A Phase 2 Open-Label Multicenter Study to Evaluate the Safety, Pharmacokinetics, and Efficacy of Nedosiran in Pediatric Patients From Birth to 11Years of Age With Primary Hyperoxaluria and Relatively Intact Renal Function
Phase: PHASE2
Conditions: Primary Hyperoxaluria, Primary Hyperoxaluria Type 1, Primary Hyperoxaluria Type 2, Primary Hyperoxaluria Type 3
Sponsor: Dicerna Pharmaceuticals, Inc., a Novo Nordisk company

Cover Page for Protocol 
Sponsor name: 
Dicerna Pharmaceuticals, Inc., a wholly owned subsidiary of 
Novo Nordisk 
NCT number: 
NCT05001269 
Sponsor trial ID: 
DCR-PHXC-203 
Official title of study: 
A Phase 2 Open-Label Multicenter Study to Evaluate the 
Efficacy, Safety, and Pharmacokinetics of Nedosiran in 
Pediatric Patients from Birth to 11 Years of Age with Primary 
Hyperoxaluria and Relatively Intact Renal Function 
Document date:* 
23-February-2023
*Document date refers to the date on which the document was most recently updated.
Redacted protocol 
Includes redaction of personal identifiable information only. 
. 

Dicerna Protocol DCR-PHXC-203 
 
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Medical Monitor and Pharmacovigilance Contact Information 
SAE Submission Coordinator:  
Novo Nordisk Safety Operations 
24-hour Safety Fax: 
+45 44427787 
Email: soclin@novonordisk.com 
Clinical Research Organization Medical Monitor: 
Premier Clinical Research 
3800 Paramount Parkway, Suite 400 
Morrisville, NC 27560-6949 
24-hour emergency telephone:  +44 118 936 4096 
 
+1 512 686 1256 
Email: 203_DCR-PHXC_MedicalMonitors@premier-research.com  
Sponsor Medical Monitor: 
Dicerna Pharmaceuticals, Inc. 
Telephone 
+1 617 621 8097 
Email: PHYOX8medicalmonitors@dicerna.com 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
DOCUMENT HISTORY 
Document 
Date 
Amendment 3, version 4.0 
23-Feb-2023 
Amendment 2, version 3.0 
01-Nov-2022 
Amendment 1, version 2.0  
21-Dec-2021 
Original Protocol, version 1.0  
15-Apr-2021 
Amendment 3, version 4.0 (23-Feb-2023) 
The 01-Nov-2022 version of the protocol was amended to provide for inclusion of participants 
weighing less than 10 kg. Additional updates and clarifications were also included. The table 
below details the summary of changes. 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
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Section # and Name 
Description of Change 
Brief Rationale 
5.1 
Inclusion Criteria 
Removed the 10 kg minimum body 
weight from the inclusion criteria. 
To align with the 0- to 1-year-old age 
group that is included in this study. 
2.3.4 Risk Management 
8.2.6 Clinical Safety 
Laboratory Assessments 
10.3 
Appendix 3 (new 
section) 
Added text regarding maximum blood 
volume collection allowed based on 
body weight and to direct the 
Investigator to the Laboratory Manual 
for the blood draw priority list. 
To provide guidance around 
maximum allowable blood volume 
collection in pediatric patients for 
whom a full collection of blood 
would exceed allowable limits 
1.1 
Synopsis 
4.1 
Overall Design 
Updated study duration from 18 to 
24 months. 
To account for enrollment delays. 
1.2 
Schema 
1.3 
Schedule of Activities 
4.1 
Overall Design 
Updated timeframe for repeat screening 
laboratory assessments. 
To expand the allowable timeframe 
from 7 to 14 days to account for 
technical or logistic issues at the 
central lab. 
5.1 
Inclusion Criteria 
6.5 
Concomitant Therapy 
Added text to allow for interval weight 
gain dose adjustments in concomitant 
therapy regimens. 
To clarify that dose adjustment based 
on interval weight gain is not 
considered a change in dose regimen. 
1.3 
Schedule of Activities 
8.1.5 Reporting Fluid Intake 
Updated text to clarify the range of 4 to 
7 days for reporting of fluid intake. 
To clarify that it is preferred for daily 
fluid intake to be reported for all 
7 days prior to each urine collection 
period, and if not possible, intake for 
at least the 4 days prior to collection 
will be reported. 
1.3 
Schedule of Activities 
Updated footnote aa to specify the ages 
of patients requiring PedsQL to be 
provided by parental proxy. 
To update that patients aged birth to 
12 months and 13 to 24 months will 
have information provided by 
parental proxy. 
8.1.1 Spot Urine Collection 
Added text regarding spot urine 
collection in infants. 
To clarify that instructions for spot 
urine collection in infants are also 
provided in the Urine Collections 
Instructions. 
2.2.3.1 Clinical Studies of 
Nedosiran 
Added additional text denoting 
differences in response between 
participants with PH1 and PH2 in study 
DCR-PHXC-201. 
To clarify that participants with PH2 
did not have a response equivalent to 
that of those with PH1. 
Sponsor Signature Page 
Updated current signatory 
titles/information for accuracy. 
To account for Sponsor signatory 
corrections. 
Medical Monitor and 
Pharmacovigilance Contact 
Information 
Updated with current personnel contact 
information. 
To account for Sponsor contact 
changes. 
Throughout protocol 
Minor text updates and grammatical 
changes 
For increased clarity. 
 
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TABLE OF CONTENTS 
TITLE PAGE .............................................................................................................................. 1 
SPONSOR SIGNATURE PAGE ................................................................................................ 2 
MEDICAL MONITOR AND PHARMACOVIGILANCE CONTACT INFORMATION ........... 3 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ....................................................... 4 
1. 
PROTOCOL SUMMARY ...................................................................................... 11 
1.1. 
Synopsis ................................................................................................................. 11 
1.2. 
Schema ................................................................................................................... 15 
1.3. 
Schedule of Activities ............................................................................................. 16 
2. 
INTRODUCTION .................................................................................................. 20 
2.1. 
Study Rationale ...................................................................................................... 20 
2.2. 
Background ............................................................................................................ 21 
2.2.1. 
Overview of Primary Hyperoxaluria ....................................................................... 21 
2.2.2. 
Nonclinical Overview ............................................................................................. 22 
2.2.3. 
Clinical Overview ................................................................................................... 23 
2.2.3.1. 
Clinical Studies of Nedosiran .................................................................................. 23 
2.3. 
Benefit/Risk Assessment ........................................................................................ 24 
2.3.1. 
Risk Assessment ..................................................................................................... 24 
2.3.1.1. 
Risks Related to the siRNA Molecule ..................................................................... 25 
2.3.1.2. 
Risks Related to LDHA Knockdown and Potential Off-target Effects ..................... 25 
2.3.2. 
Pediatric Burden Assessment .................................................................................. 25 
2.3.3. 
Benefit Assessment................................................................................................. 26 
2.3.4. 
Risk Management ................................................................................................... 27 
2.3.5. 
Overall Benefit:Risk Conclusion ............................................................................. 28 
3. 
OBJECTIVES AND ENDPOINTS ......................................................................... 29 
4. 
STUDY DESIGN ................................................................................................... 30 
4.1. 
Overall Design ........................................................................................................ 30 
4.2. 
Scientific Rationale for Study Design ..................................................................... 30 
4.3. 
Justification for Dose .............................................................................................. 30 
4.3.1. 
PK/PD Model for Dose Selection in Pediatric Participants (Birth to 11 
Years) ..................................................................................................................... 30 
4.4. 
End of Study Definition .......................................................................................... 31 
5. 
STUDY POPULATION ......................................................................................... 32 
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5.1. 
Inclusion Criteria .................................................................................................... 32 
5.2. 
Exclusion Criteria ................................................................................................... 33 
5.3. 
Lifestyle Considerations ......................................................................................... 35 
5.3.1. 
Meals and Dietary Restrictions ............................................................................... 35 
5.4. 
Screen Failures ....................................................................................................... 35 
6. 
STUDY INTERVENTION ..................................................................................... 36 
6.1. 
Study Intervention(s) Administered ........................................................................ 36 
6.2. 
Preparation/Handling/Storage/Accountability ......................................................... 37 
6.2.1. 
Handling and Accountability .................................................................................. 37 
6.2.2. 
Storage ................................................................................................................... 37 
6.2.3. 
Preparation and Administration............................................................................... 37 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ...................................... 38 
6.4. 
Study Intervention Compliance ............................................................................... 38 
6.5. 
Concomitant Therapy ............................................................................................. 38 
6.5.1. 
Prohibited During the Study.................................................................................... 38 
6.5.2. 
Rescue Medicine .................................................................................................... 38 
6.5.3. 
COVID-19 and Other Vaccine Administration ........................................................ 39 
6.6. 
Dose Modification .................................................................................................. 39 
6.7. 
Intervention After the End of the Study................................................................... 39 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL ...................................... 40 
7.1.1. 
Discontinuation of Study Intervention Stopping Rules for Individual 
Participants ............................................................................................................. 40 
7.1.1.1. 
Drug-Induced Liver Injury Monitoring ................................................................... 40 
7.1.1.2. 
Temporary Discontinuation .................................................................................... 40 
7.1.1.3. 
Rechallenge ............................................................................................................ 40 
7.1.2. 
Study Stopping Rules ............................................................................................. 40 
7.2. 
Participant Discontinuation/Withdrawal from the Study.......................................... 41 
7.3. 
Lost to Follow up.................................................................................................... 41 
8. 
STUDY ASSESSMENTS AND PROCEDURES ................................................... 42 
8.1. 
Efficacy Assessments ............................................................................................. 42 
8.1.1. 
Spot Urine Collection ............................................................................................. 42 
8.1.2. 
Plasma Oxalate (Pox) ............................................................................................. 43 
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8.1.3. 
Kidney Assessments ............................................................................................... 43 
8.1.3.1. 
Kidney Stone Events and Stone Burden .................................................................. 43 
8.1.3.2. 
Kidney Ultrasound .................................................................................................. 43 
8.1.4. 
Quality of Life Assessments ................................................................................... 44 
8.1.4.1. 
Pediatric Quality of Life Inventory ......................................................................... 44 
8.1.5. 
Reporting Fluid Intake ............................................................................................ 45 
8.2. 
Safety Assessments................................................................................................. 45 
8.2.1. 
Weight, Height, Length and Body Surface Area...................................................... 45 
8.2.2. 
Physical Examinations ............................................................................................ 46 
8.2.3. 
Vital Signs .............................................................................................................. 46 
8.2.4. 
Electrocardiograms ................................................................................................. 46 
8.2.5. 
Echocardiogram with Doppler ................................................................................ 47 
8.2.6. 
Clinical Safety Laboratory Assessments ................................................................. 47 
8.2.6.1. 
Estimated Glomerular Filtration Rate (eGFR) ......................................................... 48 
8.3. 
Adverse Events and Serious Adverse Events........................................................... 49 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information ...................... 49 
8.3.2. 
Method of Detecting AEs and SAEs ....................................................................... 49 
8.3.3. 
Follow-up of AEs and SAEs ................................................................................... 50 
8.3.4. 
Regulatory Reporting Requirements for SAEs ........................................................ 50 
8.3.5. 
Pregnancy ............................................................................................................... 50 
8.3.6. 
Adverse Events of Special Interest .......................................................................... 51 
8.4. 
Treatment of Overdose ........................................................................................... 51 
8.5. 
Pharmacokinetics .................................................................................................... 51 
8.6. 
Pharmacodynamics ................................................................................................. 51 
8.7. 
Genetics.................................................................................................................. 51 
8.8. 
Biomarkers ............................................................................................................. 51 
8.9. 
Immunogenicity Assessments ................................................................................. 52 
8.10. 
Medical Resource Utilization and Health Economics .............................................. 52 
8.10.1. 
Work Productivity and Activity Impairment Questionnaire: Primary 
Hyperoxaluria V2.0, Clinical Practice Version (WPAI:PH, V2.0, CPV) – 
Caregiver ................................................................................................................ 52 
9. 
STATISTICAL CONSIDERATIONS .................................................................... 53 
9.1. 
Statistical Hypotheses ............................................................................................. 53 
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9.2. 
Sample Size Determination ..................................................................................... 53 
9.3. 
Populations for Analyses ........................................................................................ 53 
9.4. 
Statistical Analyses ................................................................................................. 53 
9.4.1. 
General Considerations ........................................................................................... 53 
9.4.2. 
Primary Endpoint.................................................................................................... 54 
9.4.3. 
Secondary Endpoints .............................................................................................. 54 
9.4.3.1. 
Efficacy Endpoints ................................................................................................. 54 
9.4.3.2. 
Safety Endpoints ..................................................................................................... 54 
9.4.3.3. 
Pharmacokinetic Endpoints ..................................................................................... 54 
9.4.4. 
Tertiary/Exploratory Endpoint(s) ............................................................................ 55 
9.5. 
Interim Analyses ..................................................................................................... 55 
9.6. 
Safety Review Committee (SRC) ............................................................................ 55 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS .............................................................................................. 56 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ................... 56 
10.1.1. 
Regulatory and Ethical Considerations.................................................................... 56 
10.1.2. 
Financial Disclosure ............................................................................................... 56 
10.1.3. 
Informed Consent Process ...................................................................................... 57 
10.1.4. 
Data Protection ....................................................................................................... 57 
10.1.5. 
Dissemination of Clinical Study Data ..................................................................... 58 
10.1.6. 
Data Quality Assurance .......................................................................................... 58 
10.1.7. 
Source Documents .................................................................................................. 58 
10.1.8. 
Study and Site Start and Closure ............................................................................. 59 
10.1.9. 
Publication Policy ................................................................................................... 59 
10.2. 
Appendix 2: Clinical Laboratory Tests .................................................................... 60 
10.3. 
Appendix 3: Volume of Blood ................................................................................ 62 
10.4. 
Appendix 4: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting..................................................................... 63 
10.4.1. 
Definition of AE ..................................................................................................... 63 
10.4.1.1. 
Events Meeting the AE Definition .......................................................................... 63 
10.4.1.2. 
Events Not Meeting the AE Definition.................................................................... 63 
10.4.2. 
Definition of SAE ................................................................................................... 64 
10.4.3. 
Definition of Adverse Event of Special Interest ...................................................... 65 
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10.4.3.1. 
Events Meeting the AESI Definition ....................................................................... 65 
10.4.4. 
Recording and Follow-Up of AE and/or SAE ......................................................... 65 
10.4.4.1. 
AE and SAE Recording .......................................................................................... 65 
10.4.4.2. 
Assessment of Intensity .......................................................................................... 66 
10.4.4.3. 
Assessment of Causality ......................................................................................... 66 
10.4.4.4. 
Follow-up of AEs and SAEs ................................................................................... 67 
10.4.5. 
Reporting of SAEs .................................................................................................. 67 
10.5. 
Appendix 5: Contraceptive and Collection of Pregnancy Information ..................... 68 
10.5.1. 
Definitions .............................................................................................................. 68 
10.5.2. 
Contraception Guidance.......................................................................................... 68 
10.5.3. 
Pregnancy Testing .................................................................................................. 71 
10.5.4. 
Collection of Pregnancy Information ...................................................................... 71 
10.6. 
Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments ............. 73 
10.7. 
Appendix 7: Abbreviations ..................................................................................... 76 
10.8. 
Investigator Signature Page .................................................................................... 79 
10.9. 
Protocol Amendment History ................................................................................. 80 
11. 
REFERENCES ....................................................................................................... 85 
 
