Conditions: Primary Hyperoxaluria Type 1 (PH1)
Keywords: PH1 Primary Hyperoxaluria RNAi therapeutic siRNA AGT
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 52
Healthy volunteers: yes

Brief summary:
The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single-ascending doses (SAD) and multiple-ascending doses (MAD) of lumasiran in healthy adult volunteers and subjects with primary hyperoxaluria type 1 (PH1). In Part A, single ascending dose (SAD) part, healthy adults were dosed with lumasiran or placebo once. In Part B, multiple ascending doses (MAD) part, patients with primary hyperoxaluria type 1 (PH1) were dosed with lumasiran or placebo. All patients that initially received placebo received lumasiran after completing placebo dosing.

Detailed description:

Arms:
arm 1: A single dose of matching placebo will be administered subcutaneously (SC). arm 2: A single dose of 0.3 mg/kg lumasiran will be administered SC. arm 3: A single dose of 1.0 mg/kg lumasiran will be administered SC. arm 4: A single dose of 3.0 mg/kg lumasiran will be administered SC. arm 5: A single dose of 6.0 mg/kg lumasiran will be administered SC. arm 6: Participants with primary hyperoxaluria type 1 (PH1) will be treated with placebo matching one of the lumasiran dosages in the lumasiran arms (one placebo participant for each lumasiran arm). At Day 85 these placebo treated participants will cross over to their respective Part B lumasiran arms in the Part B: MAD Study Day 85-End of Study Period and will then be treated with lumasiran. The estimated total time on study was up to 546 days. arm 7: Participants with PH1 will be treated with 1.0 mg/kg lumasiran SC once monthly (qM) on Days 1, 29 and 57. The estimated total time on study is up to 546 days. One participant from the Part B: MAD: Placebo arm will cross over to this lumasiran arm at Day 85. For this participant treatment with lumasiran starts at Day 85. arm 8: Participants with PH1 will be treated with 3.0 mg/kg lumasiran SC qM on Days 1, 29 and 57. The estimated total time on study is up to 546 days. One participant from the Part B: MAD: Placebo arm will cross over to this lumasiran arm at Day 85. For this participant treatment with lumasiran starts at Day 85. arm 9: Participants with PH1 will be treated with 3.0 mg/kg lumasiran SC once every three months (q3M) on Days 1 and 85. The estimated total time on study is up to 546 days. One participant from the Part B: MAD: Placebo arm will cross over to this lumasiran arm at Day 85. For this participant treatment with lumasiran starts at Day 85.

Interventions: intervention 1: Lumasiran intervention 2: Placebo
Intervention descriptions: intervention 1: Lumasiran will be administered SC once in Part A. In Part B lumasiran will be administered SC qM (Days 1, 29 and 57) or q3M (Days 1 and 85). intervention 2: Matching placebo (sterile saline: 0.9% sodium chloride \[NaCl\]) will be administered SC once in Part A. In Part B matching placebo will be administered SC qM (Days 1, 29 and 57) or q3M (Days 1 and 85).

Protocol document:
Prot_001.pdf: 
 
 
Official Title:  
A Phase 1/2, Single‐Blind, Placebo‐Controlled, Single and Multiple 
Ascending Dose Safety, Tolerability, Pharmacokinetic and 
Pharmacodynamics Study of Subcutaneously Administered ALN‐GO1 in 
Healthy Adult Subjects, and Patients With Primary Hyperoxaluria Type 1  
 
NCT Number:    
NCT02706886 
 
Document Date:   
Clinical Study Protocol, Amendment 5, 14 February 2018 


ALN-GO1 
 
Clinical Study Protocol ALN-GO1-001 
 
 
Amendment 5_14 February 2018 
Alnylam Pharmaceuticals 
Confidential 
1 
 
 
CLINICAL STUDY PROTOCOL 
ALN-GO1-001 
 
Protocol Title: 
A Phase 1/2, Single-Blind, Placebo-Controlled, Single- and 
Multiple-Ascending Dose Safety, Tolerability, Pharmacokinetic and 
Pharmacodynamics Study of Subcutaneously Administered 
ALN-GO1 in Healthy Adult Subjects, and Patients with Primary 
Hyperoxaluria Type 1 
Investigational Drug: 
ALN-GO1 
EudraCT Number: 
2015-004407-23 
Protocol Date: 
Original Protocol 18 December 2015 
 
Amendment 1_01 July 2016 
 
Amendment 2_21 September 2016 
 
Amendment 3_09 December 2016 
Amendment 4_27 June 2017 
Amendment 5_14 February 2018 
 
Sponsor: 
Alnylam Pharmaceuticals, Inc. 
300 Third Street 
Cambridge, MA  02142 USA 
Telephone:  +1-617-551-8200 
Sponsor Contact:   
, MD  
 
 
 
The concepts and information contained in this document or generated during the study are considered 
proprietary and may not be disclosed in whole or in part without expressed written authorization of 
Alnylam Pharmaceuticals, Inc. 
 




ALN-GO1 
 
Clinical Study Protocol ALN-GO1-001 
 
 
Amendment 5_14 February 2018 
Alnylam Pharmaceuticals 
Confidential 
3 
INVESTIGATOR’S AGREEMENT 
 
I have read the ALN-GO1-001 protocol and agree to conduct the study as outlined.  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 


ALN-GO1 
 
Clinical Study Protocol ALN-GO1-001 
 
 
Amendment 5_14 February 2018 
Alnylam Pharmaceuticals 
Confidential 
4 
PROTOCOL SYNOPSIS 
Protocol Title 
A Phase 1/2, Single-Blind, Placebo-controlled, Single- and Multiple-ascending Dose Safety, 
Tolerability, Pharmacokinetic, and Pharmacodynamics Study of Subcutaneously Administered 
ALN-GO1 in Healthy Adult Subjects and Patients with Primary Hyperoxaluria Type 1 
Product Name 
ALN-GO1 
Indication 
Primary hyperoxaluria type 1 (PH1) 
Phase 
Phase 1/2 
Study center(s)   
The single-ascending dose (SAD) part in healthy adult subjects (Part A) will be conducted at 
1 clinical study center in the United Kingdom.  The multiple-ascending dose (MAD) part in patients 
with PH1 (Part B) is expected to take place at approximately 12 clinical study centers worldwide.  
Objectives 
Primary 
 
Evaluate the safety and tolerability of single- and multiple-ascending doses of ALN-GO1, 
respectively, in healthy adult subjects and in patients with PH1 
Secondary 
 
Characterize the pharmacokinetics (PK) of ALN-GO1  
 
Evaluate the pharmacodynamics (PD) of ALN-GO1  
Exploratory 
 
exploratory 
 
 
 
Study Design 
This is a randomized, single-blind, placebo-controlled study of subcutaneously administered 
ALN-GO1.  Subjects and patients will be randomized in a 3:1 ratio to receive either ALN-GO1 or 
placebo.  The study is designed to evaluate the safety, tolerability, PK, and PD of single- and 
multiple-ascending doses of ALN-GO1 and will be conducted in 2 parts: 
 
Part A:  SAD part in healthy adult subjects 
 
Part B:  MAD part in adult and pediatric patients with PH1 
In Part A, subjects in each cohort will be randomized to receive 1 dose of ALN-GO1 or placebo. 
In Part B, patients will be enrolled in up to 6 sequential dose cohorts to receive ALN-GO1 or placebo 
monthly or quarterly.  Patients dosed monthly will receive 3 doses of ALN-GO1 or placebo in a 
blinded fashion.  After completion of the blinded portion of the study, patients dosed monthly will be 
unblinded on or after Day 78.  Patients who initially received placebo will then receive 3 doses of 
open-label ALN-GO1 dosed monthly at the same dose administered to the cohort into which they 
were initially randomized and will follow the same assessment schedule.  Patients dosed quarterly will 
receive either ALN-GO1 or placebo on Day 1.  All patients in quarterly dosing cohorts, including 
those initially randomized to placebo, will receive open-label ALN-GO1 on Day 85 at the same dose 
administered to the cohort into which they were initially randomized.  Up to 2 expansion cohorts in 


ALN-GO1 
 
Clinical Study Protocol ALN-GO1-001 
 
 
Amendment 5_14 February 2018 
Alnylam Pharmaceuticals 
Confidential 
5 
Part B may be enrolled based on available safety and PD data; these patients will all receive open-
label ALN-GO1, not placebo. 
After the dosing period, patients will return to the clinical study center for continued safety, 
tolerability, PK, and PD monitoring for at least 12 weeks (84 days) following the last dose of study 
drug.  Following completion of the 12-week postdose follow-up period, patients will be invited to 
participate in an open-label extension study.   
For patients who do not enroll in the open-label extension study, safety and PD follow up will 
continue until 24-hour urinary oxalate is >80% of baseline, and plasma glycolate is <20% above 
baseline or ≤ the ULN.  If an investigator wishes to discontinue follow-up after completion of the 
postdose follow-up period and prior to oxalate and glycolate recovery, the Safety Review Committee 
(SRC) must agree based upon consideration of emerging data on the safety of ALN-GO1 knockdown 
and the individual patient’s safety and PD data.   
The SRC will perform ongoing reviews of safety, tolerability, and available PD data, with the primary 
purpose of protecting the safety of subjects/patients participating in this clinical study. 
Number of Planned Subjects and Patients 
A total of up to 64 participants (including optional and expansion cohorts) are planned to be enrolled 
in this study as follows: 
 
Part A:  Up to 40 healthy adult subjects 
 
Part B:  Up to 24 adult and pediatric patients with PH1 
Diagnosis and Main Eligibility Criteria 
Part A will include healthy subjects, aged 18 to 64 years, inclusive.  Part B will include patients 
diagnosed with PH1, aged 6 to 64 years, inclusive, with relatively well-preserved renal function.  
Diagnosis of PH1 will be based on the presence of alanine glyoxylate aminotransferase (AGXT) 
mutations or reduced hepatic AGT enzyme activity. 
Investigational Product, Dose and Mode of Administration 
ALN-GO1 is a synthetic, double-stranded small interfering RNA oligonucleotide directed against 
hydroxyacid oxidase 1 mRNA that is covalently linked to a ligand containing 3 N-
acetylgalactosamine residues.  ALN-GO1 will be supplied as a sterile solution for subcutaneous (SC) 
injection at a targeted concentration of 200 mg/mL.  The starting dose for Part A will be 0.3 mg/kg.  
The starting dose for Part B was determined to be 1.0 mg/kg by the SRC based on review of safety, 
tolerability, and available PD data, from Part A.  Additional cohorts may be enrolled at higher, lower, 
or intermediate dose levels, but will not exceed the maximum administered dose of 6.0 mg/kg, and 
will follow the protocol-specified dose escalation criteria. 
Reference Therapy, Dose and Mode of Administration 
Placebo will be supplied by the clinical study center as a sterile, preservative-free normal saline 0.9% 
solution for SC injection. 


ALN-GO1 
 
Clinical Study Protocol ALN-GO1-001 
 
 
Amendment 5_14 February 2018 
Alnylam Pharmaceuticals 
Confidential 
6 
Duration of Treatment and Overall Duration of Study 
The duration of treatment is as follows: 
 
Part A:  The estimated total time on study, inclusive of screening and safety and PD follow-up, 
for each subject is up to 405 days.  The duration of treatment is a single dose. 
 
Part B:  For all patients, the duration of screening is up to 45 days and the minimum duration of 
postdose follow-up is 84 days.  The duration of treatment and estimated total time on study, 
inclusive of screening, for each patient is as follows: 
 
For patients dosed monthly:  The duration of treatment for patients initially 
randomized to receive active study drug is 57 days.  The estimated total time on study 
is up to 462 days.  Additionally, the duration of treatment for patients initially 
randomized to receive placebo is 141 days.  The estimated total time on study for 
each patient initially randomized to receive placebo, then active study drug, is up to 
546 days.  
 
