site or offsite by a healthcare professional), the Investigator (or delegate) will verbally contact the 
patient within the study visit window to assess concomitant medications, renal stone events, adverse events, and healthcare utilization. 
• Patients who discontinue study drug after Month 6 will be asked to return for their next scheduled visit to complete ET assessments and to complete safety follow-up visits 
once every 3 months, per the safety follow-up schedule, for up to 12 months after the last dose of lumasiran, or until PD recovery (Section 3.3.1) (whichever is earlier). See 
Section 4.3.1 for instructions for patients who discontinue study drug.  


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Table 5: 
Pharmacokinetic Time Points: All Patients  
Study Visit 
Protocol Time 
(hh:mm) 
Day 1, Month 6, Month 12, Month 18, and Month 24 study 
visits. 
02:00 (±20 minutes) 
04:00 (±30 minutes) 
08:00 (±1 hour) 
12:00 (±2 hour) 
24:00 (±3 hours) 
Abbreviations:  hh:mm=hour:minute; PK=pharmacokinetic; SAE=serious adverse event 
Note:   
• 
Blood samples for PK assessment may be collected at 8, 12, and 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 healthcare 
professionals to go to patients' homes. 
• 
The hour (±range) indicate sample collection timing relative to dosing.  Precise PK sample times (hour and 
minute) are recorded. 
• 
If an SAE occurs associated with dosing, an additional PK sample may be collected at 4 to 8 hours postdose on 
the day of dosing, where blood volume permits (see Section 6.5.5.4). 
• 
See Section 7.2.7 for additional information on PK assessments. 
 


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TABLE OF CONTENTS 
SPONSOR PROTOCOL APPROVAL ...........................................................................................2 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
PROTOCOL SYNOPSIS ................................................................................................................4 
TABLE OF CONTENTS ...............................................................................................................20 
LIST OF TABLES .........................................................................................................................23 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................25 
1. 
INTRODUCTION ......................................................................................................28 
1.1. 
Disease Overview .......................................................................................................28 
1.2. 
Lumasiran ...................................................................................................................29 
1.2.1. 
Summary of Nonclinical Data with Lumasiran ..........................................................29 
1.2.2. 
Summary of Clinical Data with Lumasiran ................................................................30 
1.3. 
Study Design Rationale ..............................................................................................31 
1.4. 
Dose Rationale ............................................................................................................31 
1.5. 
Benefit-Risk Assessment ............................................................................................33 
2. 
OBJECTIVES AND ENDPOINTS ............................................................................34 
3. 
INVESTIGATIONAL PLAN .....................................................................................35 
3.1. 
Summary of Study Design ..........................................................................................35 
3.2. 
Duration of Treatment ................................................................................................36 
3.3. 
Duration of Study .......................................................................................................36 
3.3.1. 
Definition of End of Study for an Individual Patient .................................................36 
3.4. 
Number of Planned Patients .......................................................................................36 
3.5. 
Method of Assigning Patients to Treatment Groups ..................................................36 
3.6. 
Blinding ......................................................................................................................36 
3.7. 
Data Monitoring Committee .......................................................................................37 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................37 
4.1. 
Inclusion Criteria ........................................................................................................37 
4.2. 
Exclusion Criteria .......................................................................................................37 
4.3. 
Removal from Study Drug or Assessment .................................................................38 
4.3.1. 
Discontinuation of Study Drug or Declining Procedural Assessments ......................38 
4.3.2. 
Stopping a Patient’s Study Participation ....................................................................39 
4.3.2.1. 
Patient or Legal Guardian Stops Participation in the Study .......................................39 


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4.3.2.2. 
Withdrawal of Consent to Process the Patient’s Personal Data .................................40 
4.3.2.3. 
Investigator or Sponsor Stops Participation of a Patient in the Study ........................40 
4.3.2.4. 
Recording Reason for Stopping a Patient’s Study Participation ................................40 
4.3.3. 
Lost to Follow-Up.......................................................................................................40 
4.3.4. 
Replacement of Study Patients ...................................................................................41 
5. 
TREATMENTS AND OTHER REQUIREMENTS ..................................................41 
5.1. 
Treatments Administered ............................................................................................41 
5.2. 
Study Drug ..................................................................................................................41 
5.2.1. 
Description ..................................................................................................................41 
5.2.2. 
Dose and Administration ............................................................................................41 
5.2.3. 
Dose Modifications .....................................................................................................43 
5.2.3.1. 
Liver Function Test Criteria for Withholding, Monitoring and Stopping 
Lumasiran Dosing .......................................................................................................43 
5.2.4. 
Preparation, Handling, and Storage ............................................................................45 
5.2.5. 
Packaging and Labeling ..............................................................................................46 
5.2.6. 
Accountability .............................................................................................................46 
5.3. 
Concomitant Medications and Procedures .................................................................46 
5.4. 
Treatment Compliance ................................................................................................47 
5.5. 
Other Requirements ....................................................................................................47 
5.5.1. 
Contraception ..............................................................................................................47 
5.5.2. 
Dietary Restrictions ....................................................................................................48 
6. 
STUDY ASSESSMENTS ..........................................................................................48 
6.1. 
Screening Assessments ...............................................................................................48 
6.1.1. 
Retesting .....................................................................................................................49 
6.1.2. 
Rescreening .................................................................................................................49 
6.2. 
Efficacy Assessments .................................................................................................49 
6.2.1.1. 
Validity Criteria for Non-catheterized 24-hour Urine Collections .............................50 
6.3. 
Pharmacodynamic and Renal Assessments ................................................................50 
6.3.1. 
Urinary Oxalate:Creatinine Ratio ...............................................................................51 
6.3.2. 
Estimated Glomerular Filtration Rate .........................................................................51 
6.3.3. 
Renal Stone Events .....................................................................................................51 
6.3.4. 
Renal Ultrasound ........................................................................................................51 
6.4. 
Pharmacokinetic Assessments ....................................................................................52 


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6.5. 
Safety Assessments .....................................................................................................52 
6.5.1. 
Vital Signs ..................................................................................................................52 
6.5.2. 
Weight and Height/Length .........................................................................................52 
6.5.3. 
Physical Examination .................................................................................................53 
6.5.4. 
Electrocardiogram .......................................................................................................53 
6.5.5. 
Clinical Laboratory Assessments ...............................................................................53 
6.5.5.1. 
Immunogenicity ..........................................................................................................56 
6.5.5.2. 
Pregnancy Testing ......................................................................................................56 
6.5.5.3. 
Additional Liver Function Assessments .....................................................................56 
6.5.5.4. 
Maximum Blood Volume ...........................................................................................57 
6.5.6. 
Adverse Events ...........................................................................................................58 
6.5.6.1. 
Definitions ..................................................................................................................58 
6.5.6.2. 
Eliciting and Recording Adverse Events ....................................................................59 
6.5.6.3. 
Reporting Adverse Events of Clinical Interest to Sponsor/Designee .........................60 
6.5.6.4. 
Serious Adverse Events Require Immediate Reporting to Sponsor/Designee ...........60 
6.5.6.5. 
Sponsor Safety Reporting to Regulatory Authorities .................................................61 
6.5.6.6. 
Serious Adverse Event Notification to the Institutional Review 
Board/Independent Ethics Committee ........................................................................61 
6.5.6.7. 
Pregnancy Reporting ..................................................................................................61 
6.5.6.8. 
Overdose Reporting ....................................................................................................62 
6.5.7. 
COVID-19 Data Collection ........................................................................................62 
6.6. 
Biomarkers, DNA Genotyping, and Biospecimen Repository ...................................62 
6.7. 
Developmental Assessments ......................................................................................63 
6.8. 
Patient/Caregiver Experience and Impact Questionnaire ...........................................63 
7. 
STATISTICS ..............................................................................................................63 
7.1. 
Determination of Sample Size ....................................................................................63 
7.2. 
Statistical Methodology ..............................................................................................63 
7.2.1. 
Populations to be Analyzed ........................................................................................63 
7.2.2. 
Examination of Subgroups .........................................................................................64 
7.2.3. 
Handling of Missing Data ...........................................................................................64 
7.2.4. 
Baseline Evaluations ...................................................................................................64 
7.2.5. 
Efficacy Analyses .......................................................................................................64 
7.2.6. 
Pharmacodynamic Analysis........................................................................................64 


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7.2.7. 
Pharmacokinetic Analysis ..........................................................................................65 
7.2.8. 
Safety Analyses ..........................................................................................................65 
7.2.9. 
Immunogenicity Analyses ..........................................................................................65 
7.2.10. 
Interim Analysis ..........................................................................................................65 
7.2.11. 
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 
 
LIST OF TABLES 
Table 1: 
Schedule of Assessments –Primary Analysis Period (Screening through 
Month 6): All Patients ..................................................................................................8 
Table 2: 
Schedule of Assessments – Long-term Extension Period (Month 7 to Month 
35): Patient Weight <10 kg .........................................................................................11 
Table 3: 
Schedule of Assessments – Long-term Extension Period (Month 36 to End 
of Study): Patient Weight <10 kg ...............................................................................13 
Table 4: 
Schedule of Assessments – Long-term Extension Period (Month 9 to End of 
Study): Patient Weight ≥10 kg ...................................................................................16 
Table 5: 
Pharmacokinetic Time Points: All Patients ................................................................19 


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Table 6: 
Proposed Lumasiran Dosing Regimen in Pediatric and Adult PH1 Patients 
and Predicted Target Suppression and Urinary Oxalate Levels at Steady 
State ............................................................................................................................33 
Table 7: 
Weight-based Dosing Regimen ..................................................................................42 
Table 8: 
Monitoring and Dosing Rules for Asymptomatic Patients with Confirmed 
Isolated Elevations of ALT and/or AST >3× ULN, with No Alternative 
Cause Identified ..........................................................................................................45 
Table 9: 
24-hour Urine Collection Procedure by Study Visit...................................................50 
Table 10: Clinical Laboratory Assessments ...............................................................................55 
Table 11: Hepatic Assessments in Patients Who Experience Elevated Transaminases .............57 
Table 12: Maximum Allowable Total Blood Volume Collection Chart ....................................73 
 


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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 
CDC 
US Centers for Disease Control and Prevention 
Cmax 
Maximum plasma concentration 
CFR 
Code of Federal Regulations 
CL/F 
Apparent clearance 
COVID-19 
Coronavirus disease 2019 
DMC 
Data Monitoring Committee 
DNA 
Deoxyribonucleic acid  
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 
GalNAc 
N-acetylgalactosamine 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GO 
Glycolate oxidase 
24h 
24 hours 
HAO1 
Hydroxyacid oxidase 1 
HBV 
Hepatitis B virus 


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Abbreviation  
Definition 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
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 
LFT 
Liver function tests 
MAD 
Multiple-ascending dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
mMol 
Millimoles 
mRNA 
Messenger ribonucleic acid 
PD 
Pharmacodynamic 
PH1 
Primary hyperoxaluria type 1 
PK 
Pharmacokinetic 
PT 
Preferred Term 
q3M 
Once every 3 months 
qM 
Monthly (every 28 days) 
RNA 
Ribonucleic acid 
SAD 
Single-ascending dose 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SCr 
Serum creatinine 
siRNA 
Small interfering RNA 
SOC 
System Organ Class 
SUSAR 
Suspected unexpected serious adverse reaction 
t½β 
Elimination half-life 
tmax 
Time to maximum plasma concentration 


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Abbreviation  
Definition 
ULN 
Upper limit of normal 
US 
United States 
V/F 
Apparent volume of distribution 
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.[Mandrile 2014]  Overall, 43% of all patients diagnosed 
with PH1 had already progressed to ESRD at the time of diagnosis.  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 
frequent 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 
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. 
Lumasiran is currently in development for treatment of PH1 in adult and pediatric patients. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of lumasiran is 
provided in the current edition of the Investigator’s Brochure. 
1.2.1. 
Summary of Nonclinical Data with Lumasiran 
The pharmacology, safety pharmacology, drug metabolism and pharmacokinetics (PK), and 
toxicology of lumasiran were evaluated in a series of in vitro and in vivo nonclinical studies. 
Lumasiran was pharmacologically active in all tested species.  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. 
Genetic toxicity studies (bacterial reverse mutation, human peripheral blood lymphocyte 
chromosomal aberrations, and rat bone marrow micronucleus) assays were all negative at 
International Conference on Harmonisation (ICH) S2 (R1) limit doses. 