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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title:  
A Phase 2 Open-Label Multicenter Study to Evaluate the Efficacy, Safety, and 
Pharmacokinetics of Nedosiran in Pediatric Patients from Birth to 11 Years of 
Age with Primary Hyperoxaluria and Relatively Intact Renal Function 
Short Title:  
Nedosiran in Pediatric Patients from Birth to 11 Years of Age with PH and 
Relatively Intact Renal Function  
Acronym:  
PHYOX8 
Study Rationale: 
This study is designed to evaluate the efficacy, safety, and PK of nedosiran in neonates, infants, 
and children (birth to 11 years of age) with primary hyperoxaluria (type 1 [PH1], type 2 [PH2], 
and type 3 [PH3]) and relatively intact renal function based upon eGFR and serum creatinine.  
There are 3 types of PH (PH1, PH2, and PH3); each is attributed to a specific gene mutation. 
Overproduction of oxalate in the liver is a prominent observation in all 3 types of PH. As a 
genetic disease, the clinical manifestations of this excess oxalate burden start building early in 
life. The median age of symptom onset for individuals with PH is 4.5 years. It is therefore 
important to study the safety and efficacy of nedosiran in the youngest children, before late 
complications of the disease have developed.  
Nedosiran, a synthetic RNAi drug that consists of a double-stranded oligonucleotide conjugated 
to GalNAc ligands, is designed to substantially reduce the activity of a key oxalate-producing 
enzyme. The potential medical value of achieving a sustained substantial decrease and/or 
normalization of liver oxalate production in patients with PH is demonstrated by the marked 
improvement in disease outcome in patients with PH1 in whom liver oxalate production has been 
reduced to normal levels by liver transplantation. 
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Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• 
To assess the efficacy of nedosiran in neonates, 
infants, and children with PH and relatively 
intact renal function based upon eGFR and 
serum creatinine 
• 
Percent and absolute change from Baseline to 
Month 6 in spot urinary oxalate-to-creatinine 
ratio in PH1, PH2, or PH3 participant subgroups 
Secondary 
• 
To characterize the safety of nedosiran in 
neonates, infants, and children with PH and 
relatively intact renal function based upon eGFR 
and serum creatinine 
• 
The incidence and nature of TEAEs and SAEs 
• 
Change from Baseline in 12-lead ECG, physical 
examination findings, vital sign assessments, 
and clinical laboratory tests 
• 
To characterize the PK of nedosiran in neonates, 
infants, and children with PH and relatively 
intact renal function based upon eGFR and 
serum creatinine 
• 
Plasma PK parameters for nedosiran and/or its 
metabolites, including Cmax, AUCt and AUC∞ (if 
estimable) 
• 
To assess the efficacy of nedosiran in neonates, 
infants, and children with PH and relatively 
intact renal function based upon eGFR and 
serum creatinine 
• 
Percentage of participants with spot urinary 
oxalate-to-creatinine ratio ≤ the ULN or ≤ 1.5 x 
ULN at any time point through Month 6 in PH1, 
PH2, or PH3 participant subgroups 
• 
To evaluate the effect of nedosiran on eGFR in 
neonates, infants, and children with PH and 
relatively intact renal function based upon eGFR 
and serum creatinine 
• 
Change from Baseline in eGFR at Month 6 (only 
in participants ≥ 12 Months of age at Screening) 
in PH1, PH2, or PH3 participant subgroups 
Tertiary/Exploratory 
• 
To assess the effect of nedosiran on plasma 
oxalate in neonates, infants, and children with 
PH and relatively intact renal function based 
upon eGFR and serum creatinine 
• 
Percent and absolute change in plasma oxalate 
over time in PH1, PH2, or PH3 participant 
subgroups 
• 
To assess the effect of nedosiran on stone events 
in neonates, infants, and children with PH and 
relatively intact renal function based upon eGFR 
and serum creatinine 
• 
Change from Baseline in annualized stone event 
rate in PH1, PH2, or PH3 participant subgroups 
• 
To evaluate the effect of nedosiran on Quality of 
Life (QoL) assessments in neonates, infants, and 
children with PH and relatively intact renal 
function based upon eGFR and serum creatinine 
• 
Change from Baseline in the Pediatric Quality of 
Life Inventory (PedsQL™) in PH1, PH2, or PH3 
participant subgroups 
• 
To evaluate the effect of nedosiran on 
productivity loss of caregivers for neonates, 
infants, and children with PH and relatively 
intact renal function based upon eGFR and 
serum creatinine 
• 
Change from Baseline in the Work Productivity 
and Activity Impairment Questionnaire: Primary 
Hyperoxaluria V2.0, Clinical Practice Version 
(WPAI:PH, V2.0, CPV) – Caregiver in PH1, 
PH2, or PH3 participant subgroups 
Overall Design 
This is a Phase 2, multi-dose (3.5 mg/kg, not to exceed 170 mg), open-label, single-arm, 
uncontrolled, multicenter study of nedosiran in pediatric participants (birth to 11 years of age) 
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with genetically confirmed PH type 1 (PH1), type 2 (PH2), or type 3 (PH3) with relatively intact 
renal function based upon eGFR and serum creatinine.  
Participants will receive monthly SC doses (3.5 mg/kg, not to exceed 170 mg) of nedosiran over 
6 months. 
The primary objective of this study is to characterize the efficacy of nedosiran in pediatric 
participants (birth to 11 years of age) with PH1, PH2, or PH3. The efficacy of nedosiran in 
lowering Uox will be assessed via monthly spot urine samples. 
Participants completing this study may be eligible for long-term treatment with nedosiran in 
Study DCR-PHXC-301. 
Disclosure Statement: This is a sequential-group, open-label treatment study with no masking. 
Study Population: 
Male and female pediatric participants (birth to 11 years of age), with genetically confirmed 
PH1, PH2, or PH3, and relatively intact renal function based upon eGFR and serum creatinine.  
Key inclusion criteria include 
• Estimated glomerular filtration rate (eGFR) at Screening ≥ 30 mL/min normalized to 
1.73 m2 body surface area (BSA). For infants aged less than 12 months, serum 
creatinine below the 97.5th percentile of a healthy population (Boer et al., 2010).  
• Average spot Uox-to-creatinine ratio at Screening above 2 times the 95th percentile 
for age based on Matos et al, 1999: 
o > 0.44 mol/mol in participants < 6 months 
o > 0.34 mol/mol in participants from 6 months to <12 months 
o > 0.26 mol/mol in participants 12 months to < 2 years 
o > 0.20 mol/mol in participants from 2 to < 3 years and 
o > 0.16 mol/mol in participants from 3 to < 5 years  
o > 0.14 mol/mol in participants from 5 to < 7 years 
o > 0.12 mol/mol in participants from 7 to 11 years 
Key exclusion criteria include 
• Renal or hepatic transplantation (prior or planned within the study period)  
• Plasma oxalate (Pox) > 30 µmol/L at Screening  
• Documented evidence of clinical manifestations of severe systemic oxalosis 
(including preexisting retinal, heart, or skin calcifications, or history of severe bone 
pain, pathological fractures, or bone deformations) 
Number of Participants: Approximately 25 participants will be enrolled such that 
approximately 20 participants (approximately 7 aged 6 to 11 years; approximately 10 aged 1 to 
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5 years; and approximately 3 aged < 1 year) complete the study, with an overall goal of 
approximately 15 PH1.  
Intervention Groups and Duration of Participation: This study has a single intervention 
group in which all participants will receive monthly SC doses of nedosiran over a 6-month 
period. Prospective participants will be screened over an up-to-35-day period, with an extra 
14 days allowed for participants who are required to repeat initially unanalyzable screening 
laboratory assessment samples. The total time on study for each participant is approximately 
7 months. 
Study Duration: Approximately 24 months from the first participant, first visit, to the last 
participant, last visit.  
Safety Review Committee: This study will utilize an SRC to review safety and efficacy data on 
a periodic basis.   
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1.2. 
Schema 
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1.3. 
Schedule of Activities  
Table 1: Schedule of Activities 
 
 
Study Day 
(window) 
Screening 
Treatment 
EOS 
ET 
–35 a 
to –1 
1b   
2 
15 
30 
(±2) 
45 
60 
(±3) 
90 
(±3) 
120 
(±5) 
150  
(±5) 
180  
(±5) 
- 
At-clinic visit 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
At-home telehealth visit  c 
 
 
X 
 
 
 
X 
 
X 
X 
 
 
Telephone Contact d 
 
 
 
X 
 
X 
 
 
 
 
 
 
Procedure/Assessment 
Study intervention administration e 
 
X 
 
 
X 
 
X 
X 
X 
X 
 
 
Informed consent f  
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria g 
X 
X 
 
 
 
 
 
 
 
 
 
 
Demographic/baseline 
characteristics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history  
X 
 
 
 
 
 
 
 
 
 
 
 
PH disease history h 
X 
 
 
 
 
 
 
 
 
 
 
 
Medication history i 
X 
 
 
 
 
 
 
 
 
 
 
 
PH genotyping j  
X 
 
 
 
 
 
 
 
 
 
 
 
Plasma oxalate sample  
X 
 
 
 
 
 
 
 
 
 
X 
X 
Spot urine collection k 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
Plasma PK sample l 
 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
Record fluid intake m 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
12-lead ECG n 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Vital signs o  
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Physical examination p  
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Height and body weight q 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Hematology r 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Chemistry r 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
Coagulation s 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
eGFR t 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
Urinalysis u 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
Urine pregnancy test (WOCBP) v 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
Record stone events w 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Kidney ultrasound x 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Echocardiogram y 
X 
 
 
 
 
 
 
 
 
 
X 
X 
ADA sample  
X 
 
 
 
X 
 
 
X 
 
X 
X 
X 
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Study Day 
(window) 
Screening 
Treatment 
EOS 
ET 
–35 a 
to –1 
1b   
2 
15 
30 
(±2) 
45 
60 
(±3) 
90 
(±3) 
120 
(±5) 
150  
(±5) 
180  
(±5) 
- 
At-clinic visit 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
At-home telehealth visit  c 
 
 
X 
 
 
 
X 
 
X 
X 
 
 
Telephone Contact d 
 
 
 
X 
 
X 
 
 
 
 
 
 
Procedure/Assessment 
Pediatric burden assessment z 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
PedsQL aa 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Pharmacoeconomics bb 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
Record AEs and SAEs cc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications i 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
a An extra 14-day period will also be granted for participants who are required to repeat initially unanalyzable 
screening laboratory assessment samples or where lab samples are delayed due to technical/logistical issues at the 
central lab.  
b  In order to minimize blood loss in participants, samples to be drawn for screening should be collected not less than 
28 days prior to samples drawn on Day 1. 
c Visits for Days 2, 60, 120, and 150 may be conducted at the clinic or as at-home telehealth visits. During at-home 
telehealth visits, home-health nurses will collect the required blood and urine samples and perform an assessment 
of vital signs. The Investigator will contact the participant’s caregiver via telephone and/or video conference to 
assess the general well-being of the participant and determine if any adverse events have occurred. The 
Investigator must affirm that nedosiran may be administered prior to administration.  
d The Investigator will contact the participant’s caregiver via telephone and/or video conference to assess the 
general well-being of the participant and determine if any adverse events have occurred. 
e After the first 2 injections of nedosiran, visiting nurses or caregivers will administer SC injections at home for 
those months at which a study-site visit is not required. The total dose will be based upon body weight recorded on 
study Day 1. For participants < 6 months of age at Screening, the dose will be adjusted at Day 90 to capture 
changes in weight; no other dose adjustments are allowed. 
f Parental informed consent (and minor assent, if applicable per local regulations) is required prior to initiation of 
screening procedures.   
g Participant eligibility (with the exception of clinical laboratory testing) will be re-confirmed prior to administration 
of study intervention on Day 1. 
h PH history to include 12-month history of stone events, or as applicable for those less than 12 months of age 
(Section 8.1.3). 
i To include vitamin B6 (pyridoxine), if applicable. 
j Participants without documented genotyping must provide a DNA sample for testing. For participants who weigh 
≤ 11 kg, PH genotyping will be performed via buccal swab; for all other participants, while genotyping via buccal 
swab is recommended to reduce blood sample volumes, genotyping performed via whole blood sample is allowed. 
k Spot urine samples will be collected for the determination of Uox and urinary creatinine. At screening, 6 spot urine 
samples (3 of which must be second morning voids) will be collected over a 3-day period. On-treatment, 4 spot 
urine samples (2 of which must be second morning voids) will be collected over a 2-day period on a monthly 
basis. 
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l Plasma sampling times for PK analysis (see Section 8.5): 
Sampling times: 
Allowable Windows: 
Day 1: one sample in the 0- to 4-hour postdose window and 
one sample in the 4- to 24-hour postdose window 
Days 2, 30, and 90: one single sample during the visit 
Day 150: predose, one sample in the 0- to 4-hour postdose 
window, and one sample in the 4- to 24-hour postdose 
window 
Predose: within 30 minutes before administration of study 
intervention 
Not applicable for other samples 
  A single plasma sample should be collected at the final visit from participants who discontinue study intervention 
or are withdrawn from the study. When multiple assessments are due at the same time point, PK sampling should 
be performed at the nominal time point, with the preferred order of assessments ECG, vital signs, PK, and then 
other assessments.  
m Participants should maintain consistent fluid intake (i.e., hyperhydration) over the course of the study 
(Section 5.3). Participants’ caregivers will report daily fluid intake over the week prior to each urine collection 
period (Section 8.1.5). Recording of fluid intake only applies to non-breastfed participants. 
n On Days 1 and 30, ECG to be performed predose and at 6 hours postdose. A single ECG to be performed at other 
visits, as indicated (Section 8.2.4). A ± 30-minute window is allowed if multiple assessments are due at the same 
time point. 
o Vital signs on Day 1 and Day 30 to be assessed predose and at 6 hours postdose (Section 8.2.3). A ± 30-minute 
window is allowed if multiple assessments are due at the same time point. In such cases, PK sampling should be 
performed, preferably at the nominal time point, with the preferred order of assessments ECG, vitals, PK, and then 
other assessments. 
p Physical examination includes height/length, weight, inspection of injection site(s), and review of body systems. A 
full physical exam will be performed at Screening and Day 180 (or early termination). For at-home visits, the 
home-health nurse will provide in-person support to the Investigator in assessing the participant; height and weight 
will not be measured during at-home visits. The physical examination performed at other scheduled visits (Days 1 
through Day 150) or unscheduled visits may be a brief or full physical examination at the Investigator’s discretion. 
See Section 8.2.1 and Section 8.2.2. 
q The total dose will be based upon body weight recorded on study Day 1. For participants < 6 months of age at 
Screening, the dose will be adjusted at Day 90 to capture changes in weight; no other dose adjustments are 
allowed. 
r Blood samples for hematology and serum chemistry to be collected predose on dosing days. A single blood draw 
to be performed at other visits, as indicated. See Section 10.2 for the list of parameters. 
s Blood samples for coagulation studies to be collected predose. Coagulation panel will include prothrombin time 
(PT) and international normalized ratio (INR). Additional coagulation studies may be performed as clinically 
indicated. 
t Estimated glomerular filtration rate (eGFR) to be calculated only in participants aged 12 months and older, as 
described in Section 8.2.6.1.  
u Urinalysis with microscopy at Screening and as clinically indicated. Dipstick urinalysis may be performed at other 
scheduled visits. Collect sample for urinalysis before dosing. See Section 10.2 for parameters. 
v A positive urine pregnancy test will be confirmed with a serum pregnancy test. Administration of study 
intervention will be discontinued in any participant with a positive pregnancy test. A final pregnancy test will be 
conducted 2-3 weeks following the last dose of study intervention in any WOCBP who prematurely discontinues 
the study. 
w Parent(s)/legal guardian will report instances of renal stones requiring medical intervention, stone passage, and/or 
renal colic requiring medication (Section 8.1.3.1). 
x In the event of rescreening, if a participant had been screened for this study within the last 3 months and had 
ultrasound data sent to the central over-readers, repeat of the ultrasound will not be required during the rescreen. 
y For an individual participant, if the echocardiogram cannot be performed without sedation (e.g., due to age), the 
echocardiogram should not be performed. The omission of an echocardiogram due to sedation requirement should 
not be considered a protocol deviation. In the event of rescreening, if a participant had been screened for this study 
within the last 3 months and had echocardiogram data sent to the central over-readers, repeat of the 
echocardiogram will not be required during the rescreen. 
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z Participants or parent(s)/legal guardian to be queried as to the ongoing burden of the study (Section 2.3.2).  
aa For participants aged birth to 12 months, 13 to 24 months, 2 to 5 years, 5 to 7 years, and 8 to 11 years, the Peds QL 
will be completed by parental proxy, and the PedsQL family module will be completed for all participants 
(Section 8.1.4). 
bb To include medical resource utilization questions and the WPAI:PH V2.0 CPV, both to be completed by the 
parent/guardian (Section 8.10). 
cc Adverse events to be collected from the time of ICF signature through the End of Study/Early Termination Visit. 
Serious adverse events to be collected from the time of ICF signature through 30 days after the after last day of 
study participation. 
 