For patients dosed quarterly: The duration of treatment is 85 days for patients 
randomized to placebo and active study drug.  The estimated total time on study is up 
to 490 days. 
The overall duration of the study is estimated to be 4 years, including enrollment. 
Endpoints 
Primary 
 
The primary endpoint is the incidence of adverse events.  Safety will also be evaluated through 
vital signs, electrocardiograms, clinical laboratory assessments, and physical examinations. 
Secondary 
Secondary Endpoints for Part A 
o PK parameters (including, but not limited to, maximum plasma concentration [Cmax], 
time to reach maximum plasma concentration [tmax], area under the plasma 
concentration versus time curve [AUC], apparent terminal elimination half-life [t½], 
fraction eliminated in urine [fe/F], and renal clearance [CLR]) 
o Plasma and urine glycolate concentrations 
Secondary Endpoints for Part B 
o PK parameters including, but not limited to, Cmax, tmax, AUC, t½, fe/F, and CLR 
o Urinary oxalate excretion (oxalate concentration in 24-hour urine collection) 
o Urinary glycolate excretion (glycolate concentration in 24-hour urine collection) 
o Plasma glycolate concentration 
o Calculated creatinine clearance 


ALN-GO1 
 
Clinical Study Protocol ALN-GO1-001 
 
 
Amendment 5_14 February 2018 
Alnylam Pharmaceuticals 
Confidential 
7 
Exploratory 
 
Plasma oxalate concentration 
 
 
 
o 
 
o 
 
o 
 
Statistical Methods 
Statistical analyses will be primarily descriptive.  Data from Parts A and B will be analyzed 
separately.  Tabular summaries will be generated by dose level and dosing regimen of ALN-GO1 and 
placebo (pooled across all cohorts) for Part A and Part B (through Day 85). 
Safety and PD data will be summarized for Part B by dose level and dosing regimen of ALN-GO1 
compared to placebo for data collected up to, and including, study Day 85.  Data collected after 
Day 85 will be summarized separately for patients in quarterly dosing cohorts who receive a second 
dose of ALN-GO1 on Day 85.  Data from placebo patients from all cohorts will be combined.  
Additionally, all safety and PD data collected from all patients in Part B during the ALN-GO1 dosing 
period, regardless of treatment sequence, will be combined and summarized by ALN-GO1 dose level 
and regimen.  
Data collected beyond the designated dosing period will be summarized or presented in data listings. 
Descriptive statistics will be presented for continuous variables.  Frequencies and percentages will be 
presented for categorical and ordinal variables.  Percentages will be based on the number of 
non-missing values in a dose group.   
 


ALN-GO1 
 
Clinical Study Protocol ALN-GO1-001 
 
 
Amendment 5_14 February 2018 
Alnylam Pharmaceuticals 
Confidential 
8 
Table 1: Schedule of Assessments for Single-ascending Dose Cohorts in Healthy Subjects (Part A) 
Study Stage 
Screening 
Dosing Period 
Postdose Follow-up Period 
Safety and PD 
Follow-up
a 
Study Day  
Days -45 to -2 
Day -1
b 
Day 1 
Day 2
c 
Day 8 
Day 15  
Day 29  
Day 43 
Day 57/EOT
d 
Q28D 
Visit Window (days) 
 
 
 
 
 
(±2) 
(±3) 
(±3) 
(±3) 
(-2 to +5) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
Medical history
e 
X 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
Full physical examination
f 
X 
 
 
 
 
 
 
 
X 
 
Symptom-directed physical examinationf 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
Body weight and BMI
g 
X 
X 
 
 
 
 
 
 
X 
X 
Vital signs
h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG
i 
X 
X 
X 
X 
 
 
X 
 
X 
X 
Pregnancy test/FSH screening
j 
X 
X 
 
 
 
 
X 
 
X 
X 
Clinical laboratory assessments
k 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine sample for drugs of abuse
l 
X 
X 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
Study drug administration
m 
 
 
X 
 
 
 
 
 
 
 
Blood and urine samples for PK analyses
n 
 
 
X 
X 
 
 
 
 
 
 
Blood samples for PD analyses
o 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Blood and urine samples for exploratory 
 
 
 
X 
 
X 
 
X 
 
X 
 
Blood sample for ADA analysis 
 
 
X 
 
 
 
X 
 
X 
 


ALN-GO1 
 
Clinical Study Protocol ALN-GO1-001 
 
 
Amendment 5_14 February 2018 
Alnylam Pharmaceuticals 
Confidential 
9 
Table 1: Schedule of Assessments for Single-ascending Dose Cohorts in Healthy Subjects (Part A) 
Study Stage 
Screening 
Dosing Period 
Postdose Follow-up Period 
Safety and PD 
Follow-up
a 
Study Day  
Days -45 to -2 
Day -1
b 
Day 1 
Day 2
c 
Day 8 
Day 15  
Day 29  
Day 43 
Day 57/EOT
d 
Q28D 
Visit Window (days) 
 
 
 
 
 
(±2) 
(±3) 
(±3) 
(±3) 
(-2 to +5) 
Review/record AEs
p 
 
 
X 
Prior and concomitant medications 
X 
Abbreviations:  ADA=antidrug antibodies; AE=adverse event;; BMI=body mass index; D=Day; ECG=electrocardiogram; EOT=end of treatment; FSH=follicle-stimulating 
hormone; ICF=informed consent form; LFT=liver function tests; PD=pharmacodynamics; PK=pharmacokinetic; Q=every; SC=subcutaneous. 
 
Notes:   
 
When scheduled at the same time points, the assessments of vital signs and 12-lead ECGs must be performed first, before the physical examinations, blood sample 
collections, and urine collections. 
 
Assessments should be performed predose, where applicable, and unless otherwise noted. 
a Safety and PD follow-up will continue: 1) for at least 57 days, and 2) until plasma glycolate decreases to a level that is no more than 20% above of baseline or until plasma 
glycolate is below the upper limit of normal (≤14 nmol/mL). 
b Subjects will be admitted to the clinical study center for predose assessments. 
c Subjects will be discharged from the clinical study center following the completion of the assessments. 
d If a subject chooses to withdraw consent, every effort should be made to conduct the assessments performed at the EOT visit. 
e Complete medical history will be obtained at screening and any changes will be updated on admission to the clinical study center.  Events occurring after signing of the ICF and 
before study drug administration will be captured as medical history. 
f See Section 7.5.3 for assessments to be performed during a full physical examination or symptom-directed examination. 
g Day -1 body weight will be used for calculation of the ALN–GO1 or placebo (study drug) dose to be administered. 
h Vital signs (blood pressure, pulse rate, body temperature, and respiration rate) will be measured with the subject in the supine position after the subject has rested comfortably for 
10 minutes.  On Day 1 only, vital signs will be measured within 1 hour predose; and 30 (±5 minutes) and 4 hours (±15 minutes) postdose.  
i All 12-lead ECGs are triplicate.  Triplicate 12-lead ECGs will be measured approximately 5 minutes apart.  Recordings will be obtained after the subject has rested comfortably 
in the supine position for approximately 10 minutes.  Subjects should remain supine between ECGs.  ECGs should be performed at the same time of day throughout the study ±1 
hour.  On Day 1 only, ECGs will be measured predose and 1, 2, 3, and 4 hours postdose. 
j Pregnancy tests will be performed for women of childbearing potential only.  A serum pregnancy test will be performed at Screening and urine pregnancy tests will be performed 
thereafter per the Schedule of Assessments and any time pregnancy is suspected.  The results of the pregnancy test must be known before study drug administration.  FSH will be 
measured at Screening only to confirm post-menopausal status. 
k Biochemistry, hematology, coagulation, LFTs, and urinalysis parameters are described in Section 7.5.6.  Day -1 clinical laboratory assessment results must be reviewed before 
study drug administration.  Clinical laboratory tests will be evaluated by a local laboratory.  Day 1 predose LFT and creatinine measurements will be locally analyzed and 
centrally confirmed. 
l Drugs of abuse are described in Section 7.5.6.3. 
m Study drug will be administered via SC injection as described in Section 6.2.2. 
n Blood and urine samples for PK analysis will be collected at the time points listed in Table 10. 


ALN-GO1 
 
Clinical Study Protocol ALN-GO1-001 
 
 
Amendment 5_14 February 2018 
Alnylam Pharmaceuticals 
Confidential 
10 
o Fasting blood samples should be collected.  On Day 1, the blood sample for PD analysis must be collected within 1 hour predose.  The remaining PD samples should be collected 
at the same time of day (±1 hour).  See Laboratory Manual for instructions on sample processing and aliquoting of samples for storage and PD analyses. 
p AEs occurring after signing of the ICF and before study drug administration will be captured as medical history, while all AEs that occur after study drug administration, and 
baseline AEs that worsen after study drug administration, must be recorded and reported as AEs. 
 
 


ALN-GO1 
 
Clinical Study Protocol ALN-GO1-001 
 
 
Amendment 5_14 February 2018 
Alnylam Pharmaceuticals 
Confidential 
11 
Table 2: Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria Type 1 
(Part B – Monthly Dosing) 
Study Stage 
Screening 
Dosing Period 
Postdose Follow-up Perioda 
Safety and 
PD 
Follow-up 
Study Day (D) 
-45 to -2 
-1 
1 
2 
3 
15 
28 
29 
43 
56 
57/EOT 
58 
59b 
84 
85 
112 
113 
140 
141 
169; then, 
Q28D 
Visit Window (D) 
 
 
 
 
 
±2 
 
±4 
±4 
 
±4 
 
 
 
±4 
 
±4 
 
±4 
±4 
Informed consent (and assent 
for patients under the age of 
legal consent) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical historyc 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Full physical examinationd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Symptom-directed physical 
examinationd 
 
X 
X 
X 
 
X 
 
X 
X 
 
X 
 
 
 
X 
 
X 
 
 
X 
Heighte 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Body weight and BMI 
X 
Xf 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Vital signsg 
X 
X 
X 
X 
 
X 
 
X 
X 
 
X 
 
 
 
X 
 
X 
 
X 
X 
12-lead ECGh 
X 
X 
X 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
Echo 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Xi 
Pregnancy test/FSH 
screeningj 
X 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
Clinical laboratory 
assessmentsk 
X 
X 
X 
X 
 
X 
 
X 
X 
 
X 
 
 
 
X 
 
X 
 
X 
X 
Troponin Il 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
X 
Urine sample for drugs of 
abusem 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
Xn 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


ALN-GO1 
 
Clinical Study Protocol ALN-GO1-001 
 
 
Amendment 5_14 February 2018 
Alnylam Pharmaceuticals 
Confidential 
12 
Table 2: Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria Type 1 
(Part B – Monthly Dosing) 
Study Stage 
Screening 
Dosing Period 
Postdose Follow-up Perioda 
Safety and 
PD 
Follow-up 
Study Day (D) 
-45 to -2 
-1 
1 
2 
3 
15 
28 
29 
43 
56 
57/EOT 
58 
59b 
84 
85 
112 
113 
140 
141 
169; then, 
Q28D 
Visit Window (D) 
 
 
 
 
 
±2 
 
±4 
±4 
 
±4 
 
 
 
±4 
 
±4 
 
±4 
±4 
Study drug administrationo 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
Blood and urine samples for 
PK analysesp 
 
 
X 
X X 
X 
 
X 
 
 
X 
X 
X 
 
X 
 
 
 
 
 
Blood sample for PD 
analysesq 
X 
 
X 
 
 
X 
 
X 
X 
 
X 
 
 
 
X 
 
X 
 
X 
X 
24-hour urine collection for 
PD analyses 
Xr 
Xs 
 
 
 
 
Xs 
 
 
Xs 
 
 
 
Xs 
 
Xs 
 
Xs 
 
Xs 
 PD 
analysist 
 
X 
X 
X 
 
X 
 
X 
X 
 
X 
 
 
 
X 
 
X 
 
X 
X 
Blood and urine samples for 
exploratory
 
 
 
 
X 
 
 
 
 
X 
 
 
Xv 
 
 
 
X 
 
X 
 
 
 
Blood sample for pyridoxine 
(vitamin B6) levelsw 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
Blood samples for ADA 
analysis 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
Xx 
Review/record AEsy 
 
 
X 
Prior and concomitant 
medications 
X 
Abbreviations:  ADA=antidrug antibodies; AE=adverse event; BMI=body mass index; D=day; ECG=electrocardiogram; Echo=echocardiography; eGFR=estimated glomerular 
filtration rate; EOT=end of treatment; FSH=follicle-stimulating hormone; ICF=informed consent form; LFT=liver function test; PD=pharmacodynamics; PK=pharmacokinetic; 
Q=every; SC=subcutaneous. 
Notes: 
 
When scheduled at the same time points, the assessments of vital signs and 12-lead ECGs must be performed first, before the physical examinations, blood sample 
collections, and urine collections.   
 
Assessments should be performed predose, where applicable, unless otherwise noted. 


