Clinical trial NCT03847909
Conditions: Primary Hyperoxaluria Type 1 (PH1) Primary Hyperoxaluria Type 2 (PH2) Kidney Diseases Urologic Diseases Genetic Disease
Keywords: PH1 PH2 Primary Hyperoxaluria RNAi RNAi therapeutic GalNAc LDHA gene LDH siRNA
Sponsor: Novo Nordisk A/S
Start date: 2019-10-28; Completion date: 2021-06-29
Enrollment: 35 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of DCR-PHXC in Children and Adults with Primary Hyperoxaluria Type 1 (PH1) and Primary Hyperoxaluria Type 2 (PH2)

Detailed description:

Arms: arm 1: Intervention, drug, DCR-PHXC arm 2: Placebo, sterile normal saline (0.9% NaCl) for subcutaneous (SC) injection
Interventions: intervention 1: DCR-PHXC intervention 2: Sterile Normal Saline (0.9% NaCl)
Intervention descriptions: intervention 1: Multiple fixed doses of DCR-PHXC by subcutaneous (SC) injection intervention 2: Sterile Normal Saline (0.9% NaCl) for subcutaneous (SC) injection, administered at same injection volume as DCR-PHXC, to serve as placebo

Protocol documents:
Prot_000.pdf: 
Cover Page for Protocol 
Sponsor name: 
Dicema Pha1maceuticals, Inc.  
NCT number 
NCT03847909  
Sponsor trial ID: 
DCR-PHXC-201 
Official title of study: 
A Phase 2 Placebo-Controlled, Double-Blind, Multicenter 
Study to Evaluate the Efficacy, Safety, and Tolerability of 
DCR-PHXC Solution for Injection (Subcutaneous Use) in 
Patients With Primary Hyperoxaluria   
Document date*: 
13-Aug-2020 
 
*Document date refers to the date on which the document was most recently updated. 
Note: The date in the header from Page 2 is the date of compilation of the documents and not of an update to content. 




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Sponsor Signature Page 
A Phase 2 Placebo-Controlled, Double-Blind, Multicenter Study to Evaluate the Efficacy, 
Safety, and Tolerability of DCR-PHXC Solution for Injection (subcutaneous use) in 
Patients with Primary Hyperoxaluria 
Protocol Number: DCR-PHXC-201 
Version: 5.0 US 
Date: 13-Aug-2020 
Dicerna Pharmaceuticals, Inc 
 
Date 
Dicerna Pharmaceuticals, Inc 
 
Date 
Dicerna Pharmaceuticals, Inc 
 
Date 
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Protocol Update Summary of Changes 
DOCUMENT HISTORY 
Document 
Date 
Amendment 3 (v 5.0 US) 
13-Aug-2020 
Amendment 2 (v 4.0 US) 
12-Mar-2020 
Amendment 1 (v 3.0 US) 
Original protocol for use in the United States 
30-Apr-2019 
Administrative Update (v 2.0) 
16-Nov-2018 
Original Protocol 
24-Oct-2018 
Amendment 3 (version 5.0), 13-Aug-2020 
The 12 March 2020 version of the protocol was updated to include the dose of DCR-PHXC to be 
administered in children aged 6 to 11 years. An appendix detailing measures to be undertaken 
during the COVID-19 pandemic was added. A tabular summary of changes is located in 
Section 10.7. 
 
 
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Table of Contents 
Medical Monitor and Pharmacovigilance Contact Information: ................................................ 3 
Protocol Update Summary of Changes ....................................................................................... 4 
1. 
Protocol Summary ................................................................................................................ 10 
1.1. 
Synopsis ......................................................................................................................... 10 
1.1.1. 
Overall Design ........................................................................................................ 10 
1.1.2. 
Study Rationale ....................................................................................................... 11 
1.1.3. 
Objectives and Endpoints ....................................................................................... 12 
1.1.4. 
Study Population ..................................................................................................... 13 
1.1.5. 
Sites and Facilities .................................................................................................. 13 
1.1.6. 
Description of Study Intervention ........................................................................... 13 
1.2. 
Study Schema ................................................................................................................. 15 
1.3. 
Schedule of Activities .................................................................................................... 16 
2. 
Introduction ........................................................................................................................... 21 
2.1. 
Study Rationale .............................................................................................................. 21 
2.2. 
Background .................................................................................................................... 21 
2.2.1. 
Overview of Primary Hyperoxaluria ...................................................................... 21 
2.2.2. 
Nonclinical Overview ............................................................................................. 22 
2.2.3. 
Clinical Overview ................................................................................................... 22 
2.3. 
Risk/Benefit and Burden Assessment ............................................................................ 23 
2.3.1. 
Known Potential Risks ............................................................................................ 23 
2.3.2. 
Pediatric Burden Assessment .................................................................................. 25 
2.3.3. 
Known Potential Benefits ....................................................................................... 27 
2.3.4. 
Risk Management ................................................................................................... 27 
2.3.5. 
Overall Risk-Benefit Analysis ................................................................................ 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 ..................................................................................................... 31 
4.3.1. 
PK/PD Model for Dose Selection in Adults and Adolescents ................................ 31 
4.3.2. 
PK/PD Model for Dose Selection in Children Younger than 12 Years of Age ...... 31 
4.3.3. 
Placebo Comparator ................................................................................................ 31 
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4.4. 
End of Study Definition ................................................................................................. 32 
5. 
Study Population ................................................................................................................... 32 
5.1. 
Inclusion Criteria ............................................................................................................ 32 
5.2. 
Exclusion Criteria ........................................................................................................... 33 
5.3. 
Lifestyle Considerations ................................................................................................. 35 
5.4. 
Screen Failures ............................................................................................................... 35 
5.5. 
Strategies for Recruitment and Retention ...................................................................... 35 
6. 
Study Intervention ................................................................................................................. 36 
6.1. 
Study Intervention(s) Administration............................................................................. 36 
6.1.1. 
Study Intervention Description ............................................................................... 36 
6.1.2. 
Dosing and Administration ..................................................................................... 36 
6.2. 
Preparation/Handling/Storage/Accountability ............................................................... 36 
6.2.1. 
Acquisition and Accountability .............................................................................. 36 
6.2.2. 
Formulation, Appearance, Packaging, and Labeling .............................................. 37 
6.2.3. 
Product Storage and Stability.................................................................................. 37 
6.2.4. 
Preparation .............................................................................................................. 37 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................... 37 
6.4. 
Study Intervention Compliance ...................................................................................... 38 
6.5. 
Concomitant Therapy ..................................................................................................... 38 
6.5.1. 
Rescue Medicine ..................................................................................................... 38 
6.6. 
Dose Modification .......................................................................................................... 38 
6.7. 
Intervention after the End of the Study .......................................................................... 38 
7. 
Study Intervention Discontinuation and Participant Discontinuation/Withdrawal .............. 39 
7.1. 
Discontinuation of Study Intervention ........................................................................... 39 
7.1.1. 
Drug-Induced Liver Injury Monitoring .................................................................. 39 
7.2. 
Participant Discontinuation/Withdrawal from the Study ............................................... 40 
7.3. 
Lost to Follow Up .......................................................................................................... 41 
8. 
Study Assessments and Procedures ...................................................................................... 42 
8.1. 
Efficacy Assessments ..................................................................................................... 42 
8.1.1. 
24-Hour Urinary Oxalate ........................................................................................ 42 
8.1.2. 
24-Hour Urinary Creatinine Excretion ................................................................... 44 
8.1.3. 
Other Parameters Determined from 24-Hour Urine Collections ............................ 44 
8.1.4. 
Urinary Oxalate from Spot Urine ........................................................................... 44 
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8.1.5. 
Plasma Oxalate........................................................................................................ 44 
8.1.6. 
Kidney Assessments ............................................................................................... 44 
8.1.7. 
Quality of Life Assessments ................................................................................... 46 
8.2. 
Safety and Other Assessments ....................................................................................... 48 
8.2.1. 
Weight, Height, and Body Surface Area ................................................................ 48 
8.2.2. 
Physical Examination.............................................................................................. 48 
8.2.3. 
Vital Signs ............................................................................................................... 48 
8.2.4. 
Clinical Safety Laboratory Assessments ................................................................ 49 
8.2.5. 
12-Lead ECG .......................................................................................................... 50 
8.2.6. 
Echocardiogram with Doppler ................................................................................ 50 
8.2.7. 
Reporting Fluid Intake ............................................................................................ 51 
8.3. 
Adverse Events, Serious Adverse Events and Adverse Events of Special Interest ....... 51 
8.3.1. 
Time Period and Frequency for Event Assessment ................................................ 51 
8.3.2. 
Method of Detecting AEs and SAEs ...................................................................... 52 
8.3.3. 
Follow up of AEs and SAEs ................................................................................... 52 
8.3.4. 
Serious Adverse Event Reporting ........................................................................... 52 
8.3.5. 
Reporting of Pregnancy .......................................................................................... 52 
8.4. 
Treatment of Overdose ................................................................................................... 53 
8.5. 
Pharmacokinetics ........................................................................................................... 53 
8.5.1. 
Plasma Pharmacokinetics........................................................................................ 53 
8.6. 
Pharmacodynamics......................................................................................................... 53 
8.7. 
Genetics .......................................................................................................................... 53 
8.8. 
Biomarkers ..................................................................................................................... 54 
8.8.1. 
Immunogenicity Assessments ................................................................................. 54 
8.9. 
Pharmacoeconomics ....................................................................................................... 54 
9. 
Statistical Considerations ...................................................................................................... 55 
9.1. 
Statistical Hypotheses .................................................................................................... 55 
9.2. 
Sample Size Determination ............................................................................................ 55 
9.3. 
Randomization Method .................................................................................................. 56 
9.4. 
Populations for Analyses ................................................................................................ 56 
9.5. 
Statistical Analyses ........................................................................................................ 57 
9.5.1. 
Efficacy Analyses ................................................................................................... 57 
9.5.2. 
Safety Analyses ....................................................................................................... 57 
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9.5.3. 
Other Analyses ........................................................................................................ 58 
9.6. 
Interim Analyses ............................................................................................................ 59 
9.6.1. 
Data Safety Monitoring Committee (DSMC) ......................................................... 59 
9.7. 
Subgroup Analysis ......................................................................................................... 60 
10. 
Supporting Documentation and Operational Considerations ............................................ 61 
10.1. 
Regulatory, Ethical, and Study Oversight Considerations ......................................... 61 
10.1.1. 
Regulatory and Ethical Considerations ............................................................... 61 
10.1.2. 
Financial Disclosure ............................................................................................ 61 
10.1.3. 
Informed Consent Process ................................................................................... 61 
10.1.4. 
Data Protection .................................................................................................... 62 
10.1.5. 
Dissemination of Clinical Study Data ................................................................. 62 
10.1.6. 
Data Quality Assurance ....................................................................................... 62 
10.1.7. 
Source Documents............................................................................................... 63 
10.1.8. 
Study and Site Closure ........................................................................................ 63 
10.1.9. 
Publication Policy ............................................................................................... 64 
10.2. 
Clinical Laboratory Tests ........................................................................................... 64 
10.3. 
Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up, 
and Reporting ............................................................................................................................ 66 
10.3.1. 
Definition of Adverse Event (AE) ...................................................................... 66 
10.3.2. 
Definition of SAE................................................................................................ 67 
10.3.3. 
Definition of Adverse Event of Special Interest ................................................. 68 
10.3.4. 
Recording and Follow-Up of AE and/or SAE .................................................... 69 
10.3.5. 
Reporting of SAEs .............................................................................................. 71 
10.4. 
Contraceptive Guidance and Collection of Pregnancy Information ........................... 71 
10.4.1. 
Definitions ........................................................................................................... 71 
10.4.2. 
Contraception Guidance ...................................................................................... 72 
10.4.3. 
Pregnancy Testing ............................................................................................... 73 
10.4.4. 
Collection of Pregnancy Information .................................................................. 74 
10.5. 
Abbreviations, Acronyms, Initialisms ........................................................................ 75 
10.6. 
Investigator Signature Page ........................................................................................ 78 
10.7. 
Protocol Amendment History ..................................................................................... 79 
11. 
References .......................................................................................................................... 87 
Appendix A: 
COVID-19 Emergency Response Measures ................................................... 90 
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A.1. Background .................................................................................................................... 90 
A.2. Summary of Recommendations Proposed for Study DCR-PHXC-201 ......................... 90 
A.2.1. 
Adjustments to Study Visits.................................................................................... 90 
A.3. 24-hour Urine Collections .............................................................................................. 91 
A.4. Safety Laboratory Testing .............................................................................................. 92 
A.5. Protocol deviations ......................................................................................................... 92 
A.6. Informed Consent ........................................................................................................... 92 
A.7. Sponsor Risk Assessment .............................................................................................. 92 
A.8. References ...................................................................................................................... 93 
A.9. Updated Schedule of Activities ...................................................................................... 93 
 
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1. 
PROTOCOL SUMMARY 
1.1. 
SYNOPSIS 
Protocol Title:  
A Phase 2 Placebo-Controlled, Double-Blind, Multicenter Study to Evaluate 
the Efficacy, Safety, and Tolerability of DCR-PHXC Solution for Injection 
(subcutaneous use) in Patients with Primary Hyperoxaluria 
Short Title:  
PHYOX2 
1.1.1. 
Overall Design 
This is a 6-month randomized, placebo-controlled, double-blind study of DCR-PHXC in patients 
with primary hyperoxaluria (PH1 and PH2). Potential participants are screened over an up-to-
6-week period prior to randomization to DCR-PHXC or placebo. 
Disclosure statement: This is a parallel-group treatment study that is participant-, Investigator-, 
and Sponsor blinded. 
Number of arms: 2 
Number of participants: Approximately 40 participants will be screened to achieve 
36 evaluable participants. 
Intervention groups and duration of participation: Eligible participants will be randomized in 
a 2 to 1 (DCR-PHXC to placebo) ratio. Following the up-to-35-day screening period, 
participants will return to the clinic for interim visits through Day 180. Note: an extra 7 days will 
be allowed for participants who are required to repeat screening 24-hour urine collections or for 
repeat of initially unanalyzable screening laboratory assessment samples. The total time on study 
for each participant is approximately 7 months. 
Study Duration: Approximately 18 months from first participant, first visit to last participant, 
last visit. After completion of the study, eligible participants will be offered the opportunity to 
enroll into a long-term open-label extension study (DCR-PHXC-301). 
Data Safety Monitoring Committee (DSMC): A DSMC will be convened to provide periodic 
review of the efficacy and safety data. The DSMC will consist of 3 voting members, who are 
independent of the study team and Sponsor.  
At a minimum, the DSMC will meet prior to the first participant being enrolled, when the first 
5 participants have been enrolled and have completed the Day 30 visit, when the first 
3 adolescent participants (aged 12-17 years) have been enrolled in the DCR-PHXC arm and have 
completed the Day 60 visit, and periodically thereafter, depending on enrollment.  
Following completion of Modeling and Simulation (M&S) of pharmacokinetic (PK) and 
pharmacodynamic (PD) data and determination of the dose for 6- to 11-year-old children, the 
DSMC affirmed that the overall risk-benefit balance remained positive and approved the 
enrollment of 6- to 11-year old children.  
Complete details regarding the constitution and responsibilities of the DSMC are specified in the 
committee charter.  
Statistical Overview: This is a superiority study. The primary endpoint for the study is the area 
under the curve (AUC) from Day 90 to Day 180, based on percent change from baseline in 
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24-hour urinary oxalate (Uox). For the primary endpoint, the null hypothesis to be tested is: 
H0: AUCa=AUCp against the 1-sided alternative hypothesis HA: AUCa > AUCp, where AUCa is 
the area under the curve for the active arm and AUCp is the area under the curve for the placebo 
arm. The AUC is calculated based on the percent change from baseline in 24-hour Uox.  
The group sequential design, with prespecified alpha spending for the interim analysis and final 
analysis, will be utilized and no futility boundaries will be utilized. The primary hypothesis 
tested is a 1-sided superiority hypothesis at the significance level alpha of 0.025. An analysis of 
covariance (ANCOVA) model, with the baseline Uox, age category, and eGFR category as the 
covariates  will be used for the analysis.  
The AUC of 24-hour Uox in the placebo arm is assumed to be 0, as Uox values may oscillate up 
and down from baseline due to measurement variability. The AUC of 24-hour Uox in the active 
arm is assumed to be 3600, based on a 40% decrease over the 90 days. The effect size is assumed 
to be 1.2. 
Under these assumptions, the sample size of 36 patients (24 in the active arm and 12 in the 
placebo arm) will yield a power of approximately 94%. All calculations were performed using 
 
.  
An interim analysis to reassess sample size may be performed after two-thirds of participants 
have completed the study. A minimal fraction of alpha (.0001) will be spent at the interim 
analysis, as the trial will not be stopped based on the results from the interim analysis. The final 
analysis will use an alpha of 0.0249 for the primary endpoint, in order to preserve an overall 
type I error at the 1-sided 0.025 level. 
1.1.2. 
Study Rationale 
DCR-PHXC consists of the drug substance (DCR-L1360), a synthetic double-stranded 
(hybridized duplex) ribonucleic acid (RNA) oligonucleotide conjugated to N-acetyl-
D-galactosamine (GalNAc) amino-sugar residues, as a sterile solution in water for injection 
(WFI). DCR-PHXC is designed to selectively reduce LDHA messenger ribonucleic acid 
(mRNA) and lactate dehydrogenase (LDH) activity in the liver, and subsequently decrease liver 
oxalate production. DCR-PHXC is being developed as a treatment for PH, an ultra-rare 
autosomal recessive disease characterized by excessive production of oxalate in the liver.  
The proposed study is designed to evaluate the efficacy, safety, tolerability, and PK of 
DCR-PHXC versus placebo in patients with PH1 and PH2. 
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1.1.4. 
Study Population 
Male and female patients, at least 6 years of age, with genetically confirmed Type 1 or Type 2 
primary hyperoxaluria (PH1, PH2).  
Key inclusion criteria include: 
x 24-KRXU 8R[ H[FUHWLRQ   mmol (adjusted per 1.73 m2 body surface area [BSA] in 
participants < 18 years of age) in both collections performed in the screening period. Of 
the first 24 participants enrolled, at least 12 (50%) must have at least one 24-hour Uox 
H[FUHWLRQ  1.6 mmol (adjusted per 1.73 m2 BSA in participants aged < 18 years).  
x Less than 20% variation between the two 24-hour urinary creatinine excretion 
(mmol/24 hr/kg) values derived from the two 24-hour urine collections in the screening 
period. 
x Estimated GFR at screening  30 mL/min normalized to 1.73 m2 BSA calculated using 
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation in participants 
DJHG   years (Levey & Stevens, 2010), or the multivariate equation by Schwartz in 
participants aged 6 to 17 years (Schwartz et al., 2012).   
Key exclusion criteria include: 
x Renal or hepatic transplantation (prior or planned within the study period) 
x Current dialysis or anticipated requirement for dialysis during the study period 
x Plasma oxalate > 30 mol/L 
x Documented evidence of clinical manifestations of systemic oxalosis (including pre-
existing retinal, heart, or skin calcifications, or history of severe bone pain, pathological 
fractures, or bone deformations) 
x Liver function test (LFT) abnormalities: Alanine aminotransferase (ALT) and/or 
aspartate aminotransferase (AST) >1.5 times upper limit of normal (ULN) for age and 
gender 
1.1.5. 
Sites and Facilities 
The study will be conducted at approximately 35 sites in North America, Europe, Asia-Pacific 
and the Middle East. 
1.1.6. 
Description of Study Intervention 
DCR-PHXC is a synthetic ribonucleic acid interference (RNAi) drug that consists of a double-
stranded oligonucleotide conjugated to GalNAc ligands. DCR-PHXC is a colorless to pale 
yellow, preservative-free, sterile solution of DCR-L1360 (the drug substance) at a concentration 
of 170 mg/mL in WFI.  
DCR-PHXC is to be stored at 2°C to 8°C (inclusive). 
DCR-PHXC is administered monthly as a SC injection into the abdomen or thigh. 
The dose of DCR-PHXC in adults and in adolescents (12-17 years old) weighing at least 50 kg 
will be 170 mg. For adults and adolescents weighing less than 50 kg, the dose will be 136 mg. In 
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children aged 6 to 11 years of age, the dose of DCR-PHXC will be 3.5 mg/kg, with an upper 
limit of 136 mg.  
The placebo comparator is a sterile, preservative-free normal saline 0.9% solution for 
SC injection, which is of similar osmolality to the DCR-PHXC formulation. Placebo will be 
administered as a SC injection in the thigh or abdomen in a volume equivalent to the dose of 
DCR-PHXC. 
 
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1.2. 
STUDY SCHEMA 
 
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f. 
To include vitamin B6 (pyridoxine). 
g. 
Participants without documented genotyping must provide a DNA sample for testing. 
h. 
Urine drug screen to include at minimum: amphetamines, barbiturates, cocaine, opiates, and benzodiazepines. Drug screening is not required for individuals aged 12 or 
younger. Investigator discretion in excluding participants with a positive test is allowed.  
i. 
HIV 1 and 2 antibodies, hepatitis B surface antigen (HBsAg), and hepatitis C virus antibody. If tested in the past 3 months, medical record documentation of this testing may 
be used. Viral serology is not required in participants < 18 years of age. 
j. 
A sample of urine from the void immediately prior to the initiation of each 24-hour urine collection will be collected and stored apart from the 24-hour urine collection. 
Should the two 24-hour screening collections occur on consecutive days, no spot urine sample will be collected on the second day. 
k. 
Two screening samples should ideally be collected on 2 consecutive days, but with no more than 8 days between collections. Collection of on-treatment samples must  be 
performed within the 7 days prior to the scheduled study visit. It is desired that ehe elapsed time between monthly collections should be at least 3 weeks and not more than 
5 weeks. Participants should avoid taking vitamin C supplements (including multivitamins) for 24 hours prior to and during the collection of 24-hour urine samples. See 
Section 8.1.1.1.  
l. 
Urinary creatinine excretion will be determined from 24-hour urine samples in order to assess the quality of the 24-hour collection. Any post-screening sample that violates 
the urine quality review criteria should be repeated within 10 days of the scheduled study visit whenever possible. See Section 8.1.1.1.1 for details. 
m. Samples for vitamin B6 levels will only be collected in participants DJHG   \HDUV ZKR DUH taking vitamin B6 supplements. 
n. 
Plasma sampling times for PK analysis of DCR-PHXC and its metabolites (see Section 8.5.1): 
x $JHG   \HDUV  
o 
Days 1 and 30: predose and at 5, 15, and 30 minutes and 1, 2, 4, 6, 10, and 12 hours postdose  
o 
Days 2 and 31: 24 hours postdose 
o 
Day 150: predose and at 2, 6, and 12 hours postdose 
x Aged 6–17 years:  
o 
Days 1 and 30: predose and at 30 minutes and 2 and 10 hours postdose 
o 
Days 2 and 31: 24 hours postdose 
o 
Day 150: predose and at 2 and 10 hours postdose 
A single plasma sample should be collected at the final visit from participants who discontinued study intervention or were withdrawn from the study. 
Windows for the collection of PK samples are as follows: 
o 
Predose to be collected within 30 minutes before administration of study intervention   
o 
5, 15, and 30 minutes and 1 hour postdose, ± 3-minute window is allowed 
o 
2, 4, 6, 10, and 12 hours postdose, ± 30-minute window is allowed 
o 
24 hours postdose, ± 1-hour window is allowed 
o. 
In adults, blood samples for plasma oxalate analysis to be collected prior to dosing (Section 8.1.5). Participants aged 6 to 17 years will have plasma oxalate sampling only at 
Screening. 
p. 
Participants should maintain consistent fluid intake (i.e., hyperhydration) over the course of the study (Section 5.3). Participants will report average daily fluid intake over the 
4 to 7 days prior to each 24-hour urine collection (Section 8.2.7). 
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q. 
On Days 1 and 30, ECG to be performed predose and at 10 hours (± 30-minutes)  postdose. A single ECG to be performed at other visits, as indicated (Section 8.2.5). If 
multiple assessments are due at the same time point, PK sampling should be performed preferably at the nominal time point, with the preferred order of assessments ECG, 
vitals, PK, and then other assessments. 
r. 
Vital signs on Day 1 and Day 30 to be assessed predose and at 10 hours (± 30-minutes) postdose (Section 8.2.3). If multiple assessments are due at the same time point, PK 
sampling should be performed preferably at the nominal time point, with the preferred order of assessments ECG, vitals, PK, and then other assessments. 
s. 
A full physical exam will be performed at Screening and Day 180 (or ET). A brief physical examination may be performed at other scheduled visits (Day 1 through Day 150) 
or unscheduled visits at the Investigator’s discretion. See Sections 8.2.1 and 8.2.2. 
t. 
,Q SDUWLFLSDQWV   \HDUV of age, height to be recorded only at screening. In participants < 18 years of age, height will be recorded at specified visits for calculation of eGFR 
and BSA adjustment of Uox excretion. Weight to be recorded in all participants at specified visits. In participants aged 6-to-11 years, the weight on Day 1 will be used to 
calculate the mg/kg dose of study intervention. 
u. 
Blood samples for hematology and serum chemistry to be collected predose on dosing days. To include cystatin C in participants < 18 years of age for calculation of eGFR. 
See Section 10.2 for the list of parameters.  
v. 
Blood samples for coagulation studies to be collected predose. Coagulation panel will include activated partial thromboplastin time (aPTT), prothrombin time (PT), and 
international normalized ratio (INR). Additional coagulation studies should be performed as clinically indicated. 
w. eGFR to be calculated as described in Section 8.2.4.1. 
x. 
Blood samples for cytokines to be collected in participants DJHG   \HDUV within 30 minutes before administration of study intervention and 2, 10, and 24 hours postdose. A 
± 30-minute window is allowed for samples collected at 2 and 10 hours postdose. A ± 1-hour window is allowed for sample collected at 24 hours postdose. A single sample 
will be collected in participants prematurely discontinuing study intervention. See Section 10.2 for parameters. Cytokine testing is not required in participants < 18 years of 
age. 
y. 
Blood samples for complement panel to be collected in participants DJHG   \HDUV within 30 minutes before administration of study intervention and 2, 10, and 24 hours 
postdose. A ± 30-minute window is allowed for samples collected at 2 and 10 hours postdose. A ± 1-hour window is allowed for sample collected at 24 hours postdose. A 
single sample will be collected in participants prematurely discontinuing study intervention. See Section 10.2 for parameters. Complement testing is not required in 
participants < 18 years of age. 
z. 
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. 
aa. 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. 
bb. Participants will report instances of renal stones requiring medical intervention, stone passage, and/or renal colic requiring medication (Section 8.1.6.1). 
cc. In the event of rescreening, if a participant had been screened for this study within the last 3 months and had kidney ultrasound data sent to the central over-readers, repeat of 
the kidney ultrasound will not be required during the rescreen. 
dd. 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. 
ee. Blood samples for analysis of anti-drug antibodies will be analyzed once a validated methodology is available (Section 8.8.1). 
ff. Participants < 18 years of age to be queried as to the ongoing burden of the study (Section 2.3.2). 
gg. Short Form 36 Health Survey to be administered only in adults (Section 8.1.7.1). 
hh. EQ-5D-5L to be administered only in adults (Section 8.1.7.2). 
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ii. 
PedsQL to be administered only in children (Section 8.1.7.3). 
jj. 
Serious adverse events to be collected from time of ICF signature through 30 days after the last study visit. 
kk. Adverse events to be collected from the time of ICF signature through the End of Study/Early Termination Visit. Participants will be questioned as to the occurrence of 
muscle pain or weakness. 
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2. 
INTRODUCTION 
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). Most patients are diagnosed in 
childhood or early adulthood. 
There is a significant unmet need for treatment in all subtypes of PH. At present, no therapies are 
approved by regulatory authorities for the treatment of patients with PH. A number of supportive 
therapies are used in an attempt to mitigate some of the effects of the disease.  
DCR-PHXC is designed to substantially reduce the activity of a key oxalate-producing enzyme. 
The potential medical value of decreasing liver oxalate production in patients with PH has been 
demonstrated by the marked improvement in disease outcome in patients with PH1 in whom 
liver oxalate production has been reduced by liver transplantation. 
This study is being conducted to assess the effect of DCR-PHXC on urinary oxalate (Uox) 
burden in patients with either PH1 or PH2, the most severe forms of PH. 
2.2. 
BACKGROUND  
2.2.1. 
Overview of Primary Hyperoxaluria 
PH 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).  
PH is a devastating disease that presents across the age continuum with a broad range of 
medically important abnormalities (Cochat & Rumsby, 2013). 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). Renal oxalate deposition in patients 
with PH1 and some patients with PH2 and PH3 leads to nephrocalcinosis, tubular dysfunction, 
and progression to end-stage renal disease (ESRD). Systemic oxalosis occurs in patients with 
PH1 and some patients with PH2 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. 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).   
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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.  
PH2 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). PH2 is much rarer 
than PH1 and is characterized by recurrent nephrolithiasis with nephrocalcinosis and ESRD in 
some patients. 
2.2.2. 
Nonclinical Overview 
DCR-PHXC consists of the drug substance (DCR-L1360) in WFI. DCR-L1360 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 asialoglycoprotein receptors (ASGR) to deliver DCR-L1360 to hepatocytes. DCR-L1360 
reduces the level of mRNA encoding the dominant form of the LDH enzyme, specifically, the 
LDHA isoenzyme. The selective reduction of hepatic LDH reduces the production of oxalate by 
the liver.  
Administration of DCR-L1360 to mice expressing human LDHA mRNA resulted in significant 
reduction of LDHA mRNA. A single SC dose of 1 to 6 mg/kg was associated with dose-
dependent knockdown that was evident at 1-week postdose and persisted for 4 weeks postdose. 
Significant reduction in LDHA mRNA, LDH protein expression, and LDH activity in the liver 
was observed for at least 4 weeks after administration of 2 doses of DCR-L1360 in monkeys; 
however, these dose levels were well in excess of the pharmacologically relevant dose level.  
DCR-L1360 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), DCR-L1360 was well tolerated at dose levels up to 
300 mg/kg in both mice and monkeys. 
The results from these studies demonstrate 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. 
See the DCR-PHXC Investigator’s Brochure (IB) for more details on the nonclinical studies. 
2.2.3. 
Clinical Overview 
At present, no therapies are approved by regulatory authorities for the treatment of patients 
with PH. 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 
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 night-time 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 
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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, in patients with 
PH1, combined liver and kidney transplantation (Nolkemper et al., 2000; Rogers et al., 2001). 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. 
2.2.3.1. 
Clinical Studies of DCR-PHXC 
DCR-PHXC is being evaluated in 5 ongoing studies in healthy volunteers and patients with PH1 
or PH2.  
As of September 2019, in Study DCR-PHXC-101, after single-dose administration of 
DCR-PHXC, normalization of Uox (defined as Uox excretion < 0.46 mmol/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).  
No significant safety findings have emerged from this or other ongoing studies. DCR-PHXC has 
an acceptable safety profile in both healthy volunteers and participants with PH1 and PH2.  
Please see the DCR-PHXC Investigator’s Brochure for additional details of this ongoing study. 
2.3. 
RISK/BENEFIT AND BURDEN ASSESSMENT 
2.3.1. 
Known Potential Risks  
Risks associated with DCR-PHXC may be characterized into 2 broad categories: risks associated 
with the small interference RNA (siRNA) molecule and risks associated with an off-target 
knockdown of LDHA.  
2.3.1.1. 
Risks Related to the siRNA Molecule 
DCR-PHXC is conjugated to GalNAc sugars that target the molecule to the liver. Due to the lack 
of excipients in the drug product, the potential risks associated with DCR-PHXC are limited to 
the risks associated with the siRNA oligonucleotide portion of the drug product (DCR-L1360). 
To date, DCR-L1360 has been associated with little to no toxicity in the nonclinical studies. 
Results of nonclinical toxicity studies of DCR-L1360 conducted to date are presented in 
Section 2.2.2. As with all oligonucleotides, there is a potential for immunogenicity. 
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, 
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inflammation, and injection site reactions, and low elevations of liver function tests (LFT). 
Published clinical observations from older nucleic acid therapy platforms, such as single-
stranded antisense programs based on fully phosphorothioate-modified oligonucleotides, have 
included coagulopathies, thrombocytopenia, complement activation, and mild to moderate 
hepatotoxicity. Until further clinical safety information for DCR-PHXC is available, general 
precautions relevant to siRNA molecules should be considered. Participants will be monitored 
for injection site reactions, liver abnormalities, markers of inflammation (cytokine release) and 
direct (anti-drug antibodies; ADA) or indirect (anti-double-stranded deoxyribonucleic acid 
antibodies; anti-dsDNA) markers of antibody formation against DCR-L1360.  
2.3.1.2. 
Risks Related to LDHA Knockdown and Potential Off-target Effects 
LDHA deficiency (Glycogen storage disease XI) is a near complete loss of LDHA function 
caused by mutations in the LDHA gene and has been described in approximately 22 subjects. 
People with this condition experience fatigue, muscle pain, and cramps during exercise (exercise 
intolerance). In some extreme cases, high-intensity exercise or other strenuous activity may lead 
to rhabdomyolysis. Liver-associated changes have not been reported (Kanno et al.,1995; Lee 
et al., 2011; Maekawa et al., 1989; Miyajima et al., 1993, Sudo et al., 1994).  
DCR-L1360 has been designed to minimize the potential for effects outside of the liver tissue 
and, thus, an effect outside of the liver tissue is unlikely at the proposed clinical doses. 
DCR-L1360 was designed with 4 GalNAc sugar residues that direct delivery of the siRNA 
preferentially to hepatocytes, due to their high expression of ASGR. Although ASGR expression 
has been detected on extra-hepatic cells, the expression of ASGR on hepatocytes far exceeds 
expression in other tissues (D'Souza & Devarajan, 2015). Together, tissue distribution and 
turnover of the ASGR make GalNAc conjugation ideal for targeted delivery of materials to the 
hepatocytes. Tissue distribution studies in mice confirm that, after SC administration, 
DCR-L1360 is distributed primarily to the liver. In pharmacology studies in mice, knockdown of 
Ldha mRNA by DCR-m355, the murine surrogate, was specific to the liver and was not 
observed in muscle; these results suggest that DCR-L1360 will be similarly specific. 
Furthermore, no adverse skeletal muscle effects were observed in monkeys at DCR-L1360 dose 
levels up to 300 times the minimally active dose. Although the 5-week toxicity study in mice 
identified potential off-target effects on skeletal muscle (degeneration of skeletal muscle, 
esophageal muscle, and tongue in one 300-mg/kg mouse, and increased creatine kinase (CK) in 
one 100-mg/kg mouse), no effects on skeletal muscle were observed in the 6-month chronic 
study. Nonetheless, in addition to measurement of plasma CK, participants should be monitored 
for signs and symptoms of muscle weakness or pain. 
DCR-L1360 shows high sequence specificity. In silico analysis suggests that it has minimal 
potential for off-target effects via siRNA hybridization to the human genome. Among the 
off-target sites identified in non-target mRNAs, only 2 genes contained a seed region sequence 
complementarity thought to be important in affecting ribonucleic acid interference (RNAi) 
activity; both had relatively short partial homologies, which suggests the potential for only weak, 
if any, impact of DCR-L1360 treatment on these genes. SATB1 protein does not appear to be 
expressed in the liver or skeletal muscle. DCP1A protein is expressed broadly, including in liver, 
but is not expressed in the skeletal muscle. Neither gene has been reported to be associated with 
human disease. As both genes are fully conserved among primates, any off-target effects related 
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to complementarity to these genes would be detected by the toxicity studies in monkeys, but 
none have been observed.  
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 24-hour 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 1 for details). 
At each study visit, pediatric participants and their parent or guardian 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 1 
Risk/Burden Assessment  
Procedure 
Risk/Burden 
Assessment 
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. Due to the increased frequency of 
blood sampling in the trial for the purposes 
of ensuring patient safety, it is possible that 
the likelihood of patients experiencing minor 
effects from blood sampling is higher during 
the study. 
12-lead ECG 
N/A 
Conducted in supine position after 
10 minutes at rest. No risks identified. 
Blood pressure 
measurement 
N/A 
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, 
or bleeding. 
The risk/burden associated with the 
SC injection 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 patients. 
Kidney ultrasound 
N/A 
Kidney ultrasound is part of the standard 
treatment for PH patients. Kidney ultrasound 
does not involve any invasive procedures. 
No risks identified. 
Echocardiogram 
N/A 
Echocardiography is part of the standard 
treatment for PH patients. Echocardiography 
does not involve any invasive procedures. 
No risks identified. 
24-hour urine 
collection 
Due to the frequency of 
collection in the current 
protocol, minor burden is 
involved.  
24-hour 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. No risks identified. 
Abbreviations: ECG: electrocardiogram; N/A: not applicable; PH: primary hyperoxaluria 
 
