Clinical trial NCT05161936
Conditions: Recurrent Calcium Oxalate Kidney Stone Disease Elevated Urinary Oxalate Levels
Keywords: Calcium oxalate Kidney stones Elevated urinary oxalate Urinary oxalate
Sponsor: Alnylam Pharmaceuticals
Start date: 2022-01-27; Completion date: 2022-11-01
Enrollment: 2 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary purpose of this study is to evaluate the effect of lumasiran on the percent change in urinary oxalate excretion in patients with recurrent calcium oxalate kidney stone disease.

Detailed description:

Arms: arm 1: Participants will be administered lumasiran by subcutaneous (SC) injection. arm 2: Participants will be administered lumasiran by SC injection. arm 3: Participants will be administered placebo by SC injection.
Interventions: intervention 1: Lumasiran intervention 2: Placebo
Intervention descriptions: intervention 1: Lumasiran will be administered by SC injection. intervention 2: Placebo will be administered by SC injection.

Protocol documents:
Prot_000.pdf: 
 
 
Official Title:  A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO EVALUATE 
THE EFFICACY, SAFETY, PHARMACODYNAMICS, ANDPHARMACOKINETICS OF LUMASIRAN IN 
PATIENTS WITH RECURRENT CALCIUM OXALATE KIDNEY STONE DISEASE AND ELEVATED URINARY 
OXALATE LEVELS  
 
NCT Number:   
NCT05161936 
 
Document Date:   
Protocol, Version 2.0, 07 July 2022  




Clinical Study Protocol ALN-GO1-008 
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SPONSOR PROTOCOL APPROVAL 
 
I have read this protocol and I approve the design of this study. 
 
 
___________________________________________  
Date 
08-Jul-2022 | 9:15 PM EDT


Clinical Study Protocol ALN-GO1-008 
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INVESTIGATOR’S AGREEMENT 
 
I have read the ALN-GO1-008 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-GO1-008 
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PROTOCOL SYNOPSIS 
Protocol Title 
A Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy, Safety, 
Pharmacodynamics, and Pharmacokinetics of Lumasiran in Patients with Recurrent Calcium 
Oxalate Kidney Stone Disease and Elevated Urinary Oxalate Levels 
Short Title 
A Study to Evaluate Lumasiran in Adults with Recurrent Calcium Oxalate Kidney Stone Disease 
and Elevated Urinary Oxalate Levels 
Study Drug 
Lumasiran (ALN-GO1) 
Phase 
Phase 2 
Study Centers 
The study will be conducted at approximately 55 clinical study centers worldwide including in 
Europe and North America. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
• 
To evaluate the effect of lumasiran on the 
percent change in urinary oxalate 
excretion 
• 
Percent change in 24-hour urinary oxalate 
from baseline to Month 6 (average across 
Months 4 through 6) 
Secondary 
 
• 
To evaluate the percentage of patients 
who achieve a ≥20% reduction in 24-hour 
urinary oxalate with lumasiran 
• 
Percentage of patients who achieve a 
≥20% reduction in 24-hour urinary 
oxalate from baseline to Month 6 (average 
across Months 4 through 6) 
• 
To evaluate the effect of lumasiran on 
urinary calcium oxalate supersaturation 
• 
Percent change in urinary calcium oxalate 
supersaturation from baseline to Month 6 
(average across Months 4 through 6) 
Exploratory 
 
• 
To evaluate the effect of lumasiran on 
absolute levels of urinary oxalate 
excretion 
• 
Absolute change in 24-hour urinary 
oxalate from baseline to Month 6 (average 
across Months 4 through 6) 
• 
To evaluate the effect of lumasiran on the 
occurrence of kidney stones 
• 
Incidence rate of clinical and radiographic 
kidney stone events  
• 
Time to first kidney stone event 


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Objectives 
Endpoints 
• 
To evaluate additional pharmacodynamic 
(PD) parameters of plasma oxalate, 
plasma glycolate, and urinary glycolate 
• 
Change from baseline in plasma oxalate 
• 
Change from baseline in plasma glycolate 
• 
Change from baseline in urinary glycolate 
• 
To characterize the pharmacokinetics 
(PK) of lumasiran 
• 
Plasma PK of lumasiran 
• 
To assess for antidrug antibodies (ADA) 
against lumasiran 
• 
ADA frequency and titer 
• 
To evaluate the effect of lumasiran on 
maintaining 24-hour urinary oxalate 
≤upper limit of normal (ULN) over time 
• 
Percentage of patients with 24-hour 
urinary oxalate ≤ULN over time 
• 
To evaluate the effect of lumasiran on 
maintaining a 25% reduction in urinary 
calcium oxalate supersaturation over time 
• 
Percentage of patients having a 25% 
reduction in urinary calcium oxalate 
supersaturation over time 
• 
To evaluate the effect of lumasiran on 
24-hour urinary oxalate excretion after 
Month 6 
• 
Change from baseline in 24-hour urinary 
oxalate excretion after Month 6 
• 
To evaluate the effect of lumasiran on 
estimated glomerular filtration rate 
(eGFR) 
• 
Change from baseline in eGFR 
• 
To evaluate the effect of lumasiran on 
patient healthcare resource utilization 
• 
Kidney stone event related 
hospitalizations, emergency room visits, 
unscheduled office visits, or procedures  
Safety 
 
• 
To evaluate the safety and tolerability of 
lumasiran 
• 
Frequency of adverse events (AEs) 
Study Design 
This is a randomized, placebo-controlled, double-blind, multi-center, multinational, Phase 2 
study to evaluate the efficacy, safety, PD, and PK of lumasiran administered subcutaneously 
(SC) in patients with recurrent calcium oxalate kidney stone disease and elevated urinary oxalate 
levels (Figure 1). 
Consented patients meeting all eligibility criteria will be randomized 1:1:1 to receive study drug:  
lumasiran 567 mg, lumasiran 284 mg, or placebo.  Stratification will be performed at 
randomization according to baseline urinary oxalate level (≤1.25 × ULN vs >1.25 × ULN) from 
the mean of the first 2 valid 24-hour urine collections and the number of historical kidney stone 
events in the 12 months prior to screening (≤1 vs >1). 


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Number of Planned Patients 
The planned enrollment for this study is 120 patients. 
Diagnosis and Main Eligibility Criteria 
This study will include adults (≥18 years of age) with a documented diagnosis of recurrent 
kidney stone disease based on ≥2 stone events, with a minimum of 1 stone event within the 
5 years prior to screening.  A historical kidney stone event is defined as: 
• the visible passage of a kidney stone 
• a procedural intervention for removal of an asymptomatic or symptomatic stone  
− if more than 1 stone was removed in a given procedure, this counts as 1 event 
unless bilateral ureteral stones were removed, in which case this counts as 
2 events  
− if more than 1 procedure was required to remove a single stone, this counts as 
1 event 
• a new (≥1 mm) or enlarged (by ≥2 mm) kidney stone on computed tomography (CT) 
imaging 
− if a procedure was performed to remove the stone(s) identified by CT, then only 
the procedure will be counted to avoid double-counting the same stone. 
Study Drug, Dose, and Mode of Administration 
Lumasiran (ALN-GO1) is a SC administered N-acetylgalactosamine (GalNAc)-conjugated small 
interfering RNA (siRNA) targeting liver-expressed hydroxyacid oxidase (HAO1) messenger 
RNA (mRNA) for reduction of hepatic oxalate production. 
Lumasiran will be administered by SC injection at a dose of 284 mg or 567 mg on Day 1, 
Month 3, and Month 9. 
Reference Treatment, Dose, and Mode of Administration 
Placebo (sodium chloride 0.9% w/v for SC administration) will be administered at the same 
dosing interval as lumasiran. 
Duration of Treatment and Study Participation 
The duration of treatment with study drug is up to 15 months.  The estimated total time on study 
for each patient is up to 17 months, including up to 2 months of screening. 
Statistical Methods 
The study is powered to detect a difference in urinary oxalate excretion between each lumasiran 
group and the placebo group.  Assuming a standard deviation of 45% in the percent change from 
baseline in 24-hour urinary oxalate levels at Month 6, a sample size of 40 patients per group will 
enable a power of at least 80% in detecting a treatment difference of 30% between the treatment 
groups at a 2-sided significance level of 0.05. 


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The populations (analysis sets) are defined as follows: 
• Full Analysis Set (FAS):  All randomized patients who received at least 1 dose of 
study drug.  Patients in the FAS will be analyzed according to the randomized 
treatment arm. 
• Plasma Oxalate Analysis Set:  All patients who received at least 1 dose of study 
drug and have a baseline plasma oxalate level ≥1.5 times the lower limit of 
quantification/detection.   
• Safety Analysis Set:  All randomized patients who received at least 1 dose of study 
drug.  Patients in the Safety Analysis Set will be analyzed according to the treatment 
actually received. 
• PK Analysis Set:  All patients who received at least 1 full dose of study drug and 
have at least one postdose blood sample for PK parameters and have evaluable PK 
data. 
The primary efficacy endpoint will be analyzed in the FAS using a mixed-effect model for 
repeated measures (MMRM) approach.  The primary comparison is percent change from 
baseline in urinary oxalate through Month 6. 
Safety data will be summarized descriptively. 
Figure 1: 
Study Design 
LUMASIRAN 567 m  SC N=40)
LUMASIRAN 284 mg SC (N=40)
Safety Follow-up (patients who 
discontinue treatment)
Screening
(Day -60 to -1)
15-Month Double-Blind Treatment Period
6-Month Primary Analysis Period
Randomization (1:1:1)
PLACEBO (N=40)
LUMASIRAN 567 mg SC (N=40)
LUMASIRAN 284 mg SC (N=40)
PLACEBO (N=40)
9-Month Treatment Extension Period
 
Abbreviations:  SC=subcutaneous(ly) 
 
~-~I
 
 
 
 
 
 










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• 
White columns indicate visits to the clinical study center; gray-shaded columns indicate study visits that may be conducted by a home healthcare 
professional, where applicable country and local regulations and infrastructure allow (at the discretion and with oversight of the Investigator, based on 
safety and tolerability), provided (for dosing visits) that 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 symptom-directed 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, kidney stone events, and adverse events.  
Footnotes: 
a All assessments are required to be performed prior to dosing at dosing visits, except for the PK 2-hour postdose sample collection and optional CT 
scan. 
b Inclusion/exclusion criteria should be verified prior to randomization.  Laboratory assessments conducted to confirm study eligibility will not be repeated unless 
the time between screening and randomization exceeds 4 weeks. 
c Pregnancy test results must be known prior to dosing, if applicable. 
d Patients who elect to participate in optional CT scans will be requested to complete CT scans at both baseline (may be performed up to 3 days prior to Day 1), 
and at Month 15.  The CT scans may be performed after dosing, if required. 
 


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Table 2: 
Pharmacokinetic Time Points 
Study Day 
Sampling Time 
(hh:mm) 
Blood PK Sample 
Day 1 
Predose (any time before dosing) 
X 
02:00 (±30 min) 
X 
Abbreviations:  hh:mm=hour:minute; min=minute; PK=pharmacokinetics 
Notes:  
• 
The hour (±range) indicates sample collection timing relative to dosing.  Precise PK sample times (hour 
and minute) are recorded.  Refer to 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 ...............................................................................................................14 
LIST OF TABLES .........................................................................................................................17 
LIST OF FIGURES .......................................................................................................................18 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................19 
1. 
INTRODUCTION ......................................................................................................21 
1.1. 
Study Rationale ...........................................................................................................21 
1.2. 
Background .................................................................................................................21 
1.3. 
Benefit-Risk Assessment ............................................................................................22 
2. 
OBJECTIVES AND ENDPOINTS ............................................................................24 
3. 
INVESTIGATIONAL PLAN .....................................................................................25 
3.1. 
Summary of Study Design ..........................................................................................25 
3.2. 
Scientific Rationale for Study Design ........................................................................25 
3.3. 
Justification for Dose ..................................................................................................26 
3.4. 
Method of Assigning Patients to Treatment Groups ..................................................27 
3.5. 
Blinding ......................................................................................................................27 
3.5.1. 
Emergency Unblinding ...............................................................................................28 
3.6. 
Safety Review .............................................................................................................28 
3.7. 
Definition of End of Study for an Individual Patient .................................................28 
4. 
SELECTION AND REMOVAL OF PATIENTS ......................................................29 
4.1. 
Inclusion Criteria ........................................................................................................29 
4.2. 
Exclusion Criteria .......................................................................................................30 
4.3. 
Removal from Study Drug or Assessment .................................................................31 
4.3.1. 
Discontinuation of Study Drug or Declining Procedural Assessments ......................31 
4.3.2. 
Stopping a Patient’s Study Participation ....................................................................32 
4.3.2.1. 
Patient Stops Participation in the Study ......................................................................32 
4.3.2.2. 
Withdrawal of Consent to Process the Patient’s Personal Data or Objection 
to Process Patient’s Personal Data ..............................................................................33 
4.3.2.3. 
Investigator or Sponsor Stops Participation of a Patient in the Study ........................33 
4.3.2.4. 
Recording Reason for Stopping a Patient’s Study Participation ................................33 


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4.3.3. 
Lost to Follow-Up.......................................................................................................33 
4.3.4. 
Replacement of Study Patients ...................................................................................34 
5. 
TREATMENTS AND OTHER REQUIREMENTS ..................................................34 
5.1. 
Treatments Administered ............................................................................................34 
5.2. 
Study Drug ..................................................................................................................34 
5.2.1. 
Description ..................................................................................................................34 
5.2.2. 
Dose and Administration ............................................................................................34 
5.2.3. 
Dose Modifications .....................................................................................................35 
5.2.3.1. 
LFT Criteria for Withholding, Monitoring, and Stopping Study Drug Dosing..........35 
5.2.4. 
Preparation, Handling, and Storage ............................................................................37 
5.2.5. 
Packaging and Labeling ..............................................................................................37 
5.2.6. 
Accountability .............................................................................................................37 
5.3. 
Clinical Product Complaints .......................................................................................37 
5.3.1. 
Definition ....................................................................................................................37 
5.3.2. 
Reporting ....................................................................................................................38 
5.4. 
Concomitant Medications and Procedures .................................................................38 
5.5. 
Treatment Compliance ................................................................................................38 
5.6. 
Other Requirements ....................................................................................................38 
5.6.1. 
Contraception ..............................................................................................................38 
5.6.2. 
Alcohol Restrictions ...................................................................................................39 
5.6.3. 
Dietary Restrictions ....................................................................................................39 
6. 
STUDY ASSESSMENTS ..........................................................................................40 
6.1. 
Screening Assessments ...............................................................................................40 
6.1.1. 
DNA Sample ...............................................................................................................40 
6.1.2. 
Retesting .....................................................................................................................40 
6.1.3. 
Rescreening .................................................................................................................40 
6.2. 
Efficacy Assessments .................................................................................................41 
6.2.1. 
24-Hour Urine Collections .........................................................................................41 
6.2.1.1. 
Validity Criteria for 24-hour Urine Collections .........................................................42 
6.2.1.2. 
Variability Criterion for 24-hour Urine Collections at Screening ..............................42 
6.2.2. 
Kidney Stone Events ...................................................................................................42 
6.2.2.1. 
Clinical ........................................................................................................................42 
6.2.2.2. 
Radiographic ...............................................................................................................43 


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6.2.3. 
Estimated Glomerular Filtration Rate .........................................................................43 
6.3. 
Pharmacodynamic Assessments .................................................................................43 
6.4. 
Pharmacokinetic Assessments ....................................................................................43 
6.5. 
Safety Assessments .....................................................................................................44 
6.5.1. 
Vital Signs ..................................................................................................................44 
6.5.2. 
Height and Weight ......................................................................................................44 
6.5.3. 
Physical Examination .................................................................................................44 
6.5.4. 
Clinical Laboratory Assessments ...............................................................................45 
6.5.4.1. 
Immunogenicity ..........................................................................................................46 
6.5.4.2. 
Pregnancy Testing ......................................................................................................46 
6.5.4.3. 
Additional Liver Function Assessments .....................................................................47 
6.5.5. 
Adverse Events ...........................................................................................................49 
6.5.5.1. 
Definitions ..................................................................................................................49 
6.5.5.2. 
Eliciting and Recording Adverse Events ....................................................................50 
6.5.5.3. 
Reporting Adverse Events of Clinical Interest to Sponsor/Designee .........................51 
6.5.5.4. 
Serious Adverse Events Require Immediate Reporting to Sponsor/Designee ...........51 
6.5.5.5. 
Sponsor Safety Reporting to Regulatory Authorities .................................................52 
6.5.5.6. 
Serious Adverse Event Notification to the Institutional Review 
Board/Independent Ethics Committee ........................................................................52 
6.5.5.7. 
Pregnancy Reporting ..................................................................................................52 
6.5.5.8. 
Reporting of Overdose and Other Special Situations .................................................53 
6.6. 
Healthcare Utilization .................................................................................................53 
7. 
STATISTICS ..............................................................................................................54 
7.1. 
Determination of Sample Size ....................................................................................54 
7.2. 
Statistical Methodology ..............................................................................................54 
7.2.1. 
Populations to be Analyzed ........................................................................................54 
7.2.2. 
Examination of Subgroups .........................................................................................55 
7.2.3. 
Handling of Missing Data ...........................................................................................55 
7.2.4. 
Baseline Evaluations ...................................................................................................55 
7.2.5. 
Efficacy Analyses .......................................................................................................55 
7.2.6. 
Pharmacodynamic Analysis........................................................................................56 
7.2.7. 
Pharmacokinetic Analysis ..........................................................................................56 
7.2.8. 
Safety Analyses ..........................................................................................................56 


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7.2.9. 
Immunogenicity Analyses ..........................................................................................56 
7.2.10. 
Other Analyses ............................................................................................................56 
7.2.11. 
Interim Analysis ..........................................................................................................57 
7.2.12. 
Optional Additional Research .....................................................................................57 
8. 
STUDY ADMINISTRATION ...................................................................................57 
8.1. 
Ethical and Regulatory Considerations ......................................................................57 
8.1.1. 
Informed Consent .......................................................................................................57 
8.1.2. 
Ethical Review ............................................................................................................57 
8.1.3. 
Serious Breach of Protocol .........................................................................................58 
8.1.4. 
Study Documentation, Confidentiality, and Records Retention .................................58 
8.1.5. 
End of Study ...............................................................................................................59 
8.1.6. 
Termination of the Clinical Study or Site Closure .....................................................59 
8.2. 
Data Quality Control and Quality Assurance .............................................................59 
8.2.1. 
Data Handling .............................................................................................................59 
8.2.2. 
Study Monitoring ........................................................................................................59 
8.2.3. 
Audits and Inspections ................................................................................................60 
8.3. 
Publication Policy .......................................................................................................60 
9. 
LIST OF REFERENCES ............................................................................................61 
10. 
APPENDICES ............................................................................................................62 
10.1. 
Formula for Estimated Glomerular Filtration Rate Calculation .................................62 
 
LIST OF TABLES 
Table 1: 
Schedule of Assessments ..............................................................................................8 
Table 2: 
Pharmacokinetic Time Points .....................................................................................13 
Table 3: 
Monitoring and Dosing Rules for Asymptomatic Patients with Confirmed 
Isolated Elevations of ALT and/or AST >3× ULN, with No Alternative 
Cause Identified ..........................................................................................................36 
Table 4: 
24-hour Urine Collection Procedure by Study Visit...................................................41 
Table 5: 
Clinical Laboratory Assessments ...............................................................................46 
Table 6: 
Hepatic Assessments in Patients Who Experience Elevated Transaminases .............48 
Table 7: 
Sample Size Power Calculations ................................................................................54 
 


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LIST OF FIGURES 
Figure 1: 
Study Design .................................................................................................................7 
Figure 2: 
Summary of Endogenous Oxalate Synthesis ..............................................................23 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation  
Definition 
ADA 
Antidrug antibody 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical Classification System 
CKD 
Chronic kidney disease 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
Cmax 
Maximum plasma concentration 
CPC 
Clinical product complaint 
CT 
Computed tomography 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
EOS 
End of study 
ESKD 
End stage kidney disease 
ET 
Early termination 
FAS 
Full analysis set 
GalNAc 
N-acetylgalactosamine 
GCP 
Good Clinical Practice 
GO 
Glycolate oxidase 
HAO1 
Hydroxyacid oxidase 1  
HED 
Human equivalent dose 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug (application) 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ISR 
Injection site reaction 
LFT 
Liver function test 


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MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-effect model for repeated measures 
mRNA 
Messenger ribonucleic acid 
PD 
Pharmacodynamics 
PH1/2/3 
Primary hyperoxaluria type 1/2/3 
PK 
Pharmacokinetic 
PT 
Preferred term 
RNAi 
Ribonucleic acid interference 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SOC 
System Organ Class 
tmax 
Time to maximum plasma concentration 
ULN 
Upper limit of normal 
WHO 
World Health Organization 
 


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1. 
INTRODUCTION 
Alnylam Pharmaceuticals, Inc. (the Sponsor) has developed 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) messenger ribonucleic acid (mRNA), 
blocking production of glycolate oxidase (GO) and hence reducing hepatic oxalate production. 
Lumasiran is approved for the treatment of primary hyperoxaluria type 1 (PH1) in both pediatric 
and adult patients in the United States (23 November 2020) and in the European Union (19 
November 2020).  Based on lumasiran’s mechanism of action, and demonstrated reduction of 
hepatic oxalate production in patients with PH1, the Sponsor is investigating whether treatment 
with lumasiran is effective for patients with recurrent calcium oxalate kidney stone disease who 
have elevated urinary oxalate levels but have not been diagnosed with PH1 or one of the other 
primary hyperoxalurias. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of lumasiran is 
provided in the Investigator’s Brochure. 
1.1. 
Study Rationale 
Study ALN-GO1-008 is a randomized, double-blind, placebo-controlled, multi-center Phase 2 
study designed to evaluate the efficacy, safety, pharmacodynamics (PD), and pharmacokinetics 
(PK) of lumasiran, administered subcutaneously (SC), in adult patients with recurrent calcium 
oxalate kidney stone disease. 
The primary objective of the study is to evaluate the effect of lumasiran on the percent change in 
urinary oxalate excretion in patients with recurrent calcium oxalate kidney stones.  Secondary 
and exploratory objectives of the study include the evaluation of the effect of lumasiran on 
urinary calcium oxalate supersaturation, the occurrence of kidney stones, the PD effect of 
lumasiran on plasma oxalate, plasma glycolate and urinary glycolate, and the characterization of 
plasma PK. 
The full rationale for the study and design is presented in Section 3.2. 
1.2. 
Background 
Kidney stones are common, affecting approximately 1 in 11 people in the United States, and the 
prevalence of kidney stone disease has been increasing worldwide over time.[Scales 2012]  
Approximately 80% of kidney stones in adults are formed from calcium oxalate crystals, with 
the remainder being predominantly calcium phosphate, uric acid, cystine, or struvite.[Worcester 
and Coe 2008; Worcester and Coe 2010]  Stone formation occurs when a supersaturating level of 
calcium oxalate is present in the urine (Figure 2).  High levels of urinary oxalate may be derived 
from both endogenous synthesis and diet.  
Kidney stones can develop in patients of all ages; however, the highest incidence rates occur in 
individuals aged 40 to 66 years.[Shin 2018]  There is significant clinical burden associated with 
the development of kidney stones for patients with recurrent calcium oxalate kidney stone 
disease, including pain, infection/sepsis, diagnostic and therapeutic procedures, hospitalizations, 


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and a greater risk for developing chronic kidney disease (CKD) and end stage kidney disease 
(ESKD). 
The typical clinical presentation of kidney stones includes sudden onset of lumbar flank pain and 
hematuria, and may include nausea and vomiting.  Evaluation to assess etiology includes 
assessment of the patient’s medical history, medication use, and dietary and lifestyle risk factors.  
Confirmation of diagnosis may involve renal ultrasound, abdominal x-ray, and/or computed 
tomography (CT).[Heilberg and Schor 2006]  24-hour urine collections analyzed for total 
volume, calcium, oxalate, uric acid, citrate, and other analytes may help to determine the 
underlying etiology.[Pearle 2014]  Stone composition is generally determined in at least one 
instance. 
There are limited effective treatment options for patients with recurrent calcium oxalate kidney 
stone disease.  Preventive measures in American and European guidelines recommend adequate 
fluid intake to ensure a urine volume of at least 2 to 2.5 liters daily and provide dietary advice to 
limit the consumption of oxalate-rich foods, sodium chloride, and animal protein content, while 
maintaining a normal calcium intake.  In some situations, thiazide diuretics, potassium citrate, 
and/or allopurinol may be considered.[Pearle 2014; Türk 2021] 
Treatment of pain associated with kidney stone events may involve non-steroidal 
anti-inflammatory agents and/or opiate pain medications.  Depending on the clinical context, 
medical expulsive therapy, extracorporeal shock-wave lithotripsy, ureteroscopy, stenting, and 
percutaneous nephrolithotomy are some of the treatment options that may be pursued.[Türk 
2021] 
Lumasiran is a ribonucleic acid interference (RNAi) therapeutic designed to reduce hepatic 
oxalate production.  Oxalate produced by the liver is largely excreted in the urine, and lumasiran 
has been shown to reduce urinary oxalate in patients with PH1.  High levels of urinary oxalate 
increase the risk of stone formation; therefore, lumasiran may have efficacy in patients with 
recurrent calcium oxalate kidney stone disease who do not have PH1 but who produce high 
amounts of oxalate endogenously. 
1.3. 
Benefit-Risk Assessment 
Calcium oxalate stone formation occurs when a supersaturating level of calcium oxalate is 
present in the urine, with increasing risk of stone formation as urine oxalate levels 
increase.[Curhan and Taylor 2008]  More than half of oxalate is endogenous in origin and 
presumed to come largely from the liver.[Mitchell 2018]  Studies have shown that reduced 
calcium oxalate supersaturation and urinary oxalate levels are associated with reduced stone 
formation.[Borghi 2002; Ferraro 2018; Prochaska 2018] 
For patients with recurrent calcium oxalate stone formation, multiple stone removal procedures 
may be required.  These procedures are invasive and place the patient at risk of complications 
including bleeding and infection.  Patients experiencing obstructive kidney stones can also 
experience acute kidney injury with permanent loss of renal function.  As a result, patients with 
recurrent kidney stone formation have a higher risk of progression to CKD and ESKD.[Dhondup 
2018; Rule 2009] 
Lumasiran, approved in the United States and European Union for the treatment of PH1, is 
designed to reduce hepatic production of oxalate.  Based on the available data from clinical and 


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nonclinical studies, lumasiran, administered SC, demonstrated a potent, dose-dependent 
inhibition of GO resulting in decreased urinary and plasma oxalate and increased plasma and 
urinary glycolate.  Lumasiran may be effective in lowering urinary oxalate levels in patients with 
recurrent calcium oxalate kidney stone disease (Figure 2).  No adverse effects of elevated 
glycolate have been reported.  Unlike oxalate, glycolate is highly soluble and readily excreted in 
the urine. 
Figure 2: 
Summary of Endogenous Oxalate Synthesis 
 
Abbreviations:  GO=glycolate oxidase 
Lumasiran has been well tolerated with an acceptable safety profile in studies with healthy 
volunteers and patients with PH1.  Most adverse events (AEs) have been mild or moderate in 
severity.  Transient, mild injection site reactions (ISRs) have been observed.  No clinically 
significant laboratory changes related to lumasiran 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 hepatic effects.  The study has specific 
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 (LFTs).  As the risk of embryofetal toxicity in humans is currently unknown, 
females who are of 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 5.6.1). 
Based on the available efficacy and safety data from clinical and nonclinical studies, the benefit-
risk assessment supports the evaluation of lumasiran in a Phase 2 study in patients with recurrent 
calcium oxalate kidney stone disease. 
Detailed information about the known and expected benefits and risks of lumasiran are provided 
in the Investigator’s Brochure. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
 
• 
To evaluate the effect of lumasiran on the 
percent change in urinary oxalate 
excretion 
• 
Percent change in 24-hour urinary oxalate 
from baseline to Month 6 (average across 
Months 4 through 6) 
Secondary 
 
• 
To evaluate the percentage of patients 
who achieve a ≥20% reduction in 24-hour 
urinary oxalate with lumasiran 
• 
Percentage of patients who achieve a 
≥20% reduction in 24-hour urinary 
oxalate from baseline to Month 6 (average 
across Months 4 through 6) 
• 
To evaluate the effect of lumasiran on 
urinary calcium oxalate supersaturation 
• 
Percent change in urinary calcium oxalate 
supersaturation from baseline to Month 6 
(average across Months 4 through 6) 
Exploratory 
 
• 
To evaluate the effect of lumasiran on 
absolute levels of urinary oxalate 
excretion 
• 
Absolute change in 24-hour urinary 
oxalate from baseline to Month 6 (average 
across Months 4 through 6) 
• 
To evaluate the effect of lumasiran on the 
occurrence of kidney stones 
• 
Incidence rate of clinical and radiographic 
kidney stone events  
• 
Time to first kidney stone event 
• 
To evaluate additional PD parameters of 
plasma oxalate, plasma glycolate, and 
urinary glycolate 
• 
Change from baseline in plasma oxalate 
• 
Change from baseline in plasma glycolate 
• 
Change from baseline in urinary glycolate 
• 
To characterize PK of lumasiran 
• 
Plasma PK of lumasiran 
• 
To assess for antidrug antibodies (ADA) 
against lumasiran 
• 
ADA frequency and titer 
• 
To evaluate the effect of lumasiran on 
maintaining 24-hour urinary oxalate 
≤upper limit of normal (ULN) over time 
• 
Percentage of patients with 24-hour 
urinary oxalate ≤ULN over time 
• 
To evaluate the effect of lumasiran on 
maintaining a 25% reduction in urinary 
calcium oxalate supersaturation over time 
• 
Percentage of patients having a 25% 
reduction in urinary calcium oxalate 
supersaturation over time 
• 
To evaluate the effect of lumasiran on 
24-hour urinary oxalate excretion after 
Month 6 
• 
Change from baseline in 24-hour urinary 
oxalate excretion after Month 6 


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Objectives 
Endpoints 
• 
To evaluate the effect of lumasiran on 
estimated glomerular filtration rate 
(eGFR) 
• 
Change from baseline in eGFR 
• 
To evaluate the effect of lumasiran on 
patient healthcare resource utilization 
• 
Kidney stone event related 
hospitalizations, emergency room visits, 
unscheduled office visits, or procedures  
Safety 
 
• 
To evaluate the safety and tolerability of 
lumasiran 
• 
Frequency of AEs 
3. 
INVESTIGATIONAL PLAN 
3.1. 
Summary of Study Design 
This is a randomized, placebo-controlled, double-blind, multi-center, multinational, Phase 2 
study to evaluate the efficacy, safety, PD, and PK of lumasiran administered SC in patients with 
recurrent calcium oxalate kidney stone disease and elevated urinary oxalate levels (Figure 1). 
The study will consist of up to 2 months of screening and 15 months of double-blind treatment (a 
6-month Primary Analysis Period followed by a 9-month Treatment Extension Period).  Patients 
will be screened from Day -60 to Day -1 to determine eligibility.  During screening, patients will 
provide at least two 24-hour urine collections to establish baseline urinary oxalate levels.  
Consented patients meeting all eligibility criteria will be randomized 1:1:1 to receive study drug:  
lumasiran 567 mg, lumasiran 284 mg, or placebo.  Stratification will be performed at 
randomization according to baseline urinary oxalate level (≤1.25 × ULN vs >1.25 × ULN) from 
the mean of the first 2 valid 24-hour urine collections and the number of historical kidney stone 
events in the 12 months prior to screening (≤1 vs >1), as discussed in Section 3.4. 
During the 6-month Primary Analysis Period, patients will be dosed on Day 1 (baseline) and at 
Month 3.  During the Treatment Extension Period, one additional dose will be administered at 
Month 9; an end of study (EOS) visit will take place at Month 15.  Study drug will be 
administered SC as specified in Section 5.2.2.  Patients will be assessed for efficacy, safety, PD, 
and PK according to the Schedule of Assessments (Table 1 and Table 2).  Efficacy assessments 
will include evaluation of urinary oxalate excretion, urinary calcium oxalate supersaturation, and 
kidney stone events (including clinical events and radiologic events with optional low-dose 
kidney-protocol CT).  Safety assessments will include collection of AEs, clinical laboratory tests, 
vital sign assessments, physical examinations, and concomitant medications. 
Patients who discontinue study drug early will be asked to return for follow-up visits as 
described in Section 4.3.1. 
3.2. 
Scientific Rationale for Study Design 
The primary endpoint for this Phase 2 study is the percent change in 24-hour urinary oxalate 
excretion.  To confirm the optimal dosing regimen, and to facilitate the collection of kidney 


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stone event data (an exploratory endpoint), the study will continue through Month 15.  A placebo 
comparator is included because there is no approved standard of care therapy to decrease urinary 
oxalate.  
A blood DNA sample will be collected as part of standard screening assessments (if testing has 
not already been performed) to ensure the exclusion of patients with primary hyperoxaluria 
type 1 (PH1), type 2 (PH2), and type 3 (PH3).  Lumasiran is approved in some countries for the 
treatment of PH1, and patients with PH2 and PH3 are not expected to respond to lumasiran. 
Because the primary endpoint will rely on measurements of urinary oxalate, and because some 
urinary oxalate is diet-derived, diet is an important variable in this study.  In a 5-year study of 
recurrent stone formers published by Borghi et al, patients randomized to a normal calcium, low 
protein/salt diet had lower urinary oxalate levels and a lower cumulative incidence of recurrent 
kidney stones when compared to a low calcium diet.  During the current study, and as of the time 
of informed consent, patients will be asked to adhere to a diet appropriate for stone formers, 
including adequate calcium intake and avoidance of spinach and other foods that are high in 
oxalate.  
The secondary endpoint to assess meaningful reduction in 24-hour urinary oxalate from baseline 
to Month 6 (Months 4 through 6) defines a clinically meaningful reduction as ≥20% in the non-
PH1 stone former population, supported by available literature based on stone former 
populations.[Borghi 2002] 
In this study, lumasiran will be evaluated in patients with recurrent calcium oxalate kidney stone 
disease.  Due to the limited and burdensome disease management options, there is an unmet need 
for new therapies. 
3.3. 
Justification for Dose 
Two dose levels of lumasiran 284 and 567 mg given on Day 1, Month 3, and Month 9 were 
selected to evaluate urinary oxalate dose response.  The higher dose level of 567 mg is expected 
to suppress GO enzyme by ≥95%, comparable to the regimen evaluated in ALN-GO1-003 
(ILLUMINATE-A) in patients with PH1.  The lower dose of 284 mg is expected to suppress GO 
enzyme by 90%.  In addition, the fixed doses will simplify dose administration in this adult study 
population.  Both regimens are predicted to achieve near-steady state ribonucleic acid-induced 
silencing complex (RISC) concentrations and urinary oxalate suppression at Month 6.  Month 9 
dosing is intended to sustain PD effect through Month 15 and will provide data to differentiate 
the effect of every 3 months and every 6 months dosing on urinary oxalate reduction. 
Single 0.3 to 6.0 mg/kg doses of lumasiran in healthy subjects and multiple 3.0 mg/kg doses of 
lumasiran administered monthly or once every 3 months in patients with PH1 have been well 
tolerated.  Plasma and liver exposure for the lumasiran 284 and 567 mg doses are expected to be 
in the range of 3.0 to 6.0 mg/kg lumasiran doses evaluated in healthy subjects in ALN-GO1-001 
(Part A) and patients with PH1 in ALN-GO1-001 (Part B), ALN-GO1-002, and 
ILLUMINATE-A.  Based on rat and monkey NOAEL doses of lumasiran 200 mg/kg and 
300 mg/kg, a sufficient safety margin exists for the use of lumasiran 284 and 567 mg doses (refer 
to the ALN-GO1 Investigator Brochure). 
Based on a 70 kg patient, the planned doses of 284 mg and 567 mg equate to approximately 
4.0 mg/kg or 8.0 mg/kg, respectively.  The human equivalent dose (HED) margin values for the 


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approximate 4 mg/kg clinical dose were 8.1-fold for the chronic rat study and 24.2-fold for the 
chronic monkey study; the HED margin values for the approximate 8.0 mg/kg clinical dose were 
4.0-fold for the chronic rat study and 12.1-fold for the chronic monkey study (refer to the 
ALN-GO1 Investigator Brochure). 
3.4. 
Method of Assigning Patients to Treatment Groups 
Each patient will be uniquely identified in the study by a combination of the site number and 
patient identification number.  After the patient signs the informed consent form (ICF) and 
before proceeding with screening procedures, the Investigator or his/her designee will contact the 
Interactive Response Technology (IRT) to obtain a patient identification number. 
The Investigator or his/her designee will contact the IRT to randomize the patient after 
confirming that the patient fulfills all the inclusion criteria and none of the exclusion criteria. 
Patients will be randomized 1:1:1 to receive lumasiran 284 mg, lumasiran 567 mg, or placebo, 
administered at the same volume (see Section 5.2.2), for the duration of the study.  Stratification 
will be performed at randomization according to baseline urinary oxalate level (≤1.25 × ULN vs 
>1.25 × ULN) from the mean of the first 2 valid 24-hour urine collections and the number of 
historical kidney stone events in the 12 months prior to screening (≤1 vs >1). 
For stratification, the number of historical kidney stone events occurring in the 12 months prior 
to screening are considered, and defined as:  
• the visible passage of a kidney stone 
• a procedural intervention for removal of an asymptomatic or symptomatic stone  
− if more than 1 stone was removed in a given procedure, this counts as 1 event 
unless bilateral ureteral stones were removed, in which case this counts as 
2 events 
− if more than 1 procedure was required to remove a single stone, this counts as 
1 event 
• a new (≥1 mm) or enlarged (by ≥2 mm) kidney stone on CT imaging 
− it must be evident from the CT scans that the new or enlarged kidney stone event 
occurred during the 12 months prior to screening 
− if a procedure was performed to remove the stone(s) identified by CT, then only 
the procedure will be counted to avoid double-counting the same stone. 
3.5. 
Blinding 
Site personnel and patients will be blinded to study drug treatment; site personnel preparing 
study drug may be unblinded to study drug treatment only where required by documented 
institutional procedure.  The Sponsor will have access to unblinded study data during the conduct 
of the study.  Lumasiran and placebo will be packaged identically and will be administered at the 
same volume under the supervision of the Investigator at the study center or by a healthcare 
professional at the patient’s home (see Section 5.2.2).  Since lumasiran may be visually 


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distinguishable from placebo, the syringe will be masked prior to administration by a healthcare 
professional.  See the Pharmacy Manual for additional details. 
All site personnel will be blinded to laboratory results of oxalate, calcium oxalate 
supersaturation, and glycolate from after the time of the first dose until unblinding.  Results will 
not be reported to the Investigator from the first dose until the last patient completes assessments 
at the Month 15 visit.  In addition, Investigators and staff involved with this trial and all medical 
staff involved in the patient’s medical care should refrain from obtaining measurements for 
oxalate, calcium oxalate supersaturation, or glycolate from the first dose until the sites and 
patients are unblinded, or until the patient ends the study, whichever is earlier.  If oxalate, 
calcium oxalate supersaturation, or glycolate are measured during the blinded period, all 
reasonable steps must be undertaken to avoid informing the patient and site personnel of the 
results until the sites and patients are unblinded. 
Any unplanned unblinding occurring during the study period will be documented and reported in 
the clinical study report.  
3.5.1. 
Emergency Unblinding 
If the treating physician determines that the clinical management of the patient requires 
knowledge of the study drug assignment, the Investigator may break the blind, as necessary.  If 
time permits, clinical study center personnel should contact the Medical Monitor before 
unblinding to discuss the need to unblind the patient.  If contact prior to unblinding is not 
possible, personnel must contact the Medical Monitor within 1 working day after the unblinding 
event.  Unblinding information should be limited to the fewest number of people on a need-to-
know basis.  A record of when the blind was broken, who was unblinded, who broke the blind, 
and why it was broken, will be maintained in the trial master file. 
Refer to the IRT instructions for details on unblinding. 
3.6. 
Safety Review 
A safety review committee will not be utilized for this study; however, the Sponsor will monitor 
safety on an ongoing basis and in accordance with the Sponsor’s internal processes. 
3.7. 
Definition of End of Study for an Individual Patient 
A patient is considered to have reached the EOS if the patient: 
• has completed the EOS (Month 15) visit, or 
• has completed safety monitoring following the final dose of study drug as described 
in Section 4.3.1 
A definition of the end of the overall study is provided in Section 8.1.5. 


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4. 
SELECTION AND REMOVAL OF PATIENTS 
4.1. 
Inclusion Criteria 
Patients are eligible to be included in the study if all the following criteria apply: 
Age 
1. Age 18 years or older (or age of legal consent, whichever is older). 
Patient and Disease Characteristics 
2. Recurrent kidney stone disease, defined as ≥2 stone events, with a minimum of 1 stone 
event within the 5 years prior to screening.  For inclusion, a historical kidney stone event 
is defined as:  
• the visible passage of a kidney stone 
• a procedural intervention for removal of an asymptomatic or symptomatic stone  
− if more than 1 stone was removed in a given procedure, this counts as 1 event 
unless bilateral ureteral stones were removed, in which case this counts as 
2 events 
− if more than 1 procedure was required to remove a single stone, this counts as 
1 event 
• a new (≥1 mm) or enlarged (by ≥2 mm) kidney stone on CT imaging 
− if a procedure was performed to remove the stone(s) identified by CT, then only 
the procedure will be counted to avoid double-counting the same stone. 
3. The 2 most recently analyzed kidney stones prior to randomization contained 50% or 
more of calcium oxalate; if only one stone analysis is available, then it must have 
contained 50% or more of calcium oxalate. 
4. 24-hour urinary oxalate levels from 2 valid 24-hour urine collections obtained during 
screening are >ULN (ULN = 40 mg/24 hours). 
5. Willing to adhere to dietary recommendations appropriate for stone formers including 
limiting vitamin C supplementation to <200 mg daily. 
6. If taking medications and/or hydrating for kidney stone prophylaxis, or taking 
medications that alter urinary oxalate excretion and/or kidney stone formation, must have 
been on a stable regimen for at least 60 days before randomization, and willing to remain 
on this stable regimen for the duration of the study. 
7. Body mass index (the weight in kilograms divided by the square of the height in meters) 
at screening of 20 to <40 kg/m2. 
Informed Consent 
8. Patient is able to understand and is willing and able to comply with the study 
requirements and to provide written informed consent. 