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2. 
INTRODUCTION 
Nedosiran (also known as DCR-PHXC) is a synthetic RNAi drug that consists of a 
double-stranded oligonucleotide conjugated to GalNAc ligands that is being developed for 
treatment of primary hyperoxaluria (PH). 
2.1. 
Study Rationale 
Primary hyperoxaluria encompasses 3 genetically distinct, autosomal-recessive, inborn errors of 
glyoxylate metabolism characterized by the over-production of oxalate, a highly insoluble 
metabolic end product that is eliminated mainly by the kidney. Patients with PH are predisposed 
to the development of multiple and recurrent urinary tract (urolithiasis) and kidney 
(nephrolithiasis) stones. Calculi formation is accompanied by nephrocalcinosis in some patients 
with PH. This deposition of calcium oxalate in the renal parenchyma produces tubular toxicity 
and renal damage that is compounded by the effects of renal calculi-related obstruction and 
frequent superimposed infections (Cochat & Rumsby, 2013).  
Primary hyperoxaluria is present at birth and although first symptoms might occur at different 
ages, the excess oxalate burden starts building early in life. It will therefore be important to 
reduce Uox concentrations as soon as the diagnosis of PH is being made to avoid deterioration of 
renal function. According to data from the Rare Kidney Stone Consortium, median age of 
symptoms for PH patients is 4.5 years and median age of diagnosis is 8.1 years (Zhao et al., 
2016). European Society of Pediatric Nephrology and European Renal Association-European 
Dialysis and Transplant Association (ESPN/ERA-EDTA) Registry show that children less than 
2 years of age with infantile oxalosis had a higher risk of death (a HR, 3.44; 95% CI, 1.15–10.28; 
P=0.02) compared with patients with PH aged greater than 2 years with renal replacement 
therapy (Harambat et al. 2012). It is therefore important to study the safety and efficacy of 
nedosiran in the youngest children, before complications of the disease have developed. 
At present, one treatment for PH1, Oxlumo™ (lumasiran, Alnylam), is approved in a limited 
number of countries, including the European Union. There is an unmet need for treatment in all 
subtypes of PH globally and particularly for PH2 and PH3, as no therapies are presently 
approved by regulatory authorities for the treatment of patients with PH2 or PH3. When 
treatment is not available, a number of supportive therapies are used in an attempt to mitigate 
some of the effects of the disease. These interventions are burdensome to the patient and their 
caregivers and are not highly effective at preventing progression of disease. 
The Sponsor is developing nedosiran (also known as DCR-PHXC) as a treatment for PH that is 
intended to prevent the enzymatic conversion in the liver of glyoxylate to oxalate, which should 
block the production of oxalate in the liver in all genetic forms of PH (PH1, PH2, and PH3). This 
effect has been demonstrated in nonclinical studies. A study in adolescent and adult participants 
with PH1 and PH2 (DCR-PHXC-201) demonstrated that DCR-PHXC was generally well 
tolerated and safe in patients with PH1 and PH2 with intact renal function. DCR-PHXC 
demonstrated efficacy by significantly lowering Uox in participants with PH1, however efficacy 
results were inconclusive for participants with PH2. 
This study is being conducted to assess the effect of nedosiran on Uox excretion in pediatric 
participants (birth to 11 years of age) with PH1, PH2, or PH3. 
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2.2. 
Background 
2.2.1. 
Overview of Primary Hyperoxaluria 
Primary hyperoxaluria encompasses 4 related rare diseases, 3 of which are attributed to 
mutations in specific genes (PH1, PH2, and PH3) and a fourth for which there is currently no 
identified genetic cause (no-mutation-detected primary hyperoxaluria, known as NMD-PH).  
Primary hyperoxaluria is a devastating disease that presents across the age continuum with a 
broad range of medically important abnormalities (Cochat & Rumsby, 2013). As a genetic 
disease, PH is present at birth but manifestations can occur at any time. All 3 genetic forms of 
PH exhibit some extent of overlap in the clinical manifestations, where overproduction of oxalate 
is a prominent observation (Hoppe, 2012; Hoppe et al., 2009). Presenting symptoms from early 
childhood through adolescence are most often related to kidney stone disease, including 
hematuria, dysuria, pain, urinary tract infection, or stone passage (Hoppe et al., 2009). Initial 
symptoms occur in most individuals before the age of 10 years, and in 85% to 90% by age 
20 years (Hoppe et al., 2009; van der Hoeven et al., 2012; Mandrile et al., 2014). Renal oxalate 
deposition in patients with PH1 and some patients with PH2 and PH3 leads to nephrocalcinosis, 
tubular dysfunction, and progression to ESRD. Systemic oxalosis occurs in patients with PH1 
and some patients with PH2 and PH3 due to the over-production of oxalate by the liver and the 
impairment of the body’s ability to eliminate oxalate, producing a broad range of serious 
life-threatening complications (Hoppe et al., 2021). The consequences of systemic deposition of 
calcium oxalate crystals in patients with systemic oxalosis include fracturing bone disease, 
nonhealing painful cutaneous ulcers, treatment-refractory anemia, retinal calcium oxalate 
deposition, and cardiomyopathy and arrhythmias due to deposition in the cardiac conduction 
system (Hoppe et al., 2009).   
A review of 330 patients with PH1 demonstrated that the outlook for these patients without 
treatment is poor, with ESRD present in 50% of patients by the age of 15 years and in 80% by 
the third decade (Latta & Brodehl, 1990). Although early initiation of aggressive conservative 
treatment (high fluid intake, inhibitor of calcium oxalate crystallization, and pyridoxine in 
responsive cases) can help slow or delay progression to ESRD, there is still substantial morbidity 
across the age continuum. In one study of 78 infants with PH1, 33 underwent kidney, liver, or 
kidney-liver transplantation. The age at first transplantation was 6.4 ± 7.8 years (Cochat et al., 
1999). Fifty-two percent of these patients died.  
Primary hyperoxaluria type 2 was first described in 1968 based on the absence of glycolate and 
the presence of L-glyceric acid in the urine from 4 cases with hyperoxaluria (Williams & Smith, 
1968). Primary hyperoxaluria type 2 is much rarer than PH1 and is characterized by recurrent 
nephrolithiasis with nephrocalcinosis. A recent study of 101 patients with PH2 suggested that 
PH2 patients are at a much higher risk than previously anticipated to develop CKD (in ~50% of 
patients) and ESRD (in ~25% of patients) (Garrelfs et al., 2019).  
Lumasiran is approved in a limited number of countries, including the European Union as a 
treatment for PH1. Lumasiran reduces levels of glycolate oxidase (GO) enzyme, which only has 
an effect on PH1, and therefore is not a viable treatment for PH2 or PH3 (Oxlumo™ [lumasiran, 
Alnylam] Highlights of Prescribing information, 2020). For patients without a treatment option, 
a number of supportive therapies are used in an attempt to mitigate some of the effects of the 
disease. Current medical management before renal failure develops is underpinned by 
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hyperhydration, with fluid intake recommendations of at least 3 liters per day per square meter of 
body-surface area (5 L/day for a 70-kg adult) (Cochat et al., 2012). These regimens can be 
problematic in infants and toddlers, necessitating placement of a gastrostomy tube to ensure 
adequate nighttime fluid administration. Affected patients are at considerable risk of serious 
complications during periods of increased fluid loss (fever, diarrhea/vomiting, and urinary tract 
infections) or when oral hydration is compromised (following surgical procedures). Oral 
potassium citrate administration is used to inhibit crystallization and alkalinize the urine. 
Treatment with vitamin B6 is effective in decreasing Uox in approximately 10% to 30% of 
patients with PH1 with certain AGXT mutations but has not been proven effective in treating 
other forms of PH (Salido et al., 2012; Hoppe et al, 2009; Hoyer-Kuhn et al., 2014). 
For patients with more advanced disease, dialysis may be used in an attempt to remove 
endogenously over-produced oxalate. In contrast to the more typical 3-times-weekly 
hemodialysis regimens used in other types of renal failure, patients with PH may require 
hemodialysis 6 or 7 days per week. Given the limitations of dialysis and the inability to 
substantially impact oxalate over-production in most patients with PH1, most centers now 
consider liver transplantation approaches earlier in the disease course to minimize the risk of 
irreversible tissue damage.  
Other treatments include renal transplantation or combined liver and kidney transplantation 
(Nolkemper et al., 2000; Rogers et al., 2001; Dhondup et al, 2018; Del Bello et al., 2020). As 
with organ transplantation in other diseases, these procedures are associated with significant 
medical risk and a requirement for long-term treatment with immunosuppressive drugs that are 
also associated with significant side effects. 
2.2.2. 
Nonclinical Overview 
Nedosiran consists of the drug substance, nedosiran sodium (also known as DCR-L1360) in 
WFI. Nedosiran sodium is a synthetic double-stranded (hybridized duplex) RNA oligonucleotide 
conjugated to GalNAc aminosugar residues. After SC administration, the GalNAc sugars 
conjugated to the RNA oligonucleotide bind to ASGPR to deliver nedosiran sodium to 
hepatocytes. Nedosiran sodium reduces the level of mRNA encoding the dominant form of the 
LDH enzyme, specifically, the LDHA isoenzyme. Lactate dehydrogenase catalyzes the cytosolic 
conversion of glyoxylate to oxalate in the liver and this biochemical reaction is believed to be 
critical for oxalate generation for all 3 genetic forms of PH. 
Inhibition of oxalate production has been accomplished in mouse models of PH1 and PH2 and in 
an indirect mouse model of PH3.  
Nedosiran sodium was not associated with any adverse effects on cardiovascular, respiratory, or 
neurological function in cynomolgus monkeys when administered as a single SC injection at 
doses up to 300 mg/kg. In addition, in the pivotal repeat-dose toxicity studies (up to 6 months in 
mice and up to 9 months in monkeys), nedosiran sodium was well tolerated at dose levels up to 
300 mg/kg in both mice and monkeys.  
In definitive GLP fertility and early embryonic development and EFD studies in mice, no test-
article-related toxicity was observed at dose levels up to 2000 mg/kg nedosiran sodium (highest 
dose administered) or 10 mg/kg of the mouse analog. In a preliminary, non-GLP, EFD study in 
rabbits (dose levels: 20 to 600 mg/kg), lower body weight gains in dams (with accompanying 
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lower food consumption) and embryofetal effects (higher litter proportions of postimplantation 
loss and lower numbers of live fetuses) were observed from the lowest doses. In addition, 
increased incidences of cardiovascular fetal malformations were noted. The human relevance of 
these contradictory observations in mice and rabbits is unclear, as nedosiran is not 
pharmacologically active in rabbits (i.e., no Ldha knockdown) and no such observations were 
noted in the mouse EFD studies with nedosiran or the pharmacologically active mouse analog.  
See the Nedosiran IB for more details on the nonclinical studies. 
2.2.3. 
Clinical Overview 
2.2.3.1. 
Clinical Studies of Nedosiran 
Nedosiran is being evaluated for the treatment of adults and children with PH in a series of 
completed and ongoing studies. 
Study DCR-PHXC-101 was a single ascending dose study conducted to evaluate the safety, 
tolerability, PK, and PD of nedosiran in healthy volunteers and participants with PH1 and PH2. 
A total of 33 participants (15 healthy volunteers and 18 participants with PH [including 
3 adolescents]) received a single dose of nedosiran. Nedosiran was generally safe and well 
tolerated in healthy volunteers and participants with PH1 and PH2. No treatment- or dose-related 
trends in the frequency, severity, or relatedness of TEAEs were observed. Injection site reactions 
were reported in 13.3% of healthy volunteers and 27.8% of participants with PH receiving 
nedosiran. Treatment-emergent SAEs were reported in 4 participants (22.2%); no SAEs were 
considered treatment-related. No clinically significant changes in cytokine levels were reported 
for the participants experiencing ISRs. A single-dose administration of nedosiran produced 
clinically meaningful reductions in 24-hour Uox in participants with PH1 and PH2. The mean 
maximum percent reduction in 24-hour Uox across cohorts was 64% (range 28%-100%), with a 
dose-response trend observed. Normalization of Uox (defined as Uox excretion 
< 0.46mmol/24 hours) was achieved in 10 of 18 participants with PH1 or PH2, with an 
additional 4 participants achieving near-normalization (defined as Uox excretion 0.46 to 
< 0.60 mmol/24 hours).  
Study DCR-PHXC-201 was a multicenter, randomized, placebo-controlled study designed to 
evaluate the efficacy and safety of nedosiran over a 6-month treatment period in participants with 
PH1 and PH2). A total of 35 participants were randomized and received treatment: 23 to 
nedosiran and 12 to placebo; of these, 33 completed study treatment and continued onto the 
extension study, Study DCR-PHXC-301.  
The primary objective of the study was met with strong statistical significance. The reduction of 
24-hour Uox, measured as the AUC24-hour Uox, from Day 90 to Day 180 in the nedosiran group 
was significantly greater than that in the placebo group (P < 0.0001). The key secondary efficacy 
endpoint analysis confirmed the primary endpoint analysis, as a significantly greater percentage 
of participants in the nedosiran group (50%) achieved normalization or near-normalization of 
24-hour Uox on at least 2 consecutive visits starting at Day 90 compared to placebo (0; 
P = 0.0025). When results were broken down by PH type, participants with PH1 demonstrated a 
significant reduction in 24-hour Uox from Baseline in the nedosiran group compared to the 
placebo group. ANCOVA modeling was not possible in participants with PH2; however, 
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individual participant observation did not show a consistent reduction of 24-hour Uox in 
participants with PH2 receiving nedosiran. 
Nedosiran was generally safe and well tolerated. The majority of TEAEs were mild or moderate 
in severity. Treatment-related TEAEs occurring in more than 1 nedosiran participant and more 
frequently in the nedosiran group than the placebo group were injection site erythema and 
injection site pain. A total of 8.7% of participants in the nedosiran group experienced ISRs. All 
ISRs were CTCAE Grade 1 and all resolved by the end of the study. SAEs were reported by 
1 nedosiran participant and 2 placebo participants. The participant in the nedosiran group 
experienced an SAE of tachycardia considered by the Investigator to be possibly related to 
treatment due to the temporal relationship of the event to study drug exposure. The participant 
was withdrawn from treatment due to the tachycardia. Based upon external expert review of the 
case, the Sponsor assessed the event as not related. No trends indicative of clinically important 
effects of nedosiran on laboratory or other clinical parameters were observed. No new risks were 
identified.  
Study DCR-PHXC-104 was a multicenter, Phase 1, randomized, placebo-controlled, double-
blind, single-dose trial of nedosiran in patients with PH3. The primary objective was to evaluate 
the safety profile of nedosiran in patients with PH3. The secondary objectives were to 
characterize the plasma PK of nedosiran and to determine the effect of nedosiran in lowering 
Uox after single-dose administration in patients with PH3. Six participants were randomized: 
4 to nedosiran and 2 to placebo; all 6 randomized participants received one dose of study drug 
and completed the study. 
Overall, nedosiran was well tolerated. All TEAEs were mild in severity. No TEAEs were 
considered serious or treatment related and no participant was withdrawn from the study due to a 
TEAE. There were no treatment-related trends in vital sign, physical examination, or ECG data 
observed between the nedosiran and placebo groups. 
The efficacy endpoint was not met, as no participants achieved a > 30% decrease from baseline 
in 24-hour Uox on 2 consecutive visits. However, at Day 85, all participants in the nedosiran 
group experienced decreases in 24-hour Uox from Baseline, with a mean decrease of 24.5%. 
Two participants in the nedosiran had greater than 30% decreases in 24-hour Uox at a single 
visit. Similar trends were not observed in the 2 placebo-arm participants. As such, further 
evaluation of the efficacy of nedosiran in participants with PH3 is warranted.  
Studies DCR-PHXC-301 (long-term roll-over study in patients with PH1, PH2, or PH3) and 
DCR-PHXC-204 (a 6-month open-label study in patients with severe renal impairment or ESRD) 
are ongoing. Both studies include participants < 18 years of age. 
Nedosiran has an acceptable safety profile in both healthy volunteers and participants with PH1, 
PH2, and PH3. No significant safety findings have emerged from completed or ongoing studies. 
Please see the Nedosiran IB for additional details of these clinical studies. 
2.3. 
Benefit/Risk Assessment 
2.3.1. 
Risk Assessment 
Risks associated with nedosiran may be characterized into 2 broad categories: risks associated 
with the siRNA molecule and risks associated with an off-target knockdown of LDHA. 
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2.3.1.1. 
Risks Related to the siRNA Molecule 
To date, nedosiran sodium has been associated with little to no systemic toxicity in the 
nonclinical studies. Results of nonclinical toxicity studies of nedosiran sodium conducted to date 
are presented in Section 2.2.2.   
Clinical observations associated with other siRNAs have included occasional reports of 
stimulation of pattern recognition receptors (e.g., Toll-like receptors) leading to cytokine release, 
inflammation, and ISRs, and low elevations of LFT. Clinical experience with the Dicerna GalXC 
platform suggests an enhanced safety profile with little to no evidence of systemic immune 
stimulation or toxicities in more than 200 patients and healthy volunteers. Mild, self-limiting 
ISRs have been reported. 
2.3.1.2. 
Risks Related to LDHA Knockdown and Potential Off-target Effects 
LDHA deficiency (Glycogen storage disease XI) is a very rare, near complete loss of 
LDHA function caused by mutations in the LDHA gene. People with this condition may 
experience exercise intolerance, characterized by fatigue, muscle pain, and cramps during 
exercise (Kanno et al., 1980; Nishimura et al., 1983). Liver-associated changes have not been 
reported. 
Nedosiran sodium contains 4 GalNAc sugar residues that preferentially direct delivery of the 
siRNA to hepatocytes, due to their high expression of ASGPR. As such, adverse effects outside 
of the liver are unlikely at clinical doses. No changes in muscle performance were noted when 
Ldha-knockdown mice were subjected to exercise in a treadmill endurance test (Lai et al, 2018), 
and no adverse skeletal muscle effects were observed in monkeys at nedosiran sodium dose 
levels up to 300 times the minimally active dose. Nonetheless, in addition to measurement of 
plasma CK, participants should be monitored for signs and symptoms of muscle weakness or 
pain. 
Nedosiran sodium shows high sequence specificity. In silico analysis suggests that it has minimal 
potential for off-target effects via siRNA hybridization to the human genome. 
2.3.2. 
Pediatric Burden Assessment 
With respect to the overall burden of the study, patients with PH have regular visits at their 
treating physician, which includes routine measurements of hematology and chemistry, vital 
signs, kidney ultrasound, ECG, echocardiography, and analysis of spot urine (Cochat et al., 
2012). Therefore, the burdens of the current protocol procedures are considered minimal in 
comparison to the standard treatment for PH (see Table 2 for details). At-home visits have been 
incorporated into the study design to minimize burden of study participation.  
At each study visit, pediatric participants and their parent(s) or guardian(s) will be asked a few 
study-specific questions to ensure that the burden of continued study participation is not too 
extensive. This pediatric burden assessment is in line with the requirements put forth in the 
European Commission’s Ethical Considerations for Clinical Trials on Medicinal Products 
Conducted with Minors (18 September 2017). 
 
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Table 2: 
Risk/Burden Assessment 
Procedure 
Risk/Burden 
Mitigation 
Blood sampling, 
including cannulation 
Risks include acute pain, bleeding, vessel 
injury, and, in rare instances, arterial 
vessel blockage, potentially leading to 
infection. 
The risk/burden is minimal and not over 
and above the risk/burden associated 
with blood sampling as part of the 
standard treatment for PH.  
12-lead ECG 
Electrocardiography does not involve 
any invasive procedures. 
Conducted in supine position after 
10 minutes at rest. No risks identified. 
Blood pressure 
measurement 
Measurement of blood pressure may 
result in mild discomfort. 
Measurements performed at a single time 
point with an appropriately sized blood 
pressure cuff. No risks identified. 
Subcutaneous injection 
The study drug is administered via 
SC injection. Subcutaneous injection is 
associated with pain, and may cause 
vasovagal reactions, allergic reactions, 
infections, and bleeding. 
The risk/burden associated with 
SC administration of the study drug is 
minimal. This injection is outside the 
standard treatment for PH and therefore 
is assessed as a minimal risk/burden to 
participants. The investigator is obligated 
to anticipate and address injection site 
pain (for example, using a topical 
anesthetic). 
Kidney ultrasound 
Kidney ultrasound does not involve any 
invasive procedures. 
Kidney ultrasound is part of the standard 
treatment for patients with PH. No risks 
identified. 
Echocardiogram 
Echocardiography does not involve any 
invasive procedures. 
Echocardiography is part of the standard 
treatment for patients with PH. No risks 
identified. The echocardiogram should 
not be performed if it requires sedation. 
Spot urine collection 
Due to the frequency of collection in the 
current protocol, minor burden is 
involved. 
Spot urine collection is part of the 
standard treatment for PH patients. Urine 
collection in this study does not involve 
catheterization or invasive procedures of 
any kind (unless this is already part of 
the participants standard of care). No 
risks identified. 
 
