Conditions: Primary Hyperoxaluria Type 1 Primary Hyperoxaluria
Keywords: PH1 Primary Hyperoxaluria Hyperoxaluria RNAi Therapeutic siRNA AGT Systemic Oxalosis
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 21
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy, safety, pharmacokinetics (PK), and pharmacodynamics (PD) of lumasiran in patients with Advanced Primary Hyperoxaluria Type 1 (PH1).

Detailed description:

Arms:
arm 1: All patients will receive open-label lumasiran.

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

Protocol document:
Prot_000.pdf: 
 
 
Official Title:  
ILLUMINATE-C: A Single Arm Study to Evaluate Efficacy, Safety, 
Pharmacokinetics, and Pharmacodynamics of Lumasiran in Patients With 
Advanced Primary Hyperoxaluria Type 1 (PH1) 
 
NCT Number:   
NCT04152200 
 
Document Date:   
Clinical Study Protocol, 06 May 2020 






Clinical Study Protocol ALN-GO1-005 
lumasiran 
Amendment 1, 06 May 2020 
Alnylam Pharmaceuticals 
Confidential 
3 
INVESTIGATOR’S AGREEMENT 
 
I have read the ALN-GO1-005 protocol and agree to conduct the study in accordance with the 
protocol and all applicable regulations.  I agree to maintain the confidentiality of all information 
received or developed in connection with this protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 










Clinical Study Protocol ALN-GO1-005 
lumasiran 
Amendment 1, 06 May 2020 
Alnylam Pharmaceuticals 
Confidential 
8 
of lumasiran have at least 1 postdose blood sample for PK parameters and have evaluable PK 
data. 
The primary population used to evaluate efficacy will be the Efficacy Analysis Set and safety 
will be the Safety Analysis Set.  The PK Analysis Sets will be used to conduct PK analyses. 
The primary analysis is percent change from baseline in plasma oxalate (Cohort A) / pre-dialysis 
plasma oxalate (Cohort B) summarized through Month 6 by cohorts.  Secondary endpoints will 
be analyzed and reported with by-patient listings and by-patient figures of actual values, change 
from baseline and percent change (where change in percent is applicable) at each visit (scheduled 
and unscheduled visits).  Tabular summaries using descriptive statistics (mean, standard error, 
median, min, max) will be reported.  Long-term treatment effect of lumasiran will be 
summarized descriptively for the long-term extension period.  Safety data will be summarized 
descriptively and presented in by-patient listings. 


Clinical Study Protocol ALN-GO1-005 
lumasiran 
Amendment 1, 06 May 2020 
Alnylam Pharmaceuticals 
Confidential 
9 
Table 1: 
Schedule of Assessments –Primary Analysis Period (Screening through Month 6):  All Patients 
After Month 6, patients with weight <10 kg follow Table 2. Patients with weight ≥10 kg follow Table 4. 
Study Period 
Study Visit 
Screening 
6-Month Primary Analysis Period 
D1 
Wk 2 
M1 
M2 
M3 
M4 
M5 
M6 
Study Day  
(±Visit Window)* 
Notes 
-120 to -1 
1 
 
15 
(±3) 
29 
(±4) 
57 
(±4) 
85 
(±4) 
113 
(±4) 
141 
(±4) 
169 
(±7) 
Informed consent 
Section 8.1.1 
X 
 
 
 
 
 
 
 
 
Demographics 
Section 6.1 
X 
 
 
 
 
 
 
 
 
Medical history 
Section 6.1 
X 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
Section 4. 
X 
 
 
 
 
 
 
 
 
Full PE 
Section 6.5.3 
X 
 
 
 
 
 
 
 
X 
Abbreviated PE 
Section 6.5.3 
 
X 
X 
X 
X 
X 
X 
X 
 
Height/length 
Section 6.5.2 
X 
X 
 
X (<6 y) X (<6 y) 
X 
X (<6 y) X (<6 y) 
X 
Body weight 
Section 6.5.2 
X 
X 
 
X 
X 
X 
X 
X 
X 
Vital signs 
Section 6.5.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
Triplicate. Repeat if done ≥60 
days before D1. Section 6.5.4 
X 
 
 
 
 
X 
 
 
X 
Follicle-stimulating hormone 
Section 6.5.5.2  
X 
 
 
 
 
 
 
 
 
Pregnancy test 
Females of child-bearing 
potential. Section 6.5.5.2  
X 
X 
 
X 
X 
X 
 
 
X 
DNA sample for PH1/AGXT 
mutation analysis 
Section 6.1 
X 
 
 
 
 
 
 
 
 
Exploratory DNA sample 
Optional. Section 6.6 
X 
 
 
 
 
 
 
 
Clinical laboratory 
assessments 
Repeat serum creatinine and LFTs 
if collected ≥30 days before D1; 
Section 6.1. Section 6.5.5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation (PT/PTT/INR) 
 
X 
 
 
 
 
 
 
 
 
Study drug dosing  
in pts <10 kg 
Table 10. Dose after dialysis, if 
applicable. Doses must be at least 
21 days apart. Section 5.2.2  
 
X 
 
X 
X 
X 
X 
X 
X 
Study drug dosing  
in pts ≥10 kg 
 
X 
 
X 
X 
X 
 
 
X 
Blood samples for PK 
analyses 
Table 5 and Table 6  
 
X 
 
 
 
 
 
 
X 
Urine samples for PK analyses 
Table 7 
 
X 
 
 
 
 
 
 
 


Clinical Study Protocol ALN-GO1-005 
lumasiran 
Amendment 1, 06 May 2020 
Alnylam Pharmaceuticals 
Confidential 
10 
Table 1: 
Schedule of Assessments –Primary Analysis Period (Screening through Month 6):  All Patients 
After Month 6, patients with weight <10 kg follow Table 2. Patients with weight ≥10 kg follow Table 4. 
Study Period 
Study Visit 
Screening 
6-Month Primary Analysis Period 
D1 
Wk 2 
M1 
M2 
M3 
M4 
M5 
M6 
Study Day  
(±Visit Window)* 
Notes 
-120 to -1 
1 
 
15 
(±3) 
29 
(±4) 
57 
(±4) 
85 
(±4) 
113 
(±4) 
141 
(±4) 
169 
(±7) 
Blood samples for PD 
analyses (Cohort A) 
Screening collections as per 
Figure 1, Section 6.3 
X 
 
X 
X 
X 
X 
X 
X 
Blood samples for PD 
analyses (Cohort B) 
Screening collections as per 
Figure 1, Section 6.3 
X 
 
X 
X 
X 
X 
X 
X 
Blood samples for POx profile  Table 6; Pts on dialysis only. 
Screening collections as per 
Section 6.1 Figure 1. 
X 
 
 
 
 
X 
 
 
X 
24-hour urine collection 
(1 collection) 
Table 12 and Section 6.2.2  
 
 
 
 
 
X 
 
 
 
24-hour urine collection 
(3 collections) 
X 
 
 
 
 
 
 
 
X 
Single-void urine collections 
(3 collections). 
Collected within 7 days predose 
(first morning voids preferred). 
Section 6.2.2 
X 
 
 
X 
X 
X 
X 
X 
X 
Blood sample for pyridoxine 
(vitamin B6) levels 
Only in pts receiving therapeutic 
pyridoxine, collect ≥6 hrs after 
dose. Section 5.3 
X 
X 
 
 
 
X 
 
 
X 
Renal ultrasound 
Section 6.3.1 
X 
 
 
 
 
 
 
 
X 
Echocardiogram 
Repeat if done ≥60 days before 
D1. Section 6.2.3.1  
X 
 
 
 
 
 
 
 
X 
Radiographs 
Section 6.2.3.3  
X 
 
 
 
 
 
 
 
 
Ophthalmology Evaluation 
Section 6.2.3.4  
X 
 
 
 
 
 
 
 
 
Review/Record Dialysis 
Parameters 
Pts on dialysis. 
Section 6.5.5.5  
X 
X 
 
 
 
X 
 
 
X 
Vineland Behavior Scale 
Pts <6 y at consent. Section 6.7 
X 
 
 
 
 
 
 
 
X 
Quality of life questionnaires 
Section 6.8 
X 
 
 
 
 
 
 
 
X 
Patient/caregiver experience 
and impact questionnaires 
Section 6.9 
X 
 
 
 
 
 
 
 
X 
Healthcare resource utilization 
Section 6.10  
Continuous 
ADA sample 
Section 6.5.5.1 
X 
 
X 
 
X 
 
 
X 


Clinical Study Protocol ALN-GO1-005 
lumasiran 
Amendment 1, 06 May 2020 
Alnylam Pharmaceuticals 
Confidential 
11 
Table 1: 
Schedule of Assessments –Primary Analysis Period (Screening through Month 6):  All Patients 
After Month 6, patients with weight <10 kg follow Table 2. Patients with weight ≥10 kg follow Table 4. 
Study Period 
Study Visit 
Screening 
6-Month Primary Analysis Period 
D1 
Wk 2 
M1 
M2 
M3 
M4 
M5 
M6 
Study Day  
(±Visit Window)* 
Notes 
-120 to -1 
1 
 
15 
(±3) 
29 
(±4) 
57 
(±4) 
85 
(±4) 
113 
(±4) 
141 
(±4) 
169 
(±7) 
Blood and urine samples for 
exploratory analyses 
Single-void urine. Samples 
collected predose. Section 6.6 
X 
X 
 
X 
 
X 
 
 
X 
Bone scan (Optional) 
Only in adult Cohort B pts 
Section 6.2.3 
X 
 
 
 
 
 
 
 
 
Renal stone events 
Section 6.3.2 
Continuous 
Review/record AEs 
Section 6.5.6.2 
Continuous 
Prior and concomitant 
medications 
Section 5.3 
Continuous 
Abbreviations:  ADA=antidrug antibody; AE=adverse event; AGXT=alanine-glyoxylate aminotransferase gene; D=day; DNA=deoxyribonucleic acid; 
ECG=electrocardiogram; hrs=hours; LFTs=liver function tests; M=Month; Opt=optional; PD=pharmacodynamic; PE=physical examination; PH1=primary 
hyperoxaluria type 1; PK=pharmacokinetic; POx=plasma oxalate; pts=patients; SAE=serious adverse event; wk=week; y=year(s) 
* During periods of time when the COVID-19 pandemic impedes the ability of patients to travel to the study site, the visit window is expanded to ±14 days after 
Week 2. 
Notes: 
• One month is defined as 28 days. 
• Only SAEs are collected in the Screening period. Starting on D1, all AEs (including SAEs) are collected. 
• Assessments are to be performed prior to dosing, where applicable. When scheduled at the same time points and where feasible, the assessments of vital 
signs and 12-lead ECGs should be performed before physical examinations and blood sample collections. 
• Visits and study drug dosing may be conducted offsite where applicable country and local regulations and infrastructure allow (at the discretion of the 
Investigator, based on safety and tolerability), provided the patient has tolerated a dose of lumasiran administered in the clinic.  If a visit is conducted offsite, 
a body system assessment may be performed in lieu of a physical examination. 
• In situations where a study visit is unable to be completed (either at the site or offsite by a healthcare professional), the Investigator (or delegate) will 
verbally contact the patient within the study visit window to assess concomitant medications, renal stone events, adverse events, and healthcare utilization. 
• Patients who discontinue from study drug prior to completion of the Month 6 assessments should be encouraged to remain on the study and complete 
assessments (including 24-hour urine collections but excluding PK assessments) through Month 6. They will also be asked to complete safety follow-up 
visits once every 3 months, per the safety follow-up schedule (see Table 3 or Table 4), for up to 12 months after the last dose of lumasiran (Section 3.3.1). 
See Section 4.3.1 for instructions for patients who discontinue study drug.  
• Urine collections are only performed in patients who are able to produce urine, ie, ability to produce ≥100 ml per day.  
 
 


Clinical Study Protocol ALN-GO1-005 
lumasiran 
Amendment 1, 06 May 2020 
Alnylam Pharmaceuticals 
Confidential 
12 
Table 2: 
Schedule of Assessments – Long-term Extension Period (Month 7 to Month 35):  Patient Weight <10 kg 
Patients whose weight increases to ≥10 kg continue monthly dosing until the next visit that coincides with Table 4 and then 
patients will follow Table 4 until the end of the study. Patients with weight <10 kg follow Table 3 after Month 35. 
Study Period 
 
Long-term Extension Period 
Study Visit 
 
M7; 
M8 M9 M10; 
M11 M12 M13;
M14 M15 M16; 
M17 M18 M19; 
M20 M21 M22; 
M23 M24 M25; 
M26 M27 M28; 
M29 M30 M31; 
M32 M33 M34; 
M35 
Study Day  
(±Visit Window)* 
Note 
197, 
225 
(±7) 
253 
(±7) 
281, 
309 
(±7) 
337 
(±7) 
365, 
393 
(±7) 
421 
(±7) 
449, 
477 
(±7) 
505 
(±7) 
533, 
561 
(±7) 
589 
(±14) 
617, 
645 
(±14) 
673 
(±14) 
701, 
729 
(±14) 
757 
(±14) 
785, 
813 
(±14) 
841 
(±14) 
869, 
897 
(±14) 
925 
(±14) 
953, 
981 
(±14) 
Full PE 
Section 6.5.3 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Abbreviated PE 
Section 6.5.3 
X 
X 
X 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Height/length 
Section 6.5.2 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Body weight 
Section 6.5.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
Section 6.5.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
Triplicate. Section 6.5.4 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Clinical laboratory 
assessments 
LFTs within 7 days predose. 
Section 6.5.5 
X 
X 
X 
X 
X 
X 
LFT 
only X 
LFT 
only 
X 
LFT 
only X 
LFT 
only X 
LFT 
only X 
LFT 
only X 
LFT 
only 
Study drug dosing 
Table 10. Dose after dialysis, if 
applicable. Doses must be ≥21 days 
apart. Section 5.2.2  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood samples for PD 
analyses 
Section 6.3 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Blood samples for POx profile Pts on dialysis only. Table 6 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
24-hour urine collection 
(1 collection) 
Table 12 and Section 6.2.2 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Single-void urine collections 
(3 collections) 
Collected within 7 days predose 
(first morning voids preferred). 
Section 6.2.2 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Blood sample for pyridoxine 
(vitamin B6) levels 
Only in pts receiving therapeutic 
pyridoxine, collect ≥6 hrs after dose. 
Section 5.3 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Renal ultrasound 
Section 6.3.1 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Echocardiogram 
Section 6.2.3.1  
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Radiographs 
Section 6.2.3.3  
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Ophthalmology Evaluation 
Section 6.2.3.4  
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Review/Record Dialysis 
Parameters 
Pts on dialysis only. Section 6.5.5.5 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Vineland Behavior Scale 
Pts <6 y at consent. Section 6.7 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 


Clinical Study Protocol ALN-GO1-005 
lumasiran 
Amendment 1, 06 May 2020 
Alnylam Pharmaceuticals 
Confidential 
13 
Table 2: 
Schedule of Assessments – Long-term Extension Period (Month 7 to Month 35):  Patient Weight <10 kg 
Patients whose weight increases to ≥10 kg continue monthly dosing until the next visit that coincides with Table 4 and then 
patients will follow Table 4 until the end of the study. Patients with weight <10 kg follow Table 3 after Month 35. 
Study Period 
 
Long-term Extension Period 
Study Visit 
 
M7; 
M8 M9 M10; 
M11 M12 M13;
M14 M15 M16; 
M17 M18 M19; 
M20 M21 M22; 
M23 M24 M25; 
M26 M27 M28; 
M29 M30 M31; 
M32 M33 M34; 
M35 
Study Day  
(±Visit Window)* 
Note 
197, 
225 
(±7) 
253 
(±7) 
281, 
309 
(±7) 
337 
(±7) 
365, 
393 
(±7) 
421 
(±7) 
449, 
477 
(±7) 
505 
(±7) 
533, 
561 
(±7) 
589 
(±14) 
617, 
645 
(±14) 
673 
(±14) 
701, 
729 
(±14) 
757 
(±14) 
785, 
813 
(±14) 
841 
(±14) 
869, 
897 
(±14) 
925 
(±14) 
953, 
981 
(±14) 
Quality of life questionnaires Section 6.8  
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Patient/caregiver experience 
and impact questionnaires 
Section 6.9 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Healthcare resource 
utilization 
Section 6.10 
Continuous 
ADA sample 
Section 6.5.5.1 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Blood and urine samples for 
exploratory analyses 
Single-void urine. Samples collected 
predose. Section 6.6 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Renal stone events 
Section 6.3.2 
Continuous 
Review/ record AEs 
Section 6.5.6.2 
Continuous 
Prior and concomitant 
medications 
Section 5.3 
Continuous 
Abbreviations:  ADA=antidrug antibody; AE=adverse event; ECG=electrocardiogram; ET=early termination; hrs=hours; LFT=liver function tests; M=month; 
Opt=optional; PD=pharmacodynamic; PE=physical examination; PK=pharmacokinetic; POx=plasma oxalate; pts=patients; SAE=serious adverse event 
* During periods of time when the COVID-19 pandemic impedes the ability of patients to travel to the study site, study assessments and dosing may be 
performed within ±14 days of the visit unless otherwise noted. 
Notes: 
• One month is defined as 28 days.  
• Assessments are to be performed prior to dosing, where applicable. When scheduled at the same time points and where feasible, the assessments of vital 
signs and 12-lead ECGs should be performed before physical examinations and blood sample collections. 
• Visits and study drug dosing may be conducted offsite where applicable country and local regulations and infrastructure allow (at the discretion of the 
Investigator, based on safety and tolerability), provided the patient has tolerated a dose of lumasiran administered in the clinic.  If a visit is conducted offsite, 
a body system assessment may be performed in lieu of a physical examination. 
• In situations where a study visit is unable to be completed (either at the site or offsite by a healthcare professional), the Investigator (or delegate) will 
verbally contact the patient within the study visit window to assess concomitant medications, renal stone events, adverse events, and healthcare utilization. 
• Patients who discontinue study drug after Month 6 will be asked to return for their next scheduled visit to complete ET assessments and to complete safety 
follow-up visits once every 3 months, per the safety follow-up schedule (see Table 3 or Table 4), for up to 12 months after the last dose of lumasiran 
(Section 3.3.1). See Section 4.3.1 for instructions for patients who discontinue study drug.  
• Urine collections are only performed in patients who are able to produce urine, ie, ability to produce ≥100 ml per day. 
 


Clinical Study Protocol ALN-GO1-005 
lumasiran 
Amendment 1, 06 May 2020 
Alnylam Pharmaceuticals 
Confidential 
14 
Table 3: 
Schedule of Assessments – Long-term Extension Period (Month 36 to End of Study):  Patient Weight <10 kg 
Patients whose weight increases to ≥10 kg continue monthly dosing until the next visit that coincides with Table 4. Patients will 
then follow Table 4 until the end of the study. 
Study Period 
 
Long-term Extension Period 
EOT EOS/ 
ET 
Safety 
Follow-up 
(Pts who DC 
treatment) 
Study Visit 
 
M36 M37;
M38 M39 M40;
M41 M42 M43; 
M44 M45 M46; 
M47 M48 M49;
M50 M51 M52; 
M53 M54 M55;
M56 M57 M60 
Study Day  
(±Visit Window) 
Notes 
1009 
(±14) 
1037, 
1065 
(±14) 
1093 
(±14) 
1121, 
1149 
(±14) 
1177 
(±14) 
1205, 
1233 
(±14) 
1261 
(±14) 
1289, 
1317 
(±14) 
1345 
(±14) 
1373, 
1401 
(±14) 
1429 
(±14) 
1457, 
1485 
(±14) 
1513 
(±14) 
1541, 
1569 
(±14) 
1597 
(±14) 
1681 
(±14) 
Every 84 
days (±14) 
Full PE 
Section 6.5.3 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
Abbreviated PE 
Section 6.5.3 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
Height/length 
Section 6.5.2 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Body weight 
Section 6.5.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
Section 6.5.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
Triplicate. Section 6.5.4 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Clinical laboratory 
assessments 
LFTs within 7 days predose. 
Section 6.5.5  
X 
LFT 
only 
X 
LFT 
only X 
LFT 
only 
X 
LFT 
only 
X 
LFT 
only X LFT 
only X 
LFT 
only 
X 
X 
X 
Study drug dosing 
Table 10. Dose after dialysis, if 
applicable. Doses must be at least 21 
days apart. Section 5.2.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Blood samples for PD 
analyses 
Section 6.3 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Blood samples for POx 
profile 
Pts on dialysis only. M36, M48 only if 
systemic oxalosis manifestation Table 6 X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
24-hour urine collection 
(1 collection) 
Table 12 and Section 6.2.2 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
Single-void urine 
(3 collections) 
Collected within 7 days predose (first 
morning voids preferred). Section 6.2.2 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
Single-void urine 
(1 collection) 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
Renal ultrasound 
Section 6.3.1 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Echocardiogram 
Section 6.2.3.1  
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Radiographs 
Section 6.2.3.3  
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Ophthalmology 
Evaluation 
Section 6.2.3.4  
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Review/record dialysis 
parameters 
Pts on dialysis only. Section 6.5.5.5 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Vineland Behavior Scale 
Pts <6 y at consent. Section 6.7 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 


Clinical Study Protocol ALN-GO1-005 
lumasiran 
Amendment 1, 06 May 2020 
Alnylam Pharmaceuticals 
Confidential 
15 
Table 3: 
Schedule of Assessments – Long-term Extension Period (Month 36 to End of Study):  Patient Weight <10 kg 
Patients whose weight increases to ≥10 kg continue monthly dosing until the next visit that coincides with Table 4. Patients will 
then follow Table 4 until the end of the study. 
Study Period 
 
Long-term Extension Period 
EOT EOS/ 
ET 
Safety 
Follow-up 
(Pts who DC 
treatment) 
Study Visit 
 
M36 M37;
M38 M39 M40;
M41 M42 M43; 
M44 M45 M46; 
M47 M48 M49;
M50 M51 M52; 
M53 M54 M55;
M56 M57 M60 
Study Day  
(±Visit Window) 
Notes 
1009 
(±14) 
1037, 
1065 
(±14) 
1093 
(±14) 
1121, 
1149 
(±14) 
1177 
(±14) 
1205, 
1233 
(±14) 
1261 
(±14) 
1289, 
1317 
(±14) 
1345 
(±14) 
1373, 
1401 
(±14) 
1429 
(±14) 
1457, 
1485 
(±14) 
1513 
(±14) 
1541, 
1569 
(±14) 
1597 
(±14) 
1681 
(±14) 
Every 84 
days (±14) 
Quality of life 
questionnaires 
Section 6.8  
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
Patient/caregiver 
experience and impact 
questionnaires 
Section 6.9 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
Healthcare resource 
utilization 
Section 6.10 
Continuous 
ADA sample 
Section 6.5.5.1 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
Blood and urine samples 
for exploratory analyses 
Single-void urine. Samples collected 
predose. Section 6.6 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Renal stone events 
Section 6.3.2 
Continuous 
Review/record AEs 
Section 6.5.6.2 
Continuous 
Prior and concomitant 
medications 
Section 5.3 
Continuous 
Abbreviations:  ADA=antidrug antibody; AE=adverse event; DC=discontinue; ECG=electrocardiogram; EOS=end of study; EOT=end of treatment; ET=early 
termination; hrs=hours; LFT=liver function tests; M=month; PD=pharmacodynamic; PE=physical examination; PK=pharmacokinetic; POx=plasma oxalate; 
pts=patients; SAE=serious adverse event; y=years 
Notes: 
• One month is defined as 28 days.  
• Assessments are to be performed prior to dosing, where applicable. When scheduled at the same time points and where feasible, the assessments of vital 
signs and 12-lead ECGs should be performed before physical examinations and blood sample collections. 
• Visits and study drug dosing may be conducted offsite where applicable country and local regulations and infrastructure allow (at the discretion of the 
Investigator, based on safety and tolerability), provided the patient has tolerated a dose of lumasiran administered in the clinic.  If a visit is conducted offsite, 
a body system assessment may be performed in lieu of a physical examination. 
• In situations where a study visit is unable to be completed (either at the site or offsite by a healthcare professional), the Investigator (or delegate) will 
verbally contact the patient within the study visit window to assess concomitant medications, renal stone events, adverse events, and healthcare utilization. 
• Patients who discontinue study drug early will be asked to return for their next scheduled visit to complete ET assessments and to complete safety follow-up 
visits once every 3 months, per the safety follow-up schedule in this table, for up to 12 months after the last dose of lumasiran (Section 3.3.1). See Section 
4.3.1 for instructions for patients who discontinue study drug. 
• Urine collections are only performed in patients who are able to produce urine, ie, ability to produce ≥100 ml per day. 
 


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Table 4: 
Schedule of Assessments – Long-term Extension Period (Month 9 to End of Study):  Patient Weight ≥10 kg 
Patients following Table 2 or Table 3 whose weight increases to ≥10 kg continue monthly dosing until the next visit that coincides with 
this table.  Patients will then follow this table until the end of the study.  
Study Period 
 
Long-term Extension Period 
EOT EOS/ 
ET 
Safety 
Follow-up 
(Pts who DC 
treatment) 
Study Visit 
 
M9 
M12 M15 M18 M21 M24 M27 M30 M33 M36 M39 M42 M45 M48 M51 
M54 
M57 M60 
Study Day  
(±Visit Window)* Notes 
253 
(±14) 
337 
(±14) 
421 
(±14) 
505 
(±14) 
589 
(±14) 
673 
(±14) 
757 
(±14) 
841 
(±14) 
925 
(±14) 
1009 
(±14) 
1093 
(±14) 
1177 
(±14) 
1261 
(±14) 
1345 
(±14) 
1429 
(±14) 
1513 
(±14) 
1597 
(±14) 
1681 
(±14) 
Every 84 
days (±14) 
Full PE 
Section 6.5.3 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Abbreviated PE 
Section 6.5.3 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
Height/length 
Section 6.5.2 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Body weight 
Section 6.5.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
Section 6.5.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
Triplicate. 
Section 6.5.4 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Pregnancy test 
Females of child-
bearing potential. 
Section 6.5.5.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical 
laboratory 
assessments 
LFTs within 7 days 
predose. 
Section 6.5.5 
X 
X 
X 
X 
LFT 
only 
X 
LFT 
only 
X 
LFT 
only 
X 
LFT 
only 
X 
LFT 
only 
X 
LFT 
only 
X 
LFT 
only 
X 
X 
Study drug 
dosing 
Table 10. Dose 
after dialysis, if 
applicable. 
Section 5.2.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Blood samples 
for PD analyses 
M12, M36, M48, 
only if POx profile 
is not performed. 
Section 6.3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood samples 
for POx profile 
Pts on dialysis 
only. M36, M48 
only if systemic 
oxalosis 
manifestation. 
Table 6  
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
24-hour urine 
collection 
(1 collection) 
Table 12 and 
Section 6.2.2 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 


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Table 4: 
Schedule of Assessments – Long-term Extension Period (Month 9 to End of Study):  Patient Weight ≥10 kg 
Patients following Table 2 or Table 3 whose weight increases to ≥10 kg continue monthly dosing until the next visit that coincides with 
this table.  Patients will then follow this table until the end of the study.  
Study Period 
 
Long-term Extension Period 
EOT EOS/ 
ET 
Safety 
Follow-up 
(Pts who DC 
treatment) 
Study Visit 
 
M9 
M12 M15 M18 M21 M24 M27 M30 M33 M36 M39 M42 M45 M48 M51 
M54 
M57 M60 
Study Day  
(±Visit Window)* Notes 
253 
(±14) 
337 
(±14) 
421 
(±14) 
505 
(±14) 
589 
(±14) 
673 
(±14) 
757 
(±14) 
841 
(±14) 
925 
(±14) 
1009 
(±14) 
1093 
(±14) 
1177 
(±14) 
1261 
(±14) 
1345 
(±14) 
1429 
(±14) 
1513 
(±14) 
1597 
(±14) 
1681 
(±14) 
Every 84 
days (±14) 
Single-void urine 
collections 
(3 collections) 
Collected within 
7 days predose 
(first morning 
voids preferred). 
Section 6.2.2 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
X 
Single-void urine 
collection 
(1 collection) 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Blood sample for 
pyridoxine 
(vitamin B6) 
levels 
Only in pts 
receiving 
therapeutic 
pyridoxine, 
collect ≥6 hrs 
after dose. 
Section 5.3 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Renal ultrasound Section 6.3.1 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Echocardiogram 
Section 6.2.3.1  
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Radiographs 
Section 6.2.3.3  
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Ophthalmology 
Evaluation 
Section 6.2.3.4  
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Review/record 
dialysis 
parameters 
Pts on dialysis 
only. 
Section 6.5.5.5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vineland 
Behavior Scale 
Pts <6 y at 
consent. 
Section 6.7 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Quality of life 
questionnaires 
Section 6.8 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Patient/ caregiver 
experience and 
impact 
questionnaires 
Section 6.9 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 


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Table 4: 
Schedule of Assessments – Long-term Extension Period (Month 9 to End of Study):  Patient Weight ≥10 kg 
Patients following Table 2 or Table 3 whose weight increases to ≥10 kg continue monthly dosing until the next visit that coincides with 
this table.  Patients will then follow this table until the end of the study.  
Study Period 
 
Long-term Extension Period 
EOT EOS/ 
ET 
Safety 
Follow-up 
(Pts who DC 
treatment) 
Study Visit 
 
M9 
M12 M15 M18 M21 M24 M27 M30 M33 M36 M39 M42 M45 M48 M51 
M54 
M57 M60 
Study Day  
(±Visit Window)* Notes 
253 
(±14) 
337 
(±14) 
421 
(±14) 
505 
(±14) 
589 
(±14) 
673 
(±14) 
757 
(±14) 
841 
(±14) 
925 
(±14) 
1009 
(±14) 
1093 
(±14) 
1177 
(±14) 
1261 
(±14) 
1345 
(±14) 
1429 
(±14) 
1513 
(±14) 
1597 
(±14) 
1681 
(±14) 
Every 84 
days (±14) 
Healthcare 
resource 
utilization 
Section 6.10 
Continuous 
ADA sample 
Section 6.5.5.1 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Blood and urine 
samples for 
exploratory 
analyses 
Single-void 
urine. Samples 
collected predose. 
Section 6.6 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Bone scan 
(Optional) 
Only in adult 
Cohort B pts. 
Section 6.2.3 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Renal stone 
events 
Section 6.3.2 
Continuous 
Review/ 
record AEs 
Section 6.5.6.2 
Continuous 
Prior and 
concomitant 
medications 
Section 5.3 
Continuous 
Abbreviations:  ADA=antidrug antibody; AE=adverse event; DC=discontinue; ECG=electrocardiogram; EOS=end of study; EOT=end of treatment; ET=early 
termination; hrs=hours; LFT=liver function tests; M=month; PD=pharmacodynamic; PE=physical examination; PK=pharmacokinetic; POx=plasma oxalate; 
pts=patients; SAE=serious adverse event; y=years 
* During periods of time when the COVID-19 pandemic impedes the ability of patients to travel to the study site, study assessments and dosing may be 
performed within ±28 days of the visit unless otherwise noted. 
Notes: 
• One month is defined as 28 days. 
• Assessments are to be performed prior to dosing, where applicable. When scheduled at the same time points and where feasible, the assessments of vital 
signs and 12-lead ECGs should be performed before physical examinations and blood sample collections. 
• Visits and study drug dosing may be conducted offsite where applicable country and local regulations and infrastructure allow (at the discretion of the 
Investigator, based on safety and tolerability), provided the patient has tolerated a dose of lumasiran administered in the clinic.  If a visit is conducted offsite, 
a body system assessment may be performed in lieu of a physical examination. 


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• In situations where a study visit is unable to be completed (either at the site or offsite by a healthcare professional), the Investigator (or delegate) will 
verbally contact the patient within the study visit window to assess concomitant medications, renal stone events, adverse events, and healthcare utilization. 
• Patients who discontinue study drug after Month 6 will be asked to return for their next scheduled visit to complete ET assessments and to complete safety 
follow-up visits once every 3 months, per the safety follow-up schedule, for up to 12 months after the last dose of lumasiran (Section 3.3.1). See Section 
4.3.1 for instructions for patients who discontinue study drug.  
• Urine collections are only performed in patients who are able to produce urine, ie, ability to produce ≥100 ml per day.  


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Table 5: 
Pharmacokinetic Assessment Time Points for Patients Not on Dialysis 
Study Visit 
Protocol Time (hh:mm) 
Day 1 
02:00 (±20 minutes) 
04:00 (±30 minutes) 
08:00 (±1 hours) 
12:00 (±2 hours) 
24:00 (±3 hours) 
Month 6 (±3 mos) 
02:00 (±20 minutes) 
04:00 (±30 minutes) 
08:00 (±1 hours) 
12:00 (±2 hours) 
24:00 (±3 hours) 
Abbreviations:  hh:mm=hour:minute; mos=months; PK=pharmacokinetic; SAE=serious adverse event 
• 
Blood samples for PK assessment may be collected at 8 and 12 hours postdose as feasible during periods of 
time when the COVID-19 pandemic impedes the ability of patients to travel to the study site and healthcare 
professionals to go to patients' homes. 
• 
The hour (±range) indicate sample collection timing relative to dosing.  Precise PK sample times (hour and minute) are 
recorded. 
• 
If an SAE occurs associated with dosing, an additional PK sample may be collected at 4 to 8 hours postdose on the day 
of dosing, where blood volume limit permits (see Section 6.5.5.4) 
• 
See Section 6.4 for additional information on PK assessments. 
 