ALN-GO1 
 
Clinical Study Protocol ALN-GO1-001 
 
 
Amendment 5_14 February 2018 
Alnylam Pharmaceuticals 
Confidential 
13 
 
Grey columns indicate the study day when the 24-hour urine collection for PD analysis should begin.  Patients may be admitted to the clinical study center to complete 
the 24-hour urine collections. 
a. 
Patients will be invited to participate in an open-label extension study once they complete the postdose follow-up period on Study Day 141.   For patients who do 
not enroll in the open-label extension study, safety and PD follow-up will continue until plasma glycolate is <20% above baseline or ≤ the ULN AND 24-hour 
urinary oxalate is >80% of baseline, or until the SRC makes a decision per investigator request to discontinue follow-up on a case-by-case basis.  The decision 
cannot be made until after completion of the postdose follow-up period (84 days after last dose). 
b. 
Patients initially randomized to placebo may continue in the study receiving administration of open-label ALN-GO1 according to the Schedule of Assessments 
(Table 3).  Patients will be unblinded on or after Day 78. 
c. 
Complete medical history (including documentation or confirmation of PH1) will be obtained at screening and any changes will be updated on Day -1.  AEs 
occurring after signing of the ICF and before study drug administration will be captured as medical history. 
d. 
See Section 7.5.3 for assessments to be performed during a full physical examination or symptom-directed physical examination. 
e. 
During screening and at EOT, height will be measured for all patients; thereafter, height will only be measured for patients <18 years of age.  Additionally, for 
patients <18 years of age, at each time point, height will be measured in centimeters, and in triplicate, to facilitate calculation of eGFR using the Schwartz Bedside 
Formula. 
f. 
Day -1 body weight will be used for calculation of the ALN–GO1 or placebo (study drug) dose to be administered during this portion of the study. 
g. 
Vital signs (blood pressure, pulse rate, body temperature, and respiration rate) will be measured in the supine position after the patient has rested comfortably for 10 
minutes.  On Day 1 only, vital signs will be measured within 2 hours predose; and 30 (±5 minutes) and 4 hours (±15 minutes) postdose.  
h. 
All 12-lead ECGs are triplicate, using centralized equipment.  ECGs will be measured approximately 5 minutes apart.  Recordings will be obtained after the patient 
has rested comfortably in the supine position for approximately 10 minutes.  Patients should remain supine between ECGs.  On dosing days, ECGs will be measured 
within 2 hours predose; and at 1 hour (±20 minutes), 2 hours (±20 minutes), and 4 hours (±20 minutes) postdose.  On all other days, ECGs should be collected at 
approximately the same time of day corresponding to the predose collection (±1 hour). 
i. 
Echo will be performed during the first visit of the Safety and PD Follow-up Period (Day 169), and thereafter, approximately every 168 days corresponding with 
visits to the clinical study center for the duration of the study. 
j. 
Pregnancy tests will be performed for women of childbearing potential only.  A serum pregnancy test will be performed at Screening or after the onset of menarche 
if the patient was not of childbearing potential at screening, and urine pregnancy tests will be performed thereafter per the Schedule of Assessments and any time 
pregnancy is suspected.  The results of the pregnancy test must be known before study drug administration.  FSH will be measured at Screening only to confirm 
post-menopausal status. 
k. 
Biochemistry, hematology, coagulation, LFTs, and urinalysis parameters are described in Section 7.5.6.  Clinical laboratory tests will be analyzed by a central 
laboratory.  Within 4 days prior to dosing, LFT measurements will be analyzed by a local laboratory and confirmed by a central laboratory.  Local clinical 
laboratory results for LFT measurements must be available and reviewed by the Investigator before study drug administration. 
l. 
During Screening and throughout the Dosing Period, abnormal results for troponin I tests should be repeated.  During the Dosing Period only, local clinical 
laboratory results must be drawn within 4 days prior to dosing and available and reviewed by the Investigator before study drug administration.  Troponin I levels 
will be measured on the first day of the Safety and PD Follow-up Period (Day 169), and thereafter, approximately every 168 days for the duration of the study.  
Troponin I results from Day -1, Day 85, Day 169, and for the remainder of the study will be analyzed by a central laboratory.  Central laboratory results are not 
required before study drug administration. 
m. Drugs of abuse are described in Section 7.5.6.3.  Screening for drugs of abuse will be performed for patients who are above the age of legal consent. 
n. 
Randomization occurs between Day -1 and Day 1. 
o. 
Study drug will be administered via SC injection as described in Section 6.2.2. 
p. 
Blood and urine samples for PK analysis will be collected at the time points listed in Table 11. 
q. 
On Day 1, the blood sample for PD analysis must be collected within 2 hours predose.  The remaining PD samples should be collected at approximately the same 
time of day corresponding to the predose collection (±1 hour), as applicable. 
r. 
During the screening period, 24-hour urine collections will be completed at 2 separate time points.  The first screening 24-hour (±30 minutes) urine collection will 
be used to assess eligibility.  The second screening 18-24-hour urine collection will only be initiated after eligibility is confirmed. 


ALN-GO1 
 
Clinical Study Protocol ALN-GO1-001 
 
 
Amendment 5_14 February 2018 
Alnylam Pharmaceuticals 
Confidential 
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s. 
Single, 18-24-hour urine sample collections will be performed.  The 24-hour urine collection starting on Day -1 must conclude on Day 1 before administration of 
the first dose of study drug.  The 24-hour urine collection should be completed within 4 days prior to the study visit for Day 29, Day 57, Day 85, Day 113, and 
Day 141, and the Q28D Safety and PD Follow-up visits. 
t. 
On Day -1, collect 
 sample before starting the 24-hour urine sample collection.  On all other days, when a 24-hour urine collection is scheduled, collect 
 sample after the 24-hour urine collection, but before study drug administration, as applicable. 
u. 
See the Laboratory Manual for instructions on sample processing and aliquoting of exploratory 
. 
v. 
Blood samples for exploratory 
 are optional for pediatric patients who exceed the maximum blood volume collection limits listed in Table 13. 
w. Blood sample for pyridoxine (vitamin B6) is required only for patients receiving therapeutic pyridoxine.  On days when a blood sample for pyridoxine  will be 
collected, patients should be instructed not to take vitamin B6 before the blood sample is collected and study drug is administered. 
x. 
During the Safety and PD follow-up period, blood sample for ADA should be collected every 56 days after Day 141 (eg, Day 197, Day 253, Day 309) for the 
duration of the study.   
y. 
AEs occurring after signing of the ICF and before study drug administration will be captured as medical history, while all AEs that occur after study drug 
administration, and baseline AEs that worsen after study drug administration, must be recorded and reported as AEs. 
 
 


ALN-GO1 
 
Clinical Study Protocol ALN-GO1-001 
 
 
Amendment 5_14 February 2018 
Alnylam Pharmaceuticals 
Confidential 
15 
Table 3: Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria Type 1 
(Part B) who Previously Received Placebo and will Receive Open-Label ALN-GO1 – Monthly Dosing 
Study Stage 
 
Dosing Period 
Postdose Follow-up Perioda 
Safety and 
PD 
Follow-up 
Study Day (D) 
84 
85 
86 
87 
99 
112 
113 
127 
140 
141/EOTb 
142 
143 
168 
169 
196 
197 
224 
225 
253; then, 
Q28D 
Visit Window (D) 
 
 
 
 
±2 
 
±4 
±4 
 
±4 
 
 
 
±4 
 
±4 
 
±4 
±4 
Full physical examinationc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Symptom-directed 
physical examinationc 
 
X 
X 
 
X 
 
X 
X 
 
X 
 
 
 
X 
 
X 
 
 
X 
Heightd 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Body weight and BMI 
 
Xe 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Vital signsf 
 
X 
X 
 
X 
 
X 
X 
 
X 
 
 
 
X 
 
X 
 
X 
X 
12-lead ECGg 
 
X 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
Echo 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Xh 
Pregnancy testi 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
Clinical laboratory 
assessmentsj 
 
X 
X 
 
X 
 
X 
X 
 
X 
 
 
 
X 
 
X 
 
X 
X 
Troponin Ik 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
X 
Study drug administrationl 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
Blood and urine samples 
for PK analysesm 
 
X 
X 
X 
X 
 
X 
 
 
X 
X 
X 
 
X 
 
 
 
 
 
Blood sample for PD 
analysesn 
 
X 
 
 
X 
 
X 
X 
 
X 
 
 
 
X 
 
X 
 
X 
X 
24-hour urine collection 
for PD analyseso 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 PD 
analysisp 
 
X 
X 
 
X 
 
X 
X 
 
X 
 
 
 
X 
 
X 
 
X 
X 


ALN-GO1 
 
Clinical Study Protocol ALN-GO1-001 
 
 
Amendment 5_14 February 2018 
Alnylam Pharmaceuticals 
Confidential 
16 
Table 3: Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria Type 1 
(Part B) who Previously Received Placebo and will Receive Open-Label ALN-GO1 – Monthly Dosing 
Study Stage 
 
Dosing Period 
Postdose Follow-up Perioda 
Safety and 
PD 
Follow-up 
Study Day (D) 
84 
85 
86 
87 
99 
112 
113 
127 
140 
141/EOTb 
142 
143 
168 
169 
196 
197 
224 
225 
253; then, 
Q28D 
Visit Window (D) 
 
 
 
 
±2 
 
±4 
±4 
 
±4 
 
 
 
±4 
 
±4 
 
±4 
±4 
Blood and urine samples 
for exploratory 
 
 
 
Xr 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
 
 
Blood sample for 
pyridoxine (vitamin B6) 
levelss 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
Blood samples for ADA 
analysis 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
Xt 
Review/record AEs 
X 
Concomitant medications 
X 
Abbreviations:  ADA=antidrug antibodies; AE=adverse event; BMI=body mass index; D=day(s); ECG=electrocardiogram; Echo=echocardiography; eGFR=estimated 
glomerular filtration rate; EOT=end of treatment; PD=pharmacodynamics; PK=pharmacokinetic; Q=every; SC=subcutaneous. 
Notes: 
 
When scheduled at the same time points, the assessments of vital signs and 12-lead ECGs must be performed first, before the physical examinations, blood sample 
collections, and urine collections. 
 
Assessments should be performed predose, where applicable, and unless otherwise noted. 
 
Grey columns indicate the study day when the 24-hour urine collection for PD analysis should begin.  Patients may be admitted to the clinical study center to 
complete the 24-hour urine collections. 
a. 
Patients will be invited to participate in an open-label extension study once they complete the postdose follow-up period on Study Day 225.   For patients who do 
not enroll in the open-label extension study, safety and PD follow-up will continue until plasma glycolate is <20% above baseline or ≤ the ULN AND 24-hour 
urinary oxalate is >80% of baseline, or until the SRC makes a decision per investigator request to discontinue follow-up on a case-by-case basis.  The decision 
cannot be made until after completion of the postdose follow-up (84 days after last dose). 
b. 
If a patient chooses to withdraw consent, every effort should be made to conduct the assessments performed at the EOT visit. 
c. 
See Section 7.5.3 for assessments to be performed during a full physical examination or symptom-directed physical examination. 
d. 
On Day 85 and at EOT, height will be measured for all patients; thereafter, height will only be measured for patients <18 years of age.  Additionally, for patients 
<18 years of age, at each time point, height will be measured in centimeters, and in triplicate, to facilitate calculation of eGFR using the Schwartz Bedside Formula. 
e. 
The Day 57 body weight will be used for calculation of the ALN–GO1 dose to be administered during this portion of the study. 
f. 
Vital signs (blood pressure, pulse rate, body temperature, and respiration rate) will be measured in the supine position after the patient has rested comfortably for 10 
minutes.  On Day 85 only, vital signs will be measured within 2 hours predose; and 30 (±5 minutes) and 4 hours (±15 minutes) postdose. 


ALN-GO1 
 
Clinical Study Protocol ALN-GO1-001 
 
 
Amendment 5_14 February 2018 
Alnylam Pharmaceuticals 
Confidential 
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g. 
All 12-lead ECGs are triplicate, using centralized equipment.  ECGs will be measured approximately 5 minutes apart.  Recordings will be obtained after the patient 
has rested comfortably in the supine position for approximately 10 minutes.  Patients should remain supine between ECGs.  On dosing days, ECGs will be measured 
within 2 hours predose; and at 1 hour (±20 minutes), 2 hours (±20 minutes), and 4 hours (±20 minutes) postdose.  On all other days, ECGs should be collected at 
approximately the same time of day corresponding to the predose collection (±1 hour). 
h. 
Echo will be performed during the first visit of the Safety and PD Follow-up Period (Day 253), and thereafter, approximately every 168 days corresponding with 
visits to the clinical study center for the duration of the study. 
i. 
Pregnancy tests will be performed for women of childbearing potential only.  A serum pregnancy test will be performed after the onset of menarche if the patient 
was not of childbearing potential at screening, and a serum or urine pregnancy test will be performed per the Schedule of Assessments and any time pregnancy is 
suspected.  The results of the pregnancy test must be known before ALN-GO1 administration.   
j. 
Biochemistry, hematology, coagulation, LFTs, and urinalysis parameters are described in Section 7.5.6.  Clinical laboratory tests will be analyzed by a central 
laboratory.  Within 4 days prior to dosing, LFT measurements will be analyzed by a local laboratory and confirmed by a central laboratory.  Local clinical 
laboratory results for LFT measurements must be available and reviewed by the Investigator before study drug administration.   
k. 
Throughout the Dosing Period, local clinical laboratory results for troponin I must be drawn within 4 days prior to dosing and available and reviewed by the 
Investigator before study drug administration and abnormal results should be repeated.  Troponin I levels will be measured on the first day of the Safety and PD 
Follow-up Period (Day 253), and thereafter, approximately every 168 days for the duration of the study.  Troponin I results from Day 85, Day 169, and for the 
remainder of the study will be analyzed by a central laboratory. 
l. 
ALN-GO1 will be administered via SC injection as described in Section 6.2.2. 
m. Blood and urine samples for PK analysis will be collected at the time points listed in Table 11. 
n. 
On Day 85, the blood sample for PD analysis must be collected within 2 hours predose.  The remaining PD samples should be collected at approximately the same 
time of day corresponding to the predose collection (±1 hour), as applicable. 
o. 
Single, 18-24-hour urine sample collections will be performed.  On dosing days, the urine collection period should conclude in the morning before study drug 
administration.  The 24-hour urine collection should be completed within 4 days prior to the study visits for Day 85, Day 113, Day 141, Day 169, and Day 197, 
Day 225, and the Q28D Safety and PD Follow-up visits.   
p. 
On dosing days, when a 24-hour urine collection is scheduled, collect 
 sample after the 24-hour urine collection, but before study drug administration. 
q. 
See the Laboratory Manual for instructions on sample processing and aliquoting of exploratory 
 
r. 
Blood samples for exploratory 
 are optional for pediatric patients who exceed the maximum blood volume collection limits listed in Table 13. 
s. 
Blood sample for pyridoxine (vitamin B6) is required only for patients receiving therapeutic pyridoxine.  On days when a blood sample for pyridoxine will be 
collected, patients should be instructed not to take vitamin B6 before the blood sample is collected and study drug is administered.  
t. 
During the Safety and PD follow-up period, blood sample for ADA should be collected every 56 days after Day 225 (eg, Day 281, Day 337, Day 393) for the 
duration of the study.    
 