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2.3.3. 
Known Potential Benefits  
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 an independent 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 
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 DCR-PHXC 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 DCR-PHXC to patients with PH, 
who do not have systemic oxalosis, is expected to result in a measurable reduction in urinary 
oxalate. 
Results from the ongoing study DCR-PHXC-101 are summarized in Section 2.2.3.1 and 
demonstrate that single-dose administration of DCR-PHXC can reduce the urinary oxalate 
burden in patients 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: 
x An independent Data Safety Monitoring Committee (DSMC) will review all safety and 
efficacy data in an unblinded fashion, using group labels, on an ongoing basis. 
x 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 (complete blood count [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, in addition 
to interim review as defined in the DSMC charter. 
x Monitoring of signs and symptoms of muscle pain and/or weakness, along with 
measurement of plasma creatine kinase. 
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x Total blood volume collected: The following blood volumes will be collected during the 
trial: 
o Adult participants: A total of 315 mL, with a maximum of 172 mL in a 30-day 
period  
o Aged 6-17 participants: A total of 136.4 mL, with a maximum of 43.8 mL in a 
28-day period. In order to minimize blood loss, blood samples for screening tests 
should be collected not less than 28 days prior to samples drawn on Day 1. If met 
with blood draw difficulty, the Investigator team will make not more 
than 3 attempts at venipuncture. 
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.  
Wherever possible, routine clinical safety, PD, and PK blood samples will be collected at the 
same time point. If there is difficulty in obtaining a full blood collection, clinical chemistry and 
hematology tests detailed in Table 3 will be prioritized. Furthermore, indwelling catheters will 
be used where deemed appropriate by the Investigator team to minimize the potential distress of 
venipuncture.  
2.3.5. 
Overall Risk-Benefit Analysis 
At present, no therapies are approved by regulatory authorities for the treatment of patients 
with PH. A number of supportive therapies are 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. DCR-PHXC treatment has the potential benefit to 
reduce or eliminate the excess oxalate production in the liver and thus avoid the need for a 
combined liver and kidney transplantation in patients not already on renal replacement therapy. 
The potential risks with DCR-PHXC 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 injection site reactions. These risks can be monitored and 
should be reversible after drug discontinuation. The preliminary results from the ongoing study, 
DCR-PHXC-101, demonstrate the potential for DCR-PHXC 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 contract research organization (CRO), and 
the DSMC on an ongoing basis.  
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4. 
STUDY DESIGN  
4.1. 
OVERALL DESIGN 
This is Phase 2 multicenter trial of DCR-PHXC in patients with primary hyperoxaluria (PH1 and 
PH2). The primary hypothesis to be tested is that DCR-PHXC is superior to placebo in lowering 
Uox burden over a 6-month test period. 
This is a randomized, placebo-controlled, double-blind, parallel-group trial, in which participants 
will be randomized in a 2 to 1 ratio (DCR-PHXC to placebo). An adaptive randomization via 
minimization method will be used to allocate patients to treatment groups with respect to age and 
eGFR. See Section 9.3 for details of the minimization scheme. 
Following the up-to-35-day screening period, participants will return to the clinic for interim 
visits through Day 180. Note: an extra 7 days will be allowed for participants who are required to 
repeat screening 24-hour urine collections or for repeat of initially unanalyzable screening 
laboratory assessment samples. 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 the entire trial will have an 18-month duration. 
Blinding will be maintained using an unblinded pharmacist or designee and tinting or shrouding 
of the administration syringe to obscure the slight color difference between DCR-PHXC and 
placebo. 
It is expected that approximately 40 participants will be screened, such that 36 participants will 
be evaluable. 
An interim analysis of the data may be conducted when two-thirds of participants have 
completed study assessments through the Day 180 visit. See Section 9.6 for details of the interim 
analysis. 
4.2. 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
The randomized, double-blind, placebo-controlled, parallel-group trial is the optimal design for 
evaluation of efficacy and safety of an investigational drug. The 6-month duration of the 
treatment period is considered sufficient to demonstrate a sustained superiority of DCR-PHXC as 
compared with placebo in lowering Uox in patients with PH. 
The primary endpoint of this Phase 2 study will be 24-hour urinary oxalate excretion, measured 
as the AUC of percent change from baseline over the last 3 months of treatment. This endpoint is 
proposed in order to assess a reduction in oxalate burden over time rather than at a single time 
point at the end of study (EOS). The Sponsor believes the biological relationship between 
urinary oxalate supersaturation and the subsequent calcifications in kidney and extra-renal 
organs has been well established. The degree of hyperoxaluria predicts the development and 
severity of nephrocalcinosis and is an independent risk factor for ESRD in patients with PH 
(Zhao et al., 2016). In order to demonstrate a substantial change from baseline in 24-hour Uox in 
patients with highly elevated Uox levels, a population of patients with at least one baseline Uox 
value  1.6 mmol/24 hours will be enrolled and analyzed in a subgroup analysis.  
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4.3. 
JUSTIFICATION FOR DOSE 
The safety margins for this study were calculated based on the no observed adverse effect levels 
(NOAELs) determined in the chronic toxicity studies in mice and monkeys and the supporting 
pharmacology data in non-GLP exploratory studies (see the IB for additional details). 
4.3.1. 
PK/PD Model for Dose Selection in Adults and Adolescents 
In the Phase 1 study (Study No. DCR-PHXC-101), single doses of DCR-PHXC have been 
administered to patients with PH1 or PH2 at either 1.5, 3.0, or 6.0 mg/kg and to healthy 
volunteers in the dose range of 0.3 to 12 mg/kg.  
A preliminary PK/PD M&S analysis explored the relationship between model-predicted 
DCR-L1360 plasma concentrations and 24-hour Uox concentrations in patients with PH. The PK 
model was developed using the PK data from both healthy volunteers (N=15) and patients with 
PH (N=10). The PK-PD model only involved the PD data from patients with PH. The model fits 
were evaluated using several diagnostic plots and further qualification was done using prediction 
corrected visual predictive check (pcVPC). The model adequately described the observed data, 
with an even distribution of observations above and below the 10th and 90th prediction intervals. 
From the data available, the predictive performance of the model was considered acceptable. 
Various simulations were conducted to optimize both the dose and dosing regimen to predict the 
proportion of participants with a 24-hour Uox < 0.6 mmol/24 hours (near-normal range) and 
< 0.46 mmol/24 hours (normal range).  
From these simulations, a dose of 170 mg administered monthly was selected for adults and for 
adolescents weighing at least 50 kg. For adults and adolescents weighing less than 50 kg, a lower 
dose of 136 mg was selected.  
4.3.2. 
PK/PD Model for Dose Selection in Children Younger than 12 Years of Age 
The preliminary PK-PD model that was developed using the adult and adolescent data from the 
DCR-PHXC-101 study was updated to include data from studies DCR-PHXC-102, 
DCR-PHXC-103, all available adult data from Study DCR-PHXC-301, and at least 3 adolescents 
from the DCR-PHXC-201 and DCR-PHXC-301 studies. The model fits were evaluated using 
several diagnostic plots and further qualification was done using pcVPC. The model adequately 
described the observed data, with an even distribution of observations above and below the 10th 
and 90th prediction intervals. From the data available, the predictive performance of the model 
was considered acceptable. 
The dose selection for the 6- to 11-year-old participants was based on PK and PK-PD 
simulations. The dose was selected such that the 6- to11-year-old participants will have a similar 
exposure to DCR-PHXC 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. Note: the total 
dose administered in 6- to 11-year-old participants will not exceed 136 mg. 
4.3.3. 
Placebo Comparator 
Normal saline for injection is of a similar osmolality to DCR-PHXC and is approved for 
SC injection.  
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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. 
5. 
STUDY POPULATION 
5.1. 
INCLUSION CRITERIA 
In order to be eligible to participate in this study, an individual must meet all of the following 
criteria: 
Age 
1. At least 6 years of age, at the time of signing the informed consent/assent 
Type of Participant and Disease Characteristics 
2. Documented diagnosis of PH1 or PH2, confirmed by genotyping (historically available 
genotype information is acceptable for study eligibility) 
3. 24-KRXU 8R[ H[FUHWLRQ   mmol (adjusted per 1.73 m2 BSA in participants < 18 years 
of age) in both collections performed in the screening period. At least 12 participants 
must have at least one 24-KRXU 8R[ H[FUHWLRQ  1.6 mmol (adjusted per 1.73 m2 BSA in 
participants aged < 18 years). 
4. Less than 20% variation between the two 24-hour urinary creatinine excretion values 
obtained in the screening period. Individuals who do not achieve < 20% variation 
between the 2 screening values may undergo a second round of urine collection. An extra 
7 calendar days may be added to the screening window for participants to complete a 
second round of urine collection. Should potential participants again fail to achieve the 
within-20% variation, they will be excluded from participation. 
5. (VWLPDWHG *)5 DW VFUHHQLQJ   mL/min normalized to 1.73 m2 BSA, calculated using 
the CKD-EPI equation in particLSDQWV DJHG   years (Levey & Stevens, 2010) or the 
multivariate equation by Schwartz in participants aged 6 to 17 years 
(Schwartz et al., 2012) 
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 10.4.2, during the treatment period and 
for at least 12 weeks after the last dose of study intervention and refrain from 
donating sperm during this period. 
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Female participants:  
A female participant is eligible to participate if she is not pregnant (see 
Section 10.4.1), not breastfeeding, and at least 1 of the following conditions 
applies: 
Not a woman of childbearing potential (WOCBP) as defined in Section 10.4.1 
OR 
A WOCBP who agrees to follow the contraceptive guidance in Section 10.4.2 
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.  
Informed Consent/Assent 
7. Participant (and/or participant’s parent or legal guardian if participant is a minor [defined 
as patient < 18 years of age, or younger than the age of majority, according to local 
regulations]) is capable of giving signed informed consent, which includes compliance 
with the requirements and restrictions listed in the informed consent form (ICF) and in 
this protocol. 
a. Adolescents (12 to < 18 years of age, or older than 12 years but younger than the age 
of majority, according to local regulations) must be able to provide written assent for 
participation.  
b. For children younger than 12 years of age, assent will be based on local regulations. 
5.2. 
EXCLUSION CRITERIA 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
Medical Conditions 
1. Prior renal or hepatic transplantation, or planned transplantation within the study period 
2. Currently receiving dialysis, or anticipating requirement for dialysis during the study 
period 
3. Plasma oxalate > 30 mol/L 
4. Documented evidence of clinical manifestations of systemic oxalosis (including pre-
existing 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 patient 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)  
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c. physician concerns about intake of drugs of abuse or excessive alcohol intake, or 
history of excessive alcohol intake in the 2 years prior to enrollment (defined as 
 21 units of alcohol per week in men and  14 units of alcohol per week in women; 
where a “unit” of alcohol is equivalent to a 12-ounce beer, 4-ounce glass of wine, or 
1-ounce shot of hard liquor) 
d. history of serious mental illness that includes, but is not limited to, schizophrenia, 
bipolar disorder, or severe depression requiring hospitalization or pharmacological 
intervention 
e. clinically relevant history or presence of cardiovascular, respiratory, gastrointestinal, 
hematological, lymphatic, neurological, musculoskeletal, genitourinary, 
immunological diseases, including dermatological (e.g., rash, severe eczema or 
dermatitis), or connective tissue diseases or disorders 
Prior/Concomitant Therapy 
6. Use of an RNA interference (RNAi) drug within the last 6 months 
7. History of one or more of the following reactions to an oligonucleotide-based therapy: 
a. severe thrombocytopenia (platelet count  100,000/L) 
b. hepatotoxicity, defined as alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) > 3 times the upper limit of normal (ULN) and total 
bilirubin > 2 × ULN or international normalized ratio (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 
8. Participants receiving pyridoxine must have been at a stable dose for at least 4 weeks 
prior to Day 1 and must be willing to remain on the same stable dose throughout the 
study.  
Prior/Concurrent Clinical Study Experience 
9. Participation in any clinical study in which they received an investigational medicinal 
product (IMP) within 4 months 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 
10. Liver function test abnormalities: ALT and/or AST >1.5 × ULN for age and gender 
11. Positive screening for hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV) 
antibodies, or anti-human immunodeficiency virus (HIV) 1 and 2 antibodies. If 
participant has been tested in the past 3 months, medical record documentation of this 
testing can be used for screening. Viral serology testing not required in participants 
< 18 years of age. 
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12. Positive urine drug screen (to include at minimum: amphetamines, barbiturates, cocaine, 
opiates, and benzodiazepines). Investigator discretion is allowed. Urine drug screening is 
not required in participants  12 years of age. 
Other Exclusions 
13. Known hypersensitivity to DCR-PHXC, or any of its ingredients 
14. Inability or unwillingness to comply with the specified study procedures, including 
collection of 24-hour urine samples, and the lifestyle considerations detailed in 
Section 5.3 
5.3. 
LIFESTYLE CONSIDERATIONS 
During this study, participants are asked to: 
x refrain taking vitamin C supplements, including multivitamins, for 24 hours prior to and 
during the 24-hour urine specimen collections  
x avoid oxalate-rich foods  
x abstain from strenuous exercise for 24 hours before each blood collection for clinical 
laboratory tests 
x 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). 
5.4. 
SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently randomly assigned to the study intervention or entered in the study. A minimal 
set of screen failure information is required to ensure transparent reporting of screen failure 
participants, to meet the Consolidated Standards of Reporting Trials (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. 
5.5. 
STRATEGIES FOR RECRUITMENT AND RETENTION 
Given the rare-disease nature of PH, potential participants may be under the care of the 
Investigator. Others may be referred to the clinical site by their treating physicians, or through 
other patient networks. 
Participants will be reimbursed for expenses associated with study visits, such as parking, 
transportation, and meals. For car travel, mileage will be reimbursed at the current regional 
government rate. Participants must submit supporting documentation for the reimbursement(s) 
requested. 
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6. 
STUDY INTERVENTION 
6.1. 
STUDY INTERVENTION(S) ADMINISTRATION 
6.1.1. 
Study Intervention Description 
DCR-PHXC is a synthetic RNAi drug that consists of a double-stranded oligonucleotide 
conjugated to GalNAc ligands. DCR-PHXC is a sterile formulation of the drug substance 
(DCR-L1360) in WFI, intended for SC administration. 
DCR-PHXC is not commercially available in any country. 
The placebo comparator is 0.9% normal saline for injection. 
6.1.2. 
Dosing and Administration 
Study intervention will be administered in clinic as a SC injection into the abdomen or thigh 
using a 25- to 27-gauge needle, 3/8 to 5/8 inches long. 
In adults and in adolescents (aged 12-17 years) weighing  50 kg, study intervention will be 
administered once monthly at a dose of 170 mg DCR-PHXC (or the equivalent volume of 
placebo). In adults and adolescents weighing < 50 kg, study intervention will be administered 
once monthly at a dose of 136 mg DCR-PHXC (or the equivalent volume of placebo). 
Participants who begin the study weighing less than 50 kg will have their dose increased to the 
170 mg dose should they reach the 50 kg threshold. Participants receiving the 170 mg dose will 
not have their dose decreased to the 136 mg dose should they fall below the 50 kg threshold. 
The dose for participants aged 6 to 11 years will be 3.5 mg/kg monthly, not to exceed 136 mg. 
The total dose for 6- to 11-year-old participants will be based upon body weight recorded on 
study Day 1 and will be constant throughout the study, regardless of any weight gain or loss or 
change in age (i.e. an 11-year-old turns 12 during the study). The volume of a single injection 
should not exceed 0.5 mL. Should the calculated dose require a volume greater than 0.5 mL, the 
dose should be administered in 2 equally divided injections.  
An unblinded pharmacist or designee will prepare the dose of DCR-PHXC or placebo as detailed 
in Section 6.2.4.  
To prevent any blinded site staff or study participants from visually observing color differences 
between DCR-PHXC and placebo, syringes will be tinted or shrouded to mask the color 
difference. 
6.2. 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
6.2.1. 
Acquisition and Accountability 
DCR-PHXC will be provided to the site pharmacy by the Sponsor. Study intervention 
accountability records will be maintained by an unblinded pharmacist or designee to maintain the 
study blind, and an unblinded study monitor will be employed to review accountability records. 
The placebo control will be supplied by the site pharmacy. 
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6.2.2. 
Formulation, Appearance, Packaging, and Labeling 
DCR-PHXC is a colorless to pale yellow, preservative-free, sterile solution of DCR-L1360 at a 
concentration of 170 mg/mL in WFI. The product is filled into clear Type-I 2-mL glass vials 
sealed with Flurotec-coated chlorobutyl rubber stoppers with aluminum flip-off overseals. Each 
vial is intended for single use and contains an extractable volume of not less than 0.5 mL of 
DCR-PHXC. Each vial is labeled with a booklet label or a single panel label that contains 
country-specific related information, in compliance with regulatory and safety requirements.  
The placebo comparator is 0.9% sterile normal saline for injection provided by the study site. 
6.2.3. 
Product Storage and Stability 
DCR-PHXC is to be stored at 2°C to 8°C (inclusive). DCR-PHXC 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. 
The placebo comparator should be stored in accordance with the product labeling. 
6.2.4. 
Preparation 
Study intervention will be prepared by the unblinded 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. 
6.3. 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
This is a double-blind study in which treatment assignment will be blinded for the Investigators 
and any personnel (other than the unblinded pharmacist or designee) involved with the study 
conduct or evaluation at the investigational sites, the CRO, and the Sponsor. 
All participants will be centrally assigned to randomized study intervention using an Interactive 
Web Response System (IWRS). Before the study is initiated, the log in information and 
directions for the IWRS will be provided to each site. 
The randomization scheme will only be disclosed to selected personnel to ensure correct 
preparation of the study drug, correct set-up of the IWRS, safety monitoring by the DSMC, and 
expedited adverse reaction reporting. All aspects of blinding and unblinding for the study is 
outlined in the study-specific Blinding and Unblinding Plan. 
Unblinding, i.e., breaking the code for an individual patient during the study, is restricted to 
emergency situations and should only be used under circumstances where knowledge of the 
treatment is necessary for the proper handling of the participant. The decision to break the code 
must be made by the Investigator. The study monitor and Sponsor must be informed about the 
code break as soon as possible. Detailed unblinding procedures are provided in a separate 
IWRS manual. 
As DCR-PHXC is colorless to pale-yellow, an unblinded pharmacist or designee will prepare the 
syringes for delivery to the Investigator. To prevent any blinded site staff or study participants 
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from visually observing color differences between DCR-PHXC and placebo, syringes will be 
tinted or shrouded to mask the color difference. 
Results of on-treatment 24-hour Uox measurements will not be returned to the Investigator prior 
to closure of the study, so as not to potentially unblind the study. 
6.4. 
STUDY INTERVENTION COMPLIANCE 
Study intervention will be administered by a member of the study staff. 
6.5. 
CONCOMITANT THERAPY 
For this protocol, a prescription medication is defined as a medication that can be prescribed only 
by a properly authorized/licensed clinician. Concomitant therapies to be recorded in the case 
report form (CRF) at every visit include concomitant prescription medications, over-the-counter 
medications, and supplements. 
Participants taking pyridoxine (vitamin B6) must have been at a stable dose for at least 4 weeks 
prior to Day 1 and must remain on the same stable dose throughout the study.  
Participants should avoid taking vitamin C supplements, including multivitamins, for 24 hours 
prior to and during the collection of 24-hour urine samples. 
6.5.1. 
Rescue Medicine 
Not applicable. 
6.6. 
DOSE MODIFICATION 
No dose modifications are allowed, other than those described in Section 6.1.2. 
6.7. 
INTERVENTION AFTER THE END OF THE STUDY 
In order to provide continued patient access to DCR-PHXC and to expand the safety database for 
the product, a roll-over long-term extension study is planned (DCR-PHXC-301). Participants 
may be screened for entry into the roll-over study when all DCR-PHXC-201 study assessments 
have been completed; including confirmation that the Day 180/EOS 24-hour urine collection 
satisfies the urine-collection completeness criteria. Participants not eligible for, or electing not to 
roll over into, Study DCR-PHXC- ZLOO EH IROORZHG XQWLO 8R[ UHWXUQV WR   RI baseline. 
Hematology, clinical chemistry, urinalysis, and pregnancy testing (as detailed in Table 3), and 
24-hour urine collections will be repeated monthly. Should this follow-up take more than 
6 months, participants will be re-consented for additional follow-up. 
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7. 
STUDY INTERVENTION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
DISCONTINUATION OF STUDY INTERVENTION 
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 must be temporarily interrupted and may be 
permanently discontinued for the following, as determined by the DSMC: 
x any severe AE possibly, probably, or definitely related to study intervention  
Study intervention for an individual participant will be permanently discontinued for any of the 
following: 
x any SAE possibly, probably or definitely related to study intervention 
x any of the changes in hepatic function detailed in Section 7.1.1  
x pregnancy, as detailed in Section 10.4 
Re-challenge with study intervention is not allowed. 
Discontinuation from study intervention does not mean discontinuation from the study. 
Remaining visits and study procedures should be completed as indicated by the SoA. 
Additionally, participants in whom study intervention is prematurely discontinued will be 
IROORZHG XQWLO 8R[ UHWXUQV WR   RI EDVHOLQH Hematology, clinical chemistry, urinalysis, and 
pregnancy testing (as detailed in Table 3) and 24-hour urine collections will be repeated 
monthly. Should this follow-up take more than 6 months, participants will be re-consented for 
additional follow-up.  
7.1.1. 
Drug-Induced Liver Injury Monitoring 
Safety laboratory test results will be monitored by a central laboratory in real time with potential 
drug-induced liver injury (DILI) alerts sent to the Investigator. 
For participants with normal liver biochemistries at baseline:  
x 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). 
x 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. Safety laboratory 
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parameters will be monitored by a central laboratory in real time, with potential drug-
induced liver injury (DILI) alerts sent to the Investigator. 
x ALT or AST > 8 × ULN 
x ALT or AST > 5 × ULN for more than 2 weeks 
x ALT or AST > 3 × ULN and (total bilirubin >2 × ULN or INR >1.5) 
x ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%) 
Close monitoring should be continued. 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 followed until Uox returns to  80% of 
baseline. 
Patients 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 CRFs. 
For participants with elevated transaminases at baseline: The following Alternative DILI 
Monitoring Algorithm should be used.  
x Close Monitoring: If participants develop elevations of AST or ALT > 2 times the 
screening value or total bilirubin > 1.5 times the screening value 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). 
x Study Intervention Discontinuation:  Study intervention will be discontinued for 
abnormal liver function when a participant meets the following condition. Close 
monitoring should be continued. If a participant’s home is 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). 
o ALT or AST >5 × the screening value in participants with the screening 
value < 2 × ULN 
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 followed until Uox returns to  80% of baseline. 
7.2. 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Participants are free to withdraw from participation in the study at any time upon request. 
An Investigator may discontinue or withdraw a participant from the study for the following 
reasons: 
x Pregnancy 
x Significant study intervention noncompliance  
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x If any clinical AE, laboratory abnormality, or other medical condition or situation occurs 
such that continued participation in the study would not be in the best interest of the 
participant 
x If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
The reason for participant discontinuation or withdrawal from the study will be recorded on the 
CRF. Participants who sign the ICF and are randomized but do not receive the study intervention 
may be replaced. In order to ensure that there is an adequate number of participants in the 
modified intent-to-treat population (see Section 9.4) additional participants may be enrolled and 
randomized if there are participants who sign the ICF and are randomized and receive the study 
intervention, and subsequently withdraw or are withdrawn or discontinued from the study prior 
to completion of the Day 90 assessments, or who do not have any efficacy assessments after 
Day 90.  
Participants who are withdrawn from the study ZLOO EH IROORZHG XQWLO 8R[ UHWXUQV WR   RI
baseline. Hematology, clinical chemistry, urinalysis, and pregnancy testing (as detailed in 
Table 3), and 24-hour urine collections will be repeated monthly. Should this follow-up take 
more than 6 months, participants will be re-consented for additional follow-up. 
7.3. 
LOST TO FOLLOW UP 
A participant will be considered lost to follow-up if he or she fails to return for 3 consecutive 
scheduled visits and is unable to be contacted by the study site staff.  
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
x The site will attempt to contact the participant and reschedule the missed visit within 
1 business day and counsel the participant on the importance of maintaining the assigned 
visit schedule and ascertain if the participant wishes to and/or should continue in the 
study. 
x Before a participant is deemed lost to follow-up, the Investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter [or local equivalent] to the participant’s last known mailing 
address). These contact attempts should be documented in the participant’s medical 
record or study file.  
x Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
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8. 
STUDY ASSESSMENTS AND PROCEDURES 
8.1. 
EFFICACY ASSESSMENTS  
8.1.1. 
24-Hour Urinary Oxalate 
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 or GRHPR gene result 
in the overproduction of oxalate by the liver, which causes increased oxalate excretion by the 
kidneys.  
The measurement of oxalate in the urine will be via 24-hour urine collection. During the 
screening period, participants will perform two 24-hour urine collections at home. The oxalate 
level in both FROOHFWLRQV PXVW EH   mmol (adjusted per 1.73 m2 BSA in those younger than 
18 years) for a participant to be eligible for study entry. Note that 12 of the participants enrolled 
must have at least one 24-hour Uox excretion value  1.6 mmol. There must be less than a 20% 
variation between the 2 urinary creatinine excretion values obtained in the screening collections 
for a participant to be eligible for study entry (see Section 8.1.1.1.1). Potential participants will 
be allowed a second attempt at achieving a less than a 20% variation should the first pair of 
measurements differ by more than 20%. 
8.1.1.1. 
Collection of 24-hour Urine Samples 
Collection of the two 24-hour urine samples during Screening should occur on consecutive days; 
in no case should more than 8 days elapse between collections. For example, if a participant 
initiates collection of the first 24-hour sample beginning on a Saturday morning, the second 
collection must begin no later than the following Sunday morning. 
Ongoing assessment of Uox will continue at select visits throughout the study, as defined in the 
SoA. Collection of on-treatment samples must be performed within the 7 days prior to the 
scheduled study visit. The elapsed time between monthly collections should be at least 3 weeks 
and not more than 5 weeks. 
Any participant who prematurely discontinues study intervention should perform a last 24-hour 
collection as directed by the Medical Monitor. 
Participants should be instructed to avoid consuming vitamin C, including multivitamins, in the 
24 hours preceding urine collection and throughout the 24-hour collection period. The urine void 
immediately preceding initiation of the 24-hour collection will be collected and stored separately 
from the 24-hour collection for spot urine analysis (see Section 8.1.4), and the 24-hour collection 
will commence with the next void. At all visits for which 24-hour urine collections will be 
performed, the research staff will review collection instructions with the participants to ensure 
complete and timely collections. Home health aides are available to participants who desire 
assistance in completing at-home urine collection. Participants accepting home health aide 
assistance will provide additional consent for this service.  
Complete instructions for the 24-hour urine collection will be provided in the Urine Collections 
Instructions. 
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8.1.2. 
24-Hour Urinary Creatinine Excretion 
The completeness of 24-hour urine collections can be assessed by calculating the variability of 
24-hour urinary creatinine excretion. Clifford-Mobley et al. suggest that a 20% variability in 
urinary creatinine excretion exceeds biologic variation and should be considered the upper bound 
for acceptability of samples (Clifford-Mobley et al., 2016).   
The measurement of urinary creatinine excretion will be via 24-hour urine collection, as 
described in Section 8.1.1.1. 
8.1.3. 
Other Parameters Determined from 24-Hour Urine Collections 
In addition to Uox and urinary creatinine excretion, urinary citrate, calcium, phosphate, and 
magnesium will be measured via 24-hour urine collection. The calculation of the urinary oxalate-
to-creatinine ratio will also be determined from the 24-hour urine samples. 
8.1.4. 
Urinary Oxalate from Spot Urine 
In order to evaluate the relationship between Uox levels in spot urine and 24-hour urine samples, 
participants will collect a spot urine sample each time a 24-hour collection is performed. A 
sample of urine from the void immediately prior to the initiation of each 24-hour urine collection 
will be collected and stored apart from the 24-hour urine collection. Should the two 24-hour 
screening collections occur on consecutive days, no spot urine sample will be collected on the 
second day. 
Complete instructions for the spot urine collection will be provided in the Urine Collections 
Instructions. 
8.1.5. 
Plasma Oxalate 
Plasma oxalate concentration is a reflection of the body pool size. The plasma oxalate pool size 
is increased in individuals with PH and impaired renal function. When the pool increases, oxalate 
may precipitate in tissues and cause toxicity.  
In order to limit blood loss in children, plasma oxalate testing will not be conducted in 
participants aged 6 to 17 years, other than at Screening. 
Complete instructions for collection and handling of samples will be provided in the Central 
Laboratory Manual. 
8.1.6. 
Kidney Assessments  
Patients 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).  
8.1.6.1. 
Kidney Stone Events and Stone Burden 
Participants will provide a 12-month history of stone events at Screening and will report any 
stone events during the study. 
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For the purpose of this study, “stone events” are all events that meet one or more of the 
following criteria: 
x 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); 
x stone passage with or without hematuria; 
x renal colic requiring medication. 
Concurrent events will be defined as events occurring within the same 4-week (28-day) window.  
Note: Although the number of stone events is an efficacy endpoint, stone events will be 
considered AEs of special interest (Section 10.3.3), as participants may enter the study with pre-
existing stones. 
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. 
8.1.6.2. 
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. In adult participants, a curved array transducer with 
center frequencies of 3 to 6 MHz should be used. 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. 
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 electronic case report form (eCRF). Site 
personnel will be trained in the processes relating to ultrasound performance and data 
transmission.  
The end-to-end process of centralized kidney ultrasound overread is detailed in a separate 
DCR-PHXC-201 Centralized Imaging Overread plan.  
Centralized overread will include standardized nephrocalcinosis grading in accordance with the 
staging criteria outlined in Figure 2. 
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Figure 2: 
Standardized Nephrocalcinosis Grading 
 