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The nonclinical toxicology program for lumasiran includes a repeat-dose exploratory toxicology 
study in rats, and a series of Good Laboratory Practice (GLP) studies, which include 
developmental and reproductive studies in rats and rabbits, a pilot study in juvenile rats, and 
repeat-dose studies of up to 25- and 36-weeks in duration in rats and nonhuman primates, 
respectively.  To support inclusion of pediatric patients, the GLP repeat-dose rat studies were 
initiated with post-weaning animals that were 4 to 5 weeks old.  Additionally, a GLP-compliant 
pilot neonatal and juvenile rat toxicology study in the rat that was initiated in postnatal-day 4 
pups, and continued through postnatal-day 33, did not identify any evidence of potential 
developmental safety concerns due to either the toxicology or pharmacology of lumasiran. 
The results of these nonclinical toxicology studies demonstrate a favorable safety profile for 
lumasiran and supports the use of lumasiran in the planned pivotal clinical studies in pediatric (as 
young as full-term neonates) and adult patients with PH1. 
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 3 clinical studies.  Study ALN-GO1-001 is a Phase 1/2 study, 
conducted in 2 parts (single-ascending dose [SAD; Part A] and multiple-ascending dose [MAD; 
Part B]), in healthy adult subjects and adult and pediatric patients (≥ 6 years old) with PH1.  The 
primary objective of Study ALN-GO1-001 is to evaluate the safety and tolerability of 
subcutaneously-administered lumasiran.  Secondary and exploratory objectives include the 
characterization of plasma and urine PK and the evaluation of the pharmacodynamic (PD) effect, 
including glycolate and oxalate levels (Part B only).  In this study, healthy adult subjects in Part 
A were randomized to receive a single-blind dose of lumasiran (0.3-6.0 mg/kg) or placebo (6:2).  
In Part B, patients ≥6 years of age with PH1 and preserved renal function 
(eGFR >45 mL/min/1.73 m2) were randomized 3:1 to receive single-blind doses of lumasiran or 
placebo at 1.0 mg/kg monthly for 3 doses, 3.0 mg/kg monthly for 3 doses, or 3.0 mg/kg every-3-
months for 2 doses.  Patients in Part B on placebo transitioned to the open-label portion of the 
study to receive lumasiran. 
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 complete Study ALN-GO1-001. 
Study ALN-GO1-003 (ILLUMINATE-A) is a Phase 3, randomized, double-blind, placebo-
controlled study to evaluate the efficacy and safety of lumasiran in children and adults (≥6 years 
old) with a documented diagnosis of PH1, elevated urinary oxalate, and relatively preserved 
renal function (GFR >45 mL/min/1.73m2).  The study consists of a randomized, controlled, 
double-blinded primary analysis period of 6 months, followed by an extension phase for 54 
months during which all patients are treated with lumasiran. 
Available safety data from clinical studies indicate that lumasiran has an acceptable safety and 
tolerability profile across all dosing regimens with no drug-related serious adverse events (SAEs) 
or study discontinuations attributed to drug administration.  Urinary oxalate levels are an 
important measurement in patients with PH1.  Preliminary data from ALN-GO1-001 showed a 
mean maximal reduction in urinary oxalate of >60% in patients with PH1 in Part B of the study 


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and a durable suppression of urinary oxalate over time.  Reduction in urinary oxalate was evident 
at the first assessment time point at Day 29. 
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 PH1.  In preclinical models and patients with PH1, SC administration 
of lumasiran demonstrated potent, dose-dependent pharmacologic activity resulting in substantial 
reductions in urinary oxalate.[Liebow 2017]  
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 
crystallization in the kidneys and urinary tract.  Reduced urinary oxalate excretion therefore is 
expected to reduce kidney stone burden and potentially stabilize renal function. 
This is a multicenter, multinational, open-label study designed to evaluate the efficacy, safety, 
PK, and PD of lumasiran in pediatric patients younger than 6 years old at consent with PH1 and 
relatively preserved renal function.  The primary endpoint for the study is percent change in 
urinary oxalate excretion from baseline to Month 6.  To evaluate the long-term safety and 
efficacy of lumasiran, all patients will continue to receive open-label lumasiran for up to 
54 months.  Patients will continue their current standard of care regimen, which may include 
hyperhydration, crystallization inhibitors, and/or pyridoxine therapy, until the Month 6 visit, 
after which they can adjust per the recommendations of their treating physician.  Current disease 
management options are presented in Section 1.1. 
Lumasiran is currently being investigated in 3 clinical studies in children and adults (≥6 years of 
age) with PH1 and relatively preserved renal function.  In this study, lumasiran will be evaluated 
in a similar but younger patient population (infants and young children <6 years of age).  
Enrolling infants and young pediatric patients in this study is acceptable given that lumasiran has 
been well tolerated in children ≥6 years of age, that PH1 presents as a pediatric disease with life-
threatening consequences, and there is a high unmet medical need in this population. 
1.4. 
Dose Rationale 
Preclinical data and clinical data from study ALN-GO1-001 Parts A and B in healthy subjects 
and in PH1 patients 6 years old and above were used to support PKPD modeling and dose 
selection for this study.  Population PKPD modeling in patients with PH1 demonstrated dose-
dependent oxalate reductions over the dose range studied (1.0 to 6.0 mg/kg once monthly or once 
every 3 months SC administration).  The PKPD model indicated that monthly administration 
leads to a more rapid decline in urinary oxalate levels compared to every-3-months dosing.  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 


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normal or near normal levels in PH1 patients.  Thus, based on PKPD modeling and simulation, 
the proposed lumasiran dose for pediatric and adult PH1 patients ages 6 and above is as follows: 
3.0 mg/kg monthly x 3 doses (loading dose) followed by 3.0 mg/kg every-3-months 
(maintenance dose) starting 1 month after the last loading dose.  At steady state, this regimen is 
expected to achieve approximately 90% target suppression and reduce urinary oxalate to 0.44 
mMol/24h/body surface area (BSA) (see Table 6). 
For the current study (Study ALN-GO1-004), the goal of dose selection is to achieve similar 
reductions in hepatic oxalate production and similar lumasiran systemic exposure relative to PH1 
patients 6 years old and above. 
 
The modeling and simulation approach in infants and children younger than 6 years old 
considered the changing rate of body weight and relative liver size in this young population.  The 
body weight of children nearly triples during the first year of life increasing from a median 
weight of 3.5 kg at birth to about 10 kg at 1 year of age (Centers for Disease Control and 
Prevention [CDC] Growth Chart [Kuczmarski 2002]).  Subsequently, the annual rate of body 
weight gain decreases to about 20% per year up to 6 years of age.  Furthermore, published 
reports and data from the United States National Centers for Health Statistics indicate children 
have proportionally larger liver size relative to body weight compared to adults. [Johnson 2005; 
National Centers for Health Statistics 2018] For an individual in the 0 to 1 year, 1 to 6 years, and 
6 years old age categories, the mean liver weight as a percentage of body weight were 3.5%, 
2.9%, and 2.0%, respectively, indicating that younger children are expected to have lower 
hepatocyte drug concentrations at a given dose level.  Moreover, based on allometric principles, 
children have faster drug clearance and drug clearance decreases with increasing weight.  Thus, 
considering the rapid growth rate, higher relative liver size, and faster drug clearance, children 
require a higher mg/kg dose to achieve similar systemic concentration and target suppression.  It 
should be noted that mg/kg dosing leads to a smaller absolute dose in children due to their lower 
body weight. 
Body weight categories for dose selection in this study were determined using CDC growth chart 
data.  For infants from birth to 1 year of age, the corresponding median weight ranges are 3.5 to 
10 kg, respectively.  For children ages 1 to 6 years old, the corresponding median weight ranges 
are 10 to 20 kg.  For children 6 years old and above, the median weight is 20 kg and above. 
Based on PKPD modeling and simulation, for children weighing less than 10 kg, corresponding 
to children from birth up to 1 year old, the proposed regimen is 6.0 mg/kg monthly x 3 doses 
(loading) followed by 3.0 mg/kg monthly (maintenance).  For children weighing ≥10 to 20 kg, 
which represent children ages 1 to 6 years old, the proposed regimen is 6.0 mg/kg monthly x 3 
doses (loading) followed by 6.0 mg/kg every-3-months (maintenance).  The proposed regimens 
in children birth to 6 years old are expected to result in target suppression of approximately 87 to 
90% and median urinary oxalate levels 0.41 to 0.47 mMol/24h/BSA (see Table 6). 


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Table 6: 
Proposed Lumasiran Dosing Regimen in Pediatric and Adult PH1 Patients 
and Predicted Target Suppression and Urinary Oxalate Levels at Steady 
State 
Body 
Weight 
(kg) 
Regimen 
Predicted GO 
Suppressiona  
(%) 
Predicteda,b Median 
Urinary Oxalate 
(mMol/24h/BSA) 
Loading 
Maintenance 
<10 
6.0 mg/kg qM x3  
3.0 mg/kg qM 
86.5% 
0.47 
10 – <20 
6.0 mg/kg qM x3  
6.0 mg/kg q3M 
90.2% 
0.41 
≥20 
3.0 mg/kg qM x3  
3.0 mg/kg q3M 
89.7% 
0.44 
Abbreviations: BSA=body surface area; GO=glycolate oxidase; h=hour; qM=monthly (every 28 days), q3M=once 
every 3 months; UOx=urinary oxalate 
a All values are at steady state. 
b Values are for baseline UOx of 2.0 mMol/24h/BSA 
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, 
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 1/2 clinical study ALN-GO1-001, lumasiran, administered 
subcutaneously, demonstrated a potent, dose-dependent inhibition of glycolate oxidase resulting 
in decreased urinary oxalate and increased plasma and urinary glycolate.  Unlike oxalate, 
glycolate is highly soluble and readily excreted in the urine.  Thus, by reducing the production of 
oxalate, lumasiran is expected to 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. 
Based on the available safety data from the Phase 1/2 clinical study, lumasiran has been well 
tolerated with a favorable safety profile.  Most adverse events (AEs) 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, along 
with 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, females who achieve 


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child-bearing potential during the study must have a negative pregnancy test, cannot be breast 
feeding, and must be willing to use contraception as specified in the protocol (see Section 5.5.1). 
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 available safety data from the Phase 1/2 clinical study 
(ALN-GO1-001) and nonclinical studies, the benefit-risk assessment supports the evaluation of 
lumasiran in a Phase 3 study in infants and young children 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. 
2. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
 
• 
Evaluate the effect of lumasiran on urinary 
oxalate excretion 
• Percent change in urinary oxalate excretion 
from baseline to Month 6 
Secondary 
 
Extension Phase 
(Month 6 to End of Study) 
• Evaluate the long-term effects of lumasiran 
on urinary oxalate 
Extension Phase 
(Month 6 to End of Study) 
• Percent change in urinary oxalate excretion 
from baseline 
• Percentage of time that spot urinary 
oxalate:creatinine ratio is at or below the 
near-normalization threshold (≤1.5 × ULN) 
Duration of Study 
• Evaluate the effects of lumasiran on 
additional measures of urinary oxalate  
 
 
• Evaluate the effects of lumasiran on plasma 
oxalate 
• Characterize the pharmacokinetics (PK) of 
lumasiran 
• Evaluate the effect of lumasiran on renal 
function 
Duration of Study 
• Absolute change in urinary oxalate excretion 
from baseline  
• Proportion of patients with urinary oxalate 
excretion ≤ the upper limit of normal (ULN) 
and ≤ 1.5 x ULN  
• Change (percent and absolute) in plasma 
oxalate from baseline 
• Plasma PK parameters of lumasiran  
• Change from baseline in estimated 
glomerular filtration rate (eGFR) 
Exploratory 
 


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Objectives 
Endpoints 
• Evaluate effect of lumasiran on 
nephrocalcinosis 
• Evaluate the effect of lumasiran on the 
occurrence of renal stones 
• Evaluate the additional pharmacodynamic 
(PD) parameters of urinary glycolate and 
plasma glycolate 
• Evaluate growth parameters  
• Evaluate developmental milestones 
• Evaluate experiences of PH1 patients and/or 
caregivers during treatment with lumasiran 
• Assess for antidrug antibodies (ADA) against 
lumasiran 
• Change from baseline in nephrocalcinosis as 
assessed by renal ultrasound  
• Change in frequency of renal stone events 
• Change in urinary glycolate and plasma 
glycolate 
• Change in growth parameters (z-scores) from 
baseline over time 
• Changes in developmental milestones over 
time 
• Changes in patient and/or caregiver 
experience as evaluated by a 
patient/caregiver survey 
• Frequency of ADA 
Safety 
 
• To evaluate the safety and tolerability of 
lumasiran 
• Frequency of AEs 
 
3. 
INVESTIGATIONAL PLAN 
3.1. 
Summary of Study Design 
This is a multicenter, multinational, open-label study designed to evaluate the efficacy, safety, 
PK, and PD of lumasiran in pediatric patients with PH1 who are younger than 6 years old and 
have relatively preserved renal function.  All eligible patients will be administered open-label 
lumasiran; no control group will be assessed. 
Patients will be screened from Day -60 to Day -1 to determine eligibility.  Consented patients 
meeting eligibility criteria will receive their first dose of subcutaneously administered lumasiran 
on Day 1.  Lumasiran will be administered SC utilizing weight-based dosing, with dose 
adjustments for interval weight gain, as specified in Section 5.2.2. 
Patients will return to the clinical center for follow-up assessment of efficacy, safety, tolerability, 
PK, PD, and patient and caregiver experience and burden according to the schedule of 
assessments through the last study visit.  Safety assessments will include collection of AEs, 
clinical laboratory tests, vital sign assessments, electrocardiograms (ECGs), physical 
examinations, and concomitant medications. 
For all patients, single-void urine samples (in triplicate) will be collected during screening to 
establish baseline and then serially per the Schedules of Assessment (see Table 1, Table 2, 
Table 3, and Table 4). 
For patients able to provide 24-hour urine samples, three 24-hour urine collections will be 
scheduled during screening to establish baseline urinary oxalate levels.  At Month 6, three 24-
hour urine collections will be scheduled within 14 days prior to the Month 6 dose for patients 
who are able to provide 24-hour urine samples.  For patients unable to provide 24-hour urine 
samples, a single catheterized collection may be requested. 