 


ALN-GO1 
 
Clinical Study Protocol ALN-GO1-001 
 
 
Amendment 5_14 February 2018 
Alnylam Pharmaceuticals 
Confidential 
18 
Table 4: 
Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria Type 1 (Part B – 
Quarterly Dosing) 
Study Stage 
Screening 
Dosing Period 
Postdose Follow-up Perioda 
Safety 
and PD 
Follow-
up 
Study Day (D) 
-45 to -2 
-1 
1 
2 
3 
15 
28 
29 
43 
56 
57 
84 
85/ EOTb 
86 
87 
99 
112 
113 
127 
140 
141 
168 
169 
197; then, 
Q28D 
Visit Window 
(D) 
 
 
 
 
 
±2 
 
±4 
±4 
 
±4 
 
±4 
 
 
±2 
 
±4 
±4 
 
±4 
 
±4 
±4 
Informed 
consent (and 
assent for 
patients under 
the age of legal 
consent) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
historyc 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Full physical 
examinationd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Symptom-
directed 
physical 
examinationd 
 
X 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
 
 
X 
Heighte 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
Body weight 
and BMI 
X 
Xf 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
Vital signsg 
X 
X 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 


ALN-GO1 
 
Clinical Study Protocol ALN-GO1-001 
 
 
Amendment 5_14 February 2018 
Alnylam Pharmaceuticals 
Confidential 
19 
Table 4: 
Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria Type 1 (Part B – 
Quarterly Dosing) 
Study Stage 
Screening 
Dosing Period 
Postdose Follow-up Perioda 
Safety 
and PD 
Follow-
up 
Study Day (D) 
-45 to -2 
-1 
1 
2 
3 
15 
28 
29 
43 
56 
57 
84 
85/ EOTb 
86 
87 
99 
112 
113 
127 
140 
141 
168 
169 
197; then, 
Q28D 
Visit Window 
(D) 
 
 
 
 
 
±2 
 
±4 
±4 
 
±4 
 
±4 
 
 
±2 
 
±4 
±4 
 
±4 
 
±4 
±4 
12-lead ECGh 
X 
X 
X 
X 
 
 
 
X 
 
 
X 
 
X 
X 
 
 
 
X 
 
 
X 
 
X 
X 
Echo 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Xi 
Pregnancy 
test/FSH 
screeningj 
X 
X 
X 
 
 
 
 
X 
 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
Clinical 
laboratory 
assessmentsk 
X 
X 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
 
 
X 
Troponin Il 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
Urine sample 
for drugs of 
abusem 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
Xn 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug 
administrationo 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Blood and 
urine samples 
for PK 
analysesp 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
 
X 
 
 
 
 
 
 
Blood sample 
for PD 
analysesq 
X 
 
X 
 
 
X 
 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
 
X 
 
X 
X 


ALN-GO1 
 
Clinical Study Protocol ALN-GO1-001 
 
 
Amendment 5_14 February 2018 
Alnylam Pharmaceuticals 
Confidential 
20 
Table 4: 
Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria Type 1 (Part B – 
Quarterly Dosing) 
Study Stage 
Screening 
Dosing Period 
Postdose Follow-up Perioda 
Safety 
and PD 
Follow-
up 
Study Day (D) 
-45 to -2 
-1 
1 
2 
3 
15 
28 
29 
43 
56 
57 
84 
85/ EOTb 
86 
87 
99 
112 
113 
127 
140 
141 
168 
169 
197; then, 
Q28D 
Visit Window 
(D) 
 
 
 
 
 
±2 
 
±4 
±4 
 
±4 
 
±4 
 
 
±2 
 
±4 
±4 
 
±4 
 
±4 
±4 
24-hour urine 
collection for 
PD analyses 
Xr 
Xs 
 
 
 
 
Xs 
 
 
Xs 
 
Xs 
 
 
 
 
Xs 
 
 
Xs 
 
Xs 
 
Xs 
 
 PD 
analysist 
 
X 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
 
X 
 
X 
X 
Blood and 
urine samples 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
Xv 
 
 
 
 
X 
 
 
X 
 
 
 
Blood sample 
for pyridoxine 
(vitamin B6) 
levelsw 
 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
 
Blood samples 
for ADA 
analysis 
 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
Xx 
Review/record 
AEsy 
 
 
X 
Concomitant 
medications 
X 


ALN-GO1 
 
Clinical Study Protocol ALN-GO1-001 
 
 
Amendment 5_14 February 2018 
Alnylam Pharmaceuticals 
Confidential 
21 
Abbreviations:  ADA=antidrug antibodies; AE=adverse event; BMI=body mass index; D=day; ECG=electrocardiogram; Echo=echocardiography; eGFR=estimated glomerular 
filtration rate; EOT=end of treatment; FSH=follicle-stimulating hormone; ICF=informed consent form; LFT=liver function test; PD=pharmacodynamics; PK=pharmacokinetic; 
Q=every; SC=subcutaneous. 
Notes: 
• 
When scheduled at the same time points, the assessments of vital signs and 12-lead ECGs must be performed first, before the physical examinations, blood sample 
collections, and urine collections.   
• 
Assessments should be performed predose, where applicable, unless otherwise noted. 
• 
Grey columns indicate the study day when the 24-hour urine collection for PD analysis should begin.  Patients may be admitted to the clinical study center to complete 
the 24-hour urine collections. 
a. 
Patients will be invited to participate in an open-label extension study once they complete the postdose follow-up period on Study Day 169.  For patients who do 
not enroll in the open-label extension study, safety and PD follow up will continue until plasma glycolate is <20% above baseline or ≤ the ULN AND 24-hour 
urinary oxalate is >80% of baseline, or until the SRC makes a decision per investigator request to discontinue follow-up on a case-by-case basis.  The decision 
cannot be made until after completion of the postdose follow-up period (84 days after last dose). 
b. 
Patients initially randomized to placebo will receive open-label ALN-GO1.   
c. 
Complete medical history (including documentation or confirmation of PH1) will be obtained at screening and any changes will be updated on Day -1.  AEs 
occurring after signing of the ICF and before study drug administration will be captured as medical history. 
d. 
See Section 7.5.3 for assessments to be performed during a full physical examination or symptom-directed physical examination. 
e. 
During screening and at EOT, height will be measured for all patients; thereafter, height will only be measured for patients <18 years of age.  Additionally, for 
patients <18 years of age, at each time point, height will be measured in centimeters, and in triplicate, to facilitate calculation of eGFR using the Schwartz Bedside 
Formula. 
f. 
Day -1 body weight will be used for calculation of the ALN–GO1 or placebo (study drug) dose to be administered during the dosing period. 
g. 
Vital signs (blood pressure, pulse rate, body temperature, and respiration rate) will be measured in the supine position after the patient has rested comfortably for 10 
minutes.  On Day 1 only, vital signs will be measured within 2 hours predose; and 30 (±5 minutes) and 4 hours (±15 minutes) postdose.  
h. 
All 12-lead ECGs are triplicate, using centralized equipment.  ECGs will be measured approximately 5 minutes apart.  Recordings will be obtained after the patient 
has rested comfortably in the supine position for approximately 10 minutes.  Patients should remain supine between ECGs.  On dosing days, ECGs will be measured 
within 2 hours predose; and at 1 hour (±20 minutes), 2 hours (±20 minutes), and 4 hours (±20 minutes) postdose.  On all other days, ECGs should be collected at 
approximately the same time of day corresponding to the predose collection (±1 hour). 
i. 
Echo will be performed during the first visit of the Safety and PD Follow-up Period (Day 197) and approximately every 168 days corresponding with visits to the 
clinical study center for the duration of the study. 
j. 
Pregnancy tests will be performed for women of childbearing potential only.  A serum pregnancy test will be performed at Screening or after the onset of menarche 
if the patient was not of childbearing potential at screening, and urine pregnancy tests will be performed thereafter per the Schedule of Assessments and any time 
pregnancy is suspected.  The results of the pregnancy test must be known before study drug administration.  FSH will be measured at Screening only to confirm 
post-menopausal status. 
k. 
Biochemistry, hematology, coagulation, LFTs, and urinalysis parameters are described in Section 7.5.6.  Clinical laboratory tests will be analyzed by a central 
laboratory.  Within 4 days prior to dosing, LFT measurements will be analyzed by a local laboratory and confirmed by a central laboratory.  Local clinical 
laboratory results for LFT measurements must be available and reviewed by the Investigator before study drug administration. 
l. 
During Screening and throughout the Dosing Period, abnormal results for troponin I tests should be repeated.  During the Dosing Period only, local clinical 
laboratory results must be drawn within 4 days prior to dosing and available and reviewed by the Investigator before study drug administration.  Troponin I levels 
will be measured on the first day of the Safety and PD Follow-up Period (Day 197), and thereafter, approximately every 168 days for the duration of the study.  
Troponin I results from Day -1, Day 85, Day 113, Day 197, and for the remainder of the study will be analyzed by a central laboratory.  Central laboratory results 
are not required before study drug administration. 
m. Drugs of abuse are described in Section 7.5.6.3.  Screening for drugs of abuse will be performed for patients who are above the age of legal consent. 
n. 
Randomization occurs between Day -1 and Day 1. 
o. 
Study drug will be administered via SC injection as described in Section 6.2.2. 


ALN-GO1 
 
Clinical Study Protocol ALN-GO1-001 
 
 
Amendment 5_14 February 2018 
Alnylam Pharmaceuticals 
Confidential 
22 
p. 
Blood and urine samples for PK analysis will be collected at the time points listed in Table 12. 
q. 
On Day 1, the blood sample for PD analysis must be collected within 2 hours predose.  The remaining PD samples should be collected at approximately the same 
time of day corresponding to the predose collection (±1 hour), as applicable. 
r. 
During the screening period, 24-hour urine collections will be completed at 2 separate time points.  The first screening 24-hour (±30 minutes) urine collection will 
be used to assess eligibility.  The second screening 18-24-hour urine collection will only be initiated after eligibility is confirmed. 
s. 
Single, 18-24-hour urine sample collections will be performed.  The 24-hour urine collection starting on Day -1 must conclude on Day 1 before administration of 
the first dose of study drug.  The 24-hour urine collection should be completed within 4 days prior to the study visit for Day 29, Day 57, Day 85, Day 113, Day 141, 
and Day 169, and the Q28D Safety and PD Follow-up visits.   
t. 
On Day -1, collect 
 sample before starting the 24-hour urine sample collection.  On all other days, when a 24-hour urine collection is scheduled, collect 
 sample after the 24-hour urine collection, but before study drug administration, as applicable.  
u. 
See the Laboratory Manual for instructions on sample processing and aliquoting 
. 
v. 
Blood samples 
 on Day 85 are optional for pediatric patients who exceed the maximum blood volume collection limits listed in Table 13. 
w. Blood sample for pyridoxine (vitamin B6) is required only for patients receiving therapeutic pyridoxine.  On days when a blood sample for pyridoxine will be 
collected, patients should be instructed not to take vitamin B6 before the blood sample is collected and study drug is administered. 
x. 
During the Safety and PD follow-up period, blood sample for ADA should be collected every 56 days after Day 169 (eg, Day 225, Day 281, Day 337) for the 
duration of the study.   
y. 
AEs occurring after signing of the ICF and before study drug administration will be captured as medical history, while all AEs that occur after study drug 
administration, and baseline AEs that worsen after study drug administration, must be recorded and reported as AEs. 
 