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Table 6: 
Pharmacokinetic and Plasma Oxalate Profile Assessment Time Points for Patients 
on Dialysis 
Sampling Time (hh:mm) 
Blood sample for  
PK Assessment 
Blood Sample for  
POx Profile Assessment 
Study Month (Study Day) 
Day 1 
Month 6* 
Screening Period 
(Day -120 to Day -1) 
Month 3, Month 6, and Month 12** 
Pre-dialysis 
 
 
X 
30 minutes before end of dialysis (±10 minutes) 
 
 
X 
00:30 (post-dialysis) (±30 minutes) 
 
 
X  
02:00 (postdose) (±20 minutes) 
X  
X 
X 
04:00 (postdose) (±30 minutes) 
X  
X 
X 
08:00 (postdose) (±1 hour) 
X, if feasible 
X 
X 
12:00 (postdose) (±2 hours) 
X, if feasible 
X 
X 
Pre-dialysis (for HD session day after dose) 
24:00 post-dose (±3 hours) if no HD session 
scheduled the day after dosing 
X 
X 
X 
Abbreviations:  HD=hemodialysis; hh:mm=hour:minute; hrs=hours; mos=months; PK=pharmacokinetics; 
POx=plasma oxalate 
*  During periods of time when the COVID-19 pandemic impedes the ability of patients to travel to the study site, 
the blood sample for PK assessment may be collected at Month 6 (±3 months). 
**During periods of time when the COVID-19 pandemic impedes the ability of patients to travel to the study site, 
blood samples for the plasma oxalate assessment maybe collected at Month 3 (±2 months), Month 6 (±5 months), 
and Month 12 (±11 months), and may be obtained post dialysis at 2:00, 4:00, 8:00, 12:00, and 24:00 timepoints on 
non-dosing days. 
• 
The 8- and 12-hour timepoints of the POx profile assessment will only be performed at selected study 
centers. 
• 
When feasible, POx assessment should be performed after the shortest interval between dialysis sessions, 
ie, starting on or after the second dialysis session of the week.  This applies to all patients on dialysis, 
regardless of the number of days in treatment regimen.  The timing of POx assessments relative to dialysis 
should remain consistent throughout the study (ie, after the shortest interval between dialysis sessions if 
this was done during screening).  During the first 6 months on study, the starting time for the predialysis 
POx levels (including those in POx profiles) is 24 hrs (±2 hrs) after a dialysis session on the previous day 
or 48 hrs (±4 hrs) after previous session in patients on 3 days per week dialysis regimen.  See Section 6.1 
for information regarding interruption of dialysis regimen during the screening period. 
• 
After the first 6 months, the timing of the POx assessment relative to patients’ dialysis schedule should 
continue to remain consistent for each patient, when possible.   
• 
Suggested sample times are listed.  The hour (±range) indicates sample collection timing relative to dosing 
and end of dialysis session.  Precise sample times (hour and minute) are recorded. 
• 
At Screening, the timepoints described above are relative to beginning and end of dialysis sessions. See 
Figure 1 for further details about timing of POx profile assessments.   
• 
POx profile assessment will also be performed at Month 36 and Month 48 only in patients with at least one 
systemic oxalosis manifestation. 
• 
See Section 6.4 for additional information on PK assessments. 
• 
If an SAE occurs associated with dosing, an additional PK sample may be collected at 4 to 8 hrs postdose 
on the day of dosing, where blood volume permits (see Section 6.5.5.4).  
 


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Table 7: 
Urine Pharmacokinetic Assessment Time Points for Patients with Urine 
Production, in Patients >6 years old 
Study Day 
Sampling Time (postdose) 
(hh:mm) 
Pooled Urine PK Sample 
Day 1 
0-6 hours (±30 minutes) 
X 
6-12 hours (±30 minutes) 
X 
12-24 hours (±2 hours) 
X 
Abbreviations:  hh:mm=hour minute; PK=pharmacokinetics 
• 
Suggested sample times are listed.  The hour (±range) indicates sample collection timing relative to dosing.  
Precise PK sample times (hour and minute) are recorded. 
• 
Collected only in patients who are able to produce urine, ie, ability to produce ≥100 ml urine per day. 
 


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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ................................................................................................................4 
TABLE OF CONTENTS ...............................................................................................................23 
LIST OF TABLES .........................................................................................................................27 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................29 
1. 
INTRODUCTION ......................................................................................................31 
1.1. 
Disease Overview .......................................................................................................31 
1.2. 
Lumasiran ...................................................................................................................32 
1.2.1. 
Summary of Nonclinical Data with Lumasiran ..........................................................32 
1.2.2. 
Summary of Clinical Data with Lumasiran ................................................................33 
1.3. 
Study Design Rationale ..............................................................................................34 
1.4. 
Dose Rationale ............................................................................................................35 
1.5. 
Benefit-Risk Assessment ............................................................................................38 
2. 
OBJECTIVES AND ENDPOINTS ............................................................................39 
3. 
INVESTIGATIONAL PLAN .....................................................................................41 
3.1. 
Summary of Study Design ..........................................................................................41 
3.2. 
Duration of Treatment ................................................................................................42 
3.3. 
Duration of Study .......................................................................................................42 
3.3.1. 
Definition of End of Study for an Individual Patient .................................................42 
3.4. 
Number of Planned Patients .......................................................................................43 
3.5. 
Method of Assigning Patients to Treatment Groups ..................................................43 
3.6. 
Blinding ......................................................................................................................43 
3.7. 
Data Monitoring Committee .......................................................................................43 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................43 
4.1. 
Inclusion Criteria ........................................................................................................43 
4.1.1. 
Cohorts A and B .........................................................................................................43 
4.1.2. 
Cohort B Only.............................................................................................................44 
4.2. 
Exclusion Criteria (Cohorts A and B) ........................................................................44 
4.3. 
Removal from Study Drug or Assessment .................................................................45 
4.3.1. 
Discontinuation of Study Drug or Declining Procedural Assessments ......................45 
4.3.2. 
Stopping a Patient’s Study Participation ....................................................................46 
4.3.2.1. 
Patient or Legal Guardian Stops Participation in the Study .......................................46 


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4.3.2.2. 
Withdrawal of Consent to Process the Patient’s Personal Data .................................47 
4.3.2.3. 
Investigator or Sponsor Stops Participation of a Patient in the Study ........................47 
4.3.2.4. 
Recording Reason for Stopping a Patient’s Study Participation ................................47 
4.3.3. 
Lost to Follow-Up.......................................................................................................47 
4.3.4. 
Replacement of Study Patients ...................................................................................48 
5. 
TREATMENTS AND OTHER REQUIREMENTS ..................................................48 
5.1. 
Treatments Administered ............................................................................................48 
5.2. 
Study Drug ..................................................................................................................48 
5.2.1. 
Description ..................................................................................................................48 
5.2.2. 
Dose and Administration ............................................................................................48 
5.2.3. 
Dose Modifications .....................................................................................................50 
5.2.3.1. 
Liver Function Test Criteria for Withholding, Monitoring and Stopping 
Lumasiran Dosing .......................................................................................................50 
5.2.4. 
Preparation, Handling, and Storage ............................................................................52 
5.2.5. 
Packaging and Labeling ..............................................................................................52 
5.2.6. 
Accountability .............................................................................................................52 
5.3. 
Concomitant Medications and Procedures .................................................................52 
5.4. 
Treatment Compliance ................................................................................................53 
5.5. 
Other Requirements ....................................................................................................53 
5.5.1. 
Contraception ..............................................................................................................53 
5.5.2. 
Dietary Restrictions ....................................................................................................54 
6. 
STUDY ASSESSMENTS ..........................................................................................54 
6.1. 
Screening Assessments ...............................................................................................55 
6.1.1. 
Retesting .....................................................................................................................56 
6.1.2. 
Rescreening .................................................................................................................56 
6.2. 
Efficacy Assessments .................................................................................................57 
6.2.1. 
Plasma Oxalate ...........................................................................................................57 
6.2.1.1. 
Cohort A .....................................................................................................................57 
6.2.1.2. 
Cohort B......................................................................................................................57 
6.2.2. 
Urinary Oxalate ..........................................................................................................58 
6.2.2.1. 
Validity Criteria for 24-hour Urine Collections .........................................................59 
6.2.3. 
Measures of Systemic Oxalosis ..................................................................................59 
6.2.3.1. 
Cardiac ........................................................................................................................59 


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6.2.3.2. 
Dermatologic ..............................................................................................................60 
6.2.3.3. 
Skeletal .......................................................................................................................60 
6.2.3.4. 
Ocular .........................................................................................................................60 
6.3. 
Renal Assessments and Additional Pharmacodynamic Measurements......................61 
6.3.1. 
Renal Ultrasound ........................................................................................................61 
6.3.2. 
Renal Stone Events .....................................................................................................62 
6.3.3. 
Urinary Oxalate:Creatinine Ratio ...............................................................................62 
6.3.4. 
Estimated Glomerular Filtration Rate .........................................................................62 
6.4. 
Pharmacokinetic Assessments ....................................................................................62 
6.5. 
Safety Assessments .....................................................................................................63 
6.5.1. 
Vital Signs ..................................................................................................................63 
6.5.2. 
Weight and Height/Length .........................................................................................63 
6.5.3. 
Physical Examination .................................................................................................64 
6.5.4. 
Electrocardiogram .......................................................................................................64 
6.5.5. 
Clinical Laboratory Assessments ...............................................................................64 
6.5.5.1. 
Immunogenicity ..........................................................................................................66 
6.5.5.2. 
Pregnancy Testing ......................................................................................................67 
6.5.5.3. 
Additional Liver Function Assessments .....................................................................67 
6.5.5.4. 
Maximum Blood Volume ...........................................................................................68 
6.5.5.5. 
Dialysis Parameters ....................................................................................................69 
6.5.6. 
Adverse Events ...........................................................................................................69 
6.5.6.1. 
Definitions ..................................................................................................................69 
6.5.6.2. 
Eliciting and Recording Adverse Events ....................................................................71 
6.5.6.3. 
Reporting Adverse Events of Clinical Interest to Sponsor/Designee .........................72 
6.5.6.4. 
Serious Adverse Events Require Immediate Reporting to Sponsor/Designee ...........72 
6.5.6.5. 
Sponsor Safety Reporting to Regulatory Authorities .................................................72 
6.5.6.6. 
Serious Adverse Event Notification to the Institutional Review 
Board/Independent Ethics Committee ........................................................................72 
6.5.6.7. 
Pregnancy Reporting ..................................................................................................72 
6.5.6.8. 
Overdose Reporting ....................................................................................................73 
6.5.7. 
COVID-19 Data Collection ........................................................................................73 
6.6. 
Biomarkers, DNA Genotyping, and Biospecimen Repository ...................................73 
6.7. 
Developmental Assessments ......................................................................................74 


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6.8. 
Quality of Life Questionnaires ...................................................................................74 
6.8.1. 
EQ-5D .........................................................................................................................74 
6.8.2. 
PedsQL .......................................................................................................................74 
6.8.3. 
KDQOL ......................................................................................................................75 
6.9. 
Patient/Caregiver Experience Surveys and Impact Questionnaires ............................75 
6.9.1. 
Patient Experience Survey ..........................................................................................75 
6.9.2. 
Caregiver Experience Survey .....................................................................................75 
6.9.3. 
Patient and Caregiver Impact Questionnaire ..............................................................75 
6.10. 
Healthcare Resource Utilization .................................................................................76 
7. 
STATISTICS ..............................................................................................................76 
7.1. 
Determination of Sample Size ....................................................................................76 
7.2. 
Statistical Methodology ..............................................................................................76 
7.2.1. 
Populations to be Analyzed ........................................................................................76 
7.2.2. 
Examination of Subgroups .........................................................................................77 
7.2.3. 
Handling of Missing Data ...........................................................................................77 
7.2.4. 
Baseline Evaluations ...................................................................................................77 
7.2.5. 
Efficacy Analyses .......................................................................................................77 
7.2.5.1. 
Primary Endpoint ........................................................................................................77 
7.2.5.2. 
Secondary Endpoints ..................................................................................................77 
7.2.5.3. 
Exploratory Endpoints ................................................................................................78 
7.2.6. 
Pharmacodynamic Analysis........................................................................................78 
7.2.7. 
Pharmacokinetic Analysis ..........................................................................................78 
7.2.8. 
Safety Analyses ..........................................................................................................78 
7.2.9. 
Immunogenicity Analyses ..........................................................................................79 
7.2.10. 
Interim Analysis ..........................................................................................................79 
7.2.11. 
Optional Additional Research .....................................................................................79 
8. 
STUDY ADMINISTRATION ...................................................................................79 
8.1. 
Ethical and Regulatory Considerations ......................................................................79 
8.1.1. 
Informed Consent .......................................................................................................79 
8.1.2. 
Ethical Review ............................................................................................................80 
8.1.3. 
Serious Breach of Protocol .........................................................................................80 
8.1.4. 
Study Documentation, Confidentiality, and Records Retention .................................80 
8.1.5. 
End of Study ...............................................................................................................81 


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8.1.6. 
Termination of the Clinical Study or Site Closure .....................................................81 
8.2. 
Data Quality Control and Quality Assurance .............................................................81 
8.2.1. 
Data Handling .............................................................................................................81 
8.2.2. 
Study Monitoring ........................................................................................................82 
8.2.3. 
Audits and Inspections ................................................................................................82 
8.3. 
Publication Policy .......................................................................................................82 
9. 
LIST OF REFERENCES ............................................................................................83 
10. 
APPENDICES ............................................................................................................85 
10.1. 
Formulae for Estimated Glomerular Filtration Rate Calculation ...............................85 
10.2. 
Blood Volume Limits in Pediatric Patients ................................................................86 
 
LIST OF TABLES 
Table 1: 
Schedule of Assessments –Primary Analysis Period (Screening through 
Month 6):  All Patients .................................................................................................9 
Table 2: 
Schedule of Assessments – Long-term Extension Period (Month 7 to Month 
35):  Patient Weight <10 kg ........................................................................................12 
Table 3: 
Schedule of Assessments – Long-term Extension Period (Month 36 to End 
of Study):  Patient Weight <10 kg ..............................................................................14 
Table 4: 
Schedule of Assessments – Long-term Extension Period (Month 9 to End of 
Study):  Patient Weight ≥10 kg ..................................................................................16 
Table 5: 
Pharmacokinetic Assessment Time Points for Patients Not on Dialysis ....................20 
Table 6: 
Pharmacokinetic and Plasma Oxalate Profile Assessment Time Points for 
Patients on Dialysis .....................................................................................................21 
Table 7: 
Urine Pharmacokinetic Assessment Time Points for Patients with Urine 
Production, in Patients >6 years old ...........................................................................22 
Table 8: 
Comparison of PK and PD of siRNAs in Rats with and without 
Nephrectomy ...............................................................................................................36 
Table 9: 
Lumasiran Dosing Regimen in Pediatric and Adult PH1 Patients and 
Predicted Glycolate Oxidase Target Suppression at Steady State ..............................38 
Table 10: Weight-based Dosing Regimen ..................................................................................49 
Table 11: Monitoring and Dosing Rules for Asymptomatic Patients with Confirmed 
Isolated Elevations of ALT and/or AST >3× ULN, with No Alternative 
Cause Identified ..........................................................................................................51 
Table 12: 24-hour Urine Collection Procedure by Study Visit for Patients who are not 
Anuric .........................................................................................................................59 


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Table 13: Clinical Laboratory Assessments ...............................................................................66 
Table 14: Hepatic Assessments in Patients Who Experience Elevated Transaminases .............68 
Table 15: Maximum Allowable Total Blood Volume Collection Chart ....................................86 
 
LIST OF FIGURES 
Figure 1: 
Blood Sample Collection for PD Assessments During Screening .............................56 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation  
Definition 
ADA 
Antidrug antibody 
AE 
Adverse event 
AGT 
Alanine-glyoxylate aminotransferase 
AGXT 
Alanine-glyoxylate aminotransferase gene 
ALT 
Alanine aminotransferase 
ASGPR 
Asialoglycoprotein receptor 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical Classification System 
AUC 
Area under the concentration-time curve 
BSA 
Body surface area 
CDC 
US Centers for Disease Control and Prevention 
Cmax 
Maximum plasma concentration 
CFR 
Code of Federal Regulations 
CL/F 
Apparent clearance 
COVID-19 
Coronavirus disease 2019 
DMC 
Data Monitoring Committee 
DNA 
Deoxyribonucleic acid  
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
EOS 
End of study 
EOT 
End of treatment 
ET 
Early termination 
EQ-5D 
Euro Quality of Life Health State Profile Questionnaire 
ESRD 
End-stage renal disease 
GalNAc 
N-acetylgalactosamine 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
24h 
24 hours 
HAO1 
Hydroxyacid oxidase 1 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 


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Abbreviation  
Definition 
ICF 
Informed consent form  
ICH 
International Council on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ISR 
Injection site reactions 
LFT 
Liver function tests 
MAD 
Multiple-ascending dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
mMol 
Millimoles 
mRNA 
Messenger ribonucleic acid 
PD 
Pharmacodynamic 
PH1 
Primary hyperoxaluria type 1 
PK 
Pharmacokinetic 
PT 
Preferred Term 
q3M 
Once every 3 months 
qM 
Monthly (every 28 days) 
RNA 
Ribonucleic acid 
SAD 
Single-ascending dose 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SCr 
Serum creatinine 
siRNA 
Small interfering RNA 
SUSAR 
Suspected unexpected serious adverse reaction 
t½β 
Elimination half-life 
tmax 
Time to maximum plasma concentration 
ULN 
Upper limit of normal 
US 
United States 
V/F 
Apparent volume of distribution 
WHO 
World Health Organization 


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1. 
INTRODUCTION 
1.1. 
Disease Overview 
Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disease characterized by 
excessive oxalate production by the liver and consequent hyperoxaluria.  PH1 is caused by 
mutations in the alanine-glyoxylate aminotransferase (AGXT) gene, which encodes the liver 
peroxisomal enzyme alanine-glyoxylate aminotransferase (AGT).  As a consequence of AGT 
deficiency, glyoxylate accumulates and is oxidized to oxalate in the hepatocyte and ultimately 
transported to the kidneys for excretion.  Oxalate, in the form of its calcium salt, is excreted 
almost entirely by the kidney.  Due to its insolubility, calcium oxalate can crystallize readily in 
the urinary tract.  In PH1, excess urinary oxalate results in recurrent nephrolithiasis and/or 
nephrocalcinosis, which can lead to pain, infections, progressive kidney disease and failure, 
along with reduced quality of life.[Cochat 2013]  As renal function declines, elimination of 
oxalate is further reduced, such that calcium oxalate accumulates in bone, vasculature, skin, 
retina, heart, and nervous system, resulting in severe end-organ damage.[Cochat 2013]  This 
devastating condition, systemic oxalosis, arises when the estimated glomerular filtration rate 
(eGFR) has declined to below 30 to 45 mL/min/1.73 m2.[Cochat 2013]  Without treatment, the 
disease progresses inexorably, and death from end-stage renal disease (ESRD) and/or 
complications of oxalosis is inevitable.[Cochat 2013; Harambat 2010; van der Hoeven 2012] 
Over 150 mutations in AGXT have been described.[Williams 2009]  While there are broad 
genotype–phenotype associations with the underlying causative defect, patients can present with 
very different symptoms, disease course, including timing of an individual’s eGFR decline, and 
treatment response.[Danpure 2014; Hoppe 1997]  Patients progress at various rates and an event 
that leads to acute or chronic worsening, such as an obstructive kidney stone or episode of 
dehydration, can occur at any time. 
The incidence of PH1 is approximately 1 in 120,000 live births, and the prevalence is 1 to 3 per 
million in North America and Europe.[Cochat 2013; Hopp 2015; Hoppe 2010]  The disease is 
more prevalent in areas where consanguineous marriages are common, especially in the Middle 
East and Northern Africa.[Al-Eisa 2004; Boualla 2015; Frishberg 2005; Kamoun 1996] 
PH1 often presents as a pediatric disease, and many patients remain undiagnosed for years after 
the initial clinical manifestations of the disease.[Lieske 2005; Mandrile 2014; van Woerden 
2003]  A recently published analysis of 247 patients with PH1 from 206 pedigrees in the Rare 
Kidney Stone Consortium PH Registry demonstrated a median age of first symptoms at 5.2 years 
of age and a cumulative renal survival of 76%, 43%, and 12% at 20 years, 40 years, and 60 years 
of age, respectively.[Hopp 2015]  Similarly, an analysis of 526 patients with PH1 published by 
the OxalEurope Consortium indicated a median age of disease symptom onset of 3.9 years and a 
median age of diagnosis of 8.1 years; disease presented in infancy in 29% of patients, 40% of 
whom had ESRD.[Mandrile 2014]  Overall, 43% of all patients diagnosed with PH1 had already 
progressed to ESRD at the time of diagnosis.   
There are no approved therapies for the treatment of PH1 and the current standard of care is 
burdensome to patients and their families.  Disease management is based on supportive 
measures, including high fluid intake and crystallization inhibitors to increase urinary oxalate 
solubility, and treatment of disease complications such as urinary tract stones and infections in 


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those that do not yet have ESRD.  Pyridoxine can normalize hepatic oxalate production (and 
consequently urinary oxalate) in a small subset (~5%) of patients.[Hoppe 2010]  Dietary 
modification plays a minor role in treatment since endogenous oxalate production far exceeds 
dietary intake in patients with PH1.  Patients progressing to, or presenting with ESRD, require 
intense dialysis replacement therapy.  Dialysis is not viewed as an effective therapy for PH1, but 
rather serves as a step in the clinical course toward a liver-kidney transplant or as an alternative 
to no therapy at all.  Dialysis is often inadequate to effectively offload accumulating oxalate, and 
systemic oxalosis with end organ damage may develop despite this burdensome treatment.  
Dialysis regimens for PH1 are typically more frequent than conventional dialysis, predisposing 
to increased risk of complications.  Combined liver-kidney transplantation offers potentially 
curative therapy, but is limited due to restricted availability, complications associated with the 
procedure, ethical considerations in resource-poor settings[Cochat 2013], and intense use of 
health care resources. 
PH1, over time, develops into a serious, severely debilitating disease with significant morbidity 
and mortality which have a profoundly negative impact on quality of life.  In renally impaired 
patients, plasma oxalate saturation and persistent deposition across multiple organs leads to 
systemic oxalosis manifestations.  Given the clinical course and characteristics of PH1 disease 
progression, it is reasonable to expect that decreases in hepatic oxalate production may result in 
clinical benefit in PH1 patients with advanced renal disease.  Limited and burdensome 
management options for PH1 outlined above highlight the serious unmet need for a safe and 
efficacious treatment for all patients with this devastating disease, regardless of renal function. 
1.2. 
Lumasiran 
Alnylam Pharmaceuticals, Inc. (the Sponsor) is developing lumasiran (ALN-GO1), an 
investigational agent comprised of a synthetic, small interfering RNA (siRNA) (drug substance 
ALN-65585) covalently linked to a triantennary N-acetylgalactosamine (GalNAc) ligand, 
designed to target liver hydroxyacid oxidase 1 (HAO1) mRNA, blocking production of glycolate 
oxidase (GO) and hence reducing hepatic oxalate production, which is the underlying cause of 
the morbidity and mortality associated with PH1. 
Lumasiran is currently in development for treatment of PH1 in infants, pediatric, and adult 
patients. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of lumasiran is 
provided in the Investigator’s Brochure. 
1.2.1. 
Summary of Nonclinical Data with Lumasiran 
The pharmacology, safety pharmacology, drug metabolism and pharmacokinetics (PK), and 
toxicology of lumasiran were evaluated in a series of in vitro and in vivo nonclinical studies. 
Lumasiran was pharmacologically active in all tested species.  Subcutaneous (SC) administration 
of lumasiran demonstrated potent, dose-dependent pharmacologic activity resulting in reduced 
hepatic HAO1 mRNA levels with the expected increases in glycolate levels in wild-type and 
diseased animals and subsequent reductions in urinary oxalate in diseased animals. 


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Genetic toxicity studies (bacterial reverse mutation, human peripheral blood lymphocyte 
chromosomal aberrations, and rat bone marrow micronucleus) assays were all negative at 
International Conference on Harmonisation (ICH) S2 (R1) limit doses. 
The nonclinical toxicology program for lumasiran includes a repeat-dose exploratory toxicology 
study in rats, and a series of Good Laboratory Practice (GLP) studies, which include 
developmental and reproductive studies in rats and rabbits, a pilot study in juvenile rats, and 
repeat-dose studies of up to 25- and 36-weeks in duration in rats and nonhuman primates, 
respectively.  To support inclusion of pediatric patients, the GLP repeat-dose rat studies were 
initiated with post-weaning animals that were 4 to 5 weeks old.  Additionally, a GLP-compliant 
pilot neonatal and juvenile rat toxicology study in the rat that was initiated in postnatal-day 4 
pups, and continued through postnatal-day 33, did not identify any evidence of potential 
developmental safety concerns due to either the toxicology or pharmacology of lumasiran.   
Notably, an in vitro study using human hepatocyte showed that infants have similar ASGPR 
mRNA and protein levels as adults, indicating that siRNA uptake into the liver will not be 
influenced by age. 
In addition, the PK and PD evaluations of lumasiran and two additional siRNAs in subtotal 
nephrectomy model in rats, where 5/6th of the kidneys was removed to mimic severe renal 
impairment, showed no meaningful differences in plasma or liver PK, and no differences in PD 
in rats with and without nephrectomy.   
The results of these nonclinical toxicology studies demonstrate a favorable safety profile for 
lumasiran and supports the use of lumasiran in the planned pivotal clinical studies in pediatric (as 
young as full-term neonates) and adult patients with PH1. 
A summary of nonclinical studies is included in the Investigator’s Brochure. 
1.2.2. 
Summary of Clinical Data with Lumasiran  
Lumasiran is being investigated in 4 clinical studies, 3 of which are currently ongoing.  Study 
ALN-GO1-001 is a Phase 1/2 study, and was completed in 2 parts (single-ascending dose [SAD; 
Part A] and multiple-ascending dose [MAD; Part B]), in healthy adult subjects and adult and 
pediatric patients (≥ 6 years old) with PH1.  In this study, healthy adult subjects in Part A were 
randomized to receive a single-blind dose of lumasiran (0.3-6.0 mg/kg) or placebo (6:2).  In Part 
B, patients ≥6 years of age with PH1 and preserved renal function (eGFR >45 mL/min/1.73 m2) 
were randomized 3:1 to receive single-blind doses of lumasiran or placebo at 1.0 mg/kg monthly 
for 3 doses, 3.0 mg/kg monthly for 3 doses, or 3.0 mg/kg every-3-months for 2 doses.  Patients in 
Part B on placebo transitioned to the open-label portion of the study to receive lumasiran. 
Available preliminary data from Study ALN-GO1-001 demonstrate a mean maximal reduction in 
24-hour urinary oxalate of 64% (Cohorts 1 to 3) and achievement of normal to near-normal 
levels of urinary oxalate (<0.7 mmol/24h/1.73 m2) in patients dosed with lumasiran (range: 0.29 
to 0.67 mmol/24h/1.73 m2).  This suppression of urinary oxalate was maintained with repeat 
dosing, indicative of the durability of the pharmacodynamic effect of lumasiran.  In addition, in 
the multiple-ascending dose group (Part B; n=10), preliminary data showed a mean reduction of 
59% in plasma oxalate relative to baseline 28 days after the last dose.  The mean maximal 
reduction in plasma oxalate was 75% (range 57-94%), and 50% of patients achieved plasma 
oxalate levels within the normal range (<1.6 μmol/L). 


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Study ALN-GO1-002 is an ongoing Phase 2 open-label extension study to evaluate the long-term 
safety, PK, and PD of lumasiran in patients with PH1 who completed Study ALN-GO1-001.   
In the ALN-GO1-001 and ALN-GO1-002 clinical studies, available data indicate that lumasiran 
has an acceptable safety and tolerability profile across all dosing regimens with no drug-related 
serious adverse events (SAEs) or study discontinuations attributed to drug administration.   
Additional detailed information on the chemistry, pharmacology, efficacy, and safety of 
lumasiran is provided in the Investigator’s Brochure. 
1.3. 
Study Design Rationale 
Elevated oxalate is the direct cause of disease pathology (kidney stones, renal failure, and 
systemic oxalosis) in patients with PH1, and can be evaluated as plasma oxalate level, plasma 
oxalate AUC between dialysis sessions, urinary excretion of oxalate, and measures of systemic 
oxalosis.  As discussed in Section 1.2.2, meaningful reductions in urinary oxalate excretion were 
seen in the Phase 1/2 study, ALN-GO1-001.  In addition to reducing urinary oxalate, lumasiran is 
expected to significantly lower plasma oxalate levels in patients with renal impairment based on 
the observed decrease in plasma oxalate levels in clinical studies of patients with preserved renal 
function.  PH1 patients with advanced renal disease (eGFR ≤45 mL/min/1.73 m2), who have 
severe unmet medical need, are also expected to meaningfully benefit from decreased hepatic 
oxalate production, regardless of whether or not on dialysis therapy.  The majority of PH1 
patients in the United States present in early childhood and many progress to renal failure by 
early adulthood.  Up to 26% of PH1 patients present with severe infantile disease and can 
develop end stage renal disease (ESRD) as early as 4 to 6 months of age.[Harambat 2010; Hopp 
2015]  Therefore, it is justified to study the effect of lumasiran in a PH1 population with 
advanced renal disease, ranging from full term infants to adults.   
The weight-based dosing regimen of this study, for PH1 patients with advanced renal disease, is 
similar to those being studied (studies ALN-GO1-003, ALN-GO1-004) in PH1 patients of the 
same age range as this study, with less advanced renal disease and is described in Section 5.2.2.  
Preclinical and clinical data indicate renal impairment does not influence the systemic exposure, 
PD, or safety of siRNA compounds (see Section 1.4). 
This study will evaluate PH1 patients with advanced renal disease in separate cohorts to account 
for differences in patients who do not yet require dialysis (Cohort A) vs patients who are 
currently on a dialysis maintenance regimen (Cohort B).  The objectives and endpoints reflect 
the differences in clinical management between cohorts during both the Primary Analysis Period 
(Baseline to 6 months) and the Long-term Extension Period (Month 6 to End of Study; 
54 months total).  The primary objective of plasma oxalate reduction applies to both cohorts.  
Also, the following can be measured regardless of dialysis dependence status and objectives are 
the same for both cohorts:  evaluation of growth parameters and developmental milestones (in 
children <6 years of age), quality of life, caregiver resource use, patient/caregiver experiences on 
lumasiran, antidrug antibodies (ADA), and additional PD parameters of plasma and urinary 
glycolate.  In addition, to further evaluate the effect of lumasiran on disease progression, 
measures of systemic oxalosis will be assessed across multiple organ systems, ie, cardiac, 
dermatologic, skeletal, and ocular. 


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Multiple samples will be collected for evaluation of plasma oxalate level (in both cohorts) and 
2 separate plasma oxalate profile assessments (in Cohort B only, to calculate AUC between 
dialysis sessions) will be performed during Screening to establish robust baseline measurements 
of the primary and secondary endpoints.  The primary endpoint is an objective laboratory 
assessment and not subject to bias.  Due to the combination of patient heterogeneity of a 
population spanning full term infants to adults, heterogeneity of disease characteristics in the 
broad age range, and the ultra-rare orphan population, a single-arm design is employed for this 
study. 
Lumasiran is currently being investigated in 4 separate clinical studies comprising infant, 
pediatric and adult populations of patients with PH1 who have relatively preserved renal function 
with regard to oxalate excretion by the kidneys.  In this study, lumasiran will be evaluated in 
PH1 patients of all ages with advanced renal disease, including patients on dialysis.  Enrolling 
infants and young pediatric patients in this study is acceptable given that lumasiran has been well 
tolerated in children ≥6 years old, and PH1 can present as a pediatric disease with life-
threatening consequences as early as infancy, with particularly high unmet medical need in this 
subpopulation with impaired renal function. 
1.4. 
Dose Rationale 
Contribution of Renal Pathway on the Pharmacokinetics and Pharmacodynamics of 
Lumasiran 
Preclinical and clinical data indicate the renal pathway is a minor elimination route for 
lumasiran, consistent with the renal excretion properties of 5 other siRNAs with similar 
physiochemical properties, as detailed below.  Hence it is considered that the weight-based dose 
regimen should be the same regardless of degree of renal function. 
A preclinical rat model of renal impairment using lumasiran and 2 additional GalNac conjugated 
siRNAs showed that renal impairment does not influence the systemic exposure of siRNA, liver 
PK, or PD (Table 8).  The preclinical study used nephrectomized (subtotal nephrectomy) rats, 
where 5/6th of the kidneys was removed to mimic severe renal impairment.  Urinary excretion of 
siRNAs was reduced to approximately 1% in rats with nephrectomy relative to the 5% renal 
excretion seen in rats without nephrectomy.  However, no meaningful differences were observed 
in the plasma concentrations, liver PK, and PD of the siRNAs in rats with and without subtotal 
nephrectomy.  Thus, the preclinical study results infer that renal excretion plays a minor role in 
the disposition of siRNA molecules and that moderate to severe renal impairment does not 
influence the liver concentration and activity of these molecules. 