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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 at screening:  
a. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2 × ULN 
b. Total bilirubin >1.5 × ULN.  Patients with elevated total bilirubin that is secondary to 
documented Gilbert’s syndrome are eligible if the total bilirubin is <2 × ULN 
c. International normalized ratio (INR) >2.0 (patients on oral anticoagulant [eg, 
warfarin] with an INR <3.5 will be allowed) 
2. Has an eGFR of <30 mL/min/1.73m2 at screening (calculation will be based on the 
Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] creatinine formula; see 
Section 10.1). 
Prior/Concomitant Therapy 
3. Received an investigational agent within the last 30 days or 5 half-lives, whichever is 
longer, prior to the first dose of study drug, or are in follow-up of another clinical study 
prior to study enrollment.  Any agent that has received health agency authorization 
(including for emergency use) by local or regional regulatory authorities is not considered 
investigational. 
Medical Conditions 
4. Patients with a known history of secondary causes of elevated urinary oxalate and/or 
recurrent kidney stones including: 
a. Primary hyperoxaluria 
b. Severe eating disorders (anorexia or bulimia) 
c. Chronic inflammatory bowel disease  
d. Intestinal surgery with malabsorption or chronic diarrhea 
e. Sarcoidosis 
f. Primary hyperparathyroidism 
g. Complete distal renal tubular acidosis 
5. Has other medical conditions or comorbidities which, in the opinion of the Investigator, 
would interfere with study compliance or data interpretation. 
6. History of multiple drug allergies or history of allergic reaction to an oligonucleotide or 
GalNAc. 
7. History of intolerance to SC injection(s). 
Contraception, Pregnancy, and Breastfeeding 
8. Is not willing to comply with the contraceptive requirements during the study period, as 
described in Section 5.6.1. 
9. Female patient is pregnant, planning a pregnancy, or breast-feeding. 


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Alcohol Use 
10. Unwilling or unable to limit alcohol consumption throughout the course of the study.  
Alcohol intake of >2 units/day is excluded during the study (unit:  1 glass of wine 
[approximately 125 mL] = 1 measure of spirits [approximately 1 fluid ounce] = ½ pint of 
beer [approximately 284 mL]). 
11. History of alcohol abuse, within the last 12 months before screening, in the opinion of the 
Investigator. 
4.3. 
Removal from Study Drug or Assessment 
Patients 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 protocol deviation 
• Adverse event 
• Non-adherence to treatment regimen 
• Pregnancy 
• Lost to follow-up 
• Other reason (non-AE) 
• Or, study is terminated by the Sponsor 
If possible, the Investigator will confer with the Sponsor or Medical Monitor before 
discontinuing dosing in the patient.  Patients who are pregnant will be discontinued from study 
drug dosing immediately (see Section 6.5.5.7 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 


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the Schedule of Assessments (Table 1), including different options for follow-up and collection 
of data (eg, in person, by phone, by mail, 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 serious adverse events (SAEs), the event 
should be followed as described in Section 6.5.5.  When a patient discontinues study drug 
dosing, the primary reason must be recorded in the 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 Primary Analysis Period (defined 
as a discontinuation that occurs after the first dose of study drug administration on Day 1 during 
the 6-month Primary Analysis Period) will be encouraged to remain on the study and complete 
all assessments (including 24-hour urine collections) through Month 6, with early termination 
(ET) assessments at Month 9, and safety follow-up per the safety follow-up schedule (Table 1).  
Patients who do not remain on the study through Month 6 will be asked to return for their next 
scheduled visit to complete ET assessments and complete safety follow-up per the safety follow-
up schedule (Table 1). 
Patients who discontinue study drug after Month 6 will be asked to return for their next 
scheduled visit to complete ET assessments and complete a safety follow-up visit per the safety 
follow-up schedule (see Table 1). 
4.3.2. 
Stopping a Patient’s Study Participation 
4.3.2.1. 
Patient Stops Participation in the Study 
A patient may stop participation in the study at any time.  A patient 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 for the collection of important study data 
as described in Section 4.3.1.  If a patient still chooses to discontinue study drug and stop 
participation in all follow-up, every effort should be made to conduct the ET assessments (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. 
Note, in countries where the collection and processing of the patient’s personal data is based on 
consent, if a patient withdraws consent to collect and process his/her personal data (see 
Section 4.3.2.2), as applicable, personal data up to the withdrawal of consent will be included in 
the analysis of the study.  In addition, 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. 


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4.3.2.2. 
Withdrawal of Consent to Process the Patient’s Personal Data or Objection to 
Process 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.  Also, where allowed by local 
law, the patient may object to the collection, storage, and use of his/her personal data, informing 
the study doctor at any time in writing or in any other form that may be locally required.  In both 
cases, 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/objection) 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 through the Primary Analysis 
Period (Month 6). 
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 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 6.5.5. 
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 fails to return to the clinic for a required study visit: 
• The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of maintaining the assigned visit 
schedule and ascertain if the patient wishes to 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 (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 continue to be unreachable, the patient will be considered to have 
stopped participation in the study. 


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• 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 will not be replaced.  
5. 
TREATMENTS AND OTHER REQUIREMENTS 
5.1. 
Treatments Administered 
Study drug (lumasiran and placebo) 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 study drug is 
provided in the Pharmacy Manual. 
5.2.1. 
Description 
Lumasiran will be supplied as a sterile solution in water for SC injection.  See the Pharmacy 
Manual for further details of solution concentration and fill volume. 
The control drug for this study will be a placebo (sodium chloride 0.9% w/v for SC 
administration).  Placebo will be provided by the Sponsor; it will be packaged identically to 
lumasiran. 
5.2.2. 
Dose and Administration 
Patients will be administered SC injections of lumasiran (284 mg or 567 mg) and/or placebo at 
the same volume, as described below, on Day 1, Month 3, and Month 9. 
Lumasiran 567 mg 
Lumasiran 284 mg 
Placebo 
1.5 mL lumasiran 
1.5 mL lumasiran 
1.5 mL lumasiran 
1.5 mL placebo 
1.5 mL placebo 
1.5 mL placebo 
Study drug injections will be administered under the supervision of the Investigator or healthcare 
professional.  To maintain the blind, syringes are to be masked prior to the removal of study drug 
from vials.  A full description of the blinding procedure is included in the Pharmacy Manual.  
The injection site may be marked and mapped for later observation.  Injections may be 
administered in the abdomen, thigh, or the side or back of the upper arms.  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, provided the patient 
has tolerated at least 1 dose of study drug administered in the clinic.  However, continued study 


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drug administration at the study center should be considered for patients who have ongoing study 
drug-related AEs or for anyone in the opinion of the Investigator who would benefit from 
clinical observation following dosing. 
If a patient does not receive a dose of study drug within the specified visit 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. 
The definition of study drug overdose, follow-up procedures, and reporting requirements are 
provided Section 6.5.5.8. 
5.2.3. 
Dose Modifications 
If a study drug-related AE occurs in a patient that the Investigator judges as presenting a 
potential risk to the patient for further dosing, the study drug dose may be held at the discretion 
of the Investigator, and the Medical Monitor should be contacted. 
5.2.3.1. 
LFT Criteria for Withholding, Monitoring, and Stopping Study Drug Dosing  
1. Results of previous LFT assessment should be reviewed prior to dosing. 
2. For any ALT or AST elevation >3× ULN, central laboratory results should be used to 
guide subsequent monitoring as detailed in Table 3. 
3. For any ALT or AST elevation >3× ULN: 
a. If local laboratory results are obtained, confirm with a 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 5 and Table 6. 
4. For any ALT or AST elevation >3× ULN without alternative cause that is accompanied 
by clinical symptoms consistent with liver injury (eg, nausea, right upper quadrant 
abdominal pain, jaundice) or elevated bilirubin to ≥2× ULN or INR ≥1.5, permanently 
discontinue dosing. 
5. For confirmed ALT or AST elevations >3× ULN without alternative cause and not 
accompanied by symptoms or elevated bilirubin ≥2× ULN or INR ≥1.5, see Table 3. 


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Table 3: 
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 6 (all assessments to be performed once) 
- Hematology, serum chemistry, and LFT per Table 5 
- Coagulation (prothrombin time, partial thromboplastin time, 
international normalized ratio) 
• 
Monitor at least every 2 weeks:  LFT per Table 5 
• 
If elevation persists for ≥2 months, must discuss with the Medical 
Monitor before continuing dosing 
>5× to 8× ULN 
• 
Hold study drug dosing until recovery to ≤1.5× ULN or baseline; may 
resume dosing after discussion with the Medical Monitor 
• 
Evaluate the initial elevation in LFT per the following assessments: 
- Table 6 (all assessments to be performed once) 
- Hematology, serum chemistry, and LFT per Table 5 
- Coagulation (prothrombin time, partial thromboplastin time, 
international normalized ratio) 
• 
Monitor at least weekly:  LFT per Table 5 until ALT and/or AST is 
declining on 2 consecutive draws, then may decrease monitoring to 
biweekly 
• 
If ALT or AST rises to >5× ULN following resumption of dosing, 
permanently discontinue dosing 
>8× ULN 
• 
Permanently discontinue dosing after confirmation of the transaminase 
value at the central laboratory. 
• 
Evaluate the initial elevation in LFT per the following assessments until 
satisfactory resolution: 
- Table 6 (all assessments to be performed once) 
- Hematology, serum chemistry, and LFT per Table 5 
- Coagulation (prothrombin time, partial thromboplastin time, 
international normalized ratio) 
• 
Monitor at least weekly:  LFT per Table 5 until ALT and/or AST is 
declining on 2 consecutive draws, then may decrease monitoring to 
biweekly 
Abbreviations:  ALT=alanine aminotransferase; AST=aspartate aminotransferase; INR=international normalized 
ratio; LFT=liver function test(s); ULN=upper limit of normal. 
Notes:  In addition to these criteria, other assessments or evaluations may be performed per Investigator 
discretion, as appropriate. 


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5.2.4. 
Preparation, Handling, and Storage 
Staff at each clinical study center or the home healthcare professional will be responsible for 
preparation of study drug doses, according to procedures detailed in the Pharmacy Manual.  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 until dose preparation.  
Deviations from the recommended storage conditions should be reported to the Sponsor and use 
of the study drug halted until authorization for its continued use has been provided by the 
Sponsor or designee, as described in the Pharmacy Manual. 
A Sponsor representative or designee will be permitted, upon request, to audit the supplies, 
storage, dispensing procedures, and records. 
Instructions specific to unused study drug and additional storage will be provided in the 
Pharmacy Manual. 
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. 
Clinical Product Complaints 
5.3.1. 
Definition 
A clinical product complaint (CPC) is any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of the study drug and its packaging after it is released for distribution to the site at 
which study drug will be administered. 
A CPC may be detected prior to use of study drug, during use, or after use.  A CPC is typically 
non-medical in nature; however, it is possible that investigational product complaints could be 
associated with an AE.  Examples of a CPC include, but are not limited to:  illegible clinical 
label, missing clinical label, damaged vial, empty vial, and contamination of study drug. 


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5.3.2. 
Reporting 
For CPCs, the Sponsor or its designee should be notified within 24 hours using the appropriate 
eCRF.  Clinical product complaints that may be associated with an AE must be evaluated and 
reported as indicated in Section 6.5.5.  Detailed instructions on reporting CPCs will be provided 
in the Pharmacy Manual. 
5.4. 
Concomitant Medications and Procedures 
Use of concomitant medications and procedures will be recorded on the patient’s eCRF as 
specified in the Schedule of Assessments (see Table 1).  Concomitant medications include all 
prescription medications, herbal preparations, over the counter medications, vitamins, and 
minerals.  Any changes in medications during the study will also be recorded on the eCRF. 
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, acute 
kidney injury). 
Standard vitamins and topical medications are permitted (vitamin C supplementation must be 
<200 mg daily per inclusion criteria).  However, topical steroids must not be applied anywhere 
near the injection site(s) unless medically indicated. 
Patients will be allowed to receive vaccines (eg, for SARS-CoV-2) that have received health 
agency authorization (including for emergency use) by local or regional regulatory authorities. 
Any concomitant medication that is required for the patient’s welfare may be administered by the 
Investigator.  However, it is the responsibility of the Investigator to ensure that details regarding 
the medication are recorded on the eCRF.  Concomitant medication will be coded using an 
internationally recognized and accepted coding dictionary. 
5.5. 
Treatment Compliance 
Compliance with study drug administration will be verified through observation by study staff or 
trained home healthcare professionals. 
5.6. 
Other Requirements 
5.6.1. 
Contraception 
Females of child-bearing potential must be willing to use an acceptable method of contraception 
from 14 days before first dose, throughout study participation, and for 6 months after last dose 
administration or until study completion. 
Birth control methods which are considered acceptable include: 
• Placement of an intrauterine device. 
• Placement of an intrauterine hormone-releasing system. 
• Bilateral tubal occlusion. 


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• 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 associated with the inhibition of 
ovulation. 
• 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 6 months 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. 
Females of child-bearing potential include female patients who have experienced menarche (or 
begin menarche over the course of the study), and who are not postmenopausal or permanently 
sterilized (eg, bilateral oophorectomy, hysterectomy, or bilateral salpingectomy).  A 
postmenopausal state is defined as the absence of menses for 12 months without an alternative 
medical cause, confirmed by a follicle stimulating hormone level within the postmenopausal 
range.  
For male patients, no contraception is required.  However, use by males of contraception 
(condom) may be required in some countries, in order to comply with local requirements as 
described in the corresponding patient ICFs. 
Compliance with contraception requirements will be assessed on a regular basis by the 
Investigator throughout the course of the study (see Section 6.5.4.2).  
5.6.2. 
Alcohol Restrictions 
Patients will limit alcohol consumption throughout the course of the study.  Alcohol is limited to 
no more than 2 units per day (unit:  1 glass of wine [approximately 125 mL] = 1 measure of 
spirits [approximately 1 fluid ounce] = ½ pint of beer [approximately 284 mL]) for the duration 
of the study. 
5.6.3. 
Dietary Restrictions 
For the duration of the study patients should adhere to a diet appropriate for calcium oxalate 
stone formers, including adequate calcium intake and avoidance of spinach and other foods that 
are high in oxalate.  Details are provided in the Dietary Reference Sheet. 
Dietary adherence will be collected in a patient diary at the time points listed in the Schedule of 
Assessments (Table 1).  Refer to the Study Manual for more information. 


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6. 
STUDY ASSESSMENTS 
The schedule of study assessments is provided in Table 1.  All assessments are required to be 
performed prior to dosing at dosing visits, except for PK 2-hour postdose sample collection and 
optional CT scans.  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, and 
as noted in Table 1, home healthcare may take place at a location other than the clinical trial site 
to perform study assessments, which may include pregnancy testing (urine or serum), clinical 
laboratory assessments, urine collections, DNA testing, symptom-directed physical examination / 
body system assessment, vital signs, body weight, height, blood collection for PD and ADA 
analyses (at the discretion and with oversight of the Investigator). 
6.1. 
Screening Assessments 
An ICF that has been approved by the appropriate Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC) must be signed by the patient before the screening procedures are 
initiated.  All patients will be given a signed and dated version of their ICF. 
Patients will be screened to ensure that they meet all the inclusion criteria and none of the 
exclusion criteria.  To confirm study entrance criteria, 24-hour urine will be collected per 
Table 4.  
Patient demographic data and medical history/disease history will be obtained.  Any changes to 
medical history occurring between the screening assessment and prior to dosing will be updated.  
6.1.1. 
DNA Sample 
A blood sample for DNA analysis will be collected from all patients as part of the screening 
assessments.  The samples will be analyzed for PH1, PH2, and PH3 (unless tested previously) to 
confirm eligibility (see Section 4.2).  Refer to the Laboratory Manual for more information. 
6.1.2. 
Retesting  
If in the Investigator’s judgement, the screening laboratory abnormalities are likely to be 
transient, then laboratory tests may be repeated once.  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. 
6.1.3. 
Rescreening 
Rescreening of patients is permitted with approval of the Medical Monitor.  A patient who does 
not meet all study eligibility criteria due to a transient condition observed at screening (eg, 
prohibited medications that were subsequently discontinued) will be allowed to return for 
rescreening.  A patient will be re-consented if rescreening occurs outside of the 60-day screening 
window.  In this case, all screening procedures must be repeated. 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently assigned to treatment with study drug.  The site should update the patient’s 
status in the IRT to reflect this as soon as possible. 


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6.2. 
Efficacy Assessments 
Efficacy assessments are to be performed as specified in the Schedule of Assessments (Table 1). 
6.2.1. 
24-Hour Urine Collections 
Urinary oxalate excretion and calcium oxalate supersaturation (calculated from multiple 
parameters) will be determined from 24-hour urine sample collections to be completed at the 
time points specified in the Schedule of Assessment (Table 1).  The start and stop dates/times of 
collection, the volume of urine in the collection, whether there were any missed voids, and 
whether the patient complied with dietary recommendations will be recorded.  An aliquot of the 
24-hour urine collection will also be used to determine urinary creatinine content and to 
determine if the 24-hour urine collections need to be repeated (see Section 6.2.1.1). 
The 24-hour urine collection procedure by study visit is provided in Table 4.  
Table 4: 
24-hour Urine Collection Procedure by Study Visit 
Study Visit and Urine 
Collection Window 
Number of 
Collections to 
Schedule 
Validity Requirement 
Prior to Dosing/Visit  
(see Section 6.2.1.1) 
Notes 
Screening 
(within 60-day period) 
2 
2 valid collections prior to 
dosing unless variability 
criterion is not met 
(Section 6.2.1.2), in 
which case an additional 
collection is requireda.  
Supervised collectionsb are 
encouraged unless patient is already 
familiar with the collection 
procedure.  If any collections are 
invalid, the remaining collections for 
screening must be supervised.  
Months 3, 4, 5, and 6 
(within 14 days prior to 
dosing/visit) 
1 
No 
If an invalid collection is obtained for 
the timepoint, a single repeat 
collection must be supervised.  
Repeat collection, if necessary, is to 
be completed within ±14 days of 
dosing/visit. 
Months 9 and 15 
(within 14 days prior to 
dosing/visit) 
2 
1 valid collection prior to 
dosing/visit 
If a patient has had ≥2 prior invalid 
collections, both collections at these 
visits must be supervisedb.  At least 1 
valid collection must be obtained 
prior to dosing/visit.  If any 
collections for the timepoint are 
invalid, the remaining collection(s) 
for the timepoint must be supervised. 
a The additional collection is not required to be valid in order to proceed with dosing, but will be tested to confirm 
validity for the calculation of baseline 24-hour urinary oxalate. 
b A supervised collection is defined, at a minimum, as contact from study staff to the patient the day prior to the 
collection start and the day the collection will finish to ensure compliance; this may be conducted remotely.  Any 
or all of the 24-hour urine collections may be conducted supervised.  If 24-hour urine collection is not a supervised 
collection, or if a collection is supervised remotely, patients may either bring it to the clinic or have it couriered to 
the clinic.   


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6.2.1.1. 
Validity Criteria for 24-hour Urine Collections 
Throughout the study, a urine collection will be considered valid if each of the following criteria 
are met: 
• The collection is between 22 to 26 hours in duration between the initial discarded 
void and the last void or attempt to void. 
• No voids are missed between the start and end time of the collection as indicated by 
the patient's urine collection diary. 
• The 24-hour creatinine content is at least 10 mg/kg as assessed by the central 
laboratory. 
• Patient complied with dietary recommendations appropriate for oxalate stone formers 
(detailed in the Dietary Reference Sheet) for the 4 days prior to the start of the urine 
collection and during the collection. 
24-hour urine collections that are known to be invalid should still be submitted for analysis. 
6.2.1.2. 
Variability Criterion for 24-hour Urine Collections at Screening 
If the 2 valid 24-hour urine collections from screening meet eligibility requirements (both 24-
hour urinary oxalate levels >ULN), the variability between the oxalate levels (in mg/day) should 
be assessed as follows: 
 
If the variability is >20%, then an additional 24-hour urine collection should be obtained.  The 
result of the additional sample will not impact the patient’s eligibility for the study. 
6.2.2. 
Kidney Stone Events 
Since kidney stone events are recorded as an efficacy assessment, these events will not be 
captured as AEs or SAEs.  However, if a patient experiences other AEs or SAEs during a kidney 
stone event, they should be reported as an AE (see Section 6.5.5.2).   
Kidney stone events will be graded by the Investigator as mild, moderate, or severe as defined in 
Section 6.5.5.1.  If there are changes in grade during an event, only the highest grade should be 
reported. 
6.2.2.1. 
Clinical 
All relevant clinical information pertaining to kidney stone events should be obtained, including 
laboratory values, medical records, discharge summaries, and medical test results (including 
stone composition, if available, and radiology reports).  A clinical kidney stone event is defined 
as one of the following: 
• Visible passage of a kidney stone 
• A procedural intervention for removal of an asymptomatic or symptomatic stone 
(information on the location, number, and size of stones removed will be collected) 
𝑉𝑎𝑟𝑖𝑎𝑏𝑖𝑙𝑖𝑡𝑦=  (𝑂𝑥𝑎𝑙𝑎𝑡𝑒 𝑣𝑎𝑙𝑢𝑒 #1 −𝑂𝑥𝑎𝑙𝑎𝑡𝑒 𝑣𝑎𝑙𝑢𝑒 #2)
(𝐴𝑣𝑒𝑟𝑎𝑔𝑒 𝑜𝑓 𝑜𝑥𝑎𝑙𝑎𝑡𝑒 𝑣𝑎𝑙𝑢𝑒𝑠 #1 & #2)  × 100% 


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• Or, in the case of potential stone passages without visible stones, it will be up to the 
Investigator to evaluate patients’ symptoms and determine whether a stone passage 
occurred or the symptoms were due to a different cause. 
6.2.2.2. 
Radiographic 
For patients who elect to participate in optional CT scans, a non-contrast low-dose 
kidney-protocol CT scan will be performed at baseline (may be performed up to 3 days prior to 
Day 1), and at Month 15.   
For patients who elect to participate in optional CT scans and terminate the study early, a CT 
scan should be performed at the ET visit only if this visit occurs after Month 6 and at the 
discretion of the Investigator, and where permitted, following consultation with the Medical 
Monitor.  Optional CT scans will be analyzed centrally. 
6.2.3. 
Estimated Glomerular Filtration Rate 
Blood samples for the assessment of eGFR (mL/min/1.73m2) will be obtained at the time points 
specified in the Schedule of Assessment (Table 1). 
eGFR will be calculated based on the CKD-EPI formula (see Section 10.1).[Levey 2009; 
Schwartz 2009] 
6.3. 
Pharmacodynamic Assessments 
Urine and blood samples will be collected for assessment of PD parameters (plasma oxalate and 
plasma glycolate, and 24-hour urinary glycolate) at the time points specified in the Schedule of 
Assessments (Table 1).  On dosing days, all blood and urine samples will be collected prior to 
study drug administration. 
All PD assessments will be analyzed centrally.  Postdose PD results will not be distributed to the 
sites until after the last patient completes assessments at the Month 15 visit.  Site personnel 
should refrain from obtaining or viewing local oxalate, calcium oxalate supersaturation, or 
glycolate assessments, except as medically indicated, due to risk of unblinding (Section 3.5).  
Details regarding the processing and aliquoting of PD samples for shipping and storage are 
provided in the Laboratory Manual. 
Where local regulations allow and infrastructure is in place, a healthcare professional may collect 
urine or blood samples offsite. 
6.4. 
Pharmacokinetic Assessments 
Blood samples will be collected for the assessment of lumasiran PK parameters at the time points 
indicated in the Schedule of Assessments (Table 1).  A detailed schedule of time points for the 
collection of blood samples for PK analysis is in Table 2. 
The concentration of lumasiran in blood samples will be determined using a validated assay.  
Details regarding sample volumes to be collected, and the processing and shipping of the 
samples will be provided in the Laboratory Manual. 


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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, and laboratory tests.  Clinically significant abnormalities observed during the 
physical examination are recorded as either medical history or AEs, as appropriate. 
Safety assessments are to be performed as specified in the Schedule of Assessments (Table 1).  
On dosing days and as applicable, assessments of vital signs, weight/height, physical 
examination, and clinical laboratory assessments are to be completed before study drug 
administration.  
Adverse event assessments are detailed under Section 6.5.5.  
6.5.1. 
Vital Signs 
Vital signs will be measured as specified in the Schedule of Assessments (Table 1) and include 
blood pressure, heart rate, body temperature, and respiratory rate.  Vital signs will be measured 
predose, when applicable.  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 predose in the seated or supine position, after the patient has rested 
comfortably for approximately 5 minutes.  Blood pressure should be taken using the same arm 
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. 
Vital signs results will be recorded in the eCRF. 
6.5.2. 
Height and Weight 
Height will be measured in centimeters.  Body weight will be measured in kilograms.  Height 
and body weight measurements will be collected as specified in the Schedule of Assessments 
(Table 1) and will be recorded in the eCRF. 
6.5.3. 
Physical Examination 
Full and symptom-directed physical examinations will be conducted according to the Schedule 
of Assessments (Table 1); if a physical examination is scheduled for a dosing visit, it should be 
conducted prior to dosing.  Full physical examinations will include the examination of the 
following:  general appearance; head, eyes, ears, nose and throat; respiratory, cardiovascular, 
gastrointestinal, musculoskeletal, and dermatological systems; thyroid; lymph nodes; and 
neurological status.  If a visit is conducted offsite (eg, home), a body system assessment may be 
performed in lieu of a physical examination. 
Symptom-directed physical examinations will be guided by evaluation of ongoing symptoms, 
changes in symptoms, or the onset of new symptoms, since the last visit.  If there are no ongoing 
symptoms, changes in symptoms, or new symptoms, then a symptom-directed physical 
examination is not required. 


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Clinically significant abnormalities observed during the physical examination are recorded on 
the medical history eCRF (if observed during screening) or the AE eCRF (if observed at any 
post-screening visit). 
6.5.4. 
Clinical Laboratory Assessments 
The following clinical laboratory tests will be evaluated by a central laboratory.  Specific 
instructions for transaminase elevations are provided in Section 5.2.3.1.  Laboratory assessments 
conducted to confirm study eligibility (Section 4) will not be repeated unless the time between 
screening and randomization exceeds 4 weeks.  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, until it has returned to the normal range or 
stabilized, and/or a diagnosis is made to adequately explain the abnormality.  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 included in the clinical database.  Clinical laboratory assessments 
are listed in Table 5 and will be assessed as specified in the Schedule of Assessments (see 
Table 1).  
While local laboratory results may be used for urgent clinical decisions, on the day of visit 
assessments, all laboratory assessments specified in Table 5 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. 
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 5: 
Clinical Laboratory Assessments 
Hematology 
Complete blood count with differential 
 
Serum Chemistry 
Sodium 
Potassium 
BUN 
Albumin 
Total protein 
Calcium 
Glucose 
Bicarbonate 
Creatinine and eGFRa 
Chloride 
Liver Function Tests 
 
AST 
ALP 
ALT 
Bilirubin (total and direct) 
Coagulation  
International Normalized Ratio (screening only) 
 
Immunogenicity (see Section 6.5.4.1) 
Antidrug antibodies 
 
Pregnancy Testing/FSH Screening (see Section 6.5.4.2) 
β-human chorionic gonadotropin (females of 
child-bearing potential only) 
Follicle-stimulating hormone (postmenopausal 
women only) 
Abbreviations:  ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; 
BUN=blood urea nitrogen; eGFR=estimated glomerular filtration rate; FSH=follicle-stimulating hormone  
a Refer to Section 10.1 and the laboratory manual for further instructions on calculating eGFR. 
6.5.4.1. 
Immunogenicity 
Blood samples will be collected to evaluate ADA.  Blood samples for ADA testing must be 
collected before study drug administration as specified in the Schedule of Assessments (Table 1). 
Details regarding the processing and shipping of the samples will be provided in the Laboratory 
Manual. 
6.5.4.2. 
Pregnancy Testing 
A pregnancy test will be performed for females of child-bearing potential.  A serum pregnancy 
test will be performed at screening.  Urine pregnancy tests will be performed thereafter per the 
Schedule of Assessments and any time pregnancy is suspected.  More frequent pregnancy testing 
may be performed where required per local requirements.  The results of the pregnancy test must 
be known before study drug administration.  Patients who are pregnant at screening are not 
eligible for study participation.  Any woman with a positive urine pregnancy test that is 
subsequently confirmed by a positive serum pregnancy test during the study will be discontinued 
from study drug but will continue to be followed for safety.  Patients determined to be pregnant 


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while on study will be followed at least until the pregnancy outcome is known (see 
Section 6.5.5.7 for follow-up instructions). 
A blood sample will be drawn at screening to measure the levels of follicle stimulating hormone 
in order to confirm postmenopausal status in all women suspected to be postmenopausal.  
Postmenopausal women and women who are permanently sterilized will not undergo pregnancy 
testing. 
6.5.4.3. 
Additional Liver Function Assessments 
Additional laboratory assessments will be performed in patients who experience any LFT 
abnormalities as outlined in Section 5.2.3.1 (see Table 3).  Following the occurrence of elevated 
liver transaminases or other LFT abnormalities per central laboratory, all assessments in Table 6 
will be performed one time, as well as hematology, serum chemistry, LFT, and coagulation 
assessments per Table 3, and other assessments or evaluations per Investigator discretion, as 
appropriate.  
Monitoring, including criteria for dose modification or withholding the study drug, is described 
in Section 5.2.3.1. 


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Table 6: 
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.  The full panel of assessments should only be 
performed once; individual assessments may be repeated, as needed. 


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6.5.5. 
Adverse Events 
6.5.5.1. 
Definitions 
Adverse Event 
According to the International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (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. 
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: 
• ALT or AST >3× ULN 
• Severe or serious ISRs; ISRs that are associated with a recall phenomenon (reaction 
at the site of a prior injection with subsequent injections), or ISRs that lead to 
temporary dose interruption or permanent discontinuation of study drug. 
An ISR is defined as a local reaction at or near the site of injection.  “At or near” the 
injection site includes reactions at the injection site, adjacent to the injection site, or a 
reaction which may shift slightly away from the injection site due to gravity (eg, as 
may occur with swelling or hematoma).  Reactions with onset and resolution within 4 
hours of the injection (eg, transient pain/burning at injection site) do not meet the 
study definition of ISRs, unless immediate treatment is required.  A systemic reaction 
which includes the injection site, eg, generalized urticaria, other distinct entities or 
conditions like lymphadenopathy that may be near the injection site is not considered 
an ISR.   


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For information on recording and reporting of AEs of clinical interest, see Section 6.5.5.2 and 
Section 6.5.5.3, respectively. 
Adverse Event Severity 
Adverse events are to be graded according to the categories detailed below: 
Mild: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Moderate: 
Moderate; minimal, local or noninvasive intervention indicated; limiting age 
appropriate instrumental activities of daily living (eg, preparing meals, 
shopping for groceries or clothes, using the telephone, managing money). 
Severe: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care activities of daily living (ie, bathing, dressing and 
undressing, feeding self, using the toilet, taking medications, and not 
bedridden); OR life-threatening consequences; urgent intervention indicated; 
OR death related to an 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.  Adverse events characterized as intermittent 
require documentation of the start and stop of each incidence.  When changes in the severity of 
an AE occur more frequently than once a day, the maximum severity for the experience that day 
should be noted.  If the severity category changes over a number of days, then those changes 
should be recorded separately (with distinct onset dates). 
Adverse event 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. 
6.5.5.2. 
Eliciting and Recording Adverse Events 
Eliciting Adverse Events 
The patient should be asked about medically relevant changes in the patient’s health since the 
last visit.  The patient 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, or other findings 
that are relevant to patient safety. 
Recording Adverse Events 
The Investigator is responsible for recording non-serious AEs that are observed or reported by 
the patient after administration of the first dose of study drug regardless of their relationship to 


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study drug through the EOS.  Non-serious AEs will be followed until the EOS.  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 EOS.  Serious AEs will be followed until satisfactory resolution, until baseline level 
is reached, or until the SAE is considered by the Investigator to be chronic or the patient is 
stable, as appropriate. 
All AEs must be recorded in the source records for the clinical study center and in the eCRF for 
the patient, whether or not they are considered to be drug-related.  Each AE must be described in 
detail:  onset time and date, description of event, severity, relationship to study drug, action 
taken, and outcome (including time and date of resolution, if applicable). 
For SAEs, record the event(s) in the eCRF and, as applicable, the SAE form. 
For AEs that are considered AEs of clinical interest (Section 6.5.5.1), the supplemental AEs of 
Clinical Interest eCRF should be completed.  Additional clinical and laboratory information may 
be collected.  Refer to eCRF 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.). 
6.5.5.3. 
Reporting Adverse Events of Clinical Interest to Sponsor/Designee 
For AEs that are considered AEs of clinical interest (Section 6.5.5.1), the Sponsor or its designee 
should be notified within 24 hours using a supplemental AEs of Clinical Interest eCRF.  
Additional clinical and laboratory information may be collected.  Refer to eCRF completion 
guidelines for details on reporting events in the supplemental AEs of Clinical Interest eCRF.   
For all ISRs, the Investigator, or delegate, should submit a supplemental ISR eCRF, recording 
additional information (eg, descriptions, onset and resolution date, severity, treatment given, 
event outcome). 
6.5.5.4. 
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 6.5.5.1 must be reported to the 
Sponsor or designee within 24 hours from the time that clinical study center staff first learns of 
the event.  All SAEs must be reported regardless of the relationship to study drug. 
The initial report should include at least the following information: 
• Patient’s study number 
• Description and date of onset of the event 
• Criterion for serious 


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• Preliminary assignment of relationship to study drug, and 
• Investigator/site information 
To report the SAE, complete the eCRF and, as applicable, the SAE form.  Within 24 hours of 
receipt of follow-up information, the Investigator must update the eCRF and, as applicable, the 
SAE form.  Serious AEs 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. 
6.5.5.5. 
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. 
6.5.5.6. 
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. 
6.5.5.7. 
Pregnancy Reporting 
If a female patient becomes pregnant during the study through 6 months following the last dose 
of study drug, 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 6 months 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 6.5.5.4. 
The reporting of any pregnancy outcome for a female partner of a male patient participating in 
this study that results in a postpartum complication, spontaneous abortion, stillbirth, neonatal 
death, or congenital anomaly should be reported to the Investigator, who will then report this to 
the Sponsor or designee.  The pregnancy outcome is to be recorded on the pregnancy reporting 
form. 


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6.5.5.8. 
Reporting of Overdose and Other Special Situations 
An overdose is defined as any dose of study drug administered to the participant that is ≥2-fold 
the assigned dose during a single administration. 
The Sponsor does not recommend specific treatment for an overdose.  
In an event of an overdose or other special situations (eg, medication error, abuse, misuse, CPC 
associated with an AE), the Investigator should: 
• Contact the Medical Monitor within 24 hours 
• Submit the special situations reporting form within 24 hours using the contact 
information in the Pharmacy Manual 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities 
• Document the amount of study drug given 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention or 
a concomitant medication will be considered AEs/SAEs.  Overdose per se will not be 
categorized as an AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent.  Such overdoses should be reported as an SAE regardless of sequelae. 
Full details of overdose and other special situations reporting instructions will be outlined in the 
Pharmacy Manual. 
6.6. 
Healthcare Utilization 
To complement medical records, information regarding health resource use related to kidney 
stone events will be collected as specified in the Schedule of Assessments (Table 1), including 
emergency room visits, unscheduled office visits, hospitalizations, and procedures for kidney 
stone management. 


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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 principal features stated in the 
protocol. 
7.1. 
Determination of Sample Size 
The planned enrollment for this study is 120 patients. 
The study is powered to detect a difference in urinary oxalate excretion between each lumasiran 
group and the placebo group.  Assuming a standard deviation of 45% in the percent change from 
baseline in 24-hour urinary oxalate levels at Month 6, a sample size of 40 patients per group will 
enable a power of at least 80% in detecting a treatment difference of 30% between the treatment 
groups at a 2-sided significance level of 0.05.  Table 7 shows the statistical power under various 
assumptions for a sample size of 40 per group. 
Table 7: 
Sample Size Power Calculations 
Assumed standard 
deviation (SD) 
Assumed difference 
(lumasiran – placebo) 
Power 
25% 
20% 
94% 
30% 
99% 
30% 
20% 
84% 
30% 
99% 
45% 
20% 
50% 
30% 
84% 
Abbreviations:  SD=standard deviation 
7.2. 
Statistical Methodology 
The statistical and analytical plans presented below are brief summaries of planned analyses.  
More complete plans will be detailed in the SAP.  Changes to the methods described in the final 
SAP will be described and justified as needed in the clinical study report.  For information on 
study endpoints, see Section 2. 
7.2.1. 
Populations to be Analyzed 
The populations (analysis sets) are defined as follows: 
• Full Analysis Set (FAS):  All randomized patients who received at least 1 dose of 
study drug.  Patients in the FAS will be analyzed according to the randomized 
treatment arm. 
• Plasma Oxalate Analysis Set:  All patients who received at least 1 dose of study 
drug and have a baseline plasma oxalate level ≥1.5 times the lower limit of 
quantification/detection. 


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• Safety Analysis Set:  All patients who received at least 1 dose of study drug.  
Patients in the Safety Analysis Set will be analyzed according to the treatment 
actually received. 
• PK Analysis Set:  All patients who received at least 1 full dose of study drug and 
have at least one postdose blood sample for PK parameters and have evaluable PK 
data. 
The primary population used to evaluate efficacy will be the FAS.  Safety will be analyzed using 
the Safety Analysis Set.  The PK Analysis Set 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 by dose 
level and overall for the FAS and Safety Analysis Set.  
7.2.5. 
Efficacy Analyses 
The hypothesis testing for the primary endpoint will be tested comparing each lumasiran group 
to the placebo group in the FAS with a 2-sided significance level of 0.05. 
The primary endpoint will be analyzed using a mixed-effect model for repeated measures 
(MMRM) approach.  The outcome variable is percent change from baseline in urinary oxalate to 
Month 6 (average across Months 4 through 6).  The model includes baseline 24-hour urinary 
oxalate and the stratification factor of number of historical kidney stone events (>1 versus ≤1 
event in the 12 months prior to screening) as covariates, and fixed effect terms including 
treatment arm, visit and visit and treatment arm interaction.  The estimate of treatment difference 
for the average percent change from baseline of 24-hour urinary oxalate excretion across Months 
4 through 6 will be calculated via a linear contrast of the corresponding coefficients from the 
MMRM model.  
Additionally, the percent change from baseline in 24-hour urinary oxalate excretion at Month 9 
and Month 15 will be summarized and compared between lumasiran and placebo treatment 
groups. 
Baseline, Month 9, and Month 15 urinary oxalate values and urinary calcium oxalate 
supersaturation values are planned to be collected in either duplicate or triplicate (baseline) and 
duplicate (Months 9 and 15), and the calculated median of valid collections during each time 
period (visit) will be used in the analysis. 
Analysis of secondary endpoints and exploratory endpoints will be specified in the SAP.  No 
multiplicity adjustment is planned. 


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7.2.6. 
Pharmacodynamic Analysis 
The change in plasma and urinary PD parameters will be summarized over time for all patients in 
the FAS.  For the change in plasma oxalate, a separate analysis population, the Plasma Oxalate 
Analysis Set will be used. 
7.2.7. 
Pharmacokinetic Analysis 
Pharmacokinetic analyses will be conducted using noncompartmental methods. 
Pharmacokinetic parameters to be calculated include but will not be limited to maximum plasma 
concentration (Cmax) and time to maximum plasma concentration (tmax).  Other parameters may 
be calculated, if deemed necessary. 
7.2.8. 
Safety Analyses 
The primary parameter is the frequency of treatment-emergent AEs (hereafter referred to simply 
as AEs).  Safety parameters also include vital signs, clinical laboratory assessments and physical 
exams.  Extent of exposure will be summarized by dose and overall.  
Prior and concomitant medications will be coded using the World Health Organization (WHO) 
Drug Dictionary.  Results will be tabulated by Anatomical Therapeutic Chemical (ATC) 
Classification System and preferred term (PT). 
Adverse events will be classified according to the Medical Dictionary for Regulatory Activities 
(MedDRA) System Organ Class (SOC) and PT by dose level and overall.  Adverse events, 
SAEs, related AEs, AEs leading to discontinuation of study drug, and AEs leading to death will 
be summarized by SOC and PT for each treatment arm.  By-patient listings will be provided for 
deaths, SAEs, and AEs leading to discontinuation of study drug.  
Descriptive statistics, summarizing the observed values and changes from baseline over time, 
will be provided for clinical laboratory parameters and vital signs.  Laboratory shift tables from 
baseline grade (or category) to worst post-baseline grade (or category) will be presented for 
laboratory parameters that are graded or categorized.  Abnormal physical exam findings will be 
presented in listings. 
Other safety summaries will be presented as appropriate.  Further details will be specified in the 
SAP. 
7.2.9. 
Immunogenicity Analyses 
The frequency and percentage of patients with confirmed positive ADA assay at any time during 
study as well as at each scheduled visit will be summarized.  The titer results for patients with 
confirmed positive ADA results will be summarized. 
7.2.10. 
Other Analyses 
Other exploratory analyses will be described in the SAP. 


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7.2.11. 
Interim Analysis 
No formal interim analysis is planned.  The primary analysis will be conducted for the primary 
and secondary endpoints through Month 6 after the last patient has completed the Month 6 visit 
and the database is locked. 
7.2.12. 
Optional Additional Research 
Optional additional research may be conducted in the future on the biological samples and/or 
data collected during the study in accordance with the strict terms of the ICF (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. 
8.1.1. 
Informed Consent 
The Investigator will ensure that the patient is given full and adequate oral and written 
information about the nature, purpose, possible risk and benefit of the study.  Patients must also 
be notified that they are free to discontinue from the study at any time.  The patient should be 
given the opportunity to ask questions and allowed time to consider the information provided. 
The Investigator will inform the patient if new information becomes available that may be 
relevant to the patient’s willingness to continue participation in the study.  Communication of 
this information should be documented.  If circumstances warrant an updated informed consent 
during the study, and patients are required to re-consent, this may be collected remotely where 
local regulations allow. 
The patient’s signed and dated informed consent must be obtained before conducting any study 
tests or procedures that are not part of routine care. 
The Investigator must maintain the original, signed ICF.  All patients will be given a copy of the 
signed and dated ICF.   
8.1.2. 
Ethical Review 
The study protocol, including the ICF, 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.  The protocol must be reapproved by the IRB or IEC upon receipt of 
amendments and annually, as local regulations require. 