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This study will consist of 2 periods: a 6-month primary analysis period followed by a long-term 
extension period.  During the 6-month primary analysis period, patients will undergo efficacy 
and safety assessments every 2 weeks for the first month and monthly thereafter.  During the 
long-term extension period of up to 54 months, dosing will continue and visits will occur at least 
every-3-months.   
Patients who discontinue study drug early will be asked to return for follow-up visits (see 
Section 4.3.1). 
3.2. 
Duration of Treatment  
The duration of treatment with lumasiran is up to 60 months. 
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, with a month 
defined as 28 days. 
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 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 20 patients including at least 1 patient <12 months of 
age with weight <10 kg at consent.  Patients who discontinue study drug or stop participation in 
the study prior to Month 6 may be replaced (see Section 4.3.4), and the analysis of data 
collection prior to discontinuation is addressed in the statistical analysis plan. 
3.5. 
Method of Assigning Patients to Treatment Groups 
Patients will not be assigned to treatment groups.  Dosing will be determined by the patient’s 
weight (see Section 5.2.2). 
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 interactive response system (IRS). 
3.6. 
Blinding 
While this is an open-label study, pharmacodynamic assessment data will not be distributed to 
the sites until after the patient has completed the Month 6 visit.  Site personnel should refrain 
from obtaining or viewing local oxalate or glycolate assessments, except as medically indicated. 


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3.7. 
Data Monitoring Committee 
An independent Data Monitoring Committee (DMC) will oversee the safety and overall conduct 
of this study, providing input to the Sponsor.  The DMC will operate under the rules of a charter 
that will be reviewed and approved by 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. Have reached at least 37 weeks estimated gestational age (full-term infant) but less than 6 
years of age at consent. 
Patient and Disease Characteristics 
2. Documentation of PH1 as determined by genetic analysis prior to initial dosing. 
3. Urinary oxalate:creatinine ratio greater than the upper limit of normal based on age on at 
least 2 of 3 single-void collections during screening. 
4. If taking therapeutic vitamin B6 (pyridoxine), must have been on stable regimen for at 
least 90 days before screening, and is able to remain on this stable regimen until at least 
the Month 6 visit.  Dose adjustments for interval weight gain are acceptable. 
Informed Consent 
5. Legal guardian(s) is (are) willing and able to comply with the study requirements and to 
provide written informed consent; 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: 
Laboratory Assessments  
1. Has any of the following laboratory parameter assessments:  
a. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2× ULN for 
age during screening 
b. Total bilirubin >1.5×ULN during screening.  Patients with elevated total bilirubin that 
is secondary to documented Gilbert’s syndrome are eligible if the total bilirubin is 
<2× ULN 
2. Has known active human immunodeficiency virus (HIV) infection, or evidence of current 
or chronic hepatitis C virus (HCV) or hepatitis B virus (HBV) infection. 
3. If ≥12 months old at screening, has an estimated glomerular filtration (GFR) of 
≤45 mL/min/1.73m2 (calculation will be based on the Schwartz Bedside Formula) at 


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screening; if <12 months old at screening, has serum creatinine value per the central 
laboratory above the ULN for age at screening. 
Prior/Concomitant Therapy 
4. Currently enrolled in another investigational drug study including the follow-up period, 
or less than 30 days or 5 half-lives (whichever is longer) since ending the drug study(s), 
or receiving other investigational agent(s). 
Medical Conditions 
5. Medical history includes clinical evidence of extrarenal systemic oxalosis as determined 
by the Investigator. 
6. Has undergone renal or liver transplantation or a liver transplant is anticipated in the 
6 months after the initial dose of lumasiran. 
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 allergic reaction to an oligonucleotide or GalNAc. 
9. History of intolerance to subcutaneous (SC) injection(s). 
Contraception 
10. For female patients who may achieve menarche during the study, is not willing to comply 
with the contraceptive requirements during the study period, as described in 
Section 5.5.1. 
4.3. 
Removal from Study Drug or Assessment 
Patients or their legal guardians are free to discontinue study drug and/or stop protocol 
procedural assessments, or participation in the study as a whole at any time and for any reason, 
without penalty to their continuing medical care.  The Investigator or the Sponsor may 
discontinue study drug or 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 or declining procedural assessments 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. 
4.3.1. 
Discontinuation of Study Drug or Declining Procedural Assessments 
Reasons for discontinuation of study drug include any of the following: 
• Significant violation of the protocol 
• AE 
• Non-adherence to treatment regimen 
• Pregnancy 
• Lost to follow-up 


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• Other reason (non-AE) 
• Or, study is terminated by the Sponsor 
Patients who are pregnant will be discontinued from study drug dosing immediately (see 
Section 6.5.6.7 for reporting and follow-up of pregnancy).  A positive urine pregnancy test 
should be confirmed by a serum pregnancy test prior to discontinuing the study drug. 
Patients who discontinue study drug and/or decline procedural assessments should not be 
automatically removed from study.  In general, patients who discontinue study drug dosing for 
any reason will be encouraged to remain on the study to complete the remaining assessments so 
that their experience is captured in the final analyses. 
If this occurs, the Investigator is to discuss with the patient the appropriate processes for 
discontinuation from study drug and must discuss with the patient the options for continuation of 
the Schedules of Assessments (see Table 1, Table 2, Table 3, and Table 4), including different 
options for follow-up and collection of data (eg, in person, by phone, by mail, through family or 
friends, or from options not involving patient contact, such as communication with other treating 
physicians or from review of medical records), including endpoints and AEs, and must document 
this decision in the patient’s medical records. 
If a patient discontinues dosing due to an AE, including SAEs, the event should be followed as 
described in Section 6.5.6.  When a patient discontinues study drug dosing, the primary reason 
must be recorded in the electronic case report form (eCRF).  Patients who discontinue study drug 
and remain on study may receive treatment consistent with local standard practice for their 
disease per Investigator judgement, as applicable. 
Patients who discontinue from study drug during the 6-month treatment period (defined as the 
time the first dose of study drug is administered on Study Day 1 through completion of the 
Month 6 assessments) will be encouraged to remain on the study and complete assessments 
(including 24-hour urine collections, but excluding PK assessments) through Month 6 (see 
Table 1).  They will also be asked to complete safety follow-up visits, once every 3 months, per 
the safety follow-up schedule (see Table 3 or Table 4) for up to 12 months after the last dose of 
lumasiran, or until PD recovery (whichever is earlier). 
Patients who discontinue study drug after Month 6 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, per the safety follow-up schedule (see Table 3 or Table 4) for up to 
12 months after the last dose of lumasiran, or until PD recovery (whichever is earlier). 
PD recovery is defined as urinary oxalate >70% of baseline, and plasma glycolate <30% above 
baseline or ≤ the ULN (see Section 3.3.1). 
4.3.2. 
Stopping a Patient’s Study Participation 
4.3.2.1. 
Patient or Legal Guardian Stops Participation in the Study 
A patient or their legal guardian may stop participation in the study at any time.  A patient or 
legal guardian considering stopping participation in the study should be informed that the patient 
can discontinue study drug and/or decline procedural assessments and remain in the study to 
complete their study assessments, through the Month 6 visit, including follow-up, or 


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alternatively may complete any minimal assessments for which the patient or legal guardian 
consents as described in Section 4.3.1.  If a patient or legal guardian still chooses to discontinue 
study drug and stop participation in all follow-up prior to the completion of the 6-month 
treatment period, every effort should be made to conduct early the assessments scheduled to be 
performed at the Month 6 visit (see Table 1). 
If the patient does not wish to or is unable to continue further study participation, the Investigator 
is to discuss with the patient appropriate procedures for stopping participation in the study.  Data 
collected from the patient can continue to be used. 
In addition, in the countries where the collection and processing of the patient data is based on 
the patient consent, if a patient withdraws consent to collect and process his/her data (see 
Section 4.3.2.2), as applicable, patient data up to the withdrawal of consent will be included in 
the analysis of the study.  In addition, where permitted, publicly available data (such as 
appropriate national or regional vital status registry or other relevant databases) can be included 
after withdrawal of consent, where available and allowable by local law. 
4.3.2.2. 
Withdrawal of Consent to Process the Patient’s Personal Data 
Where allowed by local law, the patient may decide to withdraw consent to collect, store, and 
use biological samples and, as applicable, other personal data, 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 
the 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. 
4.3.2.3. 
Investigator or Sponsor Stops Participation of a Patient in the Study 
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 are 
best maintained if all enrolled patients continue study assessments and follow-up even if study 
drug is discontinued. 
Termination of the clinical study and site closure are described in Section 8.1.6. 
4.3.2.4. 
Recording Reason for Stopping a Patient’s Study Participation 
The primary reason that a patient’s study participation is stopped must be recorded in the 
appropriate section of the electronic case report form (eCRF) and all efforts will be made to 
complete and report the observations as thoroughly as possible.  If a patient’s study participation 
is stopped due to an AE, including SAEs, the event should be followed as described in 
Section 6.5.6. 
4.3.3. 
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:  


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• The site must attempt to contact the patient or legal guardian and reschedule the 
missed visit as soon as possible and counsel the patient or legal guardian on the 
importance of maintaining the assigned visit schedule and ascertain if the patient or 
legal guardian wishes [for the patient] to continue in the study, 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 or legal guardian (where possible, 3 
telephone calls and, if necessary, a certified letter to the patient’s last known mailing 
address or local equivalent methods).  These contact attempts should be documented 
in the patient’s medical record. 
• Should the patient or legal guardian continue to be unreachable, the patient will be 
considered to have stopped participation in the study. 
• For patients who are lost to follow-up, the Investigator can search publicly available 
records (where permitted and allowed by local law) to ascertain survival status.  This 
ensures that the outcome of the study is as comprehensive as possible. 
4.3.4. 
Replacement of Study Patients 
Patients who discontinue the study drug or stop participation in the study prior to Month 6 may 
be replaced at the Sponsor’s discretion, and the analysis of data collection prior to 
discontinuation is addressed in the statistical analysis plan.  Patients who discontinue the study 
drug or stop participation in the study after Month 6 will not be replaced. 
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 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. 
5.2.2. 
Dose and Administration 
Patients will be administered lumasiran as an SC injection at the dose and regimen based on their 
weight category as described in Table 7.  Patients will receive 3 loading doses, once monthly (at 
Day 1, Month 1, and Month 2) at a dose based on body weight category.  At Month 3 and 
beyond, patients will receive lumasiran either monthly (patients weighing <10 kg) or every 3 


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months (patients weighing ≥10 kg) at the maintenance dose.  For patients who are on a monthly 
dosing regimen, study drug administration must be at least 21 days apart. 
Study drug injections will be administered under the supervision of the Investigator.  The site 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. 
Dosing will be permitted at a location other than the study center (for example, the patient’s 
home) by a healthcare professional with the oversight of the Investigator at all time points, 
provided the patient has tolerated at least 1 dose of lumasiran administered in the clinic.  
However, continued study drug administration at the study center should be considered for 
patients who have ongoing study drug-related AEs, worsening injection site reactions with repeat 
dosing, or for anyone in the opinion of the Investigator who would benefit from clinical 
observation following dosing. 
If the patient is unable to come to the study site, and a visit by a healthcare professional is not 
possible due to circumstances related to the COVID-19 pandemic, lumasiran may be 
administered by 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 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.   
Table 7: 
Weight-based Dosing Regimen 
Weight 
Loading Dose 
(Day 1, Month 1, Month 2) 
Maintenance Dose 
(Month 3 and Beyond) 
<10 kg 
6.0 mg/kg monthly for 3 
months 
3.0 mg/kg monthly 
≥10 to <20 kg 
6.0 mg/kg monthly for 3 
months 
6.0 mg/kg every 3 months 
≥20 kg 
3.0 mg/kg monthly for 3 
months 
3.0 mg/kg every 3 months 
For patients who weigh <20 kg, the dose will be based on a weight obtained within 7 days prior 
to dosing.  During periods of time when the COVID-19 pandemic impedes the ability of these 
patients to travel to the study site or healthcare professionals to go to patients' homes, a weight 
from up to 6 weeks prior to the planned monthly dose or up to 4 months prior to the planned 
quarterly dose may be used to calculate the amount of lumasiran to be administered. 
For patients who weigh ≥20 kg, the dose may be based on a weight obtained up to 4 months prior 
to the planned quarterly dose. 
Patients with weight increases crossing the threshold for the next weight-based dosing category 
(<10 kg to ≥10 kg or <20 kg to ≥20 kg) will follow the new dosing regimen for the remainder of 
the study or until the next dosing category threshold is reached (ie, patients will not switch back 
to the lower-weight dosing schedule if their body weight subsequently decreases). 