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Table 8: 
Comparison of PK and PD of siRNAs in Rats with and without Nephrectomy  
siRNA 
Condition 
Plasmac 
Liverc 
% Urine 
Excretionc  
% mRNA 
Reductionc 
Cmax 
(µg/mL) 
AUC 
(h*µg/mL) 
Cmax 
(µg/g) 
AUC 
(h*µg/g) 
AD-57727a 
Control 
0.161 
0.501 
14.5 
ND 
42 ng/mL 
74 
Nephrectomy 
0.131 
0.606 
14.6 
ND 
13 ng/mL 
73 
AD-68364 
Control 
0.048 
0.198 
8 
752 
5 
~70 
Nephrectomy 
0.034 
0.139 
5.8 
765 
0.74 
Lumasiranb Control 
0.080 
0.303 
11.9 
ND 
3.2 
~70 
Nephrectomy 
0.081 
0.300 
14.7 
ND 
1.1 
~75 
Abbreviations:  AUC=area under curve; mRNA=messenger ribonucleic acid; ND=not determined; siRNA=small 
interfering RNA 
a  Urine excretion for AD-57727 are reported as concentrations instead of percentage.  
b  Liver concentrations were determined on Day 2 and Day 14, no statistical difference was observed on Day 2, 
apparent difference in elimination phase (~1.9-fold higher in nephrectomized) on Day 14.  
c  Mean values are reported based on 5 rats.  
The contribution of renal excretion to total plasma clearance of lumasiran in humans is low 
(<25%).  This is similar to the renal excretion profiles of other GalNAc conjugated siRNA 
molecules.  The low urinary recovery is attributable to the short plasma circulation time (about 
24 hours) for these GalNAc conjugated molecules, including lumasiran.  The GalNAc on 
lumasiran binds to abundantly expressed asialoglycoprotein receptors on hepatocytes leading to 
highly efficient and rapid uptake of lumasiran from the plasma into hepatocytes.  Consequently, 
plasma concentrations decline rapidly to less than the lower limit of quantitation within 24 to 48 
hours postdose. 
In addition, a dedicated renal impairment study of a similar GalNAc conjugated siRNA molecule 
showed that urinary drug excretion accounted for 13.3%, 13.7%, 6.68%, and 3.16 % of that 
administered study drug in subjects with normal renal function and those with mild, moderate, 
and severe renal function, respectively.  The urine PK data in renal impairment subjects show a 
small reduction in the already low urinary excretion of siRNA compounds, which suggest up to a 
10% increase in liver exposure can be expected in subjects with severe renal impairment 
compared to those with normal renal function.  This indicates that the influence of renal 
impairment on liver exposures is minimal; hence no major difference in pharmacodynamics is 
expected in renal impairment patients.   
Weight-based Dose Regimen 
Lumasiran liver concentration is the sole driver of the pharmacodynamic properties of lumasiran, 
therefore, change in body weight and liver size particularly during infancy and early childhood 
(<6 years of age) were considerations that went into dose regimen selection. 
The weight-based dosing regimen for this study was informed by preclinical and clinical data of 
lumasiran (Section 1.2), preclinical data of similar GalNAc conjugated siRNAs, and results of 


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PK/PD modeling and simulation which considered differences in body weight, liver growth, and 
metabolic rates.   
Data from Study ALN-GO1-001 Parts A and B in healthy subjects and PH1 patients and 
associated PK/PD modeling were used to support dose selection in adults and children ≥20 kg 
body weight.  The urinary oxalate reductions observed in PH1 patients serve as an indicator of 
suppression of hepatic oxalate production.  Population PK/PD modeling demonstrated dose 
dependent oxalate reductions over the dose range (1.0 to 6.0 mg/kg continuous once monthly or 
once every 3 months SC administrations), with diminishing additional effect predicted with 
higher doses consistent with an asymptotic rather than linear dose-response relationship.  For a 
given dose level, the PK/PD model indicated that monthly administration leads to a more rapid 
decline in urinary oxalate levels relative to dosing every 3 months.  Thus, a lumasiran dosing 
regimen of 3.0 mg/kg once monthly for 3 loading doses total followed by 3.0 mg/kg once every 
3 months was selected for PH1 patients ≥20 kg body weight regardless of renal function status or 
degree of renal impairment.  
The modeling and simulation approach in infants and young children considered the changing 
rate of body weight and relative liver size in this population.  The body weight of children nearly 
triples during the first year of life increasing from a median weight of 3.5 kg at birth to about 
10 kg at 1 year of age (Centers for Disease Control and Prevention [CDC] Growth Chart 
[Kuczmarski 2002]).  Subsequently, the annual rate of body weight gain decreases to about 20% 
per year up to 6 years of age.  Furthermore, published reports and data from the United States 
National Centers for Health Statistics indicate children have proportionally larger liver size 
relative to body weight compared to adults.[CDC 2018; Johnson 2005]  For an individual in the 
0 to 1 year, 1 to 6 years, and 6 years of age categories, the mean liver weight as a percentage of 
body weight were 3.5%, 2.9%, and 2.0%, respectively, indicating that younger children are 
expected to have lower hepatocyte drug concentrations at a given dose level.  Moreover, based 
on allometric principles, children have faster drug clearance and drug clearance decreases with 
increasing weight.  Thus, considering the rapid growth rate, higher relative liver size, and faster 
drug clearance, children require a higher mg/kg dose to achieve similar systemic concentration 
and target suppression.  It should be noted that although the mg/kg dose is higher in younger 
patients, the absolute amount (mg) of lumasiran administered is small due to the lower body 
weight in these younger patients. 
Body weight categories for dose selection in this study were determined using CDC growth chart 
data.  Based on PK/PD modeling and simulation, for children with body weight <10 kg, the 
regimen is 6.0 mg/kg monthly × 3 doses (loading) followed by 3.0 mg/kg monthly 
(maintenance).  For children and adults with body weight ≥10 kg, the regimen consists of a 
combination of an initial monthly loading dose for the first 3 months, followed by a quarterly 
maintenance regimen thereafter, as described in Table 9, which also shows the predicted 
glycolate oxidase suppression per body weight category. 
At steady state, these dose regimens are expected to achieve approximately 90% target 
suppression and reduce hepatic oxalate production to normal or near normal levels.  Because 
renal function is a minor pathway for the elimination of lumasiran, the lumasiran dosing regimen 
in patients with advanced renal impairment will be the same as in patients with normal renal 
function. 


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Table 9: 
Lumasiran Dosing Regimen in Pediatric and Adult PH1 Patients and 
Predicted Glycolate Oxidase Target Suppression at Steady State 
Body 
Weight, (kg) 
Regimen 
Predicted GO 
Suppressiona, (%) 
Loading 
Maintenance 
≥20 
3.0 mg/kg qM ×3  
3.0 mg/kg q3M 
89.7% 
10 to <20 
6.0 mg/kg qM ×3  
6.0 mg/kg q3M 
90.2% 
<10 
6.0 mg/kg qM ×3  
3.0 mg/kg qM 
86.5% 
Abbreviations:  GO=glycolate oxidase; h=hour; qM=monthly (every 28 days), q3M=once every 3 months 
a All values are at steady state. 
The physicochemical properties of lumasiran and the available preclinical, clinical, PK, PD, and 
safety data indicate renal impairment is not expected to influence the systemic exposure, PD, 
safety, or efficacy properties of lumasiran.  Based on these findings the Sponsor has determined 
that no dose adjustment is required in patients with varying degrees of renal impairment, and the 
weight-based regimen described in this study is therefore appropriate for patients of all ages with 
advanced renal disease. 
1.5. 
Benefit-Risk Assessment 
PH1 is a rare autosomal recessive disease characterized by excessive oxalate production by the 
liver leading to excessive urinary oxalate and varying types and degrees of renal disease, 
progressing to end-stage renal disease.  Systemic accumulation of calcium oxalate results in 
severe end-organ damage.  Without treatment, the disease progresses, and patients die from end-
stage renal disease and/or complications of systemic oxalosis. 
Lumasiran is designed to reduce hepatic production of oxalate.  Based on the available data from 
nonclinical studies and the Phase 1/2 clinical study ALN-GO1-001, lumasiran, administered 
subcutaneously, demonstrated a potent, dose-dependent inhibition of glycolate oxidase resulting 
in decreased urinary oxalate and increased plasma and urinary glycolate.  Unlike oxalate, 
glycolate is highly soluble and readily excreted in the urine.  Thus, by reducing the production of 
oxalate, lumasiran is expected to ameliorate the signs and symptoms of PH1 and alter the clinical 
course in patients across the spectrum of disease, irrespective of age, disease stage, and status of 
dialysis dependence. 
Based on the available safety data from the Phase 1/2 clinical study, lumasiran has been well 
tolerated with a favorable safety profile.  Most adverse events (AEs) have been mild or moderate 
in severity.  There have been no severe or serious adverse events related to study drug.  
Transient, mild injection site reactions (ISRs) have been observed but have not resulted in any 
treatment discontinuations.  No clinically significant laboratory or hematologic changes have 
been observed. 
Given the biological target of lumasiran, the available nonclinical and clinical data, and mode of 
administration, important potential risks for lumasiran are injection site reactions and liver 
function test abnormalities.  During the study, patients will be closely monitored, including 
evaluation of injection sites, laboratory monitoring for liver function test abnormalities, along 








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assessments, electrocardiograms (ECGs), physical examinations, and concomitant medications.  
Dialysis status and changes in dialysis regimen will be monitored.  During periods of time when 
the COVID-19 pandemic impedes the ability of patients to travel to the study site, visits by a 
healthcare professional may occur at an offsite location such as the patient's home). 
Blood samples will be collected in both cohorts for PK parameter analysis, plasma oxalate 
sample analysis, and to establish plasma oxalate profiles (in Cohort B only; the profile enables 
AUC calculation between dialysis sessions) (Table 5, Table 6).  From Screening to Day 1, 
patients will have at least 4 plasma oxalate collections (pre-dialysis in Cohort B) to establish a 
robust baseline measurement.  The plasma oxalate sample collection during Screening is 
described per cohort in Figure 1, and during the treatment period will be performed as per the 
Schedules of Assessments (see Table 1, Table 2, Table 3, and Table 4). 
Patients who are anuric are defined as producing <100 ml of urine per day.  For all patients who 
are not anuric (ie, can produce ≥100 ml of urine per day), single-void urine samples (in triplicate) 
will be collected during screening to establish baseline and then serially per the Schedules of 
Assessments. 
For patients able to provide 24-hour urine samples, three 24-hour urine collections will be 
scheduled during screening to establish baseline urinary oxalate levels.  At Month 6, three 
24-hour urine collections will be scheduled within 14 days prior to dose.  There will be a single 
24-hour urine collection at Month 3, Month 12, and every 6 months thereafter while on study.  
This study will consist of 2 periods:  a 6-month primary analysis period followed by a long-term 
extension period.  During the 6-month primary analysis period, patients will undergo efficacy 
and safety assessments every 2 weeks for the first month and monthly thereafter.  During the 
long-term extension period of up to 54 months, dosing will continue and visits will occur at least 
every-3-months.   
Patients who discontinue study drug early will be asked to return for follow-up visits as 
described in Section 4.3.1. 
3.2. 
Duration of Treatment  
The duration of treatment with lumasiran is up to 60 months, with final dose administered at the 
Month 57 visit. 
3.3. 
Duration of Study 
The estimated total time on study, inclusive of screening, for each patient is up to 64 months, 
including up to 120 days of screening followed by up to 60 months of treatment, with a month 
defined as 28 days. 
3.3.1. 
Definition of End of Study for an Individual Patient 
A patient is considered to have reached the end of the study if: 
• 
the patient has completed the end of study (EOS; Month 60) visit, or 
• 
the patient has completed 12 months of monitoring following the final lumasiran dose 


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3.4. 
Number of Planned Patients 
The planned enrollment for this study is 20 patients, including 6 patients in each cohort.  Of 
those 20 patients, the planned enrollment includes 4 patients who are <6 years of age at consent, 
and 2 patients between ≥6 to <18 years of age at consent. 
Patients who crossover from Cohort A to Cohort B (due to progressing to dialysis therapy), 
discontinue study drug, or stop participation in the study prior to completion of Month 6 
assessments may be replaced (see Section 4.3.4). 
3.5. 
Method of Assigning Patients to Treatment Groups 
Patients will all be assigned to 1 single treatment group.  Dosing will be determined by the 
patient’s weight (see Section 5.2.2). 
Each patient will be uniquely identified in the study by a combination of the site number and 
patient identification number.  Upon signing the informed consent form (ICF), the patient will be 
assigned a patient identification number by the interactive response system. 
3.6. 
Blinding 
Not applicable. 
3.7. 
Data Monitoring Committee 
An independent Data Monitoring Committee (DMC) will oversee the safety and overall conduct 
of this study, providing input to the Sponsor.  Additional assessments may be recommended by 
the DMC.  The DMC will operate under the rules of a charter that will be reviewed and approved 
by the DMC.  Details are provided in the DMC Charter. 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS 
4.1. 
Inclusion Criteria 
Patients are eligible to be included in the study if all the following criteria apply: 
4.1.1. 
Cohorts A and B 
Age 
1. Have reached at least 37 weeks estimated gestational age (full-term infant) at consent (or 
assent). 
Patient and Disease Characteristics 
2. Documentation or confirmation of PH1 as determined by genetic analysis prior to initial 
dosing. 
3. Patients with eGFR ≤45 mL/min/1.73 m2 as calculated by the MDRD formula if 
≥18 years or Schwartz Bedside Formula if ≥12 months to <18 years, or patients 
<12 months of age with serum creatinine that is considered elevated for age at consent.  


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4. The mean of the three most recent screening plasma oxalate samples collected prior to 
Day 1 is ≥20 μmol/L.  In Cohort B, these 3 collections may include the first pre-dialysis 
sample from each plasma oxalate profile. 
5. If taking therapeutic vitamin B6 (pyridoxine), must have been on stable regimen for at 
least 90 days before consent, and is able and willing to remain on this stable regimen 
until at least the Month 6 visit.  Dose adjustments for interval weight gain are acceptable. 
Informed Consent 
6. Patient is willing and able to comply with the study requirements and to provide written 
informed consent.  In the case of patients under the age of legal consent, the legal 
guardian(s) must provide informed consent and the patient should provide assent per 
local and national requirements. 
4.1.2. 
Cohort B Only 
1. On a stable hemodialysis regimen for at least 4 weeks prior to Screening plasma oxalate 
assessment; able and willing to maintain this regimen through Month 6 visit, with 
changes to dialysis regimen permitted only when medically indicated. 
4.2. 
Exclusion Criteria (Cohorts A and B) 
Patients are excluded from the study if any of the following criteria apply: 
Laboratory Assessments  
1. Has any of the following laboratory parameter assessments at Screening:  
a. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2× ULN for 
age 
b. Total bilirubin >1.5×ULN.  Patients with elevated total bilirubin that is secondary to 
documented Gilbert’s syndrome are eligible if the total bilirubin is <2× ULN 
c. International normalized ratio (INR) >1.5 for patients not on anticoagulants.  Patients 
on oral anticoagulants (eg, warfarin) with an INR <3.5 will be allowed. 
d. Hemoglobin <8.0 g/dL 
2. Has known active human immunodeficiency virus (HIV) infection; or evidence of current 
or chronic hepatitis C virus (HCV) or hepatitis B (HBV) infection. 
Prior/Concomitant Therapy 
3. Received an investigational agent within the last 30 days or 5 half-lives, whichever is 
longer, prior to the first dose of study drug, or are in follow-up of another clinical study 
during Screening.  Consultation with the Medical Monitor is required if treated with 
unapproved products prior to consent regardless of the time interval prior to the first dose 
of study drug. 
Medical Conditions 
4. Known history of allergic reaction to an oligonucleotide or GalNAc. 
5. Diagnosis of conditions other than PH1 contributing to renal insufficiency such as 
glomerulonephritis, nephrotic syndrome, or lupus nephritis. 


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6. Any condition or comorbidity, which in the opinion of the Investigator, would make the 
patient unsuitable for dosing or would interfere with study compliance, data 
interpretation, patient safety, and/or patient participation in the study.  This includes 
significant active and poorly controlled (unstable) cardiovascular, neurologic, 
gastrointestinal, endocrine, renal or psychiatric disorders unrelated to PH1 identified by 
key laboratory abnormalities or medical history. 
7. Unwilling or unable to limit alcohol consumption throughout the course of the study.  
Alcohol intake of >2 units/day is excluded during the study (unit: 1 glass of wine 
[approximately 125 mL] = 1 measure of spirits [approximately 1 fluid ounce] = ½ pint of 
beer [approximately 284 mL]. 
8. History of alcohol abuse, within the last 12 months before screening, in the opinion of the 
investigator. 
9. Patients with a previous liver transplant or for whom a liver transplant is anticipated in 
the next 6 months. 
10. Patients with a previous kidney transplant who are currently receiving 
immunosuppression to prevent transplant rejection. 
11. Patients maintained on a peritoneal dialysis regimen. 
12. Patients who in the opinion of the Investigator plan to start dialysis replacement therapy 
in the next 6 months. 
13. Any comorbidity or condition that, in the opinion of the Investigator, is anticipated to 
prevent participation in at least 12 months of the study. 
Contraception, Pregnancy, and Breastfeeding 
14. Is not willing to comply with the contraceptive requirements during the study period, as 
described in Section 5.5.1. 
15. Female patient is pregnant, planning a pregnancy, or breast feeding. 
4.3. 
Removal from Study Drug or Assessment 
Patients or their legal guardians are free to discontinue study drug and/or stop protocol 
procedural assessments, or participation in the study as a whole at any time and for any reason, 
without penalty to their continuing medical care.  The Investigator or the Sponsor may 
discontinue study drug or stop a patient’s participation in the study at any time if this is 
considered to be in the patient’s best interest.  Any discontinuation of treatment or the stopping 
of the patient’s participation in the study must be fully documented in the electronic case report 
form (eCRF) and should be followed up by the Investigator. 
Discontinuation of study drug or declining procedural assessments is described in Section 4.3.1, 
while the stopping of a patient’s participation in the study is detailed in Section 4.3.2. 
4.3.1. 
Discontinuation of Study Drug or Declining Procedural Assessments 
Reasons for discontinuation of study drug may include any of the following: 
• 
Significant violation of the protocol 


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• 
AE 
• 
Non-adherence to treatment regimen 
• 
Pregnancy 
• 
Lost to follow-up 
• 
Other reason (non-AE) 
• 
Or, study is terminated by the Sponsor 
If possible, the Investigator will confer with the Sponsor or Medical Monitor before 
discontinuing dosing in the patient.  Patients who are pregnant will be discontinued from study 
drug dosing immediately (see Section 6.5.6.7 for reporting and follow-up of pregnancy).  A 
positive urine pregnancy test should be confirmed by a serum pregnancy test prior to 
discontinuing the study drug. 
If a patient discontinues dosing due to an AE, including SAEs, the event should be followed as 
described in Section 6.5.6.  When a patient discontinues study drug dosing, the primary reason 
must be recorded in the electronic case report form (eCRF).  Patients who discontinue study drug 
and remain on study may receive treatment consistent with local standard practice for their 
disease per Investigator judgement, as applicable. 
Patients who discontinue from study drug during the 6-month primary analysis period (defined 
as the time the first dose of study drug is administered on Study Day 1 through completion of the 
Month 6 assessments) will be encouraged to remain on the study and complete assessments 
(including 24-hour urine collections, but excluding PK assessments) through Month 6 (see 
Table 1).  They will also be asked to complete safety follow-up visits, once every 3 months, per 
the safety follow-up schedule (see Table 3 or Table 4) for up to 12 months after the last dose of 
lumasiran. 
Patients who discontinue study drug after Month 6 will be asked to return for their next 
scheduled visit to complete early termination (ET) assessments and complete safety follow-up 
visits, once every 3 months, per the safety follow-up schedule (see Table 3 or Table 4) for up to 
12 months after the last dose of lumasiran. 
4.3.2. 
Stopping a Patient’s Study Participation 
4.3.2.1. 
Patient or Legal Guardian Stops Participation in the Study 
A patient or their legal guardian may stop participation in the study at any time.  A patient or 
legal guardian considering stopping participation in the study prior to the Month 6 visit should be 
informed that the patient can discontinue study drug and/or decline procedural assessments and 
remain in the study to complete their study assessments, through the Month 6 visit, including 
follow-up, or alternatively may complete any minimal assessments for which the patient or legal 
guardian consents as described in Section 4.3.1.  If a patient or legal guardian still chooses to 
discontinue study drug and stop participation prior to the completion of the 6-month treatment 
period, every effort should be made to conduct early the assessments scheduled to be performed 
at the Month 6 visit (see Table 1). 


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If the patient does not wish to or is unable to continue further study participation, the Investigator 
is to discuss with the patient appropriate procedures for stopping participation in the study.  Data 
collected from the patient can continue to be used, in countries where permitted. 
In addition, in the countries where the collection and processing of the patient data is based on 
the patient consent, if a patient withdraws consent to collect and process his/her data (see 
Section 4.3.2.2), as applicable, patient data up to the withdrawal of consent will be included in 
the analysis of the study.  In addition, where permitted, publicly available data (such as 
appropriate national or regional vital status registry or other relevant databases) can be included 
after withdrawal of consent, where available and allowable by local law. 
4.3.2.2. 
Withdrawal of Consent to Process the Patient’s Personal Data 
Where allowed by local law, the patient may decide to withdraw consent to collect, store, and 
use biological samples and, as applicable, other personal data, informing the study doctor at any 
time in writing or in any other form that may be locally required.  The Sponsor will continue to 
keep and use the patient’s study information (including any data resulting from the analysis of 
the patient’s biological samples until the time of withdrawal) according to applicable law.  The 
process for the storage and, as applicable, further use of remaining samples will be followed per 
local requirements. 
4.3.2.3. 
Investigator or Sponsor Stops Participation of a Patient in the Study 
The Investigator or Sponsor may stop the participation of a patient in the study at any time if this 
is considered to be in the patient’s best interest.  However, study integrity and interpretation are 
best maintained if all enrolled patients continue study assessments and follow-up through 
Month 6 even if study drug is discontinued. 
Termination of the clinical study and site closure are described in Section 8.1.6. 
4.3.2.4. 
Recording Reason for Stopping a Patient’s Study Participation 
The primary reason that a patient’s study participation is stopped must be recorded in the 
appropriate section of the electronic case report form (eCRF) and all efforts will be made to 
complete and report the observations as thoroughly as possible.  If a patient’s study participation 
is stopped due to an AE, including SAEs, the event should be followed as described in 
Section 6.5.6. 
4.3.3. 
Lost to Follow-Up 
A patient will be considered lost to follow-up if the patient repeatedly fails to return for 
scheduled visits and is unable to be contacted by the clinical study center.  The following actions 
must be taken if a patient misses a required study visit: 
• 
The site must attempt to contact the patient or legal guardian and reschedule the 
missed visit as soon as possible and counsel the patient or legal guardian on the 
importance of maintaining the assigned visit schedule and ascertain if the patient or 
legal guardian wishes [for the patient] to continue in the study, and/or should continue 
in the study. 


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• 
Before a patient is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the patient or legal guardian by 3 telephone calls 
and, if necessary, a certified letter to the patient’s last known mailing address or local 
equivalent methods.  These contact attempts should be documented in the patient’s 
medical record. 
• 
Should the patient or legal guardian continue to be unreachable, the patient will be 
considered to have stopped participation in the study. 
• 
For patients who are lost to follow-up, the Investigator or designee should search 
publicly available records (where permitted and allowed by local law) to ascertain 
survival status.  This ensures that the outcome of the study is as comprehensive as 
possible. 
4.3.4. 
Replacement of Study Patients 
Patients who discontinue the study drug or stop participation in the study prior to Month 6 may 
be replaced at the Sponsor’s discretion.  Patients who crossover from Cohort A to Cohort B due 
to progressing to dialysis prior to Month 6 also may be replaced at the Sponsor’s discretion.  
Patients who discontinue the study drug or stop participation in the study after Month 6 will not 
be replaced. 
5. 
TREATMENTS AND OTHER REQUIREMENTS 
5.1. 
Treatments Administered 
Study drug supplied for this study must not be used for any purpose other than the present study 
and must not be administered to any person not enrolled in the study.  Study drug that has been 
dispensed and returned unused must not be re-dispensed. 
5.2. 
Study Drug 
Detailed information describing the preparation, administration, and storage of lumasiran is 
provided in the Pharmacy Manual. 
5.2.1. 
Description 
Lumasiran will be supplied as a sterile solution in water for SC injection.  See the Pharmacy 
Manual for further details of solution concentration and fill volume. 
5.2.2. 
Dose and Administration 
Patients will be administered lumasiran as an SC injection at the dose and regimen based on their 
weight category as described in Table 10.  Liver function test clinical laboratory assessments 
(see Table 13) from the Week 2 visit must be reviewed prior to administration of the Month 1 
dose, as specified in the Schedules of Assessments (Table 1).  The LFT criteria for withholding, 
monitoring, or stopping dosing is described in Section 5.2.3.1.  Patients will receive 3 loading 
doses, once monthly (at Day 1, Month 1, and Month 2) at a dose based on body weight category.  
At Month 3 and beyond, patients will receive lumasiran either monthly (patients weighing 




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center is not available within the specified timepoints, post dialysis weight taken at the dialysis 
center may be used. 
Patients with weight increases crossing the threshold for the next weight-based dosing category 
(<10 kg to ≥10 kg or <20 kg to ≥20 kg) will follow the new dosing regimen for the remainder of 
the study or until the next dosing category threshold is reached (ie, patients will not switch back 
to the lower-weight dosing schedule if their body weight subsequently decreases). 
Patients in maintenance dosing who transition from <10 kg to ≥10 kg will continue to receive 
monthly doses at 3.0 mg/kg until the next visit that coincides with Table 4, whereby they will 
follow every-3-months dosing as per Table 4 until the end of the study. 
If a patient does not receive a dose of lumasiran within the specified dosing window, the 
Investigator should contact the Medical Monitor.  After such consultation, the dose may be 
administered or considered missed and not administered. 
If a patient misses multiple consecutive doses, the Investigator, in consultation with the Medical 
Monitor, will discuss whether the patient will be able to continue the study (see Section 4.3). 
Additional details can be found in the Pharmacy Manual.  In addition, instructions and 
procedures related to the administration of lumasiran by a patient or caregiver will be provided in 
the Patient/Caregiver Storage and Administration Instructions. 
5.2.3. 
Dose Modifications 
Dose modifications are not permitted. 
If a study drug-related AE occurs in a patient that the Investigator judges as presenting a 
potential risk to the patient for further dosing, the study drug dose may be held at the discretion 
of the Investigator and the Medical Monitor should be contacted. 
5.2.3.1. 
Liver Function Test Criteria for Withholding, Monitoring and Stopping 
Lumasiran Dosing  
1. Liver function test (LFT) results (see Table 13) are to be obtained within 7 days prior to 
dosing and results are to be reviewed prior to each dose of lumasiran.  During periods of 
time when the COVID-19 pandemic impedes the ability of patients to travel to the study 
site and healthcare professionals to go to patients' homes and LFT assessments are not 
feasible within 7 days prior to the dose, LFT test results up to 6 weeks prior to the 
planned monthly dose or up to 4 months prior to the planned quarterly dose may be 
reviewed to determine whether the dose can be administered.  Consult the Laboratory 
Manual for the blood draw priority list based on patient weight.  Central laboratory 
results are preferable.  If not available, local laboratory results may be used; however, if a 
local assessment is drawn, a serum chemistry sample must also be drawn for analysis at 
the central laboratory. 
2. For any ALT or AST elevation >3× ULN, central laboratory results should be used to 
guide subsequent monitoring as detailed in Table 11. 
3. For any ALT or AST elevation >3× ULN:  


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a. If local laboratory results are obtained, confirm using central laboratory, as soon as 
possible, ideally within 2 to 3 days, but no later than 7 days. 
b. If an alternative cause is found, provide appropriate care. 
c. If an alternative cause is not found, perform assessments per Table 11 and Table 14. 
4. For any ALT or AST elevation >3× ULN without alternative cause that is accompanied 
by clinical symptoms consistent with liver injury (eg, nausea, right upper quadrant 
abdominal pain, jaundice) or elevated bilirubin to ≥2× ULN or international normalized 
ratio (INR) ≥1.5, permanently discontinue dosing. 
5. For confirmed ALT or AST elevations >3× ULN without alternative cause and not 
accompanied by symptoms or elevated bilirubin ≥2× ULN or INR ≥1.5, see Table 11. 
Table 11: Monitoring and Dosing Rules for Asymptomatic Patients with Confirmed 
Isolated Elevations of ALT and/or AST >3× ULN, with No Alternative Cause 
Identified 
Transaminase Level 
Action 
>3× to 5× ULN 
• 
May continue dosing  
• 
Evaluate the initial elevation in LFT per the following assessments: 
• 
Table 14 (all assessments to be performed; see Section 6.5.5.4 for 
guidance on maximal pediatric blood volumes) 
• 
Hematology, serum chemistry, and LFT per Table 13 
• 
Coagulation (prothrombin time, partial thromboplastin time, 
international normalized ratio) 
• 
Monitor at least every two weeks: LFT per Table 13 
• 
If elevation persists for ≥2 months, must discuss with the Medical Monitor 
before continuing dosing 
>5× to 8× ULN 
• 
Hold lumasiran dosing until recovery to ≤1.5× ULN or baseline; may 
resume dosing after discussion with the Medical Monitor 
• 
Evaluate the initial elevation in LFT per the following assessments: 
• 
Table 14 (all assessments to be performed once) 
• 
Hematology, serum chemistry, and LFT per Table 13 
• 
Coagulation (prothrombin time, partial thromboplastin time, 
international normalized ratio) 
• 
Monitor at least weekly:  LFT per Table 13 until ALT and/or AST is 
declining on 2 consecutive draws, then may decrease monitoring to 
biweekly 
• 
If ALT or AST rises to >5× ULN following resumption of dosing, 
permanently discontinue dosing 
>8× ULN 
Permanently discontinue dosing after confirmation by the central laboratory of 
the transaminase value 
Abbreviations:  ALT=alanine aminotransferase; AST=aspartate aminotransferase; LFT=liver function tests; 
ULN=upper limit of normal. 
Notes:  In addition to these criteria, other assessments or evaluations may be performed per Investigator discretion, 
as appropriate.  See the Study Manual for sample priority list. 


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5.2.4. 
Preparation, Handling, and Storage 
Staff at each clinical study center or the healthcare professional will be responsible for 
preparation of lumasiran doses, according to procedures detailed in the Pharmacy Manual.  In 
cases where lumasiran is administered at home by a caregiver, dosing may be prepared and 
administered by the caregiver according to procedures detailed in the Patient/Caregiver Storage 
and Administration Instructions.  No special procedures for the safe handling of study drug are 
required. 
Study drug will be stored upright and refrigerated at approximately [5±3°C]. 
A Sponsor representative or designee will be permitted, upon request, to audit the supplies, 
storage, dispensing procedures, and records. 
Instructions specific to unused study drug and additional storage will be provided in the 
Pharmacy Manual and Patient/Caregiver Storage and Administration Instructions. 
5.2.5. 
Packaging and Labeling 
All packaging, labeling, and production of study drug will be in compliance with current Good 
Manufacturing Practice specifications, as well as applicable local regulations.  Study drug labels 
and external packaging will include all appropriate information as per local labeling 
requirements.  Additional details will be available in the Pharmacy Manual. 
5.2.6. 
Accountability 
The Investigator or designee will maintain accurate records of receipt and the condition of the 
study drug supplied for this study, including dates of receipt.  In addition, accurate records will 
be kept of when and how much study drug is dispensed and administered to each patient in the 
study.  Any reasons for departure from the protocol dispensing regimen must also be recorded. 
At the completion of the study, there will be a final reconciliation of all study drugs.  Used, 
partially used, and unused study drug will be returned to the Sponsor (or designee) or destroyed 
at the clinical study center according to applicable regulations. 
Further instructions about drug accountability will be detailed in the Pharmacy Manual. 
5.3. 
Concomitant Medications and Procedures 
Use of concomitant medications and procedures will be recorded on the patient’s CRF as 
specified in the Schedules of Assessments (see Table 1, Table 2, Table 3, and Table 4).  This 
includes all prescription medications, vaccines, herbal preparations, over the counter 
medications, vitamins, and minerals.  Any changes in medications or dialysis regimen during the 
study must be recorded on the CRF.  Patients should not start new medication regimens during 
the study, including regimens of vitamins or herbal medication, without consultation with the 
Investigator.  
If patients use nonsteroidal anti-inflammatory drugs intermittently or chronically, they must have 
been able to tolerate them with no previous side effects (eg, gastric distress or bleeding). 
Standard vitamins and topical medications are permitted.  However, topical steroids must not be 
applied anywhere near the injection site(s) unless medically indicated. 