From Boyce et al., 2013 
 
8.1.7. 
Quality of Life Assessments 
Health-related quality of life (HRQOL) surveys will be administered in adult and pediatric 
participants 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.  
8.1.7.1. 
Short Form 36 Health Survey – Adults Only 
As part of the Medical Outcomes Study (MOS), a multi-year study to explain variations in 
patient outcomes, RAND® developed the 36-Item Short Form Health Survey (SF-36). The SF-36 
is a set of generic, coherent, and easily administered QoL measures that taps 8 health concepts: 
physical functioning, bodily pain, role limitations due to physical health problems, role 
limitations due to personal or emotional problems, emotional well-being, social functioning, 
energy/fatigue, and general health perceptions. It also includes a single item that provides an 
indication of perceived change in health. The 36 items are identical to the MOS SF-36 described 
in Ware and Sherbourne (1992). Participants respond to each item on a categorical scale. 
Categorical answers are transformed to a 0 to 100 range so that the lowest and highest possible 
scores are 0 and 100, respectively. All items are scored so that a high score defines a more 
favorable health state. 
8.1.7.2. 
EQ-5D-5L – Adults Only 
The 5-level EQ-5D version (EQ-5D-5L) was introduced by the EuroQol Group in 2009 to 
improve the instrument’s sensitivity and to reduce ceiling effects, as compared to the previously 
3-level EQ-5D (Herdman et al., 2011). The EQ-5D-5L consists of the EQ-5D descriptive system 
and the EQ visual analog scale (EQ VAS). 
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The descriptive system comprises 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight 
problems, moderate problems, severe problems, and extreme problems. Participants are asked to 
indicate their health state by ticking the box next to the most appropriate statement in each of the 
5 dimensions. This decision results in a 1-digit number that expresses the level selected for that 
dimension. The digits for the 5 dimensions can be combined into a 5-digit number that describes 
the participant’s health state. It should be noted that the numerals 1 to 5 have no arithmetic 
properties and should not be used as a cardinal score. 
The EQ VAS records the participant’s self-rated health on a 20-cm vertical VAS, where the 
endpoints are labelled ‘The best health you can imagine’ and ‘The worst health you can 
imagine’. Participants are asked to place an “X” on the line that represents their health on that 
day. The VAS can be used as a quantitative measure of health outcome that reflect the 
participant’s judgement. 
8.1.7.3. 
Pediatric Quality of Life Inventory – Children Only 
The Pediatric Quality of Life Inventory (PedsQL™) is a modular approach to measuring 
HRQOL in healthy children and adolescents 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 World Health Organization (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.  
Age-appropriate self-reporting questionnaires are available for children aged 5 to 7, 8 to 12, and 
13 to 18. Parental proxy reports are available for children aged 5 to 7, 8 to 12, and 13 to 18. 
Parents, Children (8-12) and Teens (13-18) may self-administer the PedsQL after introductory 
instructions from the administrator. If the administrator determines that a child or teen 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 or teen. For the Young Child (5-7), the PedsQL should be 
administered by reading the instructions and each item to the young child word for word.   
If a child has difficulty understanding the age-appropriate PedsQL, the preceding age group 
version may be administered to the child (e.g., administering the Young Child [5-7] Self-Report 
version with the 3 faces response choices to an 8-year-old). However, 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. 
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 
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functioning, communication, and worry. The Module also measures parent-reported family daily 
activities and family relationships. 
8.2. 
SAFETY AND OTHER ASSESSMENTS 
8.2.1. 
Weight, Height, and Body Surface Area 
Body weight and height should be measured without shoes. 
Body weight will be recorded in kilograms (kg). Weight should be measured on the same 
calibrated scale at each scheduled visit. In participants aged 6-to-11 years, the weight on Day 1 
will be used to calculate the mg/kg dose of study intervention. 
Height will be recorded in centimeters (cm). Height is measured only at screening for adults. 
+HLJKW LQ SDUWLFLSDQWV   \HDUV RI DJH VKRXOG EH PHDVXUHG RQ WKH VDPH VWDGLRPHWHU at each 
scheduled visit. 
For the BSA-adjustment of 24-hour Uox in participants < 18 years of age, BSA will be 
calculated using the height and weight measured at the visit for which the 24-hour urine is 
collected. Should BSA adjustments be calculated in participants  18 years of age, the height 
recorded at screening will be used for all visits. 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 Examination 
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/ET. 
A brief physical examination will include, at a minimum, chest/respiratory, heart/cardiovascular, 
dermatological/skin, and gastrointestinal/liver. A brief physical examination may be performed 
at scheduled visits (Day 1 through Day 150) or unscheduled visits at the Investigator’s 
discretion.  
Study intervention injection sites should be inspected at each visit. 
8.2.3. 
Vital Signs  
Vital signs include blood pressure, pulse/heart rate, oral body temperature, and respiratory rate. 
Parameters will be measured in the supine position, using an automated instrument or manually, 
after the participant has rested comfortably for 10 minutes. In the pediatric population, an age-
appropriate cuff size should be used for blood pressure measurements. 
Temperature will be obtained in degrees Celsius (°C), 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. 
Age-appropriate normal values will be considered when evaluating pediatric participants. 
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Figure 4: 
Schwartz eGFR Equations - for Pediatric Participants (< 18 Years of Age) 
 
 
8.2.5. 
12-Lead ECG 
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 standalone 
imaging vendor, where qualified personnel will perform central overread of all ECG readouts. 
Site personnel will be trained in the processes relating to ECG acquisition and transmission. The 
end-to-end process of centralized ECG acquisition and overread is detailed in a separate 
DCR-PHXC-201 Centralized Imaging Overread plan. 
8.2.6. 
Echocardiogram with Doppler 
Echocardiography will be performed by a qualified sonographer/physician (and overread by a 
cardiologist), using a standard, commercially available ultrasound machine. The 
echocardiography technician should perform standard 2-dimensional (2-D) transthoracic 
echocardiography with Doppler, as described by the American Society of Echocardiography 
(ASE) recommendations (Picard et al., 2011). The full ASE protocol need not be followed but 
(a) 
Creatinine-based equation: 
eGFR = 36.5 x height ÷ SCr 
where  
SCr (serum creatinine) = μmol/L 
height = cm 
From ^ĐŚǁĂƌƚǌ Ğƚ Ăů͕͘ ϮϬϬϵ 
 
(b) 
Multivariate equation: 
eGFR = 39.8 × [ht/Scr]0.456[1.8/cysC]0.418[30/BUN]0.0791.076male[ht/1.4]0.179 
where 
ht (height) = meters 
Scr (serum creatinine) = mg/dL 
cysC (cystatin C) = mg/L 
BUN (blood urea nitrogen) = mg/dL 
From ^ĐŚǁĂƌƚǌ Ğƚ Ăů͕͘ ϮϬϭϮ 
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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. 
Additionally, all echocardiogram data will be transmitted to a standalone imaging vendor, where 
qualified personnel will perform postprocessing of echocardiogram data and central overread of 
all images. Site personnel will be trained in the processes relating to echocardiogram 
performance and data transmission.  
The end-to-end process of centralized echocardiogram overread and postprocessing is detailed in 
a separate DCR-PHXC-201 Centralized Imaging Overread plan. 
8.2.7. 
Reporting Fluid Intake 
Hyperhydration regimens are a central feature in the conservative management of urinary oxalate 
levels in patients with PH. As such, participants are asked to maintain a consistent fluid intake 
throughout the study (Section 5.3). Participants will be asked to report their average daily fluid 
intake during the 4- to 7-day period before each of the 24-hour urine collections, including the 
2 collections conducted during screening. 
8.3. 
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS AND ADVERSE EVENTS 
OF SPECIAL INTEREST 
The definitions of AEs, SAEs, and adverse events of special interest (AESI) are located in 
Section 10.3. 
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorized representative).  
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention (see Section 7.1). 
8.3.1. 
Time Period and Frequency for Event Assessment 
All SAEs will be collected from the signing of the ICF until 30 days after the last day of study 
participation. 
All AEs will be collected from the signing of the ICF until the EOS at the time points specified 
in the SoA (Section 1.3). 
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s condition 
deteriorates at any time during the study, it will be recorded as an AE.  
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
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related to the study intervention or study participation, the Investigator must notify the Sponsor 
promptly. 
8.3.2. 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Section 10.3.4. 
Adverse events may be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant’s legally authorized representative) as either unsolicited reports or in 
response to general questioning, such as “Have you noticed anything different since you began 
the study?” Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-
ended and non-leading verbal questioning of the participant is the preferred method to inquire 
about AE occurrences. Participants will be questioned as to the occurrence of muscle pain or 
weakness. The occurrence of an AE or SAE may also be detected upon review by a study 
monitor. 
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 AESI (as defined in 
Section 10.3.3), 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 given in Section 10.3.4. 
8.3.4. 
Serious Adverse Event Reporting  
All SAEs will be recorded and reported to the sponsor or designee immediately; under no 
circumstance should this exceed 24 hours, as indicated in Section 10.3.5. The Investigator will 
submit any updated SAE data to the Sponsor within 24 hours of it being available. 
Prompt notification by the Investigator to the Sponsor of a SAE is essential so that obligations 
and ethical responsibilities towards the safety of participants and the safety of the study 
intervention under clinical investigation are met.  
The Sponsor has a 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, Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), 
and Investigators. 
Investigator safety reports will be prepared for suspected unexpected serious adverse reactions 
(SUSAR) according to local regulatory requirements and Sponsor policy and will be forwarded 
to Investigators as necessary. 
8.3.5. 
Reporting of 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 10.4. 
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Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, and ectopic pregnancy) are considered SAEs. 
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 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 
CRF. 
Decisions regarding dose interruptions will be made by the Investigator in consultation with the 
Medical Monitor based on the clinical evaluation of the participant. 
8.5. 
PHARMACOKINETICS 
8.5.1. 
Plasma Pharmacokinetics 
Blood samples will be collected for measurement of plasma concentrations of DCR-PHXC and 
its metabolites, as 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. Drug concentration information that would unblind 
the study will not be reported to investigative sites or blinded personnel until the study has been 
unblinded. 
Pharmacokinetic parameters to be determined may include clearance (CL) and volume of 
distribution (V) estimates, along with secondary parameters of area under the concentration 
curve (AUC), maximum observed concentration (Cmax), minimum observed concentration 
(Cmin), time to maximum concentration (Tmax), and terminal elimination half-life (t1/2). The 
population PK parameters will be reported separately from the study. 
8.6. 
PHARMACODYNAMICS 
Pharmacodynamic parameters other than urinary and plasma oxalate, and urinary oxalate-to-
creatinine ratio (Sections 8.1.1, 8.1.5 and 8.1.3, respectively) are not evaluated in this study. 
8.7. 
GENETICS 
Genetics are not evaluated in this study. However, participants without documented 
PH genotyping must provide a deoxyribonucleic acid (DNA) sample for testing at screening. 
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8.8. 
BIOMARKERS 
See Sections 8.1.1 and 8.1.5 for descriptions of urinary and plasma oxalate assessments. Other 
biomarkers are not evaluated in this study. 
8.8.1. 
Immunogenicity Assessments 
Plasma samples for the detection and characterization of antibodies to DCR-PHXC will be 
collected from all participants according to the SoA. Plasma samples should also be collected at 
the final visit from participants who discontinued study intervention or were withdrawn from the 
study.  
The detection and characterization of antibodies to DCR-PHXC will be performed using a 
validated assay method by or under the supervision of the Sponsor, once a validated assay 
method is available. 
Endogenous anti-nuclear antibodies are believed to recognize oligonucleotides 40- to 50-base 
pairs in length. Anti-double-stranded DNA antibodies will be measured as long as there is no 
validated assay for direct antibodies to DCR-PHXC. Serum samples for detection of anti-dsDNA 
will be collected from all participants, as indicated in the SoA. Samples should also be collected 
at the final visit from participants who discontinued study intervention or were withdrawn from 
the study. 
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 DCR-PHXC.  
8.9. 
PHARMACOECONOMICS 
Pharmacoeconomic analysis will be performed on collected data. These data will be summarized 
separately from the Clinical Study Report. 
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For the sample size calculations, the primary endpoint of the AUC of 24-hour Uox from Day 90 
to Day 180 based on percent change from Baseline is used. The group sequential design with 
prespecified alpha spending for interim analysis and final analysis is utilized. The randomization 
ratio is 2:1 (active:placebo). The primary hypothesis tested is a 1-sided superiority hypothesis at 
the significance level of 0.025. The AUC Uox in the placebo arm is assumed to be 0, as the Uox 
values may oscillate up and down from baseline due to the measurement variability. The AUC 
Uox in the active arm is assumed to be 3600 based on 40% decrease over the 90 days. The effect 
size is assumed to be 1.2. Under these assumptions, the sample size of 36 patients (24 in the 
active arm and 12 in the placebo arm) will yield a power of approximately 94%. All calculations 
were performed using 
 
. There may be one interim analysis 
to re-estimate sample size after two-thirds of participants complete the study.  
9.3. 
RANDOMIZATION METHOD 
To balance the participants between the intervention arms based on 2 factors: age (6-11, 12-17, 
>  \HDUV DQG H*)5 H*)5   P/PLQ H*)5   P/PLQ DQ DGDSWLYH UDQGRPL]DWLRQ YLD
minimization method will be used to allocate patients to treatment groups. Minimization aims to 
ensure that the intervention arms are balanced with respect to the predefined factors, as well as 
for the number of patients in each arm. Imbalance scores are calculated for the possible patient 
allocations to treatment groups, which represent the imbalance that would be generated in each 
of the treatment arms, while taking into account these 2 factors. The participant will be assigned 
to the treatment that results in the lowest amount of imbalance with an 80% probability, and the 
treatment which results in the highest amount of imbalance with a 20% probability (Taves, 1974; 
Pocock & Simon, 1975). 
9.4. 
POPULATIONS FOR ANALYSES 
For purposes of analysis, the following populations are defined: 
x Enrolled: The enrolled population includes all participants who sign the ICF. 
x Safety Population: The safety population includes all participants randomly assigned to 
study intervention and who take at least 1 partial or full dose of study intervention. 
Participants will be analyzed according to the intervention they actually received. 
x Intent-To-Treat Population (ITT): The ITT population includes all participants who 
were randomized and have at least one post-baseline efficacy assessment. Participants 
will be analyzed according to the intervention they were randomized to.  
x Modified Intent-To-Treat Population (MITT): The MITT population includes all 
participants in the ITT population who have at least one efficacy assessment after the 
Day 90 dosing visit. 
x Evaluable:  The evaluable population includes all participants who received 6 full doses 
of study intervention and completed the study. 
x Pharmacokinetic Population: The PK Population includes all participants in the Safety 
Population without major dosing violations. Details will be provided in the 
Pharmacokinetics Analysis Plan (PKAP). 
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Descriptive statistics for clinical safety laboratory data (laboratory data) will be presented overall 
and by treatment group at each visit starting at baseline. Change from baseline to post-baseline 
visit will also be presented. Laboratory parameter shifts from baseline to abnormal post-baseline 
values will be presented. No statistical comparisons will be performed. 
x For the evaluation of eGFR over time in pediatric participants (6 to 17 years of age), the 
Schwartz et al. 2009 equation will be used for the primary analysis. As a sensitivity 
analysis, eGFR will be calculated using the multivariate Schwartz et al. 2012 equation. 
Descriptive statistics for vital signs will be presented overall and by treatment sequence for 
systolic blood pressure, diastolic blood pressure, body temperature, pulse/heart rate, and 
respiration rate, at each visit starting at baseline. Change from baseline to post-baseline visit will 
also be presented. No statistical comparisons will be performed. 
ECG parameters will be summarized by treatment group and visit. The pre-dose ECGs will be 
compared across visits. Pre- and postdose 12-lead ECGs will be compared within the dosing 
visits. 
Frequency counts will be presented per treatment for both change and absolute values, 
with changes categorized as per the bullets below. Individual listings presenting patients 
with flags will be created for both change and absolute values. The summary will be 
tabulated by treatment. 
Change from baseline for QTcF and uncorrected QT will be classified per treatment as 
follows:  
x   PVHF RU !  PVHF  
x   PVHF RU !  PVHF  
Absolute post-baseline QTcF and uncorrected QT interval will be classified per treatment 
as follows:  
x   PVHF or > 450 msec  
x   PVHF RU !  PVHF  
x   PVHF RU !  PVHF  
Additionally, the number and percentage of participants with the following overall 
ECG result will be presented:  
x Normal  
x Abnormal, clinically significant  
Descriptive statistics will be produced for echocardiogram results. Shift tables will be presented 
in reference to normal ranges. 
The results of the physical examinations will be summarized for the participants who had an 
examination post-baseline. Each site/system will be summarized with respect to being normal or 
abnormal, or not performed. Shift tables will be presented. 
9.5.3. 
Other Analyses  
Pharmacokinetic and all exploratory analyses will be described in the SAP finalized before 
database lock. The population PK analysis will be presented separately from the main Clinical 
Study Report.  
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9.6. 
INTERIM ANALYSES  
An interim analysis may be conducted upon completion of two-thirds of the participants for the 
purpose of re-evaluation of sample size. The interim unblinded analysis will be performed by an 
independent statistician other than the person responsible for the primary analysis of this study 
and treatment codes will be revealed to that party only. The re-evaluation of sample size will use 
the conditional power approach based on the test statistics from the interim analysis. A minimal 
fraction of alpha (.0001) will be spent at the interim analysis, as the trial will not be stopped early 
for efficacy or futility based on the results from the interim analysis. The final analysis will use 
alpha of 0.0249 for the primary endpoint, in order to preserve an overall type I error at the 
1-sided 0.025 level. 
Conditional power will be calculated based on the observed treatment effect and standard error at 
the interim analysis. Conditional power will be partitioned into three zones – favorable, 
promising, and unfavorable. 
x In the favorable zone, the interim analysis results are sufficiently favorable, and the 
conditional power is sufficiently high, so that the study can continue with the original 
sample size and an increase is not needed.  
x In the promising zone, the conditional power is moderately high and can be elevated by 
an increase of sample size to recover the targeted power 1-ȕ DW OHDVW   
x In the unfavorable zone, the conditional power is fairly low, and cannot achieve the 
targeted level with an increase in sample size. In this instance, the study would continue 
with the original planned sample size. 
The SAP will describe the planned interim analyses in greater detail. 
9.6.1. 
Data Safety Monitoring Committee (DSMC) 
The DSMC will consist of 3 voting members who are independent of the study team and 
Sponsor. At a minimum, the DSMC will meet prior to the first participant being enrolled, when 
the first 5 participants have been enrolled and have completed the Day 30 visit, when the first 
3 adolescent participants (aged 12-17 years) have been enrolled and have completed the 
Day 60 visit, and periodically thereafter, depending on enrollment.  
The DSMC reviewed safety data from 4 adolescent participants with at least 60 days of exposure 
in this study, as well as data from 3 adolescents with 60, 93, and 148 days of exposure in the 
open-label multi-dose study DCR-PHXC-301. Following completion of M&S of PK and PD data 
from these 7 adolescent participants, determination of the dose for 6- to 11 year-old children, and 
the aforementioned safety review, the DSMC affirmed that the overall risk-benefit balance 
remained positive and approved the enrollment of 6- to 11-year-old children. 
The DSMC will review unblinded safety and efficacy data and will make determinations on 
whether to continue the study following each periodic review of the data. At the DSMC’s 
discretion, they will be provided with participant-level unblinded data. 
Complete details regarding the constitution and responsibilities of the DSMC will be specified in 
the committee charter. 
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9.7. 
SUBGROUP ANALYSIS 
The same analysis for primary endpoint (i.e., AUC of 24-hour Uox from Day 90 to Day 180, 
based on percent change from baseline) will be performed on the subgroup of participants with at 
least one baseline 24-KRXU 8R[   PPRO (adjusted per 1.73 m2 BSA in participants aged 
< 18 years).  
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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
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: 
x Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines 
x Applicable ICH Good Clinical Practice (GCP) Guidelines 
x Applicable laws and regulations 
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.  
The Investigator will be responsible for the following: 
x 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 
x Notifying the IRB/IEC of SAEs or other significant safety findings, as required by 
IRB/IEC procedures 
x 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. 
10.1.3. 
Informed Consent Process 
The Investigator or his/her representative will explain the nature of the study to the participant or 
his/her legally authorized representative and answer all questions regarding the study.  
Participants must be informed that their participation is voluntary. 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 
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requirements of the IRB/IEC, 21 CFR 50, local regulations, ICH guidelines, and Health 
Insurance Portability and Accountability Act (HIPAA) requirements where applicable.  
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.  
A copy of the ICF(s) must be provided to the participant or the participant’s legally authorized 
representative.  
A participant who is rescreened is not required to sign another ICF if the rescreening occurs 
within (30) days from the previous ICF signature date. 
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 must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.  
The participant 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. 
10.1.5. 
Dissemination of Clinical Study Data 
After de-identification, all individual data collected during the trial will be shared with 
Investigators whose proposed use of the data has been approved by an independent review 
committee. See Section 10.1.9 for more details on the publishing of study information. 
Study results will be posted to the US National Institutes of Health’s website 
www.ClinicalTrials.gov.  
10.1.6. 
Data Quality Assurance 
All participant data relating to the study will be recorded on 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 CRF.  
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
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 
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monitoring techniques (central, remote, or on-site monitoring) are provided in the Monitoring 
Plan. 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF 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.  
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 (i.e., Contract 
Research Organizations). 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator for a minimum of 5 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 reported on the CRF or 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 previous medical records or transfer records, depending on the 
study. Also, current medical records must be available. 
10.1.8. 
Study and Site Closure 
The Sponsor reserves the right to terminate the study, or terminate an investigational site’s 
participation in the study, at any time. Should Sponsor or designee, and/or the Investigator 
discover conditions during the course of the study that indicate that it should be discontinued, an 
appropriate procedure for termination will be instituted. Reasons for study or site termination 
include the following: 
1. Investigator noncompliance with the protocol, Good Clinical Practice (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 DSMC 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. 
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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 Investigator’s Brochure (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 coordinator. 
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: 
x 
Not Related: Event for which sufficient evidence exists to conclude that the etiology is 
unrelated to study intervention. 
x 
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.  
x 
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.   
x 
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. 
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x Documented bilateral salpingectomy 
x 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 
x 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. 
x 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. 
10.4.2. 
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: 
x 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 
x 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 5, 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. 
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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 5. 
Table 5: 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependent a  
Failure rate of <1% per year when used consistently and correctly.  
x Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition 
of ovulation 
x 
Oral  
x 
Intravaginal  
x 
Transdermal  
x Progestogen-only hormonal contraception associated with inhibition of ovulation 
x 
Oral  
x 
Injectable  
Highly Effective Methods That Are User Independent a  
x Implantable progestogen-only hormonal contraception associated with inhibition of ovulation 
x 
Intrauterine device (IUD) 
x 
Intrauterine hormone-releasing system (IUS) 
x 
Bilateral tubal occlusion 
x 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.  
x 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.  
NOTES:  
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.  
 
10.4.3. 
Pregnancy Testing 
x 
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. 
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x 
Additional pregnancy testing should be performed at monthly intervals during the treatment 
period and as required locally. 
x 
Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected.  
x 
Pregnancy testing will be performed 2-3 weeks after administration of the last dose of study 
intervention in any WOCBP who prematurely discontinues the study. 
x 
Pregnancy testing with a sensitivity of at least 10 mIU/mL will be performed.  
10.4.4. 
Collection of Pregnancy Information 
Male participants with partners who become pregnant  
x 
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.  
x 
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  
x 
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.  
x 
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. 
x 
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 study intervention by the 
Investigator will be reported to the Sponsor as described in Section 10.3.5. 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.  
x 
Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention. 
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10.5. 
ABBREVIATIONS, ACRONYMS, INITIALISMS 
Term 
Description 
ADA 
antidrug antibody(ies) 
AE 
adverse event 
AESI 
AE of special interest 
AGXT 
the gene that encodes alanine:glyoxylate-aminotransferase 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
anti-dsDNA 
anti-double-stranded-DNA antibody(ies) 
aPTT 
activated partial thromboplastin time 
ASE 
American Society of Echocardiography 
ASGR 
asialoglycoprotein receptor 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BSA 
body surface area 
BUN 
blood urea nitrogen 
C 
Celsius 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CK 
creatine kinase (creatine phosphokinase) 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CL 
clearance 
Cmax 
maximum observed concentration 
Cmin 
minimum observed concentration 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
case report form 
CRO 
contract research organization 
CTCAE 
Common Terminology Criteria 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 
DSMC 
Data Safety Monitoring Committee 
ECG 
electrocardiogram 
e.g. 
for example (exempli gratia) 
EGF 
epidermal growth factor 
eGFR 
estimated GFR 
EOS 
end of study 
ESRD 
end-stage renal disease 
FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone 
g 
gram(s)  
GalNAc 
N-acetyl-D-galactosamine 
GCP 
Good Clinical Practice 
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Term 
Description 
GFR 
glomerular filtration rate 
GGT 
gamma glutamyl transferase 
GLDH 
glutamate dehydrogenase 
GRHPR 
glyoxylate reductase/hydroxypyruvate reductase 
hr 
hour(s) 
HBsAg 
hepatitis B surface antigen 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HRQoL 
health-related QoL 
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 
i.e. 
that is (id est) 
IEC 
Independent Ethics Committee 
IFN-Į 
interferon alpha 
IFN-Ȗ 
interferon gamma 
IL-1 Į 
interleukin 1 alpha 
IL-ȕ 
interleukin 1 beta 
IL-2 
interleukin 2 
IL-4 
interleukin 4 
IL-6 
interleukin 6 
IL-8 
interleukin 8 
IL-10 
interleukin 10 
IMP 
Investigational Medicinal Product  
IND 
Investigational New Drug 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ISR 
injection site reaction 
ITT 
intent to treat 
IUD 
intra-uterine device 
IUS 
intrauterine hormone-releasing system 
IWRS 
interactive web-response system 
kg 
kilogram(s) 
LDH 
lactate dehydrogenase 
LDHA 
lactate dehydrogenase type A 
LFT 
liver function test 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCP-1 
monocyte chemoattractant protein 1 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
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Term 
Description 
mg 
milligram(s) 
min 
minute(s) 
MITT 
modified ITT 
mL 
milliliter(s) 
MOS 
Medical Outcomes Study 
MPV 
mean platelet volume 
mRNA 
messenger ribonucleic acid 
M&S 
modeling and simulation 
NOAEL 
no-observed-adverse-effect level  
NMD-PH 
no mutation detected PH 
pcVPC 
prediction-corrected visual predictive check 
PD 
pharmacodynamic(s) 
PedsQL 
Pediatric Quality of Life Inventory 
PH 
primary hyperoxaluria(s) 
PH1 
primary hyperoxaluria type 1 
PH2 
primary hyperoxaluria type 2 
PH3 
primary hyperoxaluria type 3 
PK 
pharmacokinetic(s) 
PP 
per protocol 
PT 
prothrombin time 
QoL 
quality of life 
RNA 
ribonucleic acid 
RNAi 
RNA interference 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous 
SF-36 
Short Form 36 Health Survey 
siRNA 
small interfering RNA 
SoA 
schedule of activities 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2 
terminal elimination half-life 
Tmax 
time to maximum observed concentration 
TNF-Į 
tumor necrosis factor alpha 
ULN 
upper limit of normal 
Uox 
urinary oxalate excretion 
V 
volume of distribution 
VAS 
visual analog scale 
VEGF 
vascular endothelial growth factor 
WFI 
water for injection 
WOCBP 
woman(en) of childbearing potential 
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10.6. 
INVESTIGATOR SIGNATURE PAGE 
 
 
A Phase 2 Placebo-Controlled, Double-Blind, Multicenter Study to Evaluate the Efficacy, 
Safety, and Tolerability of DCR-PHXC Solution for Injection (subcutaneous use) in 
Patients with Primary Hyperoxaluria 
Protocol Number: DCR-PHXC-201 
Version: 5.0 US 
Date: 13-Aug-2020 
 
 
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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10.7. 
PROTOCOL AMENDMENT HISTORY 
Amendment 3 (version 5.0 US), 13-Aug-2020 
The 12 March 2020 version of the protocol was updated to include the dose of DCR-PHXC to be 
administered in children aged 6-to-11 years. An appendix detailing measures to be undertaken 
during the COVID-19 pandemic was added. A tabular summary of changes is detailed in the 
table that follows. 
Description of Change 
Brief Rationale 
Affected Sections 
Added the dose to be 
administered in 6- to 11-year-
old participants 
Updated language related to 
reflect that the DSMC has 
affirmed the overall risk benefit 
balance for children aged 6- to 
11-years based on updated 
M&S data and agreed to the 
enrollment of these patients 
Dose newly determined via 
modeling and simulation 
1.1.1 
Overall Design 
1.1.6 
Description of Study 
Intervention 
1.3 
Schedule of Activities 
4.3.2 
PK/PD Model for Dose 
Selection in Children Younger than 
12 Years of Age 
6.1.2 
Dosing and Administration 
9.6.1 
Data Safety Monitoring 
Committee 
Expanded the window for 
repeat of 24-hour urine samples 
that violate completeness 
criteria 
To provide additional 
flexibility for participants and 
sites 
1.3 
Schedule of Activities 
8.1.1.1 
Collection of 24-hour Urine 
Samples 
8.1.1.1.1 Completeness Criteria for 
24-hour Urine Sample 
Updated text requiring that at 
least 12 of the first 24 
participants have at least one 
24-hour Uox screening value 
> 1.6 mmol 
To clarify that the 12 “high 
baseline” participants need not 
be among the first 
24 participants enrolled 
1.1.4 
Study Population 
5.1 
Inclusion Criteria 
8.1.1 
24-Hour Urinary Oxalate 
Updated the Schwartz 2009 
eGFR equation 
To reflect that serum 
creatinine, rather than plasma 
creatinine will be utilized in 
calculation of eGFR 
8.2.4.1 Estimated Glomerular Filtration 
Rate (eGFR) 
Increased the maximum total 
blood volume to be withdrawn 
from pediatric participants by 
3 mL 
Change in laboratory testing 
vendor 
2.3.4 
Risk Management 
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Description of Change 
Brief Rationale 
Affected Sections 
Removed text restricting 
chronic use of 
acetaminophen/paracetamol 
As chronic nonclinical toxicity 
studies have shown no adverse 
effects in the liver, this 
restriction is no longer 
required. Stopping rules for 
possible drug-induced liver 
injury remain in place for the 
safety of participants. 
5.2 
Exclusion Criteria 
6.5 
Concomitant Therapy 
Added Appendix A to describe 
changes to the study conduct 
that can be employed during the 
COVID-19 pandemic 
To limit participant exposure to 
the SARS-CoV-2 virus 
Appendix A (newly added) 
Updated Sponsor contacts and 
titles 
Changes in Sponsor personnel 
Sponsor Signature Page 
Medical Monitor and 
Pharmacovigilance Contact Information 
 
 
Amendment 2 (version 4.0 US), 12-Mar-2020 
The 30 April 2019 version of the protocol was updated to incorporate revisions requested by 
regulators and IECs/IRBs and other operational changes. Principal changes include updates in 
the equations used to calculate eGFR, a change in the dose of DCR-PHXC to be administered in 
adults weighing less than 50 kg, changed laboratory testing requirements to limit blood loss in 
children, added additional immunogenicity testing, updated instructions for monitoring of liver 
injury, clarified the performance of an interim analysis, and specified that metabolites of 
DCR-PHXC will be included in pharmacokinetic analyses. A summary of changes is detailed in 
the table that follows. 
 