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Patients in maintenance dosing who transition from <10 kg to ≥10 kg will continue to receive 
monthly doses at 3.0 mg/kg until the next visit that coincides with Table 4, whereby they will  
follow every-3-months dosing as per Table 4 until the end of the study. 
If a patient does not receive a dose of lumasiran 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 consecutive doses, the Investigator, in consultation with the Medical 
Monitor, will discuss whether the patient will be able to continue the study (see Section 4.3). 
Patients whose disease progresses to requiring a dialysis regimen will continue on their planned 
dosing regimen prior to starting dialysis therapy.  The lumasiran dose will be administered as 
soon as feasible following the end of dialysis, eg, within 2 hours of completing the dialysis 
session.  If a patient does not receive a dose of lumasiran 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. 
Additional details can be found in the Pharmacy Manual.  In addition, instructions and 
procedures related to administration of lumasiran by a 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. 
Liver Function Test Criteria for Withholding, Monitoring and Stopping 
Lumasiran Dosing  
1. For patients who weigh <20 kg, liver function test (LFT) results (see Table 10) are to be 
obtained within 7 days prior to dosing and results are to be reviewed prior to each dose of 
lumasiran.  During periods of time when the COVID-19 pandemic impedes the ability of 
patients to travel to the study site or healthcare professionals to go to patients' homes and 
LFT assessments are not feasible within 7 days prior to the dose, LFT test results up to 
6 weeks prior to the planned monthly dose or up to 4 months prior to the planned 
quarterly dose may be reviewed to determine whether the dose can be administered.  
For patients who weigh ≥20 kg, LFT results may be reviewed up to 4 months prior to the 
planned quarterly dose to determine whether the dose can be administered. 
2. Consult the Laboratory Manual for the blood draw priority list based on patient weight.  
Central laboratory results are preferable.  If not available, local laboratory results may be 
used; however, if a local assessment is drawn, a serum chemistry sample must also be 
drawn for analysis at the central laboratory. 
3. For any ALT or AST elevation >3× ULN, central laboratory results should be used to 
guide subsequent monitoring as detailed in Table 8. 


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4. 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 8 and Table 11. 
5. 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 international normalized 
ratio (INR) ≥1.5, permanently discontinue dosing. 
6. 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 8: 


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Table 8: 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 11 (all assessments to be performed; see Section 6.5.5.4 for 
guidance on maximal pediatric blood volumes) 
• 
Hematology, serum chemistry, LFT per Table 10  
• 
Coagulation (prothrombin time, partial thromboplastin time, 
international normalized ratio) 
• 
Monitor at least every two weeks: LFT per Table 10 
• 
If elevation persists for ≥2 months, must discuss with the Medical Monitor 
before continuing dosing 
>5× to 8× ULN 
• 
Hold lumasiran 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 11 (all assessments to be performed once) 
• 
Hematology, serum chemistry, LFT per Table 10  
• 
Coagulation (prothrombin time, partial thromboplastin time, 
international normalized ratio) 
• 
Monitor at least weekly: LFT per Table 10 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 by the central laboratory of 
the transaminase value 
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; LFT=liver function tests; 
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 caregiver, dosing may be prepared and 
administered by the 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 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 and Procedures 
Use of concomitant medications and procedures will be recorded on the patient’s CRF as 
specified in the Schedules of Assessment (see Table 1, Table 2, Table 3, and Table 4).  This 
includes all prescription medications, vaccines, herbal preparations, over the counter 
medications, vitamins, and minerals.  Any changes in medications during the study must be 
recorded on the CRF. Patients should not start new medication regimens during the study, 
including regimens of vitamins or herbal medication, without consultation with the Investigator.  
If patients use nonsteroidal anti-inflammatory drugs 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 a stable 
regimen for at least 90 days before screening and remain on this stable regimen during the 
screening period and through at least the Month 6 visit.  Dose adjustments for interval weight 
gain are permitted.  Patients should avoid high dose vitamin C preparations within 4 days prior to 
oxalate assessments. 
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 at least until the Month 6 visit.  Standard of care treatment may be 
adjusted after Month 6 in accordance with clinical judgement.  If pyridoxine therapy is 
discontinued, pyridoxine levels should be assessed for at least the next 2 timepoints indicated in 
the Schedules of Assessment.  Consultation with the Medical Monitor is required if treated with 
any new emerging products.   


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For other permitted concomitant medications administered subcutaneously, do not administer in 
same injection site area as the study drug, for at least 7 days after the last dose of study drug. 
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 CRF.  Concomitant medication will be coded using an 
internationally recognized and accepted coding dictionary. 
5.4. 
Treatment Compliance 
Compliance with study drug administration will be verified by study staff. 
5.5. 
Other Requirements 
5.5.1. 
Contraception 
Females who experience menarche during the course of the study should be asked to commit to 
true sexual abstinence for the remainder of their study participation and for 90 days after last 
dose administration.  If a patient instead prefers to initiate contraception, the Investigator must 
approve the selected method. 
Birth control methods which are considered highly effective 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 (except low-dose gestagens), implantable, injectable, or 
transdermal hormonal methods 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 for up to 90 days after the last 
dose of study drug. 
Investigators should advise females of childbearing potential of the most appropriate birth 
control method available within their country taking into account local medical practice. 
For male patients, no contraception is required.  However, use by adolescent males of 
contraception (condom) may be required in some countries, eg, France, in order to comply with 
local requirements as described in the corresponding patient informed consent forms. 
The Investigator will ensure that adolescent patients, and their legal representatives if applicable, 
are adequately informed about contraceptive requirements and the need for contraception once a 
patient initiates heterosexual intercourse.  The need for contraception and compliance with 


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contraception requirements will be assessed at every visit for adolescent patients, and pregnancy 
testing will be performed before every dose for postmenarcheal females throughout the course of 
the study (see Section 6.5.5.2).  
5.5.2. 
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 are provided in Table 1, Table 2, Table 3, and Table 4.  
Additional information on the collection of study assessments will be detailed in the Study 
Manual. 
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 collection of blood and urine samples, measurement of vital 
signs, length/height and weight, abbreviated physical examination/body system assessment, and 
preparation and administration of study drug (at the discretion of the Investigator). 
6.1. 
Screening Assessments 
An informed consent form (ICF) that has been approved by the appropriate Institutional Review 
Board (IRB)/Independent Ethics Committee (IEC) must be signed by the legal guardian (with 
patient assent, as applicable) before the Screening procedures are initiated.  All legal guardians 
will be given a copy of the signed and dated ICF and assent form, as applicable. 
Patients will be screened to ensure that they meet all the inclusion criteria and none of the 
exclusion criteria.  Rescreening of patients is permitted with consultation of the Medical Monitor 
(see Section 6.1.2). 
Patient demographic data and medical history/disease history will be obtained.  Non-serious 
events occurring after signing of the ICF and prior to study drug administration will be captured 
as medical history.  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 AGXT mutation analysis will be collected during screening for patients who 
do not have documented PH1 genetic analysis to confirm eligibility. 
If serum creatinine and liver function laboratory assessments are collected greater than 30 days 
prior to Day 1, repeat the assessment and review results prior to initial dosing.  
For all patients, single-void urine samples (in triplicate) will be collected during screening to 
establish baseline.  In addition, for patients able to provide 24-hour urine samples, three 24-hour 
urine collections will be scheduled during screening to establish baseline urinary oxalate levels.  
24-hour urine collections are the preferred method of evaluating urinary oxalate levels and 
patients are strongly encouraged to complete these collections during supervised visits unless 
their legal guardians are already familiar with the collection procedures.  For patients unable to 


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provide 24-hour urine samples, a single catheterized collection will be obtained, when allowed, 
during screening. 
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 should be documented.  Laboratory values can be retested once during Screening 
provided that 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 due to a transient condition observed at 
Screening (eg, prohibited medications that were subsequently discontinued) may be allowed to 
return for rescreening after consultation with the Medical Monitor.  The legal guardian 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 
24-hour urine collections are the preferred method of evaluating urinary oxalate levels.  Since 
not all patients will be able to provide 24-hour urine samples, single-void urine samples (in 
triplicate) will be collected throughout the study in all patients.  Table 9 shows the 24-hour urine 
collection procedure by study visit. 
In children who are able to comply with 24-hour urine collection procedures, 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 (see Table 1, Table 2, Table 3, and Table 4).  
Urinary oxalate concentrations will be analyzed centrally using a validated assay.  Non-
catheterized 24-hour urine collections must meet pre-specified validity criteria (see 
Section 6.2.1.1).  The duration of collection and volume of urine in the collection will be 
recorded in the eCRF. 
For patients who are able to comply with the 24-hour urine collection procedure, three 24-hour 
urine collections will be scheduled during screening to establish baseline urinary oxalate 
excretion.  For Month 6, three 24-hour urine collections will be scheduled within 14 days prior to 
the Month 6 dose to evaluate changes in oxalate concentrations over the first 6-month interval.  
A single 24-hour collection will be scheduled at Month 12 and then every 6 months thereafter. 
Patients able to comply with 24-hour urine collections will either bring a 24-hour urine collection 
to the clinic, courier samples to the laboratory, or have their 24-hour urine collected during an 
inpatient stay at the time of the study visit. 
For patients who are unable to comply with 24-hour urine collections, a single catheterized 
24-hour collection will be obtained, when allowed, at both baseline and Month 6.  Catheterized 
collections may be performed at the discretion of the Investigator and with the consent of the 
legal guardian.  Catheterized collections will be considered complete if there is no documented 
urine loss during the collection. 


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All patients will have triplicate single-void samples collected within 7 days prior to dosing, as 
specified in the Schedules of Assessment (see Table 1, Table 2, Table 3, and Table 4); and either 
single or triplicate collections within 7 days prior to dosing as specified in the Schedules of 
Assessment (see Table 3 or Table 4).  First morning voids are the preferred sample, when 
feasible.  Samples may be collected as an outpatient prior to the visit or collected during the 
study visit prior to dosing, as applicable. 
Table 9: 
24-hour Urine Collection Procedure by Study Visit 
Study Visit and 24-hour Urine 
Collection Window 
Number of 24-hour 
Collections 
Notes 
Screening 
(within 60-day period prior to 
initial dosing)  
3 voided collections or 1 
catheterized collection (when 
allowed) 
Supervised 24-hour collections 
are encouraged unless 
patient/caregiver already 
familiar with collection 
procedure.  
Month 6 
(within 14 days prior to dosing) 
3 voided collections or 1 
catheterized collection (when 
allowed) 
Supervised 24-hour collections 
are encouraged unless 
patient/caregiver already 
familiar with collection 
procedure.  
Month 12 and Every 6 Months 
Through End of Study 
1 voided collection 
-- 
6.2.1.1. 
Validity Criteria for Non-catheterized 24-hour Urine Collections 
A urine collection will be considered valid if each of the following criteria are met: 
• The collection is between 18-26 hours in duration between the initial discarded void 
and the last void or attempt to void. 
• No voids are missed between the start and end time of the collection. 
• The 24-hour creatinine content is at least 5 mg/kg as assessed by the study central lab. 
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 Assessment (see Table 1, Table 2, Table 3, and Table 4).  All blood and urine 
samples will be collected prior to dosing, if applicable.  Optional collections may be performed 
at the discretion of the Investigator. 
All PD assessments will be analyzed centrally.  Pharmacodynamic assessment data will not be 
distributed to the sites until after the patient has completed the Month 6 visit.  Site personnel 
should refrain from obtaining or viewing local oxalate or glycolate assessments, except as 


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medically indicated.  Details regarding the processing and aliquoting of samples for storage and 
analyses will be provided in the Laboratory Manual. 
Where local regulations allow, and infrastructure is in place, home nursing may be used to 
collect urine and blood samples. 
6.3.1. 
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 single-void 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 (see Table 1, Table 2, Table 3, and Table 4).  eGFR (mL/min/1.73 m2) 
will be calculated in patients ≥12 months of age at the time of the assessment to evaluate renal 
function during the study.  The calculation will be based on the Schwartz Bedside Formula 
(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 6.5.6.1). 
6.3.4. 
Renal Ultrasound 
Renal ultrasounds will be obtained locally, at the timepoints specified in the Schedules of 
Assessment (see Table 1, Table 2, Table 3, and Table 4).  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 3 months after the intended timepoint for assessments scheduled prior to 
Month 12, and up to 9 months after the intended timepoint for visits at Month 12 and later.  
Renal ultrasound will be performed according to instructions provided in the Study Manual in a 
standardized manner.  Renal ultrasounds will be reviewed centrally. 