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Initial IRB or IEC approval of the protocol, and all materials approved by the IRB or IEC for this 
study including the patient consent 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 6.5.5.  In addition, the 
Investigator agrees to submit progress reports to the IRB or IEC per their local reporting 
requirements, or at least annually and at the conclusion of the study.  The reports will be made 
available to the Sponsor or designee. 
Any communications from regulatory agencies, IRBs, or IECs in regard to inspections, other 
studies that impact this protocol or the qualifications of study personnel should be promptly 
reported to the Sponsor or its designee. 
The Investigator is also responsible for providing the IRB 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 randomized under the 
amended protocol, and patients must be re-consented to the most current version of the ICF. 
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 (including personal data) relating to the study should be retained for 2 years 
after the last approval in an ICH territory or as required by local laws and regulations, 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 to be submitted to the Sponsor or designees, the names will be obliterated, and the 
assigned patient number added to the document, before sending to the Sponsor.  Documents not 
for submission to the Sponsor (eg, signed ICFs) should be maintained by the Investigator in strict 
confidence. 


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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 EOS is defined as the last patient last visit. 
8.1.6. 
Termination of the Clinical Study or Site Closure 
The Sponsor, or designee, reserves the right to terminate the study or a clinical study site at any 
time.  Conditions that may warrant this action may include, but are not limited to: 
• The discovery of an unexpected, serious, or unacceptable risk to patients participating 
in the study 
• 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. 


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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. 
Where local regulations allow, the Monitor may request remote access to source documents and 
systems.  Should this take place, it will be done in a manner that protects the confidentiality of 
the data. 
8.2.3. 
Audits and Inspections 
Periodically, the Sponsor or its authorized representatives audit clinical investigative sites as an 
independent review of core trial processes and documents to determine whether these activities 
were conducted, and data were recorded, analyzed, and accurately reported according to the 
protocol, GCP guidelines of the ICH, and any applicable regulatory requirements.  A regulatory 
authority, an IEC or an IRB may visit the site to perform audits or inspections, including source 
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 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 will detail the procedures for 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 
Borghi L, Schianchi T, Meschi T, Guerra A, Allegri F, Maggiore U, et al. Comparison of two 
diets for the prevention of recurrent stones in idiopathic hypercalciuria. N Engl J Med. 2002 Jan 
10;346(2):77-84. 
Curhan GC,Taylor EN. 24-h uric acid excretion and the risk of kidney stones. Kidney Int. 2008 
Feb;73(4):489-96. 
Dhondup T, Kittanamongkolchai W, Vaughan LE, Mehta RA, Chhina JK, Enders FT, et al. Risk 
of ESRD and Mortality in Kidney and Bladder Stone Formers. Am J Kidney Dis. 2018 
Dec;72(6):790-7. 
Ferraro PM, Ticinesi A, Meschi T, Rodgers A, Di Maio F, Fulignati P, et al. Short-Term 
Changes in Urinary Relative Supersaturation Predict Recurrence of Kidney Stones: A Tool to 
Guide Preventive Measures in Urolithiasis. J Urol. 2018 Nov;200(5):1082-7. 
Heilberg IP,Schor N. Renal stone disease: Causes, evaluation and medical treatment. Arq Bras 
Endocrinol Metabol. 2006 Aug;50(4):823-31. 
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. 
Mitchell JA, Knowles RB, Kirkby NS, Reed DM, Edin ML, White WE, et al. Kidney 
Transplantation in a Patient Lacking Cytosolic Phospholipase A2 Proves Renal Origins of 
Urinary PGI-M and TX-M. Circ Res. 2018 Feb 16;122(4):555-9. 
Pearle MS, Goldfarb DS, Assimos DG, Curhan G, Denu-Ciocca CJ, Matlaga BR, et al. Medical 
management of kidney stones: AUA guideline. J Urol. 2014 Aug;192(2):316-24. 
Prochaska M, Taylor E, Ferraro PM,Curhan G. Relative Supersaturation of 24-Hour Urine and 
Likelihood of Kidney Stones. J Urol. 2018 May;199(5):1262-6. 
Rule AD, Bergstralh EJ, Melton LJ, 3rd, Li X, Weaver AL,Lieske JC. Kidney stones and the risk 
for chronic kidney disease. Clin J Am Soc Nephrol. 2009 Apr;4(4):804-11. 
Scales CD, Jr., Smith AC, Hanley JM, Saigal CS,Urologic Diseases in America P. Prevalence of 
kidney stones in the United States. Eur Urol. 2012 Jul;62(1):160-5. 
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. 
Shin S, Srivastava A, Alli NA,Bandyopadhyay BC. Confounding risk factors and preventative 
measures driving nephrolithiasis global makeup. World J Nephrol. 2018 Nov 24;7(7):129-42. 
Türk C, Neisius A, Petřík A, Skolarikos A, Somani B, Thomas K, et al., editors. EAU Guidelines 
on Urolithiasis. EAU Annual Congress; 2021; Milan, Italy: EAU Guidelines Office. 
Worcester EM,Coe FL. Nephrolithiasis. Prim Care. 2008 Jun;35(2):369-91, vii. 
Worcester EM,Coe FL. Clinical practice. Calcium kidney stones. N Engl J Med. 2010 Sep 
2;363(10):954-63. 
 


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10. 
APPENDICES 
10.1. 
Formula for Estimated Glomerular Filtration Rate Calculation 
Source:  Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI); Levey AS, Stevens 
LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate.  Ann Intern Med. 
2009;150(9):604-612. 
• eGFR = 141 × min(Scr/κ, 1)α × max(Scr/κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 
1.159 [if Black or African American] 
where: 
− Scr is serum creatinine in mg/dL 
− κ = 0.7 (females) or 0.9 (males) 
− α = -0.329 (female) or -0.411 (male) 
− min(Scr/κ, 1) is the minimum of Scr/κ or 1.0 
− max(Scr/κ, 1) is the maximum of Scr/κ or 1.0 
− Age (years) 
 
Abbreviations:  eGFR= Estimated glomerular filtration rate; SCr=serum creatinine 


Clinical Study Protocol ALN-GO1-008 
ALN-GO1 (lumasiran) 
Amendment 2 Summary of Changes, 07 July 2022 
Alnylam Pharmaceuticals 
Confidential 
1 
ALN-GO1-008 PROTOCOL AMENDMENT 2 
SUMMARY OF CHANGES DATED 07 JULY 2022  
COMPARED TO PROTOCOL AMENDMENT 1 DATED 16 JUNE 2022 
A Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy, Safety, 
Pharmacodynamics, and Pharmacokinetics of Lumasiran in Patients with Recurrent 
Calcium Oxalate Kidney Stone Disease and Elevated Urinary Oxalate Levels 
1.
RATIONALE FOR PROTOCOL AMENDMENT
The primary purpose for this protocol amendment is to decrease participant burden and to 
simplify site execution by making computed tomography (CT) scans optional.  The incidence 
rate of radiographic kidney stone events is an exploratory endpoint, and therefore this 
amendment is not considered to impact the scientific validity of the clinical study.  Patients who 
elect to participate in optional CT scans will be requested to complete CT scans at both baseline 
and Month 15.  
The location of clinical study centers was broadened globally to help with patient recruitment.  
The definition of permanent sterilization was also corrected based on guidance from the Clinical 
Trials Facilitation and Coordination Group (CTFG).  Additionally, in the Schedule of 
Assessments, the Month 12/Day 337 Visit column was deleted as a correction to Protocol 
Amendment 1, because all assessments for the Month 12 visit were removed in Protocol 
Amendment 1.  
A detailed summary of changes is provided in Section 2.  The following changes are not 
detailed: administrative changes and corrections to typographical errors, punctuation, grammar, 
abbreviations, and formatting.  
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Purpose:  Corrected the definition of permanent sterilization.  
The primary change occurs in Section 5.6.1, Contraception. 
Revised text:   
Females of child-bearing potential include female patients who have experienced menarche (or begin menarche over the course of the 
study), and who are not postmenopausal or permanently sterilized (eg, bilateral tubal occlusion oophorectomy, hysterectomy, or 
bilateral salpingectomy). A postmenopausal state is defined as the absence of menses for 12 months without an alternative medical 
cause, confirmed by a follicle stimulating hormone level within the postmenopausal range. 
Purpose:  Make CT scans optional.  
The primary change occurs in Section 6.2.2.2, Radiographic. 
Revised text:   
A For patients who elect to participate in optional CT scans, a non-contrast low-dose kidney-protocol CT scan will be 
performed for all patients on Day 1 (may be performed up to 3 days prior to Day 1), and at Month 15.   
For patients who elect to participate in optional CT scans and terminate the study early, a CT scan should be performed at the 
ET visit only if this visit occurs after Month 6 and at the discretion of the Investigator, and where permitted, following 
consultation with the Medical Monitor.  Optional CT scans will be analyzed centrally. 
Sections also reflecting this change:   
• Table 1:  Schedule of Assessments, including relevant footnotes. 
• Section 3.1, Summary of Study Design 
• Section 6, Study Assessments 
Administrative changes and corrections to typographical errors, punctuation, grammar, abbreviations, and formatting are not listed 
individually. 
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SPONSOR PROTOCOL APPROVAL 
 
I have read this protocol and I approve the design of this study. 
 
 
___________________________________________  
Date 
16-Jun-2022 | 11:09 PM EDT
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INVESTIGATOR’S AGREEMENT 
 
I have read the ALN-GO1-008 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 
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PROTOCOL SYNOPSIS 
Protocol Title 
A Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy, Safety, 
Pharmacodynamics, and Pharmacokinetics of Lumasiran in Patients with Recurrent Calcium 
Oxalate Kidney Stone Disease and Elevated Urinary Oxalate Levels 
Short Title 
A Study to Evaluate Lumasiran in Adults with Recurrent Calcium Oxalate Kidney Stone Disease 
and Elevated Urinary Oxalate Levels 
Study Drug 
Lumasiran (ALN-GO1) 
Phase 
Phase 2 
Study Centers 
The study will be conducted at approximately 55 clinical study centers across Europe and the 
United States. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
• 
To evaluate the effect of lumasiran on the 
percent change in urinary oxalate 
excretion 
• 
Percent change in 24-hour urinary oxalate 
from baseline to Month 6 (average across 
Months 4 through 6) 
Secondary 
 
• 
To evaluate the percentage of patients 
who achieve a ≥20% reduction in 24-hour 
urinary oxalate with lumasiran 
• 
Percentage of patients who achieve a 
≥20% reduction in 24-hour urinary 
oxalate from baseline to Month 6 (average 
across Months 4 through 6) 
• 
To evaluate the effect of lumasiran on 
urinary calcium oxalate supersaturation 
• 
Percent change in urinary calcium oxalate 
supersaturation from baseline to Month 6 
(average across Months 4 through 6) 
Exploratory 
 
• 
To evaluate the effect of lumasiran on 
absolute levels of urinary oxalate 
excretion 
• 
Absolute change in 24-hour urinary 
oxalate from baseline to Month 6 (average 
across Months 4 through 6) 
• 
To evaluate the effect of lumasiran on the 
occurrence of kidney stones 
• 
Incidence rate of clinical and radiographic 
kidney stone events  
• 
Time to first kidney stone event 
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Objectives 
Endpoints 
• 
To evaluate additional pharmacodynamic 
(PD) parameters of plasma oxalate, 
plasma glycolate, and urinary glycolate 
• 
Change from baseline in plasma oxalate 
• 
Change from baseline in plasma glycolate 
• 
Change from baseline in urinary glycolate 
• 
To characterize the pharmacokinetics 
(PK) of lumasiran 
• 
Plasma PK of lumasiran 
• 
To assess for antidrug antibodies (ADA) 
against lumasiran 
• 
ADA frequency and titer 
• 
To evaluate the effect of lumasiran on 
maintaining 24-hour urinary oxalate 
≤upper limit of normal (ULN) over time 
• 
Percentage of patients with 24-hour 
urinary oxalate ≤ULN over time 
• 
To evaluate the effect of lumasiran on 
maintaining a 25% reduction in urinary 
calcium oxalate supersaturation over time 
• 
Percentage of patients having a 25% 
reduction in urinary calcium oxalate 
supersaturation over time 
• 
To evaluate the effect of lumasiran on 
24-hour urinary oxalate excretion after 
Month 6 
• 
Change from baseline in 24-hour urinary 
oxalate excretion after Month 6 
• 
To evaluate the effect of lumasiran on 
estimated glomerular filtration rate 
(eGFR) 
• 
Change from baseline in eGFR 
• 
To evaluate the effect of lumasiran on 
patient healthcare resource utilization 
• 
Kidney stone event related 
hospitalizations, emergency room visits, 
unscheduled office visits, or procedures  
Safety 
 
• 
To evaluate the safety and tolerability of 
lumasiran 
• 
Frequency of adverse events (AEs) 
Study Design 
This is a randomized, placebo-controlled, double-blind, multi-center, multinational, Phase 2 
study to evaluate the efficacy, safety, PD, and PK of lumasiran administered subcutaneously 
(SC) in patients with recurrent calcium oxalate kidney stone disease and elevated urinary oxalate 
levels (Figure 1). 
Consented patients meeting all eligibility criteria will be randomized 1:1:1 to receive study drug:  
lumasiran 567 mg, lumasiran 284 mg, or placebo.  Stratification will be performed at 
randomization according to baseline urinary oxalate level (≤1.25 × ULN vs >1.25 × ULN) from 
the mean of the first 2 valid 24-hour urine collections and the number of historical kidney stone 
events in the 12 months prior to screening (≤1 vs >1). 
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Number of Planned Patients 
The planned enrollment for this study is 120 patients. 
Diagnosis and Main Eligibility Criteria 
This study will include adults (≥18 years of age) with a documented diagnosis of recurrent 
kidney stone disease based on ≥2 stone events, with a minimum of 1 stone event within the 
5 years prior to screening.  A historical kidney stone event is defined as: 
• the visible passage of a kidney stone 
• a procedural intervention for removal of an asymptomatic or symptomatic stone  
− if more than 1 stone was removed in a given procedure, this counts as 1 event 
unless bilateral ureteral stones were removed, in which case this counts as 
2 events  
− if more than 1 procedure was required to remove a single stone, this counts as 
1 event 
• a new (≥1 mm) or enlarged (by ≥2 mm) kidney stone on computed tomography (CT) 
imaging 
− if a procedure was performed to remove the stone(s) identified by CT, then only 
the procedure will be counted to avoid double-counting the same stone. 
Study Drug, Dose, and Mode of Administration 
Lumasiran (ALN-GO1) is a SC administered N-acetylgalactosamine (GalNAc)-conjugated small 
interfering RNA (siRNA) targeting liver-expressed hydroxyacid oxidase (HAO1) messenger 
RNA (mRNA) for reduction of hepatic oxalate production. 
Lumasiran will be administered by SC injection at a dose of 284 mg or 567 mg on Day 1, 
Month 3, and Month 9. 
Reference Treatment, Dose, and Mode of Administration 
Placebo (sodium chloride 0.9% w/v for SC administration) will be administered at the same 
dosing interval as lumasiran. 
Duration of Treatment and Study Participation 
The duration of treatment with study drug is up to 15 months.  The estimated total time on study 
for each patient is up to 17 months, including up to 2 months of screening. 
Statistical Methods 
The study is powered to detect a difference in urinary oxalate excretion between each lumasiran 
group and the placebo group.  Assuming a standard deviation of 45% in the percent change from 
baseline in 24-hour urinary oxalate levels at Month 6, a sample size of 40 patients per group will 
enable a power of at least 80% in detecting a treatment difference of 30% between the treatment 
groups at a 2-sided significance level of 0.05. 
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The populations (analysis sets) are defined as follows: 
• Full Analysis Set (FAS):  All randomized patients who received at least 1 dose of 
study drug.  Patients in the FAS will be analyzed according to the randomized 
treatment arm. 
• Plasma Oxalate Analysis Set:  All patients who received at least 1 dose of study 
drug and have a baseline plasma oxalate level ≥1.5 times the lower limit of 
quantification/detection.   
• Safety Analysis Set:  All randomized patients who received at least 1 dose of study 
drug.  Patients in the Safety Analysis Set will be analyzed according to the treatment 
actually received. 
• PK Analysis Set:  All patients who received at least 1 full dose of study drug and 
have at least one postdose blood sample for PK parameters and have evaluable PK 
data. 
The primary efficacy endpoint will be analyzed in the FAS using a mixed-effect model for 
repeated measures (MMRM) approach.  The primary comparison is percent change from 
baseline in urinary oxalate through Month 6. 
Safety data will be summarized descriptively. 
Figure 1: 
Study Design 
LUMASIRAN 567 m  SC N=40)
LUMASIRAN 284 mg SC (N=40)
Safety Follow-up (patients who 
discontinue treatment)
Screening
(Day -60 to -1)
15-Month Double-Blind Treatment Period
6-Month Primary Analysis Period
Randomization (1:1:1)
PLACEBO (N=40)
LUMASIRAN 567 mg SC (N=40)
LUMASIRAN 284 mg SC (N=40)
PLACEBO (N=40)
9-Month Treatment Extension Period
 
Abbreviations:  SC=subcutaneous(ly) 
 
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• 
White columns indicate visits to the clinical study center; gray-shaded columns indicate study visits that may be conducted by a home healthcare 
professional, where applicable country and local regulations and infrastructure allow (at the discretion and with oversight of the Investigator, based on 
safety and tolerability), provided (for dosing visits) that 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 symptom-directed 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, kidney stone events, and adverse events.  
Footnotes: 
a All assessments are required to be performed prior to dosing at dosing visits, except for the CT scan and PK 2-hour postdose sample collection. 
b Inclusion/exclusion criteria should be verified prior to randomization.  Laboratory assessments conducted to confirm study eligibility will not be repeated unless 
the time between screening and randomization exceeds 4 weeks. 
c Pregnancy test results must be known prior to dosing, if applicable. 
d May be performed after dosing, if required. 
 
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Table 2: 
Pharmacokinetic Time Points 
Study Day 
Sampling Time 
(hh:mm) 
Blood PK Sample 
Day 1 
Predose (any time before dosing) 
X 
02:00 (±30 min) 
X 
Abbreviations:  hh:mm=hour:minute; min=minute; PK=pharmacokinetics 
Notes:  
• 
The hour (±range) indicates sample collection timing relative to dosing.  Precise PK sample times (hour 
and minute) are recorded.  Refer to 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 ...............................................................................................................14 
LIST OF TABLES .........................................................................................................................17 
LIST OF FIGURES .......................................................................................................................18 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................19 
1. 
INTRODUCTION ......................................................................................................21 
1.1. 
Study Rationale ...........................................................................................................21 
1.2. 
Background .................................................................................................................21 
1.3. 
Benefit-Risk Assessment ............................................................................................22 
2. 
OBJECTIVES AND ENDPOINTS ............................................................................24 
3. 
INVESTIGATIONAL PLAN .....................................................................................25 
3.1. 
Summary of Study Design ..........................................................................................25 
3.2. 
Scientific Rationale for Study Design ........................................................................25 
3.3. 
Justification for Dose ..................................................................................................26 
3.4. 
Method of Assigning Patients to Treatment Groups ..................................................27 
3.5. 
Blinding ......................................................................................................................27 
3.5.1. 
Emergency Unblinding ...............................................................................................28 
3.6. 
Safety Review .............................................................................................................28 
3.7. 
Definition of End of Study for an Individual Patient .................................................28 
4. 
SELECTION AND REMOVAL OF PATIENTS ......................................................29 
4.1. 
Inclusion Criteria ........................................................................................................29 
4.2. 
Exclusion Criteria .......................................................................................................30 
4.3. 
Removal from Study Drug or Assessment .................................................................31 
4.3.1. 
Discontinuation of Study Drug or Declining Procedural Assessments ......................31 
4.3.2. 
Stopping a Patient’s Study Participation ....................................................................32 
4.3.2.1. 
Patient Stops Participation in the Study ......................................................................32 
4.3.2.2. 
Withdrawal of Consent to Process the Patient’s Personal Data or Objection 
to Process Patient’s Personal Data ..............................................................................33 
4.3.2.3. 
Investigator or Sponsor Stops Participation of a Patient in the Study ........................33 
4.3.2.4. 
Recording Reason for Stopping a Patient’s Study Participation ................................33 
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4.3.3. 
Lost to Follow-Up.......................................................................................................33 
4.3.4. 
Replacement of Study Patients ...................................................................................34 
5. 
TREATMENTS AND OTHER REQUIREMENTS ..................................................34 
5.1. 
Treatments Administered ............................................................................................34 
5.2. 
Study Drug ..................................................................................................................34 
5.2.1. 
Description ..................................................................................................................34 
5.2.2. 
Dose and Administration ............................................................................................34 
5.2.3. 
Dose Modifications .....................................................................................................35 
5.2.3.1. 
LFT Criteria for Withholding, Monitoring, and Stopping Study Drug Dosing..........35 
5.2.4. 
Preparation, Handling, and Storage ............................................................................37 
5.2.5. 
Packaging and Labeling ..............................................................................................37 
5.2.6. 
Accountability .............................................................................................................37 
5.3. 
Clinical Product Complaints .......................................................................................37 
5.3.1. 
Definition ....................................................................................................................37 
5.3.2. 
Reporting ....................................................................................................................38 
5.4. 
Concomitant Medications and Procedures .................................................................38 
5.5. 
Treatment Compliance ................................................................................................38 
5.6. 
Other Requirements ....................................................................................................38 
5.6.1. 
Contraception ..............................................................................................................38 
5.6.2. 
Alcohol Restrictions ...................................................................................................39 
5.6.3. 
Dietary Restrictions ....................................................................................................39 
6. 
STUDY ASSESSMENTS ..........................................................................................40 
6.1. 
Screening Assessments ...............................................................................................40 
6.1.1. 
DNA Sample ...............................................................................................................40 
6.1.2. 
Retesting .....................................................................................................................40 
6.1.3. 
Rescreening .................................................................................................................40 
6.2. 
Efficacy Assessments .................................................................................................41 
6.2.1. 
24-Hour Urine Collections .........................................................................................41 
6.2.1.1. 
Validity Criteria for 24-hour Urine Collections .........................................................42 
6.2.1.2. 
Variability Criterion for 24-hour Urine Collections at Screening ..............................42 
6.2.2. 
Kidney Stone Events ...................................................................................................42 
6.2.2.1. 
Clinical ........................................................................................................................42 
6.2.2.2. 
Radiographic ...............................................................................................................43 
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6.2.3. 
Estimated Glomerular Filtration Rate .........................................................................43 
6.3. 
Pharmacodynamic Assessments .................................................................................43 
6.4. 
Pharmacokinetic Assessments ....................................................................................43 
6.5. 
Safety Assessments .....................................................................................................43 
6.5.1. 
Vital Signs ..................................................................................................................44 
6.5.2. 
Height and Weight ......................................................................................................44 
6.5.3. 
Physical Examination .................................................................................................44 
6.5.4. 
Clinical Laboratory Assessments ...............................................................................45 
6.5.4.1. 
Immunogenicity ..........................................................................................................46 
6.5.4.2. 
Pregnancy Testing ......................................................................................................46 
6.5.4.3. 
Additional Liver Function Assessments .....................................................................47 
6.5.5. 
Adverse Events ...........................................................................................................49 
6.5.5.1. 
Definitions ..................................................................................................................49 
6.5.5.2. 
Eliciting and Recording Adverse Events ....................................................................50 
6.5.5.3. 
Reporting Adverse Events of Clinical Interest to Sponsor/Designee .........................51 
6.5.5.4. 
Serious Adverse Events Require Immediate Reporting to Sponsor/Designee ...........51 
6.5.5.5. 
Sponsor Safety Reporting to Regulatory Authorities .................................................52 
6.5.5.6. 
Serious Adverse Event Notification to the Institutional Review 
Board/Independent Ethics Committee ........................................................................52 
6.5.5.7. 
Pregnancy Reporting ..................................................................................................52 
6.5.5.8. 
Reporting of Overdose and Other Special Situations .................................................53 
6.6. 
Healthcare Utilization .................................................................................................53 
7. 
STATISTICS ..............................................................................................................54 
7.1. 
Determination of Sample Size ....................................................................................54 
7.2. 
Statistical Methodology ..............................................................................................54 
7.2.1. 
Populations to be Analyzed ........................................................................................54 
7.2.2. 
Examination of Subgroups .........................................................................................55 
7.2.3. 
Handling of Missing Data ...........................................................................................55 
7.2.4. 
Baseline Evaluations ...................................................................................................55 
7.2.5. 
Efficacy Analyses .......................................................................................................55 
7.2.6. 
Pharmacodynamic Analysis........................................................................................56 
7.2.7. 
Pharmacokinetic Analysis ..........................................................................................56 
7.2.8. 
Safety Analyses ..........................................................................................................56 
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7.2.9. 
Immunogenicity Analyses ..........................................................................................56 
7.2.10. 
Other Analyses ............................................................................................................56 
7.2.11. 
Interim Analysis ..........................................................................................................57 
7.2.12. 
Optional Additional Research .....................................................................................57 
8. 
STUDY ADMINISTRATION ...................................................................................57 
8.1. 
Ethical and Regulatory Considerations ......................................................................57 
8.1.1. 
Informed Consent .......................................................................................................57 
8.1.2. 
Ethical Review ............................................................................................................57 
8.1.3. 
Serious Breach of Protocol .........................................................................................58 
8.1.4. 
Study Documentation, Confidentiality, and Records Retention .................................58 
8.1.5. 
End of Study ...............................................................................................................59 
8.1.6. 
Termination of the Clinical Study or Site Closure .....................................................59 
8.2. 
Data Quality Control and Quality Assurance .............................................................59 
8.2.1. 
Data Handling .............................................................................................................59 
8.2.2. 
Study Monitoring ........................................................................................................59 
8.2.3. 
Audits and Inspections ................................................................................................60 
8.3. 
Publication Policy .......................................................................................................60 
9. 
LIST OF REFERENCES ............................................................................................61 
10. 
APPENDICES ............................................................................................................62 
10.1. 
Formula for Estimated Glomerular Filtration Rate Calculation .................................62 
 
LIST OF TABLES 
Table 1: 
Schedule of Assessments ..............................................................................................8 
Table 2: 
Pharmacokinetic Time Points .....................................................................................13 
Table 3: 
Monitoring and Dosing Rules for Asymptomatic Patients with Confirmed 
Isolated Elevations of ALT and/or AST >3× ULN, with No Alternative 
Cause Identified ..........................................................................................................36 
Table 4: 
24-hour Urine Collection Procedure by Study Visit...................................................41 
Table 5: 
Clinical Laboratory Assessments ...............................................................................46 
Table 6: 
Hepatic Assessments in Patients Who Experience Elevated Transaminases .............48 
Table 7: 
Sample Size Power Calculations ................................................................................54 
 
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LIST OF FIGURES 
Figure 1: 
Study Design .................................................................................................................7 
Figure 2: 
Summary of Endogenous Oxalate Synthesis ..............................................................23 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation  
Definition 
ADA 
Antidrug antibody 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical Classification System 
CKD 
Chronic kidney disease 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
Cmax 
Maximum plasma concentration 
CPC 
Clinical product complaint 
CT 
Computed tomography 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
EOS 
End of study 
ESKD 
End stage kidney disease 
ET 
Early termination 
FAS 
Full analysis set 
GalNAc 
N-acetylgalactosamine 
GCP 
Good Clinical Practice 
GO 
Glycolate oxidase 
HAO1 
Hydroxyacid oxidase 1  
HED 
Human equivalent dose 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug (application) 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ISR 
Injection site reaction 
LFT 
Liver function test 
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MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-effect model for repeated measures 
mRNA 
Messenger ribonucleic acid 
PD 
Pharmacodynamics 
PH1/2/3 
Primary hyperoxaluria type 1/2/3 
PK 
Pharmacokinetic 
PT 
Preferred term 
RNAi 
Ribonucleic acid interference 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SOC 
System Organ Class 
tmax 
Time to maximum plasma concentration 
ULN 
Upper limit of normal 
WHO 
World Health Organization 
 
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1. 
INTRODUCTION 
Alnylam Pharmaceuticals, Inc. (the Sponsor) has developed 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) messenger ribonucleic acid (mRNA), 
blocking production of glycolate oxidase (GO) and hence reducing hepatic oxalate production. 
Lumasiran is approved for the treatment of primary hyperoxaluria type 1 (PH1) in both pediatric 
and adult patients in the United States (23 November 2020) and in the European Union (19 
November 2020).  Based on lumasiran’s mechanism of action, and demonstrated reduction of 
hepatic oxalate production in patients with PH1, the Sponsor is investigating whether treatment 
with lumasiran is effective for patients with recurrent calcium oxalate kidney stone disease who 
have elevated urinary oxalate levels but have not been diagnosed with PH1 or one of the other 
primary hyperoxalurias. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of lumasiran is 
provided in the Investigator’s Brochure. 
1.1. 
Study Rationale 
Study ALN-GO1-008 is a randomized, double-blind, placebo-controlled, multi-center Phase 2 
study designed to evaluate the efficacy, safety, pharmacodynamics (PD), and pharmacokinetics 
(PK) of lumasiran, administered subcutaneously (SC), in adult patients with recurrent calcium 
oxalate kidney stone disease. 
The primary objective of the study is to evaluate the effect of lumasiran on the percent change in 
urinary oxalate excretion in patients with recurrent calcium oxalate kidney stones.  Secondary 
and exploratory objectives of the study include the evaluation of the effect of lumasiran on 
urinary calcium oxalate supersaturation, the occurrence of kidney stones, the PD effect of 
lumasiran on plasma oxalate, plasma glycolate and urinary glycolate, and the characterization of 
plasma PK. 
The full rationale for the study and design is presented in Section 3.2. 
1.2. 
Background 
Kidney stones are common, affecting approximately 1 in 11 people in the United States, and the 
prevalence of kidney stone disease has been increasing worldwide over time.[Scales 2012]  
Approximately 80% of kidney stones in adults are formed from calcium oxalate crystals, with 
the remainder being predominantly calcium phosphate, uric acid, cystine, or struvite.[Worcester 
and Coe 2008; Worcester and Coe 2010]  Stone formation occurs when a supersaturating level of 
calcium oxalate is present in the urine (Figure 2).  High levels of urinary oxalate may be derived 
from both endogenous synthesis and diet.  
Kidney stones can develop in patients of all ages; however, the highest incidence rates occur in 
individuals aged 40 to 66 years.[Shin 2018]  There is significant clinical burden associated with 
the development of kidney stones for patients with recurrent calcium oxalate kidney stone 
disease, including pain, infection/sepsis, diagnostic and therapeutic procedures, hospitalizations, 
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and a greater risk for developing chronic kidney disease (CKD) and end stage kidney disease 
(ESKD). 
The typical clinical presentation of kidney stones includes sudden onset of lumbar flank pain and 
hematuria, and may include nausea and vomiting.  Evaluation to assess etiology includes 
assessment of the patient’s medical history, medication use, and dietary and lifestyle risk factors.  
Confirmation of diagnosis may involve renal ultrasound, abdominal x-ray, and/or computed 
tomography (CT).[Heilberg and Schor 2006]  24-hour urine collections analyzed for total 
volume, calcium, oxalate, uric acid, citrate, and other analytes may help to determine the 
underlying etiology.[Pearle 2014]  Stone composition is generally determined in at least one 
instance. 
There are limited effective treatment options for patients with recurrent calcium oxalate kidney 
stone disease.  Preventive measures in American and European guidelines recommend adequate 
fluid intake to ensure a urine volume of at least 2 to 2.5 liters daily and provide dietary advice to 
limit the consumption of oxalate-rich foods, sodium chloride, and animal protein content, while 
maintaining a normal calcium intake.  In some situations, thiazide diuretics, potassium citrate, 
and/or allopurinol may be considered.[Pearle 2014; Türk 2021] 
Treatment of pain associated with kidney stone events may involve non-steroidal 
anti-inflammatory agents and/or opiate pain medications.  Depending on the clinical context, 
medical expulsive therapy, extracorporeal shock-wave lithotripsy, ureteroscopy, stenting, and 
percutaneous nephrolithotomy are some of the treatment options that may be pursued.[Türk 
2021] 
Lumasiran is a ribonucleic acid interference (RNAi) therapeutic designed to reduce hepatic 
oxalate production.  Oxalate produced by the liver is largely excreted in the urine, and lumasiran 
has been shown to reduce urinary oxalate in patients with PH1.  High levels of urinary oxalate 
increase the risk of stone formation; therefore, lumasiran may have efficacy in patients with 
recurrent calcium oxalate kidney stone disease who do not have PH1 but who produce high 
amounts of oxalate endogenously. 
1.3. 
Benefit-Risk Assessment 
Calcium oxalate stone formation occurs when a supersaturating level of calcium oxalate is 
present in the urine, with increasing risk of stone formation as urine oxalate levels 
increase.[Curhan and Taylor 2008]  More than half of oxalate is endogenous in origin and 
presumed to come largely from the liver.[Mitchell 2018]  Studies have shown that reduced 
calcium oxalate supersaturation and urinary oxalate levels are associated with reduced stone 
formation.[Borghi 2002; Ferraro 2018; Prochaska 2018] 
For patients with recurrent calcium oxalate stone formation, multiple stone removal procedures 
may be required.  These procedures are invasive and place the patient at risk of complications 
including bleeding and infection.  Patients experiencing obstructive kidney stones can also 
experience acute kidney injury with permanent loss of renal function.  As a result, patients with 
recurrent kidney stone formation have a higher risk of progression to CKD and ESKD.[Dhondup 
2018; Rule 2009] 
Lumasiran, approved in the United States and European Union for the treatment of PH1, is 
designed to reduce hepatic production of oxalate.  Based on the available data from clinical and 
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nonclinical studies, lumasiran, administered SC, demonstrated a potent, dose-dependent 
inhibition of GO resulting in decreased urinary and plasma oxalate and increased plasma and 
urinary glycolate.  Lumasiran may be effective in lowering urinary oxalate levels in patients with 
recurrent calcium oxalate kidney stone disease (Figure 2).  No adverse effects of elevated 
glycolate have been reported.  Unlike oxalate, glycolate is highly soluble and readily excreted in 
the urine. 
Figure 2: 
Summary of Endogenous Oxalate Synthesis 
 
Abbreviations:  GO=glycolate oxidase 
Lumasiran has been well tolerated with an acceptable safety profile in studies with healthy 
volunteers and patients with PH1.  Most adverse events (AEs) have been mild or moderate in 
severity.  Transient, mild injection site reactions (ISRs) have been observed.  No clinically 
significant laboratory changes related to lumasiran 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 hepatic effects.  The study has specific 
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 (LFTs).  As the risk of embryofetal toxicity in humans is currently unknown, 
females who are of 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 5.6.1). 
Based on the available efficacy and safety data from clinical and nonclinical studies, the benefit-
risk assessment supports the evaluation of lumasiran in a Phase 2 study in patients with recurrent 
calcium oxalate kidney stone disease. 
Detailed information about the known and expected benefits and risks of lumasiran are provided 
in the Investigator’s Brochure. 
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2. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
 
• 
To evaluate the effect of lumasiran on the 
percent change in urinary oxalate 
excretion 
• 
Percent change in 24-hour urinary oxalate 
from baseline to Month 6 (average across 
Months 4 through 6) 
Secondary 
 
• 
To evaluate the percentage of patients 
who achieve a ≥20% reduction in 24-hour 
urinary oxalate with lumasiran 
• 
Percentage of patients who achieve a 
≥20% reduction in 24-hour urinary 
oxalate from baseline to Month 6 (average 
across Months 4 through 6) 
• 
To evaluate the effect of lumasiran on 
urinary calcium oxalate supersaturation 
• 
Percent change in urinary calcium oxalate 
supersaturation from baseline to Month 6 
(average across Months 4 through 6) 
Exploratory 
 
• 
To evaluate the effect of lumasiran on 
absolute levels of urinary oxalate 
excretion 
• 
Absolute change in 24-hour urinary 
oxalate from baseline to Month 6 (average 
across Months 4 through 6) 
• 
To evaluate the effect of lumasiran on the 
occurrence of kidney stones 
• 
Incidence rate of clinical and radiographic 
kidney stone events  
• 
Time to first kidney stone event 
• 
To evaluate additional PD parameters of 
plasma oxalate, plasma glycolate, and 
urinary glycolate 
• 
Change from baseline in plasma oxalate 
• 
Change from baseline in plasma glycolate 
• 
Change from baseline in urinary glycolate 
• 
To characterize PK of lumasiran 
• 
Plasma PK of lumasiran 
• 
To assess for antidrug antibodies (ADA) 
against lumasiran 
• 
ADA frequency and titer 
• 
To evaluate the effect of lumasiran on 
maintaining 24-hour urinary oxalate 
≤upper limit of normal (ULN) over time 
• 
Percentage of patients with 24-hour 
urinary oxalate ≤ULN over time 
• 
To evaluate the effect of lumasiran on 
maintaining a 25% reduction in urinary 
calcium oxalate supersaturation over time 
• 
Percentage of patients having a 25% 
reduction in urinary calcium oxalate 
supersaturation over time 
• 
To evaluate the effect of lumasiran on 
24-hour urinary oxalate excretion after 
Month 6 
• 
Change from baseline in 24-hour urinary 
oxalate excretion after Month 6 
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Objectives 
Endpoints 
• 
To evaluate the effect of lumasiran on 
estimated glomerular filtration rate 
(eGFR) 
• 
Change from baseline in eGFR 
• 
To evaluate the effect of lumasiran on 
patient healthcare resource utilization 
• 
Kidney stone event related 
hospitalizations, emergency room visits, 
unscheduled office visits, or procedures  
Safety 
 