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Description of Change 
Brief Rationale 
Affected Sections 
Updated equations for calculation of eGFR  
 
 
1. Changed the Schwartz 2009 equation to the 
Schwartz 2012 equation 
 
 
2. Required that the eGFR equation used at baseline 
be used throughout the study for adolescents who 
turn 18 during the study 
3. Added collection of cystatin C in pediatric 
participants 
4. Added measurement of height at each visit at 
which eGFR is calculated in pediatric participants 
1. The multivariate 2012 eGFR 
equation is considered to be more 
accurate than the univariate 2009 
equation 
2. To ensure that change over time is 
made with reference to the same 
baseline equation 
3. Cystatin C is required for calculation 
of eGFR in new equation 
4. Height is required for calculation of 
eGFR in new equation 
1.1.4 
Study Population 
1.3 
Schedule of Activities 
5.1 
Inclusion Criteria 
8.2.1 
Weight, Height and Body Surface Area 
8.2.4.1 Estimated Glomerular Filtration Rate 
(eGFR) 
9.5.2 
Safety Analyses 
10.2 
Clinical Laboratory Tests 
11 
References 
Changed the dose for adults weighing < 50 kg from 
170 mg to 136 mg 
Increased participant safety. The 136 mg 
dose was previously only specified for 
adolescents weighing < 50 kg. 
1.1.6 
Description of Study Intervention 
4.3.1 
PK/PD Model for Dose Selection in 
Adults and Adolescents 
6.1.2 
Dosing and Administration 
 
Updated the statistical calculation of 24-hour Uox AUC 
To remove time-weighted 
standardization and use multiple 
imputation instead. 
1.1.1 
Overall Design 
1.1.3 
Objectives and Endpoints 
3 
Objectives and Endpoints 
4.2 
Scientific Rationale for Study Design 
9.5.1 
Efficacy Analyses 
10.5 
Abbreviations 
Added duration-of-collection-time criteria for 
assessment of 24-hour urine collection completeness 
To ensure quality of urine collections 
8.1.1.1.1 Completeness Criteria for 24-hour 
Urine Sample 
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Description of Change 
Brief Rationale 
Affected Sections 
Updated results of ongoing DCR-PHXC studies 
To provide more up-to-date information 
2.2.3 
Clinical Overview 
Revised language around reporting of pregnancy and 
pregnancy testing in WOCBP 
1. Added pregnancy testing in women of childbearing 
potential to the screening visit in the Schedule of 
Activities  
2. Clarified that urine pregnancy testing may be 
performed locally 
3. Corrected timing of reporting of participant 
pregnancy from 2 weeks to 12 weeks after last dose 
of study intervention 
 
 
1. Correction of omission 
 
 
2. Additional clarification 
 
3. Correction of error 
1.3 
Schedule of Activities 
8.3.5 
Reporting of Pregnancy 
10.2 
Clinical Laboratory Tests 
Added anti-dsDNA antibody testing  
Increased participant safety. To clarify 
the potential for immunogenicity, as 
endogenous anti-nuclear antibodies are 
believed to recognize oligonucleotides 
40- to 50-base pairs in length.  
1.3 
Schedule of Activities 
2.3.1.1 Risks Related to the siRNA Molecule 
8.8.1 
Immunogenicity Assessments 
10.2 
Clinical Laboratory Tests 
10.6 
Abbreviation, Acronyms, Initialisms 
Deleted cytokine and complement testing, viral serology 
screening, and testing of vitamin B6 blood levels in 
participants less than 18 years of age 
To minimize blood loss volumes in 
children 
1.3 
Schedule of Activities 
2.3.4 
Risk Management 
5.2 
Exclusion Criteria 
10.2 
Clinical Laboratory Tests 
Updated instructions for the monitoring of participants 
with suspected drug-induced liver injury 
Increased participant safety. 
7.1.1 
Drug-Induced Liver Injury Monitoring 
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Description of Change 
Brief Rationale 
Affected Sections 
Added language to require that age-appropriate normal 
values will be used when evaluating pediatric 
participants 
Increased participant safety. 
8.2.3 
Vital Signs 
8.2.4 
Clinical Laboratory Assessments 
Clarified time windows for assessments: 
1. Added window for collection of samples for 
cytokine and complement testing 
2. Clarified window for performance of ECG and 
vital signs measurements 
 
1. To align with collection of blood 
samples for PK analysis 
2. Additional clarity 
1.3 
Schedule of Activities 
Updated specifications for physical examinations 
1. Removed calculation of body mass index 
 
2. Updated timing of when height should be measured 
and recorded 
 
1. Body mass index was not used for 
any study assessments 
2. To ensure that height was recorded 
when needed for calculation of 
eGFR 
1.3 
Schedule of Activities 
8.2.1 
Weight, Height and Body Surface Area 
Updated language around drug screen testing to 
indicate that investigator discretion is allowed 
Participants may be treated with 
prescribed analgesics for pain 
management 
1.3 
Schedule of Activities 
5.2 
Exclusion Criteria 
Added urinary phosphate and urinary magnesium to 
the list of parameters to be determined from 24-hour 
urine samples 
Correction of previous omission. 
8.1.3 
Other Parameters Determined from 
24-Hour Urine Collections 
10.2 
Clinical Laboratory Tests 
Removed estradiol testing for confirmation of post-
menopausal status 
Testing not required 
10.2 
Clinical Laboratory Tests 
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Description of Change 
Brief Rationale 
Affected Sections 
Added that participants are not eligible to roll over to 
Study DCR-PHXC-301 until all assessments in the 
current study are completed, including 24-hour Uox 
To ensure that the final 24-hour urine 
sample meets completeness criteria 
6.7 
Intervention After the End of the Study 
Added language to the definition of injection site 
reactions 
To clarify that events with a time to onset 
of less than 4 hours are not considered 
ISRs 
10.3.3 Definition of Adverse Event of Special 
Interest 
Deleted the criterion relating to progression of disease 
in the list of events not considered AEs 
To eliminate confusion surrounding how 
to classify PH-related signs and 
symptoms 
10.3.1 Definition of Adverse Event(s) 
Noted that kidney ultrasound and echocardiogram re-
testing is not required for rescreening if results of a 
prior screening had been sent to central over-readers 
within the past 3 months. 
To decrease burden on the participant, as 
substantial change would not be expected 
in a 3-month period. 
1.3 
Schedule of Activities 
Specified that site personnel will be trained in 
procedures surrounding performance of kidney 
ultrasound, ECG, and echocardiogram 
To ensure consistency across all sites. 
8.1.6.2. Kidney Ultrasound 
8.2.5 
12-Lead ECG 
8.2.6 
Echocardiogram 
Clarified that the DSMC may review “unblinded” 
rather than “partially unblinded” safety and efficacy 
data 
Increased participant safety 
2.3.4 
Risk Mitigation 
9.6.1 
Data Safety Monitoring Committee 
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Description of Change 
Brief Rationale 
Affected Sections 
Updated language relating to performance of interim 
analysis 
To clarify that an interim analysis “may” 
be performed, rather than “will” be. 
To describe the zones for which a 
sample size adjustment would be made.  
Updated alpha spending related to the 
interim analysis 
1.1.1 
Overall Design 
4.1 
Overall Design 
9.6 
Interim Analysis 
Added language to state that a participant will be 
assigned to the treatment that results in the lowest 
amount of imbalance with an 80% probability, and the 
treatment which results in the highest amount of 
imbalance with a 20% probability 
To clarify randomization procedures 
with respect to imbalance 
9.3 
Randomization Method 
Added language to indicate that additional participants 
may be enrolled if participants discontinue prior to 
Day 90  
To ensure that there is an adequate 
number of participants for analysis of 
the primary endpoint 
7.2. 
Participant Discontinuation/Withdrawal 
from the Study 
Added that calculation of PK parameters will also be 
performed for metabolites of DCR-PHXC 
For more complete characterization of 
pharmacokinetics 
1.3 
Schedule of Activities 
8.5.1 
Plasma Pharmacokinetics 
Corrected inconsistencies between the 2 tables of 
Objectives and Endpoints 
Correction 
1.1.3 
Objectives and Endpoints 
3 
Objectives and Endpoints 
Updated Sponsor information 
To update the corporate address, add the 
Sponsor Medical monitor email address 
and update the Title for the Executive 
Director of Regulatory Affairs 
Cover page 
Sponsor Signature page 
Medical Monitor and Pharmacovigilance Contact 
Information 
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Amendment 1 (version 3.0 US), 30-Apr-2019 
The 16 November 2018 version of the protocol was updated to include feedback from regulatory 
authorities, including the United States Food and Drug Administration (FDA). Version 3.0 
represents the initial filing of Study DCR-PHXC-201 to the FDA. 
Administrative Update (version 2.0), 16-Nov-2018 
The 24 October 2018 version of the protocol was updated to include the dose selected for 
adolescent participants aged 12 to 17. Additional detail was added to standardize the definition 
of kidney stone-related events and to describe how stone burden will be determined. Other 
administrative updates were also included. The 24 October 2018 version was not submitted to 
any Investigator, Ethics Committee, or Regulatory Authority for review, approval, or initiation. 
 
 
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11. 
REFERENCES 
Boyce AM, Shawker TH, Hill SC, Choyke PL, Hill MC, James R, et al. Ultrasound is superior to 
computed tomography for assessment of medullary nephrocalcinosis in hypoparathyroidism. 
J Clin Endocrinol Metab. 2013;98(3):989-94. 
Clifford-Mobley O, Sjögren A, Lindner E, Rumsby G. Urine oxalate biological variation in 
patients with primary hyperoxaluria. Urolithiasis. 2016;44(4):333-7. 
Cochat P, Hulton SA, Acquaviva C, Danpure CJ, Daudon M, De Marchi M, et al. Primary 
hyperoxaluria Type 1: indications for screening and guidance for diagnosis and treatment. Nephrol 
Dial Transplant. 2012 27: 1729–36. 
Cochat P, Rumsby G. Primary hyperoxaluria. N Engl J Med. 2013 Aug 15;369(7):649-58. 
Council for International Organizations of Medical Sciences. Management of Safety Information 
from Clinical Trials Report of CIOMS Working Group VI. October 2005. Available from 
https://cioms.ch/wp-content/uploads/2017/01/Mgment_Safety_Info.pdf. Accessed 17 October 
2018. 
DuBois D, DuBois EF. A formula to estimate the approximate surface area if height and weight 
be known. Arch Intern Medicine. 1916; 17:863-71. 
D’Souza A, Devarajan PV. Asialoglycoprotein receptor mediated hepatocyte targeting – Strategies 
and applications. J Controlled Release. 2015;203:126-139. 
Galanti M, Contreras A. Excellent renal function and reversal of nephrocalcinosis 8 years after 
isolated liver transplantation in an infant with primary hyperoxaluria type 1. Pediatr Nephrol 
2010;25:2359-62. 
Herdman M, Gudex C, Lloyd A, Janssen MF, Kind P, Parkin D, et al. Development and 
preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Quality Life Res. 2011 
Dec 1;20(10):1727-36. 
Hoppe B. An update on primary hyperoxaluria. Nat Rev Nephrol. 2012 Aug;8(8):467. 
Hoppe B, Beck BB, Milliner DS. The primary hyperoxalurias. Kidney Int. 2009; 75(12):1264–71. 
Hoyer-Kuhn H, Kohbrok S, Volland R, Franklin J, Hero B, Beck B, et al. Vitamin B6 in primary 
hyperoxaluria I; first prospective trial after 40 years of practice. Clin J Am Soc Nephrol 2014;9 
(3), 468-77. 
Kanno T, Maekawa M. Lactate dehydrogenase M-subunit deficiencies: clinical features, metabolic 
background, and genetic heterogeneities. Muscle Nerve Suppl. 1995;3:S54-60.  
Kemper MJ, Nolkemper D, Rogiers X, Timmermann K, Sturm E, Malago M, et al. Preemptive 
liver transplantation in primary hyperoxaluria type 1: timing and preliminary results. J Nephrol 
1998;11 S1:46-8. 
Latta K, Brodehl J. Primary hyperoxaluria type I. Eur J Pediatr, 1990;149(8):518-22. 
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Lee BJ, Zand L, Manek NJ, Hsiao LL, Babovic-Vuksanovic D, Wylam ME, Qian Q. Physical 
therapy-induced rhabdomyolysis and acute kidney injury associated with reduced activity of 
muscle lactate dehydrogenase A. Arthritis Care Res (Hoboken) 2011;63:1782-6.  
Levey AS, Stevens LA. Estimating GFR using the CKD Epidemiology Collaboration (CKD-EPI) 
creatinine equation: more accurate GFR estimates, lower CKD prevalence estimates, and better 
risk predictions. Am J Kidney Dis. 2010;55(4):622-7. 
Maekawa M, Kanno T. Laboratory and clinical features of lactate dehydrogenase subunit 
deficiencies. Clin Chim Acta 1989;15:299-308. 
Miyajima H, Takahashi Y, Suzuki M, Shimizu T, Kaneko E. Molecular characterization of gene 
expression in human lactate dehydrogenase-A deficiency. Neurology. 1993;43:1414-1419. 
Nolkemper D, Kemper MJ, Burdelski M, Vaismann I, Rogiers X, Broelsch CE, et al. Long-term 
results of pre-emptive liver transplantation in primary hyperoxaluria type 1. Pediatr 
Transplantation 2000: 4: 177-81. 
Perera MTPR, Sharif K, Lloyd C, Foster K, Hulton SA, Mirza DF, McKiernan PJ. Pre-emptive 
liver transplantation for primary hyperoxaluria (PH-I) arrests long-term renal function 
deterioration. Nephrol Dial Transplant 2011;26:354-9. 
Picard MH, Adams D, Bierig SM, Dent JM, Douglas PS, Gillam LD, et al. American Society of 
Echocardiography recommendations for quality echocardiography laboratory operations. J Am 
Soc Echocardiogr. 2011 Jan 1;24(1):1-10. 
Pocock SJ, Simon R. Sequential treatment assignment with balancing for prognostic factors in 
the controlled clinical trial. Biometrics. 1975;31:103-15. 
Rogers J, Bueno J, Shapiro R, Scantlebury V, Mazariegos G, Fung J, Reyes J. Results of 
simultaneous and sequential pediatric liver and kidney transplantation. Transplantation. 2001 Nov 
27;72(10):1666-70. 
Salido E, Pey A, Rodriguez R, Lorenzo V. Primary hyperoxalurias: disorders of glyoxylate 
detoxification. Biochim Biophys Acta 2012;1822, 1453-64. 
Schwartz GJ, Munoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, Furth SL. New equations 
to estimate GFR in children with CKD. J Am Soc Nephrol. 2009 Mar 1;20(3):629-37. 
Schwartz GJ, Schneider MF, Maier PS, Moxey-Mims M, Dharnidharka VR, Warady BA, et al. 
Improved equations estimating GFR in children with chronic kidney disease using an 
immunonephelometric determination of cystatin C. Kidney Int. 2012 Aug 2;82(4):445-53. 
Sudo K, Maekawa M, Kanno T, Li SS, Akizuki S, Magara T. Premature termination mutations in 
two patients with deficiency of lactate dehydrogenase H(B) subunit. Clin Chem. 1994; 40:1567-
70.  
Taves DR. Minimization: A new method of assigning patients to treatment and control groups. 
Clin Pharmacol Ther. 1974;15:443-53. 
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Varni JW, Seid M, Kurtin PS. PedsQL™ 4.0: Reliability and validity of the Pediatric Quality of 
Life Inventory™ Version 4.0 Generic Core Scales in healthy and patient populations. Medical 
Care. 2001 Aug 1:800-12. 
Varni JW, Seid M, Rode CA. The PedsQL: Measurement model for the Pediatric Quality of Life 
Inventory. Medical Care. 1998:37, 126-39 
Varni JW, Sherman SA, Burwinkle TM, Dickinson PE, Dixon P. The PedsQL™ family impact 
module: preliminary reliability and validity. Health Qual Life Outcomes. 2004 Dec;2(1):55. 
Ware Jr JE, Sherbourne CD. The MOS 36-item short-form health survey (SF-36): I. Conceptual 
framework and item selection. Medical Care. 1992 Jun 1:473-83. 
Williams HE, Smith LH. Disorders of oxalate metabolism. Am J Med. 1968;45(5):715-35. 
Zhao F, Bergstralh EJ, Mehta RA, Vaughan LE, Olson JB, Seide BM, et al. Predictors of 
incident ESRD among patients with primary hyperoxaluria presenting prior to kidney failure. 
Clin J Am Soc Nephrol; 2016: 11(1):119-26. 
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APPENDIX A: 
COVID-19 EMERGENCY RESPONSE MEASURES 
A.1. 
BACKGROUND 
There is currently an outbreak of respiratory disease caused by a novel coronavirus 
(“SARS-CoV-2”) that was first detected in Wuhan City, Hubei Province, China, and that has 
now been detected in many locations internationally, including cases in the United States. The 
disease caused by the SARS-CoV-2 virus has been named “Coronavirus Disease 2019,” or, 
simply, “COVID-19.” 
In response to the COVID-19 pandemic, the Food and Drug Administration (FDA) and European 
Medicines Agency (EMA) issued guidance to provide general considerations to assist Sponsors 
in assuring the safety of trial participants, maintaining compliance with good clinical practice 
(GCP), and minimizing risks to clinical trial integrity (FDA, 2020). 
In these guidances, FDA and EMA acknowledge that the pandemic may result in challenges that 
could lead to difficulties in meeting protocol-specified procedures, including administering or 
using the investigational product or adhering to protocol-mandated visits and 
laboratory/diagnostic testing. The Agencies recognize that “changes to the protocol or 
investigational plan to minimize or eliminate immediate hazards or to protect the life and well-
being of research participants (e.g., to limit exposure to COVID-19) may be implemented 
without IRB approval or before filing an amendment to the IND or IDE, but are required to be 
reported afterwards” (FDA, 2020) and “Extraordinary measures may need to be implemented 
and trials adjusted due to e.g. trial participants being in self-isolation/quarantine, limited access 
to public places (including hospitals) due to the risk of spreading infections, and health care 
professionals being committed to critical tasks” (EMA, 2020). 
Based upon this information, Dicerna proposes that the recommendations detailed below be 
made with respect to Study DCR-PHXC-201, for as long as the COVID-19 health emergency 
continues. Once the local site determines that participants are no longer at elevated risk, the site 
may return to following the currently approved version of the protocol. 
A.2. 
SUMMARY OF RECOMMENDATIONS PROPOSED FOR STUDY 
DCR-PHXC-201 
A.2.1. 
Adjustments to Study Visits 
1) Duration of the Screening Period 
a) The screening period will be extended from 35 to 60 days to allow flexibility to 
obtain all completed assessments. 
b) All screening assessments must be performed at the clinical site. 
2) Study Visits for Days 1, 30, and 60 
a) Because participants entering the Study are naïve to DCR-PHXC, administration of 
blinded study intervention at the first 3 visits (Days 1, 30, and 60) must occur at the 
clinical site, along with all protocol-specified safety assessments. 
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b) Should the site encounter difficulty with the duration or frequency of blood sampling 
for PK at Days 1 or 30: 
i) the schedule in adults may be abbreviated to include only the predose and 4-hour 
samples; with the samples scheduled at 5, 15, and 30 minutes and 1, 2, 6, 10, and 
12 hours postdose being omitted; 
ii) the schedule in children aged 6 to 17 may be abbreviated to include only predose 
and 4 hours postdose; with the samples scheduled at 30 minutes and at 2 and 
10 hours postdose being omitted. 
3) Study Visits for Days 2 and 31 
a) At-clinic site visits are not required for Visits at Days 2 and 31. A combination of 
telemedicine and home nursing care will allow participants to undergo “virtual” 
visits. 
b) The Investigator (or designee) is expected to call the participant on these visit days to 
assess the participant’s overall health status and to record any AE or SAEs. 
c) The 24-hour postdose blood sample for PK analysis should be collected as scheduled 
SDUWLFLSDQWV   \HDUV RI DJH. 
4) Study Visits for Days 15, 45, 90, 120, and 150 
a) At-clinic site visits are not required for Visits at Day 15, 45, 90, 120, and 150. A 
combination of telemedicine and home nursing care will allow participants to 
undergo “virtual” visits. 
b) Dicerna is working with the Illingworth Nursing Group to extend their 
responsibilities for collection and processing of safety labs and vital signs, as well as 
for administration of double-blind study intervention.  
c) On Days 90, 120, and 150, the home nurse will call the Investigator the day before 
the scheduled home visit to obtain permission to administer study intervention to the 
participant. The nurse will follow-up with the Investigator again on the day after the 
home visit.  
d) The Investigator (or designee) is expected to call the participant on these visit days to 
assess the participant’s overall health status and to record any AE or SAEs. 
e) The specific responsibilities of the home nurses and the execution of the virtual visits 
will be outlined in an at-home nursing visit guidance.  
5) Study Visits for Day 180 
a) The Day 180 Visit (with End-of-Study assessments) must occur at the clinical site 
due to the required imaging procedures. 
A.3. 
24-HOUR URINE COLLECTIONS 
As urinary oxalate (Uox), determined from 24-hour urine collections, is the primary endpoint of 
the study, participants are encouraged to continue collecting 24-hour urines as planned. 
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The window for repeat collection of 24-hour urine samples that violate completeness criteria will 
be extended from 10 days to 14 days due to issues with courier availability and shipping issues 
across borders. 
A.4. 
SAFETY LABORATORY TESTING 
Hematology and serum chemistry are the essential laboratory tests for the evaluation of safety.  
1) For both at-home and in-clinic visits, should delays or difficulties arise with the use of the 
central laboratory, a local laboratory may be utilized to monitor participant safety.  
a. Should the use of a local laboratory be required, the collection of samples for the 
testing of coagulation parameters, cytokines, and complement may be omitted. 
A.5. 
PROTOCOL DEVIATIONS 
Dicerna recognizes that there may be minor protocol deviations for visits and assessments that 
fall outside of the protocol-specified windows. These should be continued to be documented as 
minor deviations. 
A.6. 
INFORMED CONSENT 
All participants who will undergo virtual site visits must provide their consent to the change in 
their participation. If provision of in-person written consent is not possible, consent may be 
provided to the Investigator (or designee) orally, over the telephone. This consent must be 
documented by the Investigator. 
A.7. 
SPONSOR RISK ASSESSMENT 
Primary Hyperoxaluria Types 1 and 2 are both serious and life-threatening diseases which 
ultimately may lead to kidney or combined kidney-liver transplantation. There are no approved 
therapies available and current supportive therapy consists of hyperhydration and alkalization of 
urine.  
In Study DCR-PHXC-101, a single dose of 3 mg/kg DCR-PHXC (also called nedosiran), was 
shown to substantially lower Uox (mean 67%, range 42-80%) in participants with PH1 or PH2. 
As the magnitude of Uox levels has been shown to correlate with the risk of developing renal 
complications (Zhao et al., 2016), a lowering of Uox might potentially be of clinical benefit for 
patients with PH1 or PH2.  
Participants in Study DCR-PHXC-201 are randomized 2 to 1 to DCR-PHXC or placebo. 
Participants in the DCR-PHXC arm might have a potential for direct benefit by remaining in the 
study, based on the possibility that DCR-PHXC may lower Uox concentrations. Participants in 
the placebo arm will derive no direct benefit in this study, but they will have the opportunity to 
roll-over into an open-label study with DCR-PHXC at the end of the study (Day 180).  
Measures taken by the Sponsor in response to the COVID-19 emergency mainly consist of 
switching certain site visits to at-home visits conducted by an authorized local nurse. The 
Principal Investigator will call participants to assess their general health status and to conduct 
SAE/AE reporting with the participant. This measure is implemented as certain clinical sites are 
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no longer able to conduct site visits and/or some participants are no longer able to visit a site due 
to local travel restriction. 
Participants remaining in the clinical study could potentially receive clinical benefits either 
during the study or after the study is completed by enrolling into an open-label study. Switching 
from site visits to a combination of at-home nurse visits and telehealth assessments by the 
Investigator or designee only minimally increases the risk associated with study participation for 
study participants but does decrease their risk of acquiring COVID-19 infection by not needing 
to travel to study sites if they are open. Therefore, the overall risk/benefit for a study participant 
in study DCR-PHXC-201 with these additional COVID-19 emergency measures remains 
unchanged. 
A.8. 
REFERENCES 
European Medicines Agency. Guidance on the Management of Clinical Trials during the 
COVID-19 (Coronavirus) pandemic. Updated 27 March 2020. Accessed 27 March 2020. 
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/guidanceclinicaltrials
_covid19_en.pdf 
U.S. Department of Health and Human Services, Food and Drug Administration. FDA Guidance 
on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic; Guidance for 
Industry, Investigators, and Institutional Review Boards. March 2020. Accessed 27 March 2020. 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/fda-guidance-
conduct-clinical-trials-medical-products-during-covid-19-pandemic. 
Zhao F, Bergstralh EJ, Mehta RA, Vaughan LE, Olson JB, Seide BM, et al. Predictors of 
incident ESRD among patients with primary hyperoxaluria presenting prior to kidney failure. 
Clin J Am Soc Nephrol; 2016: 11(1):119-26. 
A.9. 
UPDATED SCHEDULE OF ACTIVITIES 
A copy of the Schedule of Activities that highlights the visits that can be performed virtually and 
the changes in the PK sampling schedule is attached as Table A1. 
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c. 
Informed consent (and assent if applicable) may be given outside of the 60-day screening period, i.e., provision of consent does not start the clock for the screening period. In 
no case should more than 2 weeks elapse between the provision of consent and initiation of the first screening procedure/assessment. Initiation of the first screening 
procedure will start the 60-day window. 
d. 
Participant eligibility (with the exception of clinical laboratory testing) will be re-confirmed prior to administration of study intervention on Day 1. 
e. 
Record 5 years of general medical history. PH history to include 12-month history of stone events, as described in Section 8.1.6.1. 
f. 
To include vitamin B6 (pyridoxine). 
g. 
Participants without documented genotyping must provide a DNA sample for testing. 
h. 
Urine drug screen to include at minimum: amphetamines, barbiturates, cocaine, opiates, and benzodiazepines. Drug screening is not required for individuals aged 12 or 
younger. Investigator discretion in excluding participants with a positive test is allowed. 
i. 
HIV 1and 2 antibodies, hepatitis B surface antigen (HBsAg), and hepatitis C virus antibody. If tested in the past 3 months, medical record documentation of this testing may 
be used. Viral serology is not required in participants < 18 years of age. 
j. 
A sample of urine from the void immediately prior to the initiation of each 24-hour urine collection will be collected and stored apart from the 24-hour urine collection. 
Should the two 24-hour screening collections occur on consecutive days, no spot urine sample will be collected on the second day. 
k. 
Two screening samples should ideally be collected on 2 consecutive days, but with no more than 8 days between collections. Collection of on-treatment samples must  be 
performed within the 7 days prior to the scheduled study visit. It is desired that the elapsed time between monthly collections should be at least 3 weeks and not more than 
5 weeks. Participants should avoid taking vitamin C supplements (including multivitamins) for 24 hours prior to and during the collection of 24-hour urine samples.  See 
Section 8.1.1.1.  
l. 
Urinary creatinine excretion will be determined from 24-hour urine samples in order to assess the quality of the 24-hour collection. Any postdose sample that violates the 
urine quality review criteria should be repeated within 14 days of the scheduled study visit whenever possible. See Section 8.1.1.1.1 for details. 
m. Samples for vitamin B6 levels will only be collected in participants DJHG   \HDUV ZKR DUH taking vitamin B6 supplements. 
n. 
Plasma sampling times for PK analysis (see Section 8.5.1): 
x $JHG   \HDUV  
o 
Days 1 and 30: predose and at 4 hours postdose 5, 15, and 30 minutes and 1, 2, 6, 10, and 12 hours postdose (shaded timepoints may be omitted if necessary) 
o 
Days 2 and 31: 24 hours postdose (may be collected by home nurse) 
o 
Day 150: predose and at 4 hours postdose 2, 6, and 12 postdose (shaded timepoints may be omitted if necessary) 
x Aged 6–17 years:  
o 
Days 1 and 30: predose and at 4 hours postdose 30 minutes and 2 and 10 hours postdose (shaded timepoints may be omitted if necessary) 
o 
Days 2 and 31: 24 hours postdose (may be collected by home nurse) 
o 
Day 150: predose and at 4 hours postdose 2 and 10 hours postdose (shaded timepoints may be omitted if necessary) 
A single plasma sample should be collected at the final visit from participants who discontinued study intervention or were withdrawn from the study. 
Windows for the collection of PK samples are as follows: 
o 
Predose to be collected within 30 minutes before administration of study intervention   
o 
5, 15, and 30 minutes and 1 hour postdose, ± 3-minute window is allowed 
o 
2, 4, 6, 10, and 12 hours postdose, ± 30-minute window is allowed 
o 
24 hours postdose, ± 1-hour window is allowed 
o. 
In adults, blood samples for plasma oxalate analysis to be collected prior to dosing (Section 8.1.5). Participants aged 6 to 17 years will have plasma oxalate sampling only at 
Screening. 
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Dicerna Protocol DCR-PHXC-201 
Version 5.0 US, 13-Aug-2020 
 