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6.4. 
Pharmacokinetic Assessments 
Blood samples will be collected for assessment of lumasiran PK parameters and possible 
metabolite analysis (as necessary) at the time points in the Schedules of Assessment (see Table 1, 
Table 2, Table 3, and Table 4). 
Plasma PK parameters, 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 calculated for the 
lumasiran plasma concentration profiles.  A detailed schedule of time points for the collection of 
blood samples for PK analysis is in Table 5.  In addition, if an SAE occurs associated with 
dosing, an additional PK sample may be collected at 4 to 8 hours postdose on the day of dosing, 
where blood volume permits (see Section 6.5.5.4). 
Lumasiran plasma concentrations will be determined using a validated assay.  Details regarding 
sample volumes to be collected, and the processing, shipping, and analysis of the samples will be 
provided in the Laboratory Manual. 
6.5. 
Safety Assessments 
The assessment of safety during the study will consist of the surveillance and recording of AEs, 
including SAEs, recording of concomitant medication and measurements of vital signs, weight 
and height/length, ECG findings, and laboratory tests.  Clinically significant abnormalities 
observed during the physical examination will be recorded.  
6.5.1. 
Vital Signs 
Vital signs will be measured as specified in the Schedules of Assessment (see Table 1, Table 2, 
Table 3, and Table 4) and include blood pressure, heart rate, body temperature, and respiratory 
rate.  On dosing days, vital signs will be measured predose.  On Day 1 only, vital signs will also 
be measured 30 ± 10 minutes postdose.  When vital signs and blood sample collection occur at 
the same time, vital signs should be performed before blood samples are drawn, where possible. 
Vital signs should be measured after the patient has rested comfortably for 10 minutes, when 
feasible.  Blood pressure should be taken using the same limb, when feasible.  Body temperature 
in degrees Celsius will be obtained via oral, tympanic, or axillary methods.  Heart rate will be 
counted for a full minute and recorded in beats per minute, and respiration rate will be counted 
for a full minute and recorded in breaths per minute. 
Additional vital sign assessments, as medically indicated, may be added at the discretion of the 
Investigator, or as per DMC advice. 
Vital signs results will be recorded in the eCRF. 
6.5.2. 
Weight and Height/Length 
Height/length will be measured in centimeters.  Standing height should be captured for patients 
≥24 months old who are able to stand independently.  Supine length should be captured for 
patients <24 months old or those unable to stand independently.  All height/length measurements 
should be performed in triplicate.  Body weight will be measured in kilograms.  Height and body 


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weight measurements will be collected as specified in the Schedules of Assessment (see Table 1, 
Table 2, Table 3, and Table 4) and in Section 5.2.2; measurements will be recorded in the eCRF. 
6.5.3. 
Physical Examination 
Full and abbreviated physical examinations will be conducted according to the Schedules of 
Assessment (see Table 1, Table 2, Table 3, and Table 4).  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. 
Abbreviated physical examinations (body system assessment) will include examination of at 
least the following:  respiratory, cardiovascular, dermatological, gastrointestinal, and 
musculoskeletal systems. 
If a visit is conducted offsite (eg, at the patient’s home), a body system assessment may be 
performed in lieu of a physical examination. 
Clinically significant abnormalities observed during the physical examination are recorded on 
the medical history or AE eCRF as appropriate. 
6.5.4. 
Electrocardiogram 
Single 12-lead ECGs will be obtained predose, when applicable, at the timepoints specified in 
the Schedules of Assessment (see Table 1, Table 2, Table 3, and Table 4).  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 3 months after the intended timepoint for assessments 
scheduled prior to Month 12, and up to 9 months after the intended timepoint for visits at Month 
12 and later.  12-lead ECGs will be locally read.   
When ECG and blood sample collection occur at the same time, ECGs should be performed 
before blood samples are drawn and when the patient is calm. 
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 on 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. 
6.5.5. 
Clinical Laboratory Assessments 
The following clinical laboratory tests will be evaluated by a central laboratory, except in cases 
where it is not feasible to perform all tests centrally due to blood draw volume limits, ie, in 
infants and very young patients, hematology, and biochemistry panels may be performed locally, 
with central laboratory confirmation of any abnormalities.  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 


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may be requested.  Clinical laboratory assessments are listed in Table 10 and will be assessed as 
specified in the Schedules of Assessment (see Table 1, Table 2, Table 3, and Table 4).  
While local laboratory results may be used for urgent clinical and dosing decisions, on the day of 
the visit assessments, all laboratory assessments specified in Table 10 which are performed at a 
local laboratory 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. 
Consult the Laboratory Manual for the blood draw priority list based on patient weight (see 
Section 6.5.5.4). 
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 10: 
Clinical Laboratory Assessments 
Hematology 
Complete blood count with differential 
 
Serum Chemistry 
Sodium 
Potassium 
BUN 
Phosphate 
Uric acid 
Albumin 
Total protein 
Calcium 
Glucose 
Carbon dioxide 
Creatinine and eGFR (using Bedside Schwartz 
formula for children ≥12 months at assessment) 
Chloride 
Pyridoxine (vitamin B6)a 
 
Liver Function Tests 
 
AST 
ALP 
ALT 
Serum bilirubin (total and direct) 
Urinalysis 
Visual inspection for appearance and color 
Bilirubin 
pH (dipstick) 
Nitrite 
Specific gravity 
RBCs 
Ketones 
Urobilinogen 
Albumin (optional) 
Leukocytes 
Glucose 
Microscopy (if clinically indicated) 
Protein 
 
Abbreviations:  ALP=alkaline phosphatase; ALT= alanine aminotransferase; AST=aspartate aminotransferase; 
BUN=blood urea nitrogen; eGFR=estimated glomerular filtration rate; PH1=primary hyperoxaluria type 1; 
RBC=red blood cell 
a Pyridoxine (vitamin B6) is required through Month 12 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. 


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6.5.5.1. 
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 Assessment (see Table 1, Table 2, Table 3, and Table 4).  A blood sample to evaluate antidrug 
antibodies will be collected at the Early Termination visit, if applicable. 
Details regarding the processing, shipping, and analysis of the samples will be provided in the 
Laboratory Manual. 
6.5.5.2. 
Pregnancy Testing 
A pregnancy test will be performed for pediatric/adolescent females upon initiation of menarche.  
A serum pregnancy test will be performed at the first visit after menarche and urine pregnancy 
tests will be performed thereafter per the Schedule of Assessment and any time pregnancy is 
suspected.  Pregnancy testing may be performed offsite by a caregiver if a caregiver will be 
administering study drug.  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 become pregnant are not eligible for continued study drug 
treatment.  Any female with a positive 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 until the pregnancy outcome is known (see Section 6.5.6.7 for follow-
up instructions). 
6.5.5.3. 
Additional Liver Function Assessments 
LFT results should be reviewed prior to dosing as described in Section 5.2.3.1. 
Additional laboratory assessments will be performed in patients who experience any LFT 
abnormalities as outlined in Section 5.2.3.1.  Consult the Laboratory Manual for the blood draw 
priority list based on patient weight. 
Following the occurrence of elevated liver transaminases or other LFT abnormalities per central 
laboratory, and as per the blood draw priority list, all assessments in Table 11 will be performed 
one time, as well as hematology, serum chemistry, and LFT assessments from Table 10, and 
other assessments or evaluations per Investigator discretion, as appropriate.  See Section 6.5.5.4 
for the maximum blood volumes that can be collected from pediatric patients in this study. 
Monitoring and dose modification will also be performed as outlined in Section 5.2.3.1. 


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Table 11: 
Hepatic Assessments in Patients Who Experience Elevated Transaminases 
Extended Hepatic Panel 
HBsAg, HBc antibody IgM and IgG 
Parvovirus B19 
HAV antibody IgM 
HHV-6 
HCV antibody 
Anti-nuclear antibodies 
HCV RNA PCR – qualitative and quantitative 
Anti-smooth muscle antibodies 
HEV antibody IgM 
Anti-LKM1 antibody 
Herpes Simplex Virus 1 and 2 antibody IgM, IgG 
Anti-mitochondrial antibodies 
Herpes Zoster Virus IgM, IgG 
Anti-SLA 
Epstein-Barr Virus antibodies, IgM and IgG 
Ferritin 
Cytomegalovirus antibodies, IgM, IgG 
Ceruloplasmin 
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 and drugs of abuse 
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; 
IgG=immunoglobulin G antibody; IgM=immunoglobulin M antibody; LKM1=liver/kidney microsome-1 antibody 
MRI=magnetic resonance imagery; PCR=polymerase chain reaction; RNA=ribonucleic acid; SLA=soluble liver 
antigen. 
Note: 
• 
All assessments will be measured in central laboratory or locally when not feasible to conduct centrally, ie, 
due to blood volume restrictions. The full panel of assessments should only be performed once; individual 
assessments may be repeated, as needed. Assessments can be staggered due to blood volume limitations (see 
Section 6.5.5.4). 
 
6.5.5.4. 
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 12 from 
the Feinstein Institute for Medical Research Human Subject Protection Program Guidance 
Document (see Appendix Section 10.2).[Feinstein_Institute 2013]  Consult the Laboratory 
Manual for the blood draw priority list based on patient weight. 


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6.5.6. 
Adverse Events 
6.5.6.1. 
Definitions 
Adverse Event  
According to the ICH E2A guideline Definitions and Standards for Expedited Reporting, and 21 
CFR 312.32, IND Safety Reporting, an 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 
An 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 inpatient 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).  A systemic reaction which includes the 


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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 6.5.6.2 and 
Section 6.5.6.3, respectively. 
Adverse Event Severity 
AEs 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 AE. 
Changes in severity should be documented in the medical record to allow assessment of the 
duration of the event at each level of severity.  AEs 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. 
6.5.6.2. 
Eliciting and Recording Adverse Events 
Eliciting Adverse Events 
The patient or legal guardian should be asked about medically relevant changes in the patient’s 
health since the last visit.  The patient or legal guardian should also be asked if the patient has 
been hospitalized, had any accidents, used any new medications, or changed concomitant 
medication routines (both prescription and over-the-counter).  In addition to patient observations, 
AEs will be documented from any clinically relevant laboratory findings, physical examination 
findings, ECG changes, or other findings that are relevant to patient safety. 


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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.  
Events occurring after signing of the ICF and before study drug administration will be captured 
as medical history (see Section 6.1), while AEs that occur after study drug administration, and  
baseline events that worsen after study drug administration, must be recorded as AEs. 
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) on both the eCRF and the SAE form. 
For AEs that are considered AEs of clinical interest (see Section 6.5.6.1), the supplemental AEs 
of Clinical Interest eCRF should be completed.  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 an Injection Site Reaction Signs or 
Symptoms eCRF, recording additional information regarding each injection site reaction that is 
entered on the AE eCRF (eg, symptom(s), injection site location, follow-up actions taken, etc.). 
6.5.6.3. 
Reporting Adverse Events of Clinical Interest to Sponsor/Designee 
For AEs that are considered AEs of clinical interest (see Section 6.5.6.1), the Sponsor or its 
designee should be notified within 24 hours using a supplemental AEs of Clinical Interest eCRF. 
6.5.6.4. 
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 6.5.6.1 must be reported to the 
Sponsor or designee within 24 hours from the time that clinical study center staff first learns of 
the event.  All SAEs must be reported regardless of the relationship to study drug. 


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The initial report should include at least the following information: 
• Patient’s study number 
• Description and date of onset of the event 
• Criterion for serious 
• Preliminary assignment of relationship to study drug, and 
• Investigator/site information 
To report the SAE, complete the eCRF and the SAE form.  Within 24 hours of receipt of follow-
up information, the Investigator must update the eCRF and 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. 
6.5.6.5. 
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. 
6.5.6.6. 
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. 
6.5.6.7. 
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 6.5.6.4. 


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6.5.6.8. 
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 for the patient’s weight category.  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. 
All reports of overdose (with or without an AE) must be reported within 24 hours to the Sponsor 
or designee. 
6.5.7. 
COVID-19 Data Collection 
Information on the 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. 
Where allowed per local regulations, ethics committee (IRB/IEC) approval, and legal guardian 
consent (and patient assent, where applicable), samples will be collected as part of this study 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. 
Biological specimens will be collected at the intervals indicated in the Schedules of Assessment 
(see Table 1, Table 2, Table 3, and Table 4).  Potential exploratory investigations may include 
DNA, RNA, or biochemical metabolite assessments as they relate to disease progression, 
efficacy or safety. 
The biospecimen repository will also include residual material from routine samples (safety 
laboratory samples, PK samples, etc.) that are obtained during the study. 
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. 
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, study participants will be advised during the 
informed consent process of these biobanking details and the potential for exploratory 
investigation of their samples. 


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6.7. 
Developmental Assessments 
The Vineland Adaptive Behavior Scale will be assessed at the timepoints specified in the 
Schedules of Assessment (see Table 1, Table 2, Table 3, and Table 4), and may be completed up 
to 4 months after the intended time point during periods of time when the COVID-19 pandemic 
impedes the ability of patients to travel to the study site, to assess the achievement of 
developmental milestones over time.  This tool assesses the domains of communication, daily 
living skills, socialization, and motor skills.  The survey can be completed in 20-60 minutes. 
6.8. 
Patient/Caregiver Experience and Impact Questionnaire 
The patient/caregiver experience and impact questionnaire will be used to assess the experiences 
of patients living with PH1 and their caregivers, including the impact of the disease on their lives 
with respect to their need to relocate/travel for treatment, and the number and type of healthcare 
providers they use.  The questionnaire will also assess the impact on patients' education and 
caregivers’ employment and education, as applicable.  This questionnaire will be completed by 
the caregiver (reporting on behalf of the patient for patient experience items) at the time points 
specified in the Schedules of Assessment (see Table 1, Table 2, Table 3, and Table 4) when 
feasible, and may be completed up to 4 months after the intended time point during periods of 
time when the COVID-19 pandemic impedes the ability of patients to travel to the study site. 
7. 
STATISTICS 
A Statistical Analysis Plan (SAP) will be finalized before database lock.  The plan will detail the 
implementation of the statistical analyses in accordance with the principle features stated in the 
protocol.  For information on study endpoints, see Section 2. 
7.1. 
Determination of Sample Size 
The planned enrollment for the study is 20 patients.  The sample size was determined based on 
feasibility considerations, not power calculations. 
7.2. 
Statistical Methodology 
Statistical analyses will be primarily descriptive in nature.   
For categorical variables, summary tabulations of the number and percentage of patients within 
each category (with a category for missing data) will be presented.  For continuous variables, 
descriptive statistics will be presented (ie, number of patients, mean, median, standard deviation, 
standard error, minimum and maximum values). 
All data will be provided in by-patient listings.  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:  
• Safety Analysis Set:  All patients who received any amount of study drug will be 
grouped according to the treatment actually received. 