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If taking pyridoxine (vitamin B6) for the treatment of PH1, patients must have been on a stable 
regimen for at least 90 days before screening and remain on this stable regimen during the 
screening period and through at least the Month 6 visit.  Dose adjustments for interval weight 
gain are permitted.  Patients should avoid high dose vitamin C preparations within 4 days prior to 
oxalate assessments. 
Patients may be treated for PH1 according to local standard of care and dialysis maintenance as 
determined by treating physician.  Patients should continue their current standard of care and 
dialysis regimen, including hyperhydration, crystallization inhibitors, and/or pyridoxine therapy 
at least until the Month 6 visit.  Changes in dialysis regimen may be permitted only if medically 
indicated.  Standard of care treatment may be adjusted after Month 6 in accordance with clinical 
judgement.  If pyridoxine therapy is discontinued, pyridoxine levels should be assessed for at 
least the next 2 timepoints indicated in the Schedules of Assessments (see Table 1, Table 2, 
Table 3, and Table 4).  Consultation with the Medical Monitor is required if treated with any new 
emerging products.   
For other permitted concomitant medications administered subcutaneously, do not administer in 
same injection site area as the study drug, for at least 7 days after the last dose of study drug. 
Any concomitant medication that is required for the patient’s welfare may be administered by the 
Investigator.  However, it is the responsibility of the Investigator to ensure that details regarding 
the medication are recorded on the CRF.  Concomitant medication will be coded using an 
internationally recognized and accepted coding dictionary. 
5.4. 
Treatment Compliance 
Compliance with study drug administration will be verified by study staff. 
5.5. 
Other Requirements 
5.5.1. 
Contraception 
Females of child-bearing potential must be willing to use a highly effective method of 
contraception from 14 days before first dose, throughout study participation, and for 90 days 
after last dose administration or until study completion.  Pediatric/adolescent female patients 
must initiate one of the birth control methods below, which includes true abstinence, at menarche 
or must discontinue study drug. 
Birth control methods which are considered highly effective include:   
• 
Placement of an intrauterine device. 
• 
Placement of an intrauterine hormone-releasing system.  
• 
Bilateral tubal occlusion. 
• 
Surgical sterilization of male partner (with the appropriate post-vasectomy 
documentation of the absence of sperm in the ejaculate; for female patients on the 
study, the vasectomized male partner should be the sole partner for that patient). 
• 
Established use of oral (except low-dose gestagens), implantable, injectable, or 
transdermal hormonal methods of contraception. 


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• 
True sexual abstinence, when in line with the preferred and usual lifestyle of the 
patient.  Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception.  Abstinent 
patients must agree to use one of the above-mentioned contraceptive methods if they 
start heterosexual relationships during the study and for up to 90 days after the last 
dose of study drug. 
Investigators should advise females of childbearing potential of the most appropriate birth 
control method available within their country taking into account local medical practice. 
Females of child-bearing potential include female patients who have experienced menarche (or 
begin menarche over the course of the study), and who are not postmenopausal or permanently 
sterilized (eg, bilateral tubal occlusion, hysterectomy, or bilateral salpingectomy).  A 
postmenopausal state is defined as the absence of menses for 12 months without an alternative 
medical cause, confirmed by follicle stimulating hormone level within the postmenopausal 
range.  
For male patients, no contraception is required.  However, use by adolescent males of 
contraception (condom) may be required in some countries, eg, France, in order to comply with 
local requirements as described in the corresponding patient informed consent forms.  Males 
with partners of child-bearing potential must agree to use a condom throughout study 
participation and for 90 days after the last dose of study drug or until study completion. 
Compliance with contraception requirements will be assessed on a regular basis by the 
Investigator throughout the course of the study.  The Investigator will ensure that adolescent 
patients, and their legal representatives if applicable, are adequately informed about 
contraceptive requirements and the need for contraception once a patient initiates heterosexual 
intercourse.  The need for contraception and compliance with contraception requirements will be 
assessed at every visit for adolescent patients, and pregnancy testing will be performed before 
every dose for postmenarcheal females throughout the course of the study (see Section 6.5.5.2).   
5.5.2. 
Dietary Restrictions 
Patients should refrain from consumption of foods with high oxalate content, including, but not 
limited to, chocolate, rhubarb, spinach, and beet root, for 1 week prior to assessments of urinary 
and plasma oxalate. 
6. 
STUDY ASSESSMENTS 
The schedules of study assessments are provided in Table 1, Table 2, Table 3, and Table 4.  
Additional information on the collection of study assessments will be detailed in the Study 
Manual. 
Urine collection assessments are not required for patients who are anuric (ie, produce <100 ml 
per day). 
Where applicable country and local regulations and infrastructure for home healthcare allow, 
home healthcare may take place at a location other than the clinical trial site to perform study 
assessments, which may include collection of blood and urine samples, measurement of vital 


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signs, length/height and weight, an abbreviated physical examination/body system assessment, 
and preparation and administration of study drug (at the discretion of the Investigator). 
6.1. 
Screening Assessments 
The Investigator will notify the Sponsor before screening patients to allow an assessment of the 
ability of the site or any new trial participant to comply with the protocol given COVID-19 
limitations. 
An informed consent form (ICF) or assent form in the case of patients under the age of legal 
consent that has been approved by the appropriate Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC) must be signed by the patient (or legal guardian if under the age of legal 
consent) before the Screening procedures are initiated.  All patients (or their legal guardians if 
under the age of legal consent) will be given a copy of the signed and dated ICF and/or assent 
form.  In the case when a patient reaches the legal age of consent during the study, the 
Investigator must obtain the patient’s informed consent, and assent if applicable, prior to 
performing any further study interventions and/or procedures involving that patient (see 
Section 8.1.1).  
Patients will be screened to ensure that they meet all the inclusion criteria and none of the 
exclusion criteria (see Section 4.1 and Section 4.2).  Rescreening of patients is permitted with 
consultation of the Medical Monitor (see Section 6.1.2). 
Patient demographic data and medical history/disease history will be obtained.  Non-serious 
events occurring after signing of the ICF and prior to study drug administration will be captured 
as medical history.  Any changes to medical history occurring between the screening assessment 
and Day 1 will be updated prior to study drug administration. 
A blood sample for AGXT mutation analysis will be collected during Screening for patients who 
do not have documented PH1 genetic analysis to confirm eligibility. 
For all patients who are not anuric, single-void urine samples (in triplicate) will be collected 
during screening to establish baseline.  Also, in patients who are able to produce urine, 24-hour 
collections will be performed during Screening to establish baseline urinary oxalate levels 
(Section 6.1.2). 
The timing of samples collected during Screening for plasma oxalate and plasma glycolate will 
be as shown in Figure 1. 
The three most recent screening plasma oxalate samples collected prior to Day 1, which may 
include the pre-dialysis sample from the plasma oxalate profile collection for Cohort B patients, 
will be used to assess eligibility.  If all 3 plasma oxalate assessments are obtained >60 days prior 
to Day 1, one additional plasma oxalate will be performed (at least 7 days prior to Day 1). 
For subjects in Cohort B, there must be 2 separate plasma oxalate profile assessments performed 
during Screening, performed at least 1 week apart. 
If a patient’s stable dialysis regimen at the time of consent is interrupted during screening for 
≤14 days, plasma oxalate levels should not be collected until the prior dialysis regimen has 
resumed for at least 2 weeks.  If a patient’s stable dialysis regimen at the time of consent is 




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examinations, exploratory DNA assessments, and blood and urine samples for exploratory 
analyses obtained within 120 days of Day 1 do not need to be repeated.  Echocardiogram and 
ECG will be repeated if obtained 60 or more days prior to Day 1.  
6.2. 
Efficacy Assessments 
The efficacy of lumasiran will be assessed in all patients in both cohorts by evaluating changes in 
plasma oxalate levels; and plasma oxalate profile assessment in Cohort B only (Section 6.2.1); 
urinary oxalate (in non-anuric patients, Section 6.2.2), and measures of systemic oxalosis 
(Section 6.2.3).   
In Cohort A patients, all blood and urine samples will be collected predose, when applicable.  In 
Cohort B patients with a dialysis session on the day of dosing, samples will be collected prior to 
the dialysis session. 
The efficacy of lumasiran on renal function will be assessed by eGFR (Section 6.3.4). 
Change in the frequency and mode of dialysis will be assessed (Section 6.5.5.5). 
In both cohorts, change in levels of urinary and plasma glycolate will be assessed. 
6.2.1. 
Plasma Oxalate 
Plasma oxalate levels will be assessed from blood samples collected in all patients; levels will be 
measured via central laboratory using a validated assay.  The collection timing during Screening 
is detailed by cohort in Figure 1.  During the treatment period, samples will be collected as 
specified in the Schedules of Assessments (see Table 1, Table 2, Table 3, and Table 4) and in 
Table 6. 
6.2.1.1. 
Cohort A 
In Cohort A patients, plasma oxalate levels will be assessed via blood samples collected 
throughout the study as specified in the Schedules of Assessments (see Table 1, Table 2, Table 3, 
and Table 4).  The three most recent screening plasma oxalate samples collected prior to Day 1 
will be used to assess eligibility; see Section 6.1 and Figure 1. 
6.2.1.2. 
Cohort B 
Plasma Oxalate Level 
In Cohort B patients, plasma oxalate levels will be assessed via pre-dialysis blood samples 
collected throughout the study as specified in the Schedules of Assessments.  From Screening to 
Day 1, at least 4 pre-dialysis blood samples obtained at least 7 days apart over the span of at least 
28 days will be collected to assess eligibility.  Up to 2 of the blood samples may originate from 
the pre-dialysis samples collected at the beginning of the plasma oxalate profile assessments 
performed during Screening (described below).  See Figure 1.   
Plasma Oxalate Profile 
Plasma oxalate profiles will be performed as specified in the Schedules of Assessments to permit 
calculation of the AUC between dialysis sessions.  The plasma oxalate profile assessment 
consists of an overnight visit requiring collection of up to 8 blood samples for plasma oxalate 
over the course of a 24-hour span, dependent on blood volume limitations and study center 


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facilities; blood sample collection schedule is described in Table 6, which includes collections 
before, during, and after the dialysis session.  During Screening, there will be 2 separate profile 
assessments performed at least 7 days apart.  See Figure 1. 
During Screening, the blood sample timepoints described in Table 6 are relative to when dialysis 
is performed.  During the treatment period, the timepoints described in Table 6 are relative to 
dialysis or when the dose is administered, as specified.  The 24-hour postdose sample will be 
collected prior to beginning the next hemodialysis session, or 24 hours (±3 hours) postdose if 
there is no hemodialysis session on the day following dosing. 
In patients with ≥1 systemic oxalosis manifestation during the study, additional plasma oxalate 
profile assessments will be performed at the Month 36 and Month 48 visits, and blood sample 
collection timepoints are the same as described above. 
6.2.2. 
Urinary Oxalate 
In patients in both Cohort A and Cohort B who are not anuric (ie, patients who are able to 
continue to produce urine ≥100 ml per day) and are able to complete the collection procedure, 
24-hour urinary oxalate excretion will be assessed.  Since not all patients will be able to provide 
24-hour urine samples, single-void urine samples (in triplicate) will be collected throughout the 
study in all patients who are not anuric.  Table 12 shows the 24-hour urine collection procedure 
by study visit. 
In patients who are able to comply with 24-hour urine collection procedures, urinary oxalate 
excretion will be determined from 24-hour urine sample collections to be completed at the time 
points specified in the Schedules of Assessment (see Table 1, Table 2, Table 3, and Table 4).  
Urinary oxalate concentrations will be analyzed centrally using a validated assay.  24-hour urine 
collections in patients not undergoing dialysis must meet pre-specified validity criteria (see 
Section 6.2.2.1).   
For patients who are able to comply with the 24-hour urine collection procedure, three 24-hour 
urine collections will be scheduled during screening to establish baseline urinary oxalate 
excretion.  For Month 6, three 24-hour urine collections will be scheduled within 14 days prior to 
dose to evaluate changes in oxalate concentrations over the 6-month interval.  A single 24-hour 
collection will be scheduled at Month 3, Month 12, and then every 6 months thereafter as 
specified in the Schedules of Assessments (see Table 1, Table 2, Table 3, and Table 4).  In 
patients undergoing dialysis, the timing of the collections relative to patients’ weekly dialysis 
schedule should remain consistent for each patient, when possible. 
Patients able to comply with 24-hour urine collections will either bring a 24-hour urine collection 
to the clinic, courier samples to the laboratory, or have their 24-hour urine collected during an 
inpatient stay at the time of the study visit. 
All patients who are not anuric will have 3 single-void urine samples collected during Screening 
(first morning voids are preferred, when feasible).  Following screening, single-void collections 
are performed within 7 days predose, as specified in the Schedules of Assessment (see Table 1, 
Table 2, Table 3, and Table 4).  Samples may be collected as an outpatient prior to the visit or 
collected during the study visit prior to dosing, as applicable. 




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In addition to safety assessments described in Section 6.5.4, as a measure of systemic oxalosis, 
ECGs will be monitored to identify conduction disorders if normal at baseline or change in 
conduction disorders if present at baseline. 
Triplicate 12-lead ECGs will be collected using standardized machines at the timepoints 
specified in the Schedules of Assessment (see Table 1, Table 2, Table 3, and Table 4 ).  During 
periods of time when the COVID-19 pandemic impedes the ability of patients to travel to the 
study site, ECG assessments may be completed up to 2 months after the Month 3 timepoint, up 
to 5 months after the Month 6 timepoint, and up to 11 months after the Month 12 timepoint.  
12-lead ECGs will be centrally read. 
6.2.3.2. 
Dermatologic 
In cases where skin manifestations due to systemic oxalosis are reported during the course of the 
study, (eg, patient presenting with skin lesion during physical examination) photographs of the 
lesions should be obtained.  The Investigator may engage a local dermatologist’s opinion if 
required.  When a skin manifestation of systemic oxalosis is observed, at each succeeding visit, 
photographs of the affected area will continue to be collected to record the resolution or 
worsening of the manifestation.  Further details will be provided in the study manual. 
6.2.3.3. 
Skeletal  
Radiographs (X-rays) of hands, hip, knee, and chest will be obtained and read centrally for 
features of skeletal oxalosis, where local IRB/IEC permits at the timepoints specified in the 
Schedules of Assessment (see Table 1, Table 2, Table 3, and Table 4 ), where feasible based on 
patient compliance.  During periods of time when the COVID-19 pandemic impedes the ability 
of patients to travel to the study site, X-rays may be completed up to 1 month after Day 1, and up 
to 11 months after the Month 12 timepoint. 
Only a subset of these x-rays will be collected at selected study centers.  In addition, a reading of 
bone age will be performed for patients who have not yet reached skeletal maturity.  Results will 
be interpreted using a scale developed in conjunction with the central reading core laboratory, as 
detailed in the study manual.   
Optional bone scans will be performed in only Cohort B patients ≥18 years of age to assess 
calcium oxalate systemic deposition, where local IRB/EC permits and if patient consents to the 
bone scan.  During periods of time when the COVID-19 pandemic impedes the ability of patients 
to travel to the study site, optional bone scans may be completed up to 1 month after Day 1, and 
up to 11 months after the Month 12 timepoint. 
6.2.3.4. 
Ocular 
Ophthalmology 
The following ophthalmologic exams will be performed: Color Fundus Photography (CFP), 
Optical Coherence Tomography (OCT), and, where available at select sites, Fundus 
Autofluorescence (FAF).  
Ophthalmologic exams with fundus photography will be standardized and the fundus 
photographs will be read centrally.  OCT assessments will also be standardized and read 
centrally.  For young children unable to cooperate, examinations will be optional.  Anesthesia 


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will not be used in any of these ocular assessments.  Results from any clinically obtained exams 
performed as standard of care may be collected. 
During periods of time when the COVID-19 pandemic impedes the ability of patients to travel to 
the study site, ophthalmologic exams may be completed up to 1 month after Day 1, and up to 11 
months after the Month 12 timepoint. 
Best Corrected Visual Acuity (BCVA) 
Where available, BCVA using Early Treatment Diabetic Retinopathy Study (ETDRS) charts will 
be assessed longitudinally throughout the course of the study to evaluate for changes which 
correspond to changes in retinal oxalate deposition.  Exams will be standardized across 
applicable sites.  In younger patients <6 years of age, alternate visual acuity testing per local 
standard practice may be performed (eg, LEA symbols).  In sites where ETDRS testing is not 
available, Snellen or LEA symbol charts may be used for BCVA.  Testing is not required in 
preverbal infants. 
6.3. 
Renal Assessments and Additional Pharmacodynamic Measurements 
Renal assessments and additional pharmacodynamic assessments include:  nephrocalcinosis as 
assessed by renal ultrasound (Section 6.3.1); frequency of renal stone events (Section 6.3.2); 
urine oxalate:creatinine ratio (in available urine collections; Section 6.3.3); and eGFR 
(Section 6.3.4).  
Glycolate concentrations may be collected at the same time as the plasma oxalate sample 
collection (Section 6.2.1) as specified for Screening (Figure 1) and as per the Schedules of 
Assessments (see Table 1, Table 2, Table 3, and Table 4).  Additional collections may be 
performed at the discretion of the Investigator. 
In Cohort A patients, all samples will be collected predose, when applicable.  In Cohort B 
patients with a dialysis session on the day of dosing, samples will be collected prior to the 
dialysis session. 
All PD assessments will be analyzed centrally.  Details regarding the processing and aliquoting 
of samples for storage and analyses will be provided in the Laboratory Manual. 
Where local regulations allow, and infrastructure is in place, home nursing may be used to 
collect urine and blood samples.  
6.3.1. 
Renal Ultrasound 
Renal ultrasounds will be obtained locally, as specified in the Schedules of Assessment (see 
Table 1, Table 2, Table 3, and Table 4) when feasible; anephric patients are exempt from renal 
ultrasound assessments.  Renal ultrasound will be performed according to instructions provided 
in the Study Manual in a standardized manner.  Renal ultrasounds will be reviewed centrally.   
During periods of time when the COVID-19 pandemic impedes the ability of patients to travel to 
the study site, renal ultrasounds may be completed up to 1 month after Day 1, up to 5 months 
after the intended timepoint for assessments scheduled prior to Month 12, and up to 11 months 
after the intended timepoint for visits at Month 12 and subsequent timepoints, if necessary. 


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6.3.2. 
Renal Stone Events 
A renal stone event is defined as an event which includes at least one of the following: 
• 
Visit to healthcare provider (eg, outpatient clinic, urgent care, emergency department, 
procedure) because of a renal stone 
• 
Medication for renal colic 
• 
Stone passage 
• 
Macroscopic hematuria due to a renal stone 
All relevant clinical information pertaining to the event should be obtained, including laboratory 
values, medical records, discharge summaries, and medical test results.   
Since renal stone events are recorded as an efficacy assessment for lumasiran, these will not be 
treated as AEs or SAEs.  However, if a patient experiences other AEs or SAEs during a renal 
stone event, they should be reported (see Section 6.5.6.1). 
6.3.3. 
Urinary Oxalate:Creatinine Ratio 
Urine oxalate:creatinine ratios will be calculated from the oxalate and creatinine levels measured 
in the available 24-hour urine collections to assess the PD effect of lumasiran on urinary 
oxalate:creatinine ratio.  Urinary oxalate:creatinine ratios from single-void urine collections will 
also be measured. 
6.3.4. 
Estimated Glomerular Filtration Rate 
In patients not undergoing dialysis, blood samples for the assessment of eGFR (mL/min/1.73 m2) 
will be obtained at the time points specified in the Schedules of Assessment (see Table 1, 
Table 2, Table 3, and Table 4).   
In patients ≥12 months to <18 years at consent, eGFR will be calculated based on the Schwartz 
Bedside Formula [Schwartz 2009] (Appendix 10.1).  In patients ≥18 years of age at consent, 
eGFR will be calculated based on the Modification of Diet in Renal Disease (MDRD) formula. 
[Levey 2009; Schwartz 2009] 
6.4. 
Pharmacokinetic Assessments 
Blood samples will be collected for assessment of lumasiran PK parameters and possible 
metabolite analysis (as necessary) at the time points in the Schedules of Assessment (see Table 1, 
Table 2, Table 3, and Table 4).  Plasma PK parameters, maximum plasma concentration (Cmax), 
time to maximum plasma concentration (tmax), elimination half-life (t½β), area under the 
concentration-time curve (AUC), apparent clearance (CL/F), and apparent volume of distribution 
(V/F), will be calculated for the lumasiran plasma concentration profiles.  A detailed schedule of 
time points for the collection of blood samples for PK analysis in patients in Cohort A is 
provided in Table 5.  In patients who are able to produce urine, a urine sample for PK analysis 
will be collected as on Day 1. 
Also, a detailed schedule of time points for the collection of blood samples for PK analysis in 
Cohort B patients is provided in Table 6.  Plasma oxalate profile assessment during Screening 


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should be conducted as explained in Section 6.2.1.  PK and plasma oxalate blood samples should 
be collected before the start of the next dialysis session. 
In patients who are not on dialysis at consent but start dialysis prior to Month 6 visit, PK and 
plasma oxalates blood samples should be collected as per Table 6 at the next scheduled protocol 
assessment in the Schedules of Assessments (Table 1, Table 2, Table 3, Table 4) and then 
continue per the timepoints in Table 6 for the rest of the study. 
In addition, if an SAE occurs associated with dosing, an additional PK sample may be collected 
at 4 to 8 hours postdose on the day of dosing, where blood volume limits permit (see 
Section 6.5.5.4). 
Lumasiran plasma concentrations will be determined using a central laboratory with a validated 
assay.  Details regarding sample volumes to be collected, sample processing, and shipping will 
be provided in the Laboratory Manual. 
6.5. 
Safety Assessments 
The assessment of safety during the study will consist of the surveillance and recording of AEs, 
including SAEs, recording of concomitant medication and measurements of vital signs, weight 
and height/length, ECG findings, and laboratory tests.  Clinically significant abnormalities 
observed during the physical examination will be recorded.  
6.5.1. 
Vital Signs 
Vital signs will be measured as specified in the Schedules of Assessment (see Table 1, Table 2, 
Table 3, and Table 4) and include blood pressure, heart rate, body temperature, and respiratory 
rate.  On dosing days, vital signs will be measured predose.  On Day 1 only, vital signs will also 
be measured 30 ± 10 minutes postdose.  When vital signs and blood sample collection occur at 
the same time, vital signs should be performed before blood samples are drawn, where possible. 
Vital signs should be measured after the patient has rested comfortably for 10 minutes, when 
feasible.  Blood pressure should be taken using the same limb, when feasible.  Body temperature 
in degrees Celsius will be obtained via oral, tympanic, or axillary methods.  Heart rate will be 
counted for a full minute and recorded in beats per minute, and respiration rate will be counted 
for a full minute and recorded in breaths per minute. 
Additional vital sign assessments, as medically indicated, may be added at the discretion of the 
Investigator, or as per DMC advice. 
Vital signs results will be recorded in the eCRF. 
6.5.2. 
Weight and Height/Length 
Height and body weight measurements will be collected as specified in the Schedules of 
Assessment (see Table 1, Table 2, Table 3, and Table 4) and will be recorded in the eCRF.  
Height/length will be measured in centimeters.  Standing height should be captured for patients 
≥24 months old who are able to stand independently.  Supine length should be captured for 
patients <24 months old or those unable to stand independently.  All height/length measurements 
should be performed in triplicate for patients <18 years of age.   


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Body weight will be measured in kilograms.  In patients <6 years of age, body weight will be 
obtained within 7 days of dosing.  In Cohort B patients, body weight will be obtained post-
dialysis.  In patients ≥6 years of age, body weight collected within 3 months prior to the study 
drug dose or the predose weight collected on the study visit day or dosing day will be used for 
dose calculations (see Section 5.2.2). 
6.5.3. 
Physical Examination 
Full and abbreviated physical examinations will be conducted according to the Schedules of 
Assessment (see Table 1, Table 2, Table 3, and Table 4).  If a physical examination is scheduled 
for a dosing visit, it should be conducted prior to dosing.  In Cohort B patients, the physical 
examination should be conducted after dialysis is completed.  Full physical examinations will 
include the examination of the following:  general appearance; head, eyes, ears, nose and throat; 
respiratory, cardiovascular, gastrointestinal, musculoskeletal, and dermatological systems; 
thyroid; lymph nodes; and neurological status. 
Abbreviated physical examinations will include examination of at least the following:  
respiratory, cardiovascular, dermatological, gastrointestinal, and musculoskeletal systems. 
If a visit is conducted offsite (eg, at the patient’s home), a body system assessment may be 
performed in lieu of a physical examination. 
Clinically significant abnormalities observed during the physical examination are recorded on 
the medical history or AE eCRF as appropriate.  Abnormal findings from dermatological 
examinations will be recorded via photography (see Section 6.2.3.2). 
6.5.4. 
Electrocardiogram 
Triplicate 12-lead ECGs will be obtained predose, when applicable, as specified in the Schedules 
of Assessment (see Table 1, Table 2, Table 3, and Table 4).  Electrocardiograms may be 
completed up to 2 months after the Month 3 timepoint, up to 5 months after the Month 6 
timepoint, and up to 11 months after the Month 12 timepoint.  12-lead ECGs will be centrally 
read. 
When ECG and blood sample collection occur at the same time, ECGs should be performed 
before blood samples are drawn and when the patient is calm, if feasible.  
Qualified staff will review all ECGs to assess whether the results have changed since the 
Baseline visit and to determine the clinical significance of the results.  These assessments will be 
recorded on the eCRF.  Additional ECGs may be collected at the discretion of the Investigator, 
or as per DMC advice.  Recordings will be archived according to the Study Manual. 
ECGs will be utilized as secondary endpoints of the pharmacodynamic effect of lumasiran on 
systemic oxalosis, as described in Section 6.2.3.1. 
6.5.5. 
Clinical Laboratory Assessments 
The following clinical laboratory tests will be evaluated by a central laboratory, except in cases 
where it is not feasible to perform all tests centrally due to blood draw volume limits, ie, in 
infants and very young patients, hematology, and biochemistry panels may be performed locally, 
with central laboratory confirmation of any abnormalities.  Specific instructions for transaminase 


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elevations are provided in Section 5.2.3.1.  For any other unexplained clinically relevant 
abnormal laboratory test occurring after study drug administration, the test should be repeated 
and followed up at the discretion of the Investigator, or as per DMC advice, until it has returned 
to the normal range or stabilized, and/or a diagnosis is made to adequately explain the 
abnormality.  For any safety event or laboratory abnormality, additional laboratory assessments, 
imaging, and consultation may be performed for clinical evaluation and/or in consultation with 
the Medical Monitor; results may be collected and should be included in the clinical database.  
Clinical laboratory assessments are listed in Table 13 and will be assessed as specified in the 
Schedules of Assessment (see Table 1, Table 2, Table 3, and Table 4).  
While local laboratory results may be used for urgent clinical decisions, on the day of visit 
assessments, all laboratory assessments specified in Table 13 which are performed at a local 
laboratory should also be sent in parallel to the central laboratory except in cases where it is not 
feasible to perform all tests centrally due to blood draw volume limits, ie, in infants and very 
young patients.  Central laboratory results (once available) should be used for subsequent clinical 
and dosing decisions in the case of discrepant local and central laboratory results on samples 
drawn on the same day. 
Consult the Laboratory Manual for the blood draw priority list based on patient weight (see 
Section 6.5.5.4). 
Clinical laboratory assessments may be collected at the clinical site or at a location other than the 
clinical study center by a trained healthcare professional. 


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Table 13: 
Clinical Laboratory Assessments 
Hematology 
Complete blood count with differential 
 
Serum Chemistry 
Sodium 
Potassium 
BUN 
Phosphate 
Uric acid 
Albumin 
Total protein 
Calcium 
Glucose 
Carbon dioxide 
Creatinine and eGFR (Bedside Schwartz formula for 
children ≥12 months to <18 years of age at consent; 
MDRD formula for adults ≥18 years of age at 
consent) 
Chloride 
Pyridoxine (vitamin B6)a 
 
Liver Function Tests 
 
AST 
ALP 
ALT 
Serum bilirubin (total and direct) 
Urinalysisb 
Visual inspection for appearance and color 
Bilirubin 
pH (dipstick) 
Nitrite 
Specific gravity 
RBCs 
Ketones 
Urobilinogen 
Albumin (optional) 
Leukocytes 
Glucose 
Microscopy (if clinically indicated) 
Protein 
 
Abbreviations:  ALP=alkaline phosphatase; ALT= alanine aminotransferase; AST=aspartate aminotransferase; 
BUN=blood urea nitrogen; eGFR=estimated glomerular filtration rate; PH1=primary hyperoxaluria type 1; 
RBC=red blood cell 
a  Pyridoxine (vitamin B6) is required through Month 12 and only for patients receiving vitamin B6 for the treatment 
of PH1.  On days when a blood sample for pyridoxine will be collected, patients should be instructed not to take 
vitamin B6 within 6 hours prior to blood sample collection. 
b  Urinalysis will not be collected in Cohort B patients who are anuric (ie, produce <100 ml of urine per day). 
6.5.5.1. 
Immunogenicity  
Blood samples will be collected to evaluate antidrug antibodies.  Blood samples for antidrug 
antibody testing must be collected before study drug administration as specified in the Schedules 
of Assessment (see Table 1, Table 2, Table 3, and Table 4).  A blood sample to evaluate antidrug 
antibodies will be collected at the Early Termination visit, if applicable. 


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Details regarding the processing, shipping, and analysis of the samples will be provided in the 
Laboratory Manual. 
6.5.5.2. 
Pregnancy Testing 
A pregnancy test will be performed for females of child-bearing potential, and for 
pediatric/adolescent females upon initiation of menarche.  A serum pregnancy test will be 
performed at Screening and at the first visit after initiation of menarche, if applicable, and serum 
or urine pregnancy tests will be performed thereafter per the Schedules of Assessments (Table 1, 
Table 2, Table 3, Table 4) and any time pregnancy is suspected.  A serum pregnancy test will be 
performed in lieu of a urine pregnancy test in Cohort B patients who are anuric (ie, produce 
<100 ml of urine per day).  Pregnancy testing may be performed offsite by a patient or patient’s 
caregiver if a patient/caregiver will be administering study drug.  More frequent pregnancy 
testing may be performed where required per local requirements.  The results of the pregnancy 
test must be known before study drug administration.  Patients who are pregnant at Screening are 
not eligible for study participation.  Patients with a positive urine pregnancy test, subsequently 
confirmed by a positive serum pregnancy test, during the study will be discontinued from study 
drug but will continue to be followed for safety.  Patients determined to be pregnant while on 
study will be followed at least until the pregnancy outcome is known (see Section 6.5.6.7 for 
follow-up instructions). 
Follicle-stimulating hormone testing may be performed to confirm suspected post-menopausal 
status. 
6.5.5.3. 
Additional Liver Function Assessments 
LFT results should be assessed and reviewed as described in Section 5.2.3.1. 
Additional laboratory assessments will be performed in patients who experience any LFT 
abnormalities as outlined in Section 5.2.3.1.  Consult the Laboratory Manual for the blood draw 
priority list based on patient weight. 
Following the occurrence of elevated liver transaminases (ie, >3 × ULN) without an alternative 
cause or other LFT abnormalities per central laboratory, and as per the blood draw priority list, 
all assessments in Table 14 will be performed one time, as well as hematology, serum chemistry, 
and LFT assessments from Table 13, and other assessments or evaluations per Investigator 
discretion, as appropriate.  See Section 6.5.5.4 for the maximum blood volumes that can be 
collected from pediatric patients in this study; assessments described below may be staggered 
accordingly due to blood volume limitations. 
Monitoring, including criteria for dose modification or withholding the study drug, is described 
in 5.2.3.1. 