2.3.3. 
Benefit Assessment 
The biological relationship between urinary oxalate supersaturation and the subsequent 
calcifications in kidney and extra-renal organs has been well established (Hoppe et al., 2009; 
Hoppe, 2012; Cochat & Rumsby, 2013). The degree of hyperoxaluria has been shown to predict 
the development and severity of nephrocalcinosis and is described as a risk factor for ESRD in 
patients with PH (Zhao et al., 2016).  
As increased urinary oxalate is an independent risk factor for the development of calcium oxalate 
crystallization, a reduction in oxalate excretion should lower the risk of calcium-oxalate 
supersaturation and the subsequent negative consequences on the renal system and beyond. 
Several researchers have demonstrated that pre-emptive liver transplantation normalizes oxalate 
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excretion and stabilizes or improves kidney function in long-term follow-up if no systemic 
oxalosis is present (Kemper et al., 1998; Galanti & Contreras, 2010; Perera et al., 2011). 
Results from nonclinical studies of nedosiran demonstrated that a reduction of hepatic Ldha 
mRNA lowered or eliminated excess oxalate production in the livers of PH model mice and 
protected the kidney from calcium oxalate crystal deposition and the resultant damage. Based on 
results achieved in the murine models of PH, administration of nedosiran to participants with PH, 
who do not have systemic oxalosis, is expected to result in a measurable reduction in urinary 
oxalate. 
Results from the completed Study DCR-PHXC-101 are summarized in Section 2.2.3.1 and 
demonstrate that single-dose administration of nedosiran can reduce the urinary oxalate burden 
in participants with PH1 and PH2 and potentially decrease the risk for the development of 
calcium oxalate crystallization. 
2.3.4. 
Risk Management 
Measures to minimize the risks to participants have been incorporated into the following study 
design elements: 
• An SRC will review all safety and efficacy data after the first 2 participants aged 2 to 
5 years old have completed Day 60 and every 3 months thereafter. Ad hoc meetings 
may also occur if needed as specified in the SRC charter.  
• Clinical Laboratory Monitoring: At time of study entry, study participants are 
required to have safety laboratory values within acceptable ranges. Serial 
measurements of safety laboratory parameters (CBC, platelet count, creatinine, 
cytokines, complement, LFTs) and coagulation parameters are planned, with regular 
medical review by the medical monitor, as outlined in the medical management plan. 
• Monitoring of signs and symptoms of muscle pain and/or weakness, along with 
measurement of plasma creatine kinase. 
• The maximum blood volume to be collected from pediatric participants over the 
course of the study will be based on weight and will not exceed those specified in 
Table 5. Consult the Laboratory Manual for the blood draw priority list based on 
participant weight. 
• If met with blood draw difficulty, the Investigator team will make not more than 3 
attempts at venipuncture in the same day. 
With regard to pediatric participants, the International Conference on Harmonisation (ICH) 
Harmonised Tripartite Guideline: Clinical Investigation of Medicinal Products in the Pediatric 
Population (E11, 20 July 2000) and the European Commission Ethical Considerations for 
Clinical Trials on Medicinal Products Conducted with Minors (18 September 2017) have been 
considered during the design of the trial, and blood volume minimized where possible. Practical 
considerations include the use of laboratories experienced in handling small volumes of blood 
for PK, PD, and laboratory safety analyses.  
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Wherever possible, routine clinical safety, efficacy, and PK blood samples will be collected at 
the same time point. Furthermore, indwelling catheters will be used where deemed appropriate 
by the Investigator team to minimize the potential distress of venipuncture. 
2.3.5. 
Overall Benefit:Risk Conclusion 
At present, no therapies are approved by regulatory authorities for the treatment of patients with 
PH2 or PH3. Lumasiran, a treatment for PH1, is approved in a limited number of countries, 
including the European Union. A number of supportive therapies are also used in an attempt to 
mitigate some of the effects of the disease, but affected patients are at considerable risk of 
serious complications like renal stones, nephrocalcinosis, renal failure, and systemic tissue 
damage due to oxalate deposition. Combined liver-and-kidney transplantation is the only 
causative therapy but is associated with short- and long-term complications as well.  
Thus far nedosiran treatment has shown potential benefit to reduce or prevent the excess oxalate 
production in the liver. If sustained, this could eliminate the need for a liver transplantation.   
The potential risks with nedosiran include low elevations of liver function tests, muscle damage, 
and stimulation of pattern recognition receptors (e.g., Toll-like receptors) leading to cytokine 
release, inflammation, and ISRs. These risks can be monitored and should be reversible after 
drug discontinuation. The results from the completed study, DCR-PHXC-101, demonstrate the 
potential for nedosiran to bring patients into a near-normal or normal range of their 24-hour Uox 
values. Continuous risk-benefit assessments will be conducted by the Sponsor, the Medical 
Monitor of the CRO, and the SRC on an ongoing basis. 
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3. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
• 
To assess the efficacy of nedosiran in neonates, 
infants, and children with PH and relatively 
intact renal function based upon eGFR and 
serum creatinine 
• 
Percent and absolute change from Baseline to 
Month 6 in spot urinary oxalate-to-creatinine 
ratio in PH1, PH2, or PH3 participant subgroups  
Secondary 
• 
To characterize the safety of nedosiran in 
neonates, infants, and children with PH and 
relatively intact renal function based upon eGFR 
and serum creatinine  
• 
The incidence and nature of TEAEs and SAEs 
• 
Change from Baseline in 12-lead ECG, physical 
examination findings, vital sign assessments, and 
clinical laboratory tests 
• 
To characterize the PK of nedosiran in neonates, 
infants, and children with PH and relatively 
intact renal function based upon eGFR and 
serum creatinine 
• 
Plasma PK parameters for nedosiran and/or its 
metabolites, including Cmax, AUCt and AUC∞ (if 
estimable)  
• 
To assess the efficacy of nedosiran in neonates, 
infants, and children with PH and relatively 
intact renal function based upon eGFR and 
serum creatinine 
• 
Percentage of participants with spot urinary 
oxalate-to-creatinine ratio ≤ the ULN or 
≤ 1.5 x ULN at any time point through Month 6 
in PH1, PH2, or PH3 participant subgroups   
• 
To evaluate the effect of nedosiran on eGFR in 
neonates, infants, and children with PH and 
relatively intact renal function based upon eGFR 
and serum creatinine 
• 
Change from Baseline in eGFR at Month 6 (only 
in participants ≥ 12 Months of age at Screening) 
in PH1, PH2, or PH3 participant subgroups 
Tertiary/Exploratory 
• 
To assess the effect of nedosiran on plasma 
oxalate in neonates, infants, and children with 
PH and relatively intact renal function based 
upon eGFR and serum creatinine 
• 
Percent and absolute change in plasma oxalate 
over time in PH1, PH2, or PH3 participant 
subgroups 
• 
To assess the effect of nedosiran on stone events 
in neonates, infants, and children with PH and 
relatively intact renal function based upon eGFR 
and serum creatinine 
• 
Change from Baseline in annualized stone event 
rate in PH1, PH2, or PH3 participant subgroups 
• 
To evaluate the effect of nedosiran on QoL 
assessments in neonates, infants, and children 
with PH and relatively intact renal function 
based upon eGFR and serum creatinine 
• 
Change from Baseline in the Pediatric Quality of 
Life Inventory (PedsQL™) in PH1, PH2, or PH3 
participant subgroups 
• 
To evaluate the effect of nedosiran on 
productivity loss of caregivers for neonates, 
infants, and children with PH and relatively 
intact renal function based upon eGFR and 
serum creatinine 
• 
Change from Baseline in the Work Productivity 
and Activity Impairment Questionnaire: Primary 
Hyperoxaluria V2.0, Clinical Practice Version 
(WPAI:PH, V2.0, CPV) – Caregiver in PH1, 
PH2, or PH3 participant subgroups 
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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a Phase 2, multi-dose (3.5 mg/kg, not to exceed 170 mg), open-label, single-arm 
uncontrolled multicenter study of nedosiran in pediatric participants (birth to 11 years of age) 
with genetically confirmed PH1, PH2, or PH3, with relatively intact renal function based upon 
eGFR and serum creatinine.  
Following the up-to-35-day screening period, participants will return to the clinic for interim 
visits through Day 180 (6 months). At the discretion of the Investigator, visits on Days 2, 60, 
120, and 150 may be conducted in the participant’s home, through a combination of telemedicine 
and home nursing care (at-home telehealth visit). The total time on study for each participant is 
approximately 7 months. Participants completing this study may be eligible for enrollment into a 
long-term, open-label, extension study (see Section 6.7). 
It is expected that approximately 25 participants will be screened such that 
approximately 20 participants will complete the study. Participants will receive monthly doses 
(3.5 mg/kg, not to exceed 170 mg) of nedosiran for 6 months.  
Participants with PH3 will only be enrolled if Study DCR-PHXC-104 establishes proof of 
concept for nedosiran in lowering Uox in participants at least 6 years of age with PH3. 
Modeling and simulation (M&S) was performed to determine the dose and dosing frequency for 
the birth to 5 years of age group in this study based on all available data for participants aged 
≥ 6 years.  
It is expected that the entire trial will have a 24-month duration. 
4.2. 
Scientific Rationale for Study Design 
This Phase 2, multi-dose, open-label, single-arm uncontrolled trial is the optimal design for 
evaluation of efficacy and safety of an investigational drug in the pediatric participants (birth to 
11 years of age). The 6-month duration of the treatment period is considered sufficient to 
demonstrate a sustained effect of nedosiran in lowering Uox in participants with PH. 
The primary endpoint of this Phase 2 study will be the percent and absolute change from 
Baseline to Month 6 in spot urinary oxalate-to-creatinine ratio. The degree of hyperoxaluria 
predicts the development and severity of nephrocalcinosis and is a risk factor for ESRD in 
participants with PH (Zhao et al., 2016). The average of 6 baseline spot urine 
oxalate-to-creatinine ratios at Screening will be above 2 times the 95th percentile for age to 
qualify for enrollment (Matos et al., 1999). 
4.3. 
Justification for Dose 
4.3.1. 
PK/PD Model for Dose Selection in Pediatric Participants (Birth to 11 Years) 
The dose selection for the 6- to 11-year-old participants was based on safety, tolerability and 
PK-PD relationship between nedosiran and Uox excretion. The dose for 6- to 11-year-old 
participants was aided by PK and PK-PD simulations from adults and adolescents in previous 
studies of nedosiran. The dose was selected such that the 6- to 11-year-old participants will have 
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a similar exposure to nedosiran as participants receiving the 170 mg dose and to provide for a 
comparable proportion of participants with normal or near-normal levels of 24-hour Uox. Based 
on these simulations, a dose regimen of 3.5 mg/kg once monthly was selected. The dose has been 
shown to be safe and tolerable (following multiple Q1M dosing in this age category) in other 
clinical studies with nedosiran. 
The dose selection for 0- to 5-year-old participants was based on safety, efficacy, PK, and PD 
considerations. Multiple doses of nedosiran (3.5 mg/kg once monthly) have been demonstrated 
to be safe and well tolerated in pediatric participants with PH in the 6- to l1-year age group 
(Study DCR-PHXC-201). No SAEs have been reported in the 6- to 11-year-old participants with 
PH.  
Selection of dose was aided by PK-PD modeling simulation of data from participants aged 
6 years and older. Based on these simulations, a dosing regimen of 3.5 mg/kg, not to exceed 
170 mg, once monthly was selected for children aged 0 to 5 years.   
The selected dosing regimen (3.5 mg/kg once monthly) for the 0 to 5-year age group is predicted 
to provide similar plasma and liver exposure (AUC0-tau) of nedosiran as compared to the 6- to 
11-year age group and a similar lowering of urinary oxalate.  
4.4. 
End of Study Definition 
A participant is considered to have completed the study if he or she has completed all phases of 
the study, including the last visit or the last scheduled procedure shown in the Schedule of 
Activities (SoA), Section 1.3. 
The end of the study is defined as completion of the last visit or procedure shown in the SoA in 
the trial globally. 
 
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5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. 
Birth to 11 years of age inclusive, at the time of signing the informed consent. 
Type of Participant and Disease Characteristics 
2. 
Documented diagnosis of PH1, PH2, or PH3 confirmed by genotyping (historically 
available genotype information is acceptable for study eligibility).  
3. 
Average spot Uox to creatinine ratio at Screening above 2 times the 95th percentile for 
age (Matos et al, 1999): 
• > 0.44 mol/mol in participants < 6 months 
• > 0.34 mol/mol in participants from 6 months to < 12 months 
• > 0.26 mol/mol in participants 12 months to < 2 years 
• > 0.20 mol/mol in participants from 2 to < 3 years and 
• > 0.16 mol/mol in participants from 3 to < 5 years 
• > 0.14 mol/mol in participants from 5 to < 7 years 
• > 0.12 mol/mol in participants from 7 to 11 years 
4. 
Estimated GFR at Screening ≥ 30 mL/min normalized to 1.73 m2 BSA. See 
Section 8.2.6.1 for equations. For infants aged less than 12 months, serum creatinine below the 
97.5th percentile of a healthy population (Boer et al., 2010).  
5. 
Participants must have been on a stable treatment regimen for PH for 3 months prior to 
Day 1 and parent(s)/legal guardian should be willing to ensure participant remains on the same 
stable treatment regimen during the study. Dose adjustments for interval weight gain are 
acceptable. 
Sex 
6. 
Male or female 
Male participants: 
A male participant with a female partner of childbearing potential must agree to 
use contraception, as detailed in Section 10.5.2, during the treatment period and 
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for at least 12 weeks after the last dose of study intervention and refrain from 
donating sperm during this period. 
Female participants:  
A female participant is eligible to participate if she is not pregnant (see 
Section 10.5.1), not breastfeeding, and at least 1 of the following conditions 
applies: 
Not a woman of childbearing potential (WOCBP) as defined in Section 10.5.1 
OR 
A WOCBP who agrees to follow the contraceptive guidance in Section 10.5.2 
during the treatment period and for at least 12 weeks after the last dose of study 
intervention. 
Contraceptive use by men or women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies. 
Note: If the childbearing potential changes after start of the study (e.g., a premenarchal 
female participant experiences menarche) or the risk of pregnancy changes (e.g., a female 
participant who is not heterosexually active becomes active), the participant must discuss 
this with the Investigator, who should determine if a female participant must begin a 
highly effective method of contraception or a male participant must use a condom. If 
reproductive status is questionable, additional evaluation should be considered. 
Informed Consent and Assent 
7. 
Participant’s parent or legal guardian is capable of giving signed informed consent, which 
includes compliance with the requirements and restrictions listed in the ICF and in this protocol.  
a. For children younger than 12 years of age, assent will be based on local regulation. If 
assent is required, participant must be able to provide written assent for participation. 
Other 
8. 
A legal guardian or primary caregiver must be available to help the study-site personnel 
ensure follow up; accompany the participant to the study site on each assessment day according 
to the SoA (e.g., able to comply with scheduled visits, treatment plan, laboratory tests and other 
study procedures); consistently and consecutively be available to provide information on the 
participant using the rating scales during the scheduled study visits; accurately and reliably 
dispense study intervention as directed. 
9. 
Affiliated with or is a beneficiary of a health insurance system (if applicable per national 
regulations) 
5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. 
Prior renal or hepatic transplantation; or planned transplantation within the study period 
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2. 
Currently receiving dialysis or anticipating requirement for dialysis during the study 
period 
3. 
Plasma oxalate (Pox) > 30 µmol/L at Screening 
4. 
Documented evidence of clinical manifestations of severe systemic oxalosis (including 
preexisting retinal, heart, or skin calcifications, or history of severe bone pain, pathological 
fractures, or bone deformations) 
5. 
Presence of any condition or comorbidities that would interfere with study compliance or 
data interpretation or potentially impact participant’s safety including, but not restricted to:  
a. Severe intercurrent illness  
b. Known causes of active liver disease/injury or transaminase elevation (e.g., alcoholic 
liver disease, nonalcoholic fatty liver disease/steatohepatitis [NAFLD/NASH])  
c. History of serious mental illness that includes, but is not limited to, schizophrenia, 
bipolar disorder, or severe depression requiring hospitalization or pharmacological 
intervention  
d. Clinically relevant history or presence of cardiovascular, respiratory, gastrointestinal, 
hematological, lymphatic, neurological, musculoskeletal, genitourinary, 
immunological diseases, including dermatological including rash, severe eczema or 
dermatitis, or connective tissue diseases or disorders 
Prior/Concomitant Therapy 
6. 
Use of an RNAi drug within the last 6 months 
7. 
History of 1 or more of the following reactions to an oligonucleotide-based therapy: 
a. Severe thrombocytopenia (platelet count ≤ 100,000/µL) 
b. Hepatotoxicity, defined as ALT or AST > 3 times the upper ULN and total bilirubin 
> 2 × ULN or INR > 1.5 
c. Severe flu-like symptoms leading to discontinuation of therapy 
d. Localized skin reaction from the injection (graded severe) leading to discontinuation 
of therapy 
e. Coagulopathy/clinically significant prolongation of clotting time 
Prior/Concurrent Clinical Study Experience 
8. 
Participation in any clinical study in which they received an IMP within 4 months or 
5 times the half-life of the drug (whichever is longer) before Screening 
a. For IMPs with the potential to reduce urine and/or plasma oxalate concentrations, 
these concentrations must have returned to historical baseline levels prior to 
Screening  
Diagnostic assessments 
9. 
Liver function test (LFT) abnormalities: ALT and/or AST > 1.5 × ULN for age and 
gender 
Other Exclusions 
10. 
Known hypersensitivity to nedosiran, or any of its ingredients  
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11. 
Inability or unwillingness to comply with the specified study procedures, including the 
lifestyle considerations detailed in Section 5.3. 
5.3. 
Lifestyle Considerations 
During this study, the parent(s)/legal guardian are asked to ensure the participant: 
• Refrain taking vitamin C supplements, including multivitamins, for 24 hours prior to 
and during the timeframe when spot urine specimens are collected  
• Continue to follow standard of care for PH, including, but not limited to 
hyperhydration regimens, oral potassium citrate administration, and treatment with 
vitamin B6 (if applicable) 
5.3.1. 
Meals and Dietary Restrictions 
During this study, the parent(s)/legal guardian are asked to ensure the participant: 
• Avoids oxalate-rich foods 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently entered in the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants, to meet the CONSORT publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any SAEs. 
Rescreened participants will be assigned a new participant number for re-screening. Potential 
participants may undergo rescreening only with approval of the Sponsor.  
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6. 
STUDY INTERVENTION 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to the 
study protocol. 
6.1. 
 Study Intervention(s) Administered 
Nedosiran (also known as DCR-PHXC) is a synthetic RNAi drug that consists of a 
double-stranded oligonucleotide conjugated to GalNAc ligands. Nedosiran is a sterile 
formulation of drug substance (nedosiran sodium) in WFI, intended for SC administration. 
Nedosiran is not commercially available in any country. 
The total dose will be based upon body weight recorded on study Day 1, and for participants 
≥ 6 months of age at Screening, the dose will remain constant throughout the study (i.e., the dose 
administered on Day 1 will be the dose administered at all following visits regardless of any 
change in body weight). For participants < 6 months of age at Screening, the dose will be 
adjusted at Day 90 to capture changes in weight; no other dose adjustments are allowed.  
 