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• Efficacy Analysis Set:  All patients who received any amount of lumasiran and have 
at least one valid spot urinary oxalate:creatinine ratio value at baseline and at least 
one valid spot urinary oxalate:creatinine ratio value from assessment(s) at Month 3 to 
Month 6. 
• PK Analysis Set:  All patients who received any amount of study drug and have at 
least 1 postdose blood sample for PK parameters and have evaluable PK data. 
The Safety Analysis Set will be used for safety analyses and sensitivity analysis of efficacy.  The 
Efficacy Analysis Set will be used to evaluate efficacy endpoints.   The PK Analysis Sets will be 
used to conduct PK analyses. 
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 
Handling of missing data will be described in the SAP. 
7.2.4. 
Baseline Evaluations 
Demographics and other disease-specific baseline characteristics will be summarized for the 
Safety Analysis Set. 
7.2.5. 
Efficacy Analyses 
The analysis of the efficacy endpoints will be based upon the Efficacy Analysis Population.  
Descriptive summaries will be provided for the primary endpoint percent change in urinary 
oxalate excretion from baseline to Month 6.  The analysis will be performed using a mixed-effect 
model for repeated measures (MMRM) approach.  The outcome variable is percent change from 
baseline in spot urine oxalate:creatinine ratio.  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 spot urine 
oxalate:creatinine ratio across Month 3 through Month 6 at which the treatment effect is 
expected to have reached steady state.  Furthermore, given the variability of spot 
oxalate:creatinine ratio, averaging the values across these visits will yield stable treatment 
estimates.  Sensitivity analyses will be conducted to assess the robustness of the estimates and 
will be detailed in the SAP.  In addition, descriptive statistics scheduled visit will be presented 
and by-patient listings and figures will be generated displaying all assessments (scheduled and 
unscheduled). 
Secondary efficacy and exploratory endpoints which are continuous will be summarized 
descriptively in the same manner as described above.  For binary endpoints, the number and 
percentages of patients in each category will be displayed at each visit. 
7.2.6. 
Pharmacodynamic Analysis 
Urinary oxalate and glycolate excretion, urinary oxalate:creatinine ratio and plasma levels of 
oxalate and glycolate will be summarized over time for all patients in the Efficacy Analysis Set. 


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7.2.7. 
Pharmacokinetic Analysis 
Pharmacokinetic analyses will be conducted using noncompartmental methods. 
Pharmacokinetic parameters include, but will not be limited to:  Cmax, tmax, t½β, AUC, CL/F, and 
V/F.  Other parameters may be calculated, if deemed necessary. 
7.2.8. 
Safety Analyses 
The main parameter is the frequency of treatment-emergent AEs (hereafter referred to simply as 
AEs). Safety parameters also include vital signs, ECGs, clinical laboratory assessments and 
physical exams.  Extent of exposure will be summarized overall. 
Prior and concomitant medications will be classified according to the World Health Organization 
(WHO) Drug Dictionary.  Results will be tabulated by Anatomical Therapeutic Chemical (ATC) 
Classification System and Preferred Term (PT). 
AEs will be classified according to the Medical Dictionary for Regulatory Activities (MedDRA) 
overall.  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 
Antidrug antibody results will be summarized descriptively by patient and overall. 
7.2.10. 
Interim Analysis 
There may be interim analyses performed to support regulatory and/or publications requests. 
7.2.11. 
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 or legal guardian is given full and adequate oral and 
written information about the nature, purpose, possible risk and benefit of the study.  The patient 
or their legal guardian must also be notified that they are free to discontinue from the study at 
any time.  The patient or legal guardian should be given the opportunity to ask questions and 
allowed time to consider the information provided.  Legal guardian(s) must provide informed 
consent and the patient should provide assent per local regulations and institutional standards. 
The patient’s or 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 or assent, as 
applicable, prior to performing any further research interventions and/or procedures involving 
that patient per local regulations and institutional standards. 
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 or 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 (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 or IEC approval of the protocol, and all materials approved by the IRB or IEC for this 
study including the legal guardian consent form and patient 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.  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. 


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The Investigator is also responsible for providing the IRB or IEC 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. 
Major changes in this research activity, except those to remove an apparent immediate hazard to 
the patient, must be reviewed and approved by the Sponsor and the IRB or IEC that approved the 
study.  Amendments to the protocol must be submitted in writing to the Investigator’s IRB or 
IEC and the Regulatory Authority for approval before patients are enrolled under the amended 
protocol, and legal guardians must be re-consented to the most current version of the ICF (and 
patient 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 potential 
serious breach of the protocol.  A serious breach is a breach that is likely to affect to a significant 
degree the safety and rights of a study participant or the reliability and robustness of the data 
generated in the clinical trial. 
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: 


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• 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 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 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 


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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 
data verification.  The Investigator should contact the Sponsor and 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 separate publication by 
Institution or Investigator may not be submitted for publication until after this primary 
manuscript is published or following the period of 12 months after completion of the study at all 
centers.  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.   
http://www.feinsteininstitute.org/wp-content/uploads/2013/02/Maximum-Blood-Draw-
Limits.pdf. 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. 
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. 
Johnson TN, Tucker GT, Tanner MS,Rostami-Hodjegan A. Changes in liver volume from birth 
to adulthood: a meta-analysis. Liver Transpl. 2005 Dec;11(12):1481-93. 
Kamoun A,Lakhoua R. End-stage renal disease of the Tunisian child: epidemiology, etiologies, 
and outcome. Pediatr Nephrol. 1996 Aug;10(4):479-82. 
Kuczmarski RJ, Ogden CL, Guo SS, Grummer-Strawn LM, Flegal KM, Mei Z, et al. 2000 CDC 
Growth Charts for the United States: methods and development. Vital Health Stat 11. 2002 
May(246):1-190. 
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. 


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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. 
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. 
National Centers for Health Statistics. The National Health and Nutrition Examination Survey 
(NHANES). CDC; 2018 [updated 31 July 2018; cited 2018]; program of studies designed to 
assess the health and nutritional status of adults and children in the United States]. Available 
from: https://www.cdc.gov/nchs/nhanes/index.htm. 
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 Schwartz Bedside Formula for patients ≥12 months of age at the 
time of assessment. 
 
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 12, which 
was adapted from the Feinstein Institute for Medical Research Human Subject Protection 
Program Guidance Document. 
Table 12: 
Maximum Allowable Total Blood Volume Collection Chart 
Body 
Weight  
Body 
Weight  
Total Blood 
Volume  
Maximum Allowable 
Volume in a 24-hour Period 
Total Volume Collected in a 
30-day Period 
2.5% of 
total blood 
volume 
3% of 
total blood 
volume  
5% of 
total blood 
volume  
10% of 
total blood 
volume  
(kg) 
(lbs) 
(mL) 
(mL) 
(mL) 
(mL) 
(mL) 
1 
2.2 
100 
2.5 
3 
5 
10 
2 
4.4 
200 
5 
6 
10 
20 
3 
6.6 
240 
6 
7.2 
12 
24 
4 
8.8 
320 
8 
9.6 
16 
32 
5 
11 
400 
10 
12 
20 
40 
6 
13.2 
480 
12 
14.4 
24 
48 
7 
15.4 
560 
14 
16.8 
28 
56 
8 
17.6 
640 
16 
19.2 
32 
64 
9 
19.8 
720 
18 
21.6 
36 
72 
10 
22 
800 
20 
24 
40 
80 
11-15 
24-33 
880-1200 
22-30 
26.4-36 
44-60 
88-120 
16-20 
35-44 
1280-1600 
32-40 
38.4-48 
64-80 
128-160 
21-25 
46-55 
1680-2000 
42-50 
50.4-60 
64-100 
168-200 
26-30 
57-66 
2080-2400 
52-60 
62.4-72 
104-120 
208-240 
31-35 
68-77 
2480-2800 
62-70 
74.4-84 
124-140 
248-280 
36-40 
79-88 
2880-3200 
72-80 
86.4-96 
144-160 
288-320 
41-45 
90-99 
3280-3600 
82-90 
98.4-108 
164-180 
328-360 
46-50 
101-110 
3680-4000 
92-100 
110.4-120 
184-200 
368-400 
51-55 
112-121 
4080-4400 
102-110 
122.4-132 
204-220 
408-440 
56-60 
123-132 
4480-4800 
112-120 
134.4-144 
224-240 
448-480 
61-65 
134-143 
4880-5200 
122-130 
146.4-156 
244-260 
488-520 
66-70 
145-154 
5280-5600 
132-140 
158.4-168 
264-280 
528-560 
71-75 
156-165 
5680-6000 
142-150 
170.4-180 
284-300 
568-600 
76-80 
167-176 
6080-6400 
152-160 
182.4-192 
304-360 
608-640 
81-85 
178-187 
6480-6800 
162-170 
194.4-204 
324-340 
648-680 
86-90 
189-198 
6880-7200 
172-180 
206.4-216 
344-360 
688-720 
91-95 
200-209 
7280-7600 
182-190 
218.4-228 
364-380 
728-760 
96-100 
211-220 
7680-8000 
192-200 
230.4-240 
384-400 
768-800 
Adapted from http://www.feinsteininstitute.org/wp-content/uploads/2013/02/Maximum-Blood-Draw-
Limits.pdf.[Feinstein_Institute 2013]  
 


Clinical Study Protocol ALN-GO1-004 
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Amendment 1.0 Summary of Changes, 09 August 2019 
 
Alnylam Pharmaceuticals 
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ALN-GO1-004 PROTOCOL AMENDMENT 1.0  
SUMMARY OF CHANGES DATED 09 AUGUST 2019 
ILLUMINATE-B: An Open-Label Study to Evaluate the Efficacy, Safety, 
Pharmacokinetics, and Pharmacodynamics of Lumasiran in Infants and Young Children 
with Primary Hyperoxaluria Type 1 
 
Rationale for Protocol Amendment 
The primary purpose for this protocol amendment is to increase the sample size of the study due 
to a lower than expected screening failure rate, and to align clinical objectives and endpoints 
across the Phase 3 program by shifting the evaluation of the effect of lumasiran on plasma 
oxalate from an exploratory objective to a secondary objective.  Several additional changes are 
being implemented as outlined below. 
An additional secondary endpoint for the Extension Phase of the study has been added to 
evaluate the effects of lumasiran on the duration of urinary oxalate reduction: 
• Percentage of time that spot urinary oxalate:creatinine ratio is at or below the near-
normalization threshold (≤1.5 × ULN) 
Clarifications have been added for the following: 
• Clarify that although the study is open-label, pharmacodynamic assessment data 
should not be distributed to sites until the patient has completed Month 6 
• Clarify that additional liver function tests are to be performed when no alternative 
cause of elevated transaminases is identified 
• Clarify that specific study assessments may be conducted at a location other than the 
study center by a home healthcare professional 
• Clarify that specific laboratory tests may be performed locally in cases where it is not 
feasible to perform laboratory tests centrally, with central confirmation of any 
laboratory abnormalities 
In addition to these changes, the following have been implemented for this study: 
• Added study drug dosing instructions for patients whose disease progresses to 
requiring a dialysis regimen during the study 
• Updated the description of the analysis populations and included description of the 
efficacy statisticial analysis methods  
A detailed summary of changes is provided in Table 1.  Corrections to typographical errors, 
punctuation, grammar, abbreviations, and formatting are not detailed. 
 