ALN-GO1 
 
Clinical Study Protocol ALN-GO1-001 
 
 
Amendment 5_14 February 2018 
Alnylam Pharmaceuticals 
Confidential 
 
23 
TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ................................................................................................................4 
TABLE OF CONTENTS ...............................................................................................................23 
LIST OF TABLES .........................................................................................................................27 
LIST OF FIGURES .......................................................................................................................27 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................28 
1. 
INTRODUCTION ......................................................................................................30 
1.1. 
Disease Overview .......................................................................................................30 
1.2. 
ALN-GO1 ...................................................................................................................31 
1.2.1. 
ALN-GO1 Description ...............................................................................................31 
1.2.2. 
Rationale for ALN-GO1 for the Treatment of Primary Hyperoxaluria Type 1 .........31 
1.2.3. 
Nonclinical Data .........................................................................................................31 
1.3. 
Study Design Rationale ..............................................................................................32 
1.4. 
Dose Rationale ............................................................................................................32 
1.5. 
Benefit-Risk Assessment ............................................................................................33 
2. 
OBJECTIVES .............................................................................................................35 
2.1. 
Primary Objective .......................................................................................................35 
2.2. 
Secondary Objectives .................................................................................................35 
2.3. 
Exploratory Objectives ...............................................................................................36 
3. 
ENDPOINTS ..............................................................................................................36 
3.1. 
Primary Endpoint ........................................................................................................36 
3.2. 
Secondary Endpoints ..................................................................................................36 
3.2.1. 
Secondary Endpoints for the Single-ascending Dose Part in Healthy Adult 
Subjects (Part A) .........................................................................................................36 
3.2.2. 
Secondary Endpoints for the Multiple-ascending Dose Part in Patients with 
Primary Hyperoxaluria Type 1 (Part B) .....................................................................36 
3.3. 
Exploratory Endpoints ................................................................................................36 
3.3.1. 
 
 .....................................................................36 
4. 
INVESTIGATIONAL PLAN .....................................................................................37 
4.1. 
Summary of Study Design ..........................................................................................37 
4.1.1. 
Single-ascending Dose Part in Healthy Adult Subjects (Part A) ................................37 


ALN-GO1 
 
Clinical Study Protocol ALN-GO1-001 
 
 
Amendment 5_14 February 2018 
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24 
4.1.2. 
Multiple-ascending Dose Part in Patients with Primary Hyperoxaluria 
Type 1 (Part B) ...........................................................................................................38 
4.2. 
Duration of Treatment and Overall Duration of Study ...............................................39 
4.3. 
Number of Subjects and Patients ................................................................................39 
4.4. 
Method of Assigning Patients to Treatment Groups ..................................................39 
4.5. 
Blinding ......................................................................................................................40 
4.6. 
Safety Review Committee ..........................................................................................40 
4.7. 
Study Drug Dosing, Study Progression, and Dose Escalation ...................................41 
4.7.1. 
Study Drug Dosing, Study Progression, and Dose Escalation in Part A ....................41 
4.7.2. 
Study Drug Dosing, Study Progression, and Dose Escalation in Part B ....................41 
4.7.3. 
Dose Suspension and Stopping Rules.........................................................................42 
4.7.3.1. 
Cohort Progression/Escalation and Suspension/Stopping Rules in Part A ................42 
4.7.3.2. 
Individual Patient Progression/Escalation and Suspension/Stopping Rules in 
Part B ..........................................................................................................................44 
4.7.3.3. 
Cohort Progression/Escalation and Suspension/Stopping Rules in Part B .................45 
4.8. 
Adaptive Study Design Features ................................................................................46 
5. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................48 
5.1. 
Inclusion Criteria ........................................................................................................48 
5.1.1. 
Inclusion Criteria for Parts A and B ...........................................................................48 
5.1.2. 
Additional Inclusion Criteria for Part A .....................................................................49 
5.1.3. 
Additional Inclusion Criteria for Part B .....................................................................49 
5.2. 
Exclusion Criteria .......................................................................................................49 
5.2.1. 
Exclusion Criteria for Parts A and B ..........................................................................49 
5.2.2. 
Additional Exclusion Criteria for Part B ....................................................................50 
5.3. 
Removal from Therapy or Assessment.......................................................................51 
5.3.1. 
Discontinuation of Study Drug ...................................................................................51 
5.3.2. 
Withdrawal From Study .............................................................................................51 
5.3.3. 
Replacement of Subjects or Patients ...........................................................................52 
6. 
TREATMENTS ..........................................................................................................52 
6.1. 
Treatments Administered ............................................................................................52 
6.2. 
Investigational Study Drug .........................................................................................52 
6.2.1. 
Description ..................................................................................................................52 
6.2.2. 
Dose and Administration ............................................................................................52 


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6.2.3. 
Dose Modifications .....................................................................................................52 
6.2.4. 
Preparation, Handling, and Storage ............................................................................53 
6.2.5. 
Packaging and Labeling ..............................................................................................53 
6.2.6. 
Accountability .............................................................................................................53 
6.3. 
Concomitant Medications ...........................................................................................53 
6.3.1. 
Permitted Concomitant Medications ..........................................................................54 
6.3.2. 
Prohibited Concomitant Medications .........................................................................54 
6.4. 
Contraceptive Requirements .......................................................................................54 
6.5. 
Treatment Compliance ................................................................................................55 
7. 
STUDY ASSESSMENTS ..........................................................................................55 
7.1. 
Screening/Baseline Assessments ................................................................................55 
7.1.1. 
Renal Function in Part B .............................................................................................55 
7.1.1.1. 
Urinary Oxalate Excretion and Creatinine Clearance ................................................55 
7.1.1.2. 
Estimated Glomerular Filtration Rate .........................................................................56 
7.2. 
Pharmacodynamic Assessments .................................................................................56 
7.3. 
Pharmacokinetic Assessments ....................................................................................56 
7.4. 
Exploratory Assessments ............................................................................................56 
7.5. 
Safety Assessments .....................................................................................................57 
7.5.1. 
Vital Signs ..................................................................................................................57 
7.5.2. 
Weight and Height ......................................................................................................57 
7.5.3. 
Physical Examination .................................................................................................57 
7.5.4. 
Electrocardiogram .......................................................................................................57 
7.5.5. 
Echocardiography (Part B only) .................................................................................58 
7.5.6. 
Clinical Laboratory Assessments ...............................................................................58 
7.5.6.1. 
Immunogenicity ..........................................................................................................59 
7.5.6.2. 
Pregnancy Testing ......................................................................................................59 
7.5.6.3. 
Drugs of Abuse ...........................................................................................................59 
7.5.6.4. 
Maximum Blood Volume ...........................................................................................60 
7.5.7. 
Adverse Events ...........................................................................................................60 
7.5.7.1. 
Definitions ..................................................................................................................60 
7.5.7.2. 
Eliciting and Recording Adverse Events ....................................................................62 
7.5.7.3. 
Serious Adverse Events Require Immediate Reporting to Sponsor/Designee ...........62 
7.5.7.4. 
Sponsor Safety Reporting to Regulatory Authorities .................................................63 


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7.5.7.5. 
Serious Adverse Event Notification to the Institutional Review 
Board/Independent Ethics Committee ........................................................................64 
7.5.7.6. 
Pregnancy Reporting ..................................................................................................64 
7.5.7.7. 
Overdose Reporting ....................................................................................................64 
8. 
STATISTICS ..............................................................................................................64 
8.1. 
Determination of Sample Size ....................................................................................64 
8.2. 
Statistical Methodology ..............................................................................................64 
8.2.1. 
Populations to be Analyzed ........................................................................................65 
8.2.2. 
Examination of Subgroups .........................................................................................65 
8.2.3. 
Handling of Missing Data ...........................................................................................65 
8.2.4. 
Baseline Evaluations ...................................................................................................65 
8.2.5. 
Pharmacodynamic Analyses .......................................................................................66 
8.2.6. 
Pharmacokinetic Analyses ..........................................................................................66 
8.2.7. 
Safety Analyses ..........................................................................................................66 
8.2.8. 
Interim Analysis ..........................................................................................................66 
9. 
STUDY ADMINISTRATION ...................................................................................67 
9.1. 
Ethical and Regulatory Considerations ......................................................................67 
9.1.1. 
Informed Consent .......................................................................................................67 
9.1.2. 
Ethical Review ............................................................................................................67 
9.1.3. 
Study Documentation, Confidentiality, and Records Retention .................................68 
9.1.4. 
End of the Study .........................................................................................................68 
9.1.5. 
Discontinuation of the Clinical Study.........................................................................68 
9.2. 
Data Quality Control and Quality Assurance .............................................................69 
9.2.1. 
Data Handling .............................................................................................................69 
9.2.2. 
Study Monitoring ........................................................................................................69 
9.2.3. 
Audits and Inspections ................................................................................................69 
9.3. 
Publication Policy .......................................................................................................69 
10. 
LIST OF REFERENCES ............................................................................................70 
11. 
APPENDICES ............................................................................................................71 
11.1. 
Pharmacokinetic Assessment Time Points .................................................................71 
11.2. 
Formulae for Estimated Glomerular Filtration Rate Calculation ...............................77 
11.3. 
Blood Volume Limits in Pediatric Patients (Part B) ..................................................78 
11.4. 
Normative Pediatric Blood Pressure Tables ...............................................................79 


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LIST OF TABLES 
Table 1: 
Schedule of Assessments for Single-ascending Dose Cohorts in Healthy 
Subjects (Part A) ...........................................................................................................8 
Table 2: 
Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients 
with Primary Hyperoxaluria Type 1 (Part B – Monthly Dosing) ...............................11 
Table 3: 
Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients 
with Primary Hyperoxaluria Type 1 (Part B) who Previously Received 
Placebo and will Receive Open-Label ALN-GO1 – Monthly Dosing .......................15 
Table 4: 
Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients 
with Primary Hyperoxaluria Type 1 (Part B – Quarterly Dosing) .............................18 
Table 5: 
No Observed Adverse Effect Level and Starting Dose Safety Margins .....................33 
Table 6: 
Cohort Progression/Escalation and Suspension/Stopping Rules for Part A ...............43 
Table 7: 
Individual Patient Progression/Escalation and Suspension/Stopping Rules for 
Part B ..........................................................................................................................45 
Table 8: 
Cohort Progression/Escalation and Suspension/Stopping Rules for Part B ...............46 
Table 9: 
Adaptive Study Design Areas, Features, and Limits ..................................................46 
Table 10: Pharmacokinetic Time Points for Single-ascending Dose Cohorts in Healthy 
Subjects (Part A) .........................................................................................................71 
Table 11: Pharmacokinetic Time Points for Multiple-ascending Dose Cohorts in 
Patients with PH1 (Part B – Monthly Dosing) ...........................................................72 
Table 12: Pharmacokinetic Time Points for Patients with PH1 (Part B – Quarterly 
Dosing) .......................................................................................................................75 
Table 13: Maximum Allowable Total Blood Collection Volumes Chart (Part B) .....................78 
Table 14: Blood Pressure Levels for Girls by Age and Height Percentile .................................80 
Table 15: Blood Pressure Levels for Boys by Age and Height Percentile .................................83 
 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................37 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or Specialist Term 
Explanation 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
AST 
aspartate aminotransferase 
BMI 
body mass index 
BUN 
blood urea nitrogen 
CRO 
contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
electrocardiogram 
Echo 
echocardiography 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
EOT 
End of Treatment 
FSH 
follicle-stimulating hormone 
GalNAc 
N-acetylgalactosamine 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GO 
glycolate oxidase  
HIV 
human immunodeficiency virus 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ISR 
injection site reaction 
MAD 
multiple-ascending dose 
MDRD 
modification of diet in renal disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
NHP 
non-human primates 
OTC 
over the counter 
PD 
pharmacodynamic 
PK 
pharmacokinetics 
QTcB 
Bazett-corrected QT interval 


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Abbreviation or Specialist Term 
Explanation 
QTcF 
Fridericia corrected QT interval 
SAD 
single-ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
Subcutaneous  
siRNA 
small interfering RNA 
SOC 
System Organ Class 
SRC 
Safety Review Committee  
SUSARs 
suspected unexpected serious adverse reactions 
ULN 
upper limit of normal 
WHO 
World Health Organization 
WOCBP 
women of child bearing potential 
 