Page 97 
p. 
Participants should maintain consistent fluid intake (i.e., hyperhydration) over the course of the study (Section 5.3). Participants will report average daily fluid intake over the 
4 to 7 days prior to each 24-hour urine collection (Section 8.2.7). 
q. 
On Days 1 and 30, ECG to be performed predose and at 10 hours (± 30 minutes) postdose. A single ECG to be performed at other visits, as indicated (Section 8.2.5). 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. 
r. 
Vital signs on Day 1 and Day 30 to be assessed predose and at 10 hours (± 30 minutes) postdose (Section 8.2.3). 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. 
s. 
A full physical exam will be performed at Screening and Day 180 (or ET). A brief physical examination may be performed at other scheduled visits (Day 1 through Day 150) 
or unscheduled visits at the Investigator’s discretion. See Sections 8.2.1 and 8.2.2. 
t. 
IQ SDUWLFLSDQWV   \HDUV RI DJH KHLJKW WR EH UHFRUGHG RQO\ DW VFUHHQLQJ ,n participants < 18 years of age, height will be recorded at specified visits for calculation of eGFR 
and BSA adjustment of Uox excretion. Weight to be recorded in all participants at specified visits. In participants aged 6-to-11 years, the weight on Day 1 will be used to 
calculate the mg/kg dose of study intervention. 
u. 
Blood samples for hematology and serum chemistry to be collected predose on dosing days. To include cystatin C in participants < 18 years of age for calculation of eGFR. 
See Section 10.2 for the list of parameters.  
v. 
Blood samples for coagulation studies to be collected predose. Coagulation panel will include activated partial thromboplastin time (aPTT), prothrombin time (PT), and 
international normalized ratio (INR). Additional coagulation studies should be performed as clinically indicated. If met with difficulty, sample collection for coagulation 
studies may be omitted. 
w. eGFR to be calculated as described in Section 8.2.4.1. 
x. 
For the first and second doses of study intervention, blood samples for cytokines to be collected in participants DJHG   \HDUV within 30 minutes before administration of 
study intervention and 2, 10, and 24 hours postdose. A ± 30-minute window is allowed for samples collected at 2 and 10 hours postdose. A ± 1-hour window is allowed for 
sample collected at 24 hours postdose. A single sample will be collected in participants prematurely discontinuing study intervention. See Section 10.2 for parameters. 
Cytokine testing is not required in participants < 18 years of age. If met with difficulty, sample collection for cytokine testing may be omitted. 
y. 
For the first and second doses of study intervention, blood samples for complement panel to be collected in participants DJHG   \HDUV within 30 minutes before 
administration of study intervention and 2, 10, and 24 hours postdose. A ± 30-minute window is allowed for samples collected at 2 and 10 hours postdose. A ± 1-hour 
window is allowed for sample collected at 24 hours postdose. A single sample will be collected in participants prematurely discontinuing study intervention. See Section 
10.2 for parameters. Complement testing is not required in participants < 18 years of age. If met with difficulty, sample collection for complement testing may be omitted. 
z. 
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. 
aa. 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. 
bb. Participants will report instances of renal stones requiring medical intervention, stone passage, and/or renal colic requiring medication (Section 8.1.6.1). 
cc. In the event of rescreening, if a participant had been screened for this study within the last 3 months and had kidney ultrasound data sent to the central over-readers, repeat of 
the kidney ultrasound will not be required during the rescreen. 
dd. 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. 
ee. Blood samples for analysis of anti-drug antibodies will be analyzed once a validated methodology is available (Section 8.8.1). 
ff. Participants < 18 years of age to be queried as to the ongoing burden of the study (Section 2.3.2). 
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Version 5.0 US, 13-Aug-2020 
 
Page 98 
gg. Short Form 36 Health Survey to be administered only in adults (Section 8.1.7.1). 
hh. EQ-5D-5L to be administered only in adults (Section 8.1.7.2). 
ii. 
PedsQL to be administered only in children (Section 8.1.7.3). 
jj. 
Serious adverse events to be collected from time of ICF signature through 30 days after the last study visit. 
kk. Adverse events to be collected from time of ICF signature through the End of Study/Early Termination Visit.  
 
  

SAP_001.pdf: 
Cover Page for Statistical Analysis Plan 
Sponsor name: 
Dicema Pha1maceuticals, Inc.  
NCT number 
NCT03847909  
Sponsor trial ID: 
DCR-PHXC-201 
Official title of study: 
A Phase 2 Placebo-Controlled, Double-Blind, Multicenter 
Study to Evaluate the Efficacy, Safety, and Tolerability of 
DCR-PHXC Solution for Injection (Subcutaneous Use) in 
Patients With Primary Hyperoxaluria   
Document date*: 
16-July-2021 
 
*Document date refers to the date on which the document was most recently updated. 
Note: The date in the header from Page 2 is the date of compilation of the documents and not of an update to content. 


AD-ST-33.05  Effective date: 22-Jan-2018
Version Final 1.0 - US Analysis Plan    16-July-2021|    AD-PR-109.01  Effective date: 26-Jun-2017
Page 1 of 59
   Statistical Analysis Plan
Sponsor
Dicerna
Protocol Title:
A Phase 2 Placebo-Controlled, Double-Blind, Multicenter Study 
to Evaluate the Efficacy, Safety, and Tolerability of DCR-PHXC 
Solution for Injection (subcutaneous use) in Patients with Primary 
Hyperoxaluria
Protocol Number:
DCR-PHXC-201
:
Document Version:
Final 1.0 - US Analysis Plan
Document Date: 
16-July-2021
Redacted VWDWLVWLFDODQDO\VLVSODQ 
Includes redaction of personal identifiable information only. 
. 


Statistical Analysis Plan, 
Sponsor Dicerna
Protocol Number DCR-PHXC-201
 Number
AD-ST-33.05  Effective date: 22-Jan-2018
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Page 2 of 59
Approvals
Role
Signatures
Date (dd-Mmm-yyyy)
Biostatistician
Print Name:  
Dicerna
Representative
Print Name:  
Dicerna
Representative
Print Name:  
Dicerna
Representative
Print Name:  


Statistical Analysis Plan, 
Sponsor Dicerna
Protocol Number DCR-PHXC-201
 Number
AD-ST-33.05  Effective date: 22-Jan-2018
Version Final 1.0 - US Analysis Plan    |    16-July-2021    |    AD-PR-109.01 Effective date: 26-Jun-2017
Page 3 of 59
Table of Contents
Approvals........................................................................................................................................ 2
Table of Contents............................................................................................................................ 3
List of Tables .................................................................................................................................. 5
List of Figures................................................................................................................................. 5
1.
Overview............................................................................................................................. 6
2.
Study Objectives and Endpoints......................................................................................... 6
2.1.
Study Objectives........................................................................................................... 6
2.1.1. Primary Objective......................................................................................................... 6
2.1.2. Key Secondary Objective ............................................................................................. 6
2.1.3. Secondary Objectives.................................................................................................... 7
2.1.4. Tertiary/Exploratory Objectives ................................................................................... 7
2.2.
Study Endpoints............................................................................................................ 7
2.2.1. Safety Endpoints........................................................................................................... 7
2.2.2. Efficacy Endpoints........................................................................................................ 8
2.2.3. Pharmacokinetic Variables ........................................................................................... 8
3.
Overall Study Design and Plan........................................................................................... 9
3.1.
Overall Design .............................................................................................................. 9
3.2.
Sample Size and Power................................................................................................. 9
3.3.
Study Population........................................................................................................... 9
3.4.
Treatments Administered.............................................................................................. 9
3.5.
Method of Assigning Participants to Treatment Groups ............................................ 10
3.6.
Blinding and Unblinding............................................................................................. 11
3.7.
Schedule of Events...................................................................................................... 12
4.
Statistical Analysis and Reporting.................................................................................... 17
4.1.
Introduction................................................................................................................. 17
4.2.
Interim Analysis and Data Monitoring ....................................................................... 17
4.3.
Final Analysis ............................................................................................................. 18
5.
Analysis Populations......................................................................................................... 18
6.
General Issues for Statistical Analysis.............................................................................. 19
6.1.
Statistical Definitions and Algorithms........................................................................ 19
6.1.1. Study Day.................................................................................................................... 19
6.1.2. Baseline....................................................................................................................... 19
6.1.3. Adjustments for Covariates......................................................................................... 19
6.1.4. Multiple Comparisons................................................................................................. 19
6.1.5. Handling of Dropouts or Missing Data....................................................................... 21


Statistical Analysis Plan, 
Sponsor Dicerna
Protocol Number DCR-PHXC-201
 Number
AD-ST-33.05  Effective date: 22-Jan-2018
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Page 4 of 59
6.1.6. Uox Measurements below the Limit of Quantitation ................................................. 24
6.1.7. Handling of Rescreened Participants.......................................................................... 24
6.1.8. Analysis Visit Windows ............................................................................................. 24
6.1.9. Derived Variables ....................................................................................................... 25
6.1.10. Data Adjustments/Handling/Conventions .................................................................. 29
6.1.11. Subgroups ................................................................................................................... 32
7.
Study Participants and Demographics .............................................................................. 32
7.1.
Disposition of Participants and Withdrawals.............................................................. 32
7.2.
Protocol Violations and Deviations ............................................................................ 32
7.3.
Demographics and Other Baseline Characteristics..................................................... 33
7.4.
Exposure and Compliance .......................................................................................... 33
8.
Efficacy Analysis.............................................................................................................. 34
8.1.
Primary Efficacy Analysis.......................................................................................... 34
8.2.
Key Secondary Efficacy Analysis .............................................................................. 34
8.3.
Secondary Efficacy Analysis...................................................................................... 35
8.4.
Tertiary/Exploratory Efficacy Analysis...................................................................... 36
8.5.
Sensitivity Analyses.................................................................................................... 37
9.
Safety and Tolerability Analysis....................................................................................... 38
9.1.
Adverse Events ........................................................................................................... 39
9.1.1. Adverse Events Summaries ........................................................................................ 39
9.1.2. Summaries for Serious Adverse Events, AEs Resulting in Early Withdrawal, 
and Deaths................................................................................................................... 40
9.1.3. Other Significant Adverse Events............................................................................... 40
9.2.
Clinical Laboratory Evaluations ................................................................................. 41
9.3.
Clinical Laboratory Evaluations – eGFR.................................................................... 45
9.4.
Clinical Laboratory Evaluations – Urinalysis............................................................. 46
9.5.
Vital Signs................................................................................................................... 46
9.6.
Electrocardiograms ..................................................................................................... 47
9.7.
Echocardiogram with Doppler.................................................................................... 50
9.8.
Physical Examination.................................................................................................. 50
9.9.
Concomitant Medication............................................................................................. 50
9.10.
Immunogenicity Assessments..................................................................................... 51
10.
Changes from Planned Analysis....................................................................................... 51
11.
Pharmacokinetic Analysis................................................................................................. 51
12.
References......................................................................................................................... 52
Appendix 1: 
 Library of Abbreviations ............................................................ 54
Appendix 2: Algorithm for Calculating SF-36 Scores ................................................................. 57


Statistical Analysis Plan, 
Sponsor Dicerna
Protocol Number DCR-PHXC-201
 Number
AD-ST-33.05  Effective date: 22-Jan-2018
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Page 5 of 59
List of Tables
Table 1: Schedule of Events ......................................................................................................... 12
Table 2: List of Subgroups............................................................................................................ 32
Table 3: Potentially Clinically Significant Criteria for Safety Laboratory Assessments for 
3DUWLFLSDQWV<HDUVRI$JH ............................................................................................. 43
Table 4: Potentially Clinically Significant Criteria for Safety Laboratory Assessments for 
Participants < 18 Years of Age............................................................................................. 44
7DEOH3RWHQWLDOO\&OLQLFDOO\6LJQLILFDQW&ULWHULDIRU9LWDO6LJQVIRU3DUWLFLSDQWV<HDUVRI
Age........................................................................................................................................ 46
Table 6: Potentially Clinically Significant Criteria for Vital Signs for Participants < 18 Years of 
Age........................................................................................................................................ 47
Table 7: Potentially Clinicall\6LJQLILFDQW&ULWHULDIRU(OHFWURFDUGLRJUDP'DWDIRU3DUWLFLSDQWV
18 Years of Age .................................................................................................................... 49
Table 8: Potentially Clinically Significant Criteria for Electrocardiogram Data for Participants < 
18 Years of Age .................................................................................................................... 49
Table 9: Demographic Data Summary Tables...............................Error! Bookmark not defined.
Table 10: Efficacy Data Summary Tables and Figures .................Error! Bookmark not defined.
Table 11: Safety Data Summary Tables ........................................Error! Bookmark not defined.
Table 12: Planned Data Listings....................................................Error! Bookmark not defined.
Table 13: Planned Figures .............................................................Error! Bookmark not defined.
List of Figures
Figure 1
Example of AUC Graphs for Primary Endpoint......................................................... 27


Statistical Analysis Plan, 
Sponsor Dicerna
Protocol Number DCR-PHXC-201
 Number
AD-ST-33.05  Effective date: 22-Jan-2018
Version Final 1.0 - US Analysis Plan    |    16-July-2021    |    AD-PR-109.01 Effective date: 26-Jun-2017
Page 6 of 59
1.
Overview
This statistical analysis plan (SAP) describes the planned analysis and reporting for Dicerna
protocol number DCR-PHXC-201 (A Phase 2 Placebo-Controlled, Double-Blind, Multicenter 
Study to Evaluate the Efficacy, Safety, and Tolerability of DCR-PHXC Solution for Injection 
[subcutaneous use] in Patients with Primary Hyperoxaluria [PH] types 1 and 2), amendment 3, 
protocol version 5.0 US CT, dated 13-AUG-2020. Planned analyses and reporting for other 
region-specific versions of the protocol are included in a separate analysis plan. Reference 
materials for this SAP include the protocol and the accompanying sample data collection 
documents. Operational aspects related to collection and timing of planned clinical assessments 
are not repeated in this SAP unless relevant to the planned analysis.
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the Food and Drug Administration (FDA), and International Council on 
Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human 
Use: Guidance on Statistical Principles in Clinical Trials1. All work planned and reported for this 
SAP will follow internationally accepted guidelines, published by the American Statistical 
Association2 and the Royal Statistical Society3 for statistical practice.
The planned analyses identified in this SAP may be included in clinical study reports (CSRs), 
regulatory submissions, or future manuscripts. Also, post-hoc exploratory analyses not identified 
in this SAP may be performed to further examine study data. Any post-hoc or unplanned, 
exploratory analysis performed will be clearly identified in the final CSR.
This SAP is an a priori plan. It will be finalized and signed off prior to clinical database lock or 
any unblinded inferential or descriptive analysis of data pertaining to Dicerna’s study DCR-
PHXC-201.
2.
Study Objectives and Endpoints
2.1.
Study Objectives
2.1.1. Primary Objective
The primary objective is to assess the efficacy of DCR-PHXC in reducing urinary oxalate burden 
in patients with PH (types 1 and 2).
2.1.2. Key Secondary Objective
The key secondary objective is to identify the proportion of participants with normalized or near-
normalized urinary oxalate excretion (Uox).


Statistical Analysis Plan, 
Sponsor Dicerna
Protocol Number DCR-PHXC-201
 Number
AD-ST-33.05  Effective date: 22-Jan-2018
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Page 7 of 59
2.1.3. Secondary Objectives
The secondary objectives are:
1. To evaluate the effect of DCR-PHXC on stone burden in patients with PH.
2. To evaluate the effect of DCR-PHXC on plasma oxalate in patients with PH.
3. To evaluate the effect of DCR-PHXC on eGFR.
4. To assess the safety of DCR-PHXC in patients with PH.
5. To characterize the pharmacokinetics (PK) of DCR-PHXC in patients with PH.
2.1.4. Tertiary/Exploratory Objectives
The tertiary/exploratory objectives are:
1. To evaluate the effect of DCR-PHXC on stone events in patients with PH.
2. To assess the efficacy of DCR-PHXC in reducing Uox burden over 6 months period in 
patients with PH.
3. To assess the efficacy of DCR-PHXC in reducing Uox burden at month 6 in patients with 
PH.
4. To evaluate the effect of DCR-PHXC on urinary oxalate-to-creatinine ratio in patients 
with PH.
5. To evaluate the effect of DCR-PHXC on quality of life (QoL) assessments in patients 
with PH.
6. To evaluate the relationship between Uox spot urine and 24-hour urine measurement in 
patients with PH.
2.2.
Study Endpoints
2.2.1. Safety Endpoints
The safety endpoints of this study include the following:
x
Adverse events (AEs), serious AEs (SAEs) and AEs of special interest (AESI)
x
Change from baseline in 12-lead ECG
x
Physical examination findings 
x
Vital signs
x
Clinical laboratory tests


Statistical Analysis Plan, 
Sponsor Dicerna
Protocol Number DCR-PHXC-201
 Number
AD-ST-33.05  Effective date: 22-Jan-2018
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Page 8 of 59
2.2.2. Efficacy Endpoints
2.2.2.1.
Primary Efficacy Endpoint
The primary efficacy endpoint of this study is the area under the curve from Day 90 to Day 180
(AUC24-hour Uox), based on percent change from baseline in 24-hour Uox (adjusted per 1.73 m2
body surface area [BSA] in participants aged <18 years). Further details of calculations are
provided in Section 6.1.9.
2.2.2.2.
Key Secondary Endpoint
The key secondary endpoint is the proportion of participants with a 24-hour Uox level 
<0.46 mmol/24 hours (normalized)RUWR mmol/24 hours (near-normalized) (adjusted 
per 1.73 m2 body surface area [BSA] in participants aged <18 years) on at least two consecutive 
visits, beginning with Day 90. Further details of calculations are provided in Section 6.1.9.
2.2.2.3.
Secondary Efficacy Endpoints
The secondary efficacy endpoints of this study include the following: 
x
Percentage change in the summed surface area and number of kidney stones identified 
via kidney ultrasound from baseline to Day 180
x
Percentage change in plasma oxalate from baseline to Day 180 (for adults only)
x
Rate of change in eGFR from baseline to Day 180.
x
Population and individual PK parameters for DCR-PHXC
2.2.2.4.
Tertiary/Exploratory Efficacy Endpoints
The tertiary/exploratory efficacy endpoints include the following: 
x
Number of stone events over a 6-month period
x
AUC24-hour Uox from Day 1 to Day 180, based on percent change from baseline
x
Percentage change in 24-hour Uox from baseline to Day 180
x
AUC of 24-hour urinary oxalate-to-creatinine ratio (AUC24-hour Uox:creatinine) from Day 90 
to Day 180, based on percent change from baseline
x
Change from baseline to Day 180 in the Short Form (36) Health Survey (SF-36) and 
EQ-5D-5L in adults; and in the PedsQL™in children (including adolescents)
x
Uox in spot urine and 24-hour urine
2.2.3. Pharmacokinetic Variables
Pharmacokinetic parameters to be analyzed will be described in detail in a separate 
Pharmacokinetic Analysis Plan (PKAP). PK TLF generation and validation will be covered in a 
separate analysis plan. 


Statistical Analysis Plan, 
Sponsor Dicerna
Protocol Number DCR-PHXC-201
 Number
AD-ST-33.05  Effective date: 22-Jan-2018
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Page 9 of 59
3.
Overall Study Design and Plan
3.1.
Overall Design
This is a 6 month, randomized, placebo-controlled, double-blind study of DCR-PHXC in patients 
with primary hyperoxaluria (PH1 and PH2). 
3.2.
Sample Size and Power
Approximately 40 participants will be screened to achieve an estimated total of 36 evaluable 
participants.
For the sample size calculations, the primary endpoint of AUC24-hour Uox from Day 90 to Day 180 
based on percent change from baseline was used. The group sequential design with pre-specified 
alpha spending for interim analysis and final analysis was utilized. The randomization ratio is 2-
to-1 (active-to-placebo). The primary hypothesis to be tested is a one-sided superiority 
hypothesis at the significance level of 0.025. The AUC24-hour Uox in the placebo arm is assumed to 
be 0, as the Uox values may oscillate up and down from baseline due to measurement variability. 
The AUC24-hour Uox in the active arm is assumed to be 3600 based on a 40% decrease over the 
90 days. The effect size is assumed to be 1.2. Under these assumptions, the sample size of 
36 patients (24 in the active arm and 12 in the placebo arm) will yield a power of approximately 
94%. All calculations were performed using 
.
The above sample size calculation was performed under the assumption that there may be an
interim analysis to re-estimate sample size after two-thirds of participants complete the study.
However due to late enrollment experienced in the study, an interim analysis will  not be 
performed.
3.3.
Study Population
The study population includes male and female patients, at least 6 years of age, with genotype-
confirmed PH1 or PH2.
3.4.
Treatments Administered
Study intervention will be administered in clinic as a subcutaneous (SC) injection into the 
abdomen or thigh. In adults and adolescents (aged 12 to \HDUVZHLJKLQJNJVWXG\
intervention will be administered once monthly at a dose of 170 mg DCR-PHXC (or the 
equivalent volume of placebo). In adults and adolescents weighing <50 kg, study intervention 
will be administered once monthly at a dose of 136 mg DCR-PHXC (or the equivalent volume of 
placebo). Participants who begin the study weighing less than 50 kg will have their dose 
increased to the 170 mg dose should they reach the 50 kg threshold. Participants receiving the 
170 mg dose will not have their dose decreased to the 136-mg dose should they fall below the 
50-kg threshold.
The dose for participants aged 6 to 11 years was determined from an evolving 
PK/pharmacodynamic (PD) modeling and simulation (M&S) model, as detailed in Section 4.3 of 
the protocol. The model-derived dose of 3.5 mg/kg was approved by the data safety monitoring 
committee (DSMC) upon review of the appropriate safety data.


Statistical Analysis Plan, 
Sponsor Dicerna
Protocol Number DCR-PHXC-201
 Number
AD-ST-33.05  Effective date: 22-Jan-2018
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Page 10 of 59
An unblinded pharmacist or designee will prepare each dose of DCR-PHXC or placebo as 
detailed in Section 6.2.4 of the protocol. 
3.5.
Method of Assigning Participants to Treatment Groups
Eligible participants will be randomized in a 2-to-1 (DCR-PHXC-to-placebo) ratio using an 
interactive web response system (IWRS).
To balance the participants between the intervention arms based on 2 factors: age (6 to 11, 12 to 
17, RU\HDUVDQGH*)5H*)5P/PLQH*)5P/PLQDQDGDSWLYH
randomization via minimization method will be used to allocate patients to treatment groups. 
Minimization aims to ensure that the intervention arms are balanced with respect to the 
predefined factors, as well as for the number of patients in each arm.  Minimization can be 
especially helpful for studies with small sample sizes as the minimization produces better 
balance than standard stratified randomization methodology. Imbalance scores are calculated for 
the possible patient allocations to treatment groups, which represent the imbalance that would be 
generated in each of the treatment arms, while taking into account these two factors. Participants 
will be assigned to the treatment that would generate the lowest amount of imbalance with a 
probability of 80%, and to the treatment that would generate the highest amount of imbalance 
with a probability of 20%.4,5 Please refer to the study adaptive randomization plan for further 
details on the minimization algorithm used for treatment assignment.  
At the beginning of the study, only two age groups were enrolled (12 to 17 and 18). Children 
aged 6 to 11 years were not enrolled until modeling and simulation of PK and PD data 
determined an appropriate dose for that age group and the DSMC reviewed safety data from at 
least the first 60 days of DCR-PHXC treatment (two doses plus 30 days of follow up) in 
three adolescent participants (aged 12 to 17 years). Concerning participants 12 to 17 years of 
age, the DSMC affirmed that the overall risk-benefit balance remains positive, and that no AEs 
of severe intensity considered to be drug-related (per selective unblinding by DSMC), and no 
SAEs suspected to be drug-related (per unblinding by DSMC) have occurred in participants 12 to 
17 years of age.  This will not affect the minimization, as age group is already one of the 
prognostic factors included in the minimization algorithm.
Additionally, in case there are participants who sign the ICF and are randomized but do not
receive the study intervention; additional patients will be enrolled in order to achieve the planned 
sample size.  Also in the case of participants who sign the ICF, are randomized, receive the study 
intervention, and subsequently withdraw, or are withdrawn or discontinued from the study prior 
to completion of Day 90 assessments, or who do not have any efficacy assessments after Day 90,
extra participants will be enrolled to achieve the planned sample size.  
When enrolling  additional participants, the participants who either did not receive study 
intervention, withdrew prior to the Day 90 assessments, or who do not have any efficacy 
assessments after Day 90 will not be included in the imbalance calculations used to implement 
the minimization algorithm, since these participants do not contribute to the primary analysis. In 
this way, participants enrolled additionally will be assigned to treatments to minimize imbalance 
across all participants expected to have data for the final analysis.


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3.6.
Blinding and Unblinding
This is a double-blind study in which treatment assignment will be blinded for investigators and 
any personnel involved with study conduct, evaluation at the investigational sites, 
, or 
the sponsor.
The randomization scheme will only be disclosed to select personnel to ensure correct 
preparation of the study drug, correct set-up of the IWRS, correct safety monitoring by the 
DSMC, and expedited adverse reaction reporting. All aspects of blinding and unblinding for the 
study (including possible interim analysis, emergency unblinding, unblinding following database 
lock) is outlined in the study-specific Blinding and Unblinding Plan.
Emergency unblinding, i.e., breaking the code for an individual patient during the study, is 
restricted to emergency situations and should only be used under circumstances where 
knowledge of the treatment is necessary for the proper handling of the participant. The decision 
to break the code must be made by the investigator. The study monitor and sponsor must be 
informed about the code break as soon as possible. 
Results of on-treatment 24-hour Uox measurements will not be revealed to the investigator, 
sponsor or blinded study team members prior to data base lock, so as not to potentially unblind 
the study. Details of the ongoing quality review of 24-hour Uox measurements by the unblinded 
members of the study team are outlined in the Unblinded Data Review and Sample Tracking
Plan.