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Table 14: 
Hepatic Assessments in Patients Who Experience Elevated Transaminases 
Extended Hepatic Panel 
HBsAg, HBc antibody IgM and IgG 
Parvovirus B19 
HAV antibody IgM 
HHV-6 
HCV antibody 
Anti-nuclear antibodies 
HCV RNA PCR – qualitative and quantitative 
Anti-smooth muscle antibodies 
HEV antibody IgM 
Anti-LKM1 antibody 
Herpes Simplex Virus 1 and 2 antibody IgM, IgG 
Anti-mitochondrial antibodies 
Herpes Zoster Virus IgM, IgG 
Anti-SLA 
Epstein-Barr Virus antibodies, IgM and IgG 
Ferritin 
Cytomegalovirus antibodies, IgM, IgG 
Ceruloplasmin 
Imaging 
Abdominal ultrasound with Doppler flow (or CT or MRI) including right upper quadrant 
Focused Medical and Travel History 
Use of any potentially hepatotoxic concomitant 
medications, including over the counter medications 
and herbal remedies 
Alcohol consumption and drugs of abuse 
Other potentially hepatotoxic agents including any 
work-related exposures 
Recent travels to areas where hepatitis A or E 
is endemic 
Abbreviations:  CT=computed tomography; HAV=hepatitis A virus; HBc=hepatitis B core; HBsAg=hepatitis B 
virus surface antigen; HCV=hepatitis C virus; HEV=hepatitis E virus; HHV-6=human herpesvirus 6; 
IgG=immunoglobulin G antibody; IgM=immunoglobulin M antibody; LKM1=liver/kidney microsome-1 antibody 
MRI=magnetic resonance imagery; PCR=polymerase chain reaction; RNA=ribonucleic acid; SLA=soluble liver 
antigen. 
Note: 
• 
Assessments will be measured in central laboratory or locally when not feasible to conduct centrally, ie, in 
very young patients.  The full panel of assessments should only be performed once; individual assessments 
may be repeated, as needed.  Assessments can be staggered due to blood volume limitations (see 
Section 6.5.5.4). 
 
6.5.5.4. 
Maximum Blood Volume 
The maximum blood volume, which will be collected from pediatric patients over the course of 
the study, will be based on age and weight and will not exceed those specified in Table 15 from 
the Feinstein Institute for Medical Research Human Subject Protection Program Guidance 
Document (see Appendix Section 10.2).[Feinstein_Institute 2013]  Consult the Laboratory 
Manual for the blood draw priority list based on patient weight. 


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6.5.5.5. 
Dialysis Parameters 
Dialysis modality evaluations will be performed in all patients in Cohort B.  To prevent potential 
confounding of study results for the primary analysis, elective changes to dialysis regimen are 
not permitted during Screening or the 6-month primary analysis period, ie, decreasing dialysis 
frequency in response to lowered plasma oxalate, or elective changes to dialysis frequency, 
duration, filter size or type, and blood flow.  Changes in dialysis due to management of renal 
failure (eg, electrolyte content, fluid withdrawal settings), will be performed throughout the 
study according to Investigator judgement in consultation with the patient’s treating physician. 
Dialysis parameters may include, but are not limited to, duration and frequency.  The dialysis 
regimen will be monitored according to the Schedules of Assessments (see Table 1, Table 2, 
Table 3, and Table 4). 
6.5.6. 
Adverse Events 
6.5.6.1. 
Definitions 
Adverse Event  
According to the ICH E2A guideline Definitions and Standards for Expedited Reporting, and 
21 CFR 312.32, IND Safety Reporting, an AE is any untoward medical occurrence in a patient or 
clinical investigational subject administered a medicinal product and which does not necessarily 
have a causal relationship with this treatment. 
Renal stone events (as defined in Section 6.3.2) are recorded for efficacy assessment of 
lumasiran.  These events will not be treated as AEs or SAEs.  Other AEs or SAEs occurring 
during a renal stone event are reported. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
• 
Results in death 
• 
Is life-threatening (an event which places the patient at immediate risk of death from 
the event as it occurred.  It does not include an event that had it occurred in a more 
severe form might have caused death) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability or incapacity 
• 
Is a congenital anomaly or birth defect 
• 
Is an important medical event that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient and may require 
intervention to prevent one of the other outcomes listed in the definition above (eg, 
events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias, convulsions, or the development of drug 
dependency or abuse). 


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Adverse Events of Clinical Interest 
The following are considered to be AEs of clinical interest:  
• 
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3× upper limit 
of normal (ULN) 
• 
Severe or serious injection site reactions (ISRs); ISRs that are associated with a recall 
phenomenon (reaction at the site of a prior injection with subsequent injections), or 
those that lead to temporary dose interruption or permanent discontinuation of study 
drug. 
An ISR is defined as a local reaction at or near the site of injection.  “At or near” the 
injection site includes reactions at the injection site, adjacent to the injection site, or a 
reaction which may shift slightly away from the injection site due to gravity (eg, as 
may occur with swelling or hematoma).  A systemic reaction which includes the 
injection site, eg, generalized urticaria, other distinct entities or conditions like 
lymphadenopathy that may be near the injection site is not considered an ISR. 
For information on recording and reporting of AEs of clinical interest, see Section 6.5.6.2 and 
Section 6.5.6.3, respectively. 
Adverse Event Severity 
AEs are to be graded according to the categories detailed below: 
Mild: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Moderate: 
Moderate; minimal, local or noninvasive intervention indicated; limiting age 
appropriate instrumental activities of daily living (eg, preparing meals, 
shopping for groceries or clothes, using the telephone, managing money). 
Severe: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care activities of daily living (ie, bathing, dressing and undressing, feeding 
self, using the toilet, taking medications, and not bedridden); OR life-
threatening consequences; urgent intervention indicated; OR death related to 
an AE. 
Changes in severity should be documented in the medical record to allow assessment of the 
duration of the event at each level of severity.  AEs characterized as intermittent require 
documentation of the start and stop of each incidence.  When changes in the severity of an AE 
occur more frequently than once a day, the maximum severity for the experience that day should 
be noted.  If the severity category changes over a number of days, then those changes should be 
recorded separately (with distinct onset dates). 
AE severity and seriousness are assessed independently.  ‘Severity’ characterizes the intensity of 
an AE.  ‘Serious’ is a regulatory definition and serves as a guide to the Sponsor for defining 
regulatory reporting obligations (see definition for SAE). 


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Relationship of the Adverse Event to Study Drug 
The relationship of each AE to study drug should be evaluated by the Investigator by a “yes” or 
“no” response to the question: “Is there a reasonable possibility that the event may have been 
caused by the study drug?”  A “yes” response indicates that the event is considered as related to 
the study drug. 
6.5.6.2. 
Eliciting and Recording Adverse Events 
Eliciting Adverse Events 
The patient or legal guardian should be asked about medically relevant changes in the patient’s 
health since the last visit.  The patient or legal guardian should also be asked if the patient has 
been hospitalized, had any accidents, used any new medications, or changed concomitant 
medication routines (both prescription and over-the-counter).  In addition to patient observations, 
AEs will be documented from any clinically relevant laboratory findings, physical examination 
findings, ECG changes, or other findings that are relevant to patient safety.  
Recording Adverse Events 
The Investigator is responsible for recording non-serious AEs that are observed or reported by 
the patient after administration of the first dose of study drug regardless of their relationship to 
study drug through the end of study.  Non-serious AEs will be followed until the end of study.  
Events occurring after signing of the ICF and before study drug administration will be captured 
as medical history (see Section 6.1), while AEs that occur after study drug administration, and 
baseline events that worsen after study drug administration, must be recorded as AEs. 
The Investigator is responsible for recording SAEs that are observed or reported by the patient 
after the time when the informed consent is signed regardless of their relationship to study drug 
through the end of study.  SAEs will be followed until satisfactory resolution, until baseline level 
is reached, or until the SAE is considered by the Investigator to be chronic or the patient is 
stable, as appropriate. 
All AEs must be recorded in the source records for the clinical study center and in the eCRF for 
the patient, whether or not they are considered to be drug-related.  Each AE must be described in 
detail:  onset time and date, description of event, severity, relationship to study drug, action 
taken, and outcome (including time and date of resolution, if applicable). 
For SAEs, record the event(s) on both the eCRF and the SAE form. 
For AEs that are considered AEs of clinical interest (see Section 6.5.6.1), the supplemental AEs 
of Clinical Interest eCRF should be completed.  Additional clinical and laboratory information 
may be collected.  Refer to CRF completion guidelines for details on reporting events in the 
supplemental AEs of Clinical Interest eCRF.   
For all ISRs, the Investigator, or delegate, should submit an Injection Site Reaction Signs or 
Symptoms eCRF, recording additional information regarding each injection site reaction that is 
entered on the AE eCRF (eg, symptom(s), injection site location, follow-up actions taken, etc). 


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6.5.6.3. 
Reporting Adverse Events of Clinical Interest to Sponsor/Designee 
For AEs that are considered AEs of clinical interest (Section 6.5.6.1), the Sponsor or its designee 
should be notified within 24 hours using the appropriate eCRF. 
6.5.6.4. 
Serious Adverse Events Require Immediate Reporting to Sponsor/Designee 
An assessment of the seriousness of each AE will be made by the Investigator.  Any AE and 
laboratory abnormality that meets the SAE criteria in Section 6.5.6.1 must be reported to the 
Sponsor or designee within 24 hours from the time that clinical study center staff first learns of 
the event.  All SAEs must be reported regardless of the relationship to study drug. 
The initial report should include at least the following information: 
• 
Patient’s study number 
• 
Description and date of onset of the event 
• 
Criterion for serious 
• 
Preliminary assignment of relationship to study drug, and 
• 
Investigator/site information 
To report the SAE, complete the eCRF and the SAE form.  Within 24 hours of receipt of follow-
up information, the Investigator must update the eCRF and the SAE form.  SAEs must be 
reported using the contact information provided in the Study Manual. 
Appropriate remedial measures should be taken by the Investigator using his/her best medical 
judgment to treat the SAE.  These measures and the patient’s response to these measures should 
be recorded.  All SAEs, regardless of relationship to study drug, will be followed by the 
Investigator until satisfactory resolution or the Investigator deems the SAE to be chronic or 
stable.  Clinical, laboratory, and diagnostic measures should be employed by the Investigator as 
needed to adequately determine the etiology of the event. 
6.5.6.5. 
Sponsor Safety Reporting to Regulatory Authorities 
The Sponsor or its representative will report certain study events in an expedited manner to the 
Food and Drug Administration, the European Medicines Agency’s EudraVigilance electronic 
system according to Directive 2001/20/EC, and to all country Regulatory Authorities where the 
study is being conducted, according to local applicable regulations. 
6.5.6.6. 
Serious Adverse Event Notification to the Institutional Review 
Board/Independent Ethics Committee 
Suspected unexpected serious adverse reactions (SUSARs) will be reported to the IRB/IEC per 
their institutional policy by the Investigator or Sponsor (or Sponsor designee) according to 
country requirements.  Copies of each report and documentation of IRB/IEC notification and 
acknowledgement of receipt will be kept in the Investigator’s study file. 
6.5.6.7. 
Pregnancy Reporting 
If a female patient becomes pregnant during the study through study completion, the Investigator 
must report the pregnancy to the Sponsor or designee within 24 hours of being notified of the 


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pregnancy.  Details of the pregnancy will be recorded on the pregnancy reporting form.  The 
patient should receive any necessary counseling regarding the risks of continuing the pregnancy, 
the possible effects on the fetus, and be counseled to not breastfeed for 90 days after the last dose 
of study drug. 
The pregnancy should be followed by the Investigator until completion.  At the completion of the 
pregnancy, the Investigator will document the outcome of the pregnancy.  If the outcome of the 
pregnancy results in a postpartum complication, spontaneous abortion, stillbirth, neonatal death, 
or congenital anomaly, then the Investigator should follow the procedures for reporting an SAE 
as outlined in Section 6.5.6.4. 
6.5.6.8. 
Overdose Reporting 
An overdose is defined as any dose administered to or taken by a patient (accidentally or 
intentionally) that exceeds the highest daily dose, or is at a higher frequency, than included in the 
protocol for the patient’s weight category.  The Investigator will decide whether a dose is to be 
considered an overdose, in consultation with the Sponsor.  In the event of an overdose, the actual 
dose administered must be recorded in the eCRF. 
All reports of overdose (with or without an AE) must be reported within 24 hours to the Sponsor 
or designee. 
6.5.7. 
COVID-19 Data Collection 
Information on the COVID-19 infection status of the patient, if known, and other information on 
the impact of the COVID-19 pandemic on the patient's participation in the study will be 
collected. 
6.6. 
Biomarkers, DNA Genotyping, and Biospecimen Repository 
Alnylam’s RNAi therapeutics platform permits the highly specific targeting of investigational 
therapies based on genetic sequence.  It is possible that variations in the target genetic sequence 
will result in variations in drug effect.  More generally, genetic variations may account for the 
well-described heterogeneous manifestations of disease in patients with PH1, as well as their 
responses to treatment. 
Where allowed per local regulations, ethics committee (IRB/IEC) approval, and legal guardian 
consent (and patient assent, where applicable), samples will be collected as part of this study to 
permit exploratory investigations and the application of novel approaches to bioanalyses that 
may further elucidate the outcomes of this study, or potentially advance understanding of the 
safety, mechanism of action, and/or efficacy of lumasiran. 
Biological specimens will be collected at the intervals indicated in the Schedules of Assessment 
(see Table 1, Table 2, Table 3, and Table 4).  Potential exploratory investigations may include 
DNA, RNA, or biochemical metabolite assessments as they relate to disease progression, 
efficacy or safety. 
The biospecimen repository will also include residual material from routine samples (safety 
laboratory samples, PK samples, etc) that are obtained during the study. 


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These specimens will be securely stored in a central biorepository for up to 10 years following 
the completion of this clinical study (ie, last patient last visit), or as per local regulations.  After 
10 years have elapsed, samples will be destroyed. 
Details regarding the collection, processing, storage, and shipping of the samples will be 
provided in the Laboratory Manual. 
Exploratory analysis of these biospecimens will be performed by Alnylam Pharmaceuticals or its 
designees. 
When biobanking is permitted by local regulation, study participants will be advised during the 
informed consent process of these biobanking details and the potential for exploratory 
investigation of their samples. 
6.7. 
Developmental Assessments 
The Vineland Adaptive Behavior Scale will be assessed at the timepoints specified in the 
Schedules of Assessment (see Table 1, Table 2, Table 3, and Table 4), and may be completed up 
to 4 months after the intended time point during periods of time when the COVID-19 pandemic 
impedes the ability of patients to travel to the study site, to assess the achievement of 
developmental milestones over time.  This tool assesses the domains of communication, daily 
living skills, socialization, and motor skills.  The survey can be completed by a legal guardian or 
caregiver in approximately 20 to 60 minutes. 
6.8. 
Quality of Life Questionnaires 
For QOL instruments described below, they will be assessed where available, and all will be 
carried forward throughout the study duration as patient age advances to qualify for each 
succeeding age-specific instrument, as appropriate.  The surveys and questionnaires described 
below will be completed at the timepoints specified in the Schedules of Assessments (see 
Table 1, Table 2, Table 3, and Table 4) and may be completed up to 4 months after the intended 
time point during periods of time when the COVID-19 pandemic impedes the ability of patients 
to travel to the study site. 
6.8.1. 
EQ-5D 
The EQ-5D is a standardized instrument for use as a measure of QOL outcome.[Herdman 2011]  
It consists of a questionnaire pertaining to 5 dimensions.  There is also a visual analog scale, 
scoring of which is based on a visual scale ranging from 0 (worst imaginable health state) to 100 
(best imaginable health state).  Higher scores indicate better health status.  Patients ≥18 years of 
age at time of assessment will complete the EQ-5D adult version of the questionnaire using the 
5-level (5L) value set, and patients ≥2 to <18 years of age at time of assessment will complete 
the youth version of this questionnaire, the EQ-5D-Y.  Legal guardians may complete 
questionnaires on behalf of younger infant to pediatric patients, as appropriate.  
6.8.2. 
PedsQL 
Peds-QL is a modular approach to measuring QOL in healthy children and adolescents and those 
with acute and chronic health conditions.  The PedsQL Generic Core Scales contain 23 items 
designed to measure core domains of health (physical, emotional, and social functioning) and 


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role (school functioning).  Scores are summarized as Total Scale Score, Physical Health 
Summary Score, and Psychosocial Health Summary Score.  The Total Scale Score, individual 
subscales of the generic and ESRD modules (parent and/or self-report versions), and ESRD 
module total score will be assessed for this study.  The PedsQL will be completed by patients (or 
caregivers, as appropriate) who are ≥2 to <18 years of age at the time of consent. 
6.8.3. 
KDQOL 
The Kidney Disease and Quality of Life (KDQOL-36) questionnaire is used to assess 3 core 
domains of kidney disease including:  burden, symptoms/problems, and effects of kidney disease 
on daily life.  The KDQOL subscales (Burden of Kidney Disease, Effect of Kidney Disease on 
Daily Life, and Symptoms and Problems of Kidney Disease), and the accompanying Short Form-
12 (SF-12) Physical Component Summary and Mental Component Summary will be assessed for 
this study.  These will be completed by patients who are ≥18 years of age at the time of consent.   
6.9. 
Patient/Caregiver Experience Surveys and Impact Questionnaires 
The surveys and questionnaires described below will be completed at the time points specified in 
the Schedules of Assessments (see Table 1, Table 2, Table 3, and Table 4), and may be 
completed up to 4 months after the intended time point during periods of time when the COVID-
19 pandemic impedes the ability of patients to travel to the study site. 
6.9.1. 
Patient Experience Survey 
The Patient Experience Survey assesses patients’ experience living with PH1, including their 
experience with PH1 treatments.  
Patients ≥13 years of age at screening will complete the survey unaided if they are able.  If the 
patient is unable to complete the Patient Experience Survey alone, their caregiver or study site 
staff may complete the survey on behalf of the patient.  If the patient is <13 years of age at 
screening, a caregiver will complete the Patient Experience Survey on behalf of the patient for as 
long as the patient remains under the legal age of consent.  
6.9.2. 
Caregiver Experience Survey 
The Caregiver Experience Survey assesses the consequences of PH1 on caregivers of PH1 
patients.  
Caregivers of patients under legal age of consent at the time of Screening will be asked to 
complete the Caregiver Experience Survey.  For patients who reach the legal age of consent per 
local regulations during the study, caregivers will be encouraged to continue completing the 
survey, but are not required to do so.  Caregivers of patients over the legal age of consent at the 
time of Screening will also be encouraged to complete the survey according to the Schedule of 
Assessments, but are not required to do so. 
6.9.3. 
Patient and Caregiver Impact Questionnaire 
The patient and caregiver impact questionnaire will be used to assess impacts of PH1 on the 
patients’ lives, including their need to relocate/travel to receive treatment, the number and type 


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of healthcare providers they use, and their ability to work and/or go to school.  The questionnaire 
will also assess the impact on caregivers’ employment and/or education.   
Patients ≥13 years of age at screening will complete the questionnaire unaided if they are able.  If 
the patient is unable to complete the survey alone, their caregiver or site staff may complete the 
survey on the patient’s behalf.  If the patient is <13 years of age at Screening, a caregiver will 
complete the questionnaire on behalf of the patient.  For patients who reach the legal age of 
consent per local regulations during the study, and whose caregivers had previously completed 
the Patient Impact Questionnaire on their behalf, caregivers will be encouraged to continue 
completing the questionnaire, but are not required to do so. 
6.10. 
Healthcare Resource Utilization 
Healthcare resource utilization will be assessed using patient or caregiver-reported information 
related to all hospitalizations, urgent healthcare visits, procedures and surgeries, and collected as 
specified in the Schedules of Assessments (see Table 1, Table 2, Table 3, and Table 4).   
7. 
STATISTICS 
A Statistical Analysis Plan (SAP) will be finalized before the dosing of the first patient in this 
study.  The plan will detail the implementation of the statistical analyses in accordance with the 
principle features stated in the protocol.  For information on study endpoints, see Section 2. 
7.1. 
Determination of Sample Size 
The planned enrollment for the study is 20 patients, including at least 6 patients in each cohort.  
Of those 20 patients, the planned enrollment includes 4 patients <6 years of age at consent, and 
2 patients between ≥6 to <18 years of age at consent.  The sample size was determined based on 
feasibility considerations, not power calculations. 
7.2. 
Statistical Methodology 
Statistical analyses will be primarily descriptive.  Summary statistics and by-patient listings/by-
patient figures will be presented.  Summaries for efficacy will be based on the Efficacy Analysis 
Set and safety endpoints will be based upon the Safety Analysis Set (Section 7.2.1).   
For categorical variables, summary tabulations of the number and percentage of patients within 
each category (with a category for missing data) will be presented.  For continuous variables, 
descriptive statistics will be presented (ie, number of patients, mean, median, standard deviation, 
standard error, minimum and maximum values). 
All data will be provided in by-patient listings.  Additional data summaries to help understand 
any impact of COVID-19 on efficacy and safety assessments will be outlined in the SAP. 
7.2.1. 
Populations to be Analyzed 
The populations (analysis sets) are defined as follows:  
• 
Safety Analysis Set:  All patients who received any amount of lumasiran during the 
study. 


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• 
Efficacy Analysis Set:  All patients who received any amount of lumasiran and have 
at least 1 valid plasma oxalate value at baseline and at the Month 3 assessment or 
beyond. 
• 
PK Analysis Set:  All patients who received any amount of lumasiran have at least 
1 postdose blood sample for PK parameters and have evaluable PK data. 
The primary population used to evaluate efficacy will be the Efficacy Analysis Set and safety 
will be the Safety Analysis Set.  The PK Analysis Sets will be used to conduct PK analyses. 
7.2.2. 
Examination of Subgroups 
Subgroup analyses may be conducted for selected endpoints.  Detailed methodology will be 
provided in the SAP. 
7.2.3. 
Handling of Missing Data 
Every effort will be made to minimize the amount of missing data in the study.  Patients who 
discontinue the study prior to Month 6 will be encouraged to remain on study and complete their 
remaining clinical visits (excluding PK assessments) through the Month 6 visit and only safety 
follow-up visits afterwards.  Details about handling of missing data will be described in the SAP. 
7.2.4. 
Baseline Evaluations 
Demographics and other disease-specific baseline characteristics will be summarized for the 
Safety Analysis Set. 
7.2.5. 
Efficacy Analyses 
There will be a Primary Analysis Period for Cohort A, and separately for Cohort B.  There will 
not be an interim analysis prior to at least 1 cohort completing the Primary Analysis Period. 
7.2.5.1. 
Primary Endpoint 
In Cohort A patients, the plasma oxalate baseline is defined as the mean of the last 4 plasma 
oxalate level values collected prior to the first dose of lumasiran.  In Cohort B patients, the 
plasma oxalate baseline is similarly defined except that the values obtained from the plasma 
oxalate profile assessment visits will only include the first pre-dialysis sample collected per visit. 
The primary analysis is percent change from baseline in plasma oxalate (Cohort A) / pre-dialysis 
plasma oxalate (Cohort B) summarized Month 3 through Month 6 by cohorts.  
For patients who crossover from Cohort A at baseline to Cohort B before Month 6, due to 
initiation of dialysis between Day 1 and the Month 6 assessments, descriptive listing and figures 
will be provided.  
Percent change in plasma oxalate from baseline (pre-dialysis levels in Cohort B) will be 
summarized through Month 6.  Further details will be included in the SAP. 
7.2.5.2. 
Secondary Endpoints 
Secondary endpoints will be analyzed and reported with by-patient listings and by-patient figures 
of actual values, change from baseline and percent change (where appropriate per endpoint) at 


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each visit (scheduled and unscheduled visits).  Tabular summaries using descriptive statistics 
(mean, standard error, median, min, max) will be reported.  For binary endpoints, the number 
and percentages of patients in each category will be displayed at each visit.  Other subgroup 
analyses may be generated if applicable. 
For patients in Cohort B, the secondary endpoint of percent change from baseline in plasma 
oxalate AUC will be summarized through the Month 6 plasma oxalate profile assessment.  
Baseline plasma oxalate AUC measurement will be obtained via the plasma oxalate profile 
assessments prior to initial dosing, after the stable dialysis regimen  is established.  Post-
treatment AUC measurements will be obtained at the Month 3 and Month 6 plasma oxalate 
profile assessments. 
Long-term treatment effect of lumasiran will be summarized descriptively for the long-term 
extension period.  Safety data will be summarized descriptively and presented in by-patient 
listings.  Further details will be included in the SAP. 
7.2.5.3. 
Exploratory Endpoints 
Details will be included in the SAP. 
7.2.6. 
Pharmacodynamic Analysis 
Urinary oxalate and glycolate excretion, urinary oxalate:creatinine ratio and plasma levels of 
oxalate and glycolate will be summarized over time for all patients in the Efficacy Analysis Set. 
7.2.7. 
Pharmacokinetic Analysis 
Pharmacokinetic analyses will be conducted using noncompartmental methods. 
Pharmacokinetic parameters include, but will not be limited to:  Cmax, tmax, tș, AUC, CL/F, and 
V/F.  Other parameters may be calculated, if deemed necessary. 
7.2.8. 
Safety Analyses 
The primary parameter is the frequency of treatment-emergent AEs (hereafter referred to simply 
as AEs).  Safety parameters also include vital signs, ECGs, clinical laboratory assessments and 
physical exams.  Extent of exposure will be summarized overall. 
Prior and concomitant medications will be classified according to the World Health Organization 
(WHO) Drug Dictionary.  Results will be tabulated by Anatomical Therapeutic Chemical (ATC) 
Classification System and Preferred Term (PT). 
AEs will be classified according to the Medical Dictionary for Regulatory Activities (MedDRA) 
overall.  AEs, SAEs, related AEs, and AEs leading to discontinuation will be summarized by 
System Organ Class and PT for each treatment arm.  By-patient listings will be provided for 
deaths, SAEs, and events leading to discontinuation of treatment. 
Descriptive statistics will be provided for clinical laboratory data, ECG, and vital signs data.  
Laboratory shift tables from baseline to worst values will be presented. 
Other safety summaries will be presented as appropriate.  Further details will be specified in the 
SAP. 


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7.2.9. 
Immunogenicity Analyses 
Antidrug antibody results will be summarized descriptively by patient and overall. 
7.2.10. 
Interim Analysis 
There may be interim analyses performed to support regulatory and/or publications requests. 
7.2.11. 
Optional Additional Research 
Optional additional research may be conducted in the future on the biological samples and/or 
data collected during the study in accordance with the strict terms of the informed consent form 
(see Section 4.3.2). 
8. 
STUDY ADMINISTRATION 
8.1. 
Ethical and Regulatory Considerations 
This study will be conducted in accordance with the protocol, all applicable regulatory 
requirements, and the current guidelines of Good Clinical Practice (GCP).  Compliance with 
GCP provides public assurance that the rights, safety, and well-being of study patients are 
protected consistent with the principles that have their origin in the Declaration of Helsinki. 
8.1.1. 
Informed Consent 
The Investigator will ensure that the patient or legal guardian is given full and adequate oral and 
written information about the nature, purpose, possible risk and benefit of the study.  The patient 
or their legal guardian must also be notified that they are free to discontinue from the study at 
any time.  The patient or legal guardian should be given the opportunity to ask questions and 
allowed time to consider the information provided.  Legal guardian(s) must provide informed 
consent and the patient should provide assent per local regulations and institutional standards. 
The patient’s or legal guardian’s signed and dated informed consent (and assent, if applicable) 
must be obtained before conducting any study tests or procedures that are not part of routine 
care. 
When a patient under the age of legal consent who has been enrolled in the study reaches the 
legal age of consent, the Investigator must obtain the patient's informed consent or assent, as 
applicable, prior to performing any further research interventions and/or procedures involving 
that patient per local regulations and institutional standards. 
The Investigator must maintain the original, signed ICF (and assent form, if applicable).  A copy 
of the signed ICF (and assent form, if applicable) must be given to the patient or legal guardian. 
The Investigator will inform the patient/legal guardian if new information becomes available that 
may be relevant to the patient’s/legal guardian’s willingness to continue participation in the 
study.  Communication of this information should be documented. 


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8.1.2. 
Ethical Review 
The study protocol, including the ICF (assent form, if applicable), must be approved or given a 
favorable opinion in writing by an IRB or IEC, as appropriate.  The Investigator must submit 
written approval before he or she can enroll any patient into the study. 
The Investigator is responsible for informing the IRB or IEC of any amendment to the protocol 
in accordance with local requirements.  In addition, the IRB or IEC must approve all patient 
materials for the study (except those that support the need to remove an apparent immediate 
hazard to the patient).  The protocol must be reapproved by the IRB or IEC upon receipt of 
amendments and annually, as local regulations require. 
Initial IRB or IEC approval of the protocol, and all materials approved by the IRB or IEC for this 
study including the patient consent form, legal guardian consent form and patient assent form, as 
applicable per institutional standards and recruitment materials must be maintained by the 
Investigator and made available for inspection. 
The Investigator will submit reports of SAEs as outlined in Section 6.5.6.  In addition, the 
Investigator agrees to submit progress reports to the IRB or IEC per their local reporting 
requirements, or at least annually and at the conclusion of the study.  The reports will be made 
available to the Sponsor or designee. 
Any communications from regulatory agencies, IRBs, or IECs in regard to inspections, other 
studies that impact this protocol or the qualifications of study personnel should be promptly 
reported to the Sponsor or its designee. 
The Investigator is also responsible for providing the IRB or IEC with reports of any reportable 
serious adverse drug reactions from any other study conducted with the study drug.  The Sponsor 
or designee will provide this information to the Investigator. 
Major changes in this research activity, except those to remove an apparent immediate hazard to 
the patient, must be reviewed and approved by the Sponsor and the IRB or IEC that approved the 
study.  Amendments to the protocol must be submitted in writing to the Investigator’s IRB or 
IEC and the Regulatory Authority for approval before patients are enrolled under the amended 
protocol, and legal guardians must be re-consented to the most current version of the ICF (and 
patient assent form, as applicable). 
8.1.3. 
Serious Breach of Protocol 
Investigators must notify the Medical Monitor within 24 hours of becoming aware of a potential 
serious breach of the protocol.  A serious breach is a breach that is likely to affect to a significant 
degree the safety and rights of a study participant or the reliability and robustness of the data 
generated in the clinical trial. 
8.1.4. 
Study Documentation, Confidentiality, and Records Retention 
All documentation relating to the study should be retained for 2 years after the last approval in an 
ICH territory or as locally required, whichever is longer.  If it becomes necessary for the 
Sponsor, the Sponsor’s designee, applicable IRB/IEC, or applicable regulatory authorities to 
review or audit any documentation relating to the study, the Investigator must permit direct 
access to all source documents/data.  Records will not be destroyed without informing the 


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Sponsor in writing and giving the Sponsor the opportunity to store the records for a longer period 
of time at the Sponsor’s expense. 
The Investigator must ensure that the patients’ confidentiality will be maintained.  On the eCRFs 
or other documents submitted to the Sponsor or designees, patients should not be identified by 
their names, but by the assigned patient number or code.  If patient names are included on copies 
of documents submitted to the Sponsor or designees, the names will be obliterated, and the 
assigned patient number added to the document.  Documents not for submission to the Sponsor 
(eg, signed ICFs) should be maintained by the Investigator in strict confidence. 
The Investigator must treat all of the information related to the study and the compiled data as 
confidential, whose use is for the purpose of conducting the study.  The Sponsor must approve 
any transfer of information not directly involved in the study. 
To comply with local and/or regional regulations, this clinical study may be registered, and study 
results may be posted on public registries, such as ClinicalTrials.gov. 
8.1.5. 
End of Study 
The end of study is defined as the last patient last visit. 
8.1.6. 
Termination of the Clinical Study or Site Closure 
The Sponsor, or designee, reserves the right to terminate the study or a clinical study site at any 
time.  Conditions that may warrant this action may include, but are not limited to: 
• 
The discovery of an unexpected, serious, or unacceptable risk to patients participating 
in the study 
• 
Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
• 
Inadequate recruitment of participants by the Investigator 
• 
The decision on the part of the Sponsor to suspend or discontinue treatment with the 
study drug 
Should the study be terminated, and/or the site closed for whatever reason, all documentation and 
study drug pertaining to the study must be returned to the Sponsor or its representative, and the 
Investigators, IRB/IEC and Regulatory Authorities will be promptly informed of the termination 
and the reason for the decision.  The Investigator should promptly inform the patients and assure 
appropriate therapy and follow-up. 
8.2. 
Data Quality Control and Quality Assurance 
8.2.1. 
Data Handling 
Study data must be recorded on CRFs (paper and/or electronic) provided by the Sponsor or 
designee on behalf of the Sponsor.  Case report forms must be completed only by persons 
designated by the Investigator.  If eCRFs are used, study data must be entered by trained site 
personnel with access to a valid and secure eCRF system.  All data entered into the eCRF must 
also be available in the source documents.  Corrections on paper CRFs must be made so as to not 


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obliterate the original data and must be initialed and dated by the person who made the 
correction. 
8.2.2. 
Study Monitoring 
The Monitor, as a representative of the Sponsor, has an obligation to closely follow the study 
conduct at the site.  The Monitor will visit the Investigator and clinical study center periodically 
and will maintain frequent telephone and written contact.  The Monitor will maintain current 
personal knowledge of the study through observation, review of study records and source 
documentation, and discussion of the conduct of the study with the Investigator and staff. 
The Monitor will review source documents, systems and CRFs to ensure overall quality and 
completeness of the data and to confirm study procedures are complied with the requirements in 
the study protocol accurately.  The Sponsor, or its designee, will be allowed to conduct site visits 
to the investigation facilities for the purpose of monitoring any aspect of the study.  The 
Investigator agrees to allow the Monitor to inspect the drug storage area, study drug stocks, drug 
accountability records, patient charts and study source documents, site standard operating 
procedures and training records, and other records relative to study conduct. 
8.2.3. 
Audits and Inspections 
Periodically, the Sponsor or its authorized representatives audit clinical investigative sites as an 
independent review of core trial processes and documents to determine whether these activities 
were conducted, and data were recorded, analyzed, and accurately reported according to the 
protocol, GCP guidelines of the ICH, and any applicable regulatory requirements.  A regulatory 
authority, an IEC or an IRB may visit the site to perform audits or inspections, including source 
data verification.  The Investigator should contact the Sponsor and designee immediately if 
contacted by a regulatory agency, an IEC or an IRB about an inspection. 
8.3. 
Publication Policy 
It is intended that after completion of the study, the data are to be submitted for publication in a 
scientific journal and/or for reporting at a scientific meeting.  A copy of any proposed 
publication (eg, manuscript, abstracts, oral/slide presentations, book chapters) based on this 
study, must be provided and confirmed received at the Sponsor at least 30 days before its 
submission.  The Clinical Trial Agreement among the institution, Investigator, and Alnylam will 
detail the procedures for Alnylam’s review of publications. 
Authorship of any publications resulting from this study will be determined on the basis of the 
Uniform Requirement for Manuscripts Submitted to Biomedical Journals (International 
Committee of Medical Journal Editors). 