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1. 
INTRODUCTION 
1.1. 
Disease Overview 
Alnylam Pharmaceuticals is developing ALN-GO1, a synthetic, small interfering RNA (siRNA) 
therapeutic directed against hydroxyacid oxidase 1 (HAO1) messenger RNA (mRNA), which is 
covalently linked to a ligand containing 3, N-acetylgalactosamine residues.  The proposed 
indication for ALN-GO1 is the treatment of Primary Hyperoxaluria Type 1 (PH1). 
PH1 is a rare, autosomal recessively inherited disease characterized by excessive production of 
oxalate and consequent hyperoxaluria.  Given the relative insolubility of oxalate, it crystallizes in 
the urinary tract, primarily as calcium oxalate.  This results in recurrent nephrolithiasis and/or 
nephrocalcinosis, with progressive renal disease leading to renal failure.[1]  As renal function 
declines, calcium oxalate is deposited systemically, with consequent end organ damage. This 
stage of the disease, called systemic oxalosis, arises when the glomerular filtration rate (GFR) 
has declined to below 30 to 45 mL/min per 1.73 m2.[1] 
PH1 is caused by mutations in both alleles of the alanine glyoxylate aminotransferase (AGXT) 
gene, which encodes the liver peroxisomal enzyme alanine-glyoxylate aminotransferase (AGT). 
Over 150 mutations in AGXT have been described.  There are broad genotype–phenotype 
associations, notably in the responsiveness of disease caused by some mutations, to treatment 
with pyridoxine (vitamin B6).  However, disease phenotype can be highly variable, including the 
responsiveness to vitamin B6 treatment, even within families.[2] 
Given the rarity and heterogeneity of PH1, many patients go undiagnosed for years after the 
initial clinical manifestations of the disease.  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.[1-3]  
The disease is more prevalent in areas where consanguineous marriages are common, especially 
in the Middle East and Northern Africa.[4, 5]   
PH1 is primarily a pediatric disease, with symptoms first appearing in approximately half 
(48.6%) of the patients in the Rare Kidney Stone Consortium Primary Hyperoxaluria Registry 
between birth and four years of age.  Approximately three-quarters of patients (74.7%) showed 
signs or symptoms before the age of 15 and 83.5% showed symptoms before 20 years of age.  In 
comparison, only 16.5% of patients first displayed symptoms after age 20.  Additionally, nearly 
one third (29.9%) of patients were diagnosed between birth and four years of age and two-thirds 
(66%) were diagnosed before 20 years of age. [Rare Kidney Stone Consortium Primary 
Hyperoxaluria. Available from: http://rarekidneystones.org/hyperoxaluria/, accessed on 
25 September 2015] The majority of patients are, therefore, diagnosed as children, and 
consequently, are more likely to have some preservation of renal function at time of diagnosis. 
Most PH1 patients exhibit urinary oxalate excretion greater than 2-fold the upper limit of normal 
(ULN), although patients with severely compromised renal function may have lower excretion 
rates.  PH1 is definitively diagnosed by gene sequencing to detect pathological mutations in 
AGXT, or by evaluation of AGT enzymatic activity in liver tissue obtained by biopsy. 
Currently, there are no approved therapies for the treatment of PH1.  Disease management is 
based on supportive measures, including high fluid intake, potassium citrate (to increase urinary 
oxalate solubility), Vitamin B6, and treatment of complications such as urinary tract stones and 
infections.  Dietary modification plays a minor role in treatment since endogenous oxalate 


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production far exceeds dietary intake.  Patients progressing to, or presenting with end-stage renal 
disease (ESRD) require intense kidney dialysis.  However, dialysis, day and night, 6 days per 
week, may be inadequate to effectively offload accumulating oxalate.[6]  Combined liver/kidney 
transplantation offers potentially curative therapy, but with limited availability, the attendant 
medical risks, and intense use of health care resources.  Therefore, there is a high unmet medical 
need for additional treatments for patients with PH1.  The deterioration of renal function that 
occurs in PH1 disease indicates the importance of investigating potentially disease-modifying 
interventions as early as possible after diagnosis. 
1.2. 
ALN-GO1 
1.2.1. 
ALN-GO1 Description 
ALN-GO1 (containing siRNA drug substance ALN-65585) is an investigational medicinal 
product that comprises a synthetic siRNA that specifically targets the mRNA of the HAO1 gene 
which encodes glycolate oxidase (GO). 
1.2.2. 
Rationale for ALN-GO1 for the Treatment of Primary Hyperoxaluria Type 1 
GO, a hepatic enzyme upstream of AGT, mediates the oxidation of glycolate to glyoxylate, 
which then is further metabolized to oxalate.  Suppression of GO by ALN-GO1 is expected to 
reduce the production of oxalate, while increasing the generation of glycolate.  Unlike oxalate, 
glycolate is highly soluble and readily excreted in the urine.  The effective substitution of 
glycolate for oxalate production is hypothesized to significantly ameliorate the course of PH1 
disease.  Moreover, the mechanism of action of ALN-GO1 suggests that plasma glycolate could 
be a biomarker for the inhibition of GO1, serving as a pharmacodynamic (PD) measure of 
ALN-GO1 activity in healthy subjects. 
1.2.3. 
Nonclinical Data 
The pharmacology, safety pharmacology, drug metabolism and pharmacokinetics (PK), and 
toxicology of ALN-GO1 were evaluated in a series of in vitro and in vivo nonclinical studies. 
Nonclinical pharmacology studies include the assessment of in vitro activity of ALN-GO1 in 
primary hepatocytes from non-human primates (NHP); and in vivo in wild-type (WT) mice 
deficient in AGXT (a genetic model of PH1), WT rats, rats with inhibited AGXT activity (an 
induced model of PH1), and WT NHP.  When subcutaneously administered, ALN-GO1 
demonstrated potent, dose-dependent pharmacologic activity, resulting in reduced liver HAO1 
mRNA levels with the expected increases in plasma glycolate levels in WT and diseased animals 
as well as subsequent reductions in urinary oxalate in diseased animals.  Modest increases 
(approximately 1.5-fold) in plasma glycolate levels were observed in NHP treated with 1 mg/kg 
of ALN-GO1 subcutaneously administered every 4 weeks, the lowest dose studied with a 4-week 
dosing interval. 
Good Laboratory Practice (GLP) -compliant toxicology studies were performed in rats at 0, 5, 
15, or 50 mg/kg weekly or 50 mg/kg monthly and in NHP at 0, 10, 30, and 100 mg/kg weekly or 
100 mg/kg monthly, with treatment administered for 8 weeks.  The no observed adverse effect 
levels (NOAEL) were 50 mg/kg in rats and 100 mg/kg in NHP (Table 5). 


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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 based on 
industry guidelines.[7]  
In summary, nonclinical studies have shown pharmacological activity in NHP at doses as low as 
1.0 mg/kg, while doses as high as 50 mg/kg and 100 mg/kg in rat and NHP, respectively, have 
resulted in no adverse effects after 8 weeks of treatment.  These data provide the justification for 
the starting dose for administration in this clinical study. 
1.3. 
Study Design Rationale 
This is a randomized, single-blind, placebo-controlled, multi-center Phase 1/2 single-ascending 
dose (SAD) and multiple-ascending dose (MAD) study designed to evaluate the safety, 
tolerability, PK, and PD of subcutaneously administered ALN-GO1 in healthy adult subjects and 
in adult and pediatric patients with PH1.  The primary objective of the study is to evaluate the 
safety and tolerability of single-ascending doses of ALN-GO1 in healthy adult subjects and 
multiple-ascending doses of ALN-GO1 in patients with PH1.  Secondary and exploratory 
objectives of the study include the characterization of plasma and urine PK for ALN-GO1 and 
the evaluation of the PD effect of ALN-GO1, including glycolate and oxalate concentration and 
excretion. 
Part B of this study will be implemented as a delayed start study; all patients will receive active 
study drug.  Patients initially randomized to receive placebo will transition to active study drug; 
thus, additional safety data will be collected from patients transitioning from placebo to active 
study drug.  The design allows for evaluation of safety and PD data at multiple dose levels in 
healthy subjects before initiating dosing in patients with PH1.  This will permit more efficient 
dose selection in patients, given the rarity of the disease, and limits exposure of patients to 
ALN-GO1 as safety is being assessed. 
1.4. 
Dose Rationale 
The proposed starting dose in healthy subjects in Part A of this study is 0.3 mg/kg.  Data in NHP 
suggest that this dose will have a low level of pharmacologic activity, while NOAELs 
determined in rat and NHP 8-week GLP toxicity studies indicate a wide margin of safety.  While 
it is expected that nonclinical PD and toxicity will translate to humans on a body weight (mg/kg) 
basis, a more conservative approach for determining the starting dose was calculated by 
converting the NOAEL in the rat and NHP to a human equivalent dose (HED) using body 
surface area (BSA; mg/m2).  Using BSA conversions, safety margins for the clinical starting dose 
of 0.3 mg/kg were 26.7-fold and 106.7-fold in the rat and NHP, respectively, whether study drug 
was administered weekly or every 4 weeks.  Collectively, the results of the ALN-GO1 
nonclinical and pharmacological studies support the starting dose of 0.3 mg/kg in this 
first-in-human study.  The starting dose in patients will be the lowest dose determined to have a 
pharmacological effect in healthy subjects that was also considered safe and well-tolerated. 


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Table 5: 
No Observed Adverse Effect Level and Starting Dose Safety Margins 
 
NOAEL 
(mg/kg) 
HED based on 
BSA (mg/kg) 
Safety margin for proposed starting 
dose of 0.3 mg/kg (Part A) 
Based on mg/kg 
Based on BSAa 
Rat (QW×9) 
50 
8 
167-fold 
26.7 
Rat (Q4W×3) 
50 
8 
167-fold 
26.7 
NHP (QW×9) 
100 
32 
333-fold 
106.7 
NHP 
(Q4W×3) 
100 
32 
333-fold 
106.7 
Abbreviations:  BSA=body surface area; HED=human equivalent dose; NHP=nonhuman primates; 
NOAEL=no observed adverse effect level; Q=every; W=week. 
a  BSA margin calculated using species-scaled conversion assumptions.[8]  
Doses were selected for this study in accordance with Committee for Medicinal Products for 
Human Use (CHMP) guidelines on Risk Identification and Mitigation in first-in-human clinical 
studies (EMEA/CHMP/SWP/28367/07). 
Preliminary data from Part A suggest that ALN-GO1 is well-tolerated and support selection of 
the starting dose for the first cohort of Part B of study ALN-GO1-001.  The Part B starting dose 
is 1.0 mg/kg, administered every 28 days, the lowest dose determined to have a pharmacological 
effect in healthy subjects in Part A that was also considered well-tolerated.  The starting dose in 
Part B is based on data derived from Part A and recommended by the Safety Review 
Committee (SRC).  Additional cohorts may be enrolled at higher, lower, or intermediate dose 
levels, but will not exceed the maximum administered dose of 6 mg/kg, and will follow the 
protocol-specified dose escalation criteria. 
1.5. 
Benefit-Risk Assessment 
ALN-GO1 is designed to reduce hepatic production of oxalate.  The potential benefit of this 
treatment is the amelioration of the clinical course of PH1 in patients across the spectrum of 
disease, irrespective of age and disease stage; however, patients with PH1 in this study may not 
receive treatment for a sufficient duration, or at an adequate dose, to experience clinical benefit.  
There is no benefit for healthy subjects participating in this clinical study of ALN-GO1.  The 
potential risks of ALN-GO1 include pathway- and disease-specific risks, and non-specific, 
off-target risks. 
Reduction of GO is expected to lead to reduction in hepatic oxalate production at the expense of 
increased glycolate, an organic acid.  Therefore, study drug-induced increases in plasma and 
urine glycolate levels are anticipated in both healthy subjects and patients administered 
ALN-GO1.  Since elevated levels of this organic acid are expected to be readily buffered, and its 
high solubility is not expected to result in crystallization in the urinary tract, the potential risk of 
increased glycolate production is considered low.  Importantly, no toxicity has been observed in 
NHP pharmacology and toxicology studies, where profound suppression of hepatic GO, with 
associated increases in plasma glycolate levels, has been demonstrated.  In particular, 


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maintenance of normal serum bicarbonate levels in these animals indicates that there is no 
evidence of acidosis.  Finally, a recent clinical case study described a child with an incidentally 
discovered homozygous defect in HAO1, the gene encoding GO.  The patient exhibited marked 
elevations of urine glycolate, but no associated metabolic abnormalities and normal renal and 
hepatic function.[9] 
The potential negative consequences of ALN-GO1 administration to patients with impaired renal 
function, including those with end stage renal disease (ESRD), are considered low.  ALN-GO1, 
in common with other Sponsor-developed RNAi compounds, is conjugated to N-acetyl 
galactosamine (GalNAc) to enable rapid and specific uptake by hepatocytes via the 
asialoglycoprotein receptor.  Clinically effective doses of ALN-GO1 are not expected to saturate 
this receptor-mediated uptake or to result in enhanced extra-hepatic uptake or significant 
extra-hepatic exposure via accumulation; however, only patients with relatively well-preserved 
renal function are eligible to participate in this study. 
PH1 is primarily a pediatric disease, with predominantly early childhood expression of 
symptoms, an early age at diagnosis, and a decline in renal function with increasing age in 
childhood through adulthood. [Rare Kidney Stone Consortium Primary Hyperoxaluria. Available 
from: http://rarekidneystones.org/hyperoxaluria/, accessed on 25 September 2015]  The 
consequence is that early treatment is required to gain the greatest potential benefit and prevent 
loss of renal function as these patients age.  Systemic oxalosis, resulting from over production 
combined with insufficient dialytic clearance of oxalate, is the most devastating complication of 
PH1 and is not prevented or effectively treated by dialysis.  Liver/kidney transplantation is 
considered curative, but has high cost, high morbidity, and relatively low availability.  Children 
with relatively well-preserved renal function are more prevalent than adults and are the primary 
target population for development of ALN-GO1.  For this reason, children are included in the 
population for evaluation in this study. 
This study is designed such that safety data in healthy adult subjects will be evaluated at dose 
levels higher than proposed for the starting dose in patients, including those as young as 6 years 
of age.  Since the intended lowest dose for administration in patients will have been 
demonstrated to result in increased plasma glycolate concentration, a marker of the PD effect of 
ALN-GO1, and adequate safety in healthy subjects, the initial starting dose in patients is 
expected to be a potentially active dose of ALN-GO1.  
Although the study includes a placebo control, all patients initially assigned to placebo will be 
administered active treatment via a delayed start study design.  Study assessments and visits have 
been reduced as much as possible to minimize the burden of the study on children without 
risking patient safety.  The potential benefit to children enrolled in this study includes possible 
reduction in oxalate production during the study period, which may have a temporarily 
ameliorating effect on their disease.  In addition, experience in children with this disease under 
carefully controlled conditions will provide data that may enhance the future development of this 
therapeutic. 
Important potential risks to healthy subjects and patients include injection site reactions (ISRs).  
Other potential risks include:  embryofetal toxicity, coagulation abnormalities, and liver function 
test abnormalities.  These potential risks have been reduced by the specific inclusion and 
exclusion criteria incorporated into the selection of healthy subjects as well as for patients with 
PH1 in this clinical study.   