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Amendment 1.0 Summary of Changes, 09 August 2019 
 
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Table 1: 
Protocol Amendment 1.0 Detailed Summary of Changes 
The primary section(s) of the protocol affected by the changes in Protocol Amendment X are indicated.  The corresponding text has 
been revised throughout the protocol.  Deleted text is indicated by strikeout; added text is indicated by bold font. 
Description:  Added an additional endpoint for the evaluation of the effects of lumasiran on additional measures of urinary oxalate, and changed 
the evaluation of lumasiran on plasma oxalate levels from exploratory to secondary objectives and endpoints 
The primary change occurs in Section 2, Objectives and Endpoint 
Now reads: 
 


Clinical Study Protocol ALN-GO1-004 
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Objectives 
Endpoints 
Primary 
 
• 
Evaluate the effect of lumasiran on urinary 
oxalate excretion 
• Percent change in urinary oxalate excretion from 
baseline to Month 6 
Secondary 
 
Extension Phase 
(Month 6 to End of Study) 
• Evaluate the long-term effects of lumasiran on 
urinary oxalate 
Extension Phase 
(Month 6 to End of Study) 
• Percent change in urinary oxalate excretion from 
baseline 
• Percentage of time that spot urinary 
oxalate:creatinine ratio is at or below the near-
normalization threshold (≤1.5 × ULN) 
 
Duration of Study 
• Evaluate the effects of lumasiran on additional 
measures of urinary oxalate  
 
 
 
• Evaluate the effects of lumasiran on plasma 
oxalate 
• Characterize the pharmacokinetics (PK) of 
lumasiran 
• Evaluate the effect of lumasiran on renal function 
Duration of Study 
• Absolute change in urinary oxalate excretion 
from baseline  
• Proportion of patients with urinary oxalate 
excretion ≤ the upper limit of normal (ULN) and 
≤ 1.5 x ULN  
• Change (percent and absolute) in plasma 
oxalate from baseline 
• Plasma PK parameters of lumasiran  
• Change from baseline in estimated glomerular 
filtration rate (eGFR) 
Exploratory 
 
• Evaluate effect of lumasiran on nephrocalcinosis 
• Evaluate the effect of lumasiran on the occurrence 
of renal stones 
• Evaluate the additional pharmacodynamic (PD) 
parameters of urinary glycolate and plasma 
glycolate, and plasma oxalate 
• Evaluate growth parameters  
• Evaluate developmental milestones 
• Evaluate experiences of PH1 patients and/or 
caregivers during treatment with lumasiran 
• Assess for antidrug antibodies (ADA) against 
lumasiran 
• Change from baseline in nephrocalcinosis as 
assessed by renal ultrasound  
• Change in frequency of renal stone events 
• Change in urinary glycolate and plasma 
glycolate, and plasma oxalate 
• Change in growth parameters (z-scores) from 
baseline over time 
• Changes in developmental milestones over time 
• Changes in patient and/or caregiver experience as 
evaluated by a patient/caregiver survey 
• Frequency of ADA 
Safety 
 


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Amendment 1.0 Summary of Changes, 09 August 2019 
 
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Objectives 
Endpoints 
• To evaluate the safety and tolerability of 
lumasiran 
• Frequency of AEs 
Sections also containing this change:  
• 
Protocol Synopsis 
Description:  Updated the study sample size and referred to statistical analysis plan for analysis details 
The primary change occurs in Section 3.4, Number of Planned Patients 
Now reads: 
The planned enrollment for this study is up to 20 8 patients, including at least 4 patients ≥12 months of age at screening, 
and 1 patient <12 months of age with weight <10 kg at consent.  Patients who discontinue study drug or stop participation 
in the study prior to Month 6 may be replaced (see Section 4.3.4), and the analysis of data collection prior to 
discontinuation is addressed in the statistical analysis plan. 
Sections also containing this change:  
• 
Protocol Synopsis  
• 
Section 7.1, Determination of Sample Size 
• 
Section 4.3.4, Replacement of Study Patients 
Description:  Clarify that while the study is open-label, pharmacodynamic assessment data should not be distritubed to sites until the patient 
has completed Month 6 
The primary change occurs in Section 3.6, Blinding 
Now reads: 
Not applicable. While this is an open-label study, pharmacodynamic assessment data will not be distributed to the 
sites until after the patient has completed the Month 6 visit.  Site personnel should refrain from obtaining or 
viewing local oxalate or glycolate assessments, except as medically indicated. 
Sections also containing this change: 
• 
Section 6.3, Pharmacodynamic and Renal Assessments 
Description:  Clarify that additional liver function tests are performed when no alternative cause is identified. 
The change occurs in Section 5.2.3.1, LFT Criteria for Withholding, Monitoring and Stopping Study Drug Dosing item #3 


Clinical Study Protocol ALN-GO1-004 
ALN-GO1 (lumasiran) 
Amendment 1.0 Summary of Changes, 09 August 2019 
 
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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. 
c. b. If an alternative cause is found, provide appropriate care. 
b. c. If an alternative cause is not found, perform assessments per Table 8 and Table 11. 
Description:  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 Section 6, Study Assessments 
Now reads: 
The schedules of study assessments is provided in Table 1, Table 2, Table 3, and Table 4.  Additional information on the 
collection of study assessments will be detailed in the Study Manual. 
Where applicable country and local regulations and infrastructure for home healthcare allow, home healthcare may 
take place at a location other than the clinical trial site to perform study assessments, which may include collection 
of blood and urine samples, measurement of vital signs and weight, abbreviated physical exam, and preparation and 
administration of study drug (at the discretion of the Investigator).   
Sections also containing this change:  
• 
Table 2 and Table 3, Schedule of Assessments: a footnote was added to highlight the study visits where study drug dosing may be 
conducted by a home healthcare professional, where applicable country and local regulations and infrastructure allow (at the discretion 
of the Investigator, based on safety and tolerability). 
Description: Clarify that laboratory tests may be performed locally in certain cases. 
The primary change occurs in Section 6.5.5, Clinical Laboratory Assessments 
First paragraph 
now reads: 
The following clinical laboratory tests will be evaluated by a central laboratory, except in cases where it is not feasible to 
perform all tests centrally due to blood draw volume limits, ie, in infants and very young patients, hematology, 
coagulation, and biochemistry panels may be performed locally, with central laboratory confirmation of any 
abnormalities.  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 


Clinical Study Protocol ALN-GO1-004 
ALN-GO1 (lumasiran) 
Amendment 1.0 Summary of Changes, 09 August 2019 
 
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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 10 
and will be assessed as specified in the Schedules of Assessment (see Table 1, Table 2, Table 3, and Table 4). 
Sections also containing this change:  
• 
Table 11, Hepatic Assessments in Patients Who Experience Elevated Transaminases, footnote 
Description:  Added study drug dosing instructions for patients whose disease progresses to requiring a dialysis regimen during the study 
The primary change occurs in Section 5.2.2, Dose and Administration 
The last 
paragraph now 
reads: 
Patients whose disease progresses to requiring a dialysis regimen will continue on their planned dosing regimen 
prior to starting dialysis therapy.  The lumasiran dose will be administered as soon as feasible following the end of 
dialysis, eg, within 2 hours of completing the dialysis session.  If a patient does not receive a dose of lumasiran 
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. 
Additional details can be found in the Pharmacy Manual. 
Description:  Updated the analysis population definitions. 
The primary change occurs in Section 7.2.1, Populations to be Analyzed 
Now reads: 
The populations (analysis sets) are defined as follows:  
• 
Safety Analysis Set:  All patients who received any amount of study drug will be grouped according to the 
treatment actually received. 
• 
Efficacy Analysis Set: All patients who received any amount of lumasiran and have at least one valid spot 
urinary o:c ratio value at baseline and at least one valid spot urinary o:c ratio value from assessment(s) at 
Month 3 to Month 6. 
• 
PK Analysis Set:  All patients who received any amount of study drug and have at least 1 postdose blood sample 
for PK parameters and have evaluable PK data. 


Clinical Study Protocol ALN-GO1-004 
ALN-GO1 (lumasiran) 
Amendment 1.0 Summary of Changes, 09 August 2019 
 
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The Safety Analysis Set will be used for safety analyses and sensitivity analysis of efficacy.  The Efficacy Analysis Set 
will be used to evaluate efficacy endpoints. primary population used to evaluate efficacy, PD, and safety will be the 
Safety Analysis Set.  The PK Analysis Sets will be used to conduct PK analyses. 
Sections also containing this change: 
• 
Protocol synopsis 
• 
Section 7.2.5, Efficacy Analyses 
• 
Section 7.2.6, Pharmacodynamic Analysis 
Description:  Included description of the efficacy analysis methods 
The primary change occurs in Section 7.2.5, Efficacy Analysis 
First paragraph now reads: 
The analysis of the efficacy endpoints will be based upon the Safety Efficacy Analysis Population.  
Descriptive summaries will be provided for the primary endpoint percent change in urinary oxalate excretion 
from baseline to Month 6.  The analysis will be performed using a mixed-effect model for repeated 
measures (MMRM) approach.  The outcome variable is percent change from baseline in spot urine 
oxalate:creatinine ratio.  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 spot urine oxalate:creatinine ratio across Month 
3 through Month 6 at which the treatment effect is expected to have reached steady state.  
Furthermore, given the variability of spot oxalate:creatinine ratio, averaging the values across these 
visits will yield stable treatment estimates.  Sensitivity analyses will be conducted to assess the 
robustness of the estimates and will be detailed in the SAP.  In addition, descriptive statistics at each 
scheduled visit will also be presented and by-patient listings and figures will be generated displaying all 
assessments (scheduled and unscheduled). 
Description:  Removed text instructing to see sample priority list in the Study Reference Manual; this text was added in error 
The primary change occurs in Table 8, Monitoring and Dosing Rules for Asymptomatic Patients with Confirmed Isolated Elevations of ALT 
and/or AST >3× ULN, with No Alternative Cause Identified 
Table footnote now reads: 
Notes:  In addition to these criteria, other assessments or evaluations may be performed per Investigator discretion, as 
appropriate.  See the Study Manual for sample priority list. 
Description:  Updated the protocol date and title of the Sponsor’s approver 
These changes are not listed individually. 


Clinical Study Protocol ALN-GO1-004 
ALN-GO1 (lumasiran) 
Amendment 1.0 Summary of Changes, 09 August 2019 
 
Alnylam Pharmaceuticals 
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Description:  Correct typographical errors, punctuation, grammar, abbreviations, and formatting. 
These changes are not listed individually. 
 


Clinical Study Protocol ALN-GO1-004 
ALN-GO1 (lumasiran) 
Amendment 2 Summary of Changes, 04 May 2020 
Alnylam Pharmaceuticals 
Confidential 
1 
ALN-GO1-004 PROTOCOL AMENDMENT 2 
SUMMARY OF CHANGES DATED 04 MAY 2020 
ILLUMINATE-B: An Open-Label Study to Evaluate the Efficacy, Safety, 
Pharmacokinetics, and Pharmacodynamics of Lumasiran in Infants and Young Children 
with Primary Hyperoxaluria Type 1 
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 31 March 
2020, to assure the safety of study participants while minimizing risks to study integrity amid the 
COVID-19 pandemic.  These changes are in line with guidance from both the European 
Medicines Agency and the United States Food and Drug Administration on the conduct of 
clinical trials during the COVID-19 pandemic.[EMA 2020; FDA 2020]  The USMs are 
summarized in Section 1.1. 
This protocol amendment also incorporates changes that are not related to USMs.  After ongoing 
review and assessment of the safety data from studies conducted with lumasiran, modifications 
are designed to enhance patient safety and reduce patient burden regarding blood sampling.  
These changes are summarized in Section 1.2 and will not be implemented until appropriate 
Health Authority and Ethics Committee (EC) and/or Institutional Review Board (IRB) approval. 
1.1. 
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 changes were to be adopted immediately by the 
Investigator site per the Dear Investigator Letter.  
• Lumasiran dosing outside the study center by caregiver 
Following appropriate training on lumasiran administration, dosing will be permitted at a 
location other than the study center (eg, at home) by the caregiver at all time points under 
the oversight of the Investigator and following consultation with the medical monitor.  In 
addition, references to patient/caregiver instructions for administration and storage of 
study drug are now included within the protocol.  This measure is intended to remain in 
effect only during periods of time when the COVID-19 pandemic impedes the ability of 
patients to travel to the study site and healthcare professionals to go to patients' homes for 
dosing. 
In order to assure uniform and comprehensive training and to assure compliance with the 
dosing instructions, the sponsor has prepared both Investigator and caregiver-facing 
written materials. The caregiver materials will provide detailed guidance on the scope of 
the self-administration allowance and detailed instructions on procedures surrounding 
dosing. These materials serve as a supplement to virtual training that caregivers will 
receive. The site-facing materials outline the investigator responsibilities under the self-
administration scheme and provide a guide to the expectations around caregiver training. 