• 
To evaluate the safety and tolerability of 
lumasiran 
• 
Frequency of AEs 
3. 
INVESTIGATIONAL PLAN 
3.1. 
Summary of Study Design 
This is a randomized, placebo-controlled, double-blind, multi-center, multinational, Phase 2 
study to evaluate the efficacy, safety, PD, and PK of lumasiran administered SC in patients with 
recurrent calcium oxalate kidney stone disease and elevated urinary oxalate levels (Figure 1). 
The study will consist of up to 2 months of screening and 15 months of double-blind treatment (a 
6-month Primary Analysis Period followed by a 9-month Treatment Extension Period).  Patients 
will be screened from Day -60 to Day -1 to determine eligibility.  During screening, patients will 
provide at least two 24-hour urine collections to establish baseline urinary oxalate levels.  
Consented patients meeting all eligibility criteria will be randomized 1:1:1 to receive study drug:  
lumasiran 567 mg, lumasiran 284 mg, or placebo.  Stratification will be performed at 
randomization according to baseline urinary oxalate level (≤1.25 × ULN vs >1.25 × ULN) from 
the mean of the first 2 valid 24-hour urine collections and the number of historical kidney stone 
events in the 12 months prior to screening (≤1 vs >1), as discussed in Section 3.4. 
During the 6-month Primary Analysis Period, patients will be dosed on Day 1 (baseline) and at 
Month 3.  During the Treatment Extension Period, one additional dose will be administered at 
Month 9; an end of study (EOS) visit will take place at Month 15.  Study drug will be 
administered SC as specified in Section 5.2.2.  Patients will be assessed for efficacy, safety, PD, 
and PK according to the Schedule of Assessments (Table 1 and Table 2).  Efficacy assessments 
will include evaluation of urinary oxalate excretion, urinary calcium oxalate supersaturation, and 
kidney stone events (including clinical events and low-dose kidney-protocol CT).  Safety 
assessments will include collection of AEs, clinical laboratory tests, vital sign assessments, 
physical examinations, and concomitant medications. 
Patients who discontinue study drug early will be asked to return for follow-up visits as 
described in Section 4.3.1. 
3.2. 
Scientific Rationale for Study Design 
The primary endpoint for this Phase 2 study is the percent change in 24-hour urinary oxalate 
excretion.  To confirm the optimal dosing regimen, and to facilitate the collection of kidney 
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stone event data (an exploratory endpoint), the study will continue through Month 15.  A placebo 
comparator is included because there is no approved standard of care therapy to decrease urinary 
oxalate.  
A blood DNA sample will be collected as part of standard screening assessments (if testing has 
not already been performed) to ensure the exclusion of patients with primary hyperoxaluria 
type 1 (PH1), type 2 (PH2), and type 3 (PH3).  Lumasiran is approved in some countries for the 
treatment of PH1, and patients with PH2 and PH3 are not expected to respond to lumasiran. 
Because the primary endpoint will rely on measurements of urinary oxalate, and because some 
urinary oxalate is diet-derived, diet is an important variable in this study.  In a 5-year study of 
recurrent stone formers published by Borghi et al, patients randomized to a normal calcium, low 
protein/salt diet had lower urinary oxalate levels and a lower cumulative incidence of recurrent 
kidney stones when compared to a low calcium diet.  During the current study, and as of the time 
of informed consent, patients will be asked to adhere to a diet appropriate for stone formers, 
including adequate calcium intake and avoidance of spinach and other foods that are high in 
oxalate.  
The secondary endpoint to assess meaningful reduction in 24-hour urinary oxalate from baseline 
to Month 6 (Months 4 through 6) defines a clinically meaningful reduction as ≥20% in the non-
PH1 stone former population, supported by available literature based on stone former 
populations.[Borghi 2002] 
In this study, lumasiran will be evaluated in patients with recurrent calcium oxalate kidney stone 
disease.  Due to the limited and burdensome disease management options, there is an unmet need 
for new therapies. 
3.3. 
Justification for Dose 
Two dose levels of lumasiran 284 and 567 mg given on Day 1, Month 3, and Month 9 were 
selected to evaluate urinary oxalate dose response.  The higher dose level of 567 mg is expected 
to suppress GO enzyme by ≥95%, comparable to the regimen evaluated in ALN-GO1-003 
(ILLUMINATE-A) in patients with PH1.  The lower dose of 284 mg is expected to suppress GO 
enzyme by 90%.  In addition, the fixed doses will simplify dose administration in this adult study 
population.  Both regimens are predicted to achieve near-steady state ribonucleic acid-induced 
silencing complex (RISC) concentrations and urinary oxalate suppression at Month 6.  Month 9 
dosing is intended to sustain PD effect through Month 15 and will provide data to differentiate 
the effect of every 3 months and every 6 months dosing on urinary oxalate reduction. 
Single 0.3 to 6.0 mg/kg doses of lumasiran in healthy subjects and multiple 3.0 mg/kg doses of 
lumasiran administered monthly or once every 3 months in patients with PH1 have been well 
tolerated.  Plasma and liver exposure for the lumasiran 284 and 567 mg doses are expected to be 
in the range of 3.0 to 6.0 mg/kg lumasiran doses evaluated in healthy subjects in ALN-GO1-001 
(Part A) and patients with PH1 in ALN-GO1-001 (Part B), ALN-GO1-002, and 
ILLUMINATE-A.  Based on rat and monkey NOAEL doses of lumasiran 200 mg/kg and 
300 mg/kg, a sufficient safety margin exists for the use of lumasiran 284 and 567 mg doses (refer 
to the ALN-GO1 Investigator Brochure). 
Based on a 70 kg patient, the planned doses of 284 mg and 567 mg equate to approximately 
4.0 mg/kg or 8.0 mg/kg, respectively.  The human equivalent dose (HED) margin values for the 
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approximate 4 mg/kg clinical dose were 8.1-fold for the chronic rat study and 24.2-fold for the 
chronic monkey study; the HED margin values for the approximate 8.0 mg/kg clinical dose were 
4.0-fold for the chronic rat study and 12.1-fold for the chronic monkey study (refer to the 
ALN-GO1 Investigator Brochure). 
3.4. 
Method of Assigning Patients to Treatment Groups 
Each patient will be uniquely identified in the study by a combination of the site number and 
patient identification number.  After the patient signs the informed consent form (ICF) and 
before proceeding with screening procedures, the Investigator or his/her designee will contact the 
Interactive Response Technology (IRT) to obtain a patient identification number. 
The Investigator or his/her designee will contact the IRT to randomize the patient after 
confirming that the patient fulfills all the inclusion criteria and none of the exclusion criteria. 
Patients will be randomized 1:1:1 to receive lumasiran 284 mg, lumasiran 567 mg, or placebo, 
administered at the same volume (see Section 5.2.2), for the duration of the study.  Stratification 
will be performed at randomization according to baseline urinary oxalate level (≤1.25 × ULN vs 
>1.25 × ULN) from the mean of the first 2 valid 24-hour urine collections and the number of 
historical kidney stone events in the 12 months prior to screening (≤1 vs >1). 
For stratification, the number of historical kidney stone events occurring in the 12 months prior 
to screening are considered, and defined as:  
• the visible passage of a kidney stone 
• a procedural intervention for removal of an asymptomatic or symptomatic stone  
− if more than 1 stone was removed in a given procedure, this counts as 1 event 
unless bilateral ureteral stones were removed, in which case this counts as 
2 events 
− if more than 1 procedure was required to remove a single stone, this counts as 
1 event 
• a new (≥1 mm) or enlarged (by ≥2 mm) kidney stone on CT imaging 
− it must be evident from the CT scans that the new or enlarged kidney stone event 
occurred during the 12 months prior to screening 
− if a procedure was performed to remove the stone(s) identified by CT, then only 
the procedure will be counted to avoid double-counting the same stone. 
3.5. 
Blinding 
Site personnel and patients will be blinded to study drug treatment; site personnel preparing 
study drug may be unblinded to study drug treatment only where required by documented 
institutional procedure.  The Sponsor will have access to unblinded study data during the conduct 
of the study.  Lumasiran and placebo will be packaged identically and will be administered at the 
same volume under the supervision of the Investigator at the study center or by a healthcare 
professional at the patient’s home (see Section 5.2.2).  Since lumasiran may be visually 
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distinguishable from placebo, the syringe will be masked prior to administration by a healthcare 
professional.  See the Pharmacy Manual for additional details. 
All site personnel will be blinded to laboratory results of oxalate, calcium oxalate 
supersaturation, and glycolate from after the time of the first dose until unblinding.  Results will 
not be reported to the Investigator from the first dose until the last patient completes assessments 
at the Month 15 visit.  In addition, Investigators and staff involved with this trial and all medical 
staff involved in the patient’s medical care should refrain from obtaining measurements for 
oxalate, calcium oxalate supersaturation, or glycolate from the first dose until the sites and 
patients are unblinded, or until the patient ends the study, whichever is earlier.  If oxalate, 
calcium oxalate supersaturation, or glycolate are measured during the blinded period, all 
reasonable steps must be undertaken to avoid informing the patient and site personnel of the 
results until the sites and patients are unblinded. 
Any unplanned unblinding occurring during the study period will be documented and reported in 
the clinical study report.  
3.5.1. 
Emergency Unblinding 
If the treating physician determines that the clinical management of the patient requires 
knowledge of the study drug assignment, the Investigator may break the blind, as necessary.  If 
time permits, clinical study center personnel should contact the Medical Monitor before 
unblinding to discuss the need to unblind the patient.  If contact prior to unblinding is not 
possible, personnel must contact the Medical Monitor within 1 working day after the unblinding 
event.  Unblinding information should be limited to the fewest number of people on a need-to-
know basis.  A record of when the blind was broken, who was unblinded, who broke the blind, 
and why it was broken, will be maintained in the trial master file. 
Refer to the IRT instructions for details on unblinding. 
3.6. 
Safety Review 
A safety review committee will not be utilized for this study; however, the Sponsor will monitor 
safety on an ongoing basis and in accordance with the Sponsor’s internal processes. 
3.7. 
Definition of End of Study for an Individual Patient 
A patient is considered to have reached the EOS if the patient: 
• has completed the EOS (Month 15) visit, or 
• has completed safety monitoring following the final dose of study drug as described 
in Section 4.3.1 
A definition of the end of the overall study is provided in Section 8.1.5. 
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4. 
SELECTION AND REMOVAL OF PATIENTS 
4.1. 
Inclusion Criteria 
Patients are eligible to be included in the study if all the following criteria apply: 
Age 
1. Age 18 years or older (or age of legal consent, whichever is older). 
Patient and Disease Characteristics 
2. Recurrent kidney stone disease, defined as ≥2 stone events, with a minimum of 1 stone 
event within the 5 years prior to screening.  For inclusion, a historical kidney stone event 
is defined as:  
• the visible passage of a kidney stone 
• a procedural intervention for removal of an asymptomatic or symptomatic stone  
− if more than 1 stone was removed in a given procedure, this counts as 1 event 
unless bilateral ureteral stones were removed, in which case this counts as 
2 events 
− if more than 1 procedure was required to remove a single stone, this counts as 
1 event 
• a new (≥1 mm) or enlarged (by ≥2 mm) kidney stone on CT imaging 
− if a procedure was performed to remove the stone(s) identified by CT, then only 
the procedure will be counted to avoid double-counting the same stone. 
3. The 2 most recently analyzed kidney stones prior to randomization contained 50% or 
more of calcium oxalate; if only one stone analysis is available, then it must have 
contained 50% or more of calcium oxalate. 
4. 24-hour urinary oxalate levels from 2 valid 24-hour urine collections obtained during 
screening are >ULN (ULN = 40 mg/24 hours). 
5. Willing to adhere to dietary recommendations appropriate for stone formers including 
limiting vitamin C supplementation to <200 mg daily. 
6. If taking medications and/or hydrating for kidney stone prophylaxis, or taking 
medications that alter urinary oxalate excretion and/or kidney stone formation, must have 
been on a stable regimen for at least 60 days before randomization, and willing to remain 
on this stable regimen for the duration of the study. 
7. Body mass index (the weight in kilograms divided by the square of the height in meters) 
at screening of 20 to <40 kg/m2. 
Informed Consent 
8. Patient is able to understand and is willing and able to comply with the study 
requirements and to provide written informed consent. 
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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 at screening:  
a. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2 × ULN 
b. Total bilirubin >1.5 × ULN.  Patients with elevated total bilirubin that is secondary to 
documented Gilbert’s syndrome are eligible if the total bilirubin is <2 × ULN 
c. International normalized ratio (INR) >2.0 (patients on oral anticoagulant [eg, 
warfarin] with an INR <3.5 will be allowed) 
2. Has an eGFR of <30 mL/min/1.73m2 at screening (calculation will be based on the 
Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] creatinine formula; see 
Section 10.1). 
Prior/Concomitant Therapy 
3. Received an investigational agent within the last 30 days or 5 half-lives, whichever is 
longer, prior to the first dose of study drug, or are in follow-up of another clinical study 
prior to study enrollment.  Any agent that has received health agency authorization 
(including for emergency use) by local or regional regulatory authorities is not considered 
investigational. 
Medical Conditions 
4. Patients with a known history of secondary causes of elevated urinary oxalate and/or 
recurrent kidney stones including: 
a. Primary hyperoxaluria 
b. Severe eating disorders (anorexia or bulimia) 
c. Chronic inflammatory bowel disease  
d. Intestinal surgery with malabsorption or chronic diarrhea 
e. Sarcoidosis 
f. Primary hyperparathyroidism 
g. Complete distal renal tubular acidosis 
5. Has other medical conditions or comorbidities which, in the opinion of the Investigator, 
would interfere with study compliance or data interpretation. 
6. History of multiple drug allergies or history of allergic reaction to an oligonucleotide or 
GalNAc. 
7. History of intolerance to SC injection(s). 
Contraception, Pregnancy, and Breastfeeding 
8. Is not willing to comply with the contraceptive requirements during the study period, as 
described in Section 5.6.1. 
9. Female patient is pregnant, planning a pregnancy, or breast-feeding. 
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Alcohol Use 
10. Unwilling or unable to limit alcohol consumption throughout the course of the study.  
Alcohol intake of >2 units/day is excluded during the study (unit:  1 glass of wine 
[approximately 125 mL] = 1 measure of spirits [approximately 1 fluid ounce] = ½ pint of 
beer [approximately 284 mL]). 
11. History of alcohol abuse, within the last 12 months before screening, in the opinion of the 
Investigator. 
4.3. 
Removal from Study Drug or Assessment 
Patients 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 protocol deviation 
• Adverse event 
• Non-adherence to treatment regimen 
• Pregnancy 
• Lost to follow-up 
• Other reason (non-AE) 
• Or, study is terminated by the Sponsor 
If possible, the Investigator will confer with the Sponsor or Medical Monitor before 
discontinuing dosing in the patient.  Patients who are pregnant will be discontinued from study 
drug dosing immediately (see Section 6.5.5.7 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 
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the Schedule of Assessments (Table 1), including different options for follow-up and collection 
of data (eg, in person, by phone, by mail, 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 serious adverse events (SAEs), the event 
should be followed as described in Section 6.5.5.  When a patient discontinues study drug 
dosing, the primary reason must be recorded in the 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 Primary Analysis Period (defined 
as a discontinuation that occurs after the first dose of study drug administration on Day 1 during 
the 6-month Primary Analysis Period) will be encouraged to remain on the study and complete 
all assessments (including 24-hour urine collections) through Month 6, with early termination 
(ET) assessments at Month 9, and safety follow-up per the safety follow-up schedule (Table 1).  
Patients who do not remain on the study through Month 6 will be asked to return for their next 
scheduled visit to complete ET assessments and complete safety follow-up per the safety follow-
up schedule (Table 1). 
Patients who discontinue study drug after Month 6 will be asked to return for their next 
scheduled visit to complete ET assessments and complete a safety follow-up visit per the safety 
follow-up schedule (see Table 1). 
4.3.2. 
Stopping a Patient’s Study Participation 
4.3.2.1. 
Patient Stops Participation in the Study 
A patient may stop participation in the study at any time.  A patient 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 for the collection of important study data 
as described in Section 4.3.1.  If a patient still chooses to discontinue study drug and stop 
participation in all follow-up, every effort should be made to conduct the ET assessments (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. 
Note, in countries where the collection and processing of the patient’s personal data is based on 
consent, if a patient withdraws consent to collect and process his/her personal data (see 
Section 4.3.2.2), as applicable, personal data up to the withdrawal of consent will be included in 
the analysis of the study.  In addition, 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. 
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4.3.2.2. 
Withdrawal of Consent to Process the Patient’s Personal Data or Objection to 
Process 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.  Also, where allowed by local 
law, the patient may object to the collection, storage, and use of his/her personal data, informing 
the study doctor at any time in writing or in any other form that may be locally required.  In both 
cases, 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/objection) 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 through the Primary Analysis 
Period (Month 6). 
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 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 6.5.5. 
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 fails to return to the clinic for a required study visit: 
• The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of maintaining the assigned visit 
schedule and ascertain if the patient wishes to 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 (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 continue to be unreachable, the patient will be considered to have 
stopped participation in the study. 
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• 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 will not be replaced.  
5. 
TREATMENTS AND OTHER REQUIREMENTS 
5.1. 
Treatments Administered 
Study drug (lumasiran and placebo) 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 study drug is 
provided in the Pharmacy Manual. 
5.2.1. 
Description 
Lumasiran will be supplied as a sterile solution in water for SC injection.  See the Pharmacy 
Manual for further details of solution concentration and fill volume. 
The control drug for this study will be a placebo (sodium chloride 0.9% w/v for SC 
administration).  Placebo will be provided by the Sponsor; it will be packaged identically to 
lumasiran. 
5.2.2. 
Dose and Administration 
Patients will be administered SC injections of lumasiran (284 mg or 567 mg) and/or placebo at 
the same volume, as described below, on Day 1, Month 3, and Month 9. 
Lumasiran 567 mg 
Lumasiran 284 mg 
Placebo 
1.5 mL lumasiran 
1.5 mL lumasiran 
1.5 mL lumasiran 
1.5 mL placebo 
1.5 mL placebo 
1.5 mL placebo 
Study drug injections will be administered under the supervision of the Investigator or healthcare 
professional.  To maintain the blind, syringes are to be masked prior to the removal of study drug 
from vials.  A full description of the blinding procedure is included in the Pharmacy Manual.  
The injection site may be marked and mapped for later observation.  Injections may be 
administered in the abdomen, thigh, or the side or back of the upper arms.  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, provided the patient 
has tolerated at least 1 dose of study drug administered in the clinic.  However, continued study 
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drug administration at the study center should be considered for patients who have ongoing study 
drug-related AEs or for anyone in the opinion of the Investigator who would benefit from 
clinical observation following dosing. 
If a patient does not receive a dose of study drug within the specified visit 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. 
The definition of study drug overdose, follow-up procedures, and reporting requirements are 
provided Section 6.5.5.8. 
5.2.3. 
Dose Modifications 
If a study drug-related AE occurs in a patient that the Investigator judges as presenting a 
potential risk to the patient for further dosing, the study drug dose may be held at the discretion 
of the Investigator, and the Medical Monitor should be contacted. 
5.2.3.1. 
LFT Criteria for Withholding, Monitoring, and Stopping Study Drug Dosing  
1. Results of previous LFT assessment should be reviewed prior to dosing. 
2. For any ALT or AST elevation >3× ULN, central laboratory results should be used to 
guide subsequent monitoring as detailed in Table 3. 
3. For any ALT or AST elevation >3× ULN: 
a. If local laboratory results are obtained, confirm with a 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 5 and Table 6. 
4. For any ALT or AST elevation >3× ULN without alternative cause that is accompanied 
by clinical symptoms consistent with liver injury (eg, nausea, right upper quadrant 
abdominal pain, jaundice) or elevated bilirubin to ≥2× ULN or INR ≥1.5, permanently 
discontinue dosing. 
5. For confirmed ALT or AST elevations >3× ULN without alternative cause and not 
accompanied by symptoms or elevated bilirubin ≥2× ULN or INR ≥1.5, see Table 3. 
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Table 3: 
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 6 (all assessments to be performed once) 
- Hematology, serum chemistry, and LFT per Table 5 
- Coagulation (prothrombin time, partial thromboplastin time, 
international normalized ratio) 
• 
Monitor at least every 2 weeks:  LFT per Table 5 
• 
If elevation persists for ≥2 months, must discuss with the Medical 
Monitor before continuing dosing 
>5× to 8× ULN 
• 
Hold study drug dosing until recovery to ≤1.5× ULN or baseline; may 
resume dosing after discussion with the Medical Monitor 
• 
Evaluate the initial elevation in LFT per the following assessments: 
- Table 6 (all assessments to be performed once) 
- Hematology, serum chemistry, and LFT per Table 5 
- Coagulation (prothrombin time, partial thromboplastin time, 
international normalized ratio) 
• 
Monitor at least weekly:  LFT per Table 5 until ALT and/or AST is 
declining on 2 consecutive draws, then may decrease monitoring to 
biweekly 
• 
If ALT or AST rises to >5× ULN following resumption of dosing, 
permanently discontinue dosing 
>8× ULN 
• 
Permanently discontinue dosing after confirmation of the transaminase 
value at the central laboratory. 
• 
Evaluate the initial elevation in LFT per the following assessments until 
satisfactory resolution: 
- Table 6 (all assessments to be performed once) 
- Hematology, serum chemistry, and LFT per Table 5 
- Coagulation (prothrombin time, partial thromboplastin time, 
international normalized ratio) 
• 
Monitor at least weekly:  LFT per Table 5 until ALT and/or AST is 
declining on 2 consecutive draws, then may decrease monitoring to 
biweekly 
Abbreviations:  ALT=alanine aminotransferase; AST=aspartate aminotransferase; INR=international normalized 
ratio; LFT=liver function test(s); ULN=upper limit of normal. 
Notes:  In addition to these criteria, other assessments or evaluations may be performed per Investigator 
discretion, as appropriate. 
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5.2.4. 
Preparation, Handling, and Storage 
Staff at each clinical study center or the home healthcare professional will be responsible for 
preparation of study drug doses, according to procedures detailed in the Pharmacy Manual.  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 until dose preparation.  
Deviations from the recommended storage conditions should be reported to the Sponsor and use 
of the study drug halted until authorization for its continued use has been provided by the 
Sponsor or designee, as described in the Pharmacy Manual. 
A Sponsor representative or designee will be permitted, upon request, to audit the supplies, 
storage, dispensing procedures, and records. 
Instructions specific to unused study drug and additional storage will be provided in the 
Pharmacy Manual. 
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. 
Clinical Product Complaints 
5.3.1. 
Definition 
A clinical product complaint (CPC) is any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of the study drug and its packaging after it is released for distribution to the site at 
which study drug will be administered. 
A CPC may be detected prior to use of study drug, during use, or after use.  A CPC is typically 
non-medical in nature; however, it is possible that investigational product complaints could be 
associated with an AE.  Examples of a CPC include, but are not limited to:  illegible clinical 
label, missing clinical label, damaged vial, empty vial, and contamination of study drug. 
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5.3.2. 
Reporting 
For CPCs, the Sponsor or its designee should be notified within 24 hours using the appropriate 
eCRF.  Clinical product complaints that may be associated with an AE must be evaluated and 
reported as indicated in Section 6.5.5.  Detailed instructions on reporting CPCs will be provided 
in the Pharmacy Manual. 
5.4. 
Concomitant Medications and Procedures 
Use of concomitant medications and procedures will be recorded on the patient’s eCRF as 
specified in the Schedule of Assessments (see Table 1).  Concomitant medications include all 
prescription medications, herbal preparations, over the counter medications, vitamins, and 
minerals.  Any changes in medications during the study will also be recorded on the eCRF. 
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, acute 
kidney injury). 
Standard vitamins and topical medications are permitted (vitamin C supplementation must be 
<200 mg daily per inclusion criteria).  However, topical steroids must not be applied anywhere 
near the injection site(s) unless medically indicated. 
Patients will be allowed to receive vaccines (eg, for SARS-CoV-2) that have received health 
agency authorization (including for emergency use) by local or regional regulatory authorities. 
Any concomitant medication that is required for the patient’s welfare may be administered by the 
Investigator.  However, it is the responsibility of the Investigator to ensure that details regarding 
the medication are recorded on the eCRF.  Concomitant medication will be coded using an 
internationally recognized and accepted coding dictionary. 
5.5. 
Treatment Compliance 
Compliance with study drug administration will be verified through observation by study staff or 
trained home healthcare professionals. 
5.6. 
Other Requirements 
5.6.1. 
Contraception 
Females of child-bearing potential must be willing to use an acceptable method of contraception 
from 14 days before first dose, throughout study participation, and for 6 months after last dose 
administration or until study completion. 
Birth control methods which are considered acceptable include: 
• Placement of an intrauterine device. 
• Placement of an intrauterine hormone-releasing system. 
• Bilateral tubal occlusion. 
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• 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 associated with the inhibition of 
ovulation. 
• 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 6 months 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. 
Females of child-bearing potential include female patients who have experienced menarche (or 
begin menarche over the course of the study), and who are not postmenopausal or permanently 
sterilized (eg, bilateral tubal occlusion, hysterectomy, or bilateral salpingectomy).  A 
postmenopausal state is defined as the absence of menses for 12 months without an alternative 
medical cause, confirmed by a follicle stimulating hormone level within the postmenopausal 
range.  
For male patients, no contraception is required.  However, use by males of contraception 
(condom) may be required in some countries, in order to comply with local requirements as 
described in the corresponding patient ICFs. 
Compliance with contraception requirements will be assessed on a regular basis by the 
Investigator throughout the course of the study (see Section 6.5.4.2).  
5.6.2. 
Alcohol Restrictions 
Patients will limit alcohol consumption throughout the course of the study.  Alcohol is limited to 
no more than 2 units per day (unit:  1 glass of wine [approximately 125 mL] = 1 measure of 
spirits [approximately 1 fluid ounce] = ½ pint of beer [approximately 284 mL]) for the duration 
of the study. 
5.6.3. 
Dietary Restrictions 
For the duration of the study patients should adhere to a diet appropriate for calcium oxalate 
stone formers, including adequate calcium intake and avoidance of spinach and other foods that 
are high in oxalate.  Details are provided in the Dietary Reference Sheet. 
Dietary adherence will be collected in a patient diary at the time points listed in the Schedule of 
Assessments (Table 1).  Refer to the Study Manual for more information. 
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6. 
STUDY ASSESSMENTS 
The schedule of study assessments is provided in Table 1.  All assessments are required to be 
performed prior to dosing at dosing visits, except for CT imaging and PK 2-hour postdose 
sample collection.  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, and 
as noted in Table 1, home healthcare may take place at a location other than the clinical trial site 
to perform study assessments, which may include pregnancy testing (urine or serum), clinical 
laboratory assessments, urine collections, DNA testing, symptom-directed physical examination / 
body system assessment, vital signs, body weight, height, blood collection for PD and ADA 
analyses (at the discretion and with oversight of the Investigator). 
6.1. 
Screening Assessments 
An ICF that has been approved by the appropriate Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC) must be signed by the patient before the screening procedures are 
initiated.  All patients will be given a signed and dated version of their ICF. 
Patients will be screened to ensure that they meet all the inclusion criteria and none of the 
exclusion criteria.  To confirm study entrance criteria, 24-hour urine will be collected per 
Table 4.  
Patient demographic data and medical history/disease history will be obtained.  Any changes to 
medical history occurring between the screening assessment and prior to dosing will be updated.  
6.1.1. 
DNA Sample 
A blood sample for DNA analysis will be collected from all patients as part of the screening 
assessments.  The samples will be analyzed for PH1, PH2, and PH3 (unless tested previously) to 
confirm eligibility (see Section 4.2).  Refer to the Laboratory Manual for more information. 
6.1.2. 
Retesting  
If in the Investigator’s judgement, the screening laboratory abnormalities are likely to be 
transient, then laboratory tests may be repeated once.  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. 
6.1.3. 
Rescreening 
Rescreening of patients is permitted with approval of the Medical Monitor.  A patient who does 
not meet all study eligibility criteria due to a transient condition observed at screening (eg, 
prohibited medications that were subsequently discontinued) will be allowed to return for 
rescreening.  A patient will be re-consented if rescreening occurs outside of the 60-day screening 
window.  In this case, all screening procedures must be repeated. 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently assigned to treatment with study drug.  The site should update the patient’s 
status in the IRT to reflect this as soon as possible. 
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6.2. 
Efficacy Assessments 
Efficacy assessments are to be performed as specified in the Schedule of Assessments (Table 1). 
6.2.1. 
24-Hour Urine Collections 
Urinary oxalate excretion and calcium oxalate supersaturation (calculated from multiple 
parameters) will be determined from 24-hour urine sample collections to be completed at the 
time points specified in the Schedule of Assessment (Table 1).  The start and stop dates/times of 
collection, the volume of urine in the collection, whether there were any missed voids, and 
whether the patient complied with dietary recommendations will be recorded.  An aliquot of the 
24-hour urine collection will also be used to determine urinary creatinine content and to 
determine if the 24-hour urine collections need to be repeated (see Section 6.2.1.1). 
The 24-hour urine collection procedure by study visit is provided in Table 4.  
Table 4: 
24-hour Urine Collection Procedure by Study Visit 
Study Visit and Urine 
Collection Window 
Number of 
Collections to 
Schedule 
Validity Requirement 
Prior to Dosing/Visit  
(see Section 6.2.1.1) 
Notes 
Screening 
(within 60-day period) 
2 
2 valid collections prior to 
dosing unless variability 
criterion is not met 
(Section 6.2.1.2), in 
which case an additional 
collection is requireda.  
Supervised collectionsb are 
encouraged unless patient is already 
familiar with the collection 
procedure.  If any collections are 
invalid, the remaining collections for 
screening must be supervised.  
Months 3, 4, 5, and 6 
(within 14 days prior to 
dosing/visit) 
1 
No 
If an invalid collection is obtained for 
the timepoint, a single repeat 
collection must be supervised.  
Repeat collection, if necessary, is to 
be completed within ±14 days of 
dosing/visit. 
Months 9 and 15 
(within 14 days prior to 
dosing/visit) 
2 
1 valid collection prior to 
dosing/visit 
If a patient has had ≥2 prior invalid 
collections, both collections at these 
visits must be supervisedb.  At least 1 
valid collection must be obtained 
prior to dosing/visit.  If any 
collections for the timepoint are 
invalid, the remaining collection(s) 
for the timepoint must be supervised. 
a The additional collection is not required to be valid in order to proceed with dosing, but will be tested to confirm 
validity for the calculation of baseline 24-hour urinary oxalate. 
b A supervised collection is defined, at a minimum, as contact from study staff to the patient the day prior to the 
collection start and the day the collection will finish to ensure compliance; this may be conducted remotely.  Any 
or all of the 24-hour urine collections may be conducted supervised.  If 24-hour urine collection is not a supervised 
collection, or if a collection is supervised remotely, patients may either bring it to the clinic or have it couriered to 
the clinic.   
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6.2.1.1. 
Validity Criteria for 24-hour Urine Collections 
Throughout the study, a urine collection will be considered valid if each of the following criteria 
are met: 
• The collection is between 22 to 26 hours in duration between the initial discarded 
void and the last void or attempt to void. 
• No voids are missed between the start and end time of the collection as indicated by 
the patient's urine collection diary. 
• The 24-hour creatinine content is at least 10 mg/kg as assessed by the central 
laboratory. 
• Patient complied with dietary recommendations appropriate for oxalate stone formers 
(detailed in the Dietary Reference Sheet) for the 4 days prior to the start of the urine 
collection and during the collection. 
24-hour urine collections that are known to be invalid should still be submitted for analysis. 
6.2.1.2. 
Variability Criterion for 24-hour Urine Collections at Screening 
If the 2 valid 24-hour urine collections from screening meet eligibility requirements (both 24-
hour urinary oxalate levels >ULN), the variability between the oxalate levels (in mg/day) should 
be assessed as follows: 
 
If the variability is >20%, then an additional 24-hour urine collection should be obtained.  The 
result of the additional sample will not impact the patient’s eligibility for the study. 
6.2.2. 
Kidney Stone Events 
Since kidney stone events are recorded as an efficacy assessment, these events will not be 
captured as AEs or SAEs.  However, if a patient experiences other AEs or SAEs during a kidney 
stone event, they should be reported as an AE (see Section 6.5.5.2).   
Kidney stone events will be graded by the Investigator as mild, moderate, or severe as defined in 
Section 6.5.5.1.  If there are changes in grade during an event, only the highest grade should be 
reported. 
6.2.2.1. 
Clinical 
All relevant clinical information pertaining to a kidney stone events should be obtained, 
including laboratory values, medical records, discharge summaries, and medical test results 
(including stone composition, if available, and radiology reports).  A clinical kidney stone event 
is defined as one of the following: 
• Visible passage of a kidney stone 
• A procedural intervention for removal of an asymptomatic or symptomatic stone 
(information on the location, number, and size of stones removed will be collected) 
𝑉𝑎𝑟𝑖𝑎𝑏𝑖𝑙𝑖𝑡𝑦=  (𝑂𝑥𝑎𝑙𝑎𝑡𝑒 𝑣𝑎𝑙𝑢𝑒 #1 −𝑂𝑥𝑎𝑙𝑎𝑡𝑒 𝑣𝑎𝑙𝑢𝑒 #2)
(𝐴𝑣𝑒𝑟𝑎𝑔𝑒 𝑜𝑓 𝑜𝑥𝑎𝑙𝑎𝑡𝑒 𝑣𝑎𝑙𝑢𝑒𝑠 #1 & #2)  × 100% 
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• Or, in the case of potential stone passages without visible stones, it will be up to the 
Investigator to evaluate patients’ symptoms and determine whether a stone passage 
occurred or the symptoms were due to a different cause. 
6.2.2.2. 
Radiographic 
A non-contrast low-dose kidney-protocol CT scan will be performed for all patients on Day 1 
(may be performed up to 3 days prior to Day 1), and at Month 15.   
For patients who terminate the study early, a CT scan should be performed at the ET visit only if 
this visit occurs after Month 6 and at the discretion of the Investigator, and where permitted, 
following consultation with the Medical Monitor.  CT scans will be analyzed centrally. 
6.2.3. 
Estimated Glomerular Filtration Rate 
Blood samples for the assessment of eGFR (mL/min/1.73m2) will be obtained at the time points 
specified in the Schedule of Assessment (Table 1). 
eGFR will be calculated based on the CKD-EPI formula (see Section 10.1).[Levey 2009; 
Schwartz 2009] 
6.3. 
Pharmacodynamic Assessments 
Urine and blood samples will be collected for assessment of PD parameters (plasma oxalate and 
plasma glycolate, and 24-hour urinary glycolate) at the time points specified in the Schedule of 
Assessments (Table 1).  On dosing days, all blood and urine samples will be collected prior to 
study drug administration. 
All PD assessments will be analyzed centrally.  Postdose PD results will not be distributed to the 
sites until after the last patient completes assessments at the Month 15 visit.  Site personnel 
should refrain from obtaining or viewing local oxalate, calcium oxalate supersaturation, or 
glycolate assessments, except as medically indicated, due to risk of unblinding (Section 3.5).  
Details regarding the processing and aliquoting of PD samples for shipping and storage are 
provided in the Laboratory Manual. 
Where local regulations allow and infrastructure is in place, a healthcare professional may collect 
urine or blood samples offsite. 
6.4. 
Pharmacokinetic Assessments 
Blood samples will be collected for the assessment of lumasiran PK parameters at the time points 
indicated in the Schedule of Assessments (Table 1).  A detailed schedule of time points for the 
collection of blood samples for PK analysis is in Table 2. 
The concentration of lumasiran in blood samples will be determined using a validated assay.  
Details regarding sample volumes to be collected, and the processing and shipping 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 
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and height, and laboratory tests.  Clinically significant abnormalities observed during the 
physical examination are recorded as either medical history or AEs, as appropriate. 
Safety assessments are to be performed as specified in the Schedule of Assessments (Table 1).  
On dosing days and as applicable, assessments of vital signs, weight/height, physical 
examination, and clinical laboratory assessments are to be completed before study drug 
administration.  
Adverse event assessments are detailed under Section 6.5.5.  
6.5.1. 
Vital Signs 
Vital signs will be measured as specified in the Schedule of Assessments (Table 1) and include 
blood pressure, heart rate, body temperature, and respiratory rate.  Vital signs will be measured 
predose, when applicable.  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 predose in the seated or supine position, after the patient has rested 
comfortably for approximately 5 minutes.  Blood pressure should be taken using the same arm 
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. 
Vital signs results will be recorded in the eCRF. 
6.5.2. 
Height and Weight 
Height will be measured in centimeters.  Body weight will be measured in kilograms.  Height 
and body weight measurements will be collected as specified in the Schedule of Assessments 
(Table 1) and will be recorded in the eCRF. 
6.5.3. 
Physical Examination 
Full and symptom-directed physical examinations will be conducted according to the Schedule 
of Assessments (Table 1); if a physical examination is scheduled for a dosing visit, it should be 
conducted prior to dosing.  Full physical examinations will include the examination of the 
following:  general appearance; head, eyes, ears, nose and throat; respiratory, cardiovascular, 
gastrointestinal, musculoskeletal, and dermatological systems; thyroid; lymph nodes; and 
neurological status.  If a visit is conducted offsite (eg, home), a body system assessment may be 
performed in lieu of a physical examination. 
Symptom-directed physical examinations will be guided by evaluation of ongoing symptoms, 
changes in symptoms, or the onset of new symptoms, since the last visit.  If there are no ongoing 
symptoms, changes in symptoms, or new symptoms, then a symptom-directed physical 
examination is not required. 
Clinically significant abnormalities observed during the physical examination are recorded on 
the medical history eCRF (if observed during screening) or the AE eCRF (if observed at any 
post-screening visit). 
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6.5.4. 
Clinical Laboratory Assessments 
The following clinical laboratory tests will be evaluated by a central laboratory.  Specific 
instructions for transaminase elevations are provided in Section 5.2.3.1.  Laboratory assessments 
conducted to confirm study eligibility (Section 4) will not be repeated unless the time between 
screening and randomization exceeds 4 weeks.  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, until it has returned to the normal range or 
stabilized, and/or a diagnosis is made to adequately explain the abnormality.  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 included in the clinical database.  Clinical laboratory assessments 
are listed in Table 5 and will be assessed as specified in the Schedule of Assessments (see 
Table 1).  
While local laboratory results may be used for urgent clinical decisions, on the day of visit 
assessments, all laboratory assessments specified in Table 5 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. 
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 5: 
Clinical Laboratory Assessments 
Hematology 
Complete blood count with differential 
 
Serum Chemistry 
Sodium 
Potassium 
BUN 
Albumin 
Total protein 
Calcium 
Glucose 
Bicarbonate 
Creatinine and eGFRa 
Chloride 
Liver Function Tests 
 
AST 
ALP 
ALT 
Bilirubin (total and direct) 
Coagulation  
International Normalized Ratio (screening only) 
 