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No data are available on the use of ALN-GO1 in pregnancy; however, human mutagenicity is not 
suggested based on the available nonclinical data (see Investigator’s Brochure for further 
information).  Embryofetal risk is limited by requiring that women of childbearing potential 
(WOCBP) must have a negative pregnancy test, cannot be breast feeding, and must be willing to 
use a highly effective method of contraception as specified in the protocol.  Male 
subjects/patients are not required to use the contraception measures required for female study 
subjects/patients.  No male contraception is considered to be required. 
The occurrence of ISRs will be carefully monitored. 
Nonclinical studies in rats showed mild to moderate decreases in fibrinogen and occasionally 
minimal prolonged prothrombin time without accompanying clinical or microscopic evidence of 
hemorrhage.  This effect is likely species-specific as it was not observed in NHPs and will be 
monitored via clinical laboratory safety assessments. 
As ALN-GO1 is a hepatically-targeted therapeutic, liver function tests will be carefully 
monitored.  Nonclinical data suggest that there is a wide margin between the proposed clinical 
doses and any hepatic findings in toxicology studies and that any findings can be monitored.  
The potential non-specific, off-target risk of ALN-GO1 administration is considered to be low, 
based on nonclinical toxicological assessment of this molecule and accumulating experience 
with this RNA interference (RNAi) therapeutics platform. 
During the course of this study, safety will be monitored by study Investigators, the Sponsor 
Medical Monitor, and a SRC.  The initial dose level for administration in the MAD part of the 
study will have been previously shown to be safe, tolerable, and pharmacologically active based 
on SRC review of safety and PD data from the SAD part of the study.  Stopping rules have also 
been designed to protect study participants.  
Overall, in this clinical study of ALN-GO1, the risk to healthy subjects is considered low and the 
benefit/risk assessment is favorable in patients with PH1.  Moreover, since evaluation of safety 
and PD effects in children will be important in the design of future studies, it is considered 
important and appropriate to enroll children in the current study. 
The complete summary of the clinical and nonclinical data relevant to the investigational drug 
and its study in human subjects is provided in the Investigator’s Brochure. 
2. 
OBJECTIVES 
2.1. 
Primary Objective 
 Evaluate the safety and tolerability of single- and multiple-ascending doses of 
ALN-GO1, respectively, in healthy adult subjects and in patients with PH1 
2.2. 
Secondary Objectives 
 Characterize the PK of ALN-GO1 
 Evaluate the PD of ALN-GO1 


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2.3. 
Exploratory Objectives 
 
 exploratory 
 
 
 
3. 
ENDPOINTS 
3.1. 
Primary Endpoint 
 The primary endpoint is the incidence of adverse events (AEs).  Safety will also be 
evaluated through vital signs, electrocardiograms (ECGs), clinical laboratory 
assessments, and physical examinations. 
3.2. 
Secondary Endpoints 
3.2.1. 
Secondary Endpoints for the Single-ascending Dose Part in Healthy Adult 
Subjects (Part A) 
 PK parameters including, but not limited to, maximum plasma concentration [Cmax], 
time to reach maximum plasma concentration [tmax], area under the plasma 
concentration versus time curve [AUC], apparent terminal elimination half-life [t½], 
fraction eliminated in urine [fe/F], and renal clearance [CLR] 
 Plasma and urine glycolate concentration 
3.2.2. 
Secondary Endpoints for the Multiple-ascending Dose Part in Patients with 
Primary Hyperoxaluria Type 1 (Part B) 
 PK parameters including, but not limited to, Cmax, tmax, AUC, t½, fe/F, and CLR 
 Urinary oxalate excretion (oxalate concentration in 24-hour urine collection) 
 Urinary glycolate excretion (glycolate concentration in 24-hour urine collection) 
 Plasma glycolate concentration 
 Calculated creatinine clearance 
3.3. 
Exploratory Endpoints 
 Plasma oxalate concentration  
 
 
3.3.1. 
Exploratory Endpoints for the Multiple-ascending Dose Part in Patients with 
Primary Hyperoxaluria Type 1 (Part B) 
 
 
 
 
 
 


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4. 
INVESTIGATIONAL PLAN 
4.1. 
Summary of Study Design 
This is a randomized, single-blind, placebo-controlled study of subcutaneously administered 
ALN-GO1.  The study is designed to evaluate the safety, tolerability, PK, and PD of single- and 
multiple-ascending doses of ALN-GO1 and will be conducted in 2 parts: 
 Part A:  single-ascending dose (SAD) part in healthy adult subjects 
 Part B:  multiple-ascending dose (MAD) part in adult and pediatric patients with PH1 
The study will be conducted in a single-blind manner, with the Investigators, SRC, and Sponsor 
unblinded to permit ongoing unblinded review of safety, tolerability, PK, and PD data. 
Part A will be conducted at 1 clinical study center in the UK.  Part B is expected to take place at 
approximately 12 clinical study centers worldwide. 
The study design is summarized in Figure 1. 
Figure 1: 
Study Design 
Screening Period                  
        (Day -45 to Day -2
Randomization                         
(3:1 ratio of ALN-G O1: placebo
Dosing Period
Part A: ALN-GO1
Part A: Placebo
Part B: ALN-GO1
Part B: Placebo
Postdose Follow-up Period
Safety and PD Follow-up
 a                 
(Q28 [± 4] days)
Open-label       
ALN-GO1
 
a Patients in Part B will be invited to participate in an open-label extension study once they complete the postdose 
follow-up period.  For patients who do not enter the open-label extension study, safety and PD follow-up will 
continue until they meet the criteria described in Section 4.1.2, or until the SRC makes a decision per investigator 
request to discontinue follow-up on a case-by-case basis. The decision cannot be made until after completion of the 
last postdose follow-up visit (84 days after last dose). 
4.1.1. 
Single-ascending Dose Part in Healthy Adult Subjects (Part A) 
Part A is the single-ascending dose part of the study in healthy adult subjects.  Subjects will be 
enrolled in 1 of 3 ascending dose cohorts, with the possibility for 2 additional optional cohorts.  
Each cohort will be comprised of 8 subjects randomized 3:1 to ALN-GO1 or placebo (study 
drug). 
Subjects will be screened from -45 to -2 days before study drug administration.  Subjects will be 
admitted to the clinical study center on Day -1 to determine continued eligibility and for predose 
assessments.  Subjects in each cohort will be randomized on Day 1 and will receive 1 SC dose of 


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study drug.  Subjects will be discharged from the clinical study center on Day 2 after completing 
the 24-hour postdose follow-up assessments. 
Subjects will return to the clinical study center on an outpatient basis for safety, tolerability, PK, 
and PD monitoring at time points specified in the Schedule of Assessments through the last 
postdose follow-up visit (Day 57).  Safety and PD follow-up will continue: 1) for at least 
57 days, and 2) until plasma glycolate decreases to a level that is no more than 20% above of 
baseline or until plasma glycolate is below the upper limit of normal (≤14 nmol/mL). 
4.1.2. 
Multiple-ascending Dose Part in Patients with Primary Hyperoxaluria Type 1 
(Part B) 
Part B is the multiple-ascending dose part of the study in up to 24 adult and pediatric patients 
with PH1 with relatively well-preserved renal function.  Two ascending dose cohorts will be 
enrolled, with the possibility to also enroll up to 3 additional optional cohorts to further explore 
the optimal dose or regimen.  Each cohort will be comprised of 4 patients, randomized 3:1 to 
ALN-GO1 or placebo.  Up to 2 cohorts in Part B may be expanded by up to 4 additional patients 
per cohort (these patients will all receive ALN-GO1, not placebo).   
Patients will be screened within 45 days prior to study drug administration.  Baseline urinary 
oxalate excretion and creatinine clearance will be assessed through 24-hour urine collections.  
Patients will be randomized between Day -1 and Day 1 and will receive the first dose of 
ALN-GO1 or placebo on Day 1.  The 24- and 48-hour postdose follow up assessments will take 
place on Day 2 and Day 3.  Patients who receive study drug monthly will return to the clinical 
study center for safety, tolerability, PK, and PD monitoring at time points specified in the 
Schedule of Assessments (Table 2) for the remaining 2 single-blind doses of study drug (through 
Day 57).  After completion of the blinded portion of the study, patients dosed monthly will be 
unblinded (on or after Day 78).  Patients who initially received placebo will then receive 
ALN-GO1 at the same dose administered to the cohort into which they were initially randomized 
and will follow the same assessment schedule as indicated in Table 3. 
Patients who receive study drug quarterly will return to the clinical study center for safety, 
tolerability, PK, and PD monitoring at time points specified in the Schedule of Assessments 
(Table 4) and will receive a 2nd dose of study drug at Day 85.  Patients who initially received 
placebo will receive a single dose of ALN-GO1 on Day 85 at the same dose administered to the 
cohort into which they were initially randomized.  Patients dosed quarterly will be unblinded to 
initial treatment assignment following completion of the postdose follow-up period. 
After the dosing period, patients will return to the clinical study center for continued safety, 
tolerability, PK, and PD monitoring for at least 12 weeks (84 days) following the last dose of 
study drug.  Following completion of the 12-week postdose follow-up period, patients will be 
invited to participate in an open-label extension study.  
For patients who do not enroll in the open-label extension study, safety and PD follow up will 
continue until 24-hour urinary oxalate is >80% of baseline, and plasma glycolate is <20% above 
baseline or ≤ the ULN.  If an investigator wishes to discontinue follow up after completion of the 
postdose follow-up period and prior to oxalate and glycolate recovery, the SRC must agree based 
upon consideration of emerging data on the safety of ALN-GO1 knockdown and the individual 
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4.2. 
Duration of Treatment and Overall Duration of Study 
The duration of treatment is as follows: 
 Part A:  The estimated total time on study, inclusive of screening, for each subject is 
up to 405 days.  The duration of treatment is a single dose. 
 Part B:  For all patients, the duration of screening is up to 45 days and the minimum 
duration of postdose follow-up is 84 days. The duration of treatment and estimated 
total time on study, inclusive of screening, for each patient is as follows: 
 For patients dosed monthly:  The duration of treatment for patients initially 
randomized to receive active study drug is 57 days.  The estimated total time on 
study is up to 462 days.  Additionally, the duration of treatment for patients 
initially randomized to receive placebo is 141 days.  The estimated total time on 
study for each patient initially randomized to receive placebo, then active study 
drug, is up to 546 days. 
 For patients dosed quarterly: The duration of treatment is 85 days for patients 
randomized to placebo and active study drug.  The estimated total time on study is 
up to 490 days. 
The overall duration of the study is estimated to be 4 years, including enrollment. 
4.3. 
Number of Subjects and Patients 
A total of up to 64 participants (including optional and expansion cohorts) are planned to be 
enrolled in this study as follows: 
 Part A:  Up to 40 healthy adult subjects  
 Part B:  Up to 24 adult and pediatric patients with PH1 
4.4. 
Method of Assigning Patients to Treatment Groups 
This is a randomized, single-blind, placebo-controlled study.  In Parts A and B, after 
confirmation of eligibility, during screening, and upon admission to the clinical study center, 
subjects/patients will be assigned to a dose level cohort and randomized in a 3:1 ratio 
(ALN-GO1:placebo).  No subject/patient will be a member of more than 1 cohort.  A unique 
subject/patient identification number, incorporating the clinical study center number, will be 
assigned sequentially to the subject/patient. 
The clinical study center pharmacy staff will randomize the subject/patient in accordance to a 
cohort-specific randomization list generated by the biostatistician at the Contract Research 
Organization (CRO), for appropriate dispensation of the study drug. 
The information furnished to the Sponsor for subject/patient identification will be the assigned 
subject/patient identification number, the randomization number of subjects/patients admitted to 
the study, the age, and sex.  The subject’s/patient’s identification number will appear on all 
documents relating to that subject/patient and will be cross-referenced by the randomization 
number for the enrolled subjects/patients.  The Sponsor may receive a copy of the randomization 
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4.5. 
Blinding 
This is a single-blind, placebo-controlled study; therefore, only the study subjects/patients will be 
blinded to treatment assignment.  Patients in Part B dosed monthly will be unblinded on or after 
Day 78 in order for patients and their families to be better prepared for the transition to receive 
ALN-GO1 if initially randomized to placebo.  Patients dosed quarterly will be unblinded to 
initial treatment assignment following completion of the postdose follow-up period.  The 
Investigators, Medical Monitors at the Sponsor and CRO, clinical study center personnel, 
pharmacokineticist, and members of the SRC will have knowledge of the treatment assignment.  
The clinical study center pharmacy staff will maintain the single-blind according to clinical study 
center-specific procedures and the Pharmacy Manual.  Syringes containing dispensed study drug 
will be masked in the pharmacy before transfer to the clinic.   
During the blinded period, if the subject/patient becomes seriously ill during the study, and the 
treating physician determines that the clinical management of the subject requires that the subject 
know the study drug assignment, the Investigator may break the blind, as necessary.  If time 
permits, clinical study center personnel should contact the Medical Monitor before unblinding to 
discuss the need to unblind the subject/patient.  A record of when the blind was broken, who 
broke the blind, and why it was broken, will be maintained in the Trial Master File. 
See the Pharmacy Manual for additional details. 
4.6. 
Safety Review Committee 
A SRC will perform ongoing reviews of safety, tolerability, and available study data collected in 
all study parts (Parts A and B) with the primary purpose of protecting the safety of 
subjects/patients participating in this clinical study.  The SRC will undertake safety data review 
before initiation of dosing in a new cohort in Part A and Part B, and before initiation of dosing in 
Part B.  After initiation of dosing in Part B, safety reviews will be conducted in accordance with 
the SRC charter at a minimum of every 3 months for the duration of the study.  Part A and Part B 
of the study will incorporate adaptive study design features, which will allow for the continuing 
modification of dosing options and/or regimen as new data emerge, and in accordance with 
recommendations of the SRC (Table 9).  Protocol-defined stopping rules will be used as criteria 
for stopping cohorts (Table 6) or individual patients (Table 7).  Additionally, the SRC may 
recommend discontinuation of the study at its discretion.  The investigator may also request that 
the SRC determine on a case-by-case basis whether study follow-up will be discontinued in 
patients in Part B who do not enroll in the open-label extension study who have completed the 
postdose-follow up period, but have not yet met the recovery criteria for plasma glycolate and 
urinary oxalate specified in Section 4.1.2.  The decision will be informed by emerging data on 
the safety of ALN-GO1 knockdown and the individual patient’s safety and PD data.  
The SRC will be comprised of the Sponsor Medical Monitor, a Medical Monitor from the CRO, 
the Principal Investigator from the clinical study center conducting Part A of the study, an 
independent pediatrician experienced in clinical investigation who is not a study Investigator, 
and 3 Investigators at the clinical study sites who will be selected by the Sponsor. 
The SRC will be governed by a charter that will be signed prior to enrollment of the first subject. 