ARM Name 
Active  
Intervention 
Name 
Nedosiran   
Type  
Drug 
Dose 
Formulation 
Sterile formulation of drug substance (nedosiran sodium) in WFI 
Unit Dose 
Strength(s) 
170 mg/mL (sodium salt; 160 mg/mL free acid) 
Dosage 
Level(s) 
(calculated 
from sodium 
salt) 
Multi dose 
3.5 mg/kg, not to exceed 170 mg 
Route of 
Administration 
SC injection (thigh or abdomen)  
Use 
Experimental 
IMP and 
NIMP 
IMP  
Sourcing 
Provided centrally by the Sponsor or designee  
Packaging and 
Labeling 
Study Intervention will be provided in vials. Each vial will be labeled 
as required per country requirement.  
Alias 
DCR-PHXC 
 
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6.2. 
Preparation/Handling/Storage/Accountability 
6.2.1. 
Handling and Accountability 
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are reported 
and resolved before use of the study intervention. 
Only participants enrolled in the study may receive study intervention and only authorized site 
staff may supply study intervention. Only authorized site staff, visiting nurses, or the 
participants’ parents/caregivers may administer study intervention.  
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(i.e., receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused study interventions are 
provided in the Study Reference Manual. 
6.2.2. 
Storage 
Nedosiran is to be stored at 2°C to 8°C (inclusive). Nedosiran is to be stored in an appropriately 
secured location in a refrigerator, and storage must comply with institutional procedures in effect 
at the study site for handling investigational products. Access must be limited to authorized 
clinic personnel. A temperature log will be maintained. 
At home, the participant’s parent or caregiver will store nedosiran in a refrigerator (2°C to 8°C). 
The product should not be allowed to freeze or be placed next to the freezer compartment or a 
freezer pack. 
6.2.3. 
Preparation and Administration 
Study intervention will be prepared by the pharmacist or designee.  
A second medically qualified person must check the dose preparation prior to administration to 
be sure the correct dose has been prepared. 
The product should be allowed to warm to room temperature for approximately 1 hour but no 
more than 4 hours before administration. 
Nedosiran is administered as a SC injection into the thigh or abdomen using a 25- to 27-gauge 
needle, 3/8 to 5/8 inches long. The maximum injection volume in participants is 0.5 mL; if the 
participant's weight requires an injection volume > 0.5 mL, the total dose will be administered as 
2 SC injections of equal volume. 
As allowed by local health authorities and ethics committees, after the first 2 injections of 
nedosiran, study intervention may be administered at home at the Investigator’s discretion for 
those months at which a study-site visit is not required. For participants 0 to 5 years old, visiting 
nurses may administer SC injections at home. For participants 6 to 11 years old, the participants’ 
caregivers or visiting nurses may administer SC injections at home. For any participant whose 
caregiver administers study drug during at home visits, the participants’ caregivers will 
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administer nedosiran in the presence of the Investigator/study staff to confirm proper technique 
at clinic visits. A portfolio of training materials will be provided for at-home reference. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
This is an open-label study; however, the specific intervention to be taken by a participant will 
be assigned using an IWRS. The site will contact the IWRS prior to the start of study 
intervention administration for each participant. The site will record the intervention assignment 
on the applicable eCRF, if required.  
6.4. 
Study Intervention Compliance 
Study intervention will be administered by a member of the study staff or a caregiver/visiting 
nurse for at-home visits. The date and time of each dose administered in the clinic will be 
recorded in the source documents and recorded in the eCRF. The dose of study intervention and 
study participant identification will be confirmed at the time of dosing by a member of the study 
site staff other than the person administering the study intervention.   
With respect to at-home dosing, participants’ caregivers will complete a dosing diary and will 
return all empty and/or unused vials to the study site at each visit. 
6.5. 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with: 
• Reason for use 
• Dates of administration, including start and end dates 
• Dosage information, including dose and frequency 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
Participants taking pyridoxine (vitamin B6) must have been at a stable dose for at least 3 months 
(or as applicable for those less than 3 months of age) prior to Day 1 and must remain on the same 
stable dose throughout the study. Dose adjustments for interval weight gain are acceptable. 
Participants should avoid taking vitamin C supplements, including multivitamins, for 24 hours 
prior to and during the timeframe when spot urine samples are collected. Other concomitant 
medication may be considered on a case-by-case basis by the Investigator in consultation with 
the Medical Monitor (if required). 
6.5.1. 
Prohibited During the Study 
Participation in any other clinical study involving an IMP is prohibited during this study. 
6.5.2. 
Rescue Medicine 
Not applicable.   
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6.5.3. 
COVID-19 and Other Vaccine Administration 
To allow discernment of AEs related to the administration of vaccines from those related to 
administration of study intervention, vaccines should not be administered in the 7 days prior to or 
following scheduled administration of study intervention. 
6.6. 
Dose Modification 
No dose modifications are allowed, except for dose adjustments based upon weight at Day 90 for 
participants < 6 months of age at Screening.   
6.7. 
Intervention After the End of the Study 
Participants successfully completing study DCR-PHXC-203 may be screened for entry into the 
roll-over study (DCR-PHXC-301) at the Day 180, EOS visit. 
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7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1.1. 
Discontinuation of Study Intervention Stopping Rules for Individual 
Participants 
Study intervention for an individual participant may be permanently discontinued at any time at 
the discretion of the Investigator. 
Study intervention for an individual participant will be permanently discontinued for any of the 
following: 
• any SAE possibly, probably, or definitely related to study intervention; unless, before 
the next scheduled dose, the SAE is reconsidered to be not related to study 
intervention or has resolved AND continued drug treatment in the study is considered 
safe by the SRC.  
• any of the changes in hepatic function detailed in Section 7.1.1.1. 
• pregnancy, as detailed in Section 10.5. 
Discontinuation from study intervention does not mean discontinuation from the study. 
Remaining visits and study procedures should be completed as indicated by the SoA.  
See the SoA for data to be collected at the time of intervention discontinuation and follow-up and 
for any further evaluations that need to be completed. 
7.1.1.1. 
Drug-Induced Liver Injury Monitoring 
See Section 10.5.  
7.1.1.2. 
Temporary Discontinuation 
Temporary discontinuation of study intervention may be allowed due to changes in hepatic 
function, see Section 10.5. 
7.1.1.3. 
Rechallenge 
Rechallenge with study intervention may be allowed following changes in hepatic function, see 
Section 10.5. 
7.1.2. 
Study Stopping Rules  
In the event of a life-threatening or fatal SAE that is determined to be at least possibly related to 
study drug, the study will be suspended (i.e., further enrollment and dosing in the study will be 
interrupted) and an ad hoc SRC meeting will happen. Continuation of the study would require 
approval by the regulatory authorities. The Sponsor will notify all sites promptly if the study is 
suspended or terminated. In the event that the study is suspended or terminated, all ongoing 
participants will continue to be followed for safety assessments as indicated in the SoA 
(Section 1.3). 
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7.2. 
Participant Discontinuation/Withdrawal from the Study 
The participant’s parent or legal guardian has the right to withdraw permission (consent) at any 
time during the study or the participant may be withdrawn at any time at the discretion of the 
Investigator for safety, behavioral, compliance, or administrative reasons.  
At the time of discontinuing from the study, if possible, an early discontinuation visit should be 
conducted, as shown in the SoA. See SoA (Section 1.3) for data to be collected at the time of 
study discontinuation and follow-up and for any further evaluations that need to be completed. 
The participant will be permanently discontinued both from the study intervention and from the 
study at that time. 
If the participant’s parent or legal guardian withdraws consent for disclosure of future 
information, the Sponsor may retain and continue to use any data collected before such a 
withdrawal of consent. 
If a participant withdraws from the study, the participant or participant’s parent or legal guardian 
may request destruction of any samples taken and not tested, and the Investigator must document 
this in the site study records.  
The reason for participant discontinuation or withdrawal from the study will be recorded on the 
eCRF. Participants who sign the ICF but do not receive the study intervention may be replaced. 
Participants who sign the ICF and receive the study intervention, and subsequently withdraw, or 
are withdrawn or discontinued from the study may be replaced at the discretion of the Sponsor. 
7.3. 
Lost to Follow up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant’s parent or legal guardian and 
reschedule the missed visit as soon as possible and counsel the participant’s parent or 
legal guardian on the importance of maintaining the assigned visit schedule and 
ascertain whether or not the participant wishes to and/or should continue in the study. 
• Before a participant is deemed lost to follow up, the Investigator or designee must 
make every effort to regain contact with the participant’s parent or legal guardian 
(where possible, 3 telephone calls and, if necessary, a certified letter to the 
participant’s last known mailing address, or local equivalent methods). These contact 
attempts should be documented in the participant’s medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1 
(Section 10.1.8). 
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8. 
STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and their timing are summarized in the SoA presented in Table 1. 
Protocol waivers or exemptions are not allowed. 
• Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention. 
• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
• Procedures conducted as part of the participant’s routine clinical management (e.g., blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes, provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA. 
8.1. 
Efficacy Assessments 
8.1.1. 
Spot Urine Collection  
Oxalate is a dicarboxylic acid that is a normal end-product of metabolism. Most oxalate in the 
body is produced in the liver. Humans lack an enzyme to degrade oxalate, and thus it must be 
eliminated by the kidney. In individuals with PH, mutations in the AGXT, GRHPR, or HOGA1 
gene result in the overproduction of oxalate by the liver, which causes increased oxalate 
excretion by the kidneys.   
The primary measurement of oxalate in the urine will be via spot urine collection. The second 
morning void is thought to offer the least variability in terms of Uox/ creatinine.  
Urine samples will be collected for the determination of Uox and creatinine. Six spot urine 
samples (3 of which must be second morning void) will be collected over a 3-day period during 
Screening. Baseline is defined as the average of the 6 screening values.   
Four on-treatment spot urine samples (2 of which must be second morning void) will be 
collected over a 2-day period on a monthly basis. 
Participants should avoid consuming vitamin C, including multivitamins, in the 24 hours 
preceding urine collection. 
Any participant who prematurely discontinues study intervention should perform 4 spot urine 
collections as directed by the Medical Monitor. 
Complete instructions for the spot urine collection, including in infants, will be provided in the 
Urine Collections Instructions. 
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8.1.2. 
Plasma Oxalate (Pox) 
Plasma oxalate concentration is a reflection of the body pool size. The Pox pool size is increased 
in individuals with PH and impaired renal function. When the pool increases, oxalate may 
precipitate in tissues and cause toxicity.  
Complete instructions for collection and handling of samples will be provided in the Central 
Laboratory Manual. 
8.1.3. 
Kidney Assessments 
Participants with PH are predisposed to the development of multiple and recurrent urinary tract 
(urolithiasis) and kidney (nephrolithiasis) stones. This deposition of calcium oxalate in the renal 
parenchyma produces tubular toxicity and renal damage that is compounded by the effects of 
renal calculi-related obstruction and frequent superimposed infections (Cochat & Rumsby, 
2013). 
8.1.3.1. 
Kidney Stone Events and Stone Burden 
Parents or legal guardians of participants will provide a 12-month history of stone events (or as 
applicable for those less than 12 months of age) experienced by the participant at Screening and 
will report any stone events during the study. 
For the purpose of this study, “stone events” are all events that meet one or more of the 
following criteria: 
• Renal stone requiring medical intervention (e.g., outpatient procedures such as 
lithotripsy, or hospitalization and/or inpatient surgical intervention for confirmed 
stone related pain and/or complications) 
• Stone passage with or without hematuria 
• Renal colic requiring medication 
Concurrent events will be defined as events occurring within the same 4-week (28-day) window.  
Note: Although a change from baseline in the rate of stone events is an efficacy endpoint, stone 
events will be considered AESIs (Section 10.4.3). 
For the purpose of the study, “stone burden” is a term used primarily as a metric for quantifying 
and qualifying changes from baseline in the overall number and 2-dimensional surface area of 
renal stones, as observed via kidney ultrasound over the course of the study.  
Taken together, the terms stone event and stone burden will be used to derive meaningful 
quantification and qualification of overall impact of clinical sequelae of renal stones during the 
course of the trial. 
8.1.3.2. 
Kidney Ultrasound 
Kidney ultrasound will be performed at time points specified in the SoA. The kidneys should be 
examined in the longitudinal (sagittal) and transverse scan planes, ideally with images acquired 
in both the supine and prone positions. A linear array transducer with higher center frequencies 
should be used in participants younger than 18 years of age. Participants should have a full 
bladder during image acquisition. 
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All kidney ultrasound data will be transmitted to a standalone imaging vendor, where qualified 
personnel will perform central overread of all images. The number and size of stones will be 
determined by the central readers. The details of any findings should be placed in the 
participant’s source record and recorded in the eCRF. The end-to-end process of centralized 
kidney ultrasound overread is detailed in a separate DCR-PHXC-203 Imaging Review Charter 
(Cardiabase).  
Centralized overread will include standardized nephrocalcinosis grading in accordance with the 
staging criteria outlined in Figure 1. 
Figure 1: 
Standardized Nephrocalcinosis Grading 
 