Clinical Study Protocol ALN-GO1-004 
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Amendment 2 Summary of Changes, 04 May 2020 
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In addition, investigators will make verbal contact with caregivers to assure compliance 
with protocol procedures and to assure that any adverse events or deviations are properly 
captured. 
• Time period to obtain weight for dose determination 
If the current procedure (weight obtained within 7 days prior to dose) is not possible due 
to the COVID-19 pandemic impacting activities at the study site or patient ability to 
access the site, the weight from up to 6 weeks prior to the planned monthly dose or up to 
4 months prior to the planned quarterly dose may be used to calculate the amount of 
lumasiran to be administered. 
Currently, the lightest patient in ALN-GO1-004 is 8.5 kilograms (kg), and the remaining 
patients are above 10 kg.  Due to the considerable deceleration in the growth curve after 
infancy, dosing based on weight obtained during prior visit or 6 weeks for those on 
monthly dosing and 4 months for those on quarterly dosing would result in minimal 
under-dosing of approximately 5% relative to dosing obtained within 7 days prior to 
dose. In addition, since all patients have received multiple doses and the expected liver 
accumulation of lumasiran at steady state, potential under-dosing by about 5% is not 
expected to meaningfully influence the efficacy of lumasiran. On the other hand, the 
flexibility of using weight from prior visit is expected to reduce the potential for missed 
doses, which will in turn result in persistent suppression of liver oxalate production and 
continued suppression of urinary oxalate levels. 
• Assessment of adverse events, concomitant medications, renal stone events, and 
healthcare utilization 
In situations where a study visit is unable to be completed at the site or offsite by a 
healthcare professional visit, the study physician (or delegate) will verbally contact the 
patient to assess any adverse events, concomitant medications, renal stone events, and 
healthcare utilization within the study visit window. 
• Liver function tests 
Liver function test (LFT) results are to be obtained within 7◦days prior to dosing and 
results are to be reviewed prior to each dose of lumasiran.  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, when LFT assessments are not feasible 
within 7 days prior to the dose, LFT test results up to 6◦weeks prior to the planned 
monthly dose or up to 4 months prior to the planned quarterly dose may be reviewed to 
determine whether the dose can be administered.  LFTs from the Week 2 visit must be 
reviewed prior to administration of the Month 1 dose. 
This change in the window for LFT assessment is supported by data from our clinical 
trials.  In the 75 patients with PH1 treated with lumasiran for a duration of up to 22 
months, no clinically significant changes in LFTs due to lumasiran have been observed.  
Based on available data, lumasiran has an acceptable hepatic safety profile. 
• Study visits windows 


Clinical Study Protocol ALN-GO1-004 
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Amendment 2 Summary of Changes, 04 May 2020 
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Except for assessments with other specified timing requirements, study assessments and 
dosing are to be performed within the following visit windows: 
Screening through Month 6 (Protocol Table 1):  Visit windows expanded from ±4 or ±7 
in protocol amendment 1 to ±14 days; visits at least 14 days apart 
After Month 7 for patients on monthly dosing (Protocol Table 2):  Visit windows 
expanded from ±7 to ±14 days; visits at least 21 days apart 
After Month 9 for patients on quarterly dosing (Protocol Table 4):  Visit windows 
expanded from ±14 to ±28 days 
• Pharmacokinetic assessments 
Blood samples for PK assessment should continue to be collected at 2 and 4 hours 
postdose. 
Blood samples for PK assessment may be collected at 8, 12, and 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 or healthcare professionals to go to patients' homes. 
• Vineland Adaptive Behavior Scale, and the Patient/Caregiver Experience and 
Impact Questionnaire 
Vineland Adaptive Behavior Scale, and the Patient/Caregiver Experience and Impact 
Questionnaire can be completed up to 4 months after the intended timepoint. 
• ECG and renal ultrasound assessments 
ECG and renal ultrasound assessments may be completed up to 3 months after the 
intended timepoint for assessments scheduled prior to Month 12, and up to 9 months after 
the intended timepoint for visits at Month 12 and later.  This expansion of the ECG 
assessment window is supported by results of a clinical QTc assessment and nonclinical 
cardiac safety assessment of lumasiran, which demonstrated that lumasiran does not have 
QTc prolongation properties. 
• Assessments required to be performed in clinic 
Abbreviated physical examination/body system assessment, safety laboratory collection 
(blood and urine), PK and PD blood collection, and blood collection for vitamin B6 
levels, ADA and exploratory analyses (blood and urine) assessments may be conducted 
offsite by a healthcare professional at all time points, where applicable country and local 
regulations and infrastructure allow. 
• Full physical examination 
If a visit is conducted offsite (eg, home), a body system assessment can be performed in 
lieu of a physical examination. 
• Impact of COVID-19 
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 CRF specific to COVID-19, will be 
provided separately. 


Clinical Study Protocol ALN-GO1-004 
ALN-GO1 (lumasiran) 
Amendment 2 Summary of Changes, 04 May 2020 
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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 
The removal of the requirement to perform coagulation studies after screening reduces patient 
burden regarding the frequency of blood samples and the volume of blood collected, while 
ensuring patient safety.  No safety signal pertaining to coagulation has been identified to date in 
any clinical study conducted with lumasiran.  This modification is particularly important for 
pediatric patients given the greater limits placed on blood collection volumes.  Additional 
changes to study conduct (outlined below) will not be implemented until appropriate HA and 
EC/IRB approval. 
• Remove the measurement of coagulation from routine chemistry surveillance 
laboratory assessments 
• Remove the requirement (after Month 12) for measurement of routine blood sample 
collection for pyridoxine (Vitamin B6) use as this was required to be stable up to 
Month 6 only.  After Month 6, changes to standard of care therapies are permitted and 
this will be captured in concomitant medications. 
• For patients on quarterly dosing (Table 4) during the long-term extension period, 
revised expectation to visit the site every 3 months to every 6 months after Month 24.  
Required assessments will be limited to weight, LFT laboratory assessments, single 
void urinary oxalate:creatinine, study dosing, and pregnancy testing if applicable, 
along with ongoing AEs, concomitant medications, and renal stone events 
information. 
A detailed summary of these changes is provided in Table 2.  Corrections to typographical 
errors, punctuation, grammar, abbreviations, and formatting (including administrative changes 
between protocol amendments 1 and 2) are not detailed. 
 
 


Clinical Study Protocol ALN-GO1-004 
ALN-GO1 (lumasiran) 
Amendment 2 Summary of Changes, 04 May 2020 
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2. 
PROTOCOL AMENDMENT 2 DETAILED SUMMARY OF CHANGES 
The primary section(s) of the protocol affected by the changes in Protocol Amendment 2 are indicated.  The corresponding text has 
been revised throughout the protocol.  Deleted text is indicated by strikeout; added text is indicated by bold font. 
Table 1: 
Urgent Safety Measures COVID-19-related Changes to be Adopted Immediately 
Purpose:  To expand study visit windows. 
The primary change occurs in Section 5.2.2, Dose and Administration 
Revised text:  For patients who weigh <20 kg, the dose will be based on a weight obtained within 7 days prior to dosing.  During 
periods of time when the COVID-19 pandemic impedes the ability of these patients to travel to the study site or healthcare 
professionals to go to patients' homes, a weight from up to 6 weeks prior to the planned monthly dose or up to 4 months prior 
to the planned quarterly dose may be used to calculate the amount of lumasiran to be administered. 
For patients who weigh ≥20 kg, the dose may be based on a weight obtained up to 4 months prior to the planned quarterly 
dose. 
Section(s) also reflecting this change:  
• Synopsis  
• Column headings of the Schedules of Assessments (Table 1 through Table 4) 
• Section 6.3.4, Renal Ultrasound  
• Section 6.5.4, Electrocardiogram 
• Section 6.7, Developmental Assessments  
• Section 6.8, Patient/Caregiver Experience and Impact Questionnaire 
Purpose:  Expand the use of offsite administration to include lumasiran dosing by the caregiver and provide additional instructions on 
self administration, and preparation, handling, and storage of the study drug. 
The primary change occurs in Section 5.2.2 Dose and Administration 
Revised text: Study drug injections will be administered under the supervision of the Investigator.  The site 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. 


Clinical Study Protocol ALN-GO1-004 
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Amendment 2 Summary of Changes, 04 May 2020 
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Dosing will be permitted at a location other than the study center (for example, the patient’s home) by a healthcare professional 
with the oversight of the Investigator at all time points, provided the patient has tolerated at least 1 dose of lumasiran 
administered in the clinic.  However, continued study drug administration at the study center should be considered for patients who 
have ongoing study drug-related AEs, worsening injection site reactions with repeat dosing, or for anyone in the opinion of the 
Investigator who would benefit from clinical observation following dosing. 
If the patient is unable to come to the study site, and a visit by a healthcare professional is not possible due to circumstances 
related to the COVID-19 pandemic, lumasiran may be administered by 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 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 or healthcare professionals to go to patients' homes for dosing. 
Section(s) also reflecting this change: 
• Bulleted notes beneath the Schedules of Assessments (Table 1 through Table 4) 
• Section 3.1, Summary of Study Design 
• Section 5.2.4. Preparation, Handling, and Storage 
• Section 5.4. Treatment Compliance 
Purpose: To reduce required collection timepoints prolonged clinic/home visits for PK assessments. 
The primary change occurs in Table 5 (Pharmacokinetic Time Points: All Patients) and the bulleted notes beneath 
Added text:  Blood samples for PK assessment may be collected at 8, 12, and 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 or healthcare professionals to go 
to patients' homes. 
Purpose:  To extend the window for LFT assessment prior to dosing.   
The primary change occurs in Section 5.2.3.1, Liver Function Test Criteria for Withholding, Monitoring and Stopping Lumasiran 
Dosing  
Revised text:  For patients who weigh <20 kg,  Lliver function test (LFT) results (see Table 10) are to be obtained within 7 days 
prior to dosing and results are to be reviewed prior to each dose of lumasiran.  During periods of time when the COVID-19 
pandemic impedes the ability of patients to travel to the study site or healthcare professionals to go to patients' homes and 
LFT assessments are not feasible within 7 days prior to the dose, LFT test results up to 6 weeks prior to the planned monthly 


Clinical Study Protocol ALN-GO1-004 
ALN-GO1 (lumasiran) 
Amendment 2 Summary of Changes, 04 May 2020 
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dose or up to 4 months prior to the planned quarterly dose may be reviewed to determine whether the dose can be 
administered.   
For patients who weigh ≥20 kg, LFT results may be reviewed up to 4 months prior to the planned quarterly dose to determine 
whether the dose can be administered.   
Section(s) also reflecting this change:  
• Section 5.2.2, Dose and Administration 
Purpose: To allow continuous assessments (collected throughout the study) to be assessed via remote contact. 
The primary change occurs in Table 1, Table 2, Table 3, and Table 4, Schedules of Assessment  
Added text: • In situations where a study visit is unable to be completed (either at the site or offsite by a healthcare 
professional), the Investigator (or delegate) will verbally contact the patient within the study visit window to assess 
concomitant medications, renal stone events, adverse events, and healthcare utilization. 
Purpose: Allow flexibility for scope of physical examination; pregnancy testing when offsite visits occur. 
The primary change occurs in 1) Section 6.5.3, Physical Examination, and 2) Section 6.5.5.2, Pregnancy Testing 
Added text:  1) Abbreviated physical examinations (body system assessment) will include examination of at least the following:  
respiratory, cardiovascular, dermatological, gastrointestinal, and musculoskeletal systems. 
If a visit is conducted offsite (eg, at the patient’s home), a body system assessment may be performed in lieu of a physical 
examination. 
2) Pregnancy testing may be performed offsite by a caregiver if a caregiver will be administering study drug.  
Purpose: Collect information related to the impact of the COVID-19 pandemic on patient participation in the study. 
The primary change occurs in an added Section 6.5.7, COVID-19 Data Collection 
Added text:  Information on the COVID-19 infection status of the patient, if known, and other information on the impact of the 
COVID-19 pandemic on the patient's participation in the study will be collected. 
Section(s) also reflecting this change:  
• Section 7.2 Statistical Methodology 
Purpose:  Revise and update informed consent instructions.  
The primary change occurs in Section 8.1.1, Informed Consent 


Clinical Study Protocol ALN-GO1-004 
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Amendment 2 Summary of Changes, 04 May 2020 
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Added text:  The Investigator will inform the patient/legal guardian if new information becomes available that may be relevant 
to the patient’s/legal guardian’s willingness to continue participation in the study.  Communication of this information should 
be documented.   
Purpose:  Revise and update ethical review instructions. 
The primary change occurs in Section 8.1.2, Ethical Review 
Added text:  In addition, the IRB or IEC must approve all advertising used to recruit patients for the study (except those that support 
the need to remove an apparent immediate hazard to the patient). 
 
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:  Removes the requirement (after Month 12) for measurement of routine blood sample collection for pyridoxine (Vitamin B6) 
use. 
The primary change occurs in the Table 2, Schedule of Assessments – Long-term Extension Period (Month 7 to Month 35): Patient Weight 
<10 kg   
Deleted text:  X was deleted from schedule of assessment timepoints later than Month 12. 
Table(s) also reflecting this change: 
• Removed entirely from Schedules of Assessments for the Long-term Extension Period (Table 3 and Table 4) 
• Table 10, Clinical Laboratory Assessments (footnote) 
Purpose:  To reduce the number of assessments conducted in the clinic after Month 24. 
The primary change occurs in Table 4, Schedule of Assessments Long-term Extension Period (Month 9 to End of Study): Patient 
Weight ≥10 kg 
Revised text: Removed Xs from Table 4 in order to: remove the abbreviated physical exam; revise routine safety laboratory 
assessments from every 3 months to once every 6 months (with the exception of LFTs); adjust blood samples collected for PD 
analyses to be optional every 3 months; reduce the number of single-void urine collections, and move exploratory blood and urine 
collections to the once every 6 months clinic visit. 
Purpose:  Removes the requirement for measurement of routine coagulation clinical laboratory assessments. 


Clinical Study Protocol ALN-GO1-004 
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Amendment 2 Summary of Changes, 04 May 2020 
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The primary change occurs in Section 6.5.5, Clinical Laboratory Assessments Table 10 
Revised text:  
Coagulation 
Prothrombin time 
International Normalized Ratio 
Partial Thromboplastin Time 
 
Section(s) also reflecting this change:  
• Section 5.2.3, Dose Modifications; Table 8: Monitoring and Dosing Rules for Asymptomatic Patients with Confirmed Isolated 
Elevations of ALT and/or AST >3× ULN, with No Alternative Cause Identified 
• Section 6.5.5.3, Additional Liver Function Assessments


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Amendment 2 Summary of Changes, 04 May 2020 
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3. 
REFERENCES 
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  
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