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9. 
LIST OF REFERENCES 
Al-Eisa AA, Samhan M,Naseef M. End-stage renal disease in Kuwaiti children: an 8-year 
experience. Transplant Proc. 2004 Jul-Aug;36(6):1788-91. 
Boualla L, Tajir M, Oulahiane N, Lyahyai J, Laarabi FZ, Chafai Elalaoui S, et al. AGXT Gene 
Mutations and Prevalence of Primary Hyperoxaluria Type 1 in Moroccan Population. Genet Test 
Mol Biomarkers. 2015 Sep 18. 
National Health and Nutrition Examination Survey [database on the Internet]. CDC National 
Center for Health Statistics. 2018 [cited August 2018]. Available from: 
https://www.cdc.gov/nchs/nhanes/index.htm. 
Cochat P,Rumsby G. Primary hyperoxaluria. N Engl J Med. 2013 Aug 15;369(7):649-58. 
Danpure CJ. Primary Hyperoxaluria. In: Beaudet AL, editor. The Online Metabolic and 
Molecular Bases of Inherited Disease. New York, NY: The McGraw-Hill Companies, Inc.; 2014. 
Feinstein_Institute. The Feinstein Institute for Medical Research.  Human Subject Protection 
Program Guidance Document:  Maximum Blood Draw Limits.   
http://www.feinsteininstitute.org/wp-content/uploads/2013/02/Maximum-Blood-Draw-
Limits.pdf. 2013. 
Frishberg Y, Rinat C, Shalata A, Khatib I, Feinstein S, Becker-Cohen R, et al. Intra-familial 
clinical heterogeneity: absence of genotype-phenotype correlation in primary hyperoxaluria type 
1 in Israel. Am J Nephrol. 2005 May-Jun;25(3):269-75. 
Harambat J, Fargue S, Acquaviva C, Gagnadoux MF, Janssen F, Liutkus A, et al. Genotype-
phenotype correlation in primary hyperoxaluria type 1: the p.Gly170Arg AGXT mutation is 
associated with a better outcome. Kidney Int. 2010 Mar;77(5):443-9. 
Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, et al. Development and 
preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011 
Dec;20(10):1727-36. 
Hopp K, Cogal AG, Bergstralh EJ, Seide BM, Olson JB, Meek AM, et al. Phenotype-Genotype 
Correlations and Estimated Carrier Frequencies of Primary Hyperoxaluria. J Am Soc Nephrol. 
2015 Feb 2. 
Hoppe B. Evidence of true genotype-phenotype correlation in primary hyperoxaluria type 1. 
Kidney Int. 2010 Mar;77(5):383-5. 
Hoppe B, Danpure CJ, Rumsby G, Fryer P, Jennings PR, Blau N, et al. A vertical 
(pseudodominant) pattern of inheritance in the autosomal recessive disease primary 
hyperoxaluria type 1: lack of relationship between genotype, enzymic phenotype, and disease 
severity. Am J Kidney Dis. 1997 Jan;29(1):36-44. 
Johnson TN, Tucker GT, Tanner MS,Rostami-Hodjegan A. Changes in liver volume from birth 
to adulthood: a meta-analysis. Liver Transpl. 2005 Dec;11(12):1481-93. 
Kamoun A,Lakhoua R. End-stage renal disease of the Tunisian child: epidemiology, etiologies, 
and outcome. Pediatr Nephrol. 1996 Aug;10(4):479-82. 


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Kuczmarski RJ, Ogden CL, Guo SS, Grummer-Strawn LM, Flegal KM, Mei Z, et al. 2000 CDC 
Growth Charts for the United States: methods and development. Vital Health Stat 11. 2002 
May(246):1-190. 
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, 3rd, Feldman HI, et al. A new 
equation to estimate glomerular filtration rate. Ann Intern Med. 2009 May 5;150(9):604-12. 
Lieske JC, Monico CG, Holmes WS, Bergstralh EJ, Slezak JM, Rohlinger AL, et al. 
International registry for primary hyperoxaluria. Am J Nephrol. 2005 May-Jun;25(3):290-6. 
Mandrile G, van Woerden CS, Berchialla P, Beck BB, Acquaviva Bourdain C, Hulton SA, et al. 
Data from a large European study indicate that the outcome of primary hyperoxaluria type 1 
correlates with the AGXT mutation type. Kidney Int. 2014 Dec;86(6):1197-204. 
Schwartz GJ, Munoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, et al. New equations to 
estimate GFR in children with CKD. J Am Soc Nephrol. 2009 Mar;20(3):629-37. 
van der Hoeven SM, van Woerden CS,Groothoff JW. Primary hyperoxaluria type 1, a too often 
missed diagnosis and potentially treatable cause of end-stage renal disease in adults: results of 
the Dutch cohort. Nephrol Dial Transplant. 2012 Oct;27(10):3855-62. 
van Woerden CS, Groothoff JW, Wanders RJ, Davin JC,Wijburg FA. Primary hyperoxaluria 
type 1 in The Netherlands: prevalence and outcome. Nephrol Dial Transplant. 2003 
Feb;18(2):273-9. 
Williams EL, Acquaviva C, Amoroso A, Chevalier F, Coulter-Mackie M, Monico CG, et al. 
Primary hyperoxaluria type 1: update and additional mutation analysis of the AGXT gene. Hum 
Mutat. 2009 Jun;30(6):910-7. 
 


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10. 
APPENDICES 
10.1. 
Formulae for Estimated Glomerular Filtration Rate Calculation 
Estimated glomerular filtration rate (eGFR; in mL/min/1.73 m2) will be calculated from serum 
creatinine (SCr) based on the Schwartz Bedside Formula for patients ≥12 months to <18 years of 
age, and the Modification of Diet in Renal Disease Formula for patients ≥18 years of age. 
 
Schwartz Bedside Formula [Schwartz 2009] 
• Conventional units 
o eGFR (mL/min/1.73 m2) = (0.413 × height [cm])/SCr (mg/dL) 
• SI units 
o eGFR (mL/min/1.73 m2) = (36.2 × height [cm])/SCr (µmol/L) 
 
Modification of Diet in Renal Disease Formula[Levey 2009] 
• Conventional units 
o eGFR (mL/min/1.73m2) = 175 × (SCr [mg/dL])-1.154 × (age)-0.203 × (0.742, if 
female), or × (1.212, if African American) 
• SI units 
o eGFR (mL/min/1.73m2) = 175 × (SCr [μmol/L]/88.4)-1.154 × (age)-0.203 × (0.742, if 
female), or × (1.212, if African American) 
 
 


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10.2. 
Blood Volume Limits in Pediatric Patients 
The maximum blood volume, which will be collected from pediatric patients over the course of 
the study, will be based on age and weight and will not exceed those specified in Table 15, which 
was adapted from the Feinstein Institute for Medical Research Human Subject Protection 
Program Guidance Document. 
Table 15: 
Maximum Allowable Total Blood Volume Collection Chart 
Body 
Weight  
Body 
Weight  
Total Blood 
Volume  
Maximum Allowable 
Volume in a 24-hour Period 
Total Volume Collected in a 
30-day Period 
2.5% of 
total blood 
volume 
3% of 
total blood 
volume  
5% of 
total blood 
volume  
10% of 
total blood 
volume  
(kg) 
(lbs) 
(mL) 
(mL) 
(mL) 
(mL) 
(mL) 
1 
2.2 
100 
2.5 
3 
5 
10 
2 
4.4 
200 
5 
6 
10 
20 
3 
6.6 
240 
6 
7.2 
12 
24 
4 
8.8 
320 
8 
9.6 
16 
32 
5 
11 
400 
10 
12 
20 
40 
6 
13.2 
480 
12 
14.4 
24 
48 
7 
15.4 
560 
14 
16.8 
28 
56 
8 
17.6 
640 
16 
19.2 
32 
64 
9 
19.8 
720 
18 
21.6 
36 
72 
10 
22 
800 
20 
24 
40 
80 
11-15 
24-33 
880-1200 
22-30 
26.4-36 
44-60 
88-120 
16-20 
35-44 
1280-1600 
32-40 
38.4-48 
64-80 
128-160 
21-25 
46-55 
1680-2000 
42-50 
50.4-60 
84-100 
168-200 
26-30 
57-66 
2080-2400 
52-60 
62.4-72 
104-120 
208-240 
31-35 
68-77 
2480-2800 
62-70 
74.4-84 
124-140 
248-280 
36-40 
79-88 
2880-3200 
72-80 
86.4-96 
144-160 
288-320 
41-45 
90-99 
3280-3600 
82-90 
98.4-108 
164-180 
328-360 
46-50 
101-110 
3680-4000 
92-100 
110.4-120 
184-200 
368-400 
51-55 
112-121 
4080-4400 
102-110 
122.4-132 
204-220 
408-440 
56-60 
123-132 
4480-4800 
112-120 
134.4-144 
224-240 
448-480 
61-65 
134-143 
4880-5200 
122-130 
146.4-156 
244-260 
488-520 
66-70 
145-154 
5280-5600 
132-140 
158.4-168 
264-280 
528-560 
71-75 
156-165 
5680-6000 
142-150 
170.4-180 
284-300 
568-600 
76-80 
167-176 
6080-6400 
152-160 
182.4-192 
304-360 
608-640 
81-85 
178-187 
6480-6800 
162-170 
194.4-204 
324-340 
648-680 
86-90 
189-198 
6880-7200 
172-180 
206.4-216 
344-360 
688-720 
91-95 
200-209 
7280-7600 
182-190 
218.4-228 
364-380 
728-760 
96-100 
211-220 
7680-8000 
192-200 
230.4-240 
384-400 
768-800 
Adapted from http://www feinsteininstitute.org/wp-content/uploads/2013/02/Maximum-Blood-Draw-
Limits.pdf.[Feinstein_Institute 2013]  
 


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ALN-GO1-005 PROTOCOL AMENDMENT 1 
SUMMARY OF CHANGES DATED 06 MAY 2020 
 
ILLUMINATE-C:  A Single Arm Study to Evaluate Efficacy, Safety, Pharmacokinetics, 
and Pharmacodynamics of Lumasiran in Patients with Advanced Primary Hyperoxaluria 
Type 1 (PH1) 
1. 
RATIONALE FOR PROTOCOL AMENDMENT 
The purpose of this protocol amendment is to incorporate Urgent Safety Measures (USMs) that 
were communicated to investigators in a Dear Investigator Letter dated 07 April 2020 to assure 
the safety of study participants while minimizing risks to study integrity amid the COVID-19 
pandemic. These changes are in line with guidance from both the European Medicines Agency 
and the United States Food and Drug Administration on the conduct of clinical trials during the 
COVID-19 pandemic.[EMA 2020; FDA 2020] 
This protocol amendment also incorporates the following changes that are not related to USMs.  
After ongoing review and assessment of the safety data from studies conducted with lumasiran, 
modifications are designed to enhance patient safety, reduce patient burden regarding blood 
sampling, and clarify a study procedure pertaining to urine collection.  These changes are 
summarized in Section 1.2 in Table 2 and will not be implemented until appropriate Health 
Authority and Ethics Committee (EC) and/or Institutional Review Board (IRB) approval. 
1.1. 
Urgent Safety Measures due to the Impact of the COVID-19 
Pandemic 
The USM modifications and new procedures are outlined below, and a detailed summary of the 
protocol changes is provided in Section 2 (Table 1).  These measures were to be adopted 
immediately by the Investigator site as specified in the Dear Investigator Letter. 
• Screening period (notification of new patients) 
The Investigator will notify the Sponsor before screening patients to allow an assessment 
of the ability of the site or any new trial participant to comply with the protocol given 
COVID-19 limitations. 
• Screening period and plasma oxalate eligibility (expanded windows) 
To ensure adequate time to complete screening assessments, the screening window will 
be expanded from 60 days to 120 days; screening assessments previously obtained within 
120 days prior to Day 1 may be used.  However, echocardiogram and ECG will be 
repeated if obtained 60 or more days prior to Day 1, and 1 additional plasma oxalate will 
be performed if all 3 plasma oxalate assessments were obtained 60 or more days prior to 
Day 1.  The plasma oxalate repeat collection should occur at least 7 days before Day 1. 
The three most recent screening plasma oxalate samples collected prior to Day 1, which 
may include the pre-dialysis sample from the plasma oxalate profile collection for 
Cohort B patients, will be used to assess eligibility. 


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• Lumasiran dosing outside the study center by patient or caregiver 
Following appropriate training and after consultation with the Medical Monitor, dosing 
will be permitted at a location other than the study center (eg, home), by the patient or 
patient’s caregiver with the oversight of the Investigator, provided the patient has 
tolerated at least 1 dose of lumasiran administered in the clinic.  In addition, references to 
patient/caregiver instructions for administration and storage of study drug are now 
included within the protocol. This measure is intended to remain in effect only during 
periods of time when the COVID-19 pandemic impedes the ability of patients to travel to 
the study site and healthcare professionals to go to patients' homes for dosing.  
In order to assure uniform and comprehensive training and to assure compliance with the 
dosing instructions, the sponsor has prepared both Investigator and caregiver-facing 
written materials. The caregiver materials will provide detailed guidance on the scope of 
the self-administration allowance and detailed instructions on procedures surrounding 
dosing. These materials serve as a supplement to virtual training that caregivers will 
receive. The site-facing materials outline the investigator responsibilities under the self-
administration scheme and provide a guide to the expectations around caregiver training. 
In addition, investigators will make verbal contact with caregivers to assure compliance 
with protocol procedures and to assure that any adverse events or deviations are properly 
captured. 
• Study visit window 
Except for assessments with other specified timing requirements (as noted below), study 
assessments and dosing are to be performed within a visit window of ±14 days 
(previously ±7 days) for all patients through Month 6, and for patients who weigh <10 kg 
from Month 7 through the end of study, and within a visit window of ±28 days 
(previously ±14 days) for patients who weigh ≥10 kg from Month 7 through end of study.  
Study drug doses must be administered at least 21 days apart. 
• Assessment of adverse events, concomitant medications, renal stone events, and 
healthcare utilization 
In situations where a study visit is unable to be completed (either at the site or offsite by a 
healthcare professional visit), the study Investigator (or delegate) may verbally contact 
the patient within the expected study visit window to assess adverse events, concomitant 
medications, renal stone events, and healthcare utilization. 
• Liver function tests 
Liver function test (LFT) results are to be obtained within 7◦days prior to dosing and 
results are to be reviewed prior to each dose of lumasiran.  During periods of time when 
the COVID-19 pandemic impedes the ability of patients to travel to the study site and 
healthcare professionals to go to patients' homes, when LFT assessments are not feasible 
within 7 days prior to the dose, LFT test results up to 6◦weeks prior to the planned 
monthly dose or up to 4 months prior to the planned quarterly dose may be reviewed to 
determine whether the dose can be administered.  LFTs from the Week 2 visit must be 
reviewed prior to administration of the Month 1 dose. 


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This change in the window for LFT assessment is supported by data from our clinical 
trials.  In the 75 patients with PH1 treated with lumasiran for a duration of up to 
22 months, no clinically significant changes in LFTs due to lumasiran have been 
observed.  Based on available data, lumasiran has an acceptable hepatic safety profile.    
• Time period to obtain weight for dose determination 
If the current procedure (weight obtained within 7 days or within 3 months prior to 
monthly or quarterly dose, respectively) is not possible due to the COVID-19 pandemic 
impacting activities at the study site or patient ability to access the site, dose will be 
based on weight obtained within 6 weeks prior to dosing for patients who are <10 kg and 
within 4 months for patients who are ≥10 kg.   
For Cohort B patients, if a post dialysis weight taken at the study center is not available 
within the above specified timeframes, weight taken at the dialysis center may be used.  
• 24-hour urine sample collection 
To avoid risks associated with use of urinary catheters and prolonged hospitalization, the 
option to use catheterization for 24-hour urine sample collection has been removed. 
• Vineland Adaptive Behavior Scale, and the Patient/Caregiver Experience and 
Impact Questionnaire 
The Vineland Behavior Scale, Quality of Life questionnaires, and Patient/Caregiver 
Experience and Impact questionnaires may be completed up to 4 months after the 
intended timepoint. 
• Systemic oxalosis assessments 
Broader windows will be applied for systemic oxalosis assessments:  
− 12-lead ECGs may be completed up to 2 months after the Month 3 timepoint, 
5 months after Month 6, and 11 months after Month 12  
− Renal ultrasounds may be completed up to 1 month after Day 1, 5 months after 
Month 6, and 11 months after Month 12 
− Echocardiogram may be completed up to 5 months after Month 6, and up to 
11 months after Month 12 
− Radiographs, ophthalmology evaluation, and optional bone scan may be 
completed up to 1 month after Day 1 and up to 11 months after the Month 12 
timepoint 
• Plasma oxalate profile 
Plasma oxalate profile samples can be collected up to 2 months after the Month 3 
timepoint, up to 5 months after the Month 6 timepoint, and up to 11 months after the 
Month 12 timepoint. 
If a patient’s stable dialysis regimen at the time of consent is interrupted during screening 
for ≤14 days, plasma oxalate levels should not be collected until the prior dialysis 
regimen has resumed for at least 2 weeks. 


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If a patient’s stable dialysis regimen at the time of consent is interrupted for >14 days, 
plasma oxalate should not be collected until the stable dialysis regimen has resumed for 
at least 4 weeks. 
If a patient’s stable dialysis regimen at the time of consent is permanently changed during 
screening, plasma oxalate should not be collected until the new dialysis regimen has been 
established for at least 4 weeks.  Any plasma oxalate profiles and pre-dialysis plasma 
oxalate samples collected prior to this point will not be used for the study.  A total of 
2 plasma oxalate profiles and a pre-dialysis plasma oxalate sample need to be collected 
AFTER the new stable dialysis regimen has been established for at least 4 weeks. 
The sampling times for plasma oxalate profile samples in protocol Table 6 are listed 
relative to dosing.  If plasma oxalate profile samples are taken on a non-dosing day, these 
times (2:00, 4:00, 8:00, 12:00 and 24:00 hours post-dose) should correspond to the end of 
dialysis. 
• Assessments required to be performed in clinic 
Where applicable country and local regulations and infrastructure allow for home 
healthcare, healthcare may take place at a location other than the clinical trial site to 
perform study assessments including blood and urine collection, vital signs, weight, 
administration of study drug, an abbreviated physical examination/body system 
assessment, and a height/length measurement . 
• Pregnancy tests 
Given the expanded use of offsite dosing, pregnancy tests will be permitted at an offsite 
location (eg, home) by a healthcare professional or the patient/patient’s caregiver at all 
timepoints as of Month 1.  
• Pharmacokinetic assessments 
In situations where the full PK profile (2, 4, 8, 12, and 24 hours post-dose plasma PK 
samples) cannot be drawn on the Day 1 visit, PK samples should be collected at 2, 4, and 
24 hours.  The next full PK profile will be drawn at Month 6 with a window of ±3 
months. 
• Impact of COVID-19 
Information related to the impact of the COVID-19 pandemic on patient participation in 
the study will be collected for each patient. Additional information regarding collection 
of this information, including completion of a new CRF specific to COVID-19, will be 
provided separately. 
This change is implemented to enable analysis of the impact of the COVID-19 global 
pandemic on clinical trial data. 
• Updates to study administration text 
Text was updated to provide clarification of Investigator responsibilities regarding 
communication of new study information to patients and IRB/IECs. 


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1.2. 
Changes Not Related to Urgent Safety Measures 
Additional changes to study conduct (outlined below) will not be implemented until appropriate 
HA and EC/IRB approval.  The removal of the requirement to perform routine coagulation 
studies after screening reduces patient burden regarding the frequency of blood samples and the 
volume of blood collected, while ensuring patient safety.  No safety signal pertaining to 
coagulation has been identified to date in any clinical study conducted with lumasiran.  This 
modification is particularly important for pediatric patients given the greater limits placed on 
blood collection volumes.   
• Remove the collection of blood samples to assess pyridoxine (Vitamin B6) levels 
after Month 12 and after discontinuation of pyridoxine therapy.  After a patient 
discontinues pyridoxine therapy, measurement of pyridoxine is no longer medically 
indicated to verify medication compliance. 
• Increase sample size based on feasibility; additional patients were identified since 
original protocol was implemented.  
• Revise renal ultrasound and urine collection assessments as anephric patients are 
exempt from renal ultrasound and procedures requiring urine samples, and anuric 
patients are exempt from procedures requiring urine samples. 
• Clarify ophthalmologic exams: Fundus photography (FP), Optical Coherence Test 
(OCT) and Fundus Autofluorescence (FAF) will be performed for all patients at 
specified timepoints; however, FAF will not be performed if unavailable at the study 
site. 
A detailed summary of these changes is provided in Section Section 2 (Table 2).  Corrections to 
typographical errors, punctuation, grammar, abbreviations, and formatting (including 
administrative changes between the original protocol and protocol amendment 1) are not 
detailed. 


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2. 
PROTOCOL AMENDMENT 2 DETAILED SUMMARY OF CHANGES 
Table 1: 
Urgent Safety Measures COVID-19-related Changes to be Adopted Immediately 
The primary section(s) of the protocol affected by the changes in Protocol Amendment 1 are indicated.  Deleted text is indicated by 
strikeout; added text is indicated by bold font. 
Purpose: Ensure, to the extent possible, that study integrity is maintained. 
The primary change occurs in Section 6.1, Screening Assessments 
Added text: 
The Investigator will notify the Sponsor before screening patients to allow an assessment of the ability of the site or any new 
trial participant to comply with the protocol given COVID-19 limitations. 
Purpose:  Expand the screening window and ensure adequate time to complete screening assessments. 
The primary change occurs in Table 1 Schedule of Assessments Primary Analysis Period (Screening through Month 6): All Patients. 
Revised text:   
Study Period 
Study Visit 
Screening 
Study Day  
(±Visit Window) 
Notes 
60 to -1 
-120 to -1 
Section(s) also reflecting this change: 
• Synopsis 
• Synopsis Table 6, Pharmacokinetic and Plasma Oxalate Profile Assessment Time Points for Patients on Dialysis 
• Section 3.1, Summary of Study Design 
• Section 3.3, Duration of Study 
• Section 6.1, Figure 1: Blood Sample Collection for PD Assessments During Screening 
• Section 6.1.2, Rescreening 
• Section 6.2.2 Urinary Oxalate, Table 12 


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Purpose:  Expand the use of offsite administration to include lumasiran dosing by the patient or caregiver and provide additional 
instructions on self-administration, and preparation, handling, and storage of the study drug 
The primary change occurs in Section 5.2.2, Dose and Administration 
Revised text: Study drug injections will be administered under the supervision of the Investigator.  The site of injection may be the 
abdomen, the upper arms or thighs.  If a local reaction around the injection site occurs, photographs may be obtained.  Detailed 
instructions for study drug administration are found in the Pharmacy Manual. 
Dosing will be permitted at a location other than the study center (for example, the patient’s home) by a healthcare 
professional with the oversight of the Investigator at all time points, provided the patient has tolerated at least 1 dose of 
lumasiran administered in the clinic.  However, continued study drug administration at the study center should be considered 
for patients who have ongoing study drug-related AEs, worsening injection site reactions with repeat dosing, or for anyone in 
the opinion of the Investigator who would benefit from clinical observation following dosing. 
If the patient is unable to come to the study site, and a visit by a healthcare professional is not possible due to circumstances 
related to the COVID-19 pandemic, lumasiran may be administered by the patient or patient’s caregiver under the oversight 
of the Investigator, and following consultation with the Medical Monitor, as allowed by applicable country and local 
regulations.  In such cases, the patient/caregiver must receive appropriate training on lumasiran administration prior to 
dosing.  This measure is intended to remain in effect only during periods of time when the COVID-19 pandemic impedes the 
ability of patients to travel to the study site and healthcare professionals to go to patients' homes for dosing. 
Additional details can be found in the Pharmacy Manual.  In addition, instructions and procedures related to the administration 
of lumasiran by a patient or caregiver will be provided in the Patient/Caregiver Storage and Administration Instructions. 
Section(s) also reflecting this change: 
• Synopsis Tables 1, 2, 3, and 4, Schedules of Assessments 
Purpose: Allow additional offsite assessments 
The primary change occurs in Section 6, Study Assessments 
Revised text:  Where applicable country and local regulations and infrastructure for home healthcare allow, home healthcare may take 
place at a location other than the clinical trial site to perform study assessments, which may include collection of blood and urine 
samples, measurement of vital signs, length/height and weight, an abbreviated physical examination/body system assessment, and 
preparation and administration of study drug (at the discretion of the Investigator). 
Section(s) also reflecting this change: 
• Section 6.5.3, Physical Examination 


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• Section 6.5.5.2, Pregnancy Testing 
Purpose:  Remove optional catheterization to avoid risks associated with use of urinary catheters and prolonged hospitalization. 
The primary change occurs in Section 3.1, Summary of Study Design 
Revised text:  For patients able to provide 24-hour urine samples, three 24-hour urine collections will be scheduled during screening to 
establish baseline urinary oxalate levels.  At Month 6, three 24-hour urine collections will be scheduled within 14 days prior to dose.  
There will be a single 24-hour urine collection at Month 3, Month 12, and every 6 months thereafter while on study.  For patients 
unable to provide 24 hour urine samples, a single catheterized 24 hour collection may be obtained, when allowed, at both baseline and 
Month 6.  Catheterized collections may be performed at the discretion of the Investigator and with legal guardian assent or consent, 
and per local IRB/IEC approval. 
Section(s) also reflecting this change:  
• Section 6.2.2, Urinary Oxalate 
• Section 6.2.2.1, Validity Criteria for 24-hour Urine Collection 
Purpose:  Extend the window for LFT assessment prior to dosing.   
The primary change occurs in Section 5.2.3.1, Liver Function Test Criteria for Withholding, Monitoring and Stopping Lumasiran 
Dosing  
Revised text:  Liver function test (LFT) results (see Table 13) are to be obtained within 7 days prior to dosing and results are to be 
reviewed prior to each dose of lumasiran.  During periods of time when the COVID-19 pandemic impedes the ability of patients 
to travel to the study site and healthcare professionals to go to patients' homes and LFT assessments are not feasible within 7 
days prior to the dose, LFT test results up to 6 weeks prior to the planned monthly dose or up to 4 months prior to the planned 
quarterly dose may be reviewed to determine whether the dose can be administered.   
Section(s) also reflecting this change:  
• Section 5.2.2, Dose and Administration 
• Section 6.5.5.3, Additional Liver Function Assessments 
Purpose: Allow flexibility for plasma oxalate assessments. 
The primary change occurs in Section 6.1, Screening Assessments 
Revised text: The timing of samples collected during Screening for plasma oxalate and plasma glycolate will be as shown in Figure 1.  
The four plasma oxalate assessments used to establish the baseline should be assessed over the span of at least 28 days and should be 
measured at least 7 days apart. The results of the first 3 baseline assessments will be used to determine eligibility.  For patients in 


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Cohort B, 2 of the 4 baseline plasma oxalate assessments will be the pre dialysis sample drawn at the beginning of the plasma oxalate 
profile.   
The three most recent screening plasma oxalate samples collected prior to Day 1, which may include the pre-dialysis sample 
from the plasma oxalate profile collection for Cohort B patients, will be used to assess eligibility.  If all 3 plasma oxalate 
assessments are obtained >60 days prior to Day 1, one additional plasma oxalate will be performed (at least 7 days prior to 
Day 1). 
For subjects in Cohort B, there must be 2 separate plasma oxalate profile assessments performed during Screening, performed 
at least 1 week apart. 
If a patient’s stable dialysis regimen at the time of consent is interrupted during screening for ≤14 days, plasma oxalate levels 
should not be collected until the prior dialysis regimen has resumed for at least 2 weeks.  If a patient’s stable dialysis regimen 
at the time of consent is interrupted for >14 days, plasma oxalate should not be collected until the stable dialysis regimen has 
resumed for at least 4 weeks. 
If a patient’s stable dialysis regimen at the time of consent is permanently changed during screening, plasma oxalate should 
not be collected until the new dialysis regimen has been established for at least 4 weeks.  Any plasma oxalate profiles and pre-
dialysis plasma oxalate samples collected prior to this point will not be used for the study.  A total of 2 plasma oxalate profiles 
and a pre-dialysis plasma oxalate sample need to be collected AFTER the new stable dialysis regimen has been established for 
at least 4 weeks. 
Section(s) also reflecting this change: 
• Synopsis Table 6, Pharmacokinetic and Plasma Oxalate Profile Assessment Time Points for Patients on Dialysis 
• Section 6.2.1.1, Cohort A 
• Section 6.2.1.2, Cohort B 
Purpose: Expand windows for measures of systemic oxalosis 
The primary change occurs in Section 6.2.3, Measures of Systemic Oxalosis 
Revised text:  Triplicate 12-lead ECGs will be collected using standardized machines at the timepoints specified in the Schedules of 
Assessment (see Table 1, Table 2, Table 3, and Table 4 ).  During periods of time when the COVID-19 pandemic impedes the 
ability of patients to travel to the study site, ECG assessments may be completed up to 2 months after the Month 3 timepoint, 
up to 5 months after the Month 6 timepoint, and up to 11 months after the Month 12 timepoint.  12-lead ECGs will be centrally 
read. 


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Radiographs (X-rays) of hands, hip, knee, and chest will be obtained and read centrally for features of skeletal oxalosis, where local 
IRB/IEC permits at the timepoints specified in the Schedules of Assessment (see Table 1, Table 2, Table 3, and Table 4 ), where 
feasible based on patient compliance.  During periods of time when the COVID-19 pandemic impedes the ability of patients to 
travel to the study site, X-rays may be completed up to 1 month after Day 1, and up to 11 months after the Month 12 
timepoint. 
Optional bone scans will be performed in only Cohort B patients ≥18 years of age to assess calcium oxalate systemic deposition, 
where local IRB/EC permits and if patient consents to the bone scan.  During periods of time when the COVID-19 pandemic 
impedes the ability of patients to travel to the study site, optional bone scans may be completed up to 1 month after Day 1, and 
up to 11 months after the Month 12 timepoint. 
Section(s) also reflecting this change: 
• Section 6.2.3.1, Cardiac 
• Section 6.2.3.3, Skeletal 
• Section 6.2.3.4, Ocular 
Purpose: Expand windows for Quality of Life assessments 
The primary change occurs in Section 6.7, Developmental Assessments 
Revised text: The Vineland Adaptive Behavior Scale will be assessed at the timepoints specified in the Schedules of Assessment (see 
Table 1, Table 2, Table 3, and Table 4), and may be completed up to 4 months after the intended time point during periods of 
time when the COVID-19 pandemic impedes the ability of patients to travel to the study site, to assess the achievement of 
developmental milestones over time.  This tool assesses the domains of communication, daily living skills, socialization, and motor 
skills.  The survey can be completed by a legal guardian or caregiver in approximately 20 to 60 minutes. 
Section(s) also reflecting this change: 
• Section 6.8, Quality of Life Questionnaires 
• Section 6.9, Patient/Caregiver Experience Surveys and Impact Questionnaires 
Purpose: Allow continuous assessments (collected throughout the study) to be assessed via remote contact. 
The primary change occurs in Schedules of Assessment (see Table 1, Table 2, Table 3, and Table 4) 


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Added text: • In situations where a study visit is unable to be completed (either at the site or offsite by a healthcare 
professional), the Investigator (or delegate) will verbally contact the patient within the study visit window to assess 
concomitant medications, renal stone events, adverse events, and healthcare utilization. 
Section(s) also reflecting this change: 
• Section 4.3.3, Lost to Follow-up 
Purpose:  To expand study window for assessment of weight prior to dosing. 
The primary change occurs in Section 5.2.2, Dose and Administration 
Revised text:  During periods of time when the COVID-19 pandemic impedes the ability of patients to travel to the study site 
and healthcare professionals to go to patients' homes, the dose will be based on weight obtained within 6 weeks prior to dosing for 
patients who are <6 years of age<10 kg and within 4 months for patients ≥6 years of age who weigh ≥10 kg.  For Cohort B patients, 
if a post dialysis weight taken at the study center is not available within the specified timepoints, post dialysis weight taken at 
the dialysis center may be used. 
Purpose: To adjust the plasma oxalate sampling times to accommodate profile samples taken on non-dosing days to ensure patient 
safety and, to the extent possible, that study integrity is maintained amid travel and other restrictions related to the COVID-19 
pandemic. 
The primary change occurs in Table 6, Pharmacokinetic and Plasma Oxalate Profile Assessment Time Points for Patients on Dialysis 
Added text: The plasma oxalate profile can be obtained on non-dosing days and the 2:00, 4:00, 8:00, 12:00, and 24:00 
timepoints will be post dialysis. 
Section(s) also reflecting this change: 
• Section 6.2.1, Plasma Oxalate 
Purpose: Reduce required collection timepoints for PK assessments to limit the potential exposure of the patient to COVID-19. 
The primary change occurs in Table 5, Pharmacokinetic Time Points: All Patients  
Added text:  Day 1 and Month 6 (±3 mos) 
• Blood samples for PK assessment may be collected at 8 and 12 hours postdose as feasible during periods of time when 
the COVID-19 pandemic impedes the ability of patients to travel to the study site and healthcare professionals to go to 
patients' homes. 