Immunogenicity (see Section 6.5.4.1) 
Antidrug antibodies 
 
Pregnancy Testing/FSH Screening (see Section 6.5.4.2) 
β-human chorionic gonadotropin (females of 
child-bearing potential only) 
Follicle-stimulating hormone (postmenopausal 
women only) 
Abbreviations:  ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; 
BUN=blood urea nitrogen; eGFR=estimated glomerular filtration rate; FSH=follicle-stimulating hormone  
a Refer to Section 10.1 and the laboratory manual for further instructions on calculating eGFR. 
6.5.4.1. 
Immunogenicity 
Blood samples will be collected to evaluate ADA.  Blood samples for ADA testing must be 
collected before study drug administration as specified in the Schedule of Assessments (Table 1). 
Details regarding the processing and shipping of the samples will be provided in the Laboratory 
Manual. 
6.5.4.2. 
Pregnancy Testing 
A pregnancy test will be performed for females of child-bearing potential.  A serum pregnancy 
test will be performed at screening.  Urine pregnancy tests will be performed thereafter per the 
Schedule of Assessments and any time pregnancy is suspected.  More frequent pregnancy testing 
may be performed where required per local requirements.  The results of the pregnancy test must 
be known before study drug administration.  Patients who are pregnant at screening are not 
eligible for study participation.  Any woman with a positive urine pregnancy test that is 
subsequently confirmed by a positive serum pregnancy test during the study will be discontinued 
from study drug but will continue to be followed for safety.  Patients determined to be pregnant 
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while on study will be followed at least until the pregnancy outcome is known (see 
Section 6.5.5.7 for follow-up instructions). 
A blood sample will be drawn at screening to measure the levels of follicle stimulating hormone 
in order to confirm postmenopausal status in all women suspected to be postmenopausal.  
Postmenopausal women and women who are permanently sterilized will not undergo pregnancy 
testing. 
6.5.4.3. 
Additional Liver Function Assessments 
Additional laboratory assessments will be performed in patients who experience any LFT 
abnormalities as outlined in Section 5.2.3.1 (see Table 3).  Following the occurrence of elevated 
liver transaminases or other LFT abnormalities per central laboratory, all assessments in Table 6 
will be performed one time, as well as hematology, serum chemistry, LFT, and coagulation 
assessments per Table 3, and other assessments or evaluations per Investigator discretion, as 
appropriate.  
Monitoring, including criteria for dose modification or withholding the study drug, is described 
in Section 5.2.3.1. 
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Table 6: 
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.  The full panel of assessments should only be 
performed once; individual assessments may be repeated, as needed. 
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6.5.5. 
Adverse Events 
6.5.5.1. 
Definitions 
Adverse Event 
According to the International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (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. 
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: 
• ALT or AST >3× ULN 
• Severe or serious ISRs; ISRs that are associated with a recall phenomenon (reaction 
at the site of a prior injection with subsequent injections), or ISRs that lead to 
temporary dose interruption or permanent discontinuation of study drug. 
An ISR is defined as a local reaction at or near the site of injection.  “At or near” the 
injection site includes reactions at the injection site, adjacent to the injection site, or a 
reaction which may shift slightly away from the injection site due to gravity (eg, as 
may occur with swelling or hematoma).  Reactions with onset and resolution within 4 
hours of the injection (eg, transient pain/burning at injection site) do not meet the 
study definition of ISRs, unless immediate treatment is required.  A systemic reaction 
which includes the injection site, eg, generalized urticaria, other distinct entities or 
conditions like lymphadenopathy that may be near the injection site is not considered 
an ISR.   
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For information on recording and reporting of AEs of clinical interest, see Section 6.5.5.2 and 
Section 6.5.5.3, respectively. 
Adverse Event Severity 
Adverse events are to be graded according to the categories detailed below: 
Mild: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Moderate: 
Moderate; minimal, local or noninvasive intervention indicated; limiting age 
appropriate instrumental activities of daily living (eg, preparing meals, 
shopping for groceries or clothes, using the telephone, managing money). 
Severe: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care activities of daily living (ie, bathing, dressing and 
undressing, feeding self, using the toilet, taking medications, and not 
bedridden); OR life-threatening consequences; urgent intervention indicated; 
OR death related to an 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.  Adverse events characterized as intermittent 
require documentation of the start and stop of each incidence.  When changes in the severity of 
an AE occur more frequently than once a day, the maximum severity for the experience that day 
should be noted.  If the severity category changes over a number of days, then those changes 
should be recorded separately (with distinct onset dates). 
Adverse event 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. 
6.5.5.2. 
Eliciting and Recording Adverse Events 
Eliciting Adverse Events 
The patient should be asked about medically relevant changes in the patient’s health since the 
last visit.  The patient 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, or other findings 
that are relevant to patient safety. 
Recording Adverse Events 
The Investigator is responsible for recording non-serious AEs that are observed or reported by 
the patient after administration of the first dose of study drug regardless of their relationship to 
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study drug through the EOS.  Non-serious AEs will be followed until the EOS.  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 EOS.  Serious AEs will be followed until satisfactory resolution, until baseline level 
is reached, or until the SAE is considered by the Investigator to be chronic or the patient is 
stable, as appropriate. 
All AEs must be recorded in the source records for the clinical study center and in the eCRF for 
the patient, whether or not they are considered to be drug-related.  Each AE must be described in 
detail:  onset time and date, description of event, severity, relationship to study drug, action 
taken, and outcome (including time and date of resolution, if applicable). 
For SAEs, record the event(s) in the eCRF and, as applicable, the SAE form. 
For AEs that are considered AEs of clinical interest (Section 6.5.5.1), the supplemental AEs of 
Clinical Interest eCRF should be completed.  Additional clinical and laboratory information may 
be collected.  Refer to eCRF 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.). 
6.5.5.3. 
Reporting Adverse Events of Clinical Interest to Sponsor/Designee 
For AEs that are considered AEs of clinical interest (Section 6.5.5.1), the Sponsor or its designee 
should be notified within 24 hours using a supplemental AEs of Clinical Interest eCRF.  
Additional clinical and laboratory information may be collected.  Refer to eCRF completion 
guidelines for details on reporting events in the supplemental AEs of Clinical Interest eCRF.   
For all ISRs, the Investigator, or delegate, should submit a supplemental ISR eCRF, recording 
additional information (eg, descriptions, onset and resolution date, severity, treatment given, 
event outcome). 
6.5.5.4. 
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 6.5.5.1 must be reported to the 
Sponsor or designee within 24 hours from the time that clinical study center staff first learns of 
the event.  All SAEs must be reported regardless of the relationship to study drug. 
The initial report should include at least the following information: 
• Patient’s study number 
• Description and date of onset of the event 
• Criterion for serious 
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• Preliminary assignment of relationship to study drug, and 
• Investigator/site information 
To report the SAE, complete the eCRF and, as applicable, the SAE form.  Within 24 hours of 
receipt of follow-up information, the Investigator must update the eCRF and, as applicable, the 
SAE form.  Serious AEs 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. 
6.5.5.5. 
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. 
6.5.5.6. 
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. 
6.5.5.7. 
Pregnancy Reporting 
If a female patient becomes pregnant during the study through 6 months following the last dose 
of study drug, 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 6 months 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 6.5.5.4. 
The reporting of any pregnancy outcome for a female partner of a male patient participating in 
this study that results in a postpartum complication, spontaneous abortion, stillbirth, neonatal 
death, or congenital anomaly should be reported to the Investigator, who will then report this to 
the Sponsor or designee.  The pregnancy outcome is to be recorded on the pregnancy reporting 
form. 
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6.5.5.8. 
Reporting of Overdose and Other Special Situations 
An overdose is defined as any dose of study drug administered to the participant that is ≥2-fold 
the assigned dose during a single administration. 
The Sponsor does not recommend specific treatment for an overdose.  
In an event of an overdose or other special situations (eg, medication error, abuse, misuse, CPC 
associated with an AE), the Investigator should: 
• Contact the Medical Monitor within 24 hours 
• Submit the special situations reporting form within 24 hours using the contact 
information in the Pharmacy Manual 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities 
• Document the amount of study drug given 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention or 
a concomitant medication will be considered AEs/SAEs.  Overdose per se will not be 
categorized as an AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent.  Such overdoses should be reported as an SAE regardless of sequelae. 
Full details of overdose and other special situations reporting instructions will be outlined in the 
Pharmacy Manual. 
6.6. 
Healthcare Utilization 
To complement medical records, information regarding health resource use related to kidney 
stone events will be collected as specified in the Schedule of Assessments (Table 1), including 
emergency room visits, unscheduled office visits, hospitalizations, and procedures for kidney 
stone management. 
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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 principal features stated in the 
protocol. 
7.1. 
Determination of Sample Size 
The planned enrollment for this study is 120 patients. 
The study is powered to detect a difference in urinary oxalate excretion between each lumasiran 
group and the placebo group.  Assuming a standard deviation of 45% in the percent change from 
baseline in 24-hour urinary oxalate levels at Month 6, a sample size of 40 patients per group will 
enable a power of at least 80% in detecting a treatment difference of 30% between the treatment 
groups at a 2-sided significance level of 0.05.  Table 7 shows the statistical power under various 
assumptions for a sample size of 40 per group. 
Table 7: 
Sample Size Power Calculations 
Assumed standard 
deviation (SD) 
Assumed difference 
(lumasiran – placebo) 
Power 
25% 
20% 
94% 
30% 
99% 
30% 
20% 
84% 
30% 
99% 
45% 
20% 
50% 
30% 
84% 
Abbreviations:  SD=standard deviation 
7.2. 
Statistical Methodology 
The statistical and analytical plans presented below are brief summaries of planned analyses.  
More complete plans will be detailed in the SAP.  Changes to the methods described in the final 
SAP will be described and justified as needed in the clinical study report.  For information on 
study endpoints, see Section 2. 
7.2.1. 
Populations to be Analyzed 
The populations (analysis sets) are defined as follows: 
• Full Analysis Set (FAS):  All randomized patients who received at least 1 dose of 
study drug.  Patients in the FAS will be analyzed according to the randomized 
treatment arm. 
• Plasma Oxalate Analysis Set:  All patients who received at least 1 dose of study 
drug and have a baseline plasma oxalate level ≥1.5 times the lower limit of 
quantification/detection. 
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• Safety Analysis Set:  All patients who received at least 1 dose of study drug.  
Patients in the Safety Analysis Set will be analyzed according to the treatment 
actually received. 
• PK Analysis Set:  All patients who received at least 1 full dose of study drug and 
have at least one postdose blood sample for PK parameters and have evaluable PK 
data. 
The primary population used to evaluate efficacy will be the FAS.  Safety will be analyzed using 
the Safety Analysis Set.  The PK Analysis Set 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 by dose 
level and overall for the FAS and Safety Analysis Set.  
7.2.5. 
Efficacy Analyses 
The hypothesis testing for the primary endpoint will be tested comparing each lumasiran group 
to the placebo group in the FAS with a 2-sided significance level of 0.05. 
The primary endpoint will be analyzed using a mixed-effect model for repeated measures 
(MMRM) approach.  The outcome variable is percent change from baseline in urinary oxalate to 
Month 6 (average across Months 4 through 6).  The model includes baseline 24-hour urinary 
oxalate and the stratification factor of number of historical kidney stone events (>1 versus ≤1 
event in the 12 months prior to screening) as covariates, and fixed effect terms including 
treatment arm, visit and visit and treatment arm interaction.  The estimate of treatment difference 
for the average percent change from baseline of 24-hour urinary oxalate excretion across Months 
4 through 6 will be calculated via a linear contrast of the corresponding coefficients from the 
MMRM model.  
Additionally, the percent change from baseline in 24-hour urinary oxalate excretion at Month 9 
and Month 15 will be summarized and compared between lumasiran and placebo treatment 
groups. 
Baseline, Month 9, and Month 15 urinary oxalate values and urinary calcium oxalate 
supersaturation values are planned to be collected in either duplicate or triplicate (baseline) and 
duplicate (Months 9 and 15), and the calculated median of valid collections during each time 
period (visit) will be used in the analysis. 
Analysis of secondary endpoints and exploratory endpoints will be specified in the SAP.  No 
multiplicity adjustment is planned. 
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7.2.6. 
Pharmacodynamic Analysis 
The change in plasma and urinary PD parameters will be summarized over time for all patients in 
the FAS.  For the change in plasma oxalate, a separate analysis population, the Plasma Oxalate 
Analysis Set will be used. 
7.2.7. 
Pharmacokinetic Analysis 
Pharmacokinetic analyses will be conducted using noncompartmental methods. 
Pharmacokinetic parameters to be calculated include but will not be limited to maximum plasma 
concentration (Cmax) and time to maximum plasma concentration (tmax).  Other parameters may 
be calculated, if deemed necessary. 
7.2.8. 
Safety Analyses 
The primary parameter is the frequency of treatment-emergent AEs (hereafter referred to simply 
as AEs).  Safety parameters also include vital signs, clinical laboratory assessments and physical 
exams.  Extent of exposure will be summarized by dose and overall.  
Prior and concomitant medications will be coded using the World Health Organization (WHO) 
Drug Dictionary.  Results will be tabulated by Anatomical Therapeutic Chemical (ATC) 
Classification System and preferred term (PT). 
Adverse events will be classified according to the Medical Dictionary for Regulatory Activities 
(MedDRA) System Organ Class (SOC) and PT by dose level and overall.  Adverse events, 
SAEs, related AEs, AEs leading to discontinuation of study drug, and AEs leading to death will 
be summarized by SOC and PT for each treatment arm.  By-patient listings will be provided for 
deaths, SAEs, and AEs leading to discontinuation of study drug.  
Descriptive statistics, summarizing the observed values and changes from baseline over time, 
will be provided for clinical laboratory parameters and vital signs.  Laboratory shift tables from 
baseline grade (or category) to worst post-baseline grade (or category) will be presented for 
laboratory parameters that are graded or categorized.  Abnormal physical exam findings will be 
presented in listings. 
Other safety summaries will be presented as appropriate.  Further details will be specified in the 
SAP. 
7.2.9. 
Immunogenicity Analyses 
The frequency and percentage of patients with confirmed positive ADA assay at any time during 
study as well as at each scheduled visit will be summarized.  The titer results for patients with 
confirmed positive ADA results will be summarized. 
7.2.10. 
Other Analyses 
Other exploratory analyses will be described in the SAP. 
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7.2.11. 
Interim Analysis 
No formal interim analysis is planned.  The primary analysis will be conducted for the primary 
and secondary endpoints through Month 6 after the last patient has completed the Month 6 visit 
and the database is locked. 
7.2.12. 
Optional Additional Research 
Optional additional research may be conducted in the future on the biological samples and/or 
data collected during the study in accordance with the strict terms of the ICF (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. 
8.1.1. 
Informed Consent 
The Investigator will ensure that the patient is given full and adequate oral and written 
information about the nature, purpose, possible risk and benefit of the study.  Patients must also 
be notified that they are free to discontinue from the study at any time.  The patient should be 
given the opportunity to ask questions and allowed time to consider the information provided. 
The Investigator will inform the patient if new information becomes available that may be 
relevant to the patient’s willingness to continue participation in the study.  Communication of 
this information should be documented.  If circumstances warrant an updated informed consent 
during the study, and patients are required to re-consent, this may be collected remotely where 
local regulations allow. 
The patient’s signed and dated informed consent must be obtained before conducting any study 
tests or procedures that are not part of routine care. 
The Investigator must maintain the original, signed ICF.  All patients will be given a copy of the 
signed and dated ICF. 
8.1.2. 
Ethical Review 
The study protocol, including the ICF, 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.  The protocol must be reapproved by the IRB or IEC upon receipt of 
amendments and annually, as local regulations require. 
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Initial IRB or IEC approval of the protocol, and all materials approved by the IRB or IEC for this 
study including the patient consent 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 6.5.5.  In addition, the 
Investigator agrees to submit progress reports to the IRB or IEC per their local reporting 
requirements, or at least annually and at the conclusion of the study.  The reports will be made 
available to the Sponsor or designee. 
Any communications from regulatory agencies, IRBs, or IECs in regard to inspections, other 
studies that impact this protocol or the qualifications of study personnel should be promptly 
reported to the Sponsor or its designee. 
The Investigator is also responsible for providing the IRB 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 randomized under the 
amended protocol, and patients must be re-consented to the most current version of the ICF. 
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 (including personal data) relating to the study should be retained for 2 years 
after the last approval in an ICH territory or as required by local laws and regulations, 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 to be submitted to the Sponsor or designees, the names will be obliterated, and the 
assigned patient number added to the document, before sending to the Sponsor.  Documents not 
for submission to the Sponsor (eg, signed ICFs) should be maintained by the Investigator in strict 
confidence. 
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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 EOS is defined as the last patient last visit. 
8.1.6. 
Termination of the Clinical Study or Site Closure 
The Sponsor, or designee, reserves the right to terminate the study or a clinical study site at any 
time.  Conditions that may warrant this action may include, but are not limited to: 
• The discovery of an unexpected, serious, or unacceptable risk to patients participating 
in the study 
• 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. 
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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. 
Where local regulations allow, the Monitor may request remote access to source documents and 
systems.  Should this take place, it will be done in a manner that protects the confidentiality of 
the data. 
8.2.3. 
Audits and Inspections 
Periodically, the Sponsor or its authorized representatives audit clinical investigative sites as an 
independent review of core trial processes and documents to determine whether these activities 
were conducted, and data were recorded, analyzed, and accurately reported according to the 
protocol, GCP guidelines of the ICH, and any applicable regulatory requirements.  A regulatory 
authority, an IEC or an IRB may visit the site to perform audits or inspections, including source 
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 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 will detail the procedures for 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 
Borghi L, Schianchi T, Meschi T, Guerra A, Allegri F, Maggiore U, et al. Comparison of two 
diets for the prevention of recurrent stones in idiopathic hypercalciuria. N Engl J Med. 2002 Jan 
10;346(2):77-84. 
Curhan GC,Taylor EN. 24-h uric acid excretion and the risk of kidney stones. Kidney Int. 2008 
Feb;73(4):489-96. 
Dhondup T, Kittanamongkolchai W, Vaughan LE, Mehta RA, Chhina JK, Enders FT, et al. Risk 
of ESRD and Mortality in Kidney and Bladder Stone Formers. Am J Kidney Dis. 2018 
Dec;72(6):790-7. 
Ferraro PM, Ticinesi A, Meschi T, Rodgers A, Di Maio F, Fulignati P, et al. Short-Term 
Changes in Urinary Relative Supersaturation Predict Recurrence of Kidney Stones: A Tool to 
Guide Preventive Measures in Urolithiasis. J Urol. 2018 Nov;200(5):1082-7. 
Heilberg IP,Schor N. Renal stone disease: Causes, evaluation and medical treatment. Arq Bras 
Endocrinol Metabol. 2006 Aug;50(4):823-31. 
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. 
Mitchell JA, Knowles RB, Kirkby NS, Reed DM, Edin ML, White WE, et al. Kidney 
Transplantation in a Patient Lacking Cytosolic Phospholipase A2 Proves Renal Origins of 
Urinary PGI-M and TX-M. Circ Res. 2018 Feb 16;122(4):555-9. 
Pearle MS, Goldfarb DS, Assimos DG, Curhan G, Denu-Ciocca CJ, Matlaga BR, et al. Medical 
management of kidney stones: AUA guideline. J Urol. 2014 Aug;192(2):316-24. 
Prochaska M, Taylor E, Ferraro PM,Curhan G. Relative Supersaturation of 24-Hour Urine and 
Likelihood of Kidney Stones. J Urol. 2018 May;199(5):1262-6. 
Rule AD, Bergstralh EJ, Melton LJ, 3rd, Li X, Weaver AL,Lieske JC. Kidney stones and the risk 
for chronic kidney disease. Clin J Am Soc Nephrol. 2009 Apr;4(4):804-11. 
Scales CD, Jr., Smith AC, Hanley JM, Saigal CS,Urologic Diseases in America P. Prevalence of 
kidney stones in the United States. Eur Urol. 2012 Jul;62(1):160-5. 
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. 
Shin S, Srivastava A, Alli NA,Bandyopadhyay BC. Confounding risk factors and preventative 
measures driving nephrolithiasis global makeup. World J Nephrol. 2018 Nov 24;7(7):129-42. 
Türk C, Neisius A, Petřík A, Skolarikos A, Somani B, Thomas K, et al., editors. EAU Guidelines 
on Urolithiasis. EAU Annual Congress; 2021; Milan, Italy: EAU Guidelines Office. 
Worcester EM,Coe FL. Nephrolithiasis. Prim Care. 2008 Jun;35(2):369-91, vii. 
Worcester EM,Coe FL. Clinical practice. Calcium kidney stones. N Engl J Med. 2010 Sep 
2;363(10):954-63. 
 
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10. 
APPENDICES 
10.1. 
Formula for Estimated Glomerular Filtration Rate Calculation 
Source:  Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI); Levey AS, Stevens 
LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate.  Ann Intern Med. 
2009;150(9):604-612. 
• eGFR = 141 × min(Scr/κ, 1)α × max(Scr/κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 
1.159 [if Black or African American] 
where: 
− Scr is serum creatinine in mg/dL 
− κ = 0.7 (females) or 0.9 (males) 
− α = -0.329 (female) or -0.411 (male) 
− min(Scr/κ, 1) is the minimum of Scr/κ or 1.0 
− max(Scr/κ, 1) is the maximum of Scr/κ or 1.0 
− Age (years) 
 
Abbreviations:  eGFR= Estimated glomerular filtration rate; SCr=serum creatinine 
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ALN-GO1-008 PROTOCOL AMENDMENT 1 
SUMMARY OF CHANGES DATED 16 JUNE 2022  
COMPARED TO ORIGINAL PROTOCOL DATED 24 JUNE 2021  
A Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy, Safety, 
Pharmacodynamics, and Pharmacokinetics of Lumasiran in Patients with Recurrent 
Calcium Oxalate Kidney Stone Disease and Elevated Urinary Oxalate Levels 
1. 
RATIONALE FOR PROTOCOL AMENDMENT 
The primary purpose for this protocol amendment is to decrease participant burden and to 
simplify site execution. 
Inclusion Criterion 
• Expanded Inclusion Criterion 2 to allow ≥2 stone events with a minimum of 1 stone 
required in the 5 years prior to screening.  Rationale:  To widen eligibility criteria 
from ≥2 stones in the previous 5 years to help with patient recruitment. 
Outcome Assessments 
• Removed exploratory endpoint of change from baseline in spot urinary 
oxalate:creatinine ratios and corresponding spot urine assessments from schedule of 
assessments.  Rationale:  To reduce participant burden and to simplify site execution. 
• Removed all exploratory blood and urine samples including exploratory DNA 
assessments.  Rationale:  To simplify site execution. 
• Removed electronic diary modality option from the patient diary for urine collection 
and dietary restriction details.  Rationale:  To reduce participant burden including 
technology-related considerations and to simplify site execution. 
• Removed all patient-reported outcomes, including Brief Pain Inventory Short Form 
and Wisconsin Stone Quality of Life.  Rationale:  To reduce participant burden 
including technology-related considerations and to simplify site execution. 
Schedule of Assessments 
• Removed validity requirement before dosing if an additional 24-hour urine sample is 
required during screening (also in Section 6.2.1, Table 4 and in Section 6.2.1.2).  
Rationale:  To reduce participant burden at the Day 1 visit.  There is already 
flexibility in urine validity requirements prior to dosing/visit activities at the Month 
(M)3, M4, M5, M6, M9, and M15 visits in the Schedule of Assessments (Protocol 
Table 4).  It is expected that most participants will not be required to collect an 
additional 24-hour urine sample, and the risk of a participant submitting an invalid 
collection after 2 confirmed valid collections in the screening period is deemed to be 
low.  A sensitivity analysis is planned to account for any participants whose 
additional screening urine collection is found to be invalid. 
• Removed urinalysis from clinical laboratory assessments (also in Section 6.5.4).  
Rationale:  To reduce participant burden and to simplify site execution. 
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Pharmacokinetic Time Points 
• Added predose pharmacokinetic (PK) time point to protocol Table 2.  
Rationale:  Clarification that a predose sample is required.  
• Removed PK time point of 4 hours post-dose from protocol Table 2.  Rationale:  To 
reduce participant burden. 
 
Several additional changes are being implemented as outlined below.  
Additional Changes: 
• The number of sites was changed from approximately 25 to approximately 55 to help 
with patient recruitment.  
• The Schedule of Assessments Visit Day for Month 12 was corrected from 309 to 337. 
• In Section 3.1 and Section 3.4, language describing stratification was clarified to 
align with the study Statistical Analysis Plan (SAP). 
• In Section 3.5, laboratory language was clarified to remove “central,” and blinding 
language was clarified to allow unblinded site personnel to prepare study drug in 
accordance with documented institutional procedures. 
• In Section 4.1:  
− Inclusion Criterion 4 was changed to clarify the upper limit of normal (ULN) for 
24-hour urinary oxalate. 
− Inclusion Criterion 7 was changed to clarify that body mass index (BMI) is at 
screening. 
• In Section 6.1, informed consent form (ICF) language was modified because 
electronic format is not available without the electronic diary modality. 
• In Section 6.2.1, language was clarified to allow patients to have 24-hour urine 
collection samples couriered to the clinic. 
• In Section 6.2.1.2, language was clarified regarding the collection of additional 
24-hour urine samples. 
• In Section 7 and Section 7.2.11, blinding language was clarified. 
• In Section 7.2.1: 
− The Plasma Oxalate Analysis Set was added to align with the study SAP. 
− Language for the Safety Analysis Set was clarified. 
• In Section 7.2.5, language for the mixed-effect model for repeated measures 
(MMRM) was clarified to align with the study SAP. 
• In Section 7.2.6, the Plasma Oxalate Analysis Set was added to align with the study 
SAP.  
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• In Appendix 10.1, the formula provided was corrected to reflect the 2009 Chronic 
Kidney Disease Epidemiology Collaboration (CKD-EPI) equation for estimated 
glomerular filtration rate (eGFR) calculation. 
A detailed summary of changes is provided in Section 2.  The following changes are not 
detailed: administrative changes and corrections to typographical errors, punctuation, grammar, 
abbreviations, and formatting.  
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2. 
PROTOCOL AMENDMENT 1 DETAILED SUMMARY OF CHANGES 
The primary section(s) of the protocol affected by the changes in Protocol Amendment 1 are indicated.  The corresponding text has 
been revised throughout the protocol.  Deleted text is indicated by strikeout; added text is indicated by bold font. 
 
Purpose:  Expand the number of sites from approximately 25 to approximately 55. 
The change occurs in the Protocol Synopsis. 
Revised text:  The study will be conducted at approximately 2555 clinical study centers across Europe and the United States. 
Purpose:  Remove exploratory endpoint of change from baseline in spot urinary oxalate:creatinine ratios and corresponding spot 
urine assessments.  
The primary change occurs in Section 2, Objectives and Endpoints. 
Removed text:   
Objectives  
• To evaluate the effect of lumasiran on spot urinary oxalate:creatinine ratios. 
Endpoints 
• Change from baseline in spot urinary oxalate:creatinine ratios 
Sections also reflecting this change:   
• Table 1:  Schedule of Assessments; spot urine assessments were removed from all study visits. 
• Section 6.2.3, Spot Urinary Oxalate:Creatinine Ratios (removed) 
Purpose:  Removed all patient-reported outcomes, including Brief Pain Inventory Short Form and Wisconsin Stone Quality of Life.  
The primary change occurs in Section 2, Objectives and Endpoints. 
Removed text:   
Objectives  
• To assess the impact of kidney stone events on patient-reported pain and quality of life (QoL). 
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Endpoints 
• Patient-reported severity and symptomatic and functional impact of kidney stone events 
Sections also reflecting this change:   
• Table 1:  Schedule of Assessments; patient reported outcomes were removed from all study visits. 
• Section 6.7, Quality of Life Outcomes (removed) 
Purpose:  Clarify language describing stratification to align with the study SAP. 
The primary change occurs in Section 3.1, Summary of Study Design. 
Revised text:  Stratification will be performed at randomization according to mean baseline urinary oxalate level (≤1.25 × ULN vs 
>1.25 × ULN) from the mean of the first 2 valid 24-hour urine collections and the number of historical kidney stone events in the 
12 months prior to screening (≤1 vs >1), as discussed in Section 3.4. 
Sections also reflecting this change:   
• Protocol Synopsis 
• Section 3.4, Method of Assigning Patients to Treatment Groups 
Purpose:  Clarify language describing stratification to align with changes to Inclusion Criterion 2. 
The change occurs in Section 3.4, Method of Assigning Patients to Treatment Groups. 
Revised text:   
For stratification, athe number of historical kidney stone event isevents occurring in the 12 months prior to screening are 
considered, and defined as:  
• the visible passage of a kidney stone 
• a procedural intervention for removal of an asymptomatic or symptomatic stone  
− if more than 1 stone was removed in a given procedure, this counts as 1 event unless bilateral ureteral stones were 
removed, in which case this counts as 2 events 
− if more than 1 procedure was required to remove a single stone, this counts as 1 event 
• a new (≥1 mm) or enlarged (by ≥2 mm) kidney stone on CT imaging 
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 it must be evident from the CT scans that the new or enlarged kidney stone event occurred during the 12 months prior 
to screening 
− if a procedure was performed to remove the stone(s) identified by CT, then only the procedure will be counted to avoid 
double-counting the same stone. 
Purpose:  Clarify blinding language. 
The changes occur in Section 3.5, Blinding. 
Revised text:  All siteSite personnel and patients will be blinded to study drug treatment; site personnel preparing study drug may 
be unblinded to study drug treatment only where required by documented institutional procedure. 
… 
All site personnel will be blinded to central laboratory results of oxalate, calcium oxalate supersaturation, and glycolate from after the 
time of the first dose until unblinding.   
Purpose:  Expand Inclusion Criterion 2 to allow ≥2 stone events with a minimum of 1 stone required in the 5 years prior to screening. 
The primary change occurs in Section 4.1, Inclusion Criteria. 
Revised text:  
2. Recurrent kidney stone disease, defined as ≥2 stone events, with a minimum of 1 stone event within the 5 years prior to 
screening.  For inclusion, a historical kidney stone event is defined as:  
• the visible passage of a kidney stone 
• a procedural intervention for removal of an asymptomatic or symptomatic stone  
− if more than 1 stone was removed in a given procedure, this counts as 1 event unless bilateral ureteral stones were 
removed, in which case this counts as 2 events 
− if more than 1 procedure was required to remove a single stone, this counts as 1 event 
• a new (≥1 mm) or enlarged (by ≥2 mm) kidney stone on CT imaging 
 it must be evident from the CT scans that the new or enlarged kidney stone event occurred during 5 years prior to 
screening 
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− if a procedure was performed to remove the stone(s) identified by CT, then only the procedure will be counted to avoid 
double-counting the same stone. 
Section also reflecting this change:   
• Protocol Synopsis 
Purpose:  Clarify the ULN for 24-hour urinary oxalate. 
The change occurs in Section 4.1, Inclusion Criteria. 
Revised text:  4. 24-hour urinary oxalate levels from 2 valid 24-hour urine collections obtained during screening are >ULN. (ULN = 
40 mg/24 hours). 
Purpose:  Clarify that BMI in Inclusion Criterion 7 is at screening. 
The change occurs in Section 4.1, Inclusion Criteria. 
Revised text:  7. Body mass index (the weight in kilograms divided by the square of the height in meters) at screening of 20 to 
<40 kg/m2. 
Purpose:  Remove eDiary modality. 
The primary change occurs in Section 5.6.3, Dietary Restrictions. 
Revised text:  Dietary adherence will be collected electronically in an eDiaryin a patient diary at the time points listed in the 
Schedule of Assessments (Table 1).  Refer to the Study Manual for more information. 
Purpose:  Remove electronic ICF option. 
The primary change occurs in Section 6.1, Screening Assessments. 
Revised text:  An ICF that has been approved by the appropriate Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) must be signed (in paper or electronic format per local regulations and institutional standards) by the patient before the 
screening procedures are initiated.  All patients will be given a signed and dated version of their ICF. 
Sections also reflecting this change:   
• Section 8.1.1, Informed Consent 
Purpose:  Remove validity requirement for 24-hour urine sample prior to dosing and clarify patient procedures for providing samples. 
The change occurs in Section 6.2.1, 24-Hour Urine Collection and Table 4:  24-hour Urine Collection Procedure by Study Visit. 
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Revised text:  2 valid collections prior to dosing unless variability criterion is not met (Section 6.2.1.2), in which case 3 valid collections are requiredan 
additional collection is requireda 
a  The additional collection is not required to be valid in order to proceed with dosing, but will be tested to confirm validity for the calculation of 
baseline 24-hour urinary oxalate. 
ab  A supervised collection is defined, at a minimum, as contact from study staff to the patient the day prior to the collection start and the day the collection will 
finish to ensure compliance; this may be conducted remotely.  Any or all of the 24-hour urine collections may be conducted supervised.  If 24-hour urine 
collection is not a supervised collection, or if a collection is supervised remotely, patients may either bring it to the clinic or have it couriered to the designated 
laboratory.clinic 
Section also reflecting this change:   
• Table 1:  Schedule of Assessments 
Purpose:  Clarify language regarding the collection of additional 24-hour urine samples. 
The change occurs in Section 6.2.1.2, Variability Criterion for 24-hour Urine Collections at Screening 
Revised text:  If the variability is >20%, then a third validan additional 24-hour urine collection should be obtained.  The result of the 
thirdadditional sample will not impact the patient’s eligibility for the study.  
Purpose:  Removed all exploratory blood and urine samples including exploratory DNA assessments. 
The primary change occurs in Section 6.3, Pharmacodynamic Assessments. 
Revised text:  Urine and blood samples will be collected for assessment of PD parameters (plasma oxalate, and plasma glycolate, and 
urinary glycolate) at the time points specified in the Schedule of Assessments (Table 1).  Urine samples for exploratory analysis will 
be aliquoted from the samples provided for PD analysis.  On dosing days, all blood and urine samples will be collected prior to study 
drug administration. 
Sections also reflecting this change:   
• Table 1:  Schedule of Assessments  
• Section 6.6, Biomarkers, Exploratory DNA Genotyping, and Biospecimen Repository (removed) 
Purpose:  Remove urinalysis from clinical laboratory assessments. 
The change occurs in Section 6.5.4, Clinical Laboratory Assessments and Table 5:  Clinical Laboratory Assessments. 
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Removed text:  Urinalysis, Visual inspection for appearance and color, Bilirubin, pH (dipstick), Nitrite, Specific gravity RBCs, 
Ketones, Urobilinogen, Albumin, Leukocytes, Glucose, Microscopy (if clinically indicated), Protein 
Purpose:  Clarify blinding language. 
The primary change occurs in Section 7, Statistics. 
Revised text:  A Statistical Analysis Plan (SAP) will be finalized before database lock and study unblinding for the primary analysis.  
The plan will detail the implementation of the statistical analyses in accordance with the principal features stated in the protocol. 
Section also reflecting this change:   
• Section 7.2.11, Interim Analysis 
Purpose:  Added Plasma Oxalate Analysis Set in alignment with the study SAP; clarified language for the Safety Analysis Set. 
The primary changes occur in Section 7.2.1, Populations to be Analyzed. 
Revised text:   
• Plasma Oxalate Analysis Set:  All patients who received at least 1 dose of study drug and have a baseline plasma 
oxalate level ≥1.5 times the lower limit of quantification/detection. 
• Safety Analysis Set:  All randomized patients who received at least 1 dose of study drug.  Patients in the Safety Analysis 
Set will be analyzed according to the treatment actually received. 
Sections also reflecting these changes:   
• Protocol Synopsis 
• Section 7.2.6, Pharmacodynamic Analysis 
Purpose:  Clarified language from MMRM model in alignment with the study SAP. 
The primary change occurs in Section 7.2.5, Efficacy Analyses. 
Revised text:  The model includes baseline value24-hour urinary oxalate and the stratification factor of number of historical kidney 
stone events (>1 versus ≤1 event in the 12 months prior to screening) as covariates, and fixed effect terms including treatment arm, 
visit and visit and treatment arm interaction.   
Purpose:  Remove 4 hour PK timepoint and clarify predose PK timepoint. 
The change occurs in Table 2:  Pharmacokinetic Time Points. 
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Purpose:  Correct the provided formula for 2009 CKD-EPI equation for eGFR calculation. 
The change occurs in Appendix 10.1, Formula for Estimated Glomerular Filtration Rate Calculation. 
Revised text:   
CKD-EPI (Source:  Chronic Kidney Disease Epidemiology Collaboration).  (CKD-EPI); Levey AS, Stevens LA, Schmid CH, et al. 
A new equation to estimate glomerular filtration rate.  Ann Intern Med. 2009 May 5;150(9):604-12612. 
• Conventional units 
• eGFR (mL/= 141 × min/(Scr/κ, 1.73m2) = 175 × (SCr [mg/dL]) )α × max(Scr/κ, 1.154 × (age) )-1.209 × 0.203 × (0.742, 993Age × 
1.018 [if female),] × 1.159 [if Black or × (1.212, if African American)] 
• SI units 
 eGFR (mL/min/1.73m2) = 175 × (SCr [μmol/L]/88.4) 1.154 × (age) 0.203 × (0.742, if female), or × (1.212, if African 
American) 
where: 
− Scr is serum creatinine in mg/dL 
− κ = 0.7 (females) or 0.9 (males) 
− α = -0.329 (female) or -0.411 (male) 
− min(Scr/κ, 1) is the minimum of Scr/κ or 1.0 
− max(Scr/κ, 1) is the maximum of Scr/κ or 1.0 
− Age (years) 
 
Abbreviations:  eGFR= Estimated glomerular filtration rate; SCr=serum creatinine; SI=International System of Units 
Administrative changes and corrections to typographical errors, punctuation, grammar, abbreviations, and formatting are not listed 
individually. 
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INVESTIGATOR’S AGREEMENT 
 
I have read the ALN-GO1-008 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 
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PROTOCOL SYNOPSIS 
Protocol Title 
A Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy, Safety, 
Pharmacodynamics, and Pharmacokinetics of Lumasiran in Patients with Recurrent Calcium 
Oxalate Kidney Stone Disease and Elevated Urinary Oxalate Levels 
Short Title 
A Study to Evaluate Lumasiran in Adults with Recurrent Calcium Oxalate Kidney Stone Disease 
and Elevated Urinary Oxalate Levels 
Study Drug 
Lumasiran (ALN-GO1) 
Phase 
Phase 2 
Study Centers 
The study will be conducted at approximately 25 clinical study centers across Europe and the 
United States. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
• 
To evaluate the effect of lumasiran on the 
percent change in urinary oxalate 
excretion 
• 
Percent change in 24-hour urinary oxalate 
from baseline to Month 6 (average across 
Months 4 through 6) 
Secondary 
 
• 
To evaluate the percentage of patients 
who achieve a ≥20% reduction in 24-hour 
urinary oxalate with lumasiran 
• 
Percentage of patients who achieve a 
≥20% reduction in 24-hour urinary 
oxalate from baseline to Month 6 (average 
across Months 4 through 6) 
• 
To evaluate the effect of lumasiran on 
urinary calcium oxalate supersaturation 
• 
Percent change in urinary calcium oxalate 
supersaturation from baseline to Month 6 
(average across Months 4 through 6) 
Exploratory 
 
• 
To evaluate the effect of lumasiran on 
absolute levels of urinary oxalate 
excretion 
• 
Absolute change in 24-hour urinary 
oxalate from baseline to Month 6 (average 
across Months 4 through 6) 
• 
To evaluate the effect of lumasiran on the 
occurrence of kidney stones 
• 
Incidence rate of clinical and radiographic 
kidney stone events  
• 
Time to first kidney stone event 
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Objectives 
Endpoints 
• 
To evaluate additional pharmacodynamic 
(PD) parameters of plasma oxalate, 
plasma glycolate, and urinary glycolate 
• 
Change from baseline in plasma oxalate 
• 
Change from baseline in plasma glycolate 
• 
Change from baseline in urinary glycolate 
• 
To characterize the pharmacokinetics 
(PK) of lumasiran 
• 
Plasma PK of lumasiran 
• 
To assess for antidrug antibodies (ADA) 
against lumasiran 
• 
ADA frequency and titer 
• 
To evaluate the effect of lumasiran on 
spot urinary oxalate:creatinine ratios 
• 
Change from baseline in spot urinary 
oxalate:creatinine ratios 
• 
To evaluate the effect of lumasiran on 
maintaining 24-hour urinary oxalate 
≤upper limit of normal (ULN) over time 
• 
Percentage of patients with 24-hour 
urinary oxalate ≤ULN over time 
• 
To evaluate the effect of lumasiran on 
maintaining a 25% reduction in urinary 
calcium oxalate supersaturation over time 
• 
Percentage of patients having a 25% 
reduction in urinary calcium oxalate 
supersaturation over time 
• 
To evaluate the effect of lumasiran on 
24-hour urinary oxalate excretion after 
Month 6 
• 
Change from baseline in 24-hour urinary 
oxalate excretion after Month 6 
• 
To evaluate the effect of lumasiran on 
estimated glomerular filtration rate 
(eGFR) 
• 
Change from baseline in eGFR 
• 
To evaluate the effect of lumasiran on 
patient healthcare resource utilization 
• 
Kidney stone event related 
hospitalizations, emergency room visits, 
unscheduled office visits, or procedures  
• 
To assess the impact of kidney stone 
events on patient-reported pain and 
quality of life (QoL) 
• 
Patient-reported severity and symptomatic 
and functional impact of kidney stone 
events 
Safety 
 
• 
To evaluate the safety and tolerability of 
lumasiran 
• 
Frequency of adverse events (AEs) 
Study Design 
This is a randomized, placebo-controlled, double-blind, multi-center, multinational, Phase 2 
study to evaluate the efficacy, safety, PD, and PK of lumasiran administered subcutaneously 
(SC) in patients with recurrent calcium oxalate kidney stone disease and elevated urinary oxalate 
levels (Figure 1). 
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Consented patients meeting all eligibility criteria will be randomized 1:1:1 to receive study drug:  
lumasiran 567 mg, lumasiran 284 mg, or placebo.  Stratification will be performed at 
randomization according to mean baseline urinary oxalate level and the number of kidney stone 
events in the 12 months prior to screening. 
Number of Planned Patients 
The planned enrollment for this study is 120 patients. 
Diagnosis and Main Eligibility Criteria 
This study will include adults (≥18 years of age) with a documented diagnosis of recurrent 
kidney stone disease based on ≥2 stone events within 5 years prior to screening.  A historical 
clinical kidney stone event is defined as: 
• the visible passage of a kidney stone 
• a procedural intervention for removal of an asymptomatic or symptomatic stone  
− if more than 1 stone was removed in a given procedure, this counts as 1 event 
unless bilateral ureteral stones were removed, in which case this counts as 
2 events  
− if more than 1 procedure was required to remove a single stone, this counts as 
1 event 
• a new (≥1 mm) or enlarged (by ≥2 mm) kidney stone on computed tomography (CT) 
imaging 
− it must be evident from the CT scans that the new or enlarged kidney stone event 
occurred during the 5 years prior to screening 
− if a procedure was performed to remove the stone(s) identified by CT, then only 
the procedure will be counted to avoid double-counting the same stone. 
Study Drug, Dose, and Mode of Administration 
Lumasiran (ALN-GO1) is a SC administered N-acetylgalactosamine (GalNAc)-conjugated small 
interfering RNA (siRNA) targeting liver-expressed hydroxyacid oxidase (HAO1) messenger 
RNA (mRNA) for reduction of hepatic oxalate production. 
Lumasiran will be administered by SC injection at a dose of 284 mg or 567 mg on Day 1, 
Month 3, and Month 9. 
Reference Treatment, Dose, and Mode of Administration 
Placebo (sodium chloride 0.9% w/v for SC administration) will be administered at the same 
dosing interval as lumasiran. 
Duration of Treatment and Study Participation 
The duration of treatment with study drug is up to 15 months.  The estimated total time on study 
for each patient is up to 17 months, including up to 2 months of screening. 
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Statistical Methods 
The study is powered to detect a difference in urinary oxalate excretion between each lumasiran 
group and the placebo group.  Assuming a standard deviation of 45% in the percent change from 
baseline in 24-hour urinary oxalate levels at Month 6, a sample size of 40 patients per group will 
enable a power of at least 80% in detecting a treatment difference of 30% between the treatment 
groups at a 2-sided significance level of 0.05. 
The populations (analysis sets) are defined as follows: 
• Full Analysis Set (FAS):  All randomized patients who received at least 1 dose of 
study drug.  Patients in the FAS will be analyzed according to the randomized 
treatment arm. 
• Safety Analysis Set:  All randomized patients who received at least 1 dose of study 
drug.  Patients in the Safety Analysis Set will be analyzed according to the treatment 
actually received. 
• PK Analysis Set:  All patients who received at least 1 full dose of study drug and 
have at least one postdose blood sample for PK parameters and have evaluable PK 
data. 
The primary efficacy endpoint will be analyzed in the FAS using a mixed-effect model for 
repeated measures (MMRM) approach.  The primary comparison is percent change from 
baseline in urinary oxalate through Month 6. 
Safety data will be summarized descriptively. 
Figure 1: 
Study Design 
LUMASIRAN 567 m  SC N=40)
LUMASIRAN 284 mg SC (N=40)
Safety Follow-up (patients who 
discontinue treatment)
Screening
(Day -60 to -1)
15-Month Double-Blind Treatment Period
6-Month Primary Analysis Period
Randomization (1:1:1)
PLACEBO (N=40)
LUMASIRAN 567 mg SC (N=40)
LUMASIRAN 284 mg SC (N=40)
PLACEBO (N=40)
9-Month Treatment Extension Period
 
Abbreviations:  SC=subcutaneous(ly) 
 
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Abbreviations:  BPI=Brief Pain Inventory; CT=computed tomography; D/C=discontinue; DNA=deoxyribonucleic acid; ET=early termination; EOS=end of 
study; EOT=end of treatment; M=month; PD=pharmacodynamic; PK=pharmacokinetic; WISQOL=Wisconsin Stone Quality of Life Questionnaire; 
WOCBP=women of child-bearing potential 
Notes:  
• 
When scheduled at the same time points, assessments of vital signs should be performed before physical examinations and blood sample collections, where 
feasible. 
• 
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 (refer to Section 4.3.1). 
• 
White columns indicate visits to the clinical study center; gray-shaded columns indicate study visits that may be conducted by a home healthcare 
professional, where applicable country and local regulations and infrastructure allow (at the discretion and with oversight of the Investigator, based on 
safety and tolerability), provided (for dosing visits) that 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 symptom-directed 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, kidney stone events, and adverse events.  
Footnotes: 
a All assessments are required to be performed prior to dosing at dosing visits, except for the CT scan and PK sample collection. 
b Inclusion/exclusion criteria should be verified prior to randomization.  Laboratory assessments conducted to confirm study eligibility will not be repeated unless 
the time between screening and randomization exceeds 4 weeks. 
c Samples for exploratory analysis will only be collected at these visits and will be aliquoted from the samples provided for PD analysis. 
d Pregnancy test results must be known prior to dosing, if applicable. 
e May be performed after dosing, if required. 
 