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3.7.
Schedule of Events
A detailed schedule of events for the study is provided in Table 1.
Table 1: Schedule of Events
Screening
Treatment
EOS
ET
Study Day
(window)
–35 ato
–1
1
2
15
(±2)
30
(±2)
31 b
45
(±2)
60
(±3)
90
(±3)
120
(±5)
150 
(±5)
180 
(±5)
-
Procedure/Assessment
Informed consent/assent c
X
Inclusion and exclusion criteria d
X
X
Demographic/baseline characteristics
X
Medical history e
X
PH disease history e
X
Medication history f
X
AGXT/GRHPR genotyping g
X
Urine drug screen h
X
Viral serology i
X
FSH (postmenopausal women)
X
Study intervention administration
X
X
X
X
X
X
Spot urine collection j
X
X
X
X
X
X
X
X
24-hr urinary oxalate k
X
X
X
X
X
X
X
X
24-hr urinary creatinine l
X
X
X
X
X
X
X
X
Blood draw for vitamin B6 levels m
X
X
X
X
X
X
X
Plasma PK sample n
X
X
X
X
X
X
Plasma oxalate sample o
X
X
X
X
X
X
X
X
X
Record fluid intake p
X
X
X
X
X
X
X
X
12-lead ECG q
X
X
X
X
X
X
X
X
X
X
X
Vital signs r
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination s
X
X
X
X
X
X
X
X
X
X
X
X
X


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Screening
Treatment
EOS
ET
Study Day
(window)
–35 ato
–1
1
2
15
(±2)
30
(±2)
31 b
45
(±2)
60
(±3)
90
(±3)
120
(±5)
150 
(±5)
180 
(±5)
-
Procedure/Assessment
Body weight and height t
X
X
X
X
X
X
X
X
X
Hematology and serum chemistry u
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation studies v
X
X
X
X
X
X
X
X
X
X
X
X
X
eGFR w
X
X
X
X
X
X
X
X
X
Cytokines x
X
X
X
X
X
Complement y
X
X
X
X
X
Urinalysis z
X
X
X
X
X
X
X
X
X
Urine pregnancy test (WOCBP) aa
X
X
X
X
X
X
X
X
X
Record stone events (as applicable) bb
X
X
X
X
X
X
X
X
X
X
X
X
Kidney ultrasound cc
X
X
X
Echocardiogram dd
X
X
X
ADA & anti-dsDNA sample ee
X
X
X
X
Pediatric burden assessment ff
X
X
X
X
X
X
X
X
X
X
SF-36 gg
X
X
X
EQ-5D-5L hh
X
X
X
PedsQL ii
X
X
X
Record SAEs jj
X
X
X
X
X
X
X
X
X
X
X
X
X
Record AEs kk
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications f
X
X
X
X
X
X
X
X
X
X
X
X
Abbreviations: ADA = antidrug antibody; AE = adverse event; AGXT = the gene that codes for alanine–glyoxylate aminotransferase; anti-dsDNA = anti-double-stranded 
deoxyribonucleic acid antibody; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; EOS = end of study; ET = early termination; FSH = follicle stimulating 
hormone; GRHPR = the gene that codes for glyoxylate and hydroxypyruvate reductase; PedsQL = Pediatric Quality of Life Inventory; PH = primary hyperoxaluria; 
PK = pharmacokinetic; SAE = serious adverse event; SF-36 = Short Form 36 Health Survey; WOCBP = women of childbearing potential


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Table footnotes:
a.
Potential participants allowed a second attempt at achieving < 20% variation in 24-hour urinary creatinine excretion, as described in protocol section 8.1.1.1, will be given an 
extra 7 days within which to complete the second pair of collections. An additional 7 days will also be granted for retest of initially unanalyzable screening laboratory 
samples. 
b.
Day 31 visit to be conducted the day after the Day 30 visit, regardless of when the Day 30 visit occurs within the ± 2-day window.
c.
Informed consent (and assent if applicable) may be given outside of the 35-day screening period, i.e., provision of consent does not start the clock for the screening period. In 
no case should more than 2 weeks elapse between the provision of consent and initiation of the first screening procedure/assessment. Initiation of the first screening 
procedure will start the 35-day window.
d.
Participant eligibility (with the exception of clinical laboratory testing) will be re-confirmed prior to administration of study intervention on Day 1.
e.
Record 5 years of general medical history. PH history to include 12-month history of stone events, as described in protocol section 8.1.6.1.
f.
To include vitamin B6 (pyridoxine).
g.
Participants without documented genotyping must provide a DNA sample for testing.
h.
Urine drug screen to include at minimum: amphetamines, barbiturates, cocaine, opiates, and benzodiazepines. Drug screening is not required for individuals aged 12 or 
younger. Investigator discretion in excluding participants with a positive test is allowed. 
i.
HIV 1 and 2 antibodies, hepatitis B surface antigen (HBsAg), and hepatitis C virus antibody. If tested in the past 3 months, medical record documentation of this testing may 
be used. Viral serology is not required in participants < 18 years of age.
j.
A sample of urine from the void immediately prior to the initiation of each 24-hour urine collection will be collected and stored apart from the 24-hour urine collection.
Should the two 24-hour screening collections occur on consecutive days, no spot urine sample will be collected on the second day.
k.
Two screening samples should ideally be collected on 2 consecutive days, but with no more than 8 days between collections. Collection of on-treatment samples must be 
performed within the 7 days prior to the scheduled study visit. It is desired that the elapsed time between monthly collections should be at least 3 weeks and not more than 
5 weeks. Participants should avoid taking vitamin C supplements (including multivitamins) for 24 hours prior to and during the collection of 24-hour urine samples. See 
protocol section 8.1.1.1. 
l.
Urinary creatinine excretion will be determined from 24-hour urine samples in order to assess the quality of the 24-hour collection. Any post-screening sample that violates 
the urine quality review criteria should be repeated within 10 days of the scheduled study visit whenever possible. See protocol section 8.1.1.1.1 for details.
m.
Samples for vitamin B6 levels will only be collected in participants DJHG8 years who are taking vitamin B6 supplements.
n.
Plasma sampling times for PK analysis of DCR-PHXC and its metabolites (see protocol section 8.5.1):
x
$JHG\HDUV
o
Days 1 and 30: predose and at 5, 15, and 30 minutes and 1, 2, 4, 6, 10, and 12 hours postdose 
o
Days 2 and 31: 24 hours postdose
o
Day 150: predose and at 2, 6, and 12 hours postdose
x
Aged 6–17 years: 
o
Days 1 and 30: predose and at 30 minutes and 2 and 10 hours postdose
o
Days 2 and 31: 24 hours postdose


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o
Day 150: predose and at 2 and 10 hours postdose
A single plasma sample should be collected at the final visit from participants who discontinued study intervention or were withdrawn from the study.
Windows for the collection of PK samples are as follows:
o
Predose to be collected within 30 minutes before administration of study intervention 
o
5, 15, and 30 minutes and 1 hour postdose, ± 3-minute window is allowed
o
2, 4, 6, 10, and 12 hours postdose, ± 30-minute window is allowed
o
24 hours postdose, ± 1-hour window is allowed
o.
In adults, blood samples for plasma oxalate analysis to be collected prior to dosing (protocol section 8.1.5). Participants aged 6 to 17 years will have plasma oxalate sampling 
only at Screening.
p.
Participants should maintain consistent fluid intake (i.e., hyperhydration) over the course of the study (protocol section 5.3). Participants will report average daily fluid intake 
over the 4 to 7 days prior to each 24-hour urine collection (protocol section 8.2.7).
q.
On Days 1 and 30, ECG to be performed predose and at 10 hours (± 30-minutes) postdose. A single ECG to be performed at other visits, as indicated (protocol section 8.2.5). 
If multiple assessments are due at the same time point, PK sampling should be performed preferably at the nominal time point, with the preferred order of assessments ECG, 
vitals, PK, and then other assessments.
r.
Vital signs on Day 1 and Day 30 to be assessed predose and at 10 hours (± 30-minutes) postdose (protocol section 8.2.3). If multiple assessments are due at the same time 
point, PK sampling should be performed preferably at the nominal time point, with the preferred order of assessments ECG, vitals, PK, and then other assessments.
s.
A full physical exam will be performed at Screening and Day 180 (or ET). A brief physical examination may be performed at other scheduled visits (Day 1 through Day 150) 
or unscheduled visits at the Investigator’s discretion. See protocol sections 8.2.1 and 8.2.2.
t.
,QSDUWLFLSDQWV\HDUV of age, height to be recorded only at screening. In participants < 18 years of age, height will be recorded at specified visits for calculation of eGFR
and BSA adjustment of Uox excretion. Weight to be recorded in all participants at specified visits. In participants aged 6-to-11 years, the weight on Day 1 will be used to 
calculate the mg/kg dose of study intervention.
u.
Blood samples for hematology and serum chemistry to be collected predose on dosing days. To include cystatin C in participants < 18 years of age for calculation of eGFR.
See protocol section 10.2 for the list of parameters.
v.
Blood samples for coagulation studies to be collected predose. Coagulation panel will include activated partial thromboplastin time (aPTT), prothrombin time (PT), and 
international normalized ratio (INR). Additional coagulation studies should be performed as clinically indicated.
w.
eGFR to be calculated as described in protocol section 8.2.4.1.
x.
Blood samples for cytokines to be collected in participants DJHG\HDUV within 30 minutes before administration of study intervention and 2, 10, and 24 hours postdose. A 
± 30-minute window is allowed for samples collected at 2 and 10 hours postdose. A ± 1-hour window is allowed for sample collected at 24 hours postdose. A single sample 
will be collected in participants prematurely discontinuing study intervention. See protocol section 10.2 for parameters. Cytokine testing is not required in participants < 18 
years of age.
y.
Blood samples for complement panel to be collected in participants DJHG\HDUV within 30 minutes before administration of study intervention and 2, 10, and 24 hours 
postdose. A ± 30-minute window is allowed for samples collected at 2 and 10 hours postdose. A ± 1-hour window is allowed for sample collected at 24 hours postdose. A 
single sample will be collected in participants prematurely discontinuing study intervention. See protocol section 10.2 for parameters. Complement testing is not required in 
participants < 18 years of age.


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z.
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 protocol section 10.2 for parameters.
aa. 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.
bb. Participants will report instances of renal stones requiring medical intervention, stone passage, and/or renal colic requiring medication (protocol section 8.1.6.1).
cc. In the event of rescreening, if a participant had been screened for this study within the last 3 months and had kidney ultrasound data sent to the central over-readers, repeat of 
the kidney ultrasound will not be required during the rescreen.
dd. 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.
ee. Blood samples for analysis of anti-drug antibodies will be analyzed once a validated methodology is available (protocol section 8.8.1).
ff.
Participants < 18 years of age to be queried as to the ongoing burden of the study (protocol section 2.3.2).
gg. Short Form 36 Health Survey to be administered only in adults (protocol section 8.1.7.1).
hh. EQ-5D-5L to be administered only in adults (protocol section 8.1.7.2).
ii.
PedsQL to be administered only in children (protocol section 8.1.7.3).
jj.
Serious adverse events to be collected from time of ICF signature through 30 days after the last study visit.
kk. Adverse events to be collected from the time of ICF signature through the End of Study/Early Termination Visit. Participants will be questioned as to the occurrence of 
muscle pain or weakness.


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4.
Statistical Analysis and Reporting
4.1.
Introduction
Data processing, tabulation of descriptive statistics, calculation of inferential statistics, and 
graphical representations, except for PK parameter estimation, will be performed primarily using 
SAS (release 9.4 or higher). Pharmacokinetic parameter estimation and analysis of DCR-PHXC 
concentrations in serum will be described in detail in a separate analysis plan (PKAP).
Descriptive summaries for continuous (quantitative) data include the number of participants (n) 
with non-missing values, mean, standard deviation (SD), median, minimum, and maximum.
Descriptive summaries for categorical (qualitative) data include the frequency and percentage of 
participants who are in the particular category or each possible value. In general, the 
denominator for a percentage calculation will be based upon the total number of participants in 
the study population within each Group (or overall), unless otherwise specified. The denominator 
for by-visit displays will be the number of participants in the relevant study population with non-
missing data at each visit.
Unless specified otherwise, all summaries/tabulations will be presented by each treatment 
(placebo and DCR-PHXC) and overall.
The minimum and maximum will be reported with the same degree of precision (i.e., the same 
number of decimal places) as the observed data. Measures of location (mean and median) will be 
reported to 1 decimal more than the observed data and measures of spread (e.g., SD) will be 
reported to 2 decimals more than the observed data.
Percentages will be presented to 1 decimal place, unless otherwise specified.
Participant data will be listed.
4.2.
Interim Analysis and Data Monitoring
No interim analysis will be conducted. The final analysis will use an alpha of 0.025. 
A DSMC was convened to provide periodic review of the efficacy and safety data. The DSMC is 
comprised of three voting members independent of the study team and sponsor. At a minimum, 
the DSMC meets:
x
prior to the first participant enrolled, 
x
after the first five participants have completed the Day 30 Visit, 
x
after three adolescent participants (aged 12 to 17 years) have been enrolled in the DCR 
PHXC arm and have completed the Day 60 Visit, and 
x
periodically thereafter (depending on enrollment). 
Children aged 6 to 11 years were not enrolled until  modelling and simulation of the PK and PD 
data determined an appropriate dose for that age group and the DSMC has reviewed safety data 
from at least the first 60 days of DCR-PHXC treatment (2 doses plus 30 days of follow up) in 
three adolescent participants (aged 12 to 17 years). For participants 12 to 17 years of age, the 


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DSMC affirmed that the overall risk-benefit balance remains positive. Moreover for this age 
group no AEs of severe intensity considered to be drug related (per selective unblinding by 
DSMC) and no SAEs suspected to be drug related (per unblinding by DSMC) were observed to 
have occurred.
The DSMC will review unblinded safety and efficacy data and will make determinations on 
whether to continue the study following each periodic review of the data. A DSMC charter 
containing details of the operation of the DSMC will be developed in conjunction with the 
members of the DSMC before the first meeting and will be modified as required. The sponsor 
may request additional reviews should any other findings/issues pertaining to safety or efficacy 
emerge requiring DSMC review. 
The unblinded analyses will be performed by the 
 unblinded statistician and 
 
unblinded SAS programmers. The 
 unblinded statistician is an independent statistician 
other than the author of this plan or the person responsible for the primary analysis of this study.  
Treatment codes will be revealed to those parties only.
4.3.
Final Analysis
An unblinded analysis of the efficacy data will occur after all study participants have completed 
the study. The data will be cleaned, frozen, and a blinded data review will take place. 
Subsequently, data will be locked, protocol deviations will be adjudicated, and study populations 
will be defined before breaking the study blind.
5.
Analysis Populations
The following analysis populations are planned for this study:
x
Randomized Population (RAND): The randomized population includes all participants 
who were randomized.
x
Enrolled Population (ENRL): The enrolled population includes all participants who 
sign the informed consent form.
x
Safety Population (SAF): The safety population includes all participants randomly 
assigned to study intervention and who take at least one partial or full dose of study 
intervention. Participants will be analyzed according to the intervention they actually 
received.
x
Intent-To-Treat Population (ITT): The ITT population includes all participants who 
were randomized and have at least one postbaseline efficacy assessment. Participants will 
be analyzed according to the intervention they were randomized to. 
x
Modified Intent-To-Treat Population (MITT): The MITT population includes all 
participants in the ITT population who have at least one efficacy assessment after the Day 
90 dosing visit.
x
Evaluable Population (EVAL): The evaluable population includes all participants who 
received 6 full doses of study intervention and completed the study.


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x
Pharmacokinetic Population (PK): The PK population includes all participants in the 
safety population without major dosing violations. Details will be provided in the PKAP.
x
Per-Protocol Population (PP): The PP population includes all participants who were 
randomized and had no major protocol deviations that affect efficacy endpoint 
assessment as adjudicated by the sponsor.
The primary and the key secondary efficacy analyses will be performed on the MITT population
and repeated in further analysis populations as described in section 8.
6.
General Issues for Statistical Analysis
6.1.
Statistical Definitions and Algorithms
6.1.1. Study Day
Study Day 1 is defined as the first dose date (i.e., date of first administration of randomized study 
intervention). The first dose date is used as the reference start date for analysis. 
For days prior to Study Day 1:
Study Day = reference date – first dose date. 
For days on or following Study Day 1, Study Day = reference date – first dose date + 1.
6.1.2. Baseline
Post baseline assessments will be those assessed after the date/time of the first dose.  
For all AUC24-hour Uox endpoints, the baseline is an average of the two 24-hour Uox Screening 
results.
For the remaining endpoints, the last observation recorded prior to the first dose of study 
intervention will be used as the baseline observation for all calculations of change from baseline. 
6.1.3. Adjustments for Covariates
Statistical models based on Uox results will include covariates for age category [6 to 11, 12 to 
RU\HDUV@DQG H*)5FDWHJRU\>P/PLQRU mL/min]The baseline for the endpoint 
being analyzed will be included as a covariate.
6.1.4. Multiple Comparisons
A hierarchical testing procedure will be used to control type I error. If the superiority is 
established for the primary endpoint, statistical testing and p-value estimation for the secondary 
endpoints will be performed in a pre-specified sequence. 
The primary and secondary endpoints will be tested in the following sequence.


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1.
AUC from Day 90 to Day 180, based on percent change from Baseline in 24-hour Uox
2.
The proportion of participants with a normalization (< 0.46 mmol/24 hours) or 
near-QRUPDOL]DWLRQWRPPROKRXUVRI-hour Uox on at least 
2 consecutive visits, beginning with Day 90
3.
Percent change in plasma oxalate from Baseline to Day 180 (for adults only)
4.
Percent change in the number of kidney stones identified via kidney ultrasound from 
Baseline to Day 180
5.
Percent change in the summed surface area identified via kidney ultrasound from 
Baseline to Day 180
6. Rate of change in eGFR from Baseline to Day 180
The hierarchical testing steps will be:
Step 1.      Test for superiority of the AUC for DCR-PHXC versus control, and record the 
one-sided p-value, p1. If p1 <0.025, then declare the test for primary endpoint to 
be statistically significant and proceed to Step 2; otherwise record the nominal 
p-values for all the secondary endpoints.
Step 2.      Test for superiority of the DCR-PHXC versus control with respect to the 
proportion of participants with normalized or near-normalized Uox, and record 
the one-sided p-value, p2. If p2 < 0.025, then declare the test for the first 
secondary endpoint to be statistically significant and proceed to Step 3; otherwise 
record the nominal p-values for the remaining secondary endpoints.
Step 3.      Test for superiority of the DCR-PHXC versus control with respect to the percent 
change in plasma oxalate from Baseline to Day 180, and record the one-sided 
p-value, p5. If p5 < 0.025, then declare the test for fourth secondary endpoint to 
be statistically significant and proceed to Step 6; otherwise record the nominal 
p-values for the remaining secondary endpoints.
Step 4.      Test for superiority of the DCR-PHXC versus control with respect to the percent 
change in the number of kidney stones identified via kidney ultrasound from 
Baseline to Day 180, and record the one-sided p-value, p4. If p4 < 0.025, then 
declare the test for third secondary endpoint to be statistically significant and 
proceed to Step 5; otherwise record the nominal p-values for the remaining 
secondary endpoints.
Step 5.      Test for superiority of the DCR-PHXC versus control with respect to the percent 
change in the summed surface area identified via kidney ultrasound from Baseline 
to Day 180, and record the one-sided p-value, p3. If p3 < 0.025, then declare the 
test for second secondary endpoint to be statistically significant and proceed to 
Step 4; otherwise record the nominal p-values for the remaining secondary 
endpoints.


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Step 6.      Test for superiority of the DCR-PHXC versus control with respect to the rate of 
change in eGFR from Baseline to Day 180, and record the one-sided p-value, p6. 
If p6 < 0.025, then declare the test for the last secondary endpoint to be 
statistically significant.
6.1.5. Handling of Dropouts or Missing Data
6.1.5.1.
Missing Efficacy Endpoint Data
While all possible efforts will be made to ensure that participants stay in the study and all data is 
collected as scheduled, the occurrence of missing data cannot be completely eliminated.
For the analysis of AUC related efficacy endpoints, based on the MITT or ITT populations, a 
multiple imputation (MI) approach under the missing-at-random (MAR) assumption will be used 
to handle missing endpoint data. Subsequently, the AUC related efficacy endpoints will be 
calculated.
That is, any participant who withdraws or is discontinued from the study or who misses a 
scheduled visit or assessment through Day 180 will have their missing AUC related efficacy data 
analyzed as imputed using MI techniques.  
Multiple imputation based on a standard MAR imputation approach will be performed in SAS®
software using the general approach described below. This strategy is appropriate for data sets 
that have an arbitrary missing data pattern.
Step 1: The Missing at Random (MAR) imputation model will impute missing values using a 
fully conditional specification (FCS) regression-based multiple imputation model.7 For 
participants with missing data at a particular visit, a multiple regression model will be fit that 
includes the outcome at that visit as the dependent variable and observed data (e.g., outcomes at 
other visits, treatment, age category [6 to 11, 12 to RU\HDUV@H*)5FDWHJRU\>
P/PLQRU mL/min], and baseline value of the primary response variable (e.g., Uox or Uox-
to-creatinine ratio) as independent variables. This process will be repeated 50 times, resulting in 
50 complete analysis data sets. The seed number of 3216549 will be used for the imputation 
procedure described in Step 1.
SAS pseudo code is provided below:
PROC MI DATA=indata OUT=outdata SEED=3216549 NIMPUTE=50;
CLASS <treatment> <age category> <eGFR category>;
FCS REG (<day 90> <day120> <day 150> <day 180>);
VAR <treatment> <age category> <eGFR category> <baseline> <day 90> <day120> 
<day 150> <day 180>;
RUN;


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Step 2:  The corresponding derived efficacy endpoints (e.g., AUC24-hour Uox from Day 90 to 
Day 180) will be calculated based on the imputed data for each participant and for each of the 
completed analysis datasets.  The standard SAS code that is developed to calculate the derived 
efficacy endpoints (e.g. AUC24-hour Uox from Day 90 to Day 180) will be applied to each of the 50 
imputed datasets.
Step 3: The ANCOVA analyses will be performed separately for each of the 50 completed 
analysis data sets, and the results will be combined into one multiple imputation inference 
(estimated treatment effect, standard error, p-value and associated 95% CI) using the SAS 
MIANALYZE procedure.7,8 The treatment difference will be tested at the one-sided 2.5% level 
and corresponding 95% CIs will be calculated.  SAS Note: As PROC GLM does not report 
standard error for the difference of two LSMeans, GLM cannot be used in conjunction with 
PROC MIANALYZE.  However, the equivalent code using PROC MIXED can be used to obtain 
the combined results.
SAS pseudo code is provided below:
PROC SORT DATA=outdata1 OUT=efficacydat;
BY <imputation number> <treatment>;
RUN;
PROC MIXED DATA=efficacydat;
BY <imputation number>;
CLASS <treatment> <age category> <eGFR category>;
MODEL <efficacy variable> = <treatment> <age category> <eGFR category> 
<baseline> ;
LSMEANS <treatment> / DIFF;
ODS OUTPUT LSMeans=lsmeans_ds Diffs=diffs_ds;
RUN;
*COMBINES THE LS MEANS ACROSS THE MI DATASETS;
PROC SORT DATA=lsmeans_ds;
BY <treatment> <imputation number>;
RUN:
PROC MIANALYZE DATA=lsmeans_ds;
BY <treatment>;
MODELEFFECTS estimate;
STDERR stderr;
RUN;
*COMBINES THE LS MEAN DIFFERENCES ACROSS THE MI DATASETS;
PROC SORT DATA=diffs_ds;
BY <treatment> <imputation number>;
RUN:


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PROC MIANALYZE DATA=diffs_ds;
BY <treatment>;
MODELEFFECTS estimate;
STDERR stderr;
RUN;
6.1.5.2.
24 Hr Uox Measurements Which Do Not Meet Completeness Criteria
To maintain the integrity of all analyses related to 24-hour Uox measurement, urine 
completeness criteria have been established to ensure adequate, valid collection of all 24-hour 
Uox samples.
Screening Period 24-hour Urine Collection Completeness:
According to the protocol, there must be no more than 20% variation between the two 24-hour 
urinary creatinine values measured in the screening period. Should the initial pair of screening 
values not meet this criterion, participants will be given the opportunity to perform a second pair 
of collections. The screening period may be extended by 7 days (for a total of 42 days in 
screening) to allow time to repeat the additional 24-hour urine collections. Additionally, the site 
will review the 24-Hour Urine Collection Schedule worksheets completed by the participant. 
Any collection with a duration of less than 22 hours or greater than 26 hours will be considered 
invalid and must be repeated.
Treatment Period 24-hour Urine Collection Completeness:
As detailed in the Study Unblinded Clinical Monitoring Plan, certain members of the unblinded 
study team will conduct an ongoing review of treatment-period 24-hour urinary creatinine 
excretion values, to ensure all weight-adjusted 24-hour urinary creatinine excretion values are no 
more than 20% of baseline. If the percentage change in any weight-adjusted 24-hour urinary 
creatinine excretion values are more than 20% of baseline, then this is a violation of the 
completeness criteria. If weight is missing at a visit, LOCF (last observation carry forward) 
weight should be used in creatinine excretion values per kg calculation. Baseline is defined as the 
mean of the 2 screening values. Additionally, the site will review the 24-Hour Urine Collection 
Schedule worksheets completed by the participant. Any collection with a duration of less than 22 
hours or greater than 26 hours will be considered invalid.
Should a treatment-period value not meet these criteria, participants will be required to complete 
another 24-hour urine collection. Recollection should occur within 10 calendar days from the 
time of the visit for which the collection was intended whenever possible. In the event the 
repeated 24-hour urine collection violates the completeness criteria, the 24-hour urine collection 
for that visit will not be repeated a second time. 
For the analyses of AUC related endpoints, only 24 hour urine oxalate measurements that meet 
the completeness criteria will be used for each visit to calculate AUC. That usually would be the 
latest measurement in case of recollection if criteria are not met. In case there is more than one 
measurement that does not violate the completion criteria, the average will be taken.


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Measurements that violate the completeness criteria will not be included in the AUC 
calculations.  Rather those values will be treated as missing data and will be imputed via the MI 
methods described in section 6.1.5.1 prior to calculating the AUC values for analysis. 
As a sensitivity analysis, when there is no measurement that meets completeness criteria for that 
visit, if the changes from baseline of both 24-hour urinary creatinine excretion values go in the 
same direction (i.e., positive or negative), then the 24-hour Uox measurement with the smallest 
absolute change will be used; otherwise, if they go in different direction, then the 24-hour Uox 
measurement with the positive change from baseline of 24-hour urinary creatinine excretion will 
be used. The conservative approach is to refrain from observing any effect due to an under-
collection
6.1.6. Uox Measurements below the Limit of Quantitation
If a reported Uox measurement is below the limit of quantification (LLOQ), then the 24 hour
Uox value will be imputed as 0. For oxalate values < 50 umol/L, the 24 hour Uox value will be 
imputed as 0 umol/24h.
6.1.7. Handling of Rescreened Participants
Rescreening of participants is allowed.  If a patient initially screen fails and is subsequently 
enrolled then that participant will have two subject IDs within the EDC system (one ID for the 
screen failure and associated data collection, and one ID for the subsequently enrolled 
participant).  The demographics CRF will collect the previous subject ID for rescreened 
participants.  In these cases, the initial screening data collection will be tied to the enrolled 
subject ID in order to ensure compliance with CDISC standards.
6.1.8. Analysis Visit Windows
By-visit summaries will be based on electronic case report form (eCRF)-defined nominal visits.
In general, analysis of all variables for this study will use the nominal visit or time point as 
collected on the electronic case report form (eCRF) and/or database. Scheduled visits will be 
selected over unscheduled visits.
For those subjects who discontinue early from the study and the Early Termination (ET) visit 
satisfies the following condition:
x
20 days <= the date of ET - the date of the last visit before ET +1 <= 40 days
then the ET visit will be mapped to the next scheduled visit. Otherwise, the ET will not be 
mapped into any analysis visits. 
Adverse events (AEs) and concomitant medications are exceptions to the above rule; all 
treatment-emergent AEs (TEAEs) and concomitant medications will be presented.    


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6.1.9. Derived Variables
Change from baseline = value at current time point – baseline value
Percentage change from baseline = ቀ
௩௔௟௨௘௔௧௖௨௥௥௘௡௧௧௜௠௘௣௢௜௡௧ି௕௔௦௘௟௜௡௘௩௔௟௨௘
௕௔௦௘௟௜௡௘௩௔௟௨௘
ቁכ 100%
Treatment-emergent AE (TEAE) = any AE with an onset date/time on or after administration 
(including any partial administration) of the first dose of study intervention and through the study 
completion date from the end of study CRF. That is, if the start time for the AE is provided, then 
the AE start date and time will be compared with the first dose date and time in order to 
determine whether the AE is a TEAE.  If the start time for the AE is not provided, then the AE 
start date will be compared with the first dose date.  In this case if the AE start date is on or after 
the first dose date, then the AE is considered a TEAE.
Body Surface Area (BSA)
BSA will be calculated via the DuBois formula: 
x
BSA (m2) = 0.007184 × height(cm)0.725 × weight(kg)0.425
BSA Adjusted Uox: for participants aged <18 years, the 24-hour Uox values will be adjusted for 
BSA using the following formula prior to using the values in any analyses. The adjusted values 
ZLOOEHXVHGIRUDOOHQGSRLQWFDOFXODWLRQV3DUWLFLSDQWVDJHGyears will not have any 
adjustments performed to their 24-hour Uox results for the primary analysis.  BSA Adjusted Uox 
values for all participants will be used for sensitivity analysis. All BSA Adjusted Uox values will 
use the BSA for the participant using the height and weight taken at same visit as the 24-hour 
Uox value.  
x
BSA Adjusted Uox = 24-hour Uox value * (1.73/BSA of participant)
If the height and weight are not available from the same visit as the 24-hour Uox value, then the 
imputation rules described in section 6.1.10.3 Missing Height/Weight Measurements to be used 
for BSA Adjusted Uox Calculations will be used to impute the height and weight in order to 
calculate the BSA Adjusted Uox values.  


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eGFR Equations
Chronic Kidney Disease Epidemiology Collaboration9 (CKD-EPI) equation – for Adult 
3DUWLFLSDQWV\HDUV
x
eGFR = 141 x min (SCr/k, 1)Į x max (SCr/k, 1)-1.209 x 0.993Age x 1.018 (if female) x 
1.159 (if Black)
SCr = standardized serum creatinine in mg/dL
k = 0.7 for females or 0.9 for males
Į -0.329 for females or -0.411 for males
min = minimum value
max = maximum value
age is in years
Schwartz 2009 creatinine-based equation10 – for Pediatric Participants (< 18 years of age)
x
eGFR = 36.5 x height/SCr
height is in centimeters
SCr = serum creatinine in mol/L
Schwartz 2012 multivariate equation11 – for Pediatric Participants (< 18 years of age)
x
eGFR = 39.8 x [ht/Scr]0.456 x [1.8/cysC]0.418 x [30/BUN]0.079 x 1.076male x [ht/1.4]0.179
ht = height in meters
Scr = serum creatinine in mg/dL
cysC = cystatin C in mg/L
BUN = blood urea nitrogen in mg/dL 
male = 1 if the patient is a male; 0 otherwise
Matsuo eGFR Equation - For Adult Participants in Japan
x
H*)5 î>&U@íî>$JH@íîLQIHPDOHV
The above eGFR calculations will be performed by the central laboratory.
For adolescents who turn 18 during the course of the study, the equation used at baseline (eGFR 
2009 Schwartz Creatinine-based equation) will be used throughout the study.


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Weight Adjusted 24-hour Urinary Creatinine Excretion (WTCREA24)
24-hour urinary creatinine excretion values (SDTM.LB CREAT24) will be merged with 
SDTM.VS records where VSTESTCD=WEIGHT and VSSTRESN is not missing. 
Calculate WTCREA24 = [CREAT24] / [WEIGHT]
Area Under the Curve (AUC)
AUC24-hour Uox is calculated based on the percent change from baseline in Uox. The x-axis will be 
time in days and y-axis will be percent change from baseline in Uox. A percent decrease from 
baseline in Uox will be denoted as negative. A percent increase from baseline in Uox will be 
denoted as positive. The curve might be in its entirety, or at least in part, below the x-axis (Panel 
A, Figure 1). The area below the x-axis will be calculated and presented as a positive value. For 
an increase from baseline the percent change from baseline will be positive and that part of curve 
will be above the x-axis. The AUC would then be calculated as area below the axis minus area 
above the x-axis (Panel B, Figure 1). The AUC will be calculated using the trapezoidal rule; 
however, given that the percent change from baseline in Uox can change sign, we will use the 
approach outlined in the PharmaSUG by Jianfeng Ye12.
The AUC will be calculated using the actual time in days between Uox collections, and not the 
nominal visit days. See Figure 1 for examples of the AUC, where the portion of the data to be 
used in calculation of the primary endpoint is contained within the orange box. 
Figure 1
Example of AUC Graphs for Primary Endpoint
Panel A: All values below 0
Panel B: Values both above and below 0
AUC24-hour Uox: creatinine will be calculated as described above for Uox except that the AUC24-hour 
Uox: creatinine will be based on the percent change from baseline in the values of the Uox-to-
creatinine ratio.
-50%
-40%
-30%
-20%
-10%
0%
10%
0
3 0
6 0
9 0
1 2 0
1 5 0
1 8 0
Study Day
-50%
-40%
-30%
-20%
-10%
0%
10%
0
30
60
90
120
150
180
Study Day


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As illustrated in figure 1 above, the AUC for Day 90 to Day 180 is calculated based on the area 
underneath the 0 percent line between Day 90 and Day 180. For improvement in the subjects’ 
condition, i.e. area below the zero percent line, we define the AUC as a positive number. For 
worsening of the subjects’ condition, i.e. area above zero percent line, we define the AUC as a 
negative number. The final AUC will be the area below the zero percent line minus the area 
above zero percent line. The final AUC for each subject will be standardized based on 90 days.
x
AUC_standardized = (AUC/actual days from Day90 visit to Day180) x 90
If data are only partially available between day 90 and day 180 (i.e. assessment dates are missing 
at either day 90 or day 180), the standardization will assume the actual number of days elapsed to 
be 90. 
Quality-of-life Questionnaires
Adults - SF-36
As part of the Medical Outcomes Study (MOS), a multi-year study to explain variations in 
participant outcomes, RAND developed the 36-Item Short Form Health Survey (SF-36). The SF-
36 is a set of generic, coherent, and easily administered quality-of-life measures that taps 8 
health concepts: physical functioning, bodily pain, role limitations due to physical health 
problems, role limitations due to personal or emotional problems, emotional well-being, social 
functioning, energy/fatigue, and general health perceptions. It also includes a single item that 
provides an indication of perceived change in health. The 36 items are identical to the MOS SF-
36 described in Ware and Sherbourne13. Participants respond to each item on a categorical scale. 
Categorical answers are transformed to a range of 0 to 100. In addition to the eight health 
concept scales, two component summary measures are also calculated: PCS (physical component 
summary), and MCS (mental component summary). All items are scored so that a high score 
defines a more favorable health state.
For this study, the SF-36 questionnaires will be scored by the algorithm outlined in Appendix 2 
based on the manual “How to Score version 2 of the SF-36 Health Survey” (Ware JE, et al. 
2000). Additional detail on each of the domain and summary scores are contained therein.
Adults - EQ-5D-5L
The 5-level EQ-5D version (EQ-5D-5L) was introduced by the EuroQol Group in 2009 to 
improve the instrument’s sensitivity and to reduce ceiling effects, as compared to the previously 
3-level EQ-5D14. The EQ-5D-5L consists of the EQ-5D descriptive system and the EQ visual 
analog scale (EQ VAS).
The descriptive system comprises 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight 
problems, moderate problems, severe problems and extreme problems. Participants are asked to 
indicate their health state by ticking the box next to the most appropriate statement in each of the 


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5 dimensions. This decision results in a 1-digit number that expresses the level selected for that 
dimension. The digits for the 5 dimensions can be combined into a 5-digit number that describes 
the participant’s health state. It should be noted that the numerals 1 to 5 have no arithmetic 
properties and should not be used as a cardinal score.
The values collected for the 5 health dimensions will be used to calculate an EQ-5D-5L index 
value.  Index values will be calculated based on the US value set. Additional details are 
contained in a separate users guide document.
The EQ VAS records the participant’s self-rated health on a 20-cm vertical VAS, where the 
endpoints are labelled ‘The best health you can imagine’ and ‘The worst health you can 
imagine’. Participants are asked to place an “X” on the line that represents their health on that 
day. The VAS can be used as a quantitative measure of health outcome that reflect the 
participant’s judgement.
Pediatrics - PedsQL
The PedsQL™ is a modular approach to measuring health related quality of life (HRQOL) in 
healthy children and adolescents 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 World Health Organization (WHO) in 1948 (physical, emotional, 
and social functioning), as well as role (school) functioning15, 16. 
Questionnaires are administered to the participant and the participant’s parent.  The 23-item 
PedsQLTM 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. The 
questionnaire has specific versions for the child and the child’s parent based on the age of the 
participant (5-7 years old, 8-12 years old, 13-18 years old).  Questionnaires are administered 
based on the age of participant at baseline.  The same version of the questionnaire will be used 
throughout the course of the study for a given participant based on age at baseline.  Additionally, 
the family impact module is administered to the participant’s parent.
Items are reverse-scored on a 0 to 4 Likert scale and linearly transformed to a 0 to 100 scale.
Scale scores are computed as the sum of the items divided by the number of items answered (this 
accounts for missing data). If more than 50% of the items in the scale are missing, the scale score 
is not computed.  Higher scores indicate better functioning and HRQOL.  Further details and 
scoring instructions are provided in a separate document.
6.1.10. Data Adjustments/Handling/Conventions
All collected data will be presented in listings. Data not subject to analysis according to this plan 
will not appear in any tables or graphs but will be included in the data listings.
All p-values will be displayed in four decimals and rounded using standard scientific notation 
(e.g., 0.XXXX). A p-value less than 0.0001 will be shown in tables as <0.0001.