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Purpose: Added collection of information related to the impact of the COVID-19 pandemic on patient participation in the study for 
each patient to enable an evaluation of the impact of the COVID-19 global pandemic on clinical study data. 
The primary change occurs in an added Section 6.5.7, COVID-19 Data Collection 
Added text:  Information on the COVID-19 infection status of the patient, if known, and other information on the impact of the COVID-19 
pandemic on the patient's participation in the study will be collected. 
Section(s) also reflecting this change:  
• Section 7.2 Statistical Methodology 
Purpose: To provide clarification on Investigator responsibilities regarding communication of new study information to patients and 
IRB/IECs. 
The primary changes occur in Section 8.1.1, Informed Consent and Section 8.1.2, Ethical Review 
Added text:   
The Investigator will inform the patient/legal guardian if new information becomes available that may be relevant to the 
patient’s/legal guardian’s willingness to continue participation in the study.  Communication of this information should be 
documented. 
The Investigator is responsible for informing the IRB or IEC of any amendment to the protocol in accordance with local requirements.  
In addition, the IRB or IEC must approve all patient materials for the study (except those that support the need to remove an 
apparent immediate hazard to the patient).  The protocol must be reapproved by the IRB or IEC upon receipt of amendments and 
annually, as local regulations require.  


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Table 2: 
Changes Not Related to Urgent Safety Measures to be Implemented After Health Authority and Ethics 
Committee (EC)/Institutional Review Board (IRB) Approval, where applicable 
Purpose: To increase sample size 
The primary change occurs in Section 3.4, Number of Planned Patients 
Revised text: 
The planned enrollment for this study is 16 20 patients, including 6 patients in each cohort. 
Section(s) also reflecting this change: 
• Synopsis 
• Section 7.1, Determination of Sample Size 
Purpose:  To remove the requirement for measurement of routine coagulation  
The primary change occurs in Section 6.5.5, Clinical Laboratory Assessments: Table 13, Clinical Laboratory Assessments;  
Revised text:  
Coagulation 
Prothrombin time 
International Normalized Ratio 
Partial Thromboplastin Time 
 
Section(s) also reflecting this change:  
• Section 5.2.3.1, Liver Function Test Criteria for Withholding, Monitoring and Stopping Lumasiran Dosing 
• Table 8: Monitoring and Dosing Rules for Asymptomatic Patients with Confirmed Isolated Elevations of ALT and/or AST 
>3× ULN, with No Alternative Cause Identified  
• Section 6.5.5.3, Additional Liver Function Assessments 
Purpose:  Remove the requirement for measurement of pyridoxine after Month 12. 
The primary change occurs in Table 2 Schedule of Assessments – Long-term Extension Period (Month 7 to Month 35): Patient Weight 
<10 kg; and Table 4, Schedule of Assessments – Long-term Extension Period (Month 9 to End of Study): Patient Weight ≥10 kg 
Deleted text: Deleted X in schedule of assessment table cells for timepoints after Month 12. 
Sections also reflecting this change:  
• Table 3, Schedule of Assessments – Long-term Extension Period (Month 36 to End of Study): Patient Weight <10 kg 


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• Table 13, Clinical Laboratory Assessments 
Purpose:  To clarify renal ultrasound and urine collection assessments as anephric patients are exempt from renal ultrasound and 
procedures requiring urine samples, and anuric patients are exempt from procedures requiring urine samples. 
The primary change occurs in Section 6.3.1, Renal Ultrasound 
Added text:  Renal ultrasounds will be obtained locally, as specified in the Schedules of Assessment (see Table 1, Table 2, Table 3, 
and Table 4) when feasible; anephric patients are exempt from renal ultrasound assessments.  Renal ultrasound will be 
performed according to instructions provided in the Study Manual in a standardized manner.  Renal ultrasounds will be reviewed 
centrally.   
Section(s) also reflecting this change: 
• Section 6, Study Assessments 
Purpose:  To clarify Fundus Autofluorescence (FAF) will be performed for all patients at specified timepoints; however, FAF needs to 
be performed only at select sites where the procedure is available. 
The primary change occurs in Section 6.2.3.4, Ocular 
Revised text: The following ophthalmologic exams will be performed: Color Fundus Photography (CFP), Optical Coherence 
Tomography (OCT), and, where available at select sites, Fundus Autofluorescence (FAF).  along with color fundus photography 
(where available at select sites), and retinal Optical Coherence Tomography (OCT) with autofluorescence. 
Ophthalmologic exams with fundus photography will be standardized and the fundus photographs will be read centrally.  OCT 
assessments will also be standardized and read centrally.  For young children unable to cooperate, examinations will be optional.  
Anesthesia will not be used in any of these ocular assessments.  Results from any clinically obtained exams performed as standard of 
care may be collected. 
Best Corrected Visual Acuity (BCVA) 
Where available, BCVA using Early Treatment Diabetic Retinopathy Study (ETDRS) charts will be assessed longitudinally 
throughout the course of the study to evaluate for changes which correspond to changes in retinal oxalate deposition.  Exams will be 
standardized across applicable sites.  In younger patients <6 years of age, alternate visual acuity testing per local standard practice 
may be performed (eg, LEA symbols).  In sites where ETDRS testing is not available, Snellen or LEA symbol charts may be 
used for BCVA.  Testing is not required in preverbal infants. 


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

SAP_001.pdf: 
 
 
Official Title:  
ILLUMINATE-C: A Single Arm Study to Evaluate Efficacy, Safety, 
Pharmacokinetics, and Pharmacodynamics of Lumasiran in Patients With 
Advanced Primary Hyperoxaluria Type 1 (PH1) 
 
NCT Number:   
NCT04152200 
 
Document Date:   
Statistical Analysis Plan, 15 Mar 2021 






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TABLE OF CONTENTS 
APPROVAL SIGNATURE PAGE .................................................................................................2 
TABLE OF CONTENTS .................................................................................................................3 
ABBREVIATIONS .........................................................................................................................6 
1. 
INTRODUCTION ........................................................................................................8 
2. 
STUDY OVERVIEW ...................................................................................................9 
2.1. 
Synopsis of Study Design .............................................................................................9 
2.2. 
Randomization Methodology .....................................................................................10 
2.3. 
Blinding ......................................................................................................................10 
2.4. 
Data Monitoring Committee .......................................................................................10 
2.5. 
Study Procedures ........................................................................................................10 
3. 
ENDPOINTS ..............................................................................................................11 
3.1. 
Primary Endpoints ......................................................................................................11 
3.2. 
Secondary Endpoints ..................................................................................................11 
3.3. 
Exploratory Endpoints ................................................................................................12 
3.4. 
Safety Endpoint ..........................................................................................................12 
4. 
PATIENT POPULATION ..........................................................................................13 
4.1. 
Patient Definitions ......................................................................................................13 
4.2. 
Protocol Deviations ....................................................................................................13 
5. 
GENERAL STATISTICAL METHODS ...................................................................15 
5.1. 
Sample Size Justification ............................................................................................15 
5.2. 
General Methods .........................................................................................................15 
5.3. 
Computing Environment ............................................................................................16 
5.4. 
Baseline Definitions ....................................................................................................16 
5.5. 
Missing Data ...............................................................................................................16 
5.6. 
Visit Windows ............................................................................................................18 
5.7. 
Interim Analysis ..........................................................................................................19 
5.8. 
Analysis for Primary Endpoint and Database lock .....................................................19 
6. 
STUDY ANALYSES .................................................................................................20 
6.1. 
Patient Disposition ......................................................................................................20 
6.2. 
Demographics and Baseline Characteristics ...............................................................20 
6.3. 
Medical History ..........................................................................................................21 


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6.4. 
Prior and Concomitant Medications ...........................................................................21 
7. 
STATISTICAL ANALYSIS ......................................................................................22 
7.1. 
Primary Endpoint ........................................................................................................22 
7.1.1. 
Sensitivity Analysis ....................................................................................................23 
7.2. 
Subgroup Analysis ......................................................................................................23 
7.3. 
Secondary Endpoints ..................................................................................................23 
7.3.1. 
Percent Change from Baseline to Month 6 in Plasma Oxalate AUC between 
Dialysis Sessions ........................................................................................................23 
7.3.2. 
Change from baseline to Month 6 in other Plasma and Urinary Oxalate 
Parameters ...................................................................................................................24 
7.3.3. 
Quality of Life (QoL) .................................................................................................25 
7.3.4. 
Long-term Extension Period .......................................................................................25 
7.3.4.1. 
Percent Change from Baseline in Plasma Oxalate AUC between Dialysis 
Sessions.......................................................................................................................25 
7.3.4.2. 
Percent and Absolute Change from Baseline in Plasma Oxalate, 24-hr 
Urinary Oxalate, and Spot Urinary Oxalate: Creatinine Ratio ...................................25 
7.3.4.3. 
Nephrocalcinosis .........................................................................................................25 
7.3.4.4. 
Frequency and Mode of Dialysis (Cohort B) .............................................................26 
7.3.4.5. 
Frequency of Renal Stone Events ...............................................................................26 
7.3.4.6. 
Measures of Systemic Oxalosis ..................................................................................26 
7.3.4.7. 
Quality of Life (QoL) .................................................................................................27 
7.3.5. 
Pharmacokinetics ........................................................................................................27 
7.4. 
Exploratory Efficacy Analysis ....................................................................................27 
7.4.1. 
Change from Baseline in Cardiac Systemic Oxalosis at Month 6 ..............................27 
7.4.2. 
Growth Parameters (z-scores) and Change in Developmental Milestones ................27 
7.4.3. 
Quality of Life (QoL) .................................................................................................27 
7.4.4. 
Patient and Caregiver Resource Use...........................................................................28 
7.4.5. 
Patient and Caregiver Experience ...............................................................................28 
7.4.6. 
Anti-drug Antibody ....................................................................................................28 
7.4.7. 
Percent and Absolute Change from Baseline in Urinary and Plasma 
Glycolate .....................................................................................................................28 
7.5. 
Pharmacokinetic Analysis ..........................................................................................28 
7.6. 
Safety Analyses ..........................................................................................................28 
7.6.1. 
Adverse Events ...........................................................................................................28 


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7.6.2. 
Dosing and Extent of Exposure ..................................................................................30 
7.6.3. 
Clinical Laboratory Data ............................................................................................30 
7.6.4. 
Vital Signs ..................................................................................................................31 
7.6.5. 
Physical Examinations ................................................................................................31 
7.6.6. 
Electrocardiogram .......................................................................................................32 
7.7. 
Anti-Drug Antibody ....................................................................................................32 
7.8. 
COVID-19 Pandemic Impact Analyses ......................................................................32 
7.8.1. 
General Impact ............................................................................................................32 
7.8.2. 
Impact on Efficacy ......................................................................................................33 
7.8.3. 
Impact on Adverse Events ..........................................................................................33 
7.8.4. 
Other Impacts ..............................................................................................................33 
8. 
CHANGES TO PLANNED ANALYSES..................................................................34 
9. 
REFERENCES ...........................................................................................................35 
10. 
APPENDICES ............................................................................................................36 
10.1. 
Medical History Adjustment .......................................................................................36 
10.2. 
Category of Vineland Adaptive Behavior Scale .........................................................36 
10.3. 
COVID-19 Pandemic Phase Start Dates by Country .................................................36 
 


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ABBREVIATIONS 
 
Abbreviation 
Definition 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AGT 
Alanine-glyoxylate aminotransferase 
AGXT 
Alanine glyoxylate aminotransferase gene 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical Classification System 
AUC 
Area under the concentration-time curve 
BMI 
Body mass index 
BSA 
Body surface area 
CDC 
Center for disease control and prevention  
CI 
Confidence interval 
Cmax 
Maximum plasma concentration 
CFR 
Code of Federal Regulation 
CL/F 
Apparent clearance 
COVID-19 
Coronavirus Disease 2019 
CSR 
Clinical study report 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
EOS 
End of study 
EOT 
End of treatment 
ET 
Early termination 
ESRD 
End-stage renal disease 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GO 
Glycolate oxidase 
ICF 
Informed consent form 
LFT 
Liver function test 
LLOD 
lower limit of detection 


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


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1. 
INTRODUCTION 
Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disease characterized by 
excessive oxalate production by the liver and consequent hyperoxaluria.  PH1 is caused by 
mutations in the alanine glyoxylate aminotransferase (AGXT) gene, which encodes the liver 
peroxisomal enzyme alanine-glyoxylate aminotransferase (AGT).  As a consequence of AGT 
deficiency, glyoxylate accumulates and is oxidized to oxalate in the hepatocyte and ultimately 
transported to the kidneys for excretion.  Oxalate, in the form of its calcium salt, is excreted 
almost entirely by the kidney.  Due to its insolubility, calcium oxalate can crystallize readily in 
the urinary tract.  In PH1, excess urinary oxalate results in recurrent nephrolithiasis and/or 
nephrocalcinosis, which can lead to pain, infections, progressive kidney disease including kidney 
failure, along with reduced quality of life.[Cochat and Rumsby 2013]  As renal function declines, 
elimination of oxalate is further reduced, such that calcium oxalate accumulates in bone, 
vasculature, skin, retina, heart, and nervous system, resulting in severe end-organ 
damage.[Cochat and Rumsby 2013]  This devastating condition, systemic oxalosis, arises when 
the estimated glomerular filtration rate (eGFR) has declined to below 30 to 45 mL/min/1.73 
m2.[Cochat and Rumsby 2013]  Without treatment, the disease progresses inexorably, and death 
from end-stage renal disease (ESRD) and/or complications of oxalosis can occur.[Cochat and 
Rumsby 2013; Harambat 2010; van der Hoeven 2012]   
The ILLUMINATE-C Study (ALN-GO1-005) is a multicenter, single arm study designed to 
evaluate the efficacy, safety, pharmacokinetics (PK) and pharmacodynamics (PD) of lumasiran 
in patients with a documented diagnosis of PH1 who have advanced renal disease, as evident by 
eGFR ≤45 ml/min/1.73 m2 (or serum creatinine above the upper limit of normal (ULN) for age, 
in patients <12 months of age). All eligible patients will be administered lumasiran; no control 
group will be assessed. This statistical analysis plan (SAP) has been developed based on the 
protocol of the ILLUMINATE-C study (original dated 16 May 2019 and amendment 1 dated 06 
May 2020).  
The analysis methods described in the protocol may be updated in this SAP. Any change to the 
data analysis methods described in the protocol, as well as the justification for the change, will 
be described in the SAP (Section 8) and clinical study report (CSR). Additional exploratory 
analyses of the data may be conducted when deemed appropriate.  


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2. 
STUDY OVERVIEW 
2.1. 
Synopsis of Study Design 
The ILLUMINATE-C study (ALN-GO1-005) is a multicenter, multinational, open-label, single 
arm Phase 3 study designed to evaluate the efficacy, safety, PK and PD of lumasiran in patients 
with a documented diagnosis of PH1 who have advanced renal disease, as evident by eGFR ≤45 
ml/min/1.73 m2 (or serum creatinine elevated for age, in patients <12 months of age).  All 
eligible patients will be administered open-label lumasiran; no control group will be assessed.  
This study will consist of 2 periods: a 6-month Primary Analysis Period followed by a long-term 
(54 months) extension period. 
Lumasiran will be administered as a subcutaneous (SC) injection with weight-based dosing, with 
dose adjustments for interval weight gain, as follows:  
Weight 
Loading Dose 
(Day 1, Month 1, Month 2) 
Maintenance Dose 
(Month 3 and Beyond) 
<10 kg 
6.0 mg/kg monthly for 3 months 
3.0 mg/kg monthly 
≥10 to <20 kg 
6.0 mg/kg monthly for 3 months 
6.0 mg/kg every 3 months 
≥20 kg 
3.0 mg/kg monthly for 3 months 
3.0 mg/kg every 3 months 
For patients <6 years of age, the dose will be based on a weight obtained within 7 days prior to 
dosing. In patients ≥6 years of age, body weight collected within 3 months prior to the study 
drug dose or the predose weight collected on the study visit day or dosing day will be used for 
dose calculations. 
Patients with weight increases crossing the threshold for the next weight-based dosing category 
(for example, <10 kg to ≥10 kg or <20 kg to ≥20 kg) will follow the new dosing regimen for the 
remainder of the study or until the next dosing category threshold is reached (ie, patients will not 
switch back to the lower-weight dosing schedule if their body weight subsequently decreases).  
Patients in maintenance dosing who transition from <10 kg to ≥10 kg will continue to receive 
monthly doses at 3.0 mg/kg until the next quarterly visit (ie Month 3, Month 6, Month 9, etc.) 
whereby they will follow every 3-months dosing until the end of the study. 
This study will include 2 cohorts. Cohort A will include patients who do not yet require dialysis.  
Cohort B will include patients who are on hemodialysis therapy.    Enrollment to both cohorts 
will occur concurrently.  Cohort A patients who experience progression of renal impairment over 
time and begin to require long-term dialysis therapy will cross-over to Cohort B.  Patients in 
Cohort A who cross-over to Cohort B prior to their Month 6 visit may be replaced. Patients in 
Cohort B who stop dialysis during the study will continue in Cohort B. 
Patients will be screened from Day -120 to Day -1 to determine eligibility.  Consented patients 
meeting all eligibility criteria will receive their first dose of lumasiran on Day 1.  From 
Screening to Day 1, patients will have at least 4 plasma oxalate collections to establish a robust 
baseline measurement for plasma oxalate.  
As specified in the Schedules of Assessments of ALN-GO1-005 protocol, blood samples will be 
collected in both cohorts for plasma oxalate sample analysis, to establish plasma oxalate profiles 


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(AUC) in Cohort B, and for PK parameter analysis in both cohorts.  In Cohort B, dialysis status 
and changes in dialysis regimen will also be monitored and documented.  During the first 6 
months of the study, changes to the dialysis regimen will not be permitted, except when 
medically necessary. 
Safety assessments will include collection of adverse events (AEs), clinical laboratory tests, vital 
sign assessments, electrocardiograms (ECGs), physical examinations, and concomitant 
medications.   
2.2. 
Randomization Methodology 
Not applicable 
2.3. 
Blinding 
ALN-GO1-005 is an open label study, though pharmacodynamic assessment data will not be 
distributed to the sites until after the patient has completed the Month 6 visit.  
2.4. 
Data Monitoring Committee 
An independent Data Monitoring Committee (DMC) will oversee the safety and overall conduct 
of this study, providing input to the Sponsor.  The DMC will operate under the rules of a charter 
that will be reviewed and approved by the DMC.  Details are provided in the DMC Charter. 
2.5. 
Study Procedures 
The Schedules of Assessments are described in the study protocol (Tables 1, 2, 3 and 4). 


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3. 
ENDPOINTS 
3.1. 
Primary Endpoints 
Cohort A 
• Percent change in plasma oxalate from baseline to Month 6 
Cohort B 
• Percent change in pre-dialysis plasma oxalate from baseline to Month 6 
3.2. 
Secondary Endpoints 
The following are the secondary endpoints in the Primary Analysis Period: 
Primary Analysis Period (Baseline to 6 months) 
• Percent change in plasma oxalate AUC between dialysis sessions (Cohort B) 
• Absolute change in plasma oxalate 
• Change in the following parameters: 
− Urinary oxalate, which is measured by percent and absolute change in 24-hour 
urinary oxalate excretion corrected for BSA and spot urinary oxalate:creatinine 
ratio, when available.  
− QoL assessed by the PedsQL Total Score for patients ≥2 to <18 years of age at 
consent, and as assessed by KDQOL Burden of Kidney Disease and Effect of 
Kidney Disease on Daily Life subscales, and SF-12 Physical Component 
Summary and Mental Component Summary, in patients ≥18 years at consent 
• Plasma PK parameters of lumasiran 
The following are the secondary endpoints in the Long-term Extension Period: 
Long-term Extension Period (6 months to end of study) 
• Percent change in plasma oxalate AUC between dialysis sessions (Cohort B) 
• Percent and absolute change in plasma oxalate 
• Change in the following parameters: 
− Nephrocalcinosis as assessed by renal ultrasound  
− Frequency and mode of dialysis (Cohort B) 
− Frequency of renal stone events 
− Urinary oxalate, measured by 24-hour urinary oxalate excretion corrected for 
BSA, and spot urinary oxalate:creatinine ratio  
− Renal function as assessed by eGFR (Cohort A) 
− Measures of systemic oxalosis in the following systems:  
 Cardiac 


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 Dermatologic 
 Skeletal 
 Ocular 
− QoL (quality of life) assessed by the PedsQL Total Score for patients ≥2 to <18 
years of age at consent, and as assessed by KDQOL Burden of Kidney Disease 
and Effect of Kidney Disease on Daily Life subscales, and SF-12 Physical 
Component Summary and Mental Component Summary, in patients ≥18 years at 
consent 
3.3. 
Exploratory Endpoints 
The following are the exploratory endpoints: 
• Growth parameters in patients who are <6 years of age at consent  
• Change in developmental milestones over time in patients <6 years of age at consent  
• Change in QoL as assessed by EQ-5D-Y and PedsQL (individual subscales of the 
generic and ESRD modules, and ESRD module total score) for patients ≥2 to 18 
years of age at consent, and as assessed by EQ-5D-5L in patients ≥18 years of age at 
consent  
• Change in QoL as assessed by KDQOL Symptoms and Problems of Kidney Disease 
subscale in patients ≥18 years of age at consent  
• Change in patient and caregiver resource use (eg, work/school attendance, visits to 
doctor/hospital)  
• Change in patient and caregiver experiences as evaluated by a patient experience 
questionnaire and a caregiver experience questionnaire  
• Frequency of ADA  
• Change in urinary and plasma glycolate, where urinary glycolate is measured by 
urinary glycolate:creatinine ratio 
3.4. 
Safety Endpoint 
• Frequency of AEs 


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4. 
PATIENT POPULATION 
4.1. 
Patient Definitions 
The populations (analysis sets) are defined as follows:  
• Safety Analysis Set:  All patients who received any amount of lumasiran during 
study. 
• Full Analysis Set: All patients who received any amount of lumasiran and have at 
least one evaluable plasma oxalate value (pre-dialysis in Cohort B) at baseline and at 
least one evaluable plasma oxalate value from assessment(s) at Month 3 through 
Month 6 
• PK Analysis Set: All patients who received any amount of lumasiran, have at least 1 
postdose blood sample for PK parameters, and have evaluable PK data.   
The Safety Analysis Set will be used for safety analyses and the sensitivity analysis of efficacy.  
The Full Analysis Set will be used to evaluate efficacy endpoints. The PK Analysis Sets will be 
used to conduct PK analyses.  
This study will consist of 2 periods: a 6-month Primary Analysis Period followed by a long-term 
(54 months) extension period. The Primary Analysis Period starts at the first date/time of 
lumasiran dose administration and ends at either the date/time of lumasiran dose administration 
at Month 6 (exception being that Month 6 assessments (eg,plasma oxalate and PK assessments) 
which occur after the Month 6 dose will be included) or the date of the Month 6 visit (Day 169) 
for patients who discontinued treatment prematurely. Primary analysis will be conducted using 
the Primary Analysis Period data collected through 6 months.   
The Long-term Extension Period, starts at the date/time of lumasiran dose administration at 
Month 6 and is through the end of the study.  Analysis of the Long-term Extension Period will 
focus on long-term efficacy and safety effects of lumasiran. 
Patients who discontinue from study drug during the 6-month Primary Analysis Period (defined 
above) will be encouraged to remain on the study and complete assessments (including plasma 
oxalate but excluding PK assessments) through Month 6. They will also be asked to complete 
safety follow-up visits, once every 3 months, per the safety follow-up schedule for up to 12 
months after the last dose of lumasiran. 
Patients who discontinue study drug after Month 6 will be asked to return for their next 
scheduled visit to complete early termination (ET) assessments and complete safety follow-up 
visits, once every 3 months, per the safety follow-up schedule for up to 12 months after the last 
dose of lumasiran. 
4.2. 
Protocol Deviations 
Protocol deviations will be classified into major or minor deviations by medical review. A major 
deviation is defined as a deviation that may significantly impact the completeness, accuracy 
and/or reliability of the trial data; that may significantly affect a patient’s rights, safety and well-
being (ICH.E3 R1 Structure and Contents of Clinical Study Reports Guidance for Industry. 
2013).  Deviations not classified as major will be assigned as minor. Major protocol deviations 


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will be reviewed and approved by Alnylam prior to an interim or full database lock. All protocol 
deviations will be presented in a listing. 
Major protocol deviations will be summarized in the CSR. 


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5. 
GENERAL STATISTICAL METHODS 
5.1. 
Sample Size Justification 
The planned enrollment for the study is 20 patients, including at least 6 patients in each cohort. 
Of those 20 patients, the planned enrollment includes at least 4 patients <6 years of age at 
consent, and at least 2 patients between ≥6 to <18 years of age at consent. 
The sample size was determined based on feasibility considerations, not power calculations.  
5.2. 
General Methods 
Continuous data will be described using descriptive statistics such as the number of observations 
(n), mean, standard deviation, standard error, median, quartiles, minimum, and maximum. For 
the summary statistics of all numerical variables unless otherwise specified, minimum and 
maximum will be displayed to the same level of precision as reported. Median and mean will be 
presented to the level of precision collected in the database plus one additional decimal. The 
standard deviation and standard error will be presented to the level of precision collected in the 
database plus 1 additional decimal.  For any assessments with repeated collections at a given 
study visit (eg height) the mean will represent the value at that visit unless otherwise noted. For 
biomarker and/or lab data, if any value is recorded as <lower limit of detection (LLOD) then the 
value assigned for calculations will be the LLOD. 
Categorical and ordinal data will be described using the patient count and percentages in each 
category. When count data are presented, the percentage will not be presented when the count is 
zero.  
Summaries of tables and figures for each study period will include all data collected during the 
corresponding period as defined in Section 4.1.  
The per-patient listings will include all data collected during each study period.  For per-patient 
listings of the extension periods, there will be a variable to indicate the period of the data 
collection (Primary Analysis Period or Extension Period).  
Day 1 will be defined as the day of the first dose of lumasiran. Study day is calculated relative to 
the first dose date of lumasiran for all patients:   
If the assessment date is after the date of first lumasiran dose, then the study day will be 
calculated as: 
Study Day = Date of assessment – date of first dose of lumasiran + 1, 
If the assessment date is before the date of the first dose of lumasiran, then the study day will be 
calculated as:  
Study Day = Date of assessment – date of first dose of lumasiran  
Summary statistics will be presented, as well as 2-sided 95% confidence interval (CI)s for 
primary/secondary endpoints or selected parameters, as described in the sections below.  
All data recorded on the CRF will be displayed in data listings. 


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5.3. 
Computing Environment 
All statistical analyses will be performed using validated SAS statistical software Version 9.4 (or 
later), unless otherwise noted.  
5.4. 
Baseline Definitions 
In Cohort A patients, the plasma oxalate baseline is defined as the mean of all plasma oxalate 
level values collected prior to the first dose of lumasiran. In Cohort B patients, the plasma 
oxalate baseline is similarly defined except that the values obtained from the plasma oxalate 
profile assessment visits will only include the first pre-dialysis sample collected per visit. 
For all patients who are not anuric (anuria is defined as <100 ml of urine per day), single-void 
urine samples (in triplicate) will be collected during screening, with the mean of values for the 
various parameters measured in these single-void samples used to establish baseline. In these 
patients, three 24-hour collections will be performed during Screening, with the median values of 
all the valid samples used to establish baseline urinary oxalate levels.  
A 24-hour urine collection will be considered valid if each of the following criteria are met: 
• The collection is between 18 to 26 hours in duration between the initial discarded 
void and the last void or attempt to void.  
• No voids are missed between the start and end time of the collection. 
• In patients not undergoing dialysis, the 24-hour creatinine content is at least 5 mg/kg 
for patients <6 years of age, and 10 mg/kg for patients ≥6 years of age as measured in 
the study central laboratory. 
In patients undergoing dialysis, 24-hour collections are not required to have a minimum 
creatinine content to be considered valid. 
Urine data collected from patients that are anuric is considered unreliable; thus there will be no 
analyses performed for patients that were anuric, from whom urine samples are not collected.    
In Cohort B, baseline plasma oxalate AUC measurements will be obtained via the plasma oxalate 
profile assessments prior to the first dose of lumasiran. Plasma oxalate profile assessments will 
be performed during Screening, with the mean value of all valid AUC profiles (see Section 7.3.1) 
being computed to establish the baseline AUC. 
For other parameters, baseline is defined as the last non-missing value prior to the first dose 
date/time of lumasiran, unless otherwise specified. The baseline value for any measurements 
with multiple values at a visit (eg labs, etc.) will be defined as the mean of all values collected on 
the most recent date of assessment prior to the first dose date/time of lumasiran. 
Parameters capturing disease history (eg reported history of renal stone episodes in the past 12 
months) at screening will represent the baseline value (adjusted events based on age category 
will be applied, see Section 10.1). 
5.5. 
Missing Data  
Patients who discontinue the study treatment prior to Month 6 will be encouraged to remain on 
study and complete their remaining clinical visits (excluding PK assessments) through the visit at 


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Month 6 and only safety follow-up visits afterwards. All data collected regardless of whether it 
was collected before or after treatment discontinuation will be used for efficacy analysis. 
However, it is possible that data will remain missing. 
Plasma oxalate AUC(0-24h) is considered missing if a plasma sample from any of the four, key 
collection timepoints (ie, pre-dialysis, 30 minutes before the end of dialysis, 4 hours postdose, 
and 24 hours post dialysis) is missing. Linear interpolation or extrapolation may be applied to 
determine the availability of values for these timepoints, if appropriate. For calculation of an 
AUC for plasma oxalate profile, details are provided in Section 7.3.  
For safety analyses, no date will be assigned to any AEs with fully missing dates or partially 
missing dates. An AE will be considered treatment emergent unless it can be unequivocally 
determined (from the partial onset date and/or a partial or complete stop date) that the event 
occurred prior to the first dose of lumasiran.  
For medications with partial start or stop dates: the first day/month will be imputed for start date, 
and the last day/month will be imputed for stop date. For medications with a completely missing 
start date, the medications will be considered as started prior to the first dose of study drug in this 
study; medications will be classified as prior or both prior and concomitant depending on the 
medication stop dates. If any medications have a completely missing stop date, then the 
medication will be assumed as ongoing. 
For partial dates of renal stone events (start and stop dates): the first day/month will be imputed 
for start date, and the last day/month will be imputed for stop date. It is not expected that renal 
stone dates will be completely missing. 
Due to blood sample volume limitations related to patient age/size, missing data in blood sample 
tests are expected.  
The following are considerations for the evaluability of plasma oxalate due to potential post-dose 
dialysis treatments in Cohort A. 
• If a Cohort A patient has at least one plasma oxalate value during Months 3-6 with 
intervening transient dialysis (<=2 weeks), then the patient’s plasma oxalate values 
that are prior to dialysis and at least 48 hours after the end of the last dialysis session 
are evaluable and will be included in primary analysis.  
• If a patient has at least one plasma oxalate value during Months 3-6 before long-term 
(>2 weeks) dialysis, then: 
− The patient’s plasma oxalate values before the start of dialysis are evaluable and 
will be included in the primary analysis  
− The patient’s plasma oxalate values after the dialysis are unevaluable and will be 
excluded from the primary analysis 
• If a Cohort A patient begins long-term (>2 weeks) dialysis between baseline and 
Month 3, then the patient’s plasma oxalate values post dialysis are unevaluable. 
Hence, the patient will be excluded from primary analysis for Cohort A and only 
included in sensitivity analysis 


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• If a Cohort A patient begins transient (≤2 weeks) dialysis between baseline and 
Month 3, then: 
− Data collected during the patient’s dialysis and recovery period (48 hours) are 
unevaluable and will be set as missing and be excluded from the primary analysis 
− The remainder of the patient’s data including baseline to Month 6 are evaluable 
and will be used in the primary analysis  
The following are considerations for the evaluability of plasma oxalate due to potential dialysis 
modification (clinically significant change in dialysis prescription as assessed by investigator, 
e.g., frequency or access modality such as catheter to AV fistula) in Cohort B. 
• If a Cohort B patient’s dialysis is modified for at least 4 weeks after the Month 3 
assessment, plasma oxalate collected before dialysis modification are evaluable and 
will be included in the primary analysis. Data collected after the dialysis modification 
will be censored.  
• If a Cohort B patient’s dialysis is modified for at least 4 weeks prior to the Month 3 
assessment, patient data after modification of dialysis are considered unevaluable. 
Hence, the patient will not be included in primary analysis, but will be included in 
safety analysis set for the sensitivity analysis. 
• If a Cohort B patient's dialysis regimen is modified for less than 4 weeks (from the 
start of the change to the resumption of the prior dialysis regimen), plasma oxalate 
values during this modification or within 48 hours following the resumption of the 
prior dialysis regimen are considered unevaluable and will not be included in the 
primary analysis. 
Data collected after an organ transplant or protocol prohibited treatment may be censored for 
analysis. 
5.6. 
Visit Windows 
For tabular and graphical summaries, all data will be tabulated and analyzed per the evaluation 
visit as recorded on the electronic case report forms (eCRF) even if the assessment is outside of 
window.  
Unless otherwise specified, data collected at an unscheduled visit will be included in by-patient 
listings and/or spaghetti plot figures, but no assignment of the scheduled visit will be made for 
the purposes of summary tabulations. However, unscheduled study visits will be used in the 
calculation of baseline values if prior to first dosing and for any categorical shift tables (eg shift 
from baseline to worst post-baseline value). 