 
 
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Table 2: 
Pharmacokinetic Time Points 
Study Day 
Sampling Time 
(hh:mm) 
Blood PK Sample 
Day 1 
02:00 (±20 min) 
X 
04:00 (±30 min) 
X 
Abbreviations:  hh:mm=hour:minute; PK=pharmacokinetics 
Notes:  
• 
The hour (±range) indicates sample collection timing relative to dosing.  Precise PK sample times (hour 
and minute) are recorded.  Refer to 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 ...............................................................................................................14 
LIST OF TABLES .........................................................................................................................17 
LIST OF FIGURES .......................................................................................................................18 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................19 
1. 
INTRODUCTION ......................................................................................................21 
1.1. 
Study Rationale ...........................................................................................................21 
1.2. 
Background .................................................................................................................21 
1.3. 
Benefit-Risk Assessment ............................................................................................22 
2. 
OBJECTIVES AND ENDPOINTS ............................................................................24 
3. 
INVESTIGATIONAL PLAN .....................................................................................25 
3.1. 
Summary of Study Design ..........................................................................................25 
3.2. 
Scientific Rationale for Study Design ........................................................................26 
3.3. 
Justification for Dose ..................................................................................................26 
3.4. 
Method of Assigning Patients to Treatment Groups ..................................................27 
3.5. 
Blinding ......................................................................................................................27 
3.5.1. 
Emergency Unblinding ...............................................................................................28 
3.6. 
Safety Review .............................................................................................................28 
3.7. 
Definition of End of Study for an Individual Patient .................................................28 
4. 
SELECTION AND REMOVAL OF PATIENTS ......................................................29 
4.1. 
Inclusion Criteria ........................................................................................................29 
4.2. 
Exclusion Criteria .......................................................................................................30 
4.3. 
Removal from Study Drug or Assessment .................................................................31 
4.3.1. 
Discontinuation of Study Drug or Declining Procedural Assessments ......................31 
4.3.2. 
Stopping a Patient’s Study Participation ....................................................................32 
4.3.2.1. 
Patient Stops Participation in the Study ......................................................................32 
4.3.2.2. 
Withdrawal of Consent to Process the Patient’s Personal Data or Objection 
to Process Patient’s Personal Data ..............................................................................33 
4.3.2.3. 
Investigator or Sponsor Stops Participation of a Patient in the Study ........................33 
4.3.2.4. 
Recording Reason for Stopping a Patient’s Study Participation ................................33 
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4.3.3. 
Lost to Follow-Up.......................................................................................................33 
4.3.4. 
Replacement of Study Patients ...................................................................................34 
5. 
TREATMENTS AND OTHER REQUIREMENTS ..................................................34 
5.1. 
Treatments Administered ............................................................................................34 
5.2. 
Study Drug ..................................................................................................................34 
5.2.1. 
Description ..................................................................................................................34 
5.2.2. 
Dose and Administration ............................................................................................34 
5.2.3. 
Dose Modifications .....................................................................................................35 
5.2.3.1. 
LFT Criteria for Withholding, Monitoring, and Stopping Study Drug Dosing..........35 
5.2.4. 
Preparation, Handling, and Storage ............................................................................37 
5.2.5. 
Packaging and Labeling ..............................................................................................37 
5.2.6. 
Accountability .............................................................................................................37 
5.3. 
Clinical Product Complaints .......................................................................................37 
5.3.1. 
Definition ....................................................................................................................37 
5.3.2. 
Reporting ....................................................................................................................38 
5.4. 
Concomitant Medications and Procedures .................................................................38 
5.5. 
Treatment Compliance ................................................................................................38 
5.6. 
Other Requirements ....................................................................................................38 
5.6.1. 
Contraception ..............................................................................................................38 
5.6.2. 
Alcohol Restrictions ...................................................................................................39 
5.6.3. 
Dietary Restrictions ....................................................................................................39 
6. 
STUDY ASSESSMENTS ..........................................................................................40 
6.1. 
Screening Assessments ...............................................................................................40 
6.1.1. 
DNA Sample ...............................................................................................................40 
6.1.2. 
Retesting .....................................................................................................................40 
6.1.3. 
Rescreening .................................................................................................................40 
6.2. 
Efficacy Assessments .................................................................................................41 
6.2.1. 
24-Hour Urine Collections .........................................................................................41 
6.2.1.1. 
Validity Criteria for 24-hour Urine Collections .........................................................42 
6.2.1.2. 
Variability Criterion for 24-hour Urine Collections at Screening ..............................42 
6.2.2. 
Kidney Stone Events ...................................................................................................42 
6.2.2.1. 
Clinical ........................................................................................................................42 
6.2.2.2. 
Radiographic ...............................................................................................................43 
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6.2.3. 
Spot Urinary Oxalate:Creatinine Ratios .....................................................................43 
6.2.4. 
Estimated Glomerular Filtration Rate .........................................................................43 
6.3. 
Pharmacodynamic Assessments .................................................................................43 
6.4. 
Pharmacokinetic Assessments ....................................................................................43 
6.5. 
Safety Assessments .....................................................................................................44 
6.5.1. 
Vital Signs ..................................................................................................................44 
6.5.2. 
Height and Weight ......................................................................................................44 
6.5.3. 
Physical Examination .................................................................................................44 
6.5.4. 
Clinical Laboratory Assessments ...............................................................................45 
6.5.4.1. 
Immunogenicity ..........................................................................................................46 
6.5.4.2. 
Pregnancy Testing ......................................................................................................47 
6.5.4.3. 
Additional Liver Function Assessments .....................................................................47 
6.5.5. 
Adverse Events ...........................................................................................................49 
6.5.5.1. 
Definitions ..................................................................................................................49 
6.5.5.2. 
Eliciting and Recording Adverse Events ....................................................................50 
6.5.5.3. 
Reporting Adverse Events of Clinical Interest to Sponsor/Designee .........................51 
6.5.5.4. 
Serious Adverse Events Require Immediate Reporting to Sponsor/Designee ...........51 
6.5.5.5. 
Sponsor Safety Reporting to Regulatory Authorities .................................................52 
6.5.5.6. 
Serious Adverse Event Notification to the Institutional Review 
Board/Independent Ethics Committee ........................................................................52 
6.5.5.7. 
Pregnancy Reporting ..................................................................................................52 
6.5.5.8. 
Reporting of Overdose and Other Special Situations .................................................53 
6.6. 
Biomarkers, Exploratory DNA Genotyping, and Biospecimen Repository ...............53 
6.7. 
Quality of Life Outcomes ...........................................................................................54 
6.7.1. 
Pain Assessment .........................................................................................................54 
6.7.2. 
Wisconsin Stone Quality of Life Questionnaire .........................................................54 
6.8. 
Healthcare Utilization .................................................................................................54 
7. 
STATISTICS ..............................................................................................................55 
7.1. 
Determination of Sample Size ....................................................................................55 
7.2. 
Statistical Methodology ..............................................................................................55 
7.2.1. 
Populations to be Analyzed ........................................................................................55 
7.2.2. 
Examination of Subgroups .........................................................................................56 
7.2.3. 
Handling of Missing Data ...........................................................................................56 
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7.2.4. 
Baseline Evaluations ...................................................................................................56 
7.2.5. 
Efficacy Analyses .......................................................................................................56 
7.2.6. 
Pharmacodynamic Analysis........................................................................................56 
7.2.7. 
Pharmacokinetic Analysis ..........................................................................................57 
7.2.8. 
Safety Analyses ..........................................................................................................57 
7.2.9. 
Immunogenicity Analyses ..........................................................................................57 
7.2.10. 
Other Analyses ............................................................................................................57 
7.2.11. 
Interim Analysis ..........................................................................................................57 
7.2.12. 
Optional Additional Research .....................................................................................57 
8. 
STUDY ADMINISTRATION ...................................................................................58 
8.1. 
Ethical and Regulatory Considerations ......................................................................58 
8.1.1. 
Informed Consent .......................................................................................................58 
8.1.2. 
Ethical Review ............................................................................................................58 
8.1.3. 
Serious Breach of Protocol .........................................................................................59 
8.1.4. 
Study Documentation, Confidentiality, and Records Retention .................................59 
8.1.5. 
End of Study ...............................................................................................................59 
8.1.6. 
Termination of the Clinical Study or Site Closure .....................................................59 
8.2. 
Data Quality Control and Quality Assurance .............................................................60 
8.2.1. 
Data Handling .............................................................................................................60 
8.2.2. 
Study Monitoring ........................................................................................................60 
8.2.3. 
Audits and Inspections ................................................................................................61 
8.3. 
Publication Policy .......................................................................................................61 
9. 
LIST OF REFERENCES ............................................................................................62 
10. 
APPENDICES ............................................................................................................63 
10.1. 
Formula for Estimated Glomerular Filtration Rate Calculation .................................63 
 
LIST OF TABLES 
Table 1: 
Schedule of Assessments ..............................................................................................8 
Table 2: 
Pharmacokinetic Time Points .....................................................................................13 
Table 3: 
Monitoring and Dosing Rules for Asymptomatic Patients with Confirmed 
Isolated Elevations of ALT and/or AST >3× ULN, with No Alternative 
Cause Identified ..........................................................................................................36 
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Table 4: 
24-hour Urine Collection Procedure by Study Visit...................................................41 
Table 5: 
Clinical Laboratory Assessments ...............................................................................46 
Table 6: 
Hepatic Assessments in Patients Who Experience Elevated Transaminases .............48 
Table 7: 
Sample Size Power Calculations ................................................................................55 
 
LIST OF FIGURES 
Figure 1: 
Study Design .................................................................................................................7 
Figure 2: 
Summary of Endogenous Oxalate Synthesis ..............................................................23 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation  
Definition 
ADA 
Antidrug antibody 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical Classification System 
CKD 
Chronic kidney disease 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
Cmax 
Maximum plasma concentration 
CPC 
Clinical product complaint 
CT 
Computed tomography 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
EOS 
End of study 
ESKD 
End stage kidney disease 
ET 
Early termination 
FAS 
Full analysis set 
GalNAc 
N-acetylgalactosamine 
GCP 
Good Clinical Practice 
GO 
Glycolate oxidase 
HAO1 
Hydroxyacid oxidase 1  
HED 
Human equivalent dose 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug (application) 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ISR 
Injection site reaction 
LFT 
Liver function test 
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MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-effect model for repeated measures 
mRNA 
Messenger ribonucleic acid 
PD 
Pharmacodynamics 
PH1/2/3 
Primary hyperoxaluria type 1/2/3 
PK 
Pharmacokinetic 
PT 
Preferred term 
QoL 
Quality of life 
RNAi 
Ribonucleic acid interference 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SOC 
System Organ Class 
tmax 
Time to maximum plasma concentration 
ULN 
Upper limit of normal 
WHO 
World Health Organization 
WISQOL 
Wisconsin Stone Quality of Life Questionnaire 
 
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1. 
INTRODUCTION 
Alnylam Pharmaceuticals, Inc. (the Sponsor) has developed 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) messenger ribonucleic acid (mRNA), 
blocking production of glycolate oxidase (GO) and hence reducing hepatic oxalate production. 
Lumasiran is approved for the treatment of primary hyperoxaluria type 1 (PH1) in both pediatric 
and adult patients in the United States (23 November 2020) and in the European Union (19 
November 2020).  Based on lumasiran’s mechanism of action, and demonstrated reduction of 
hepatic oxalate production in patients with PH1, the Sponsor is investigating whether treatment 
with lumasiran is effective for patients with recurrent calcium oxalate kidney stone disease who 
have elevated urinary oxalate levels but have not been diagnosed with PH1 or one of the other 
primary hyperoxalurias. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of lumasiran is 
provided in the Investigator’s Brochure. 
1.1. 
Study Rationale 
Study ALN-GO1-008 is a randomized, double-blind, placebo-controlled, multi-center Phase 2 
study designed to evaluate the efficacy, safety, pharmacodynamics (PD), and pharmacokinetics 
(PK) of lumasiran, administered subcutaneously (SC), in adult patients with recurrent calcium 
oxalate kidney stone disease. 
The primary objective of the study is to evaluate the effect of lumasiran on the percent change in 
urinary oxalate excretion in patients with recurrent calcium oxalate kidney stones.  Secondary 
and exploratory objectives of the study include the evaluation of the effect of lumasiran on 
urinary calcium oxalate supersaturation, the occurrence of kidney stones, the PD effect of 
lumasiran on plasma oxalate, plasma glycolate and urinary glycolate, and the characterization of 
plasma PK. 
The full rationale for the study and design is presented in Section 3.2. 
1.2. 
Background 
Kidney stones are common, affecting approximately 1 in 11 people in the United States, and the 
prevalence of kidney stone disease has been increasing worldwide over time.[Scales 2012]  
Approximately 80% of kidney stones in adults are formed from calcium oxalate crystals, with 
the remainder being predominantly calcium phosphate, uric acid, cystine, or struvite.[Worcester 
and Coe 2008; Worcester and Coe 2010]  Stone formation occurs when a supersaturating level of 
calcium oxalate is present in the urine (Figure 2).  High levels of urinary oxalate may be derived 
from both endogenous synthesis and diet.  
Kidney stones can develop in patients of all ages; however, the highest incidence rates occur in 
individuals aged 40 to 66 years.[Shin 2018]  There is significant clinical burden associated with 
the development of kidney stones for patients with recurrent calcium oxalate kidney stone 
disease, including pain, infection/sepsis, diagnostic and therapeutic procedures, hospitalizations, 
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and a greater risk for developing chronic kidney disease (CKD) and end stage kidney disease 
(ESKD). 
The typical clinical presentation of kidney stones includes sudden onset of lumbar flank pain and 
hematuria, and may include nausea and vomiting.  Evaluation to assess etiology includes 
assessment of the patient’s medical history, medication use, and dietary and lifestyle risk factors.  
Confirmation of diagnosis may involve renal ultrasound, abdominal x-ray, and/or computed 
tomography (CT).[Heilberg and Schor 2006]  24-hour urine collections analyzed for total 
volume, calcium, oxalate, uric acid, citrate, and other analytes may help to determine the 
underlying etiology.[Pearle 2014]  Stone composition is generally determined in at least one 
instance. 
There are limited effective treatment options for patients with recurrent calcium oxalate kidney 
stone disease.  Preventive measures in American and European guidelines recommend adequate 
fluid intake to ensure a urine volume of at least 2 to 2.5 liters daily and provide dietary advice to 
limit the consumption of oxalate-rich foods, sodium chloride, and animal protein content, while 
maintaining a normal calcium intake.  In some situations, thiazide diuretics, potassium citrate, 
and/or allopurinol may be considered.[Pearle 2014; Türk 2021] 
Treatment of pain associated with kidney stone events may involve non-steroidal 
anti-inflammatory agents and/or opiate pain medications.  Depending on the clinical context, 
medical expulsive therapy, extracorporeal shock-wave lithotripsy, ureteroscopy, stenting, and 
percutaneous nephrolithotomy are some of the treatment options that may be pursued.[Türk 
2021] 
Lumasiran is a ribonucleic acid interference (RNAi) therapeutic designed to reduce hepatic 
oxalate production.  Oxalate produced by the liver is largely excreted in the urine, and lumasiran 
has been shown to reduce urinary oxalate in patients with PH1.  High levels of urinary oxalate 
increase the risk of stone formation; therefore, lumasiran may have efficacy in patients with 
recurrent calcium oxalate kidney stone disease who do not have PH1 but who produce high 
amounts of oxalate endogenously. 
1.3. 
Benefit-Risk Assessment 
Calcium oxalate stone formation occurs when a supersaturating level of calcium oxalate is 
present in the urine, with increasing risk of stone formation as urine oxalate levels 
increase.[Curhan and Taylor 2008]  More than half of oxalate is endogenous in origin and 
presumed to come largely from the liver.[Mitchell 2018]  Studies have shown that reduced 
calcium oxalate supersaturation and urinary oxalate levels are associated with reduced stone 
formation.[Borghi 2002; Ferraro 2018; Prochaska 2018] 
For patients with recurrent calcium oxalate stone formation, multiple stone removal procedures 
may be required.  These procedures are invasive and place the patient at risk of complications 
including bleeding and infection.  Patients experiencing obstructive kidney stones can also 
experience acute kidney injury with permanent loss of renal function.  As a result, patients with 
recurrent kidney stone formation have a higher risk of progression to CKD and ESKD.[Dhondup 
2018; Rule 2009] 
Lumasiran, approved in the United States and European Union for the treatment of PH1, is 
designed to reduce hepatic production of oxalate.  Based on the available data from clinical and 
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nonclinical studies, lumasiran, administered SC, demonstrated a potent, dose-dependent 
inhibition of GO resulting in decreased urinary and plasma oxalate and increased plasma and 
urinary glycolate.  Lumasiran may be effective in lowering urinary oxalate levels in patients with 
recurrent calcium oxalate kidney stone disease (Figure 2).  No adverse effects of elevated 
glycolate have been reported.  Unlike oxalate, glycolate is highly soluble and readily excreted in 
the urine. 
Figure 2: 
Summary of Endogenous Oxalate Synthesis 
 
Abbreviations:  GO=glycolate oxidase 
Lumasiran has been well tolerated with an acceptable safety profile in studies with healthy 
volunteers and patients with PH1.  Most adverse events (AEs) have been mild or moderate in 
severity.  Transient, mild injection site reactions (ISRs) have been observed.  No clinically 
significant laboratory changes related to lumasiran 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 hepatic effects.  The study has specific 
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 (LFTs).  As the risk of embryofetal toxicity in humans is currently unknown, 
females who are of 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 5.6.1). 
Based on the available efficacy and safety data from clinical and nonclinical studies, the benefit-
risk assessment supports the evaluation of lumasiran in a Phase 2 study in patients with recurrent 
calcium oxalate kidney stone disease. 
Detailed information about the known and expected benefits and risks of lumasiran are provided 
in the Investigator’s Brochure. 
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2. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
 
• 
To evaluate the effect of lumasiran on the 
percent change in urinary oxalate 
excretion 
• 
Percent change in 24-hour urinary oxalate 
from baseline to Month 6 (average across 
Months 4 through 6) 
Secondary 
 
• 
To evaluate the percentage of patients 
who achieve a ≥20% reduction in 24-hour 
urinary oxalate with lumasiran 
• 
Percentage of patients who achieve a 
≥20% reduction in 24-hour urinary 
oxalate from baseline to Month 6 (average 
across Months 4 through 6) 
• 
To evaluate the effect of lumasiran on 
urinary calcium oxalate supersaturation 
• 
Percent change in urinary calcium oxalate 
supersaturation from baseline to Month 6 
(average across Months 4 through 6) 
Exploratory 
 
• 
To evaluate the effect of lumasiran on 
absolute levels of urinary oxalate 
excretion 
• 
Absolute change in 24-hour urinary 
oxalate from baseline to Month 6 (average 
across Months 4 through 6) 
• 
To evaluate the effect of lumasiran on the 
occurrence of kidney stones 
• 
Incidence rate of clinical and radiographic 
kidney stone events  
• 
Time to first kidney stone event 
• 
To evaluate additional PD parameters of 
plasma oxalate, plasma glycolate, and 
urinary glycolate 
• 
Change from baseline in plasma oxalate 
• 
Change from baseline in plasma glycolate 
• 
Change from baseline in urinary glycolate 
• 
To characterize PK of lumasiran 
• 
Plasma PK of lumasiran 
• 
To assess for antidrug antibodies (ADA) 
against lumasiran 
• 
ADA frequency and titer 
• 
To evaluate the effect of lumasiran on 
spot urinary oxalate:creatinine ratios 
• 
Change from baseline in spot urinary 
oxalate:creatinine ratios 
• 
To evaluate the effect of lumasiran on 
maintaining 24-hour urinary oxalate 
≤upper limit of normal (ULN) over time 
• 
Percentage of patients with 24-hour 
urinary oxalate ≤ULN over time 
• 
To evaluate the effect of lumasiran on 
maintaining a 25% reduction in urinary 
calcium oxalate supersaturation over time 
• 
Percentage of patients having a 25% 
reduction in urinary calcium oxalate 
supersaturation over time 
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Objectives 
Endpoints 
• 
To evaluate the effect of lumasiran on 
24-hour urinary oxalate excretion after 
Month 6 
• 
Change from baseline in 24-hour urinary 
oxalate excretion after Month 6 
• 
To evaluate the effect of lumasiran on 
estimated glomerular filtration rate 
(eGFR) 
• 
Change from baseline in eGFR 
• 
To evaluate the effect of lumasiran on 
patient healthcare resource utilization 
• 
Kidney stone event related 
hospitalizations, emergency room visits, 
unscheduled office visits, or procedures  
• 
To assess the impact of kidney stone 
events on patient-reported pain and 
quality of life (QoL) 
• 
Patient-reported severity and symptomatic 
and functional impact of kidney stone 
events 
Safety 
 
• 
To evaluate the safety and tolerability of 
lumasiran 
• 
Frequency of AEs 
3. 
INVESTIGATIONAL PLAN 
3.1. 
Summary of Study Design 
This is a randomized, placebo-controlled, double-blind, multicenter, multinational, Phase 2 study 
to evaluate the efficacy, safety, PD, and PK of lumasiran administered SC in patients with 
recurrent calcium oxalate kidney stone disease and elevated urinary oxalate levels (Figure 1). 
The study will consist of up to 2 months of screening and 15 months of double-blind treatment (a 
6-month Primary Analysis Period followed by a 9-month Treatment Extension Period).  Patients 
will be screened from Day -60 to Day -1 to determine eligibility.  During screening, patients will 
provide at least two 24-hour urine collections to establish baseline urinary oxalate levels.  
Consented patients meeting all eligibility criteria will be randomized 1:1:1 to receive study drug:  
lumasiran 567 mg, lumasiran 284 mg, or placebo.  Stratification will be performed at 
randomization according to mean baseline urinary oxalate level and the number of kidney stone 
events in the 12 months prior to screening as discussed in Section 3.4. 
During the 6-month Primary Analysis Period, patients will be dosed on Day 1 (baseline) and at 
Month 3.  During the Treatment Extension Period, one additional dose will be administered at 
Month 9; an end of study (EOS) visit will take place at Month 15.  Study drug will be 
administered SC as specified in Section 5.2.2.  Patients will be assessed for efficacy, safety, PD, 
and PK according to the Schedule of Assessments (Table 1 and Table 2).  Efficacy assessments 
will include evaluation of urinary oxalate excretion, urinary calcium oxalate supersaturation, and 
kidney stone events (including clinical events and low-dose kidney-protocol CT).  Safety 
assessments will include collection of AEs, clinical laboratory tests, vital sign assessments, 
physical examinations, and concomitant medications. 
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Patients who discontinue study drug early will be asked to return for follow-up visits as 
described in Section 4.3.1. 
3.2. 
Scientific Rationale for Study Design 
The primary endpoint for this Phase 2 study is the percent change in 24-hour urinary oxalate 
excretion.  To confirm the optimal dosing regimen, and to facilitate the collection of kidney 
stone event data (an exploratory endpoint), the study will continue through Month 15.  A placebo 
comparator is included because there is no approved standard of care therapy to decrease urinary 
oxalate.  
A blood DNA sample will be collected as part of standard screening assessments (if testing has 
not already been performed) to ensure the exclusion of patients with primary hyperoxaluria 
type 1 (PH1), type 2 (PH2), and type 3 (PH3).  Lumasiran is approved in some countries for the 
treatment of PH1, and patients with PH2 and PH3 are not expected to respond to lumasiran. 
Because the primary endpoint will rely on measurements of urinary oxalate, and because some 
urinary oxalate is diet-derived, diet is an important variable in this study.  In a 5-year study of 
recurrent stone formers published by Borghi et al, patients randomized to a normal calcium, low 
protein/salt diet had lower urinary oxalate levels and a lower cumulative incidence of recurrent 
kidney stones when compared to a low calcium diet.  During the current study, and as of the time 
of informed consent, patients will be asked to adhere to a diet appropriate for stone formers, 
including adequate calcium intake and avoidance of spinach and other foods that are high in 
oxalate.  
The secondary endpoint to assess meaningful reduction in 24-hour urinary oxalate from baseline 
to Month 6 (Months 4 through 6) defines a clinically meaningful reduction as ≥20% in the non-
PH1 stone former population, supported by available literature based on stone former 
populations.[Borghi 2002] 
In this study, lumasiran will be evaluated in patients with recurrent calcium oxalate kidney stone 
disease.  Due to the limited and burdensome disease management options, there is an unmet need 
for new therapies. 
3.3. 
Justification for Dose 
Two dose levels of lumasiran 284 and 567 mg given on Day 1, Month 3, and Month 9 were 
selected to evaluate urinary oxalate dose response.  The higher dose level of 567 mg is expected 
to suppress GO enzyme by ≥95%, comparable to the regimen evaluated in ALN-GO1-003 
(ILLUMINATE-A) in patients with PH1.  The lower dose of 284 mg is expected to suppress GO 
enzyme by 90%.  In addition, the fixed doses will simplify dose administration in this adult study 
population.  Both regimens are predicted to achieve near-steady state ribonucleic acid-induced 
silencing complex (RISC) concentrations and urinary oxalate suppression at Month 6.  Month 9 
dosing is intended to sustain PD effect through Month 15 and will provide data to differentiate 
the effect of every 3 months and every 6 months dosing on urinary oxalate reduction. 
Single 0.3 to 6.0 mg/kg doses of lumasiran in healthy subjects and multiple 3.0 mg/kg doses of 
lumasiran administered monthly or once every 3 months in patients with PH1 have been well 
tolerated.  Plasma and liver exposure for the lumasiran 284 and 567 mg doses are expected to be 
in the range of 3.0 to 6.0 mg/kg lumasiran doses evaluated in healthy subjects in ALN-GO1-001 
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(Part A) and patients with PH1 in ALN-GO1-001 (Part B), ALN-GO1-002, and 
ILLUMINATE-A.  Based on rat and monkey NOAEL doses of lumasiran 200 mg/kg and 
300 mg/kg, a sufficient safety margin exists for the use of lumasiran 284 and 567 mg doses (refer 
to the ALN-GO1 Investigator Brochure). 
Based on a 70 kg patient, the planned doses of 284 mg and 567 mg equate to approximately 
4.0 mg/kg or 8.0 mg/kg, respectively.  The human equivalent dose (HED) margin values for the 
approximate 4 mg/kg clinical dose were 8.1-fold for the chronic rat study and 24.2-fold for the 
chronic monkey study; the HED margin values for the approximate 8.0 mg/kg clinical dose were 
4.0-fold for the chronic rat study and 12.1-fold for the chronic monkey study (refer to the 
ALN-GO1 Investigator Brochure). 
3.4. 
Method of Assigning Patients to Treatment Groups 
Each patient will be uniquely identified in the study by a combination of the site number and 
patient identification number.  After the patient signs the informed consent form (ICF) and 
before proceeding with screening procedures, the Investigator or his/her designee will contact the 
Interactive Response Technology (IRT) to obtain a patient identification number. 
The Investigator or his/her designee will contact the IRT to randomize the patient after 
confirming that the patient fulfills all the inclusion criteria and none of the exclusion criteria. 
Patients will be randomized 1:1:1 to receive lumasiran 284 mg, lumasiran 567 mg, or placebo, 
administered at the same volume (see Section 5.2.2), for the duration of the study.  Stratification 
will be performed at randomization according to mean baseline urinary oxalate level (>1.25 × 
ULN vs ≤1.25 × ULN) and the number of historical kidney stone events in the 12 months prior 
to screening (>1 vs ≤1). 
For stratification, a historical kidney stone event is defined as:  
• the visible passage of a kidney stone 
• a procedural intervention for removal of an asymptomatic or symptomatic stone  
− if more than 1 stone was removed in a given procedure, this counts as 1 event 
unless bilateral ureteral stones were removed, in which case this counts as 
2 events 
− if more than 1 procedure was required to remove a single stone, this counts as 
1 event 
• a new (≥1 mm) or enlarged (by ≥2 mm) kidney stone on CT imaging 
− it must be evident from the CT scans that the new or enlarged kidney stone event 
occurred during the 12 months prior to screening 
− if a procedure was performed to remove the stone(s) identified by CT, then only 
the procedure will be counted to avoid double-counting the same stone. 
3.5. 
Blinding 
All site personnel and patients will be blinded to study drug treatment.  The Sponsor will have 
access to unblinded study data during the conduct of the study.  Lumasiran and placebo will be 
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packaged identically and will be administered at the same volume under the supervision of the 
Investigator at the study center or by a healthcare professional at the patient’s home (see 
Section 5.2.2).  Since lumasiran may be visually distinguishable from placebo, the syringe will 
be masked prior to administration by a healthcare professional.  See the Pharmacy Manual for 
additional details. 
All site personnel will be blinded to central laboratory results of oxalate, calcium oxalate 
supersaturation, and glycolate from after the time of the first dose until unblinding.  Results will 
not be reported to the Investigator from the first dose until the last patient completes assessments 
at the Month 15 visit.  In addition, Investigators and staff involved with this trial and all medical 
staff involved in the patient’s medical care should refrain from obtaining measurements for 
oxalate, calcium oxalate supersaturation, or glycolate from the first dose until the sites and 
patients are unblinded, or until the patient ends the study, whichever is earlier.  If oxalate, 
calcium oxalate supersaturation, or glycolate are measured during the blinded period, all 
reasonable steps must be undertaken to avoid informing the patient and site personnel of the 
results until the sites and patients are unblinded. 
Any unplanned unblinding occurring during the study period will be documented and reported in 
the clinical study report.  
3.5.1. 
Emergency Unblinding 
If the treating physician determines that the clinical management of the patient requires 
knowledge of the study drug assignment, the Investigator may break the blind, as necessary.  If 
time permits, clinical study center personnel should contact the Medical Monitor before 
unblinding to discuss the need to unblind the patient.  If contact prior to unblinding is not 
possible, personnel must contact the Medical Monitor within 1 working day after the unblinding 
event.  Unblinding information should be limited to the fewest number of people on a need-to-
know basis.  A record of when the blind was broken, who was unblinded, who broke the blind, 
and why it was broken, will be maintained in the trial master file. 
Refer to the IRT instructions for details on unblinding. 
3.6. 
Safety Review 
A safety review committee will not be utilized for this study; however, the Sponsor will monitor 
safety on an ongoing basis and in accordance with the Sponsor’s internal processes. 
3.7. 
Definition of End of Study for an Individual Patient 
A patient is considered to have reached the EOS if the patient: 
• has completed the EOS (Month 15) visit, or 
• has completed safety monitoring following the final dose of study drug as described 
in Section 4.3.1 
A definition of the end of the overall study is provided in Section 8.1.5. 
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4. 
SELECTION AND REMOVAL OF PATIENTS 
4.1. 
Inclusion Criteria 
Patients are eligible to be included in the study if all the following criteria apply: 
Age 
1. Age 18 years or older (or age of legal consent, whichever is older). 
Patient and Disease Characteristics 
2. Recurrent kidney stone disease, defined as ≥2 stone events within the 5 years prior to 
screening.  For inclusion, a historical kidney stone event is defined as:  
• the visible passage of a kidney stone 
• a procedural intervention for removal of an asymptomatic or symptomatic stone  
− if more than 1 stone was removed in a given procedure, this counts as 1 event 
unless bilateral ureteral stones were removed, in which case this counts as 
2 events 
− if more than 1 procedure was required to remove a single stone, this counts as 
1 event 
• a new (≥1 mm) or enlarged (by ≥2 mm) kidney stone on CT imaging 
− it must be evident from the CT scans that the new or enlarged kidney stone event 
occurred during 5 years prior to screening 
− if a procedure was performed to remove the stone(s) identified by CT, then only 
the procedure will be counted to avoid double-counting the same stone. 
3. The 2 most recently analyzed kidney stones prior to randomization contained 50% or 
more of calcium oxalate; if only one stone analysis is available, then it must have 
contained 50% or more of calcium oxalate. 
4. 24-hour urinary oxalate levels from 2 valid 24-hour urine collections obtained during 
screening are >ULN. 
5. Willing to adhere to dietary recommendations appropriate for stone formers including 
limiting vitamin C supplementation to <200 mg daily. 
6. If taking medications and/or hydrating for kidney stone prophylaxis, or taking 
medications that alter urinary oxalate excretion and/or kidney stone formation, must have 
been on a stable regimen for at least 60 days before randomization, and willing to remain 
on this stable regimen for the duration of the study. 
7. Body mass index (the weight in kilograms divided by the square of the height in meters) 
of 20 to <40 kg/m2. 
Informed Consent 
8. Patient is able to understand and is willing and able to comply with the study 
requirements and to provide written informed consent. 
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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 at screening:  
a. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2 × ULN 
b. Total bilirubin >1.5 × ULN.  Patients with elevated total bilirubin that is secondary to 
documented Gilbert’s syndrome are eligible if the total bilirubin is <2 × ULN 
c. International normalized ratio (INR) >2.0 (patients on oral anticoagulant [eg, 
warfarin] with an INR <3.5 will be allowed) 
2. Has an eGFR of <30 mL/min/1.73m2 at screening (calculation will be based on the 
Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] creatinine formula; see 
Section 10.1). 
Prior/Concomitant Therapy 
3. Received an investigational agent within the last 30 days or 5 half-lives, whichever is 
longer, prior to the first dose of study drug, or are in follow-up of another clinical study 
prior to study enrollment.  Any agent that has received health agency authorization 
(including for emergency use) by local or regional regulatory authorities is not considered 
investigational. 
Medical Conditions 
4. Patients with a known history of secondary causes of elevated urinary oxalate and/or 
recurrent kidney stones including: 
a. Primary hyperoxaluria 
b. Severe eating disorders (anorexia or bulimia) 
c. Chronic inflammatory bowel disease  
d. Intestinal surgery with malabsorption or chronic diarrhea 
e. Sarcoidosis 
f. Primary hyperparathyroidism 
g. Complete distal renal tubular acidosis 
5. Has other medical conditions or comorbidities which, in the opinion of the Investigator, 
would interfere with study compliance or data interpretation. 
6. History of multiple drug allergies or history of allergic reaction to an oligonucleotide or 
GalNAc. 
7. History of intolerance to SC injection(s). 
Contraception, Pregnancy, and Breastfeeding 
8. Is not willing to comply with the contraceptive requirements during the study period, as 
described in Section 5.6.1. 
9. Female patient is pregnant, planning a pregnancy, or breast-feeding. 
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Alcohol Use 
10. Unwilling or unable to limit alcohol consumption throughout the course of the study.  
Alcohol intake of >2 units/day is excluded during the study (unit:  1 glass of wine 
[approximately 125 mL] = 1 measure of spirits [approximately 1 fluid ounce] = ½ pint of 
beer [approximately 284 mL]). 
11. History of alcohol abuse, within the last 12 months before screening, in the opinion of the 
Investigator. 
4.3. 
Removal from Study Drug or Assessment 
Patients 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 protocol deviation 
• Adverse event 
• Non-adherence to treatment regimen 
• Pregnancy 
• Lost to follow-up 
• Other reason (non-AE) 
• Or, study is terminated by the Sponsor 
If possible, the Investigator will confer with the Sponsor or Medical Monitor before 
discontinuing dosing in the patient.  Patients who are pregnant will be discontinued from study 
drug dosing immediately (see Section 6.5.5.7 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 
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the Schedule of Assessments (Table 1), including different options for follow-up and collection 
of data (eg, in person, by phone, by mail, 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 serious adverse events (SAEs), the event 
should be followed as described in Section 6.5.5.  When a patient discontinues study drug 
dosing, the primary reason must be recorded in the 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 Primary Analysis Period (defined 
as a discontinuation that occurs after the first dose of study drug administration on Day 1 during 
the 6-month Primary Analysis Period) will be encouraged to remain on the study and complete 
all assessments (including 24-hour urine collections) through Month 6, with early termination 
(ET) assessments at Month 9, and safety follow-up per the safety follow-up schedule (Table 1).  
Patients who do not remain on the study through Month 6 will be asked to return for their next 
scheduled visit to complete ET assessments and complete safety follow-up per the safety follow-
up schedule (Table 1). 
Patients who discontinue study drug after Month 6 will be asked to return for their next 
scheduled visit to complete ET assessments and complete a safety follow-up visit per the safety 
follow-up schedule (see Table 1). 
4.3.2. 
Stopping a Patient’s Study Participation 
4.3.2.1. 
Patient Stops Participation in the Study 
A patient may stop participation in the study at any time.  A patient 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 for the collection of important study data 
as described in Section 4.3.1.  If a patient still chooses to discontinue study drug and stop 
participation in all follow-up, every effort should be made to conduct the ET assessments (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. 
Note, in countries where the collection and processing of the patient’s personal data is based on 
consent, if a patient withdraws consent to collect and process his/her personal data (see 
Section 4.3.2.2), as applicable, personal data up to the withdrawal of consent will be included in 
the analysis of the study.  In addition, 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. 
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4.3.2.2. 
Withdrawal of Consent to Process the Patient’s Personal Data or Objection to 
Process 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.  Also, where allowed by local 
law, the patient may object to the collection, storage, and use of his/her personal data, informing 
the study doctor at any time in writing or in any other form that may be locally required.  In both 
cases, 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/objection) 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 through the Primary Analysis 
Period (Month 6). 
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 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 6.5.5. 
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 fails to return to the clinic for a required study visit: 
• The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of maintaining the assigned visit 
schedule and ascertain if the patient wishes to 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 (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 continue to be unreachable, the patient will be considered to have 
stopped participation in the study. 
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• 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 will not be replaced.  
5. 
TREATMENTS AND OTHER REQUIREMENTS 
5.1. 
Treatments Administered 
Study drug (lumasiran and placebo) 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 study drug is 
provided in the Pharmacy Manual. 
5.2.1. 
Description 
Lumasiran will be supplied as a sterile solution in water for SC injection.  See the Pharmacy 
Manual for further details of solution concentration and fill volume. 
The control drug for this study will be a placebo (sodium chloride 0.9% w/v for SC 
administration).  Placebo will be provided by the Sponsor; it will be packaged identically to 
lumasiran. 
5.2.2. 
Dose and Administration 
Patients will be administered SC injections of lumasiran (284 mg or 567 mg) and/or placebo at 
the same volume, as described below, on Day 1, Month 3, and Month 9. 
Lumasiran 567 mg 
Lumasiran 284 mg 
Placebo 
1.5 mL lumasiran 
1.5 mL lumasiran 
1.5 mL lumasiran 
1.5 mL placebo 
1.5 mL placebo 
1.5 mL placebo 
Study drug injections will be administered under the supervision of the Investigator or healthcare 
professional.  To maintain the blind, syringes are to be masked prior to the removal of study drug 
from vials.  A full description of the blinding procedure is included in the Pharmacy Manual.  
The injection site may be marked and mapped for later observation.  Injections may be 
administered in the abdomen, thigh, or the side or back of the upper arms.  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, provided the patient 
has tolerated at least 1 dose of study drug administered in the clinic.  However, continued study 
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drug administration at the study center should be considered for patients who have ongoing study 
drug-related AEs or for anyone in the opinion of the Investigator who would benefit from 
clinical observation following dosing. 
If a patient does not receive a dose of study drug within the specified visit 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. 
The definition of study drug overdose, follow-up procedures, and reporting requirements are 
provided Section 6.5.5.8. 
5.2.3. 
Dose Modifications 
If a study drug-related AE occurs in a patient that the Investigator judges as presenting a 
potential risk to the patient for further dosing, the study drug dose may be held at the discretion 
of the Investigator, and the Medical Monitor should be contacted. 
5.2.3.1. 
LFT Criteria for Withholding, Monitoring, and Stopping Study Drug Dosing  
1. Results of previous LFT assessment should be reviewed prior to dosing. 
2. For any ALT or AST elevation >3× ULN, central laboratory results should be used to 
guide subsequent monitoring as detailed in Table 3. 
3. For any ALT or AST elevation >3× ULN: 
a. If local laboratory results are obtained, confirm with a 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 5 and Table 6. 
4. For any ALT or AST elevation >3× ULN without alternative cause that is accompanied 
by clinical symptoms consistent with liver injury (eg, nausea, right upper quadrant 
abdominal pain, jaundice) or elevated bilirubin to ≥2× ULN or INR ≥1.5, permanently 
discontinue dosing. 
5. For confirmed ALT or AST elevations >3× ULN without alternative cause and not 
accompanied by symptoms or elevated bilirubin ≥2× ULN or INR ≥1.5, see Table 3. 
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Table 3: 
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 6 (all assessments to be performed once) 
- Hematology, serum chemistry, and LFT per Table 5 
- Coagulation (prothrombin time, partial thromboplastin time, 
international normalized ratio) 
• 
Monitor at least every 2 weeks:  LFT per Table 5 
• 
If elevation persists for ≥2 months, must discuss with the Medical 
Monitor before continuing dosing 
>5× to 8× ULN 
• 
Hold study drug dosing until recovery to ≤1.5× ULN or baseline; may 
resume dosing after discussion with the Medical Monitor 
• 
Evaluate the initial elevation in LFT per the following assessments: 
- Table 6 (all assessments to be performed once) 
- Hematology, serum chemistry, and LFT per Table 5 
- Coagulation (prothrombin time, partial thromboplastin time, 
international normalized ratio) 
• 
Monitor at least weekly:  LFT per Table 5 until ALT and/or AST is 
declining on 2 consecutive draws, then may decrease monitoring to 
biweekly 
• 
If ALT or AST rises to >5× ULN following resumption of dosing, 
permanently discontinue dosing 
>8× ULN 
• 
Permanently discontinue dosing after confirmation of the transaminase 
value at the central laboratory. 
• 
Evaluate the initial elevation in LFT per the following assessments until 
satisfactory resolution: 
- Table 6 (all assessments to be performed once) 
- Hematology, serum chemistry, and LFT per Table 5 
- Coagulation (prothrombin time, partial thromboplastin time, 
international normalized ratio) 
• 
Monitor at least weekly:  LFT per Table 5 until ALT and/or AST is 
declining on 2 consecutive draws, then may decrease monitoring to 
biweekly 
Abbreviations:  ALT=alanine aminotransferase; AST=aspartate aminotransferase; INR=international normalized 
ratio; LFT=liver function test(s); ULN=upper limit of normal. 
Notes:  In addition to these criteria, other assessments or evaluations may be performed per Investigator 
discretion, as appropriate. 
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5.2.4. 
Preparation, Handling, and Storage 
Staff at each clinical study center or the home healthcare professional will be responsible for 
preparation of study drug doses, according to procedures detailed in the Pharmacy Manual.  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 until dose preparation.  
Deviations from the recommended storage conditions should be reported to the Sponsor and use 
of the study drug halted until authorization for its continued use has been provided by the 
Sponsor or designee, as described in the Pharmacy Manual. 
A Sponsor representative or designee will be permitted, upon request, to audit the supplies, 
storage, dispensing procedures, and records. 
Instructions specific to unused study drug and additional storage will be provided in the 
Pharmacy Manual. 
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. 
Clinical Product Complaints 
5.3.1. 
Definition 
A clinical product complaint (CPC) is any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of the study drug and its packaging after it is released for distribution to the site at 
which study drug will be administered. 
A CPC may be detected prior to use of study drug, during use, or after use.  A CPC is typically 
non-medical in nature; however, it is possible that investigational product complaints could be 
associated with an AE.  Examples of a CPC include, but are not limited to:  illegible clinical 
label, missing clinical label, damaged vial, empty vial, and contamination of study drug. 
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5.3.2. 
Reporting 
For CPCs, the Sponsor or its designee should be notified within 24 hours using the appropriate 
eCRF.  Clinical product complaints that may be associated with an AE must be evaluated and 
reported as indicated in Section 6.5.5.  Detailed instructions on reporting CPCs will be provided 
in the Pharmacy Manual. 
5.4. 
Concomitant Medications and Procedures 
Use of concomitant medications and procedures will be recorded on the patient’s eCRF as 
specified in the Schedule of Assessments (see Table 1).  Concomitant medications include all 
prescription medications, herbal preparations, over the counter medications, vitamins, and 
minerals.  Any changes in medications during the study will also be recorded on the eCRF. 
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, acute 
kidney injury). 
Standard vitamins and topical medications are permitted (vitamin C supplementation must be 
<200 mg daily per inclusion criteria).  However, topical steroids must not be applied anywhere 
near the injection site(s) unless medically indicated. 
Patients will be allowed to receive vaccines (eg, for SARS-CoV-2) that have received health 
agency authorization (including for emergency use) by local or regional regulatory authorities. 
Any concomitant medication that is required for the patient’s welfare may be administered by the 
Investigator.  However, it is the responsibility of the Investigator to ensure that details regarding 
the medication are recorded on the eCRF.  Concomitant medication will be coded using an 
internationally recognized and accepted coding dictionary. 
5.5. 
Treatment Compliance 
Compliance with study drug administration will be verified through observation by study staff or 
trained home healthcare professionals. 
5.6. 
Other Requirements 
5.6.1. 
Contraception 
Females of child-bearing potential must be willing to use an acceptable method of contraception 
from 14 days before first dose, throughout study participation, and for 6 months after last dose 
administration or until study completion. 
Birth control methods which are considered acceptable include: 
• Placement of an intrauterine device. 
• Placement of an intrauterine hormone-releasing system. 
• Bilateral tubal occlusion. 
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• 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 associated with the inhibition of 
ovulation. 
• 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 6 months 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. 
Females of child-bearing potential include female patients who have experienced menarche (or 
begin menarche over the course of the study), and who are not postmenopausal or permanently 
sterilized (eg, bilateral tubal occlusion, hysterectomy, or bilateral salpingectomy).  A 
postmenopausal state is defined as the absence of menses for 12 months without an alternative 
medical cause, confirmed by a follicle stimulating hormone level within the postmenopausal 
range.  
For male patients, no contraception is required.  However, use by males of contraception 
(condom) may be required in some countries, in order to comply with local requirements as 
described in the corresponding patient ICFs. 
Compliance with contraception requirements will be assessed on a regular basis by the 
Investigator throughout the course of the study (see Section 6.5.4.2).  
5.6.2. 
Alcohol Restrictions 
Patients will limit alcohol consumption throughout the course of the study.  Alcohol is limited to 
no more than 2 units per day (unit:  1 glass of wine [approximately 125 mL] = 1 measure of 
spirits [approximately 1 fluid ounce] = ½ pint of beer [approximately 284 mL]) for the duration 
of the study. 
5.6.3. 
Dietary Restrictions 
For the duration of the study patients should adhere to a diet appropriate for calcium oxalate 
stone formers, including adequate calcium intake and avoidance of spinach and other foods that 
are high in oxalate.  Details are provided in the Dietary Reference Sheet. 
Dietary adherence will be collected electronically in an eDiary at the time points listed in the 
Schedule of Assessments (Table 1).  Refer to the Study Manual for more information. 
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6. 
STUDY ASSESSMENTS 
The schedule of study assessments is provided in Table 1.  All assessments are required to be 
performed prior to dosing at dosing visits, except for CT imaging and PK postdose sample 
collection.  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, and 
as noted in Table 1, home healthcare may take place at a location other than the clinical trial site 
to perform study assessments, which may include pregnancy testing (urine or serum), clinical 
laboratory assessments, urine collections, DNA testing, symptom-directed physical examination / 
body system assessment, vital signs, body weight, height, blood collection for PD, ADA and 
exploratory analyses assessments (at the discretion and with oversight of the Investigator). 
6.1. 
Screening Assessments 
An ICF that has been approved by the appropriate Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC) must be signed (in paper or electronic format per local regulations and 
institutional standards) by the patient before the screening procedures are initiated.  All patients 
will be given a signed and dated version of their ICF. 
Patients will be screened to ensure that they meet all the inclusion criteria and none of the 
exclusion criteria.  To confirm study entrance criteria, 24-hour urine will be collected per 
Table 4.  
Patient demographic data and medical history/disease history will be obtained.  Any changes to 
medical history occurring between the screening assessment and prior to dosing will be updated.  
6.1.1. 
DNA Sample 
A blood sample for DNA analysis will be collected from all patients as part of the screening 
assessments.  The samples will be analyzed for PH1, PH2, and PH3 (unless tested previously) to 
confirm eligibility (see Section 4.2).  Refer to the Laboratory Manual for more information. 
6.1.2. 
Retesting  
If in the Investigator’s judgement, the screening laboratory abnormalities are likely to be 
transient, then laboratory tests may be repeated once.  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. 
6.1.3. 
Rescreening 
Rescreening of patients is permitted with approval of the Medical Monitor.  A patient who does 
not meet all study eligibility criteria due to a transient condition observed at screening (eg, 
prohibited medications that were subsequently discontinued) will be allowed to return for 
rescreening.  A patient will be re-consented if rescreening occurs outside of the 60-day screening 
window.  In this case, all screening procedures must be repeated. 
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Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently assigned to treatment with study drug.  The site should update the patient’s 
status in the IRT to reflect this as soon as possible. 
6.2. 
Efficacy Assessments 
Efficacy assessments are to be performed as specified in the Schedule of Assessments (Table 1). 
6.2.1. 
24-Hour Urine Collections 
Urinary oxalate excretion and calcium oxalate supersaturation (calculated from multiple 
parameters) will be determined from 24-hour urine sample collections to be completed at the 
time points specified in the Schedule of Assessment (Table 1).  The start and stop dates/times of 
collection, the volume of urine in the collection, whether there were any missed voids, and 
whether the patient complied with dietary recommendations will be recorded.  An aliquot of the 
24-hour urine collection will also be used to determine urinary creatinine content and to 
determine if the 24-hour urine collections need to be repeated (see Section 6.2.1.1).  
The 24-hour urine collection procedure by study visit is provided in Table 4.  
Table 4: 
24-hour Urine Collection Procedure by Study Visit 
Study Visit and Urine 
Collection Window 
Number of 
Collections to 
Schedule 
Validity Requirement 
Prior to Dosing/Visit  
(see Section 6.2.1.1) 
Notes 
Screening 
(within 60-day period) 
2 
2 valid collections prior to 
dosing unless variability 
criterion is not met 
(Section 6.2.1.1), in 
which case 3 valid 
collections are required.  
Supervised collectionsa are 
encouraged unless patient is already 
familiar with the collection 
procedure.  If any collections are 
invalid, the remaining collections for 
screening must be supervised.  
Months 3, 4, 5, and 6 
(within 14 days prior to 
dosing/visit) 
1 
No 
If an invalid collection is obtained for 
the timepoint, a single repeat 
collection must be supervised.  
Repeat collection, if necessary, is to 
be completed within ±14 days of 
dosing/visit. 
Months 9 and 15 
(within 14 days prior to 
dosing/visit) 
2 
1 valid collection prior to 
dosing/visit 
If a patient has had ≥2 prior invalid 
collections, both collections at these 
visits must be superviseda.  At least 1 
valid collection must be obtained 
prior to dosing/visit.  If any 
collections for the timepoint are 
invalid, the remaining collection(s) 
for the timepoint must be supervised. 
a A supervised collection is defined, at a minimum, as contact from study staff to the patient the day prior to the 
collection start and the day the collection will finish to ensure compliance; this may be conducted remotely.  Any 
or all of the 24-hour urine collections may be conducted supervised.  If 24-hour urine collection is not a supervised 
collection, or if a collection is supervised remotely, patients may either bring it to the clinic or have it couriered to 
the designated laboratory.   
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6.2.1.1. 
Validity Criteria for 24-hour Urine Collections 
Throughout the study, a urine collection will be considered valid if each of the following criteria 
are met: 
• The collection is between 22 to 26 hours in duration between the initial discarded 
void and the last void or attempt to void. 
• No voids are missed between the start and end time of the collection as indicated by 
the patient's urine collection diary. 
• The 24-hour creatinine content is at least 10 mg/kg as assessed by the central 
laboratory. 
• Patient complied with dietary recommendations appropriate for oxalate stone formers 
(detailed in the Dietary Reference Sheet) for the 4 days prior to the start of the urine 
collection and during the collection. 
24-hour urine collections that are known to be invalid should still be submitted for analysis. 
6.2.1.2. 
Variability Criterion for 24-hour Urine Collections at Screening 
If the 2 valid 24-hour urine collections from screening meet eligibility requirements (both 24-
hour urinary oxalate levels >ULN), the variability between the oxalate levels (in mg/day) should 
be assessed as follows: 
 