From Boyce et al., 2013 
8.1.4. 
Quality of Life Assessments 
Health-related quality of life (HRQOL) surveys will be administered to pediatric participants or 
their parents or legal guardians at Screening and EOS as indicated in the SoA. For consistency, 
the same member of the study staff should administer the surveys to a participant at both 
Screening and EOS. When possible, HRQOL surveys should be completed prior to other 
study-specific assessments and procedures. 
8.1.4.1. 
Pediatric Quality of Life Inventory  
The Pediatric Quality of Life Inventory (PedsQL™) is a modular approach to measuring 
HRQOL in healthy pediatric participants and in those with acute and chronic health conditions. 
The multidimensional PedsQL Generic Core Scales were designed to measure the 3 core 
dimensions of health as delineated by the WHO in 1948 (physical, emotional, and social 
functioning), as well as role (school) functioning (Varni et al., 1998; Varni et al., 2001).  
The 23-item PedsQL is comprised of 5 items in the Emotional, Social, and School Functioning 
dimensions (Psychosocial Health) and 8 items in the Physical Functioning (Physical Health) 
dimension. Items are reverse-scored on a 0 to 4 Likert scale and linearly transformed to a 0 to 
100 scale, so that higher scores indicate better functioning and HRQOL. Scale Scores are the 
sum of the items in each dimension, divided by the number of items answered.  
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Age-appropriate self-reporting questionnaires are available for children aged 5 to 7 years and 8 
to 11 years. Children (8-11) may self-administer the PedsQL after introductory instructions from 
the administrator. If the administrator determines that a child is unable to self-administer the 
PedsQL (e.g., due to illness, fatigue, or reading difficulties), the PedsQL should be read aloud to 
the child. For children aged 5 to 7 years, the PedsQL should be administered by reading the 
instructions and each item to the young child word for word. Parental proxy reports are available 
for children aged 1 to 12 months, 13 to 24 months, 2 to 4 years, 5 to 7 years, and 8 to 11 years. 
Parents may self-administer the PedsQL after introductory instructions from the administrator.  
If a child presents with severe cognitive impairments (as determined by the administrator), the 
PedsQL may not be appropriate for that child. In such cases, only the Parent-Proxy Report 
should be administered to the child’s parent/guardian. 
As children age, the same questionnaire administered at baseline should continue to be used 
throughout the study, even if the child “ages out” of the baseline questionnaire. 
In addition to the PedsQL Generic Core Scales, parents of pediatric participants will complete 
the PedsQL Family Impact Module (Varni et al., 2004). The PedsQL Family Impact Module was 
designed to measure the impact of pediatric chronic health conditions on parents and the family. 
The 36-item Module measures parent self-reported physical, emotional, social, and cognitive 
functioning, communication, and worry. The Module also measures parent-reported family daily 
activities and family relationships. 
8.1.5. 
Reporting Fluid Intake 
Hyperhydration regimens are a central feature in the conservative management of urinary oxalate 
levels in patients with PH. As such, the participant’s parent or legal guardian are asked to ensure 
the participant maintains a consistent fluid intake throughout the study (Section 5.3). For 
non-breastfed participants, the participant’s parent or legal guardian will be asked to report the 
participant’s average daily fluid intake during the 4- to 7-day period before each of the spot urine 
collection periods, including the collections conducted during Screening. It is preferred that 
intake for each of the 7 days be recorded, however, should logistic difficulties require a shorter 
recording period, intake over at least the 4 days prior to the collection will be recorded. 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1. 
Weight, Height, Length and Body Surface Area 
Body weight and height should be measured without shoes. 
Length, measured in the recumbent position, is the correct linear measurement for participants 
younger than 24 months of age or children aged 24 to 36 months who cannot stand unassisted. 
Length will be measured via a calibrated length board. 
Body weight will be recorded in kg. Weight should be measured on the same calibrated scale at 
each scheduled visit.  
Height will be recorded in cm and should be measured on the same calibrated stadiometer at 
each scheduled visit. 
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Body surface area will be calculated using the following formula (DuBois & DuBois, 1916):  
BSA = (Weight0.425 × Height0.725) × 0.007184; with weight in kilograms and height in 
centimeters. 
8.2.2. 
Physical Examinations 
A full physical examination will include a complete review of body systems: eyes, ears, nose, 
and throat, chest/respiratory, heart/cardiovascular, gastrointestinal/liver, 
musculoskeletal/extremities, dermatological/skin, thyroid/neck, lymph nodes, and neurological. 
A full physical exam will be conducted at Screening and EOS/early termination (ET). 
A brief physical examination will include, at a minimum, chest/respiratory, heart/cardiovascular, 
dermatological/skin, and gastrointestinal/liver. The physical examination performed at other 
scheduled visits (Day 1 through Day 150) or unscheduled visits may be a brief or full physical 
examination at the Investigator’s discretion. For at-home visits, the home-health nurse will 
provide in-person support to the Investigator in assessing the participant.  
Study intervention injection sites should be inspected at each visit. 
8.2.3. 
Vital Signs 
Body temperature, pulse rate, respiratory rate, and blood pressure will be assessed. 
Blood pressure and pulse measurements will be assessed in the supine position with a completely 
automated device. Manual techniques will be used only if an automated device is not available. 
An age-appropriate cuff size should be used for blood pressure measurements.  
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for the 
participant in a quiet setting without distractions (e.g., television, cell phones). 
Temperature will be obtained in degrees Celsius (°C) via the same method throughout the study, 
pulse rate will be counted for a full minute and recorded in beats per minute, and respirations 
will be counted for a full minute and recorded in breaths per minute. Note that when a 12-lead 
ECG is performed at the same time as vital signs, heart rate should be taken from the ECG. 
If multiple assessments are due at the same time point, PK sampling should be performed at the 
nominal time point, with the preferred order of assessments ECG, vital signs, PK, and then other 
assessments. 
8.2.4. 
Electrocardiograms 
Standard 12-lead ECGs will be performed with the participant in the supine position, after the 
participant has rested comfortably for 10 minutes. The parameters assessed will be rhythm, 
ventricular rate, PR interval, QRS duration, QT interval, and corrected QT interval (QTcF, 
Fridericia correction). The Investigator or designee is responsible for reviewing the ECG(s) to 
assess whether the results are within normal limits and to determine the clinical significance of 
the results. These assessments will be recorded on the eCRF. 
Standardized ECG acquisition equipment will be provided to all clinical trial sites at the start of 
the trial, to ensure parity across all sites. All ECG data will be transmitted to a stand-alone 
imaging vendor, where qualified personnel will perform central overread of all ECG readouts. 
The end-to-end process of centralized ECG acquisition and overread is detailed in a separate 
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DCR-PHXC-203 Imaging Review Charter (Cardiabase). Site personnel will be trained in the 
processes relating to ECG acquisition and transmission. Sites that have completed training for a 
similar Dicerna-sponsored study within the past 2 years are not required to repeat ECG training. 
If multiple assessments are due at the same time point, PK sampling should be performed at the 
nominal time point, with the preferred order of assessments ECG, vital signs, PK, and then other 
assessments. 
8.2.5. 
Echocardiogram with Doppler 
Echocardiography will be performed by a qualified pediatric sonographer/physician (and 
overread by a pediatric cardiologist) using a standard, commercially available ultrasound 
machine. The echocardiography technician should perform standard 2-D transthoracic 
echocardiography with Doppler as described by the ASE recommendations (Picard et al., 2011). 
The full ASE protocol need not be followed but should include a gross assessment of the overall 
cardiac anatomy and quantitative evaluation of basic ventricular systolic function. The final 
echocardiogram report should note the details of the protocol that were followed. The 
overreading cardiologist should note any findings in the department’s standard reporting format. 
Findings from the echocardiogram should be included in the participant’s source record and 
documented in the eCRF. Any findings that, in the opinion of the Investigator, may disqualify 
the participant should be discussed with the Medical Monitor. NOTE: If for an individual 
participant the echocardiogram cannot be performed without sedation (e.g., due to age), the 
echocardiogram should not be performed. The omission of an echocardiogram due to sedation 
requirement should not be considered a protocol deviation. 
Additionally, all echocardiogram data will be transmitted to a stand-alone imaging vendor, where 
qualified personnel will perform postprocessing of echocardiogram data and central overread of 
all images. The end-to-end process of centralized echocardiogram overread and postprocessing is 
detailed in a separate DCR-PHXC-203 Imaging Review Charter (Cardiabase). 
8.2.6. 
Clinical Safety Laboratory Assessments 
See Table 4 for the list of clinical laboratory tests to be performed and the SoA for the timing 
and frequency. See Section 10.3 for directives regarding prioritization of blood draws. 
The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless judged 
by the Investigator to be more severe than expected for the participant's condition. 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the Investigator or medical monitor. 
• If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified and the Sponsor 
notified. 
• All protocol-required laboratory assessments, as defined in Table 4, must be 
conducted in accordance with the laboratory manual and the SoA.  
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Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant or participant’s parent or legal guardian is the 
preferred method to inquire about AE occurrences. 
Study-site staff should instruct the participant’s parent or legal guardian on how to report signs 
and symptoms (e.g., crying and pain) in the individual pediatric participant. They will be 
instructed to report both specific and non-specific symptoms (including vomiting, diarrhea, 
sleepiness, variation in the intensity and pattern of crying, etc.). These non-specific symptoms 
may be the only manifestations of some adverse reaction observed in neonates, infants, and 
toddlers.  
8.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, and non-serious AESIs (as defined in 
Section 10.4.3), will be followed until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3). Further information on follow-
up procedures is provided in Section 10.3. 
8.3.4. 
Regulatory Reporting Requirements for SAEs 
Prompt notification (within 24 hours of learning of the event) by the Investigator to the SAE 
Submission Coordinator of a SAE is essential so that legal obligations and ethical responsibilities 
towards the safety of participants and the safety of a study intervention under clinical 
investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, IRB/IEC, and Investigators. 
For all studies, Investigator safety reports must be prepared for SUSAR according to local 
regulatory requirements and Sponsor policy and forwarded to Investigators as necessary. 
An Investigator who receives an Investigator safety report describing a SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the Sponsor will review and then file 
it along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to 
local requirements. 
8.3.5. 
Pregnancy 
Details will be collected of all pregnancies in female participants occurring after the start of 
study intervention and until 12 weeks after the last dose of study intervention.  
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Section 10.5. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, and ectopic pregnancy) are considered SAEs.  
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8.3.6. 
Adverse Events of Special Interest  
See Section 10.4.3. 
8.4. 
Treatment of Overdose 
For this study, any dose of study intervention greater than the protocol specified dose will be 
considered an overdose. 
In the event of an overdose, the Investigator should: 
1. 
Contact the CRO Medical Monitor immediately. 
2. 
Closely monitor the participant for any AE/SAE and laboratory abnormalities until study 
intervention can no longer be detected systemically (at least 28 days). 
3. 
Obtain a plasma sample for PK analysis if requested by the Medical Monitor (determined 
on a case-by-case basis).  
4. 
Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF. 
Decisions regarding dose continuation, dose interruptions, or modifications will be made by the 
Investigator in consultation with the CRO and Sponsor Medical Monitor based on the clinical 
evaluation of the participant. 
8.5. 
Pharmacokinetics 
Blood samples will be collected for measurement of plasma concentrations of nedosiran at the 
timepoints specified in the SoA. Instructions for the collection and handling of biological 
samples will be provided in the Central Laboratory Manual. The actual date and time (24-hour 
clock time) of each sample will be recorded. 
Pharmacokinetic parameters to be determined may include AUC, Cmax, Cmin, tmax, and t½, as 
calculable. Additional parameters may be reported if deemed appropriate. The population PK 
parameters may be reported separately from the CSR. 
8.6. 
Pharmacodynamics 
Pharmacodynamic parameters other than urinary oxalate and Pox (Section 8.1.1 and 
Section 8.1.2) are not evaluated in this study.  
8.7. 
Genetics 
Genetics will not be evaluated in this study. However, participants without documented PH 
genotyping must provide a DNA sample for testing at Screening. 
8.8. 
Biomarkers 
See Section 8.1.1 and Section 8.1.2 for descriptions of urinary and plasma oxalate assessments. 
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8.9. 
Immunogenicity Assessments 
Antibodies to nedosiran will be evaluated in plasma samples collected from all participants 
according to the SoA. Additionally, plasma samples should also be collected at the final visit 
from participants who discontinued study intervention or were withdrawn from the study. These 
samples will be tested by the Sponsor or Sponsor's designee. 
The detection and characterization of antibodies to nedosiran will be performed by or under the 
supervision of the Sponsor. 
Antibodies may be further characterized and/or evaluated for their ability to neutralize the 
activity of the study intervention(s). Samples may be stored for a maximum of 5 years (or 
according to local regulations) following the last participant’s last visit for the study at a facility 
selected by the Sponsor to enable further analysis of immune responses to nedosiran.  
8.10. 
Medical Resource Utilization and Health Economics 
In order to understand how a participant’s use of health care services (e.g., number of physician 
visits, emergency room visits) and the parent or legal guardian’s out-of-pocket expenses vary 
across time, and if their utilization changes with PH outcomes, there will be several questions on 
the eCRF around medical care for PH. The parent/guardian will respond regarding the treatment 
for their child. Parent/guardian will be asked to report the number of physician visits (by 
specialty: nephrologist, urologist, PCP, and ophthalmologist) and the number of ER, urgent care, 
and/or inpatient visits due to the participant’s PH.  
Two health economics queries will also be made. The first is to ask the participant’s 
parent/guardian what was spent out of pocket for PH treatment (i.e., hyperhydration). The second 
question will ask how much work time was lost to care for their child. This is only for 
parents/guardians employed full time outside of the home; if the parent/guardian is a full-time 
student, they will be asked how much classroom time was lost due to their child’s PH.  
8.10.1. 
Work Productivity and Activity Impairment Questionnaire: Primary 
Hyperoxaluria V2.0, Clinical Practice Version (WPAI:PH, V2.0, CPV) – 
Caregiver 
The WPAI:PH, V2.0, CPV (Reilly et al, 1993) measures work productivity of the caregiver, 
including missed time at work, because of a child’s PH. The assessment includes 6 questions 
related to the effect of the participant’s PH on caregiver’s ability to work and perform regular 
activities. 
The 6 items are as follows:  
1. currently employed  
2. hours missed due to specified problem (caregiving for PH child) 
3. hours missed other reasons 
4. hours actually worked 
5. degree problem affected productivity while working 
6. degree problem affected regular activities 
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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
No statistical hypothesis testing will be performed. Statistical analysis will be primarily 
descriptive. 
9.2. 
Sample Size Determination 
It is expected that approximately 25 participants will be screened, such that approximately 
20 participants will complete the Day 180 assessments. 
No formal sample size estimations were performed. A sample size of 20 participants was 
considered sufficient to provide an initial assessment of the efficacy and safety of nedosiran in 
pediatric participants (birth to 11 years of age) with PH1, PH2 or PH3 and relatively intact renal 
function. 
9.3. 
Populations for Analyses 
For the purposes of analysis, the following populations are defined: 
Population 
Description 
Modified Intent-To-Treat 
(MITT) Population 
The MITT Population includes all participants who received at least 
1 dose of study intervention and have at least 1 post-baseline spot 
urinary oxalate to creatinine ratio. The MITT Population is for efficacy 
analysis. 
Evaluable Population  
The evaluable population includes all participants in the MITT 
Population who received 6 full doses of study intervention and 
completed through the Day 180 Study Visit.  
Safety Population 
All participants who received at least 1 dose of study intervention  
Pharmacokinetic Population 
The PK Population includes all participants who received at least 
1 dose of study intervention (without major dosing violations) and have 
at least 1 evaluable postdose PK assessment 
9.4. 
Statistical Analyses 
The SAP will be finalized prior to database lock and it will include a more technical and detailed 
description of the statistical analyses described in this section, including the procedures for 
accounting for missing, unused, and spurious data.  
This section is a summary of the planned statistical analyses of the most important endpoints 
including primary and secondary endpoints. 
Sensitivity analyses may be conducted and will be described in further detail in the SAP.  
9.4.1. 
General Considerations 
All statistical analyses will be descriptive in nature. No tests of statistical inference are planned. 
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9.4.2. 
Primary Endpoint 
The primary endpoint in this study is change from Baseline to Month 6 in spot urinary oxalate-
to-creatinine ratio by PH1, PH2, or PH3 participant subgroups. The percent and absolute change 
in average spot urinary oxalate-to-creatinine ratio from Baseline to Day 180 will be summarized 
by PH1, PH2, or PH3 participant subgroups. 
9.4.3. 
Secondary Endpoints 
9.4.3.1. 
Efficacy Endpoints 
Secondary efficacy endpoints are listed below. Additional details will be provided in the SAP. 
Endpoint 
Statistical Analysis  
Percentage of participants with 
spot urinary oxalate-to-creatinine 
ratio ≤ the ULN or ≤ 1.5 x ULN 
at any time point through Month 
6 
The percentage of participants with spot urinary oxalate-to-
creatinine ratio ≤ the ULN or ≤ 1.5 x ULN at any time point 
through Month 6 will be summarized by PH1, PH2, or PH3 
participant subgroups. 
Change from Baseline in eGFR 
at Month 6 
The percent change from baseline in eGFR at Month 6 (only in 
participants ≥ 12 Months of age at Screening) will be summarized 
by PH1, PH2, or PH3 participant subgroups. 
9.4.3.2. 
Safety Endpoints 
All safety analyses will be performed on the Safety Population. The incidence and nature of 
TEAEs and SAEs, along with change from Baseline in 12-lead ECG, physical examination 
findings, vital sign assessments, and clinical laboratory tests will be summarized. 
Adverse events will be defined as treatment emergent if they have an onset or worsen in severity 
after a participant receives the study intervention. Treatment-emergent AEs will be summarized 
by SOC and preferred term according to the MedDRA. Treatment-emergent AEs will be further 
summarized by severity and relationship to study intervention. Adverse events leading to 
discontinuation, SAEs, and deaths will be summarized/listed.  
Descriptive statistics will be provided for absolute values and changes from baseline in physical 
examination findings, vital sign measurements, ECGs, and clinical laboratory results at each 
timepoint. 
9.4.3.3. 
Pharmacokinetic Endpoints 
Pharmacokinetic analyses will be described in the SAP finalized before database lock. The 
population PK analysis will be presented separately from the main CSR. 
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9.4.4. 
Tertiary/Exploratory Endpoint(s) 
Exploratory efficacy endpoints are listed below. Additional details will be provided in the SAP. 
Endpoint 
Statistical Analysis  
Percent and absolute change in plasma 
oxalate over time 
The percent and absolute change in plasma oxalate will 
be summarized by PH1, PH2, or PH3 participant 
subgroups.  
Change from Baseline in annualized stone 
event rate 
The change from Baseline in annualized stone event 
rate will be summarized by PH1, PH2, or PH3 
participant subgroups. 
Change from Baseline in the Pediatric 
Quality of Life Inventory (PedsQL™) 
The change from Baseline in the PedsQL™ will be 
summarized by PH1, PH2, or PH3 participant 
subgroups. 
Change from Baseline in the Work 
Productivity and Activity Impairment 
Questionnaire: Primary Hyperoxaluria V2.0, 
Clinical Practice Version (WPAI:PH, V2.0, 
CPV) – Caregiver 
The change from Baseline in the WPAI:PH, V2.0, 
CPV – Caregiver will be summarized by PH1, PH2, or 
PH3 participant subgroups. 
 
9.5. 
Interim Analyses  
No formal interim analyses are planned, but the Sponsor reserves the right to conduct interim 
analyses if needed to support regulatory activities. Safety and efficacy data will be provided to 
the SRC on an as-needed basis. 
9.6. 
Safety Review Committee (SRC) 
The SRC will review safety and efficacy data on a periodic basis as described in the SRC charter. 
In addition, the SRC will closely monitor any changes in the PK (as appropriate), PD, or clinical 
efficacy, as well as any emerging events, such as anaphylaxis or hypersensitivity reactions that 
may suggest the development of ADAs. 
The SRC will be comprised of an independent SRC chair (pediatric nephrologist), the Principal 
Investigator from each study site with a participant currently in the study (either having been 
dosed, or about to be dosed), or their designee, the Sponsor Medical Monitor, an independent 
ethicist, and the CRO Medical Monitor. Further operational details, including the timing of SRC 
meetings, will be pre-specified in the SRC charter.  
On 13-Sept-2022, the SRC reviewed safety data from four 2- to 5-year-old participants with at 
least 60 days of exposure in this study. No related severe AEs or related SAEs were reported in 
these participants. Following the safety review, the SRC affirmed that the overall risk-benefit 
balance remained positive and approved the enrollment of participants younger than 2 years of 
age. 
 
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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines (CIOMS VI, 
2005) 
• Applicable ICH GCP Guidelines 
• Applicable laws and regulations, including privacy laws 
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant documents 
(e.g., advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.  
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. Any substantial modifications to the protocol will require competent 
authority approval before implementation, except for changes necessary to eliminate an 
immediate hazard to study participants.  
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations 
10.1.2. 
Financial Disclosure 
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
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10.1.3. 
Informed Consent Process 
Each interested prospective participant (or legally authorized representative) will receive an 
informed consent document that contains study information and be given ample time to read the 
information and consider participation. The Investigator or his/her representative will explain the 
nature of the study and its risks and potential benefits to the prospective participant or his/her 
legally authorized representative and answer all questions regarding the study. If the participant’s 
treating physician is also the Investigator, he/she may not administer and witness the provision of 
informed consent. Administration of consent must be performed by another physician from the 
study team, to keep the roles of physician and researcher separated. 
Prospective participants must be informed that the study involves research, their participation is 
voluntary, and that the choice not to participate or to discontinue the study at any time will 
involve no penalty or loss of benefits to which the individual is otherwise entitled. Consenting 
participants, or their legally authorized representative (parent or legal guardian for participants 
younger than 18 years or the local age of majority), will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
Health Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, 
and the IRB/IEC or study center. For children younger than 12 years of age, assent will be based 
on local regulations.  
The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. As children and adolescents age, they must be re-consented to the 
appropriate ICF based on current age. Participants must be informed of any new information that 
arises during the course of the study which might be relevant to their willingness to continue in 
the study. 
A copy of the ICF(s) must be provided to the participant or the participant’s legally authorized 
representative.  
10.1.4. 
Data Protection 
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names or 
any information which would make the participant identifiable will not be transferred.  
The participant (or legally authorized representative) must be informed that his/her personal 
study-related data will be used by the Sponsor in accordance with local data protection law, 
including the General Data Protection Regulation for all clinical studies conducted in the 
European Union. The level of disclosure must also be explained to the participant (or legally 
authorized representative) who will be required to give consent for their data to be used as 
described in the informed consent.  
The participant (or legally authorized representative) must be informed that his/her medical 
records may be examined by Clinical Quality Assurance auditors or other authorized personnel 
appointed by the Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
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10.1.5. 
Dissemination of Clinical Study Data 
After completion and publication of the study, and de-identification, all individual data collected 
during the trial will be shared with investigators, whose proposed use of the data will have been 
approved by an independent review committee immediately following the publication of the 
entire study results. 
Study results will be posted to the European Clinical Trials database (EudraCT) not later than 
6 months after the database is locked. Study results will be posted at www.clinicaltrials.gov not 
later than 12 months after the database is locked.  
10.1.6. 
Data Quality Assurance 
All participant data relating to the study will be recorded on printed or eCRF unless transmitted 
to the Sponsor or designee electronically (e.g., laboratory data). The Investigator is responsible 
for verifying that data entries are accurate and correct by physically or electronically signing the 
eCRF.  
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents.  
Monitoring details describing strategy (e.g., risk-based initiatives in operations and quality such 
as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), methods, 
responsibilities and requirements, including handling of noncompliance issues and monitoring 
techniques (central, remote, or on-site monitoring) are provided in the Monitoring Plan. 
The Sponsor or designee is responsible for the data management of this study including quality 
checking of the data.  
The Sponsor assumes accountability for actions delegated to other individuals (e.g., CROs). 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.  
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator for 2 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the Sponsor. No records may be transferred to 
another location or party without written notification to the Sponsor.  
10.1.7. 
Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site. 
Data entered in the eCRF that are transcribed from source documents must be consistent with the 
source documents or the discrepancies must be explained. The Investigator may need to request 
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previous medical records or transfer records, depending on the study. Also, current medical 
records must be available. 
10.1.8. 
Study and Site Start and Closure 
The Sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
1. 
Investigator noncompliance with the protocol, GCP, or regulatory requirements  
2. 
Unsatisfactory enrollment with respect to quantity or quality 
3. 
Incomplete data collection; inaccurate or knowingly false data submission 
4. 
The Principal Investigator is no longer capable of performing the tasks of the principal 
investigator, and no replacement can be found. 
5. 
The SRC determines that termination of the study is in the best interest of the research 
participants 
6. 
The Sponsor, Investigator or IRB/IEC determines that continuation of the study will not 
serve any scientific purpose 
7. 
Circumstances beyond the control of the Sponsor or Investigator make it unreasonable to 
require the study’s continuation 
8. 
A request to discontinue the study by a regulatory or health authority 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of the 
reason for termination or suspension, as specified by the applicable regulatory requirements. The 
Investigator shall promptly inform the participant and should assure appropriate participant 
therapy and/or follow-up. 
10.1.9. 
Publication Policy 
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission. 
This allows the Sponsor to protect proprietary information and to provide comments.  
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating Investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 
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10.2. 
Appendix 2: Clinical Laboratory Tests 
Table 3 summarizes the parameters that will be determined spot urine collections. Additional 
laboratory results may be reported on these samples. These additional tests would not require 
additional collection of urine. 
Table 3: 
Parameters Determined from Urine 
Laboratory Assessment 
Parameters 
Spot urine 
urinary oxalate 
urinary creatinine 
urinary oxalate-to-creatinine ratio 
The tests detailed in Table 4 will be performed by the central laboratory. 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in Section 5 
of the protocol. 
Additional tests may be performed at any time during the study as determined necessary by the 
Investigator or required by local regulations. 
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Table 4: 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
red blood cell count 
hemoglobin 
hematocrit 
mean corpuscular volume (MCV) 
mean corpuscular hemoglobin (MCH) 
mean corpuscular hemoglobin 
concentration (MCHC)  
reticulocytes 
platelet count 
mean platelet volume (MPV) 
White blood cell count: 
Lymphocytes, abs and % 
Monocytes, abs and % 
Eosinophils, abs and % 
Neutrophils, abs and % 
Basophils, abs and % 
 