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The following are time windows for the analysis of Plasma Oxalate Profile samples in Cohort B: 
Blood Collection Sampling time 
Window 
Pre-Dialysis 
Prior to dialysis on the same day as the dialysis 
30 minutes before end of dialysis 
from 1 hour prior to end of dialysis through the end 
of dialysis 
30 minutes post-dialysis 
after the end of dialysis through 1 hour post-dialysis 
2 hours post-dialysis 
>1 hour post-dialysis through 3 hours post-dialysis 
4 hours post-dialysis 
>3 hours post-dialysis through 6 hours post dialysis 
8 hours post-dialysis 
>6 hours post-dialysis through 10 hours post-
dialysis 
12 hours post-dialysis 
>10 hours post-dialysis through 16 hours post-
dialysis 
24 hours post-dialysis 
>18 hours post-dialysis through pre-dialysis the 
next day (if dialysis session scheduled day after 
current dialysis) or 29 hours post-dialysis (if no 
dialysis session scheduled day after current dialysis) 
 
5.7. 
Interim Analysis 
Potential interim database extractions may be planned for lumasiran regulatory submission 
purposes and/or publication requests.  
5.8. 
Analysis for Primary Endpoint and Database lock  
As this study will be ongoing at the time of the primary analysis, the study database will have a 
Primary Analysis Period database lock when the last patient completes all Month 6 visit 
assessments. All data entered as of the date of the Primary Analysis Period database lock will be 
included in the summary of the Primary Analysis Period CSR.  
After the study is completed (ie all patients complete the Long-term Extension Period and/or 
required safety follow-up visit(s)), the final database lock will occur, and all data will be 
summarized in a final CSR.  


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6. 
STUDY ANALYSES 
6.1. 
Patient Disposition 
Number and percentage of patients will be tabulated by Cohort for the following categories:  
• Safety Analysis Set 
• Full Analysis Set 
• PK Analysis Set 
Summaries of the number and percentage of patients who discontinued treatment and/or 
withdrew from the study will be presented, along with the primary reasons for discontinuation of 
treatment and/or withdrawal from the study. Additionally, the number of patients who completed 
the Month 6 visit will also be displayed. A patient is defined as having completed the Month 6 
visit if the patient has at least one blood sample for plasma oxalate (Cohort A) or pre-dialysis 
plasma oxalate (Cohort B) for the Month 6 visit.  
An individual patient is considered to have reached the end of the study if: 
• the patient has completed the end of study (EOS; Month 60) visit, or 
• the patient has completed 12 months of monitoring following the final lumasiran 
dose. 
The number and percentage of patients enrolled by country and site will be summarized.  
Data listings of those patients who withdrew and/or discontinued treatment including the 
associated reasons will also be presented. Disposition will be summarized throughout the study. 
All disposition analyses will be presented by cohort. 
6.2. 
Demographics and Baseline Characteristics 
Descriptive statistics of demographic characteristics including but not limited to: age, weight 
(kg), weight category (0-<10kg, 10-<20kg, ≥20kg), gender, race, ethnicity, region, height (cm), 
and body mass index (BMI) will be presented. The modified Z-score for patients under age 18 
will be calculated and summarized for height, weight and body mass index (BMI) according to 
the Centers for Disease Control and Prevention (CDC) growth chart.[CDC National Center for 
Health Statistics 2019] 
Additional disease characteristics will be summarized using descriptive statistics. These include 
but are not limited to: spot urinary oxalate:creatinine ratio (mmol/mmol), plasma oxalate 
(umol/L), plasma oxalate AUC [umol/L/24hr] (Cohort B only), 24-hour urinary oxalate excretion 
corrected for BSA (mmol/24hours/1.73m2), 24-hour urinary oxalate:creatinine ratio 
(mmol/mmol), eGFR (Cohort A only), spot and 24 hr. urinary glycolate:creatinine ratio 
(mmol/mmol), plasma glycolate (nmol/L), number of episodes with renal stone events,  number 
of patients reporting pyridoxine (vitamin B6) use at the time of study entry, and presence of 
systemic oxalosis (Cohort B).    
All analyses will be presented by Cohort. 


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6.3. 
Medical History 
A complete medical and surgical history will be collected at the screening visit. The medical and 
surgical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA 
Version 21.1 or later) and will be summarized for the Safety Analysis Sets.  
A tabular summary of historical disease characteristic information will be generated and include 
information on disease characteristics such as: time from diagnosis to first dose date (months), 
time from first symptoms to first dose date (months), time from first symptoms to diagnosis 
(months), number of siblings with PH1, reported history of disease events (eg pyelonephritis, 
renal stones, kidney stones, urinary tract infection). Reported medical history events may be 
adjusted based on age category, see Section 10.1. 
Separate by-patient listings will be generated.  
6.4. 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the World Health Organization (WHO) 
Drug Dictionary (September 2018 or later). Prior medications are defined as medications that 
were taken prior to and were either ongoing at the time of or stopped before the first dose of the 
study medication. Concomitant medications are defined as medications which were taken prior 
to and were ongoing while on lumasiran or medication(s) taken on or after the first dose date of 
the lumasiran.  
A tabular summary of the number and percentage of subjects taking concomitant medications 
will be generated by anatomic therapeutic class (ATC) and preferred term. Data will be 
presented for the Safety Analysis Set.  
By-patient listings will be generated separately for prior medications, concomitant medications 
and pyridoxine (vitamin B6). By-patient listings for crystallization inhibitors and erythropoietin 
(EPO) stimulating agents may also be provided.    


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7. 
STATISTICAL ANALYSIS 
All endpoints in ALN-GO1-005 will be analyzed by Cohort. 
7.1. 
Primary Endpoint 
The primary objective in Cohort A is to evaluate the effect of lumasiran on plasma oxalate in 
patients who are not on dialysis therapy. The primary objective in Cohort B is to evaluate the 
effect of lumasiran on pre-dialysis plasma oxalate levels in patients who are on hemodialysis 
therapy. The primary endpoint is percent change from baseline in plasma oxalate (Cohort A) / 
pre-dialysis plasma oxalate (Cohort B) to Month 6. 
The primary analysis in Cohort A will be performed using a restricted maximum likelihood 
(REML) based Mixed-effect Model Repeated Measures (MMRM) approach using the FAS. 
Analysis will include evaluable plasma oxalate values of all scheduled visits through Month 6, 
which will be modeled with fixed effects of scheduled visits and baseline plasma oxalate, 
including patient as a random factor. Autoregressive (1) will be used to model the within-patient 
error given the small sample size for this study. The primary estimate is the least square (LS) 
mean of the percent change in plasma oxalate from baseline at Month 3 to Month 6, averaged 
over these timepoints. This LS mean will be presented along with corresponding standard errors 
(SEMs), 95% confidence intervals (CI) and p-value from the model (ie, testing against the null 
hypothesis of mean of primary outcome being equal to 0).  
If the fit of the autoregressive (1) covariance structure matrix fails to converge, the primary 
estimate is the LS mean of the primary outcome variable average across scheduled visits from 
Month 3 to Month 6, according to analysis of covariance (ANCOVA) model with covariate of 
baseline plasma oxalate. This LS mean will be presented along with corresponding SEMs, 95% 
CI and p-value from the model.     
The primary analysis in Cohort B will be performed using a REML based MMRM approach 
using FAS. Analysis will include evaluable pre-dialysis plasma oxalate values of all scheduled 
visits through Month 6, which will be modeled with fixed effects of scheduled visits and pre-
dialysis baseline plasma oxalate, including patient as a random factor. Autoregressive (1) will be 
used to model the within-patient error given the small sample size for this study. The primary 
estimate is the LS mean of the percent change in plasma oxalate from baseline at Month 3 to 
Month 6, averaged over these timepoints. This LS mean will be presented along with 
corresponding standard errors (SEMs), 95% confidence intervals (CI) and p-value from the 
model (ie, testing against the null hypothesis of mean of primary outcome being equal to 0).  
If the fit of the autoregressive (1) covariance structure matrix fails to converge, the primary 
estimate is the LS mean of the primary outcome variable average across scheduled visits from 
Month 3 to Month 6, according to the ANCOVA model with covariate of pre-dialysis baseline 
plasma oxalate. This LS mean will be presented along with corresponding SEMs, 95% CI and p-
value from the model.     
For each cohort, descriptive statistics and LS mean will also be generated at each scheduled visit. 
Mean (+/- SEM) figures of percent reduction will be plotted as well as individual spaghetti plots. 
A table of the mean maximum percent reduction during the 6-months will also be generated. The 
forgoing analyses will be performed using data from Primary Analysis Period of each cohort.  


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7.1.1. 
Sensitivity Analysis  
Sensitivity analyses include: 
• Percent change from baseline in plasma oxalate (Cohort A) or pre-dialysis plasma 
oxalate (Cohort B) values to Month 6 by cohorts in Safety Analysis Sets 
The sensitivity analyses performed will be similar to that described for the primary analysis 
above but conducted using the Safety Analysis Set, of which the MMRM models include those 
patients who have no plasma oxalate assessment Month 3 or beyond.  
7.2. 
Subgroup Analysis 
Subgroup analyses will include analyses of primary endpoints by age groups and weight-based 
dosing groups defined according to the baseline values: 
Age group: <2 years, 2 to <6 years, 6 to <18years, ≥18 years 
Weight-based dosing category: <10 kg, 10 to <20 kg, and ≥20 kg. 
Other subgroups (eg, eGFR for Cohort A) may be examined, if deemed appropriate. Some 
subgroups (eg, age) may be collapsed due to the small number of subjects in each category.  
Subgroup descriptive statistical analysis (N, mean, standard error, median, min, max) will be 
conducted for primary analysis of percent change from baseline in plasma oxalate (Cohort A) / 
pre-dialysis plasma oxalate (Cohort B) summarized through Month 6 in Full Analysis Set.  
The subgroup analyses may be performed for secondary endpoints in Section 7.3.  
7.3. 
Secondary Endpoints 
For secondary efficacy endpoints, Full Analysis Set will be used; for secondary PK endpoints, 
the PK Analysis Set will be used.  
All secondary efficacy endpoints will be analyzed and reported with by-patient listings and by-
patient figures of actual values, change from baseline and percent change (where appropriate per 
endpoint) at each visit. Tabular summaries using descriptive statistics (N, mean, standard error, 
median, min, max) will be reported. For binary endpoints, the number and percentages of 
patients in each category will be displayed at each visit. Other analyses may be generated if 
applicable.  
7.3.1. 
Percent Change from Baseline to Month 6 in Plasma Oxalate AUC between 
Dialysis Sessions 
The objective of the AUC analysis in Cohort B is to evaluate the effect of lumasiran on the 
change from baseline in plasma oxalate AUC for a patient between dialysis sessions. The plasma 
oxalate profile assessment consists of an overnight visit requiring collection of up to 8 blood 
samples for plasma oxalate over the course of a 24-hour span. The plasma oxalate AUC will be 
measured during screening to establish baseline, Month 3, and Month 6 in the Primary Analysis 
Period, and at Month 12, Month 36, and Month 48 during the Long-term Extension Period. 
For patients in Cohort B, a secondary endpoint of percent change from baseline in plasma 
oxalate AUC(0-24h) will be summarized at Month 6.  Plasma oxalate AUC(0-24h) is defined as 


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the plasma oxalate area under the curve of the 24 hour window after the pre-dialysis assessment. 
The AUC(0-24h) plasma oxalate assessment for a patient visit will be considered valid only if 
both of the following criteria are met: 
• Results are available from at least the four key sampling collection timepoints 
(specifically, pre-dialysis (t = 0), 30 minutes before the end of dialysis (t ~ 4 hr), 4 
hours postdose (t ~ 8 hr), and 24 hours post dialysis (t ~ 24 hr);  
• The number of days since last dialysis session for a given post-baseline profile is the 
same as the number of days since last dialysis session during the screening period. 
AUC(0-24h) will be calculated using plasma oxalate results with the linear-trapezoidal method 
using actual collection times relative to pre-dialysis sampling time. An exact 24h assessment for 
the purpose of calculating the AUC(0-24h) will be calculated using linear interpolation or 
extrapolation on the two non-missing scheduled assessments closest to the 24-hour timepoint.  
Plasma oxalate profiles will be compared across visits within patients. LS mean percent change 
from baseline plasma oxalate AUC(0-24h) at Month 6 and its associated 95% confidence interval 
will be estimated using MMRM model including data evaluated at Month 3 and Month 6. 
Additionally, the AUC(0-24h) parameter will be listed and descriptively summarized by study 
visit. The Full Analysis Set will be used for this analysis. A similar approach as used for the 
primary analysis will apply, in case when the model fails to converge.  
Additionally, AUC(4-24h) will be similarly analyzed. AUC(4-24h) is defined as the plasma 
oxalate area under the curve of the 20 hour window from the end of dialysis (30 minutes before 
the end of dialysis assessment) until the next dialysis session (24h timepoint). This approach is 
intended to reduce the variability introduced by different dialysis parameters between patients. 
The percent change from baseline in plasma oxalate AUC(4-24h) will be summarized through 
Month 6 in a similar manner to the percent change from baseline in plasma oxalate AUC(0-24h) 
as a sensitivity analysis to the secondary endpoint. The pre-dialysis scheduled assessment will 
not be required for a valid AUC or utilized in this assessment, otherwise this analysis will remain 
consistent with methodology to assess the percent change from baseline in plasma oxalate 
AUC(0-24h).   
7.3.2. 
Change from baseline to Month 6 in other Plasma and Urinary Oxalate 
Parameters  
The analyses for the following secondary endpoints will also be performed using a restricted 
maximum likelihood based Mixed-effect Model Repeated Measures approach.  
• Absolute change from baseline to Month 6 in plasma oxalate during the Primary 
Analysis Period  
• Percent change and absolute change from baseline to Month 6 in 24-hr urinary 
oxalate corrected for BSA during the Primary Analysis Period  
• Percent change and absolute change in spot urinary oxalate: creatinine ratio during 
the Primary Analysis Period  
Analysis by cohort will include evaluable assessments through Month 6, which will be modeled 
with fixed effects of scheduled visits and baseline covariate of corresponding assessment, 








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Descriptive statistics for the actual and change from baseline will be presented for each 
scheduled visit.  
7.4.4. 
Patient and Caregiver Resource Use 
The patient caregiver resource use (eg, work/school attendance, visits to doctor/hospital) will be 
summarized descriptively for each scheduled visit. 
7.4.5. 
Patient and Caregiver Experience  
The patient caregiver experience will be summarized descriptively for each scheduled visit. 
7.4.6. 
Anti-drug Antibody 
Analysis of ADA is included in Section 7.7. 
7.4.7. 
Percent and Absolute Change from Baseline in Urinary and Plasma Glycolate 
The percent and absolute change from baseline in plasma glycolate and spot urinary glycolate: 
creatinine ratio will each be summarized at each scheduled assessment. 
7.5. 
Pharmacokinetic Analysis 
Pharmacokinetic analyses will be conducted using noncompartmental methods. PK parameters 
will be calculated using a validated version of Phoenix® WinNonlin.  
7.6. 
Safety Analyses 
Primary safety analysis is a descriptive summary of frequency of AEs using the Safety Analysis 
Set. Other safety parameters will include vital signs, ECGs, clinical laboratory assessments and 
physical exams. 
Safety analysis will be conducted for the Primary Analysis Period and extension period.  
7.6.1. 
Adverse Events 
The primary safety parameter is treatment emergent AEs. A treatment emergent AE will be 
defined as an AE that occurs or worsens on/after the first dose date/time of lumasiran through 84 
days after the last dose. In addition, any AE that worsened in intensity or was subsequently 
considered related to lumasiran will be considered treatment emergent.  
AEs will be classified using the Medical Dictionary for Regulatory Activities (MedDRA Version 
21.1 or later) and displayed in tables using System Organ Class (SOC) and Preferred Terms 
(PT). All treatment emergent AEs hereafter will be referred to as AEs in this document.  
An overview table of AEs will be generated. The overview table will include the number and 
percentage of patients in categories such as, but not limited to:  
• At least 1 AE 
− At least 1 drug related AE  
• At least 1 severe AE 


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− At least 1 drug related severe AE  
• At least 1 Serious Adverse Event (SAE) 
− At least 1 drug related SAE  
• At least 1 AE leading to treatment discontinuation 
− At least 1 drug related AE leading to treatment discontinuation  
• At least 1 AE leading to study withdrawal 
− At least 1 drug related AE leading to study withdrawal 
• At least 1 AE leading to treatment interruption 
− At least 1 drug related AE leading to treatment interruption  
• Death 
Tabulations by System Organ Class (SOC) and Preferred Term (PT) displaying the number of 
patients (percentage) and total events will be produced for the following tables:  
• All AEs 
• Severe AEs 
• AEs by Maximum Severity 
• AEs related to treatment 
• AEs related to treatment by Maximum Severity 
• All SAEs 
• SAEs related to treatment 
• AEs leading to treatment discontinuation 
• AEs leading to treatment interruption 
• AEs leading to study withdrawal  
Tabulations by PT in decreasing order of frequency will be generated for the following tables:  
• All AEs 
• All SAEs 
• AEs related to treatment 
• SAEs related to treatment 
There will also be an All AE table generated displaying rates of AEs adjusted for exposure-time.  
Patients who report multiple occurrences of the same AE (preferred term) will be classified 
according to the most severe occurrence or most related.  
Separate listings will be provided for deaths, SAEs, and AEs leading to discontinuation of study 
drug, withdrawal of study drug and/or dose interruption. By-patient AE listings will be provided.  


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Additional summaries will also be generated:  
Injection Site Reactions [ISRs]: AEs mapping to the High-Level Term (HLT)= “Injection Site 
Reactions” using MedDRA dictionary will be included in the summary. Frequency (percentages) 
of ISRs by HLT and PT will be generated. A separate listing will be generated to display all 
patients who reported ISRs. In addition, a table of the number of patients with at least 1 ISR, 
total number of doses ( any dose split into multiple injections will be considered 1 dose), total 
number of doses with ISRs and corresponding % of injections with ISR with the most common 
signs and symptoms reported due to ISRs will be generated. 
Hepatic AEs, including Liver Function Test (LFT) abnormalities: Analysis of hepatic AEs 
will include AEs mapping to the Standardized MedDRA Query (SMQ) Drug-related hepatic 
disorders - comprehensive search (includes all narrow and broad terms). Frequency (percentages) 
of Drug-related hepatic disorders will be summarized by SOC and PT.  A separate listing will be 
generated of all patients reporting these events. 
7.6.2. 
Dosing and Extent of Exposure  
Summaries of exposure will include the following characteristics such as, but not limited to: the 
total number of doses received per patient, mean number of doses per subject, cumulative 
number of doses received, duration of drug exposure (months), cumulative drug exposure time 
(months), the total dose administered (mg) and total volume administered (mL).   
Definition of drug exposure (days) will be defined as the minimum of [Exposure time= (date of 
last exposure – date of first dose +1)] where date of last exposure will represent either the date of 
the last dose administered dose +84, analysis cut-off date or end of study date, whichever occurs 
first.  The exposure during the Primary Analysis Period will be right censored; that is, the date of 
the last exposure will not be later than the first date of dosing in the Extension Period. 
Dose interruptions and compliance are not taken into account. 
7.6.3. 
Clinical Laboratory Data 
Clinical laboratory parameters will be expressed in Standard International (SI) units. Laboratory 
data collected and recorded as below the lower limit of detection (LLOD) will be set to the 
LLOD for calculation of summary statistics. Summaries will only include data from central 
laboratory.  For any local collections of LFTs, these will be included in a separate data listing.  
Key laboratory parameters will be graded according to NCI CTCAE v5.0 or later. 
Summaries for each lab parameter (hematology, chemistry, liver function tests, and urinalysis) 
that are continuous variables, will have a tabular summary of descriptive statistics at each 
scheduled visit. Descriptive statistics include actual value, change from baseline and percent 
change from baseline at each scheduled visit. 
Shift tables will be generated to summarize shifts from baseline category to the worst post-
baseline category with directionality specified (eg hyper and hypo), including eGFR when 
applicable.    
Clinical laboratory tests with normal ranges will be classified as Low, Normal, and High. For 
these tests, abnormal values will be flagged in the listings with H when the value is higher than 


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the upper limit of the reference ranges and with L when the value is lower than the lower limit of 
the reference ranges.  
For hematology and chemistry labs, summary tables of potentially clinically significant 
abnormalities may also be provided.  
All laboratory data will be presented in data listings. Separate listings will be included for those 
laboratory data collected from local labs such as LFTs. Out of range laboratory results will be 
identified in listings.   
LFTs: A listing will be generated for all patients with abnormal liver function tests as defined by 
alanine aminotransferase (ALT)>3xULN, aspartate aminotransferase (AST)>3xULN or total 
bilirubin >2x ULN at any visit, where age specific ULN (when applicable) may be used.  
A tabular summary for LFTs will be generated to summarize the number and associated 
percentage of patients in each of the categories at any post-baseline visit:  
• Within normal limit (WNL), 1<ALT≤3, 3<ALT≤5, 5<ALT≤10, 10<ALT≤20, 
ALT>20xULN 
• WNL, 1<AST≤3, 3<AST≤5, 5<AST≤10, 10<AST≤20, AST>20xULN 
• WNL, 1<ALT or AST≤3, 3<ALT or AST≤5, 5<ALT or AST≤10, 10<ALT or 
AST≤20, AST or ALT>20xULN 
• WNL, ALP>1.5xULN 
• WNL, 1.5<Total Bilirubin ≤2, 2<Total Bilirubin≤3, 3<Total Bilirubin≤5 and Total 
Bilirubin>5x ULN 
eDISH plots of peak bilirubin at any time versus peak ALT or AST at any time will also be 
presented. 
For selected labs (eg ALT/ULN and AST/ULN), a table and figure of the values across the entire 
study will be generated.  
7.6.4. 
Vital Signs 
Descriptive statistics for each vital sign (eg systolic blood pressure, diastolic blood pressure, 
pulse rate, body temperature, respiratory rate, height, weight, body mass index) will be 
summarized at scheduled visits. Summaries will include actual values and changes from 
baseline. A summary table of potentially clinically significant shifts in vital signs will be 
generated. 
For any patient < 18 years old at screening, a summary table of descriptive statistics of modified 
z-scores of patient height, weight, and BMI by visits will be generated. A tabular summary of the 
proportion of patients with z-scores at various cut-points (ie ≥ ±2 SD) will also be generated.   
A by-patient listing of vital sign data will be generated. Per patient plots of z-scores over time 
may also be generated.  
7.6.5. 
Physical Examinations 
 Full physical examinations and symptom-directed physical examinations will be conducted 
throughout the study. Clinical significant abnormalities observed during the physical 


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examination are recorded on the medical history or AE eCRF as appropriate. A separate listing 
per patient will be generated to display the date and time of the physical exam.  
7.6.6. 
Electrocardiogram   
Electrocardiogram (ECG) parameters include rhythm, ventricular rate, PR interval, QRS 
duration, QT interval, and QTc interval. Corrected QT interval (QTc), if not collected, will be 
calculated using the Fridericia’s correction formula. 
Fridericia’s cube-root corrected QT: QTcF (ms) = QT (ms) × 3
60
)
(bpm
HR
.  
The number and percentage of patients with normal, abnormal, and clinically significant 
abnormal results at baseline and each timepoint will be summarized. For electrocardiogram 
parameters, these will be summarized using descriptive statistics for actual values and for 
changes from baseline by scheduled time of evaluation. Baseline, post baseline maximum QTcF 
and post baseline maximum change from baseline in QTcF during the study will be summarized 
with descriptive statistics. The incidence of notable ECG changes from baseline in maximum 
absolute QTcF, intervals (≤ 450, > 450, > 480, and > 500 ms) over all post-treatment evaluations, 
as well as in QTcF, maximum changes from baseline (≤ 30 ms, > 30-60 ms and > 60 ms) over all 
post-treatment evaluations will be summarized.  
A listing of all ECG data will be provided. 
7.7. 
Anti-Drug Antibody  
The number and associated percentage of patients who have confirmed ADA positive results at 
baseline and/or any post-baseline visit will be summarized. A listing of patients with ADA 
positivity with their AEs will be provided.  
A listing of all ADA data with associated titers will be provided.  
7.8. 
COVID-19 Pandemic Impact Analyses  
Additional data were collected to characterize the impact of the COVID-19 pandemic on general 
study conduct, disposition, and subsequently additional analyses and summaries will be provided 
in acknowledgement of multiple regulatory guidance (FDA Guidance on Conduct of Clinical 
Trials of Medical Products during COVID-19 Pandemic: Guidance for Industry, Investigators, 
and Institutional Review Boards, US Food and Drug Administration, 2020; Statistical 
Considerations for Clinical Trials During the COVID-19 Public Health Emergency, US Food 
and Drug Administration, 2020; Guidance on the Management of Clinical Trials during the 
COVID-19 (Coronavirus) Pandemic, European Medicines Agency, 2020; Points to consider on 
implications of Coronavirus disease (COVID-19) on methodological aspects of ongoing clinical 
trials, European Medicines Agency, 2020). 
7.8.1. 
General Impact  
Patients who discontinue treatment or stop study participation due to the COVID-19 pandemic 
will be included in patient disposition summaries. Impact on study participation due to the 
COVID-19 pandemic, including visit completion, visit location changes, and study drug dosing 


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and location changes, will be summarized overall on the patient level, and overall and by visit on 
the event level.  
7.8.2. 
Impact on Efficacy  
The final analyses will include COVID-19 pandemic impacted efficacy analyses. These analyses 
will evaluate the impact of changes in the visit windows for the efficacy assessments made in 
protocol amendment 1 (dated 06 May 2020) due to the COVID-19 pandemic. Missing efficacy 
data due to the COVID-19 pandemic will be summarized.   
For the primary analysis, the primary and secondary endpoints missed or assessed out of the 
original protocol window will be noted in the efficacy subject listing.  
7.8.3. 
Impact on Adverse Events  
An overall summary of AEs mapping to a COVID-19 custom query will include the number and 
percentage of patients, as well as events and event rates, with any AE, any AE related to study 
drug, any severe AE, any severe AE related to study drug, any SAE, any SAE related to study 
drug, any AE leading to treatment discontinuation, any study drug related AE leading to 
treatment discontinuation, any AE leading to study withdrawal, any study drug related AE 
leading the study withdrawal, and any deaths. AEs mapping to the COVID-19 custom query will 
be summarized by high level term and preferred term. Due to the evolving nature of COVID-19-
related MedDRA terminology, the COVID-19 custom query will be based on the latest 
information available at the specified time points. For patients reporting an AE mapped to the 
COVID-19 custom query, prior medications and concomitant medications will also be presented 
in separate data listings. 
An overall summary of AEs by COVID-19 pandemic phase (ie, pre-, during, post) will include 
the number and percentage of patients, as well as events and event rates, with any AE and any 
SAE. Events will be considered during the COVID-19 pandemic if the event occurs on or after 
the first confirmed case of COVID-19 based on the country where the study site is located, 
described in Section 10.3. 
7.8.4. 
Other Impacts  
Treatment duration may also be summarized by pandemic phase. Protocol deviation due to 
COVID-19 pandemic will be summarized and will be indicated in the listing of protocol 
deviations.  


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8. 
CHANGES TO PLANNED ANALYSES  
Summary of Changes 
Rationale 
The PK analysis set definition was updated. 
The definition in the protocol 
was updated in the Protocol 
Amendment 1 dated 06May2020 
The Sample Size was modified. 
The sample size in the protocol 
was changed in the Protocol 
Amendment 1 dated 06May2020 
Changes were made in sections 5.5, 5.6, and 7.3.1 to 
clarify the analyses related to plasma oxalate AUC. 
Provided additional details for 
plasma oxalate AUC related 
definitions, derivations, and 
analyses. 
Subsections in 7.3 and 7.4 were provided for various 
endpoints including secondary endpoint analyses during 
the extension period, exploratory efficacy analyses for the 
quality of life and patient and caregiver resource use 
endpoints. 
This modification was made to 
improve readability. 
Cardiac Systemic Oxalosis at Month 6 was added to the 
exploratory endpoints. 
To specify the analysis for the 
primary analysis period. 
A section was added for the COVID-19 Pandemic 
Analyses. 
The COVID-19 pandemic 
occurred after the original SAP. 
The COVID-19 Pandemic Phase Start Dates by Country 
was added to the appendix. 
This information was not in the 
original SAP. 
Various editorial changes were made. 
To improve clarity 
 


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9. 
REFERENCES 
Clinical Growth Charts [database on the Internet]. CDC. 2019 [cited 12 Nov 2019]. Available 
from: https://www.cdc.gov/growthcharts/clinical_charts.htm. 
Cochat P,Rumsby G. Primary hyperoxaluria. N Engl J Med. 2013 Aug 15;369(7):649-58. 
Harambat J, Fargue S, Acquaviva C, Gagnadoux MF, Janssen F, Liutkus A, et al. Genotype-
phenotype correlation in primary hyperoxaluria type 1: the p.Gly170Arg AGXT mutation is 
associated with a better outcome. Kidney Int. 2010 Mar;77(5):443-9. 
van der Hoeven SM, van Woerden CS,Groothoff JW. Primary hyperoxaluria type 1, a too often 
missed diagnosis and potentially treatable cause of end-stage renal disease in adults: results of 
the Dutch cohort. Nephrol Dial Transplant. 2012 Oct;27(10):3855-62. 
 


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10. 
APPENDICES 
10.1. 
Medical History Adjustment 
Baseline disease history within the preceding year is required at enrollment. For infants less than 
one year old, reported values may need to be adjusted to represent a medically meaningful 
baseline value. Below is an example of the adjustment criteria to be used in such situations, for 
the outcome of renal stone events: 
1. Patients less than 6 months old, baseline records will be presented in by-patient listings, 
however will not be used in summary tables 
2. Patients (≥0.5 and <1 year old): Annualized rate will be calculated from reported data 
ie if a patient of 8 months old has had 2 renal stone events prior to screening, his/her 
renal stone event rate at baseline will be 2*(8/12) = 3 events per year 
3. Patients (≥1 year old): records at screening for the preceding year will be used to 
calculate baseline annual stone event rate without adjustment 
10.2. 
Category of Vineland Adaptive Behavior Scale 
Vineland adaptive behavior composite scores are collected and summarized using Vineland-II. 
The adaptive level of the composite scores can be categorized from “Low” to “High” in the table 
below. 
Adaptive Level of Vineland Composite Scores 
Adaptive Level 
v-Scale 
Standard Score 
Low 
1 to 9 
20 to 70 
Moderately Low 
10 to 12 
71 to 85 
Adequate 
13 to 17 
86 to 114 
Moderately High 
18 to 20 
115 to 129 
High 
21 to 24 
130 to 160 
10.3. 
COVID-19 Pandemic Phase Start Dates by Country 
These dates are as reported by the World Health Organization. 
Country 
Date of 1st Confirmed Case 
Australia 
26JAN2020 
Belgium 
04FEB2020 
France 
24JAN2020 
Germany 
28JAN2020 
Israel 
27FEB2020 


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Jordan 
02MAR2020 
Lebanon 
21FEB2020 
Netherlands 
28FEB2020 
Switzerland 
24FEB2020 
Turkey 
11MAR2020 
United Arab Emirates 
01FEB2020 
United Kingdom 
01FEB2020 
United States 
20JAN2020