If the variability is >20%, then a third valid 24-hour urine collection should be obtained.  The 
result of the third sample will not impact the patient’s eligibility for the study. 
6.2.2. 
Kidney Stone Events 
Since kidney stone events are recorded as an efficacy assessment, these events will not be 
captured as AEs or SAEs.  However, if a patient experiences other AEs or SAEs during a kidney 
stone event, they should be reported as an AE (see Section 6.5.5.2).   
Kidney stone events will be graded by the Investigator as mild, moderate, or severe as defined in 
Section 6.5.5.1.  If there are changes in grade during an event, only the highest grade should be 
reported. 
6.2.2.1. 
Clinical 
All relevant clinical information pertaining to a kidney stone events should be obtained, 
including laboratory values, medical records, discharge summaries, and medical test results 
(including stone composition, if available, and radiology reports).  A clinical kidney stone event 
is defined as one of the following: 
• Visible passage of a kidney stone 
• A procedural intervention for removal of an asymptomatic or symptomatic stone 
(information on the location, number, and size of stones removed will be collected) 
𝑉𝑎𝑟𝑖𝑎𝑏𝑖𝑙𝑖𝑡𝑦=  (𝑂𝑥𝑎𝑙𝑎𝑡𝑒 𝑣𝑎𝑙𝑢𝑒 #1 −𝑂𝑥𝑎𝑙𝑎𝑡𝑒 𝑣𝑎𝑙𝑢𝑒 #2)
(𝐴𝑣𝑒𝑟𝑎𝑔𝑒 𝑜𝑓 𝑜𝑥𝑎𝑙𝑎𝑡𝑒 𝑣𝑎𝑙𝑢𝑒𝑠 #1 & #2)  × 100% 
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• Or, in the case of potential stone passages without visible stones, it will be up to the 
Investigator to evaluate patients’ symptoms and determine whether a stone passage 
occurred or the symptoms were due to a different cause. 
6.2.2.2. 
Radiographic 
A non-contrast low-dose kidney-protocol CT scan will be performed for all patients on Day 1 
(may be performed up to 3 days prior to Day 1), and at Month 15.   
For patients who terminate the study early, a CT scan should be performed at the ET visit only if 
this visit occurs after Month 6 and at the discretion of the Investigator, and where permitted, 
following consultation with the Medical Monitor.  CT scans will be analyzed centrally. 
6.2.3. 
Spot Urinary Oxalate:Creatinine Ratios 
Urine oxalate:creatinine ratios will be calculated from the oxalate and creatinine levels measured 
in single-void urine collections.  Single-void urine collections should be collected as a first 
morning void when possible; if this is not possible then the reason should be documented. 
6.2.4. 
Estimated Glomerular Filtration Rate 
Blood samples for the assessment of eGFR (mL/min/1.73m2) will be obtained at the time points 
specified in the Schedule of Assessment (Table 1). 
eGFR will be calculated based on the CKD-EPI formula (see Section 10.1).[Levey 2009; 
Schwartz 2009] 
6.3. 
Pharmacodynamic Assessments 
Urine and blood samples will be collected for assessment of PD parameters (plasma oxalate, 
plasma glycolate, and urinary glycolate) at the time points specified in the Schedule of 
Assessments (Table 1).  Urine samples for exploratory analysis will be aliquoted from the 
samples provided for PD analysis.  On dosing days, all blood and urine samples will be collected 
prior to study drug administration. 
All PD assessments will be analyzed centrally.  Postdose PD results will not be distributed to the 
sites until after the last patient completes assessments at the Month 15 visit.  Site personnel 
should refrain from obtaining or viewing local oxalate, calcium oxalate supersaturation, or 
glycolate assessments, except as medically indicated, due to risk of unblinding (Section 3.5).  
Details regarding the processing and aliquoting of PD samples for shipping and storage are 
provided in the Laboratory Manual. 
Where local regulations allow and infrastructure is in place, a healthcare professional may collect 
urine or blood samples offsite. 
6.4. 
Pharmacokinetic Assessments 
Blood samples will be collected for the assessment of lumasiran PK parameters at the time points 
indicated in the Schedule of Assessments (Table 1).  A detailed schedule of time points for the 
collection of blood samples for PK analysis is in Table 2. 
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The concentration of lumasiran in blood samples will be determined using a validated assay.  
Details regarding sample volumes to be collected, and the processing and shipping 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, and laboratory tests.  Clinically significant abnormalities observed during the 
physical examination are recorded as either medical history or AEs, as appropriate. 
Safety assessments are to be performed as specified in the Schedule of Assessments (Table 1).  
On dosing days and as applicable, assessments of vital signs, weight/height, physical 
examination, and clinical laboratory assessments are to be completed before study drug 
administration.  
Adverse event assessments are detailed under Section 6.5.5.  
6.5.1. 
Vital Signs 
Vital signs will be measured as specified in the Schedule of Assessments (Table 1) and include 
blood pressure, heart rate, body temperature, and respiratory rate.  Vital signs will be measured 
predose, when applicable.  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 predose in the seated or supine position, after the patient has rested 
comfortably for approximately 5 minutes.  Blood pressure should be taken using the same arm 
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. 
Vital signs results will be recorded in the eCRF. 
6.5.2. 
Height and Weight 
Height will be measured in centimeters.  Body weight will be measured in kilograms.  Height 
and body weight measurements will be collected as specified in the Schedule of Assessments 
(Table 1) and will be recorded in the eCRF. 
6.5.3. 
Physical Examination 
Full and symptom-directed physical examinations will be conducted according to the Schedule 
of Assessments (Table 1); if a physical examination is scheduled for a dosing visit, it should be 
conducted prior to dosing.  Full physical examinations will include the examination of the 
following:  general appearance; head, eyes, ears, nose and throat; respiratory, cardiovascular, 
gastrointestinal, musculoskeletal, and dermatological systems; thyroid; lymph nodes; and 
neurological status.  If a visit is conducted offsite (eg, home), a body system assessment may be 
performed in lieu of a physical examination. 
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Symptom-directed physical examinations will be guided by evaluation of ongoing symptoms, 
changes in symptoms, or the onset of new symptoms, since the last visit.  If there are no ongoing 
symptoms, changes in symptoms, or new symptoms, then a symptom-directed physical 
examination is not required. 
Clinically significant abnormalities observed during the physical examination are recorded on 
the medical history eCRF (if observed during screening) or the AE eCRF (if observed at any 
post-screening visit). 
6.5.4. 
Clinical Laboratory Assessments 
The following clinical laboratory tests will be evaluated by a central laboratory.  Specific 
instructions for transaminase elevations are provided in Section 5.2.3.1.  Laboratory assessments 
conducted to confirm study eligibility (Section 4) will not be repeated unless the time between 
screening and randomization exceeds 4 weeks.  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, until it has returned to the normal range or 
stabilized, and/or a diagnosis is made to adequately explain the abnormality.  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 included in the clinical database.  Clinical laboratory assessments 
are listed in Table 5 and will be assessed as specified in the Schedule of Assessments (see Table 
1).  
While local laboratory results may be used for urgent clinical decisions, on the day of visit 
assessments, all laboratory assessments specified in Table 5 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. 
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 5: 
Clinical Laboratory Assessments 
Hematology 
Complete blood count with differential 
 
Serum Chemistry 
Sodium 
Potassium 
BUN 
Albumin 
Total protein 
Calcium 
Glucose 
Bicarbonate 
Creatinine and eGFRa 
Chloride 
Liver Function Tests 
 
AST 
ALP 
ALT 
Bilirubin (total and direct) 
Urinalysis  
Visual inspection for appearance and color 
Bilirubin 
pH (dipstick) 
Nitrite 
Specific gravity 
RBCs 
Ketones 
Urobilinogen 
Albumin 
Leukocytes 
Glucose 
Microscopy (if clinically indicated) 
Protein 
 
Coagulation  
International Normalized Ratio (screening only) 
 
Immunogenicity (see Section 6.5.4.1) 
Antidrug antibodies 
 
Pregnancy Testing/FSH Screening (see Section 6.5.4.2) 
β-human chorionic gonadotropin (females of 
child-bearing potential only) 
Follicle-stimulating hormone (postmenopausal 
women only) 
Abbreviations:  ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; 
BUN=blood urea nitrogen; eGFR=estimated glomerular filtration rate; FSH=follicle-stimulating hormone; 
RBCs=red blood cells 
a Refer to Section 10.1 and the laboratory manual for further instructions on calculating eGFR. 
6.5.4.1. 
Immunogenicity 
Blood samples will be collected to evaluate ADA.  Blood samples for ADA testing must be 
collected before study drug administration as specified in the Schedule of Assessments (Table 1). 
Details regarding the processing and shipping of the samples will be provided in the Laboratory 
Manual. 
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6.5.4.2. 
Pregnancy Testing 
A pregnancy test will be performed for females of child-bearing potential.  A serum pregnancy 
test will be performed at screening.  Urine pregnancy tests will be performed thereafter per the 
Schedule of Assessments and any time pregnancy is suspected.  More frequent pregnancy testing 
may be performed where required per local requirements.  The results of the pregnancy test must 
be known before study drug administration.  Patients who are pregnant at screening are not 
eligible for study participation.  Any woman with a positive urine pregnancy test that is 
subsequently confirmed by a positive serum pregnancy test during the study will be discontinued 
from study drug but will continue to be followed for safety.  Patients determined to be pregnant 
while on study will be followed at least until the pregnancy outcome is known (see 
Section 6.5.5.7 for follow-up instructions). 
A blood sample will be drawn at screening to measure the levels of follicle stimulating hormone 
in order to confirm post-menopausal status in all women suspected to be post-menopausal.  Post-
menopausal women and women who are permanently sterilized will not undergo pregnancy 
testing. 
6.5.4.3. 
Additional Liver Function Assessments 
Additional laboratory assessments will be performed in patients who experience any LFT 
abnormalities as outlined in Section 5.2.3.1 (see Table 3).  Following the occurrence of elevated 
liver transaminases or other LFT abnormalities per central laboratory, all assessments in Table 6 
will be performed one time, as well as hematology, serum chemistry, LFT, and coagulation 
assessments per Table 3, and other assessments or evaluations per Investigator discretion, as 
appropriate.  
Monitoring, including criteria for dose modification or withholding the study drug, is described 
in Section 5.2.3.1. 
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Table 6: 
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.  The full panel of assessments should only be 
performed once; individual assessments may be repeated, as needed. 
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6.5.5. 
Adverse Events 
6.5.5.1. 
Definitions 
Adverse Event 
According to the International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (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. 
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: 
• ALT or AST >3× ULN 
• Severe or serious ISRs; ISRs that are associated with a recall phenomenon (reaction 
at the site of a prior injection with subsequent injections), or ISRs that lead to 
temporary dose interruption or permanent discontinuation of study drug. 
An ISR is defined as a local reaction at or near the site of injection.  “At or near” the 
injection site includes reactions at the injection site, adjacent to the injection site, or a 
reaction which may shift slightly away from the injection site due to gravity (eg, as 
may occur with swelling or hematoma).  Reactions with onset and resolution within 4 
hours of the injection (eg, transient pain/burning at injection site) do not meet the 
study definition of ISRs, unless immediate treatment is required.  A systemic reaction 
which includes the injection site, eg, generalized urticaria, other distinct entities or 
conditions like lymphadenopathy that may be near the injection site is not considered 
an ISR.   
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For information on recording and reporting of AEs of clinical interest, see Section 6.5.5.2 and 
Section 6.5.5.3, respectively. 
Adverse Event Severity 
Adverse events are to be graded according to the categories detailed below: 
Mild: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Moderate: 
Moderate; minimal, local or noninvasive intervention indicated; limiting age 
appropriate instrumental activities of daily living (eg, preparing meals, 
shopping for groceries or clothes, using the telephone, managing money). 
Severe: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care activities of daily living (ie, bathing, dressing and 
undressing, feeding self, using the toilet, taking medications, and not 
bedridden); OR life-threatening consequences; urgent intervention indicated; 
OR death related to an 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.  Adverse events characterized as intermittent 
require documentation of the start and stop of each incidence.  When changes in the severity of 
an AE occur more frequently than once a day, the maximum severity for the experience that day 
should be noted.  If the severity category changes over a number of days, then those changes 
should be recorded separately (with distinct onset dates). 
Adverse event 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. 
6.5.5.2. 
Eliciting and Recording Adverse Events 
Eliciting Adverse Events 
The patient should be asked about medically relevant changes in the patient’s health since the 
last visit.  The patient 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, or other findings 
that are relevant to patient safety. 
Recording Adverse Events 
The Investigator is responsible for recording non-serious AEs that are observed or reported by 
the patient after administration of the first dose of study drug regardless of their relationship to 
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study drug through the EOS.  Non-serious AEs will be followed until the EOS.  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 EOS.  Serious AEs will be followed until satisfactory resolution, until baseline level 
is reached, or until the SAE is considered by the Investigator to be chronic or the patient is 
stable, as appropriate. 
All AEs must be recorded in the source records for the clinical study center and in the eCRF for 
the patient, whether or not they are considered to be drug-related.  Each AE must be described in 
detail:  onset time and date, description of event, severity, relationship to study drug, action 
taken, and outcome (including time and date of resolution, if applicable). 
For SAEs, record the event(s) in the eCRF and, as applicable, the SAE form. 
For AEs that are considered AEs of clinical interest (Section 6.5.5.1), the supplemental AEs of 
Clinical Interest eCRF should be completed.  Additional clinical and laboratory information may 
be collected.  Refer to eCRF 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.). 
6.5.5.3. 
Reporting Adverse Events of Clinical Interest to Sponsor/Designee 
For AEs that are considered AEs of clinical interest (Section 6.5.5.1), the Sponsor or its designee 
should be notified within 24 hours using a supplemental AEs of Clinical Interest eCRF.  
Additional clinical and laboratory information may be collected.  Refer to eCRF completion 
guidelines for details on reporting events in the supplemental AEs of Clinical Interest eCRF.   
For all ISRs, the Investigator, or delegate, should submit a supplemental ISR eCRF, recording 
additional information (eg, descriptions, onset and resolution date, severity, treatment given, 
event outcome). 
6.5.5.4. 
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 6.5.5.1 must be reported to the 
Sponsor or designee within 24 hours from the time that clinical study center staff first learns of 
the event.  All SAEs must be reported regardless of the relationship to study drug. 
The initial report should include at least the following information: 
• Patient’s study number 
• Description and date of onset of the event 
• Criterion for serious 
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• Preliminary assignment of relationship to study drug, and 
• Investigator/site information 
To report the SAE, complete the eCRF and, as applicable, the SAE form.  Within 24 hours of 
receipt of follow-up information, the Investigator must update the eCRF and, as applicable, the 
SAE form.  Serious AEs 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. 
6.5.5.5. 
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. 
6.5.5.6. 
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. 
6.5.5.7. 
Pregnancy Reporting 
If a female patient becomes pregnant during the study through 6 months following the last dose 
of study drug, 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 6 months 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 6.5.5.4. 
The reporting of any pregnancy outcome for a female partner of a male patient participating in 
this study that results in a postpartum complication, spontaneous abortion, stillbirth, neonatal 
death, or congenital anomaly should be reported to the Investigator, who will then report this to 
the Sponsor or designee.  The pregnancy outcome is to be recorded on the pregnancy reporting 
form. 
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6.5.5.8. 
Reporting of Overdose and Other Special Situations 
An overdose is defined as any dose of study drug administered to the participant that is ≥2-fold 
the assigned dose during a single administration. 
The Sponsor does not recommend specific treatment for an overdose.  
In an event of an overdose or other special situations (eg, medication error, abuse, misuse, CPC 
associated with an AE), the Investigator should: 
• Contact the Medical Monitor within 24 hours 
• Submit the special situations reporting form within 24 hours using the contact 
information in the Pharmacy Manual 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities 
• Document the amount of study drug given 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention or 
a concomitant medication will be considered AEs/SAEs.  Overdose per se will not be 
categorized as an AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent.  Such overdoses should be reported as an SAE regardless of sequelae. 
Full details of overdose and other special situations reporting instructions will be outlined in the 
Pharmacy Manual. 
6.6. 
Biomarkers, Exploratory 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 recurrent calcium 
oxalate kidney stone disease, as well as their responses to treatment. 
Where allowed per local regulations, ethics committee (IRB/IEC) approval, and patient consent 
(and 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 Schedule of Assessments 
(Table 1).  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. 
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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. 
6.7. 
Quality of Life Outcomes 
6.7.1. 
Pain Assessment 
Patients will be asked to assess their "worst daily pain" (0=no pain at all; 10=pain as bad as you 
can imagine) from Question 3 of the Brief Pain Inventory - Short Form.  This will be 
administered at screening, on Day 1, and daily while experiencing stone-related pain until the 
conclusion of the associated stone event.  
6.7.2. 
Wisconsin Stone Quality of Life Questionnaire  
The Wisconsin Stone Quality of Life Questionnaire (WISQOL) will be administered on Day 1 
and upon conclusion of each clinical kidney stone event (as defined in Section 6.2.2.1) and will 
assess the degree of kidney stone impacts in terms of: 
• Fatigue 
• Sleep 
• Social function 
• Daily activities 
• Physical / psychosocial symptoms 
6.8. 
Healthcare Utilization 
To complement medical records, information regarding health resource use related to kidney 
stone events will be collected as specified in the Schedule of Assessments (Table 1), including 
emergency room visits, unscheduled office visits, hospitalizations, and procedures for kidney 
stone management. 
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7. 
STATISTICS 
A Statistical Analysis Plan (SAP) will be finalized before database lock and study unblinding for 
the primary analysis.  The plan will detail the implementation of the statistical analyses in 
accordance with the principal features stated in the protocol. 
7.1. 
Determination of Sample Size 
The planned enrollment for this study is 120 patients. 
The study is powered to detect a difference in urinary oxalate excretion between each lumasiran 
group and the placebo group.  Assuming a standard deviation of 45% in the percent change from 
baseline in 24-hour urinary oxalate levels at Month 6, a sample size of 40 patients per group will 
enable a power of at least 80% in detecting a treatment difference of 30% between the treatment 
groups at a 2-sided significance level of 0.05.  Table 7 shows the statistical power under various 
assumptions for a sample size of 40 per group. 
Table 7: 
Sample Size Power Calculations 
Assumed standard 
deviation (SD) 
Assumed difference 
(lumasiran – placebo) 
Power 
25% 
20% 
94% 
30% 
99% 
30% 
20% 
84% 
30% 
99% 
45% 
20% 
50% 
30% 
84% 
Abbreviations:  SD=standard deviation 
7.2. 
Statistical Methodology 
The statistical and analytical plans presented below are brief summaries of planned analyses.  
More complete plans will be detailed in the SAP.  Changes to the methods described in the final 
SAP will be described and justified as needed in the clinical study report.  For information on 
study endpoints, see Section 2. 
7.2.1. 
Populations to be Analyzed 
The populations (analysis sets) are defined as follows: 
• Full Analysis Set (FAS):  All randomized patients who received at least 1 dose of 
study drug.  Patients in the FAS will be analyzed according to the randomized 
treatment arm. 
• Safety Analysis Set:  All randomized patients who received at least 1 dose of study 
drug.  Patients in the Safety Analysis Set will be analyzed according to the treatment 
actually received. 
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• PK Analysis Set:  All patients who received at least 1 full dose of study drug and 
have at least one postdose blood sample for PK parameters and have evaluable PK 
data. 
The primary population used to evaluate efficacy will be the FAS.  Safety will be analyzed using 
the Safety Analysis Set.  The PK Analysis Set 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 by dose 
level and overall for the FAS and Safety Analysis Set.  
7.2.5. 
Efficacy Analyses 
The hypothesis testing for the primary endpoint will be tested comparing each lumasiran group 
to the placebo group in the FAS with a 2-sided significance level of 0.05. 
The primary endpoint will be analyzed using a mixed-effect model for repeated measures 
(MMRM) approach.  The outcome variable is percent change from baseline in urinary oxalate to 
Month 6 (average across Months 4 through 6).  The model includes baseline value and the 
stratification of number of historical kidney stone events (>1 versus ≤1 event in the 12 months 
prior to screening) as covariates, and fixed effect terms including treatment arm, visit and visit 
and treatment arm interaction.  The estimate of treatment difference for the average percent 
change from baseline of 24-hour urinary oxalate excretion across Months 4 through 6 will be 
calculated via a linear contrast of the corresponding coefficients from the MMRM model.  
Additionally, the percent change from baseline in 24-hour urinary oxalate excretion at Month 9 
and Month 15 will be summarized and compared between lumasiran and placebo treatment 
groups. 
Baseline, Month 9, and Month 15 urinary oxalate values and urinary calcium oxalate 
supersaturation values are planned to be collected in either duplicate or triplicate (baseline) and 
duplicate (Months 9 and 15), and the calculated median of valid collections during each time 
period (visit) will be used in the analysis. 
Analysis of secondary endpoints and exploratory endpoints will be specified in the SAP.  No 
multiplicity adjustment is planned. 
7.2.6. 
Pharmacodynamic Analysis 
The change in plasma oxalate and plasma and urinary glycolate will be summarized over time 
for all patients in the FAS. 
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7.2.7. 
Pharmacokinetic Analysis 
Pharmacokinetic analyses will be conducted using noncompartmental methods. 
Pharmacokinetic parameters to be calculated include but will not be limited to maximum plasma 
concentration (Cmax) and time to maximum plasma concentration (tmax).  Other parameters may 
be calculated, if deemed necessary. 
7.2.8. 
Safety Analyses 
The primary parameter is the frequency of treatment-emergent AEs (hereafter referred to simply 
as AEs).  Safety parameters also include vital signs, clinical laboratory assessments and physical 
exams.  Extent of exposure will be summarized by dose and overall.  
Prior and concomitant medications will be coded using the World Health Organization (WHO) 
Drug Dictionary.  Results will be tabulated by Anatomical Therapeutic Chemical (ATC) 
Classification System and preferred term (PT). 
Adverse events will be classified according to the Medical Dictionary for Regulatory Activities 
(MedDRA) System Organ Class (SOC) and PT by dose level and overall.  Adverse events, 
SAEs, related AEs, AEs leading to discontinuation of study drug, and AEs leading to death will 
be summarized by SOC and PT for each treatment arm.  By-patient listings will be provided for 
deaths, SAEs, and AEs leading to discontinuation of study drug.  
Descriptive statistics, summarizing the observed values and changes from baseline over time, 
will be provided for clinical laboratory parameters and vital signs.  Laboratory shift tables from 
baseline grade (or category) to worst post-baseline grade (or category) will be presented for 
laboratory parameters that are graded or categorized.  Abnormal physical exam findings will be 
presented in listings. 
Other safety summaries will be presented as appropriate.  Further details will be specified in the 
SAP. 
7.2.9. 
Immunogenicity Analyses 
The frequency and percentage of patients with confirmed positive ADA assay at any time during 
study as well as at each scheduled visit will be summarized.  The titer results for patients with 
confirmed positive ADA results will be summarized. 
7.2.10. 
Other Analyses 
Other exploratory analyses will be described in the SAP. 
7.2.11. 
Interim Analysis 
No formal interim analysis is planned.  The primary analysis will be conducted for the primary 
and secondary endpoints through Month 6 after the last patient has completed the Month 6 visit, 
the database is locked, and data are unblinded. 
7.2.12. 
Optional Additional Research 
Optional additional research may be conducted in the future on the biological samples and/or 
data collected during the study in accordance with the strict terms of the ICF (see Section 4.3.2). 
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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. 
8.1.1. 
Informed Consent 
The Investigator will ensure that the patient is given full and adequate oral and written 
information about the nature, purpose, possible risk and benefit of the study.  Patients must also 
be notified that they are free to discontinue from the study at any time.  The patient should be 
given the opportunity to ask questions and allowed time to consider the information provided. 
The Investigator will inform the patient if new information becomes available that may be 
relevant to the patient’s willingness to continue participation in the study.  Communication of 
this information should be documented.  If circumstances warrant an updated informed consent 
during the study, and patients are required to re-consent, this may be collected remotely where 
local regulations allow. 
The patient’s signed and dated informed consent (in paper or electronic format per local 
regulations and institutional standards) must be obtained before conducting any study tests or 
procedures that are not part of routine care. 
The Investigator must maintain the original, signed ICF.  All patients will be given a copy of the 
signed and dated ICF. 
8.1.2. 
Ethical Review 
The study protocol, including the ICF, 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.  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 patient consent 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 6.5.5.  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 randomized under the 
amended protocol, and patients must be re-consented to the most current version of the ICF. 
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 (including personal data) relating to the study should be retained for 2 years 
after the last approval in an ICH territory or as required by local laws and regulations, 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 to be submitted to the Sponsor or designees, the names will be obliterated, and the 
assigned patient number added to the document, before sending to the Sponsor.  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 EOS 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. 
Where local regulations allow, the Monitor may request remote access to source documents and 
systems.  Should this take place, it will be done in a manner that protects the confidentiality of 
the data. 
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8.2.3. 
Audits and Inspections 
Periodically, the Sponsor or its authorized representatives audit clinical investigative sites as an 
independent review of core trial processes and documents to determine whether these activities 
were conducted, and data were recorded, analyzed, and accurately reported according to the 
protocol, GCP guidelines of the ICH, and any applicable regulatory requirements.  A regulatory 
authority, an IEC or an IRB may visit the site to perform audits or inspections, including source 
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 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 will detail the procedures for 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 
Borghi L, Schianchi T, Meschi T, Guerra A, Allegri F, Maggiore U, et al. Comparison of two 
diets for the prevention of recurrent stones in idiopathic hypercalciuria. N Engl J Med. 2002 Jan 
10;346(2):77-84. 
Curhan GC,Taylor EN. 24-h uric acid excretion and the risk of kidney stones. Kidney Int. 2008 
Feb;73(4):489-96. 
Dhondup T, Kittanamongkolchai W, Vaughan LE, Mehta RA, Chhina JK, Enders FT, et al. Risk 
of ESRD and Mortality in Kidney and Bladder Stone Formers. Am J Kidney Dis. 2018 
Dec;72(6):790-7. 
Ferraro PM, Ticinesi A, Meschi T, Rodgers A, Di Maio F, Fulignati P, et al. Short-Term 
Changes in Urinary Relative Supersaturation Predict Recurrence of Kidney Stones: A Tool to 
Guide Preventive Measures in Urolithiasis. J Urol. 2018 Nov;200(5):1082-7. 
Heilberg IP,Schor N. Renal stone disease: Causes, evaluation and medical treatment. Arq Bras 
Endocrinol Metabol. 2006 Aug;50(4):823-31. 
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. 
Mitchell JA, Knowles RB, Kirkby NS, Reed DM, Edin ML, White WE, et al. Kidney 
Transplantation in a Patient Lacking Cytosolic Phospholipase A2 Proves Renal Origins of 
Urinary PGI-M and TX-M. Circ Res. 2018 Feb 16;122(4):555-9. 
Pearle MS, Goldfarb DS, Assimos DG, Curhan G, Denu-Ciocca CJ, Matlaga BR, et al. Medical 
management of kidney stones: AUA guideline. J Urol. 2014 Aug;192(2):316-24. 
Prochaska M, Taylor E, Ferraro PM,Curhan G. Relative Supersaturation of 24-Hour Urine and 
Likelihood of Kidney Stones. J Urol. 2018 May;199(5):1262-6. 
Rule AD, Bergstralh EJ, Melton LJ, 3rd, Li X, Weaver AL,Lieske JC. Kidney stones and the risk 
for chronic kidney disease. Clin J Am Soc Nephrol. 2009 Apr;4(4):804-11. 
Scales CD, Jr., Smith AC, Hanley JM, Saigal CS,Urologic Diseases in America P. Prevalence of 
kidney stones in the United States. Eur Urol. 2012 Jul;62(1):160-5. 
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. 
Shin S, Srivastava A, Alli NA,Bandyopadhyay BC. Confounding risk factors and preventative 
measures driving nephrolithiasis global makeup. World J Nephrol. 2018 Nov 24;7(7):129-42. 
Türk C, Neisius A, Petřík A, Skolarikos A, Somani B, Thomas K, et al., editors. EAU Guidelines 
on Urolithiasis. EAU Annual Congress; 2021; Milan, Italy: EAU Guidelines Office. 
Worcester EM,Coe FL. Nephrolithiasis. Prim Care. 2008 Jun;35(2):369-91, vii. 
Worcester EM,Coe FL. Clinical practice. Calcium kidney stones. N Engl J Med. 2010 Sep 
2;363(10):954-63. 
 
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10. 
APPENDICES 
10.1. 
Formula for Estimated Glomerular Filtration Rate Calculation 
CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration).  A new equation to estimate 
glomerular filtration rate.  Ann Intern Med. 2009 May 5;150(9):604-12. 
• Conventional units 
− eGFR (mL/min/1.73m2) = 175 × (SCr [mg/dL])-1.154 × (age)-0.203 × (0.742, if 
female), or × (1.212, if African American) 
• SI units 
− eGFR (mL/min/1.73m2) = 175 × (SCr [μmol/L]/88.4)-1.154 × (age)-0.203 × (0.742, if 
female), or × (1.212, if African American) 
 
Abbreviations:  eGFR= Estimated glomerular filtration rate; SCr=serum creatinine; SI=International System of 
Units 
200

SAP_001.pdf: 
 
 
Official Title:  A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO EVALUATE 
THE EFFICACY, SAFETY, PHARMACODYNAMICS, ANDPHARMACOKINETICS OF LUMASIRAN IN 
PATIENTS WITH RECURRENT CALCIUM OXALATE KIDNEY STONE DISEASE AND ELEVATED URINARY 
OXALATE LEVELS  
 
NCT Number:   
NCT05161936 
 
Document Date:   
SAP, Version 1.0, 31 March 2022  


Statistical Analysis Plan, Study ALN-GO1-008 
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STATISTICAL ANALYSIS PLAN 
ALN-GO1-008 
Protocol Title: 
A Randomized, Double-blind, Placebo-controlled Study to Evaluate 
the Efficacy, Safety, Pharmacodynamics, and Pharmacokinetics of 
Lumasiran in Patients with Recurrent Calcium Oxalate Kidney 
Stone Disease and Elevated Urinary Oxalate Levels 
Short Title: 
A Study to Evaluate Lumasiran in Adults with Recurrent Calcium 
Oxalate Kidney Stone Disease and Elevated Urinary Oxalate 
Levels 
Study Drug: 
Lumasiran (ALN-GO1) 
Phase: 
2 
Protocol Date: 
Original Protocol: 24 June 2021 
SAP Date: 
Original SAP: 31 March 2022 
Sponsor: 
Alnylam Pharmaceuticals, Inc. 
300 Third Street 
Cambridge, MA 02142 USA 
Telephone: +1-617-551-8200 
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, Study ALN-GO1-008 
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APPROVAL SIGNATURE PAGE 
 
This document has been authored, approved, and signed electronically on the final page by 
the following: 
 
 
 
Alnylam Pharmaceuticals, Inc. 
 
 
This document has been approved and signed electronically on the final page by the 
following: 
 
 
 
Alnylam Pharmaceuticals, Inc. 
 
 
 
Alnylam Pharmaceuticals, Inc. 
 
 
 
Alnylam Pharmaceuticals, Inc. 