Clinical Chemistry 
alanine transaminase (ALT) 
aspartate transaminase (AST) 
glutamate dehydrogenase (GLDH) 
gamma-glutamyl transferase (GGT) 
alkaline phosphatase (ALP) 
bilirubin (total and direct) 
lactate dehydrogenase (LDH) 
total protein 
albumin 
creatine kinase (CK) 
sodium 
chloride 
potassium 
creatinine 
blood urea nitrogen (BUN) 
 
cystatin C (for calculation of eGFR) 
Routine Urinalysis 
specific gravity 
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase 
by dipstick 
microscopic examination (if blood or protein is abnormal) 
Pregnancy testing 
Serum or urine human chorionic gonadotropin (hCG) pregnancy test (WOCBP) 
Coagulation Parameters 
International normalized ratio (INR) 
Prothrombin time (PT) 
Antibodies 
Antidrug antibodies (samples will be tested when an assay is available) 
Other Tests 
Plasma oxalate 
Investigators must document their review of each laboratory safety report. 
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10.3. 
Appendix 3: Volume of Blood 
The maximum blood volume to be collected from pediatric participants over the course of the 
study will be based on weight and will not exceed those specified in Table 5. Consult the 
Laboratory Manual for the blood draw priority list based on participant weight. 
Table 5: 
Maximum Allowable Research-related Blood Sample Volumes 
Body Weight 
(kg) 
Circulating Total 
Blood Volume 
(mL) 
Max. Allowable Sample Volume 
over 4 Weeks (mL) – 3% of 
Total Blood Volume 
Max. Allowable Sample Volume 
at Single Time (mL) – 1% of Total 
Blood Volume 
0.5 – 1.5 
50 – 150 
1.5 – 4.5 
0.5 – 1.5 
2.5 – 5 
250 – 500 
7.5 – 15 
2.5 – 5 
5 – 12 
480 – 960 
14.4 – 28.8 
4.8 – 9.6 
12 – 20 
960 – 1600 
28.8 – 48 
9.6 – 16 
20 – 30 
1600 – 2400 
48 – 72 
16 – 24 
30 – 70 
2400 – 5600 
48 – 168 
24 – 56 
Note: Total blood volume is approximately 80 to 90 mL/kg body weight, in neonates approximately 100 mL/kg 
body weight. Of note: when routine health care requires significant blood sampling, these maximums may even be 
excessive. 
Source: European Commission’s Ethical Considerations for Clinical Trials on Medicinal Products Conducted with 
Minors (18 September 2017) 
 
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10.4. 
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.4.1. 
Definition of AE 
An AE is any untoward medical occurrence in a patient or clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the study 
intervention. 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use 
of study intervention. 
10.4.1.1. Events Meeting the AE Definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the Investigator (i.e., not related to progression of underlying 
disease). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose itself will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported, regardless of sequelae. 
• “Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfil the definition of an AE or SAE. 
10.4.1.2. Events Not Meeting the AE Definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
• Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads 
to the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
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• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
10.4.2. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
An SAE is defined as any untoward medical occurrence that, at any dose: 
1. 
Results in death 
2. 
Is life-threatening 
The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
3. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually involving 
at least an overnight stay) at the hospital or emergency ward for observation and/or treatment 
that would not have been appropriate in the physician’s office or outpatient setting. 
Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to 
whether “hospitalization” occurred or was necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. Pre-planned hospitalizations scheduled, prior to signing the 
ICF, for an elective medical/surgical procedure do not meet this criterion. 
4. 
Results in persistent disability/incapacity 
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental 
trauma (e.g., sprained ankle) which may interfere with or prevent everyday life functions but 
do not constitute a substantial disruption. 
5. 
Is a congenital anomaly/birth defect 
6. 
Other situations 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the participant or may 
require medical or surgical intervention to prevent one of the other outcomes listed in the 
above definition. These events should usually be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that 
do not result in hospitalization, or development of drug dependency or drug abuse. 
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10.4.3. 
Definition of Adverse Event of Special Interest 
An AESI is a noteworthy event for the particular product or class of products that a Sponsor may 
wish to monitor carefully (CIOMS VI, 2005).  
10.4.3.1. Events Meeting the AESI Definition 
Injection site reaction (ISR): 
An ISR is a disorder characterized by an intense adverse reaction (usually immunologic) 
developing at the site of an injection. Potential ISRs will be graded as follows: 
Signs or symptoms at the injection site (e.g., erythema, swelling) with a time to onset of 4 or 
more hours from the time of study intervention administration will be evaluated according to the 
Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 criteria for ISR, detailed 
below. If any of the CTCAE criteria for ISR are met, the event will be recorded as an ISR and 
graded in accordance with Table 6. 
Table 6: 
Grading of Injection Site Reactions, CTCAE v 5.0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Tenderness with or 
without associated 
symptoms (e.g., 
warmth, erythema, 
itching) 
Pain; 
lipodystrophy; 
edema; phlebitis 
Ulceration or necrosis; 
severe tissue damage; 
operative intervention 
indicated 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Death 
Individual signs or symptoms at the injection site with a time to onset of less than 4 hours from 
the time of study intervention administration will be recorded as AEs (not as an ISR) and graded 
in accordance with the intensity categories detailed in Section 10.4.4.2.  
Muscle pain or weakness: 
Because the nonclinical safety program in mice identified potential off-target effects on skeletal 
muscle, participants should be monitored for signs and symptoms of muscle weakness or pain, in 
addition to measurement of plasma CK. 
Kidney Stone Events 
Patients with PH are predisposed to the development of multiple and recurrent urinary tract and 
kidney stones. As participants may enter the study with pre-existing stones, stone events (as defined in 
Section 8.1.3.1), while being considered in the evaluation of efficacy, will be considered AESI. 
10.4.4. 
Recording and Follow-Up of AE and/or SAE 
10.4.4.1. AE and SAE Recording 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all documentation 
(e.g., hospital progress notes, laboratory reports, and diagnostics reports) related to the event. 
The Investigator will then record all relevant AE/SAE information in the eCRF. 
• It is not acceptable for the Investigator to send photocopies of the participant’s 
medical records in lieu of completion of the AE/SAE eCRF page.  
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• There may be instances when copies of medical records for certain cases are 
requested by the Sponsor or Medical Monitor. In this case, all participant identifiers, 
with the exception of the participant number, will be redacted on the copies of the 
medical records before submission. 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 
10.4.4.2. Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to one of the following categories:  
• Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities. 
• Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities. 
• Severe: An event that prevents normal everyday activities.  
An AE that is assessed as severe should not be confused with an SAE. Severe is a 
category utilized for rating the intensity of an event; and both AEs and SAEs can be 
assessed as severe. 
An event is defined as ‘serious’ when it meets at least one of the predefined outcomes 
as described in the definition of an SAE (see Section 10.4.2), NOT when it is rated as 
severe. 
10.4.4.3. Assessment of Causality 
The Investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE. 
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
The Investigator will use clinical judgment to determine the relationship. 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as 
well as the temporal relationship of the event to study intervention administration will be 
considered and investigated. 
The Investigator will also consult the IB and/or Product Information, for marketed products, in 
his/her assessment. 
For each AE/SAE, the Investigator must document in the medical notes that he/she has reviewed 
the AE/SAE and has provided an assessment of causality. 
There may be situations in which an SAE has occurred, and the Investigator has minimal 
information to include in the initial report. However, it is very important that the Investigator 
always make an assessment of causality for every event before the initial transmission of the 
SAE data to the SAE Submission Coordinator. 
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The Investigator may change his/her opinion of causality in light of follow-up information and 
send a SAE follow-up report with the updated causality assessment. 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
The following definitions will be used in assessing causality: 
• Not Related: Event for which sufficient evidence exists to conclude that the etiology 
is unrelated to study intervention. 
• Possibly Related: There is some temporal relationship between the event and the 
administration of the study intervention, and the event is unlikely to be explained by 
the participant’s medical condition or other therapies.  
• Probably Related: The temporal relationship between the event and administration 
of the study intervention is suggestive and the event is unlikely explained by the 
participant’s medical condition or other therapies.   
• Definitely Related: The event follows reasonable temporal sequence from 
administration of the study intervention, follows a known or suspected response 
pattern to the study intervention, is confirmed by improvement upon stopping the 
study intervention, and reappears upon repeated exposure, if that occurs. 
10.4.4.4. Follow-up of AEs and SAEs 
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated, or as requested by Sponsor and/or 
Medical Monitor, to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
• If a participant dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide the Sponsor with a copy of any postmortem 
findings including histopathology. 
• New or updated information will be recorded in the originally completed eCRF. 
• The Investigator will submit any updated SAE data to the SAE coordinator within 
24 hours of receipt of the information. 
10.4.5. 
Reporting of SAEs 
Facsimile or electronic transmission of the SAE Report Form is the preferred method to transmit 
this information to the SAE Submission Coordinator. 
In rare circumstances and in the absence of facsimile equipment, notification by telephone is 
acceptable with a copy of the SAE data collection tool sent by overnight mail or courier service. 
Initial notification via telephone does not replace the need for the Investigator to complete and 
sign the SAE Report Form within the designated reporting time frames. 
Contacts for SAE reporting can be found on page 3.  
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10.5. 
Appendix 5: Contraceptive and Collection of Pregnancy Information 
10.5.1. 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). If fertility is unclear (e.g., amenorrhea in adolescents or athletes) 
and a menstrual cycle cannot be confirmed before the first dose of study intervention, additional 
evaluation should be considered. 
Women in the following categories are not considered WOCBP 
1. 
Premenarchal 
2. 
Premenopausal with one of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (e.g., müllerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry. 
Note:  Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
3. 
Postmenopausal 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle-stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a postmenopausal state in women not 
using hormonal contraception or hormonal replacement therapy (HRT). However, in 
the absence of 12 months of amenorrhea, confirmation with more than one FSH 
measurement is required. 
• Female participants on HRT and whose menopausal status is in doubt will be required 
to use one of the non-estrogen hormonal highly effective contraception methods if 
they wish to continue their HRT during the study. Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment. 
10.5.2. 
Contraception Guidance 
Male participants 
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to ONE of the following from Day 1 through 12 weeks after the last dose of study 
intervention: 
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• Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent 
• Agree to use a male condom plus partner use of a contraceptive method with a failure 
rate of < 1% per year, as described in Table 7, when having penile-vaginal intercourse 
with a WOCBP who is not currently pregnant 
Male participants must refrain from donating sperm for the duration of the study and for 
12 weeks after the last dose of study intervention. 
Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse, or use a male condom during each episode of penile penetration 
during the protocol-defined time frame. 
Female participants 
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly throughout the study and for 
12 weeks following the last dose of study intervention, as described in Table 7. 
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Table 7: 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependent a 
Failure rate of < 1% per year when used consistently and correctly.  
• Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation 
− Oral  
− Intravaginal  
− Transdermal  
• Progestogen-only hormonal contraception associated with inhibition of ovulation 
− Oral  
− Injectable  
Highly Effective Methods That Are User Independent a  
• Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation 
− Intrauterine device (IUD) 
− Intrauterine hormone-releasing system (IUS) 
− Bilateral tubal occlusion 
• Vasectomized partner  
A vasectomized partner is a highly effective contraception method, provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.  
• Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.  
a Typical-use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies.  
Note: In Japan, contraceptive drugs or devices used must be approved or certified in Japan. 
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10.5.3. 
Pregnancy Testing 
• WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive urine or serum pregnancy test. Positive urine tests should be 
confirmed with a serum test. 
• Additional pregnancy testing should be performed at monthly intervals during the 
treatment period and as required locally. 
• Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected.  
• Pregnancy testing will be performed 2 to 3 weeks after administration of the last dose 
of study intervention in any WOCBP who prematurely discontinues the study. 
• Pregnancy testing with a sensitivity of at least 10 mIU/mL will be performed. 
10.5.4. 
Collection of Pregnancy Information 
Male participants with partners who become pregnant  
• The Investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is in 
this study.  
• After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the Investigator will record pregnancy information on the appropriate 
form and submit it to the Sponsor within 24 hours of learning of the partner’s 
pregnancy. The female partner will also be followed to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded to the 
Sponsor. Generally, the follow-up will be no longer than 6 to 8 weeks following the 
estimated delivery date. Any termination of the pregnancy will be reported regardless 
of fetal status (presence or absence of anomalies) or indication for the procedure.  
Female Participants who become pregnant  
• The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on 
the appropriate form and submitted to the Sponsor within 24 hours of learning of a 
participant’s pregnancy.  
• The participant will be followed to determine the outcome of the pregnancy. The 
Investigator will collect follow-up information on the participant and the neonate and 
the information will be forwarded to the Sponsor. Generally, follow-up will not be 
required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. A spontaneous abortion is always considered to be an SAE and will be reported 
as such. Any post-study pregnancy-related SAE considered reasonably related to the 
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study intervention by the Investigator will be reported to the Sponsor as described in 
Section 10.4.5. While the Investigator is not obligated to actively seek this 
information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.  
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention. 
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10.6. 
Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments   
All participants will be monitored for possible signs of DILI. Safety laboratories will be 
monitored by a central laboratory in real time with potential DILI alerts sent to the Investigator. 
PARTICIPANTS AGED ≥ 6 YEARS OF AGE 
For participants with normal liver biochemistries at baseline:  
• Close Monitoring: An increase of serum ALT or AST to > 3 x ULN should be 
followed by repeat testing of ALT, AST, alkaline phosphatase, and total bilirubin 
within 48 to 72 hours to confirm the abnormalities and to determine if they are 
increasing or decreasing. Inquiry should also be made about symptoms, strenuous 
exercise, or previous seizures. Repeat testing 2 or 3 times weekly is recommended. 
All participants showing possible DILI should be followed until abnormalities return 
to normal or to the baseline state. If a participant lives remote from the study site, 
local testing may be performed, and the test results reported to the Investigator (along 
with the reference ranges for the local laboratory). 
• Study Intervention Discontinuation: Study intervention will be discontinued when 
a participant meets one of the conditions outlined below (from 2009 FDA Guidance 
for Industry-Drug Induced Liver Injury: Premarketing Clinical Evaluation) or if the 
Investigator believes that it is in best interest of the participant.  
− ALT or AST > 8 × ULN 
− ALT or AST > 5 × ULN for more than 2 weeks 
− ALT or AST > 3 × ULN and (total bilirubin > 2 × ULN or INR > 1.5) 
− ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%) 
For participants with elevated transaminases at baseline:  
The following Alternative DILI Monitoring Algorithm should be used.  
• Close Monitoring: If participants develop elevations of AST or ALT > 2 times 
baseline or total bilirubin > 1.5 times baseline while on study, testing should be 
repeated within 48 to 72 hours. Persistent elevations should be followed by repeat 
testing and physical examination 2 to 3 times per week, with or without study 
intervention discontinuation (see below). 
• Study Intervention Discontinuation: Study intervention will be discontinued for 
abnormal liver function when a participant meets the following condition:  
− ALT or AST > 5 × baseline, with baseline < 2 × ULN 
Close monitoring should be continued. If a participant lives remote from the study site, local 
testing may be performed, and the test results reported to the Investigator (along with the 
reference ranges for the local laboratory).  
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Discontinuation from study intervention does not mean discontinuation from the study, and 
remaining study procedures should be completed as indicated by the SoA. 
Participants should be monitored at each study visit and instructed to call the Investigator for 
new or worsening symptoms of clinical hepatitis. Both symptoms and calls should be captured in 
dedicated case report forms. 
PARTICIPANTS AGED < 6 YEARS OF AGE 
Close Monitoring 
For participants with normal liver biochemistries at baseline:  
• An increase of serum ALT or AST to > 3 × ULN should be followed by repeat testing 
of ALT, AST, alkaline phosphatase, and total bilirubin within 48 to 72 hours to 
confirm the abnormalities and to determine if they are increasing or decreasing. 
Inquiry should be also made about symptoms, strenuous exercise, viral infections, or 
previous seizures. Repeat testing 2 or 3 times weekly is recommended. All 
participants showing possible DILI should be followed until abnormalities return to 
normal or to the baseline state.  
For participants with elevated transaminases at baseline the following Alternative DILI 
Monitoring Algorithm should be used:  
• If participants develop elevations of AST or ALT > 2 times baseline or total 
bilirubin > 1.5 times baseline while on study, testing should be repeated within 48 to 
72 hours. Persistent elevations should be followed by repeat testing and physical 
examination 2 to 3 times per week. 
Study Intervention Interruption/Discontinuation 
Study drug must be interrupted if any of the following criteria are met (applies to 
participants with normal and elevated transaminases at baseline): 
• ALT or AST > 8 x ULN 
• ALT or AST > 5x ULN for 2 weeks or longer 
• ALT or AST > 3 x ULN in association with total bilirubin > 2x ULN and/or 
clinical jaundice or other signs of liver dysfunction (hepatomegaly, pruritus, 
bleeding, etc). 
As children can have LFT elevation from viral infections and medications, an investigation 
of potential alternative causes (acetaminophen use, EBV, CMV infection, etc) and physical 
examination should be conducted, and the participant should be closely monitored for 
clinical progression. If no alternative etiology is identified, the participant should be 
discontinued from the study, even if the participant has a normal physical exam. 
If an alternative, reversible cause of transaminase elevation has been identified, and the 
physical examination is normal the medical monitor should be consulted, and study drug may 
be resumed after the investigator has confirmed the participant’s clinical stability and the 
transaminases are back to < 2 x ULN. Transaminases and bilirubin should be monitored at 
least weekly for 4 weeks after resuming study drug. If a protocol defined transaminase 
elevation (> 3 x ULN for participants with normal baseline or > 2 x baseline for those 
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with elevated baseline) recurs after re-challenge with the study drug the study drug 
should be permanently discontinued, regardless of the etiology.  
If a participant lives remote from the study site, local testing may be performed, and the test 
results reported to the Investigator (along with the reference ranges for the local laboratory). 
Participants should be monitored at each study visit and instructed to call the Investigator for 
new or worsening symptoms of clinical hepatitis and/or liver dysfunction. Both symptoms and 
calls should be captured in dedicated eCRFs. 
 