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6.1.10.1.
Missing or Partial Dates/Times for Adverse Events (AE) and 
Prior/Concomitant Medications (CM), AE Intensity, and AE Relationship
The following list describes how partially missing date information will be handled as it relates 
to partial or missing AE start dates. Partial AE start dates will be imputed as the following:
1. If year is not missing and is after the year of first dose:
a.
If month is missing, then month will be imputed as January.
b. If day is missing, then day will be imputed as the first of the month.
2. If year is not missing and is the same as the year of the first dose:
a.
If month is missing, then impute the month as the month of the first dose date.
b. If day is missing, and the month is the same as the month of the first dose date, then 
impute day as the day of the first dose date.
c.
If day is missing but month is after the month of first dose date, then impute day as 
the first day of the month.
3. If year is missing then impute the year as the year of the first dose date:
a.
If month is missing, then impute the month as the month of the first dose date.
b. If day is missing, then impute the day as the day of the first dose date.
4. If the start date is completely missing, but the AE is either ongoing or the stop date is 
after the first dose date then impute the start date as the first dose date.
5. For any cases involving the rules above, if the AE end date is before the AE start date, 
then leave the AE start date missing and assume that AE is treatment emergent for the 
purpose of the analysis. Further, if the AE stop date is complete and occurs prior to first 
dose date, leave the AE start date missing and assume that AE is not treatment emergent.
Dates will not be imputed if not considered potentially treatment-emergent.  For example, if 
the AE year matches that of the first dose date but the AE month is prior to that of the first 
dose date the event is not considered potentially treatment-emergent and no imputed date will 
be assigned.  No imputations will be applied to AE stop dates. No imputations will be applied 
to AE start or stop times.
Imputation for medication start dates will be handled similarly.
Relationship of the AE to study intervention and intensity will not be imputed for analyses.
6.1.10.2.
Missing/Partial Dates for PH Diagnosis
PH diagnosis dates with partial dates will be imputed as follows: missing day values will be 
imputed as 15, and missing month values will be imputed as June in order to calculate the time 
since PH diagnosis or other related variables.


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6.1.10.3.
Missing Height/Weight Measurements to be Used for BSA Adjusted Uox 
Calculations
If the height and weight are not available from the same visit as the 24-hour Uox value, then the 
following imputation rules will be used to impute the height and weight in order to calculate the 
BSA Adjusted Uox values.  Please note that the imputed height and weight values will not be 
summarized in any tables or provided in any listings.  These imputed values will be used for the 
BSA Adjusted Uox calculations only.
Weight Imputations Rules for BSA Adjusted Uox Calculation
For all participants, regardless of age, missing weight values will be imputed by fitting a mixed 
model with weight at the dependent variable and study month as the main effect. Random 
coefficients will be used for the intercept and study month.  In this way, the coefficients will vary 
by subject.  The fitted line will be used to impute the missing weight value for a given value of 
study month. Example SAS pseudo code is shown below:
ODS OUTPUT SolutionF = fixed SolutionR = random
PROC MIXED DATA=weightdata;
CLASS <subject>;
MODEL <weight> = <study month> / SOLUTION;
RANDOM INTERCEPT <study month> / SUBJECT = <subject> SOLUTION;
RUN;
PROC TRANSPOSE DATA = fixed (KEEP = estimate effect) OUT = fixed1 (DROP = _name_ 
RENAME = (<study month> = fmonth <intercept> = fintercept));
ID effect;
RUN;
PROC TRANSPOSE DATA = random (KEEP = <subject> estimate effect) OUT = random1 
(DROP = _name_);
BY <subject>;
ID effect;
RUN;
DATA coefficients;
IF _n_ = 1 THEN SET fixed1;
SET random1;
<intercept> = fintercept + intercept;
<month slope> = fmonth + <study month>;
RUN;


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To calculate a missing weight value from a known study month, take the corresponding subject 
specific coefficients from the dataset above and plug them into the formula <weight> = 
<intercept> + <month slope> * <study month>.
Height Imputation Rules for BSA Adjusted Uox Calculation:
x
For participants <18 years, missing height values will be imputed in the same way as 
described above for weight except that height will be the dependent variable for the 
model.
x
)RUDGXOWV\HDUVKHLJKWDWVFUHHQLQJZLOOEHXVHGIRU%6$DGMXVWHG8R[
calculation.  Height will not be imputed for post-screening visits. 
6.1.11. Subgroups
The same analysis for the primary endpoint (i.e. AUC24-hour Uox from Day 90 to Day 180, based 
on percent change from baseline) will be performed on the subgroup of participants with at least 
one baseline 24-KRXU8R[PPRODGMXVWHGSHUP2 BSA in participants aged <18 years).
Subgroup analysis of the primary endpoint may be performed on the list of subgroups provided 
in Table 2, if data permitting.  
Table 2: List of Subgroups
1.
Age WR\HDUVLIDYDLODEOHWR\HDUVRU\HDUV
2.
Baseline eGFR P/PLQVXUIDFHDUHDRUP/PLQ/surface area) 
3.
PH Type (PH1 or PH2)
4.
Gender (male or female)
7.
Study Participants and Demographics
7.1.
Disposition of Participants and Withdrawals
Disposition will include tabulations by treatment group and over-all for the number of 
participants enrolled, and either screen failed or randomized into each treatment group.  The 
number and percentage of participants who: received treatment, completed treatment, completed 
study, reasons for treatment discontinuation/study withdrawal (overall and by reason for 
discontinuation/study withdrawal), and continue on to protocol DCR-PHXC-301 will be reported 
by treatment group and overall. The number and percentage of participants in each analysis 
population will also be displayed by treatment group and overall.
7.2.
Protocol Violations and Deviations
Prior to database lock and unblinding, all protocol deviations will be reviewed and categorized as 
either ‘Important’ or ‘Non-important’: 


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Protocol Number DCR-PHXC-201
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AD-ST-33.05  Effective date: 22-Jan-2018
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x
Important PDs are a subset of protocol deviations that may significantly impact the 
completeness, accuracy, and/or reliability of key study data or that may significantly 
affect a subject's rights, safety, or well-being. 
x
Non-important PDs will be identified as any protocol deviation that does not meet the 
criteria for Important PD.
Subjects with at least 1 deviation classified in the major protocol deviation list included in the 
appendix to this SAP will be excluded from the PP analysis population.
7.3.
Demographics and Other Baseline Characteristics
Summary statistics for age, age category, gender, race, ethnicity (where available, as ethnicity 
may not be collected at all sites), height, weight, and BSA will be presented by treatment group
and overall. Body mass index will be calculated at the site and recorded in the eCRF. Body 
surface area will be computed as described in Section 6.1.10.
Summary statistics will be presented by treatment group and overall for baseline eGFR category, 
baseline 24-hour Uox results, PH type, time since PH diagnosis, number of kidney stone events 
in the last 12 months, and the number and surface area of kidney stones at baseline.
These summaries will be conducted for the MITT and SAF populations.
The number and percentage of participants reporting various medical histories, grouped by 
medical dictionary for regulatory activities (MedDRA) system organ class (SOC) and preferred 
term (PT) (MedDRA; Version 23.0 or higher), will be tabulated by treatment group and overall. 
This analysis will be conducted for the SAF population.
Prior medications will be presented separately from concomitant medications. Medications that 
started prior to dosing on Day 1 will be considered prior medications whether or not they were 
stopped prior to Day 1 dosing. Missing dates will be handled using the methodology described 
in Section 6.1.11.1. Medications will be coded using world health organization drug dictionary
(WHO-DD) version B3 September, 2019 or higher. The number and percentage of participants 
reporting prior medication use, grouped by ATC Level 2 and ATC Level 4, will be tabulated by 
treatment group and overall. This analysis will be conducted for the SAF population. A listing of 
prior medications will be provided; the analysis on concomitant medications is described in 
Section 9.7.
All collected demographics and other baseline characteristics will be listed by participant.
7.4.
Exposure and Compliance
Study intervention will be administered in clinic once monthly as described in Section 3.4. Any 
deviations from the planned dose will be reported.
Summary statistics of the number of doses received, the number of participants who received
study drug for each dosing visit, and the percent of scheduled doses received will be presented 
by treatment group.


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These summaries will be conducted for the SAF population. All study drug administration 
information will be presented in participant data listings.
8.
Efficacy Analysis
All AUC parameters referenced in the efficacy analysis refer to the standardized AUCs defined 
in section 6.1.9.
8.1.
Primary Efficacy Analysis
The primary efficacy endpoint of this study is the AUC24-hour Uox from Day 90 to Day 180, based 
on percent change from baseline. The primary endpoint will be compared between the active 
treatment group and the placebo group.
This is a superiority study. For the primary endpoint, the null hypothesis to be tested is: 
x
H0: AUC24-hour Uox, a = AUC24-hour Uox, p against one-sided alternative hypothesis 
x
HA: AUC24-hour Uox, a > AUC24-hour Uox, p.   
where
x
AUC24-hour Uox, a is the AUC24-hour Uox for the active treatment arm (DCR-PHXC),
x
AUC24-hour Uox, p is the AUC24-hour Uox for the placebo arm
All hypotheses will be tested at the one-sided significance level alpha of 2.5%.  
Mean AUC24-hour Uox from Day 90 to Day 180 will be compared between treatment groups using 
an ANCOVA model with treatment group as a main effect in the model; and age category [6 to 
11, 12 to 17, or \HDUV], eGFR category [<45 mL/min or P/PLQ], and baseline Uox as 
covariates, where the BSA adjustment is applied to the 24 hour urinary oxalate values for all 
pediatric subjects.  The adjusted means for each treatment will be presented together with their 
95% confidence intervals.  The adjusted mean difference will be presented along with its 95% 
confidence interval and p-value.
The primary efficacy analysis will be based on the MITT dataset. This analysis will be repeated 
for the PP population and in addition as sensitivity analyses in ITT and EVAL population (see 
section 8.5).
Uox concentrations which do not meet completeness criteria (see section 6.1.5.2) will be 
excluded from the primary efficacy analysis. Multiple imputation will be used for those excluded 
values as well as for all other missing values.
Descriptive statistics for actual Uox concentrations and for percent change from baseline will be 
presented by visit.  
8.2.
Key Secondary Efficacy Analysis
The key secondary endpoint of the proportion of participants whose Uox values normalized or 
near-normalized on at least 2 consecutive visits starting at Day 90 will be summarized by 


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treatment group. A one-sided Fisher’s exact test at significance level alpha of 2.5% will be used 
for comparison between treatment groups within the hierarchical testing framework described in 
section 6.1.4 Multiple Comparisons. 
Two separate analyses of the key secondary efficacy endpoint will be presented:
1. Primary analysis: applying the BSA Uox adjustment only to subjects < 18 years old
2. Secondary (sensitivity) analysis: applying the BSA Uox adjustment to all subjects 
(pediatrics and adults)
The analyses will be performed based on MITT population.
8.3.
Secondary Efficacy Analysis
The secondary efficacy endpoints listed below will be summarized by treatment group.  A 
one-sided Wilcoxon Rank Sum test will be used for the comparison between treatment groups
for both change and percentage change from baseline for the following outcome variables.  
x
Change/Percentage change from baseline to Day 180 in the summed surface area of 
kidney stones
x
Change/Percentage change from baseline to Day 180 in the number of kidney stones
x
Change/Percentage change from baseline to Day 180 in plasma oxalate (for adults only)
The stone surface area and stone count are defined as follows:
x
Stone Surface Area: sum of the measured and calculated surfaces of the stone larger than 
5 mm (the longest diameter)
x
Stone Count: Stones will be categorized measurable or non-measurable as follows, only 
measurable stones will be used in the analyses:
o
Measurable : with a minimum size of 5 mm in the longest diameter the surface 
area of the stones
o
Non Measurable: all other stones, including small stones (longest diameter < 5 
mm); if the number is too high, they may just say “too many to count”, and / or 
provide an approximate number
Percentage change will also be calculated for the summed surface area of kidney stones and 
number of kidney stones using the CT results. These will be listed for each subject for the 
subgroup of participants from CT sub-study as described in the Protocol Appendix B.


Statistical Analysis Plan, 
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A linear mixed model with observed eGFR as the dependent variable and treatment, study month 
and the interaction between treatment and month as independent variable, will be used to 
estimate rate of decline in eGFR response between DCR-PHXC and placebo treatments. A 
random intercept and slope will be included in the mixed model to fit a different intercept and 
slope for each subject.  In this analysis nominal month will be modeled as a continuous 
independent factor.
The Least Squares adjusted means will be reported for each treatment group as well as the 
standard errors and 95% confidence intervals for the LS means. The estimate of treatment effect 
will be reported as the difference in treatment means, 95% confidence interval for the difference 
in means, the standard error for the mean difference, and the p-value for the treatment difference.
Example SAS code is provided below for reference:
PROC MIXED DATA=<input data> METHOD=REML;
   CLASS <treatment> <participant ID>;
   MODEL <observed eGFR value> = <treatment> <Month> <treatment*Month> /  SOLUTION  
DDFM=KWR;
RANDOM int <Month>  / SUB= <participant ID> TYPE=<covariance structure>;
ESTIMATE "Slope for Treatment='DCR-PHXC " Month 1 <treatment*Month> 1 0 ;
ESTIMATE "Slope for Treatment=Placebo" Month 1 <treatment*Month> 0 1;
ESTIMATE “DCR-PHXC versus Placebo” <treatment*Month> 1 -1 / alpha=0.05 CL;
RUN;
To handle the repeated measures data an unstructured variance-covariance matrix will be 
considered. In the event of convergence issues, a compound symmetric variance-covariance 
matrix will be used. 
Separate ANOVA models will be considered for the following two eGFR parameters:
x
Parameter 1: including all subjects using eGFR CKD-EPI equation and Schwartz et al. 
2009 creatinine-based equation.  
x
Parameter 2: including all subjects using eGFR CKD-EPI equation and Schwarz 2012 
Cystatin C-based equation
These analyses will be performed based on the ITT population.  All hypotheses will be tested at 
the one-sided significance level alpha of 2.5% within the hierarchical testing framework 
described in section 6.1.4 Multiple Comparisons.  
Descriptive statistics for the summed surface area of kidney stones, number of kidney stone, 
plasma oxalate, eGFR, and for the percent change from baseline will be presented by visit.
8.4.
Tertiary/Exploratory Efficacy Analysis
The same statistical model described above for the primary efficacy analysis will be applied to 
the following tertiary/exploratory efficacy endpoints.


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x
AUC24-hour Uox from Day 1 to Day 180, based on percent change from baseline (ITT 
population)
x
Percent change in 24-hour Uox from baseline to Day 180 (ITT population)
x
AUC24-hour Uox:creatinine from Day 90 to Day 180, based on percent change from baseline
(MITT population)
x
Change from baseline to Day 180 in the SF-36, EQ-5D-5L in adults, and in the 
PedsQLTM in children (ITT population)
The number of stone events over a 6-month period will be analyzed using an exact Poisson 
regression model.  The model will include treatment group and baseline stone events rate 
(continuous). Baseline stone events rate will be the number of stone events observed over the 
past 12 months prior to dosing. The model will include an offset term for total follow-up time as 
the ‘number of months exposed’ equal to the total elapsed time between first dose date and last 
day of visit in the study, divided by 30.4375. Annualized stone event rate (number of stone 
events per year per person) will be derived as number of stone events in the exposure period / 
total number of years exposed.
Example SAS code is given below:
PROC GENMOD DATA=;
  CLASS TREATMENT;
  MODEL ‘Number_stone_evts_6month’=Treatment Kidney_Stone_Event_Baseline 
/OFFSET=Ln_Number_Of_Months_Exposed DIST=POISSON LINK=LOG DSCALE;
  EXACT Treatment Kidney_Stone_Event_Baseline / ESTIMATE;
RUN;
The number of stone events will be calculated as the number of discreet (non-concurrent)
adverse events marked as a Kidney Stone Event on the adverse event CRF.  Kidney stone events 
include: renal stone requiring medical intervention, stone passage with or without hematuria, and 
renal colic requiring medication.  Concurrent events will be defined as events occurring within 
the same 4-week (28-day) window. For example, renal colic treated with medication on Monday 
12 November 2019 followed by stone passage without hematuria on Friday 30 November 2019 
is a single (concurrent) stone event (18 days between start and stop of single stone event). Renal 
colic treated with medication on Monday 12 November 2019 followed by stone passage without 
hematuria on Wednesday 13 December 2019 is considered two separate stone events (30 days 
between discreet event one and event two).
To evaluate the relationship between Uox in spot urine and 24-hour urine, the correlation
between the two measurements will be examined for the ITT population.
Descriptive statistics for SF-36 and EQ-5D-5L scores in adults, PedsQL scores in children, and 
Uox in spot urine samples, and the percent change from baseline will be presented by visit.
8.5.
Sensitivity Analyses
The following sensitivity analyses will be performed for the primary endpoint:


Statistical Analysis Plan, 
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x
Same analysis as described in Section 8.1, but performed on the ITT population.
x
Same analysis as described in Section 8.1, but performed on the EVAL population.
x
Non-parametric analysis of the primary endpoint (AUC24-hour Uox) using Wilcoxon Rank 
Sum test for the comparison between treatment groups
x
Same analysis as described in Section 8.1, but performed on BSA adjusted Uox 
concentration for all participants.
x
Same analysis as described in Section 8.1, but rather than using the mean of the two 
screening 24-hour Uox values as the baseline value the lowest of the two screening 24-
hour Uox values.
x
Same analysis as described in Section 8.1, but using all Uox concentrations, including 
those which do not meet completeness criteria (see section 6.1.5.2)
x
Same analysis as described in Section 8.1 but performed using an MI approach assuming 
that the data are missing not at random (MNAR). Control-based pattern imputation will 
be used together with FCS. Control-based pattern imputation explores the assumption 
that patients revert to control group after drop-out. Thus, it is assumed that after drop-out, 
the unobserved values in experimental group follow the path of observed values in 
control group. 
Section 6.1.5.1 describes the details of the MI approach used in the primary analysis
using MAR.  For this sensitivity analysis, Step 1 of section 6.1.5.1 will be replaced with 
the following:
o
Step 1: The MNAR imputation model will impute missing values using an FCS 
regression-based multiple imputation model. 
The further description of step 1 still applies, the SAS pseudo code will be 
amended using additional MNAR statement within PROC MI:
MNAR model (<day 90> <day120> <day 150> <day 180> / modelobs= 
(<treatment> ='Placebo'));
x
Same analysis as described in Section 8.1 but performed without using an MI approach
9.
Safety and Tolerability Analysis
Safety will be evaluated from reported AEs, reported concomitant medications, changes in 
clinical laboratory values, changes in vital signs, electrocardiogram (ECG), echocardiogram with 
Doppler, and physical examination results.
All safety analyses will be performed on the SAF population. All summaries will be descriptive 
in nature. No statistical comparisons will be performed.


Statistical Analysis Plan, 
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Protocol Number DCR-PHXC-201
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9.1.
Adverse Events
All AEs, TEAEs, and SAEs will be coded using the MedDRA v23.0 or higher.  AEs will be 
classified as treatment-emergent for analysis in summary tables where applicable. 
A TEAE is defined as any event that started, changed in intensity, or changed relationship to the 
study treatment at the time of or after the first dose date and through the study completion date. 
An overview summary of AEs, including counts and percentages, the risk difference and their 
95% CI will be presented for subjects with: any TEAEs, TEAEs related to study treatment; 
TEAEs leading to treatment discontinuation, treatment-emergent SAEs, treatment-emergent 
SAEs related to study treatment, TEAEs of special interest (i.e., injection site reactions; muscle 
pain or weakness; kidney stones: renal stone requiring medical intervention, stone passage with 
or without hematuria, and renal colic requiring intervention), and fatal TEAEs.
9.1.1. Adverse Events Summaries
The number and percentage of participants with AEs will be summarized by SOC and PT. This 
summary will further be tabulated by strongest relationship to study intervention (related: 
definitely, probably, and possibly related; unrelated: unrelated; missing). A similar summary of 
TEAEs will be produced by maximum intensity (mild, moderate, severe, missing). In addition, 
the number and percentage of participants who experienced non-serious TEAEs (all TEAEs 
except serious TEAEs) that occurred in more than 5% of participants in either treatment group 
will be presented by SOC and PT for each treatment. 
To count the number of participants who experienced each TEAE, a participant experiencing the 
same TEAE multiple times will only be counted once for the corresponding PT. Similarly, if a 
participant experiences multiple TEAEs within the same SOC, the participant will be counted 
only once for that SOC. For summaries by maximum severity, if a participant experiences more 
than one TEAE with different intensities severity (e.g., the same SOC and PT), only the worst 
intensity/severity will be reported. If a participant has both missing and non-missing intensity for 
a given SOC and PT, the missing intensity is selected for reporting unless the non-missing 
severity is noted as Severe. Treatment-emergent AEs will be sorted alphabetically by SOC and 
PT and presented by decreasing order of overall frequency. Treatment-emergent AEs analyzed 
by strongest relationship will be selected similarly for participants experiencing more than one 
TEAE with different relationships. If a participant has both missing and non-missing relationship
for a given SOC and PT, the missing relationship is selected for reporting unless the non-missing 
relationship is noted as Related.
The number of TEAEs will be presented by SOC and PT.  The total number of TEAEs will also 
be presented in the display.
In addition, all TEAEs will be provided in a listing, which will include the participant identifier, 
study intervention start date/time, SOC, PT, verbatim term, intensity, seriousness, relationship, 
action taken, outcome, date/time of onset, study day, date/time of resolution, and event duration 
in days. Event duration will be calculated as: (resolution date – start date) +1.


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9.1.2. Summaries for Serious Adverse Events, AEs Resulting in Early Withdrawal, and 
Deaths
The number and percentage of participants who experienced treatment-emergent SAEs will be 
presented by SOC and by PT within each SOC. Treatment-related treatment-emergent SAEs,
TEAEs resulting in treatment withdrawal from the study, TEAEs will be presented similarly in 
separate analyses. 
Moreover, the number of SAEs (as opposed to the number and percentage of participants) and 
TEAEs resulting in early withdrawal from the study will be presented by SOC and PT within 
SOC.
Listings by participant for serious adverse events, deaths, and TEAEs resulting in early 
withdrawal will be generated. 
9.1.3. Other Significant Adverse Events
Adverse events of special interest (AESI) will be summarized and include injection site 
reactions, muscle pain or weakness, and kidney stone events.
An injection site reaction 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:
Individual signs or symptoms at the injection site (e.g., erythema, swelling, etc.) reported within 
4 hours of study intervention administration will be recorded as AEs at injection site (not as an 
injection site reactions) and graded in accordance with the intensity categories detailed in Section
9.1.1.
After 4 hours post dose, signs or symptoms at the injection site will be evaluated according to the 
Common Terminology Criteria for Adverse Events (CTCAE; Version 5.0) criteria for injection 
site reactions. 
Because the nonclinical safety program in mice identified potential off-target effects on skeletal 
muscle, participants will also be monitored for signs and symptoms of muscle weakness or pain, 
and plasma creatine kinase measurements.
Participants with PH are predisposed to the development of multiple and recurrent urinary tract 
and kidney stones. Stone events, while being considered in the evaluation of efficacy, will also 
be considered AESIs.
Injection site reactions and treatment-emergent signs of muscle weakness or pain will be 
summarized by SOC and PT using the methods described in Section 9.1.1. Summaries for these 
events by maximum severity, as described in Section 9.1.1, will also be produced. However, 
summaries by maximum intensity for injection site reactions >4 hours postdose will be based on 
CTCAE grading criteria (Grades 1 through 5; where Grade 1 is least severe and Grade 5 is most 
severe) for injection site reactions.  If a participant has both missing and non-missing missing 
CTCAE grades for a given SOC and PT, the missing CTCAE grade is selected for reporting 
unless the non-missing CTCAE grades is noted as Grade 4 or Grade 5. Kidney stone events will 
be summarized by the specific kidney stone event type that is collected on the adverse event 


Statistical Analysis Plan, 
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CRF:  renal stone requiring medical intervention, stone passage with or without hematuria, and 
renal colic requiring medication.  Kidney stone events will also be summarized by maximum 
severity.
By-participant data listings for injection site reactions, treatment-emergent signs of muscle 
weakness or pain, and treatment-emergent kidney stones will be provided.
9.2.
Clinical Laboratory Evaluations
Descriptive summaries for safety laboratory assessments will be presented at each visit starting 
at baseline. Changes from baseline to each post       baseline visit will also be presented for 
continuous outcomes. 
Baseline for safety laboratory assessments will be identified as defined in Section 6.1.2
regardless of whether an evaluation was scheduled, retested, or unscheduled. Since laboratory 
retests can occur for individual parameters, it will be necessary to define the baseline and all 
subsequent visit-specific laboratory values individually for each parameter. 
In the case where below the limit of quantitation (BLQ) results are observed, and the LLOQ 
value is known, the BLQ values will be included in the numeric summary as the reported LLOQ 
value.  In for those lab results reported as ‘<x’ where x is numeric value, descriptive summaries 
will impute x as the lab result.
The following imputation rules will be applied to safety laboratory results where LLOQ value is 
unknown:
x
If the patient has quantifiable concentrations of that analyte from other study visits, BLQ 
results will be imputed as ½ of the patient’s lowest concentration for that analyte
x
If the patient does NOT have any quantifiable concentrations of that analyte from other 
study visits, BLQ results will be imputed as ½ of the lowest concentration of that analyte 
based on all quantifiable results within the patient’s dosing group/cohort
By visit summary tables will be presented for each category of data separately. Routine clinical 
laboratory data will include hematology, clinical chemistry, coagulation parameters, and 
urinalysis. Total complement (hemolytic activity and factors) will be reported similarly but will 
include reporting of the first quartile and third quartile in presentations; these summaries of total 
complement will be based on the log-transformed values. Shift tables for baseline to maximum 
and minimum post baseline values, based on laboratory normal ranges (below lower limit of 
normal [LLN], normal, above upper limit of normal [ULN]), will be provided for hematology, 
coagulation, complement, cytokines and clinical chemistry parameters. This analysis of extreme 
value shifts (e.g., maximum and minimum post baseline values) will be based on all post
baseline assessments whether scheduled or unscheduled. The set of laboratory parameters 
included in each table will correspond to the study protocol. 
The number and percentage of potentially clinically significant (PCS) laboratory values will be 
tabulated by laboratory parameter: the summary will indicate the number of participants with 
PCS-low or PCS-high values at any time post baseline, as identified in Table 3 and Table 4. This 


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analysis will be based on all post baseline assessments whether scheduled or unscheduled.  It is 
possible for participants to appear in both categories (PCS-low and PCS-high) for any parameter. 