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TABLE OF CONTENTS 
APPROVAL SIGNATURE PAGE .................................................................................................2 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF TABLES ...........................................................................................................................5 
LIST OF FIGURES .........................................................................................................................5 
LIST OF ABBREVIATIONS ..........................................................................................................6 
1. 
INTRODUCTION ........................................................................................................8 
2. 
STUDY DESIGN .........................................................................................................8 
2.1. 
Synopsis of Study Design .............................................................................................8 
2.2. 
Objectives and Endpoints .............................................................................................8 
2.2.1. 
Objectives .....................................................................................................................8 
2.2.1.1. 
Primary Objective .........................................................................................................8 
2.2.1.2. 
Secondary Objectives ...................................................................................................9 
2.2.1.3. 
Exploratory Objectives .................................................................................................9 
2.2.1.4. 
Safety Objective ............................................................................................................9 
2.2.2. 
Endpoints ......................................................................................................................9 
2.2.2.1. 
Primary Endpoint ..........................................................................................................9 
2.2.2.2. 
Secondary Endpoints ....................................................................................................9 
2.2.2.3. 
Exploratory Endpoints ................................................................................................10 
2.2.2.4. 
Safety Endpoint ..........................................................................................................10 
2.3. 
Study Procedures ........................................................................................................10 
2.4. 
Randomization Methodology .....................................................................................10 
2.5. 
Blinding ......................................................................................................................11 
2.6. 
Determination of Sample Size ....................................................................................11 
3. 
ANALYSIS POPULATIONS ....................................................................................12 
4. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................13 
4.1. 
General Considerations ...............................................................................................13 
4.2. 
Multiple Comparisons/Multiplicity Procedure ...........................................................13 
4.3. 
Handling of Missing Data ...........................................................................................13 
4.4. 
Baseline Definitions ....................................................................................................13 
4.5. 
Randomization Stratification Factors .........................................................................14 
4.6. 
Planned Analyses ........................................................................................................14 


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4.7. 
Visit Windows ............................................................................................................14 
5. 
STATISTICAL ANALYSES FOR THE DOUBLE-BLIND PERIOD .....................15 
5.1. 
Patient Disposition ......................................................................................................15 
5.2. 
Demographics and Baseline Characteristics ...............................................................15 
5.3. 
Medical History ..........................................................................................................16 
5.4. 
Protocol Deviations ....................................................................................................16 
5.5. 
Study Drug Exposure and Compliance .......................................................................16 
5.6. 
Prior and Concomitant Medications ...........................................................................17 
5.7. 
Efficacy Analyses .......................................................................................................17 
5.7.1. 
Primary Endpoint(s) ....................................................................................................17 
5.7.1.1. 
Definition of Estimand ...............................................................................................17 
5.7.1.2. 
Primary Analysis ........................................................................................................18 
5.7.1.3. 
Sensitivity Analyses ....................................................................................................19 
5.7.1.4. 
Other Analyses ............................................................................................................19 
5.7.2. 
Secondary Endpoints ..................................................................................................19 
5.7.3. 
Exploratory Endpoints ................................................................................................20 
5.7.3.1. 
Kidney Stone Events ...................................................................................................20 
5.7.3.2. 
Pharmacodynamics .....................................................................................................21 
5.7.3.3. 
Change from Baseline in eGFR ..................................................................................21 
5.7.3.4. 
Healthcare Utilization and Quality of Life .................................................................21 
5.7.4. 
Evaluation of Subgroups .............................................................................................22 
5.8. 
Pharmacodynamic Analyses .......................................................................................23 
5.9. 
Pharmacokinetic Analyses ..........................................................................................23 
5.10. 
Anti-Drug Antibodies .................................................................................................23 
5.11. 
Safety Analyses ..........................................................................................................23 
5.11.1. 
Adverse Events ...........................................................................................................24 
5.11.2. 
Laboratory Data ..........................................................................................................25 
5.11.3. 
Vital Signs and Physical Examination ........................................................................26 
5.12. 
Interim Analysis ..........................................................................................................26 
5.13. 
Other Analyses ............................................................................................................27 
5.13.1. 
General Impact ............................................................................................................27 
5.13.2. 
Impact on Efficacy ......................................................................................................27 
5.13.3. 
Impact on Adverse Events ..........................................................................................27 


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6. 
CHANGES FROM PLANNED ANALYSES............................................................27 
7. 
APPENDICES ............................................................................................................29 
7.1. 
Protocol Schedule of Assessments .............................................................................29 
 
 
7.3. 
Imputation for Missing or Partial Dates .....................................................................35 
 
LIST OF TABLES 
Table 1: 
Sample Size Power Calculations ................................................................................12 
Table 2: 
Intercurrent Event Strategies for the Primary Analysis of Primary Endpoint ............18 
 
LIST OF FIGURES 
Figure 1: 
Study Design .................................................................................................................8 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADA 
Antidrug antibodies  
AE 
Adverse event 
ALT 
Alanine transaminase 
AST 
Aspartate transaminase 
ATC 
Anatomical therapeutic chemical 
AUC 
Area under the curve 
BMI 
Body mass index 
CI 
Confidence interval 
CMH 
Cochran–Mantel–Haenszel test  
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DB 
Double-blind 
EDC 
Electronic Data Capture 
eGFR 
Estimated glomerular filtration rate 
eCRF 
Electronic case report form 
EOS 
End of study 
EOT 
End of treatment 
FA 
Final analysis 
FAS 
Full Analysis Set 
HLT 
High Level Term 
IRT 
Interactive Response Technology 
LFT 
Liver function test 
LLN 
Lower limit of normal 
LLOQ 
Lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-effect model for repeated measures 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PT 
Preferred term 
Q1 
First quartile 


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Abbreviation 
Definition 
Q3 
Third quartile 
QOL 
Quality of life 
RBP 
Randomization and blinding plan 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation  
SE 
Standard error 
SEM 
Standard error of the mean 
SMQ 
Standardized MedDRA queries 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
ULOQ 
Upper limit of quantification 


Statistical Analysis Plan, Study ALN-GO1-008 
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1. 
INTRODUCTION 
This statistical analysis plan (SAP) details comprehensive specifications of the statistical 
analyses of efficacy, safety, pharmacokinetic (PK) and pharmacodynamic (PD) data in support of 
the clinical study report for Study ALN-GO1-008. Table, figure, and listing (TFL) mocked shells 
and specifications are contained in a separate document. 
2. 
STUDY DESIGN  
2.1. 
Synopsis of Study Design  
The ALN-GO1-008 study is a multi-center, multinational, Phase 2 study designed to evaluate the 
efficacy, safety, PD, and PK of lumasiran administered subcutaneously (SC) in patients with 
recurrent calcium oxalate kidney stone disease and elevated urinary oxalate levels. The study 
consists of a screening period of up to 2 months, a 1:1:1 randomized, placebo-controlled, double-
blind (DB) treatment period of 15 months (a 6-month Primary Analysis Period followed by a 9-
month Treatment Extension Period), and a safety follow-up for patients who discontinue 
treatment early. 
The study design schema is presented in Figure 1.  
Figure 1: 
Study Design 
 
2.2. 
Objectives and Endpoints 
2.2.1. 
Objectives 
2.2.1.1. 
 Primary Objective 
• To evaluate the effect of lumasiran on the percent change in urinary oxalate excretion 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2.2.1.2. 
Secondary Objectives 
• To evaluate the percentage of patients who achieve a ≥20% reduction in 24-hour 
urinary oxalate with lumasiran 
• To evaluate the effect of lumasiran on urinary calcium oxalate supersaturation 
2.2.1.3. 
Exploratory Objectives 
• To evaluate the effect of lumasiran on absolute levels of urinary oxalate excretion 
• To evaluate the effect of lumasiran on the occurrence of kidney stones 
• To evaluate additional PD parameters of plasma oxalate, plasma glycolate, and 
urinary glycolate 
• To characterize PK of lumasiran 
• To assess for antidrug antibodies (ADA) against lumasiran 
• To evaluate the effect of lumasiran on spot urinary oxalate:creatinine ratios 
• To evaluate the effect of lumasiran on maintaining 24-hour urinary oxalate ≤upper 
limit of normal (ULN) over time 
• To evaluate the effect of lumasiran on maintaining a 25% reduction in urinary 
calcium oxalate supersaturation over time 
• To evaluate the effect of lumasiran on 24-hour urinary oxalate excretion after Month 
6 
• To evaluate the effect of lumasiran on estimated glomerular filtration rate (eGFR) 
• To evaluate the effect of lumasiran on patient healthcare resource utilization 
• To assess the impact of kidney stone events on patient-reported pain and quality of 
life (QoL) 
2.2.1.4. 
Safety Objective 
• To evaluate the safety and tolerability of lumasiran 
2.2.2. 
Endpoints 
2.2.2.1. 
Primary Endpoint 
• Percent change in 24-hour urinary oxalate from baseline to Month 6 (average across 
Months 4 through 6) 
2.2.2.2. 
Secondary Endpoints 
• Percentage of patients who achieve a ≥20% reduction in 24-hour urinary oxalate from 
baseline to Month 6 (average across Months 4 through 6) 
• Percent change in urinary calcium oxalate supersaturation from baseline to Month 6 
(average across Months 4 through 6) 


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2.2.2.3. 
Exploratory Endpoints 
• Absolute change in 24-hour urinary oxalate from baseline to Month 6 (average across 
Months 4 through 6) 
• Incidence rate of clinical and radiographic kidney stone events 
• Time to first kidney stone event 
• Change from baseline in plasma oxalate 
• Change from baseline in plasma glycolate 
• Change from baseline in urinary glycolate 
• Plasma PK of lumasiran 
• ADA frequency and titer 
• Change from baseline in spot urinary oxalate:creatinine ratios 
• Percentage of patients with 24-hour urinary oxalate ≤ULN over time 
• Percentage of patients having a 25% reduction in urinary calcium oxalate 
supersaturation over time 
• Change from baseline in 24-hour urinary oxalate excretion after Month 6 
• Change from baseline in eGFR 
• Kidney stone event related hospitalizations, emergency room visits, unscheduled 
office visits, or procedures 
• Patient-reported severity and symptomatic and functional impact of kidney stone 
events 
2.2.2.4. 
Safety Endpoint 
• Frequency of AEs 
2.3. 
Study Procedures 
The Schedule of Assessments from the protocol is included as Section 7.1. 
2.4. 
Randomization Methodology 
Patients will be randomized 1:1:1 to receive lumasiran 284 mg, lumasiran 567 mg, or placebo in 
a DB manner. Stratification will be performed at randomization according to baseline urinary 
oxalate level (≤1.25 × ULN vs >1.25 × ULN) from the mean of the first 2 valid 24-hour urine 
collections and the number of historical kidney stone events in the 12 months prior to screening 
(≤1 vs >1). 
For stratification, a historical kidney stone event is defined as: 
• the visible passage of a kidney stone 
• a procedural intervention for removal of an asymptomatic or symptomatic stone 


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−  if more than 1 stone was removed in a given procedure, this counts as 1 event 
unless bilateral ureteral stones were removed, in which case this counts as 2 
events 
− if more than 1 procedure was required to remove a single stone, this counts as 1 
event 
• a new (≥1 mm) or enlarged (by ≥2 mm) kidney stone on computed tomography (CT) 
imaging 
− it must be evident from the CT scans that the new or enlarged kidney stone event 
occurred during the 12 months prior to screening 
− if a procedure was performed to remove the stone(s) identified by CT, then only 
the procedure will be counted to avoid double counting the same stone. 
2.5. 
Blinding  
The randomization schedule is maintained by the interactive response technology (IRT) vendor. 
Alnylam is unblinded throughout the entire study. However, during the 15-month DB treatment 
period, investigators, site personnel, patients, and selected vendor personnel as outlined in the 
Randomization and Blinding Plan (RBP), will remain blinded to treatment assignment and any 
clinical laboratory results that could potentially unblind them, including PK data, ADA, and PD 
data (post-baseline results for 24-hour urinary oxalate, spot urinary oxalate:creatine, plasma 
oxalate, plasma and urinary glycolate, urinary calcium oxalate supersaturation), until study 
unblinding which will occur after all patients have completed Month 15 visits. 
Unblinding is only to occur in the case of patient emergencies, or when necessary from a 
regulatory reporting perspective (eg, Suspected Unexpected Serious Adverse Reaction 
[SUSAR]), or after all patients have completed the 15-month DB treatment period and the 
unblinding authorization has been executed. 
Details about the specifics of the blinding aspects for the study are outlined in the RBP. 
2.6. 
Determination of Sample Size 
The planned enrollment for this study is 120 patients. 
The study is powered to detect a difference in urinary oxalate excretion between each lumasiran 
group and the placebo group. Assuming a standard deviation of 45% in the percent change from 
baseline in 24-hour urinary oxalate levels at Month 6, a sample size of 40 patients per group will 
enable a power of at least 80% in detecting a treatment difference of 30% between the treatment 
groups at a 2-sided significance level of 0.05. Table 1 shows the statistical power under various 
assumptions for a sample size of 40 per group. 


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Table 1: 
Sample Size Power Calculations 
Assumed standard 
deviation (SD) 
Assumed difference 
(lumasiran – placebo) 
Power 
25% 
20% 
94% 
30% 
99% 
30% 
20% 
84% 
30% 
99% 
45% 
20% 
50% 
30% 
84% 
Abbreviations:  SD=standard deviation 
No multiplicity adjustment is considered in the sample size calculation.  
3. 
ANALYSIS POPULATIONS 
The populations (analysis sets) are defined as follows: 
• Full Analysis Set (FAS): All randomized patients who received at least 1 dose of 
study drug. Patients in the FAS will be analyzed according to the randomized 
treatment arm. 
• Safety Analysis Set: All patients who received at least 1 dose of study drug. Patients 
in the Safety Analysis Set will be analyzed according to the treatment actually 
received. 
• PK Analysis Set: All patients who received at least 1 full dose of study drug and have 
at least 1 post-dose blood sample for PK parameters and have evaluable PK data. 
• Plasma Oxalate Analysis Set: All patients who received at least 1 dose of study drug 
and have a baseline plasma oxalate level ≥1.5 times the lower limit of 
quantification/detection (LLOQ). The LLOQ of the plasma oxalate assay is 5.55 
µmol/L. Because it is not possible to quantify plasma oxalate levels below LLOQ 
using the assay, patients with baseline plasma oxalate levels near the LLOQ (ie 
<1.5*LLOQ) are excluded from the analysis to ensure that meaningful reductions in 
plasma oxalate can be evaluated for the study population. 
The primary population used to evaluate efficacy will be the FAS. Safety will be analyzed using 
the Safety Analysis Set. The PK Analysis Set will be used to conduct PK analyses. Both the FAS 
and Safety Analysis Set will be used to summarize demographic and baseline disease 
characteristics. The Safety Analysis Set will be used for medical history, prior and concomitant 
medications, and protocol deviations. The Plasma Oxalate Analysis Set will be used to evaluate 
the endpoint for the change from baseline in plasma oxalate. 


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4. 
GENERAL STATISTICAL CONSIDERATIONS 
Statistical analyses will be conducted using SAS software Version 9.4 or newer or R version 3.6 
or newer. 
4.1. 
General Considerations 
Categorical variables will be summarized using counts and percentages. The percentage will not 
be presented for a count of zero.  
Continuous variables will be summarized using the following descriptive summary statistics: 
number of patients (n), mean, standard deviation (SD), standard error of the mean (SEM), 
median, first quartile (Q1), third quartile (Q3), minimum, and maximum. The same level of 
precision collected in the database will be displayed for the minimum and maximum, plus one 
additional decimal for the mean and median, plus 2 additional decimals for SD and SEM.  
For 24-hour urinary oxalate, urinary calcium oxalate supersaturation, and 24-hour urinary 
glycolate:creatinine ratios, the median of valid collections will be used as the value at any visit 
where multiple collections are done because of the variability of these parameters. For other PD 
parameters, the mean of all assessments will be used if multiple collections are done at a given 
visit. For safety laboratory parameters, assessments collected and recorded as lower than the 
LLOQ will be replaced by the LLOQ. Any assessment collected and recorded as greater than the 
upper limit of quantification (ULOQ) will be replaced by the ULOQ. The day of the first dose of 
study drug administered is defined as Day 1. The Study Day of a time point of interest is 
calculated as follows. 
If on or after Day 1, Study Day = date of interest – date of the first dose of study drug + 1 
If prior to Day 1, Study Day = date of interest – date of the first dose of study drug 
There is no Day 0. For example, the day before the first study drug dose is defined as Day -1. 
All descriptive summaries will be presented by treatment arm (lumasiran 284 mg, lumasiran 567 
mg, placebo) and overall, where applicable. In addition to presentation by treatment arm, a pool 
of lumasiran 284 mg and 567 mg will also be presented as all lumasiran treatment for the safety 
analysis. 
4.2. 
Multiple Comparisons/Multiplicity Procedure 
No multiplicity adjustment is planned.  
4.3. 
Handling of Missing Data 
No explicit imputation will be done for missing values for the analyses of the primary, 
secondary, or exploratory endpoints. For all analyses using mixed-effect model for repeated 
measures (MMRM), the model makes use of all available data, including patients with partial 
data (i.e., with missing data), to estimate the mean treatment effect without employing formal 
imputation. 
4.4. 
Baseline Definitions 
Baselines for efficacy parameters are defined as follows: 


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• For 24-hour urinary oxalate, urinary calcium oxalate supersaturation, and 24-hour 
urinary glycolate:creatinine ratios, baseline will be defined using the median value 
from all valid 24-hour urine collections obtained prior to the date of the first dose of 
study drug. 
• For other PD parameters, baseline will be defined as the mean of all measurements 
collected prior to the first dose of study drug. 
For laboratory parameters and vital signs, baseline will be defined as the last non-missing value 
available (scheduled and unscheduled) prior to the date and time of the first dose of lumasiran. 
4.5. 
Randomization Stratification Factors 
The baseline urinary oxalate level (≤1.25 × ULN vs >1.25 × ULN) from the mean of the first 2 
valid 24-hour urine collections and the number of historical kidney stone events in the 12 months 
prior to screening (≤1 vs >1) will be used as stratification factors. These stratification factors are 
recorded in both the IRT and the clinical database. In statistical analyses that use randomization 
stratification factors as covariates, the stratum assignment will reflect the values as recorded in 
the clinical database (EDC). In the presence of stratification errors, the stratification used in 
analysis may not match that in the IRT. A comparison of the number and percentage of patients 
in each randomization stratification factor in IRT versus the clinical database will be summarized 
by randomized treatment arm and overall. 
4.6. 
Planned Analyses  
The primary analysis will be performed after all randomized patients have completed the Month 
6 visit or discontinued from the study. For the primary analysis, as this study will be ongoing 
with some patients in the 9-Month Treatment Extension Period, the study database will be locked 
with all data up to a prespecified cutoff date quality controlled, ie, data in the EDC system will 
be cleaned and frozen and external laboratory data will be cleaned and quality controlled (and 
quality assured, where appropriate).  
The primary analysis will include data on or prior to this prespecified cutoff date. For the 
efficacy summaries, all data up to and including the Month 6 visit will be presented. For 
assessments with start and end dates (eg, AEs, medications), the start date will be compared with 
the pre-specified cutoff date. Data records with start dates after the specified data cutoff date will 
be excluded. 
The final analysis will be conducted after all patients have completed the Month 15 visit or 
discontinued from the study. The database will undergo a final lock. 
Additional details regarding the database lock process are located in the study Data Management 
Plan. 
4.7. 
Visit Windows 
For PD and safety parameters, no window rules will be implemented, and the reported eCRF 
visits will be used for analysis. 
The following general conventions for unscheduled assessments will apply unless otherwise 
specified: 


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• If by-visit summaries are based on CRF Visit, only scheduled assessments will be 
included in by-visit summaries. Unscheduled assessments will not be included. 
• Unscheduled assessments will be used in the calculation of baseline values and for 
shift from baseline to worst post-baseline tables. They will also be included in by-
patient listings and spaghetti plots.  
5. 
STATISTICAL ANALYSES FOR THE DOUBLE-BLIND PERIOD 
5.1. 
Patient Disposition 
The number and percentage of patients in the following categories will be summarized by 
treatment arm and overall, for the FAS and Safety Analysis Set: 
• Randomized 
• Treated 
• Completed the Month 6 visit  
• Completed treatment 
• Completed the study 
• Discontinued treatment and primary reason for discontinuation of treatment 
• Withdrew from study and primary reason for withdrawal from study 
A patient is defined as having completed the Month 6 visit if the patient has any of the 
assessments required for the Month 6 visit. 
The number and percentage of patients who met criteria for the FAS, Safety Analysis Set, and 
PK Analysis Set will be summarized by all randomized patients.  
The number and percent of patients enrolled by country and site will be summarized by 
randomized arm and overall.  
Screen failures and the reason for screen failure will be summarized by all screened patients.  
A data listing for treatment/study completion information along with the primary reasons for 
treatment discontinuation and/or study withdrawal will be generated.  
5.2. 
Demographics and Baseline Characteristics 
Demographic and baseline disease characteristics will be summarized by treatment arm and 
overall using the FAS and Safety Analysis Set, and also presented in listings. 
Demographic characteristics including age at screening (years), height (cm), weight (kg), and 
body mass index (BMI [kg/m2]) will be summarized using descriptive statistics. Age group (18 
to <65, ≥65), sex, race, ethnicity, and region (US, Europe) will be summarized by presenting the 
frequencies and percentages of patients in each category.   
Baseline disease characteristics including 24-hour urinary oxalate excretion (mg/24hr), urinary 
calcium oxalate supersaturation (DG), plasma oxalate (µmol/L), plasma glycolate (µmol/L), 24-


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hour urinary glycolate:creatinine ratios (mmol/mmol), spot urinary oxalate:creatinine ratios 
(mmol/mmol), and eGFR (mL/min/1.73m2) will be summarized by descriptive statistics. 
Heterozygosity for any AGXT mutation (Yes/No) will be summarized by the number and 
percentage of patients in each category. 
A tabulation of historical kidney stone events that occurred within 5 years prior to screening and 
within 12 months prior to screening will be presented. The number of kidney stone events will be 
summarized using descriptive statistics. Additional characteristics will be summarized by 
presenting the numbers and percentages of patients in each category: 
• Patients with at least one kidney stone event (visible passage of kidney stones, a 
procedural intervention for removal of an asymptomatic or symptomatic stone, a new 
or enlarged kidney stone on CT imaging) 
• Patients with at least one kidney stone event related hospitalizations, emergency room 
visits, urgent care, or urgent/unscheduled office visits 
• Patients with a stone composition >50% calcium oxalate from the 2 most recently 
analyzed kidney stones (Yes/No) 
• Patients for whom only 1 kidney stone was available for composition analysis  
5.3. 
Medical History 
Medical or surgical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA), version 24.1 or newer. Unique patients who report medical history events will be 
summarized and listed for the Safety Analysis Set by MedDRA system organ class (SOC), high 
level term (HLT) and preferred term (PT). 
5.4. 
Protocol Deviations 
Protocol deviations will be classified by medical review prior to the 6-month primary analysis 
and prior to the FA database lock. Major protocol deviations will be identified in the protocol 
deviation file. A major protocol deviation is a deviation that may significantly impact the 
completeness, accuracy, and/or reliability of the trial data; that may significantly affect a 
subject's rights, safety, or well-being (ICH E3 R1 Structure and Contents of Clinical Study 
Reports Guidance for Industry, 2013). 
The Sponsor or designee will be responsible for producing the protocol deviation file. This file 
will include a description of each protocol deviation and whether each deviation is classified as 
major. The file will be reviewed and finalized prior to the 6-month primary analysis database 
lock and prior to the FA database lock. 
All protocol deviations and major protocol deviations will be summarized and listed for the 
Safety Analysis Set. 
5.5. 
Study Drug Exposure and Compliance 
The following variables will be summarized by descriptive statistics and/or frequency tabulation 
for the Safety Analysis Set: 


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• Duration of study drug exposure (months), defined as: (date of last exposure – date of 
first dose +1)/30.44. Date of last exposure is the earliest date of the following:  
− date of last dose + 168 days (eg, the length of the longest dosing interval) 
− date of end of study 
− date of data cutoff for the analysis 
• Cumulative study drug exposure time (patient-years) 
• Number of patients on study drug for ≥1 day, ≥3 months, ≥6 months 
• Number of doses received as continuous and categorical variables (1, 2, or 3) 
• Cumulative number of doses received 
• Number of missed doses (0, 1, 2, or 3) as a categorical variable 
• Total study drug exposure (mg) as a continuous variable 
• Total volume administered (mL) 
5.6. 
Prior and Concomitant Medications 
Medications will be coded using the World Health Organization (WHO) Drug Dictionary, 
version B3 WHO Drug Global - Sep 2018 or newer. Unique patients who reported medications 
will be summarized by Anatomical Therapeutic Chemical (ATC) level 3 class (or level 2 if not 
available) and PT. Summaries and listings for the Safety Analysis Set will be provided for prior 
and concomitant medications separately. 
Prior medications are defined as medications with start date and stop date prior to the first dose 
of study drug. Concomitant medications are medications, other than the study drug, administered 
on or after the first dose date of study drug, as well as medications that started prior to the first 
dose of study drug and are ongoing after the first dose of study drug. If medication start date is 
on or after the date of first dose of study drug, the medication will be summarized as a 
concomitant medication even if the medication end date is missing. If the end date of a 
medication is missing or incomplete such that it cannot be determined whether it is after the first 
dose of study drug, it will be counted as a concomitant medication. 
For missing or partial dates for medications, the imputation of start and end dates is described in 
Section 7.3. 
5.7. 
Efficacy Analyses 
5.7.1. 
Primary Endpoint(s) 
5.7.1.1. 
Definition of Estimand 
For the primary objective of evaluating the efficacy of the study drug lumasiran compared with 
placebo on the percent change in urinary oxalate excretion, the primary estimand is defined as 
follows: 


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• Target population: Patients with recurrent calcium oxalate kidney stone disease and 
elevated urinary oxalate levels. 
• Treatment condition: Lumasiran 284 mg, lumasiran 567 mg, or placebo 
administered by SC injection at Day 1, Month 3, and Month 9 
• Endpoint: the percent change in 24-hour urinary oxalate from baseline to Month 6 
(average across Months 4 through 6) 
• Population-level summary: the least square (LS) mean difference in percent change 
in 24-hour urinary oxalate from baseline to Month 6 (average across Months 4 
through 6) between each lumasiran dose group and the placebo arm. 
• Strategies for intercurrent events (ICE):  
Table 2: 
Intercurrent Event Strategies for the Primary Analysis of Primary Endpoint 
Intercurrent Event 
Strategy with Rationale 
Selected medication of 
vitamin C equivalence1 
Hypothetical strategy: 24-hour urinary oxalate collection will be 
excluded from the analysis if dose of vitamin C equivalent to ≥500 mg 
in a single day is taken at any point within 4 days prior to the start of 
or during the urine collection. Rationale: vitamin C can be converted 
to oxalate, confounding urinary oxalate measurement. 
1 To identify vitamin C equivalence, two Alnylam physicians will each conduct an independent review of the 
concomitant medications to identify medications containing vitamin C. If there are any discrepancies, a meeting 
will be held to reach a consensus on each discrepancy. Once the medications are identified, the Alnylam DSS team 
will programmatically identify the total dose of vitamin C taken in a single day. 
5.7.1.2. 
Primary Analysis  
The hypothesis testing for the primary endpoint will be tested comparing each lumasiran group 
to the placebo group during the 6-month primary analysis period in the FAS with a 2-sided 
significance level of 0.05. 
The primary endpoint will be analyzed using an MMRM approach using the ICE strategy 
described in Table 2. The outcome variable is percent change from baseline in 24-hour urinary 
oxalate to Month 6. The model includes baseline 24-hour urinary oxalate (as defined in 
Section 4.4) and the stratification factor of number of historical kidney stone events (≤1 versus 
>1 event in the 12 months prior to screening) as covariates, and fixed effect terms including 
treatment arm (lumasiran 567 mg or lumasiran 284 mg vs placebo), visit (Months 3, 4, 5, 6) and 
treatment-by-visit interaction. The primary treatment effect estimate from this model will 
represent the average percent change from baseline in 24-hour urinary oxalate across months 4 
through 6, which is calculated via a linear contrast of the corresponding coefficients from the 
MMRM model. An unstructured covariance structure matrix will be used to model within-patient 
error. If the fit of the unstructured covariance structure matrix fails to converge, then the 
following covariance structure will be assessed in this order: autoregressive (1), compound 
symmetry, Toeplitz. The Satterthwaite approximation will be used to estimate the denominator 
degrees of freedom.  
The LS mean, standard error of the mean (SEM), 95% confidence interval (CI), and p-value will 
be generated for each treatment arm and the treatment difference between each lumasiran dose 


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and placebo from Months 4 through 6. In addition, the LS means, SEM, and 95% CI will also be 
generated for each visit (Months 3, 4, 5, 6) by treatment arm.  
5.7.1.3. 
Sensitivity Analyses  
A sensitivity analysis will be conducted including all data without censoring assessments after 
the initiation of select vitamin C equivalent medications.  
5.7.1.4. 
Other Analyses  
Descriptive statistics will also be generated for the actual values, change from baseline, and 
percent change from baseline at each scheduled visit by treatment arm. LS Mean (+/- SEM) 
figures of percent reduction by treatment arm will be plotted as well as individual spaghetti plots. 
Listings will also be generated. 
The exploratory endpoint of absolute change in 24-hour urinary oxalate from baseline to Month 
6 (average across Months 4 through 6) will be analyzed using the MMRM model specified for 
the primary endpoint. 
5.7.2. 
Secondary Endpoints 
The percentage of patients who achieve a ≥20% reduction in 24-hour urinary oxalate from 
baseline to Month 6 (average across Months 4 through 6) will be analyzed using the Cochran-
Mantel-Haenszel (CMH) test stratified by the 2 stratification factors (Section 4.5). The odds ratio 
with the corresponding 95% CI and associated p-value will be presented. In addition, the 
differences in proportion of responders and corresponding 95% CI using the Newcombe method 
based on the Wilson score will also be presented. In addition, a tabulation and a bar chart 
showing the proportion of patients with a ≥20% reduction in 24-hour urinary oxalate from 
baseline to each visit and on average across Months 4 through 6 will be presented.  
For the analysis of urinary calcium oxalate, selected medication could potentially impact the 
endpoint, therefore the assessments will be excluded from analysis if patients start, stop, or 
change any of the following medications within a specified time frame of the data collection:  
• Vitamin C equivalent to ≥500 mg in a single day is taken at any point within 4 days 
prior to the start of or during the urine collection (see Table 2) 
• The patient is on a new daily dose (relative to screening) of hydrochlorothiazide, 
allopurinol, topiramate, acetazolamide or furosemide at any point within 4 days prior 
to the start of or during the collection 
• Urine alkalinization agents (potassium citrate, potassium citrate-citric acid, sodium 
citrate-citric acid, sodium citrate-potassium citrate-citric acid, sodium bicarbonate, 
potassium bicarbonate, or potassium bicarbonate-potassium citrate) started, stopped, 
or changed at any point within 2 days prior to the start of or during the collection 
(relative to screening) 
Percent change in urinary calcium oxalate supersaturation from baseline to Month 6 (average 
across Months 4 through 6) will be analyzed using the same MMRM approach as for the primary 
endpoint. Descriptive statistics will also be generated for the actual values, change from baseline, 
and percent change from baseline at each scheduled visit by treatment arm. LS Mean (+/- SEM) 


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figures of percent reduction by treatment arm will be plotted as well as individual spaghetti plots. 
Listings will also be generated.  
A sensitivity analysis of the percent change in urinary calcium oxalate supersaturation from 
baseline to Month 6 (average across Months 4 through 6) will also be analyzed using the same 
approach as the main analysis above including all data without excluding assessments that could 
potentially be impacted by selected mediations. 
5.7.3. 
Exploratory Endpoints 
Apart from the 24-hr urinary oxalate, all other exploratory endpoints will be by treatment arm 
(lumasiran 567 mg, lumasiran 284 mg, placebo) during the 6-month primary analysis period 
using the FAS. These endpoints will also be summarized for the 15-month DB period by 
treatment arm using the FAS. The change from baseline in 24-hr urinary oxalate will be 
summarized after Month 6.  Listings will also be generated for each exploratory endpoint below. 
5.7.3.1. 
Kidney Stone Events 
CT scans for radiographic kidney stone events are read in pairs blinded to visit date (baseline and 
Month 15). All kidney stone-related analyses in this section will be done with all data collected. 
A clinical kidney stone event is defined as one of the following: 
• Visible passage of a kidney stone 
• A procedural intervention for removal of an asymptomatic or symptomatic stone 
(information on the location, number, and size of stones removed will be collected) 
• Or, in the case of potential stone passages without visible stones, it will be up to the 
Investigator to evaluate patients’ symptoms and determine whether a stone passage 
occurred or the symptoms were due to a different cause. 
A radiographic kidney stone event is defined as a kidney stone that is increased in size by ≥2 mm 
in at least one dimension or a new stone (≥1 mm in size) observed on CT at Month 15 relative to 
baseline. 
Time to first kidney stone event 
Time to first event is defined as date of the first study drug to the first date of a kidney stone 
event. Censoring applies to patients who do not have a kidney stone event during the study. The 
follow-up time of these patients will be censored at the lost to follow-up date, study 
discontinuation, data cut-off date, or end of study, whichever occurs first.  
Time to the first kidney stone event will be analyzed for a combination of both clinical and 
radiographic kidney stone events and for clinical kidney stone events separately for both the 6-
month primary analysis period and the 15-month DB period (FA). All available data at the time 
of each database lock will be used. Kaplan-Meier estimator will be used to estimate the 
distribution of time to first kidney stone event in each treatment group. A log-rank test will be 
used to evaluate the treatment differences between each dose and the placebo. In addition, Cox 
proportional hazard regression will be performed to estimate the hazard ratio along with the 95% 
CI and p-value for each dose compared to the placebo. The model includes treatment, number of 
historical kidney stone events (>1 versus ≤1) in the 12 months prior to screening. 


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Incidence rate of clinical and radiological kidney stone events 
The incidence rate of kidney stone events will be analyzed for a combination of both clinical and 
radiographic kidney stone events and for clinical kidney stone events separately for both the 6-
month primary analysis period and the 15-month DB period (FA).  
The incidence rate will be calculated as the total number of kidney stone events divided by total 
person-years at risk during the respective period (ie, 6-month primary analysis period and 15-
month DB period). Years at risk is defined as (time from first lumasiran dose until 168 days after 
the last dose of lumasiran, lost to follow-up date, study discontinuation, data cut-off date, or end 
of study, whichever occurs first)/365.25.  
The endpoint will be analyzed using a negative binomial regression model that include fixed 
effects of the treatment arm and the number of historical kidney stone events (>1 versus ≤1) in 
the 12 months prior to screening. The logarithm of the follow-up time of each patient will be 
included in the model as an offset variable. The p value and the ratio of mean kidney stone event 
rate between two treatment arms with the corresponding 95% CI will be estimated. 
The total number of patients with at least one kidney stone event, total number of kidney stone 
events, total number of person-years will be presented. Descriptive statistics for the median and 
interquartile range of the kidney stone event rate will also be presented by treatment arm. 
Other radiographic assessments 
Change from baseline in radiographic assessments of kidney stones (eg stone volume) will be 
summarized descriptively.  
5.7.3.2. 
Pharmacodynamics  
The PD exploratory endpoints are described in Section 5.8. 
5.7.3.3. 
Change from Baseline in eGFR  
Descriptive statistics of eGFR along with mean (+/-SEM) figures and individual spaghetti plots 
will be presented for the actual values, change from baseline, and percent change from baseline 
for each treatment arm by visit.  
5.7.3.4. 
Healthcare Utilization and Quality of Life  
Kidney stone event related hospitalizations, emergency room visits, unscheduled office 
visits, or procedures  
Healthcare utilization associated with a kidney stone event will be descriptively summarized for 
the number of visit type (hospitalization, emergency room, urgent care center, unscheduled 
office visit, other) per patient, cumulative length of hospital stay (days), and cumulative length of 
stay in the ICU. The number of, and percent of, patients with different type of visits 
(hospitalization, emergency room, urgent care center, unscheduled office visit, other) will also be 
presented.   
Patient-reported severity and symptomatic and functional impact of kidney stone events 
Quality of life (QoL) outcomes will be summarized using a two-sample t-test for the difference 
between the mean scores of each lumasiran dose to the placebo. The analyses will be performed 




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• Calcium oxalate stone composition (≤75%, >75%) 
• History of diabetes (Yes, No) 
Subgroup analyses will be performed for the primary endpoint of percent change in 24-hour 
urinary oxalate to Month 6 using the FAS population. A forest plot will be generated to illustrate 
the estimated treatment effect along with the associated 95% CI. If the number of patients in a 
subgroup for either arm is less than 10 patients, then only descriptive statistics will be generated. 
Other subgroups may be examined, if deemed appropriate.  The subgroup analyses may also be 
performed for other efficacy endpoints. 
5.8. 
Pharmacodynamic Analyses 
The PD parameters include plasma oxalate, plasma glycolate, 24-hour urinary 
glycolate:creatinine ratios, and spot urinary oxalate:creatinine ratios. Summary tables, mean (+/-
SEM) figures, and individual spaghetti plots will be provided for observed values, absolute 
changes, and percentage changes from baseline for each scheduled time point by treatment 
group. FAS is used for all PD parameters except for plasma oxalate where a separate analysis 
population, Plasma Oxalate Analysis Set is used.     
The number and percent of patients with 24-hour urinary oxalate ≤ULN (40 mg) and the number 
and percent of patients having a 25% reduction in urinary calcium oxalate supersaturation will be 
presented over time.  
5.9. 
Pharmacokinetic Analyses 
Plasma lumasiran concentrations by visit will be summarized descriptively for the PK Analysis 
Set. 
5.10. 
Anti-Drug Antibodies 
The number and percentage of patients with confirmed positive anti-drug antibody (ADA) assay 
results at baseline and at any post-baseline visit during the 6-month primary analysis period, as 
well as treatment-emergent ADA during the 6-month primary analysis period, will be 
summarized and listed for the Safety Analysis Set. The same summary and listing will also be 
done for the Month-15 DB period.  
Treatment-emergent ADA consist of treatment-induced ADA and treatment-boosted ADA, as 
defined below: 
• Treatment-induced ADA: Confirmed positive ADA developed de novo after drug 
administration in patients without preexisting (baseline) confirmed positive ADA 
• Treatment-boosted ADA: Confirmed positive ADA after drug administration with 
ADA titer > 4x baseline ADA titer in patients with preexisting (baseline) confirmed 
positive ADA 
5.11. 
Safety Analyses  
Safety analyses will compare both doses of lumasiran combined and separately versus placebo 
using the Safety Analysis Set. 


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5.11.1. 
Adverse Events 
Adverse events (AEs) will be classified by the MedDRA coding system (version 24.1) and 
displayed in tables and data listings using SOC and PT.  
Treatment-emergent AEs (TEAEs) will be summarized, where TEAE is defined as any AE 
occurring or worsening on or after the first dose of study drug and through 168 days after the last 
dose or any study drug-related AE. Because any worsening AE is reported as a new AE with 
higher severity, programmatical comparison of severity is not needed for the classification of 
TEAE. For missing or partial dates for AEs, the imputation of start and end date can be found in 
Section 7.3. Events with a fully or partially missing onset date will be assumed to be 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 study drug. All TEAEs 
hereafter will be referred to as AEs in this document. 
AEs will be summarized by the numbers and percentages of patients reporting a given AE. An 
overall table of TEAEs will include, 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 AE leading to drug interruption 
• 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 (based on SAE CRFs) 
Tabulations by SOC and PT will be produced for the following:  
• AEs, 
• Treatment-related AEs, 
• AEs by maximum severity, 
• Treatment-related AEs by maximum severity, 
• Severe AEs, 
• Treatment-emergent SAEs, 
• AEs leading to treatment discontinuation. 


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Tabulations by PT in decreasing order in frequency within each treatment arm will be produced 
for the following: 
• AEs 
• Treatment-related AEs 
• SAEs 
AEs and AEs related to treatment will also be summarized by severity. A patient contributes only 
once to the count for a given AE (overall, by SOC, by preferred term). Patients who report 
multiple occurrences of the same AE (preferred term) will be classified according to the most 
severe occurrence. An AE with missing severity will be assumed to be severe. An AE with 
missing study drug relatedness will be assumed to be related. 
Listings of all deaths, SAEs, and AEs leading to treatment discontinuation will be provided.  
Selected AE tabulations will include number of AEs and event rates per patient-year. In these 
summaries, multiple occurrences of the same AE in a patient will be counted multiple times for 
that patient. 
AE summary tables (by SOC and PT) will be separately generated for each of the subgroups 
below: 
• Sex (Male, Female) 
• Race (White, Black, All other) 
• Region (US, Europe) 
AEs of Clinical Interest 
The following AECI will be summarized by SOC and PT:  
• Severe or serious injection site reactions (ISRs): AEs mapping to the HLT “Injection 
Site Reactions” using MedDRA dictionary. 
A tabulation will also be generated to display the number of patients with at least 1 
ISR, total number of doses (any dose split into multiple injections will be considered 
1 dose in summary), total number of doses with ISRs, and the signs and symptoms 
reported due to ISRs. If there are multiple ISRs that occur in between 2 consecutive 
injections, then these events will be considered as 1 ISR and considered related to the 
earlier injection. 
• ALT or AST >3xULN: AEs mapping to certain standardized MedDRA queries 
(SMQs) will be summarized by SOC and PT. 
All AEs will be presented in patient data listings. AEs mapping to the SMQs as described above 
will also be listed. 
5.11.2. 
Laboratory Data 
Clinical laboratory values will be expressed in SI units. Missing laboratory data will not be 
imputed. 


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For each continuous clinical laboratory parameter (hematology, serum chemistry, and liver 
function tests), descriptive statistics will be presented for the actual values, change from baseline, 
and percent change from baseline by visit. These by-visit tables will use central laboratory data 
only. eGFR will not be reported in this section, as this is summarized in the efficacy section 
(Section 5.7.3.3). For any local collections of LFTs and others, these will be included in a 
separate data listing. 
Select clinical laboratory parameters may be graded according to the National Cancer Institute 
CTCAE Version 5.0 or above. Shift summary from baseline CTCAE grade to maximum (worst) 
post-baseline grade will be presented for all graded parameters with directionality specified (e.g., 
hyper or hypo). To determine the worst post-baseline value, all scheduled and unscheduled test 
results will be used. For hematology and serum chemistry, frequency tables of potentially 
clinically significant abnormalities will be provided. For select shift and summary tables such as 
LFT summaries, one or both of the following approaches may be utilized: 1) Only central 
laboratory data will be included; 2) Both central and local laboratory data will be included. 
All laboratory data (both central and local) will be provided in data listings.  Out-of-range 
laboratory results will be presented in a separate listing with proper flags. Local laboratory data, 
if available, will also be flagged. 
Liver Function Tests 
A frequency table and a shift table will be produced to summarize the number and percentage of 
patients in each of the below categories at any post-baseline time point.  
• ALT >1 & ≤3, >3 & ≤5, >5 & ≤8, >8 & ≤20, >20×ULN, 
• AST >1 & ≤3, >3 & ≤5, >5 & ≤8, >8 & ≤20, >20×ULN, 
• ALT or AST >1 & ≤3, >3 & ≤5, >5 & ≤8, >8 & ≤20, >20×ULN, 
• ALP > 1.5×ULN, 
• Total Bilirubin >1.5 & ≤2, >2 & ≤3, >3 & ≤5 and >5×ULN, 
• Total Bilirubin > 2×ULN concurrent with ALT or AST > 3×ULN 
In separate figures, the peak total bilirubin (as multiple of ULN) at any time post-baseline will be 
plotted against the peak ALT level and (peak AST and the peak AST or ALT levels) at any time 
post-baseline. 
A listing for all patients with abnormal liver function tests, defined as an ALT >3×ULN, AST 
>3×ULN, or total bilirubin >2×ULN at any time point, will also be provided. 
5.11.3. 
Vital Signs and Physical Examination 
For vital signs and body weight and height, descriptive statistics for actual values and change 
from baseline by visit will be provided for each variable. Vital sign measurements will be 
presented for each patient in a data listing, with abnormal vital signs flagged. 
5.12. 
Interim Analysis 
No formal interim analysis is planned for this study. 


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5.13. 
Other Analyses 
Additional data are collected to characterize the impact of the COVID-19 pandemic on general 
study conduct and disposition, and subsequently, additional analyses and summaries will be 
provided in acknowledgement of multiple regulatory guidance (including 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). 
5.13.1. 
General Impact 
Patients who discontinue treatment or stop study participation due to COVID-19 will be included 
in patient disposition summaries. 
Impact on study participation due to COVID-19, including missing visits, visit location changes, 
study drug dosing changes and missing doses, will be summarized descriptively overall and by 
visit on the patient level, and overall on the event level. Patient- and event-level summaries of 
the impact on study participation due to COVID-19 may also be generated by site and/or region. 
Impact on study participation due to COVID-19 will be presented in data listings at patient and 
visit level. 
5.13.2. 
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) missed due to COVID-19 
pandemic are expected to be minimal. 
Given the measures specified in the protocol designed to ensure data integrity, analyses 
excluding patients with COVID-19 related protocol deviations will not be prespecified, but may 
be considered post hoc, if warranted.  
5.13.3. 
Impact on Adverse Events 
An overall summary of AEs mapping to a COVID-19 custom query will be presented. AEs 
mapping to the COVID-19 custom query will be summarized by HLT and PT. 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 timepoint. 
AEs mapping to the COVID-19 custom query will also be presented in a data listing. 
6. 
CHANGES FROM PLANNED ANALYSES 
Below is a summary of changes/clarification from the protocol  
SAP Original  


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Section of the SAP Summary of change from protocol 
Rationale 
Section 2.4 and 
Section 4.5 
Added the first 2 valid 24-hour urine 
collections to the calculation of the 
mean baseline urinary oxalate level 
stratification factor.  
The addition of the first 2 valid 24-hr 
urine collections to the stratification 
mean baseline urinary oxalate 
improves clarity. 
Section 3 and 
Section 5.8 
Plasma Oxalate Analysis Set is added 
for the analysis of the plasma oxalate 
endpoint. 
The LLOQ of the plasma oxalate 
assay is 5.55 µmol/L. Due to the 
inability of quantify oxalate level 
below LLOQ by the assay, patients 
with baseline plasma oxalate level 
measured near to or at LLOQ are 
excluded from the analysis to ensure 
the meaningful reduction can be 
evaluated for the study population. 
Section 3 
Removed “randomized” from the Safety 
Analysis Set definition. 
 “Randomized” was erroneously 
entered in the protocol.  
 












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• 
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 (refer to Section 4.3.1). 
• 
White columns indicate visits to the clinical study center; gray-shaded columns indicate study visits that may be conducted by a home healthcare 
professional, where applicable country and local regulations and infrastructure allow (at the discretion and with oversight of the Investigator, based on 
safety and tolerability), provided (for dosing visits) that 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 symptom-directed 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, kidney stone events, and adverse events.  
Footnotes: 
a All assessments are required to be performed prior to dosing at dosing visits, except for the CT scan and PK sample collection. 
b Inclusion/exclusion criteria should be verified prior to randomization.  Laboratory assessments conducted to confirm study eligibility will not be repeated unless 
the time between screening and randomization exceeds 4 weeks. 
c Samples for exploratory analysis will only be collected at these visits and will be aliquoted from the samples provided for PD analysis. 
d Pregnancy test results must be known prior to dosing, if applicable. 
e May be performed after dosing, if required. 




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• AE onset dates with missing day and non-missing month will be imputed to occur on 
the first day of the non-missing month, except for AEs occurring in the first month of 
dosing, in which case the date will be the first day of dosing. 
• AE onset dates with missing month will be imputed to occur on the first day of the 
non-missing year (i.e., January 1), except for AEs occurring in the first year of 
dosing, in which case the date will be the first day of dosing.  
• If year of the AE start date is missing, the onset date will be imputed as the first day 
of dosing, except it can be unequivocally determined (from the partial or complete 
stop date) that the event occurred prior to the first dose of study drug, in which case 
the AE onset date will not be imputed.  
• If an imputed onset date is after the collected AE end date, the end date will be used 
as the imputed onset date.