 
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10.7. 
Appendix 7: Abbreviations 
 
Term 
Definition 
abs 
absolute 
ADA 
anti-drug antibody 
AE 
adverse event 
AESI 
AE of special interest 
AGXT 
the gene that codes for alanine–glyoxylate aminotransferase 
aHR 
adjusted hazard ratio 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
anti-dsDNA 
anti-double-stranded DNA antibody 
ASE 
American Society of Echocardiography 
AST 
aspartate aminotransferase 
ASGPR 
asialoglycoprotein receptor 
AUC 
area under the curve 
AUC∞  
area under the concentration-time curve from time zero to infinity 
AUCt  
area under the concentration-time curve calculated to the last observable 
concentration at time t. 
BSA 
body surface area 
BUN 
blood urea nitrogen 
°C 
degrees Celsius 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CK 
creatine kinase (creatine phosphokinase) 
CKD 
chronic kidney disease 
cm 
centimeters 
Cmax  
maximum observed concentration 
Cmin  
minimum observed concentration 
CMV 
Cytomegalovirus 
CONSORT 
Consolidated Standards of Reporting Trials 
CRO 
contract research organization 
CSR 
clinical study report 
CTCAE 
Common Terminology for Adverse Events 
DCR-L1360 
drug substance for this IMP 
DCR-PHXC 
drug product for this IMP 
DILI 
drug-induced liver injury 
DNA 
deoxyribonucleic acid 
EBV 
Epstein-Barr virus 
ECG 
electrocardiogram 
eCRF 
electronic CRF 
EFD 
embryofetal development 
e.g. 
for example 
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Term 
Definition 
eGFR 
estimated glomerular filtration rate 
EOS 
End of Study 
ER 
emergency room 
ERA-EDTA 
European Renal Association-European Dialysis and Transplant 
Association 
ESPN 
European Society of Pediatric Nephrology  
ESRD 
end-stage renal disease 
ET 
early termination 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GalNAc 
N-acetyl-D-galactosamine 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transferase 
GLDH 
glutamate dehydrogenase 
GLP 
Good Laboratory Practice 
GO 
glycolate oxidase 
GRHPR 
the gene that codes GRHPR 
HIPAA 
Health Insurance Portability and Accountability Act 
HOGA 
4-hydroxy-2-oxoglutarate aldolase 
HOGA1 
gene that codes for HOGA 
hr 
hour(s) 
HRQOL 
Health-related quality of life 
HRT 
hormone replacement therapy 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
The International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use (formerly International Conference 
on Harmonisation) 
i.e. 
that is 
IEC 
Independent Ethics Committee 
IMP 
investigational medicinal product  
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ISR 
injection site reaction 
IWRS 
Interactive Web Response System 
kg 
kilogram(s) 
LDH 
lactate dehydrogenase 
LDHA 
primate (human and nonhuman) lactate dehydrogenase type A 
LDHA 
the gene that encodes LDHA 
Ldha 
the gene that encodes LDHA in mice 
LFT 
liver function test(s) 
M&S 
modeling and simulation 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
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Term 
Definition 
MITT 
modified intent-to-treat population 
MedDRA 
Medical Dictionary for Regulatory Activities 
MPV 
mean platelet volume 
mRNA 
messenger ribonucleic acid 
mg 
milligram(s) 
min 
minute(s) 
mL 
milliliter(s) 
NAFLD 
nonalcoholic fatty liver disease 
NASH 
nonalcoholic steatohepatitis 
NIMP 
non-investigational medicinal product 
NMD-PH 
no-mutation-detected primary hyperoxaluria 
PCP 
primary care physician 
PD 
pharmacodynamic(s) 
PE 
physical examination 
PedsQL™ 
Pediatric Quality of Life Inventory 
PH 
primary hyperoxaluria 
PH1 
primary hyperoxaluria type 1 
PH2 
primary hyperoxaluria type 2 
PH3 
primary hyperoxaluria type 3 
PK 
pharmacokinetic(s) 
Pox 
plasma oxalate 
PT 
prothrombin time 
QoL 
quality of life 
QTcF 
QT interval (Fridericia correction) 
RNA 
ribonucleic acid 
RNAi 
RNA interference 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
siRNA 
small interfering RNA 
SoA 
schedule of activities 
SOC 
system organ class 
SRC 
Safety Review Committee 
SUSAR 
suspected unexpected serious adverse reaction 
t½  
terminal elimination half-life 
TEAE 
treatment-emergent adverse event 
tmax  
time to maximum observed concentration 
ULN 
upper limit of normal 
Uox 
urinary oxalate excretion 
WFI 
water for injection 
WHO 
World Health Organization 
WOCBP 
women of childbearing potential 
WPAI:PH, V2.0, 
CPV 
Work Productivity and Activity Impairment Questionnaire: Primary 
Hyperoxaluria V2.0, Clinical Practice Version 
 
 
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10.8. 
Investigator Signature Page 
 
A Phase 2 Open-Label Multicenter Study to Evaluate the Efficacy, Safety, and 
Pharmacokinetics of Nedosiran in Pediatric Patients from Birth to 11 Years of Age with 
Primary Hyperoxaluria and Relatively Intact Renal Function 
Protocol Number: DCR-PHXC-203 
Version: 4.0  
Date: 23-Feb-2023 
 
 
I have read this protocol and agree to conduct this trial in accordance with all stipulations of the 
protocol and in accordance with Good Clinical Practice (GCP) guidelines, the Declaration of 
Helsinki, and local regulations (as applicable). 
 
 
Signature 
 
Date 
Name: 
 
 
Institution: 
 
Site Number: 
 
 
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10.9. 
Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Amendment 2, version 3.0 (01-Nov-2022) 
The 21-Dec-2021 version of the protocol was amended to expand the population to include 
<2-year-old participants.  
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Section # and Name 
Description of Change 
Brief Rationale 
2.2.3 Clinical Overview 
4.1 
Overall Design 
9.6 
Safety Review Committee 
(SRC) 
Expanded population to include 
0- to 2-year-old participants. 
The SRC performed the protocol-
specified review of safety data to 
allow enrollment of children from 
birth to 2 years in the study 
population. 
2.2.3 Clinical Overview 
Added results for 
DCR-PHXC-201 and 
DCR-PHXC-104 and included 
updates for DCR-PHXC-301 and 
DCR-PHXC-204. 
To provide updated information on 
completed and ongoing studies. 
1.1  
Synopsis 
Updated the key inclusion 
criteria for consistency with 
those listed in Section 5.1 
To correct previously omitted text. 
1.3 
Schedule of Activities 
Corrected errors in the SoA 
relating to recording of fluid 
intake. 
No recording of fluid intake is 
needed on Day 1. Fluid intake 
should be recorded in case of early 
termination. 
Sponsor Signature Page 
Updated to replace previous 
signatory. 
To account for Sponsor personnel 
changes. 
Medical Monitor and 
Pharmacovigilance Contact 
Information 
Updated for accuracy with 
current personnel contact 
information. 
To account for Sponsor personnel 
changes. 
 
Amendment 1, version 2.0 (21-Dec-2021) 
The 15-Apr-2021 version of the protocol was amended to expand the population to include 6- to 
11-year-old participants. Other principal changes included changing the primary objective from 
safety to efficacy, adding pregnancy and contraception requirements, adding a maximum dose of 
170 mg, updating the number of planned participants from 15 to 25, and clarifying that the 
efficacy endpoints will be presented by PH1, PH2, or PH3 subgroups.  
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
 
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Section # and Name 
Description of Change 
Brief Rationale 
Title Page 
Sponsor Signature Page 
1.1. 
   Synopsis 
1.2. 
   Schema 
1.3. 
Schedule of Activities 
2.1. 
Study Rationale 
3. 
Objectives and Endpoints 
4.1. 
Overall Design 
4.2. 
Scientific Rationale for Study 
Design 
4.3.1. 
PK/PD Model for Dose 
Selection in Pediatric 
Participants (Birth to 11 
Years) 
5.1. 
Inclusion Criteria 
6.2.1. 
Handling and Accountability 
6.2.3. 
Preparation and 
Administration 
6.4. 
Study Intervention 
Compliance 
7.1.1. 
Discontinuation of Study 
Intervention Stopping Rules 
for Individual Participants 
8.1.4.1. Pediatric Quality of Life 
Inventory 
8.3.5. 
Pregnancy 
9.2. 
Sample Size Determination 
9.6. 
Safety Review Committee 
(SRC) 
10.2. 
Appendix 2: Clinical 
Laboratory Tests 
10.4. 
Appendix 4: Contraceptive 
and Collection of Pregnancy 
Information (New) 
10.5. 
Appendix 5: Liver Safety: 
Suggested Actions and 
Follow-up Assessments   
10.7. 
Investigator Signature Page 
Expanded population to include 
6- to 11-year-old participants: 
1. Updated Study title and 
study description 
2. Updated average spot 
Uox-to-creatinine ratio 
inclusion criteria to 
include values for 6 to 
11 year olds 
3. Removed word the word 
‘young’ from the phrase 
‘in neonates, infants, 
and young children 
with PH’  
4. Added in details 
regarding dose selection 
for 6- to 11-year-olds 
5. Clarified that 6- to 11-
year-olds may have 
home dosing performed 
by caregivers or home 
nurses 
6. Updated QoL assessment 
text to account for 6- to 
11-year-olds 
7. Clarified that is still 
required to have 60 
days’ worth of data 
from children aged 2 to 
5 years old prior to 
enrolling participants 
< 2 years  
8. Updated liver safety 
suggested actions and 
follow-up  
9. Added contraception and 
pregnancy guidelines 
 
 
1. To update upper age limit 
to 11 years of age 
2. To account for the correct 
values for 6- to 11-year-
olds  
3. Children up to 11 years old 
can now be enrolled 
4. Although the dose is the 
same, the dose selection 
for 6- to 11-year-olds was 
separate from the 0 to 5 
year olds  
5.  For older children, it may 
be possible for caregivers 
to administer the study 
drug at home.  
6. To account for the 
questionnaires to be used 
by 6- to 11-year-olds 
7. For participant safety, it is 
required to review data 
from children aged 2 to 5 
prior to enrolling 
participants < 2 years 
8. Added liver safety 
suggested actions and 
follow-up for 6- to 11-
year-olds 
9. To account for 6- to 11-
year-olds who may be of 
childbearing potential 
1.1. 
Synopsis 
3. 
Objectives and Endpoints 
4.2. 
Scientific Rationale for Study 
Design 
9.4.2. 
Primary Endpoints 
9.4.3.1. Efficacy Endpoints 
Updated the primary endpoint to 
efficacy based upon spot urinary 
oxalate-to-creatinine ratio; safety 
endpoint was moved to 
secondary 
To support regulatory objectives 
for the DCR-PHXC clinical 
development program 
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Section # and Name 
Description of Change 
Brief Rationale 
1.1 
Synopsis 
4.1. 
Overall Design 
4.3.1. 
PK/PD Model for Dose 
Selection in Pediatric 
Participants (Birth to 
11 Years) 
6.1. 
Study Intervention(s) 
Administered 
 
Added a maximum dose of 
170 mg  
To ensure the dose in children does 
not exceed the maximum dose 
given to adult participants across 
the program 
6.1. 
Study Intervention(s) 
Administered 
 
Clarified for participants 
≥ 6 months of age at Screening, 
the dose will remain constant 
throughout the study (i.e., the 
dose administered on Day 1 will 
be the dose administered at all 
following visits regardless of 
any change in body weight) 
Clarification 
1.1. 
   Synopsis 
1.2. 
   Schema 
4.1. 
Overall Design 
9.2. 
Sample Size Determination 
 
Updated number of planned 
participants from 15 to 25: 
1. Added new number of 
expected participants 
aged 6 to 11 years old 
2. Added goal of enrolling 
approximately 15 
participants with PH1 
1. To account for additional 
participants aged 6 to 
11 years old 
2. To help achieve regulatory 
goals related to PH1  
1.2. 
Schema 
1.3. 
Schedule of Activities 
 
 
Clarified in the schedule of 
activities table that 12-lead ECG 
should be assessed at Day 30 
(noted in Administrative Letter 
1, dated 07 June 2021) 
Clarification 
5.1. 
Inclusion Criteria 
Corrected the inclusion criterion 
related to serum creatinine cut 
off for participants aged less 
than 12 months to be below the 
97.5th percentile of a healthy 
population (noted in 
Administrative Letter 3, dated 
07 July 2021) 
This inclusion criterion is based 
upon the Boer et al 2010 article, 
which presents the 97.5th percentile 
serum creatinine 
1.1. 
Synopsis 
3. 
Objectives and Endpoints 
9.4.3.1. Efficacy Endpoints 
 
Clarified that the secondary 
efficacy endpoint related to 
normalization of spot urinary 
oxalate-to-creatinine ratio 
includes participants with spot 
urinary oxalate-to-creatinine 
ratio ≤ the ULN or ≤ 1.5 x ULN 
at any time point 
This endpoint will include the 
percentage of participants who had 
spot urinary oxalate-to-creatinine 
ratio ≤ the ULN or ≤ 1.5 x ULN  
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Section # and Name 
Description of Change 
Brief Rationale 
1.3. 
Schedule of Activities  
2.3.2. 
Pediatric Burden Assessment 
8.2.5. 
Echocardiogram with Doppler 
Clarified that if for an individual 
participant the echocardiogram 
cannot be performed without 
sedation, the echocardiogram 
should not be performed (noted 
in Administrative Letter 4, dated 
20 August 2021) 
The intent of the protocol is that 
the echocardiogram will not 
involve any invasive procedures 
2.3.4. 
Risk Management 
Clarified details surrounding the 
SRC review  
Clarification 
2.1. 
Study Rationale 
2.2.3.1. Clinical Studies of Nedosiran 
Added preliminary findings from 
Study DCR-PHXC-201 and 
status updated of Study 
DCR-PHXC-104 
To provide updated information 
4.1. 
Overall Design 
Clarified that a substantial 
amendment will be submitted 
when the data are available to 
support enrollment for 
applicable cohorts before any 
participants < 2 years of age are 
enrolled. 
Clarification 
6.5. 
Concomitant Therapy 
Clarified that the requirement to 
have a stable dose of pyridoxine 
for 3 months prior to the study 
did not apply to those under 
3 months of age; for such 
participants, the timeframe 
requirement for stable dose is 
relative to their age 
It is not possible for participants 
under 3 months of age to have had 
a stable dose for at least 3 months 
Title Page 
Added the EudraCT Number 
(noted in Administrative Letter 
2, dated 09 June 2021) and the 
NCT Number 
Newly available 
2.1. 
Study Rationale 
2.2.3.1. Clinical Studies of Nedosiran 
Added preliminary findings from 
Study DCR-PHXC-201 and 
status updated of Study 
DCR-PHXC-104 
To provide updated information 
2.2.1. 
Overview of Primary 
Hyperoxaluria 
Clarified that systemic oxalosis 
can occur in patients with PH3 
Newly available literature 
1.1. 
Synopsis 
3. 
Objectives and Endpoints 
9.4.2. 
Primary Endpoint 
9.4.3.1. Efficacy Endpoints 
9.4.4.  
Tertiary/Exploratory 
Endpoint(s) 
Clarified that the efficacy 
endpoints will be presented by 
PH1, PH2, or PH3 subgroups 
To allow analysis of the PH 
subtypes separately  
1.3  
Schedule of Activities 
8.9. 
Immunogenicity Assessments 
Removed text that stated blood 
samples for analysis of ADA 
will be analyzed once a validated 
methodology is available 
The ADA assay is now fully 
validated 
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Section # and Name 
Description of Change 
Brief Rationale 
1.3  
Schedule of Activities 
8.2.2. 
Physical Examinations 
 
Clarified text regarding physical 
examination to ensure the 
physical examination is 
conducted according to the 
schedule of activities table 
Clarification 
8.5. 
Pharmacokinetics 
Removed reference to blood 
samples collected for 
measurement of plasma 
concentrations of nedosiran 
metabolites  
Concentrations of nedosiran 
metabolites will not be measured 
from blood samples 
2.1. 
Study Rationale 
2.2.1. 
Overview of Primary 
Hyperoxaluria 
Clarified that a treatment for 
PH1 has been approved in a 
limited number of countries 
Clarification 
1.3. 
Schedule of Activities 
8.1.5. 
Reporting Fluid Intake 
Throughout the protocol, the text 
‘non-breastfeeding’ was updated 
to ‘non-breastfed’ 
This text is referring to a child that 
is breastfed 
6.5.3. 
COVID-19 and other 
Vaccines Administration 
Updated text to clarify that no 
vaccines should be administered 
in the 7 days prior to or 
following scheduled 
administration of study 
intervention 
To allow discernment of AEs 
related to the administration of 
other vaccines from those related 
to administration of study 
intervention 
9.6. 
Safety Review Committee 
(SRC) 
Added an ethicist as a member 
of the SRC 
To add an additional member 
given the age of the study 
population 
10.1.1. Regulatory and Ethical 
Considerations 
Corrected the CIOMS 
International Ethical Guidelines 
reference to CIOMS VI, 2005 
Corrected an error in the previous 
version of the protocol that 
referred to the guidance as CIOMS 
IV 
10.1.1. Regulatory and Ethical 
Considerations 
Clarified that applicable privacy 
laws will be followed  
For protection of participant 
privacy  
10.1.3. Informed Consent Process 
Added language stating 
participants must be informed of 
any new information that arises 
during the course of the study 
which might be relevant to their 
willingness to continue in the 
study and addressed changes in 
age related to ICF and clarified 
that as children and adolescents 
age, they must be re-consented 
to the appropriate ICF based on 
current age  
To ensure participants are provided 
with necessary information to 
make an informed decision about 
continuing participation in the 
study 
Protocol Amendment Summary of 
Changes 
10.8. 
Protocol Amendment History 
New section added to describe 
amendment summary of changes 
To accommodate amendment 
summary of changes 
Additional editorial changes and minor clarifications were made throughout the protocol. 
 
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11.
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