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Table 3: Potentially Clinically Significant Criteria for Safety Laboratory Assessments for 
3DUWLFLSDQWV 18 Years of Age
Parameter 
Units
PCS Low
PCS High
Sex
Hemoglobin 
g/L
<95
-
F
g/L
<115
-
M
Hematocrit 
%
<32
-
F
%
<37
-
M
RBC count 
10^12/L
-
>10
F
10^12/L
-
>8
M
WBC count 
10^9/L
<2.8
>16
B
Neutrophils (total) 
10^9/L
<1.5

B
Lymphocytes 
%
-

B
Monocytes 
%
-

B
Eosinophils 
%
-

B
Basophils 
%
-

B
Platelet count 
10^9/L
<75
>700
B
BUN 
mmol/L
-
10.71
B
Serum creatinine 
umol/L
-
176.8
B
Total bilirubin 
umol/L
-
34.2
B
Alkaline phosphatase 
U/L
-
>390
B
AST 
U/L
-
>150
B
ALT 
U/L
-
>165
B
Abbreviations: ALT= alanine aminotransferase; AST= aspartate aminotransferase; B= both; BUN= blood urea 
nitrogen; F= female; HDL= high density lipoprotein; LDL= low density lipoprotein; M= male; PCS = potentially 
clinically significant; RBC= red blood cell; WBC= white blood cell


Statistical Analysis Plan, 
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Table 4: Potentially Clinically Significant Criteria for Safety Laboratory Assessments for 
Participants < 18 Years of Age
Parameter 
Units
PCS Low
PCS High
Sex
Hemoglobin (5y to 14y)
g/L
<114
>151
B
Hemoglobin (15y to 17y)
g/L
<135
>175
M
Hemoglobin (15y to 17y)
g/L
<120
>160
F
Hematocrit (5y to 14y)
%
<36
>47
B
Hematocrit  (15y to 17y)
%
<40
>52
M
Hematocrit (15y to 17y)
%
<36
>46
F
RBC count (5y to 14y)
10^12/L
<4.0
>5.6
B
RBC count (15y to 17y)
10^12/L
<4.6
>5.8
M
RBC count (15y to 17y)
10^12/L
<4.1
>5.2
F
WBC count (5y to 17y)
10^9/L
<4.0
>10.7
B
Neutrophils (Abs; 2y to 6y) 
10^9/L
<2.1
>8.9
B
Neutrophils (Abs; 7y to 17y)
10^9/L
<1.6
>7.4
B
Lymphocytes (2y to 6y)
%
<16
>60
B
Lymphocytes (7y to 12y)
%
<12
>49
B
Lymphocytes (13y to 17y)
%
<20
>44
B
Monocytes (2y to 6y)
%
<3
>8
B
Monocytes (7y to 17y)
%
<3
>10
B
Eosinophils (183days to 6y)
%
-
>4
B
Eosinophils (7y to 12y)
%
-
>6
B
Eosinophils (13y to 17y)
%
-
>7
B
Basophils (31days to 17y)
%
-
>2
B
Platelet count (5y to 14y)
10^9/L
<175
>420
B
Platelet count (15y to 17y)
10^9/L
<150
>350
B
Urea (0y to 9y)
mmol/L
-
>5.712
B
Urea (10y to 15y)
mmol/L
-
>6.426
B
Urea (16y to 17y)
mmol/L
-
>7.14
B


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Serum creatinine (4y to 12y)
umol/L
-
>68.068
B
Serum creatinine (13y to 17y)
umol/L
-
>106.08
M
Serum creatinine (13y to 17y)
umol/L
-
>88.4
F
Total bilirubin (8days to 17y)
umol/L
-
>20.52
B
Alkaline phosphatase (1y to 12y)
U/L
-
>299
B
Alkaline phosphatase (13y to 17y)
U/L
-
>389
M
Alkaline phosphatase (13y to 17y)
U/L
-
>186
F
AST (4y to 6y)
U/L
-
>47
M
AST (4y to 6y)
U/L
-
>58
F
AST (7y to 17y)
U/L
-
>41
B
ALT (0y to 9y)
U/L
-
>30
B
ALT (10y to 17y)
U/L
-
>30
M
ALT (10y to 17y)
U/L
-
>20
F
Abbreviations: ALT= alanine aminotransferase; AST= aspartate aminotransferase; B= both; BUN= blood urea 
nitrogen; F= female; M= male; PCS = potentially clinically significant; RBC= red blood cell; WBC= white blood 
cell
Results of urine pregnancy tests (females only) will be presented in a listing only. Viral serology 
data and anti-drug antibody tests will be handled similarly.
Data listings for all laboratory results will be generated. Where appropriate, assessments 
considered to be PCS will be noted; abnormal values (e.g., above the upper limit of normal or 
below the lower limit of normal) will be identified. A separate listing of PCS safety laboratory 
data will be provided.  
Participant data listings will include the type of visit (e.g., scheduled test, retest, unscheduled), 
age, sex, laboratory test, test units, laboratory test result, and the laboratory standard normal 
ranges adjusted as appropriate for age and sex, if available.
9.3.
Clinical Laboratory Evaluations – eGFR 
The statistical analysis of eGFR in adult participants (>= 18 years old) will be based on eGFR 
calculated using the Chronic Kidney Disease Epidemiology Collaboration equation (eGFR CKD-
EPI). The main statistical analysis of eGFR in pediatric participants (< 18 years old) will use the 
Schwartz10 et al. 2009 creatinine-based equation.  For all pediatric subjects (< 18 years old) a
secondary analysis will be included in the descriptive summary tables where eGFR is calculated 
using the Schwarz 2012 Cystatin C-based equation11.


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9.4.
Clinical Laboratory Evaluations – Urinalysis 
All safety laboratory results obtained from 24 hour urinalysis which do not meet the 
completeness criteria described in section 6.1.5.2 will be set to missing in the descriptive 
summary tables. These safety urinalysis tests will include: 
x
24 Hour Urinary Creatinine
x
24 Hour Urinary Oxalate to Creatinine Ratio
x
24 Hour Urinary Calcium
x
24 Hour Urinary Magnesium
x
24 Hour Urinary Phosphate
x
24 Hour Urinary Citrate Excretion Rate
x
24 Hour Urinary Citrate 
9.5.
Vital Signs
Descriptive summaries for vital signs (systolic blood pressure, diastolic blood pressure, body 
temperature, pulse/heart rate, and respiration rate) will be presented for each visit starting at 
baseline (as defined in Section 6.1.2). Changes from baseline to each post baseline visit will also 
be presented. 
The incidence of PCS vital sign values (Table 5 and Table 6) at any time post baseline will be 
summarized in a manner similar to that described for safety laboratory assessments in Section 
9.2. This analysis will be based on all post baseline assessments whether scheduled or 
unscheduled. It is possible for participants to appear in both categories (PCS-low and PCS-high) 
for any parameter.
Table 5: Potentially Clinically Significant Criteria for Vital Signs IRU3DUWLFLSDQWV
Years of Age
Vital sign 
Criteria 
Heart Rate
ESPDWDQ\WLPHSRVW GRVHDQGESPLQFUHDVHIURPEDVHOLQH
ESPDWDQ\WLPHSRVW GRVHDQGESPGHFUHDVHIURPEDVHOLQH
Systolic blood pressure 
PP+JDWDQ\WLPHSRVW GRVHDQG20 mm Hg increase from 
baseline
PP+JDWDQ\WLPHSRst GRVHDQG20 mm Hg decrease from 
baseline
Diastolic blood pressure 
PP+JDWDQ\WLPHSRVW GRVHDQG15 mm Hg increase from 
baseline
PP+JDWDQ\WLPHSRVW GRVHDQG15 mm Hg decrease from 
baseline
Abbreviations: bpm = beats per minute; mm Hg = millimeters mercury


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Table 6: Potentially Clinically Significant Criteria for Vital Signs for Participants < 18 
Years of Age
Vital sign 
Criteria 
Heart Rate
Both (6y to 11y): ESPDQGDQLQFUHDVHIURPEDVHOLQH15 bpm
Both (12y to 17y): ESPDWDQ\WLPHSRVW dose and an increase 
from baseline ESP
Both (6y to 11y): 60 bpm at any time post dose and a decrease from 
EDVHOLQH15 bpm
Both (12y to 17y): ESPDWDQ\WLPHSRVW dose and a decrease from 
basHOLQHESP  
Systolic blood pressure 
Both (6y to 11y): 25 mmHg at any time post GRVHDQG15 mmHg 
increase from baseline
Males (12y to 17y): 40 mmHg at any time post GRVHDQG15 mmHg 
increase from baseline
Females (12y to 17y): 32 mmHg at any time post dose and 
15 mmHg increase from baseline
Both (6y to 11y): 80 mmHg at any time post GRVHDQG15 mmHg 
decrease from baseline
Both (12y to 17y): 90 mmHg at any time post GRVHDQG15 mmHg 
decrease from baseline
Diastolic blood pressure 
Both (6y to 11y): 80 mmHg at any time post GRVHDQG mmHg 
increase from baseline 
Both (12y to 17y): 5 mmHg at any time post GRVHDQGPPHg 
increase from baseline
%RWK\WR\PPHg at any time post GRVHDQG mmHg 
decrease from baseline
Abbreviations: bpm = beats per minute; mm Hg = millimeters mercury
Participant data listings of vital sign data will be provided and, where appropriate, assessments 
considered to be PCS will be noted. A separate listing of PCS vital sign data will be provided.
9.6.
Electrocardiograms
Electrocardiograms will be conducted at each visit except for Day 2 and Day 31.  On Day 1 and 
Day 30, the ECGs will be conducted twice (predose and 10 hours post dose). 
All reporting for ECG data will be presented for central lab ECG results only.  Descriptive 
summaries for ECG data (HR, PR interval, QRS duration, QT interval, corrected QT interval 
[QTcF, Fridericia correction], and RR) will be presented at each visit starting at baseline.  
Changes from baseline to each post baseline visit will also be presented. The predose ECGs will 
be compared between Days 1 and 30. Predose and post dose ECGs will be compared for Days 1 
and 30 as well.


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If the RR is not collected it will be derived as follows: RR = (60/HR). 
Change from baseline for QTcF and uncorrected QT will be classified as follows: 
x
PVHFRU!PVHF
x
PVHFRU!PVHF
Absolute postbaseline QTcF and uncorrected QT interval will be classified as follows: 
x
PVHFRU!PVHF
x
PVHFRU!PVHF
x
PVHFRU!PVHF
Frequency counts and percentages will be tabulated for change from baseline and absolute post
baseline QTcF values at each visit starting at baseline; participant listings will identify records 
where participant data falls into these regions. These summaries will also be presented for 
minimum and maximum post baseline values. The analysis of extreme values (e.g., maximum 
and minimum post baseline values) will be based on all post baseline assessments whether 
scheduled or unscheduled.  
The number and percentage of participants with the following overall ECG results will also be 
tabulated at each visit. Shift tables for baseline to maximum post baseline overall ECG results, 
based on the three categories below will be provided. This analysis of extreme value shifts (e.g.,
maximum post baseline values) will be based on all post baseline assessments whether scheduled
or unscheduled.
x
Normal 
x
Abnormal, not clinically significant
x
Abnormal, clinically significant 
The incidence of PCS ECG values (Table 7 and Table 8) at any time post baseline will be 
summarized in a manner similar to that described for safety laboratory assessment in Section 9.2.
This analysis will be based on all post baseline assessments whether scheduled or unscheduled. It 
is possible for participants to appear in both categories (PCS-low and PCS-high) for any 
parameter.
All ECG data will be presented in data listings and where appropriate, assessments considered to 
be PCS will be noted. A separate listing of PCS ECG data will be provided.


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Table 7: Potentially Clinically Significant Criteria for Electrocardiogram Data for 
3DUWLFLSDQWV<HDUVRI$JH
Parameter
Value 
QRS duration
PVHF
>120 msec
Heart rate
$EVROXWHYDOXHESPDQGGHFUHDVHIURPEDVHOLQHESP
$EVROXWHYDOXH!ESPDQGLQFUHDVHIURPEDVHOLQHESP
Frederica’s QTc
>450 msec or >60 msec increase from baseline
Abbreviations: bpm = beats per minute
Table 8: Potentially Clinically Significant Criteria for Electrocardiogram Data for 
Participants < 18 Years of Age
Parameter
Value 
QRS duration
Males (6y to 8y):  <63 msec
Females (6y to 8y): <59 msec
Males (9y to 12y): <67 msec
Females (9y to 12y): <66 msec
Males (13y to 17y): <78 msec
Females (13y to 17y): <72 msec
Males (6y to 8y):  >98 msec
Females (6y to 8y): >95 msec
Males (9y to 12y): >103 msec
Females (9y to 12y): >99 msec
Males (13y to 17y): >111 msec
Females (13y to 17y): >106 msec
Heart rate
6y to 11y: ESPDQGDQLQFUHDVHIURPEDVHOLQHESP
12y to 17y: ESPDWDQ\WLPHSRVWGRVHDQG an increase from 
baseline ESP
6y to 11y: 60 bpm at any time postdose and a decrease from 
EDVHOLQH 15 bpm
12y to 17y: ESPDWDQ\WLPHSRVWGRVHDQGa decrease from 
EDVHOLQHESP  
Frederica’s QTc
440 msec or >30 msec increase from baseline
Abbreviations: bpm = beats per minute


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9.7.
Echocardiogram with Doppler
Echocardiography will be performed at the Screening and final visits by a qualified 
sonographer/physician (and over-read by a cardiologist) using a standard, commercially 
available ultrasound machine. All echocardiogram data will be transmitted to a standalone imaging 
vendor, where qualified personnel will perform postprocessing of echocardiogram data and central 
over-read of all images. Only the central lab data will be reported. The report includes an overall 
assessment of cardiac anatomy, and quantitative evaluation of basic ventricular systolic function.
Descriptive statistics will be produced. Shift tables will be presented in reference to normal 
ranges.
9.8.
Physical Examination
Descriptive summaries for physical examination findings (normal, abnormal, or not performed) 
will be presented for each body system/category at each visit starting at baseline (as defined in 
Section 6.1.2). For participants who had a physical examination postbaseline, shift tables for 
baseline to the most abnormal result postbaseline will be presented for each body system.
The supportive data listing will include the information collected (e.g., body system, result of the 
observation, any investigator comment).
9.9.
Concomitant Medication
Medications used at any time after the first dose date will be considered concomitant; this 
includes medications which initially start prior to the first dose date and continue during the 
posttreatment period, as well as new medications which are first recorded to have been taken 
after the first dose date. Missing medication start date handling will be based on the methodology 
described in Section 6.1.10.1. Medications will be coded using WHO-DD version B3 September 
1, 2019 or higher.  
Concomitant medications will be summarized according to the anatomical therapeutic chemical
(ATC) level-2 class and ATC level-4 class within each treatment group and overall. To count the 
number of participants who took a medication, a participant taking the same medication multiple 
times will only be counted once for that medication. Medication use will be tabulated in 
decreasing order of the overall number of participants who took each medication. In addition, the 
total number of participants to ever take any concomitant medications will be presented.
Participant medication data will be presented in data listings.  
Treatment with vitamin B6 is effective in decreasing Uox in approximately 10%-30% of patients 
with PH1 with certain AGXT mutations, but has not been proven effective in treating other 
forms of PH.  Given this, some participants may be taking vitamin B6 as part of their standard of 
care for PH.  Participants taking vitamin B6 must have been at a stable dose for at least 4 weeks 
prior to Day 1 and must remain on the same stable dose throughout the study.  In order to 


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evaluate this requirement, vitamin B6 intake will be collected on a separate CRF within the 
database.  Participant vitamin B6 intake will be presented in a data listing.
Participant fluid intake will be presented in a data listing.
9.10.
Immunogenicity Assessments
Frequency counts and percentages will be tabulated for anti-drug antibodies results 
(Positive/Negative) at each visit starting at baseline. Descriptive statistics for titer results and for 
change from baseline will be presented by visit.   
The primary endpoint AUC of 24-hour Uox from Day 90 to Day 180 will be summarized
separately for the Positive and Negative results.
Participant anti-drug antibody testing results will be presented in a data listing.  If it happens that 
an adequate assay cannot be developed, then no data will be reported.
Anti-double-stranded DNA antibodies will be measured as long as there is no validated assay for 
direct antibodies to DCR-PHXC. Serum samples for detection of anti-dsDNA will be collected 
from all participants as indicated in the schedule of activities. Samples should also be collected at 
the final visit from participants who discontinued study intervention or were withdrawn from the 
study.  Participant anti-dsDNA antibody testing results will be presented in a data listing.
10.
Changes from Planned Analysis
Not Applicable.
11.
Pharmacokinetic Analysis
Analysis of the pharmacokinetic blood samples is being performed by AxoLabs.
Pharmacokinetic parameters to be analyzed will be described in detail in a separate 
Pharmacokinetic Analysis Plan (PKAP). 


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12.
References
1. US Federal Register. (1998) International Conference on Harmonization; Guidance on 
Statistical Principles for Clinical Trials. Department of Health and Human Services: Food 
and Drug Administration [Docket No. 97D-0174]. Federal Register Volume 63, Number 
179, pages 49583-49598. September 16, 1998.
2. ASA. (2016) Ethical Guidelines for Statistical Practice. Prepared by the Committee on 
Professional Ethics, April 2016. http://www.amstat.org/about/ethicalguidelines.cfm
3. RSS. (2014) The Royal Statistical Society: Code of Conduct, 2014. 
http://www.rss.org.uk/Images/PDF/join-us/RSS-Code-of-Conduct-2014.pdf.
4. Taves DR, 1974, Minimization: A new method of assigning patients to treatment and 
control groups. Clinical Pharmacology and Therapeutics, 15:443-453.
5. Pocock SJ, Simon R, 1975, Sequential treatment assignment with balancing for prognostic 
factors in the controlled clinical trial. Biometrics, 31:103-115.
6. Mehta CR, Pocock SJ, 2011, Adaptive increase in sample size when interim results are 
promising: A practical guide with examples. Statistics in Medicine, 30: 3267-3284.
7.
Little R., Yau L. 1996. Intent-to-Treat Analysis for Longitudinal Studies with Drop-Outs, 
Biometrics. 52. 1324-1333.
8.
Schafer J. L. 1997. Analysis of Incomplete Multivariate Data. New York: Chapman & 
Hall.
9.
Levey A.S., Stevens L.A. Estimating GFR using the CKD Epidemiology Collaboration 
(CKD-EPI) Creatinine Equation: More Accurate GFR Estimates, Lower CKD Prevalence 
Estimates, and Better Risk Predictions, Am J Kidney Dis. 2010: 55(4):622-7.
10. Schwartz G.J., Munoz A., Schneider M.F., Mak R.H., Kaskel F., Warady B.A., Furth 
S.L. New Equations to Estimate GFR in Children with CKD. J Am Soc Nephrol. 2009 
Mar 1;20(3):629-37.
11. Schwartz G.J., Schneider M.F., Maier P.S., Moxey-Mims M., Dharnidharka V.R., 
Warady B.A. Improved equations estimating GFR in children with chronic kidney 
disease using an immunonephelometric determination of cystatin C. Kidney Int. 2012 
Aug 2;82(4):445-53.
12. PharmaSUG. (2016) Ye J. General AUC calculated based on the trapezoidal rule 
https://www.lexjansen.com/pharmasug-cn/2016/DS/PharmaSUG-China-2016-DS02.pdf
13. Ware J.E. Jr., Sherbourne C. D. 1992.  The MOS 36-item short-form health survey (SF-
36). I. Conceptual Framework and Item Selection, MedCare. Jun;30(6): 473-83. 


Statistical Analysis Plan, 
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Page 53 of 59
14. Herdman M., Gudex C., Lloyd A., Janssen M., Kind P., Parkin D., Bonsel G., Badia X.  
2011. Development and Preliminary Testing of the New Five-Level Version of EQ-5D 
(EQ-5D-5L), Qual Life Res.  Dec;20(10): 1727-36. doi: 10.1007/s11136-011-9903-x.
15. Varni J.W., Seid M., Kurtin P. S., PedsQLTM 4.0: Reliability and Validity of the Pediatric 
Quality of Life InventoryTM Version 4.0 Generic Core Scales in Healthy and Patient 
Populations, Medical Care. 2001 Aug 1: 800-12.
16. Varni J.W., Seid M, Rode C.A., The PedsQLTM Measurement Model for the Pediatric 
Quality of Life InventoryTM, Medical Care. 1998: 37, 126-39.


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Appendix 1: 
 Library of Abbreviations
Abbreviation
Definition
AE
adverse event
AESI
adverse events special interest
ANCOVA
analysis of covariance
ATC
anatomical therapeutic chemical
AUC
area under the curve
BLQ
below the limit of quantitation
BMI
body mass index
BSA
body surface area
CI
confidence intervals
CP
conditional power
CRF
case report form
CS
clinically significant
CSR
clinical study report
CT
computed tomography
DSMC
data safety monitoring committee
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture


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Abbreviation
Definition
eGFR
estimated glomerular filtration rate
EU
European Union
FCS
fully conditional specification
FDA
food and drug administration
HR
heart rate
HRQOL
health related quality of life
IC or ICF
informed consent or informed consent form
ICH
international council for harmonization 
ITT
intent-to-treat
IWRS
interactive web response system
LLOQ
lower limit of quantitation
MAR
missing at random
MedDRA
medical dictionary for regulatory activities
MI
multiple imputation
MNAR
missing not at random
M&S
modeling and simulation
N
number
PD
pharmacodynamic
PE
physical examination
PH
primary hyperoxaluria


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Abbreviation
Definition
PK
pharmacokinetic
PKAP
pharmacokinetic analysis plan
PP
per-protocol
PT
preferred term
QOL
quality of life
RR
respiratory rate
SAE
serious adverse event
SAP
statistical analysis plan
SAS® 
a software system used for data analysis
SD
standard deviation
SF-36
Short form 36 health survey 
SFT or SFTP
secure file transfer or secure file transfer plan
SOC
system organ class
TEAE
treatment-emergent adverse event
Uox
urinary oxalate excretion
WHO
world health organization
WHO-DD
world health organization drug dictionary


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Appendix 2: Algorithm for Calculating SF-36 Scores
This protocol uses the SF-36 version 2 form (SF36v2). Scoring this form is as follows, based on 
the manual “How to Score version 2 of the SF-36 Health Survey” (Ware JE, et al. 2000):
Each item on the 36-item short-form health survey (SF-36) will be answered by a patient. Some 
of the answers will then be re-coded so that across all questions, a higher score will indicate a 
better health state. Question 2 (Compared to one year ago, how would you rate your health in 
general now?) is not used in the calculation of domain scores. Questions 3, 4, 5, 9b, 9c, 9f, 9g, 9i, 
10, 11a, 11c will scored as recorded; the other scores will be transformed as follows:
x
Question 1:
Original Response
1
2
3
4
5
Re-coded Response
5
4.4
3.4
2
1
x
Question 6, 9a, 9d, 9e, 9h, 11b, 11d:
Original Response
1
2
3
4
5
Re-coded Response
5
4
3
2
1
x
Question 7:
Original Response
1
2
3
4
5
6
Re-coded Response
6
5.4
4.2
3.1
2.2
1
x
Question 8 (If Question 7 is answered):
Original Response to #8
1
1
2
3
4
5
Original Response to #7
1
2-6
1-6
1-6
1-6
1-6
Re-coded Response
6
5
4
3
2
1
x
Question 8 (If Question 7 is NOT answered):
Original Response
1
2
3
4
5
Re-coded Response
6
4.75
3.5
2.25
1


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The raw score for the following 8 domains will be calculated by summing the re-coded scores for 
the set of questions listed in the table below if all the questions within the domain are answered. 
If < 50% of the questions within a domain are answered, the raw score will not be calculated.
Domain
Questions
Physical Functioning (PF)
3a – 3j
Role limitations due to physical health (RP)
4a – 4d
Bodily Pain (BP)
7 – 8
General Health (GH)
1, 11a – 11d
Vitality (VT)
9a, 9e, 9g, 9i
Social Functioning (SF)
6, 10
Role limitations due to emotional problems (RE)
5a – 5c
Mental Health (MH)
9b, 9c, 9d, 9f, 9h
,IEXWQRWDOORIWKHTXHVWLRQVDUHDQVZHUHGWKHQRQ-missing questions are re-coded (if 
necessary, per above) and then summed. An average score is calculated for those non-missing 
scores and that average score is imputed as the score to be used for the value of the missing 
questions. The raw score is then calculated as the sum of all the questions in the domain. For 
example, for the vitality domain, if questions 9a, 9e, and 9g are answered but question 9i is 
missing, the algorithm will proceed as followed from left to right:
Question
Recoded 
Response
Re-coded 
Response
Average of non-
missing scores
Average 
imputed for 
missing 
responses
Raw Score
9a
2
4
= (4 + 2 + 5) / 3 
= 3.666…
4
= 4 + 2 + 5 + 3.666..
= 14.666…
9e
4
2
2
9g
5
5
5
9i
Missing
Missing
3.666…
After the raw score is calculated, it is then converted into a normalized score (on a scale of 0 to 
100) using the following transformation:
ܰ݋ݎ݈݉ܽ݅ݖ݁݀ܦ݋݉ܽ݅݊ܵܿ݋ݎ݁= ܴܽݓܵܿ݋ݎ݁െܮ݋ݓ݁ݏݐܲ݋ݏݏܾ݈ܴ݅݁ܽݓܵܿ݋ݎ݁
ܲ݋ݏݏܾ݈ܴ݅݁ܽݓܵܿ݋ݎܴ݁ܽ݊݃݁
כ 100
The normalized domain scores will then be standardized using the following formula:
ܵݐܽ݊݀ܽݎ݀݅ݖ݁݀ܦ݋݉ܽ݅݊ܵܿ݋ݎ݁= ܰ݋ݎ݈݉ܽ݅ݖ݁݀ܵܿ݋ݎ݁െܽ
ܾ
The lowest possible raw score, possible raw score range, (a) values, and (b) values for each 
domain are as follows:


Statistical Analysis Plan, 
Sponsor Dicerna
Protocol Number DCR-PHXC-201
 Number
AD-ST-33.05  Effective date: 22-Jan-2018
Version Final 1.0 - US Analysis Plan    |    16-July-2021    |    AD-PR-109.01 Effective date: 26-Jun-2017
Page 59 of 59
Domain
Lowest 
Possible 
Raw Score
Possible 
Raw Score 
Range
a
b
Physical Functioning (PF)
10
20
82.62455
24.43176
Role limitations due to 
physical health (RP)
4
16
82.65109
26.19282
Bodily Pain (BP)
2
10
73.86999
24.00884
General Health (GH)
5
20
70.78372
21.28902
Vitality (VT)
4
16
58.41968
20.87823
Social Functioning (SF)
2
8
85.11568
23.24464
Role limitations due to 
emotional problems (RE)
3
12
87.50009
22.01216
Mental Health (MH)
5
20
75.76034
18.04746
The two raw component scores will be calculated based on multiplying each standardized 
domain score by a constant, and then adding the 8 domains together. The constants to use for the 
two component scores are as follows:
Domain
Physical Component 
Summary (PCS)
Mental Component 
Summary (MCS)
Physical Functioning (PF)
0.42402
-0.22999
Role limitations due to 
physical health (RP)
0.35119
-0.12329
Bodily Pain (BP)
0.31754
-0.09731
General Health (GH)
0.24954
-0.01571
Vitality (VT)
0.02877
0.23534
Social Functioning (SF)
-0.00753
0.26876
Role limitations due to 
emotional problems (RE)
-0.19206
0.43407
Mental Health (MH)
-0.22069
0.48581
The norm-based scores for the two component summaries will then be calculated by multiplying 
the raw score by 10 and adding 50.
The norm-based scores for the 8 individual domains will be calculated by multiplying the 
standardized domains score by 10 and adding 50.
The norm-based scores will be used in the analyses.


Protocol Number: DCR-PHXC-201
Page 1 of 5
DCR-PHXC-201 - Major Clinical Protocol Deviation List, v1.0 16Mar2021
Major Protocol Deviation List
Deviation 
Category
Deviation Description
Date 
Deviation 
Added
Exclude from Per Protocol Population
Informed 
consent 
criteria 
Subject did not sign informed consent before the 
initiation of study procedures (including deviations 
regarding protected health information / data 
protection forms (e.g. PHI, PIPEDA etc.)
16 Mar 2021
No
Eligibility 
criteria
Subject was randomized without meeting one or 
more entry criteria
1. Genetically confirmed PH
2. Uox >0.7
3. Less than 20% variation in Ucr
4. eGFR >30
5. Agree to use contraception and not pregnant 
6. Prior renal/liver transplant
7. Dialysis
8. Pox>30
9. Systemic oxalosis
10. Intercurrent illness
11. Active liver disease
12. Alcohol/Drug of abuse intake
13. Serious mental illness
14. Relevant history of disorders including 
dermatitis and connective tissue disorder
16 Mar 2021
1. Genetically confirmed PH -Yes, those not 
confirmed with PH should be excluded
2. Uox <0.7 should be excluded - Yes
3. More than 20% variation in Ucr should be 
excluded- Yes
4. eGFR <30 should be excluded- Yes
5. Agree to use contraception and not pregnant –
No
6. Prior renal/liver transplant should be excluded-
Yes
7. Dialysis should be excluded - Yes
8. Participants with Pox>30 should be excluded-
Yes
9. If they have Systemic oxalosis should be 
excluded - Yes
10. Intercurrent illness - No
11. Active liver disease - No
12. Alcohol/Drug of abuse intake – No
13. Serious mental illness- No need to exclude if 
not affecting urine collection
14. Relevant history of disorders including 
dermatitis and connective tissue disorder - No
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Protocol Number: DCR-PHXC-201
Page 2 of 5
DCR-PHXC-201 - Major Clinical Protocol Deviation List, v1.0 16Mar2021
Deviation 
Category
Deviation Description
Date 
Deviation 
Added
Exclude from Per Protocol Population
Eligibility 
criteria
(continued)
15. Use of RNAi in past 6 months
16. Prior history of reaction to RNAi
17. Pyridoxine dose not stable for 4 weeks prior 
to enrolment
18. Clinical study participation in the past 4 
months (if related to Uox need to return to 
baseline)
19. LFT abnormalities
20. Positive viral screen
21. Positive drug screen
22. Hypersensitivity to DCR-PHXC
23. Unwilling to comply with section 5.3 –
vitamin C intake, follow standard of care, 
refrain from exercise, avoid oxalate rich foods
16 Mar 2021
15. Use of RNAi in past 6 months – No not unless 
it is Lumasiran
16. Prior history of reaction to RNAi – No, as 
long as no reaction is noted during the study
17. Those whose Pyridoxine dose was not stable 
for 4 weeks prior to enrolment should be 
excluded - Yes
18. Clinical study participation in the past 4 
months (if related to Uox need to return to 
baseline) – Yes if participant did not have 
Uox back at baseline it should be excluded
19. LFT abnormalities - No
20. Positive viral screen - No
21. Positive drug screen - No
22. Hypersensitivity to DCR-PHXC- Yes
participant should be excluded as study drug 
may not be effective
23. Unwilling to comply with section 5.3 –
vitamin C intake, follow standard of care, 
refrain from exercise, avoid oxalate rich foods
– Yes participants who are not compliant 
should be excluded
IP criteria
Patient received and dosed incorrect drug
16 Mar 2021
Yes (if subject received less than 5 or more than 7 
doses)
IP criteria
Subject received IP despite failure to adhere to the 
storage, preparation, or handling of study drug
according to the protocol and assessed as non-
acceptable by quality assurance
16 Mar 2021
Yes (if more than 1 dose is affected and assessed 
as non-acceptable by QA).
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Protocol Number: DCR-PHXC-201
Page 3 of 5
DCR-PHXC-201 - Major Clinical Protocol Deviation List, v1.0 16Mar2021
Deviation 
Category
Deviation Description
Date 
Deviation 
Added
Exclude from Per Protocol Population
IP Criteria
Subject received IP despite discontinuation or 
withdrawal criteria
16 Mar 2021
No
Concomitant 
medication 
criteria
The subject used prohibited concomitant medications
or therapies
16 Mar 2021
Yes, for medications that can affect efficacy (e.g.
Lumasiran, vitamin C)
No, for medications that can affect safety (e.g. 
acetaminophen)
Efficacy 
evaluation 
criteria 
Subject is missing 2 or greater  Uox assessments
during the period from day 90 to day 180
Subject is missing 3 Uox assessments in a row at any 
given point
16 Mar 2021
Yes
Efficacy 
evaluation 
criteria
Subject has greater than 20% variance in 2 or greater 
Uox assessments during the period from day 90 to 
day 180 
Subject has greater than 20% creatinine variance in 3 
Uox assessments in a row
16 Mar 2021
Yes
Efficacy 
evaluation 
criteria
Subject did not collect 24 hour urine for full 24 hours 
and did not perform a repeat for 2 timepoints between 
day 90 to day 180 or 3 times in a row
16 Mar 2021
Yes
Safety 
monitoring
Subject is a child-bearing female who missed a 
pregnancy test prior to dosing and was pregnant on 
the subsequent pregnancy test.
16 Mar 2021
No
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Protocol Number: DCR-PHXC-201
Page 4 of 5
DCR-PHXC-201 - Major Clinical Protocol Deviation List, v1.0 16Mar2021
Deviation 
Category
Deviation Description
Date 
Deviation 
Added
Exclude from Per Protocol Population
Safety 
reporting
Subject’s SAE was reported late or was not reported
16 Sep 2020
No
Other criteria
The subject or site was accidentally unblinded to the 
subject’s treatment information during the study.
16 Sep 2020
Yes
Other criteria
Any deviations that constitute fraud, scientific 
misconduct or Serious Breach will be classified as 
major.
16 Sep 2020
Yes
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Protocol Number: DCR-PHXC-201
Page 5 of 5
DCR-PHXC-201 - Major Clinical Protocol Deviation List, v1.0 16Mar2021
Version History
Version No.
Version Date
Description of Change
1.0
16-Mar-2021
Initial version of the Major Clinical Protocol Deviation List
Signatures of Approval:
Clinical Lead:         
Medical
Monitor:
Biostatistician:
Date
Signature
Date
Signature
Date
Signature
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