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4.7. 
Study Drug Dosing, Study Progression, and Dose Escalation 
For the purpose of this study, progression rules are based on toxicity.  The Common 
Terminology Criteria for Adverse Events (CTCAE; Version 4.0, or higher) will be used to grade 
AEs.  The decision to enroll an optional cohort or extend an existing cohort will be made by the 
SRC based on available safety, tolerability, and PD data, if further elucidation of dose response 
is considered necessary to better understand dose response and/or safety and tolerability. 
4.7.1. 
Study Drug Dosing, Study Progression, and Dose Escalation in Part A 
The following are the planned dose levels for Part A; however, the actual dose administered may 
be modified based on SRC review of emerging safety, tolerability, and available PD data in 
previous cohorts.  The initial starting dose level is expected to have an adequate safety margin 
and a low level of pharmacologic activity based on GLP toxicology study results and nonclinical 
pharmacology.   
 Cohort 1:  0.3 mg/kg 
 Cohort 2:  1.0 mg/kg 
 Cohort 3:  3.0 mg/kg 
 Cohort (optional) 
 Cohort (optional) 
The SRC will review a minimum of 48 hours of safety data from at least 6 subjects before 
escalation to the next dose level.  The SRC will review AEs and clinical laboratory evaluation 
data in order to proceed to the next cohort. 
Based on SRC review of accumulated safety and PD data, 2 additional optional subject cohorts 
may be enrolled and dosed according to the same eligibility criteria and randomization scheme as 
Cohorts 1 to 3.  The additional cohorts may be enrolled at higher, lower, or intermediate dose 
levels, but will not exceed the maximum administered dose of 6.0 mg/kg. 
4.7.2. 
Study Drug Dosing, Study Progression, and Dose Escalation in Part B 
Preliminary safety and PD data from Part A was evaluated by the SRC.  The initial dose level of 
1.0 mg/kg for administration in Part B was shown to be well-tolerated, and the lowest 
pharmacologically active dose.  In Part B, all patients in a cohort dosed monthly will receive the 
same dose for each of the 3 study drug doses.  Patients initially receiving 3 doses of placebo will 
receive 3 doses of ALN-GO1, with all 3 doses being the same for each of the 3 administrations 
of ALN-GO1.  Patients in a cohort dosed quarterly who are randomized to ALN-GO1 will 
receive the same dose for each of the 2 study drug doses.  Patients initially receiving 1 dose of 
placebo on Day 1 will receive 1 dose of ALN-GO1 on study Day 85.  The maximum dose 
administered will not exceed 6.0 mg/kg. 
Dose levels and/or dosing regimen in each cohort in Part B may be modified by the SRC.  The 
next higher dose cohort can be enrolled after at least 3 patients in the previous cohort receive 
their first and second dose and have been followed for at least 14 days following the second dose 
of study drug.  The SRC must review accumulating safety data from both single- and multiple-
ascending dose cohorts to confirm the dose level and permit dosing in the next MAD cohort.  In 


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Part B, patients randomized to placebo will be administered active ALN-GO1 in an open-label 
manner according to the same dose and assessment schedule for the cohort to which they were 
initially assigned. 
Based on SRC review of accumulated safety, tolerability, and PD data, 3 additional cohorts may 
be enrolled and dosed according to the same eligibility criteria in Part B to better define safety or 
PD effects.  Additional cohorts may be enrolled at higher, lower, or intermediate dose levels, but 
will not exceed the maximum administered dose of 6.0 mg/kg, and will follow the 
protocol-specified dose escalation criteria. 
Based on SRC review of accumulated safety, tolerability, and available PD data, up to 2 cohorts 
in Part B may be extended by up to 4 additional patients per cohort based on study progression 
and stopping rules.  These patients will all receive active drug, not placebo. 
4.7.3. 
Dose Suspension and Stopping Rules 
For the purpose of this study, dose suspension and stopping rules are based on toxicity.  Standard 
toxicity grading according to the CTCAE will be used to grade AEs.  The term ‘suspension’ 
means that no further study drug will be administered at the dose level and that further dose 
escalation/progression will be suspended.  If a suspension/stopping rule is met, there will be no 
further enrollment or dosing in the current cohort, or escalation to another cohort, in that part of 
the study and an ad hoc SRC meeting will be held.  Following SRC review and 
recommendations, dosing may be resumed at the same or higher dose level following approval 
from the concerned Regulatory Authority and the independent ethics committee 
(IEC)/institutional review board (IRB), if required by local regulations.  However, de-escalation 
to a lower dose or intermediate may be allowed without prior Regulatory Authority or IEC/IRB 
approval. 
4.7.3.1. 
Cohort Progression/Escalation and Suspension/Stopping Rules in Part A 
Study cohort progression/escalation and suspension/stopping rules for AEs considered possibly 
or definitely related to study drug for Part A are described in Table 6.  If a subject meets a 
stopping rule, the subject will be managed as clinically indicated and asked to complete all safety 
assessments according to the protocol. 


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Table 6: 
Cohort Progression/Escalation and Suspension/Stopping Rules for Part A 
CTCAE 
Gradea 
Severity/ 
Seriousness Reversibility 
Number 
of 
Subjects 
Affected 
Action 
Effect on Dose 
Progression/Escalation 
I 
Mild 
N/A 
N/A 
Next dose 
determined by 
SRC 
N/A 
II 
Moderate 
Showing 
signs of 
reversibility 
(ie, AE 
which shows 
signs of 
improvement 
in the 
judgment of 
Investigator)  
≤2 
subjects 
in 
different 
SOC 
≤2 
subjects 
in same 
SOC 
OR 
3 subjects 
in 
different 
SOCb 
Dose level 
may continue 
OR 
be extended 
AND  
dose 
escalation on 
hold until 
results of 
continuation 
or extension 
are available 
Following continuation 
or extension, dose 
escalation may proceed 
as per clinical study 
protocol 
 
≥3 
subjects 
in same 
SOC 
OR 
≥4 
subjects 
in 
different 
SOCb 
Dose level 
suspended 
A lower (intermediate) 
dose level may be 
administered in the next 
cohort 
AND  
dose continuation, 
extension, or escalation 
requires Regulatory 
Agency, IEC/IRB, and 
SRC approval 
Showing no 
signs of 
reversibility  
≥2 
subjectsb 


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Table 6: 
Cohort Progression/Escalation and Suspension/Stopping Rules for Part A 
CTCAE 
Gradea 
Severity/ 
Seriousness Reversibility 
Number 
of 
Subjects 
Affected 
Action 
Effect on Dose 
Progression/Escalation 
III 
Severe, not 
serious 
Showing 
signs of 
reversibility 
(ie, AE 
which shows 
signs of 
improvement 
in the 
judgment of 
Investigator) 
1 subjectb 
Dose level 
may continue 
OR 
be extended 
AND 
dose 
escalation 
on-hold until 
results of 
continuation 
or extension 
are available 
Following continuation 
or expansion, dose 
escalation may proceed 
as per the clinical study 
protocol 
≥2 
subjectsb 
Dose level 
suspended 
A lower (intermediate) 
dose level may be 
administered in the next 
cohort 
AND 
dose continuation, 
extension or escalation 
requires Regulatory 
Agency, IEC/IRB, and 
SRC approval 
Showing no 
signs of 
reversibility  
≥1 
subject 
Severe, 
serious 
N/A 
IV/V 
Life-
threatening/ 
Fatal 
N/A 
≥1 
subject 
Study 
suspended 
Study continuation 
requires Regulatory 
Agency, IEC/IRB, and 
SRC approval 
Abbreviations:  AEs=adverse events; IEC=Independent Ethics Committee; IRB=Institutional Review Board; 
N/A=not applicable; SOC=System, Organ, Class; SRC=Safety Review Committee. 
a  Common Terminology Criteria for Adverse Events, Version 4.0 or higher, will be used to grade AEs. 
b  SRC review of Part A cohorts for escalation to the next dose level will occur following at least 48 hours of safety 
monitoring after the prior cohort has been dosed. 
4.7.3.2. 
Individual Patient Progression/Escalation and Suspension/Stopping Rules in 
Part B 
Individual progression/escalation and suspension/stopping rules applying only to individual 
patients enrolled in Part B are presented in Table 7.  If an individual patient meets a 
suspension/stopping rule, the SRC will meet to determine whether dosing of the remaining 


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patients in the cohort can continue.  Table 7 applies to AEs considered likely to be related to the 
underlying disease, or AEs considered possibly or definitely related to study drug. 
CTCAE criteria will be used to grade AEs.  For patients with abnormal renal function consistent 
with the underlying disease at baseline, evidenced by elevated serum creatinine, the change in 
this parameter from baseline should be used in grading AEs, rather than laboratory normal 
values. 
Table 7: 
Individual Patient Progression/Escalation and Suspension/Stopping 
Rules for Part B 
CTCAE 
Gradea 
Severity/Seriousness Action 
I 
Mild 
No action required. 
II 
Moderate 
Dose administration will be discontinued unless the 
AE is considered unrelated to study drug or reversible 
and continued dosing in the study is considered safe 
by the SRC. 
III 
Severe, not serious 
Severe, serious 
Dose administration will be discontinued. 
IV/V 
Life-
threatening/Fatal 
Dose administration will be discontinued. 
Abbreviations:  AEs=adverse events; SRC=Safety Review Committee. 
a Common Terminology Criteria for Adverse Events will be used to grade AEs. 
4.7.3.3. 
Cohort Progression/Escalation and Suspension/Stopping Rules in Part B 
Study cohort progression/escalation and suspension/stopping rules for AEs considered likely to 
be related to the underlying disease and for AEs considered possibly or definitely related to study 
drug for Part B are described in Table 8.  If a patient meets a stopping rule, the patient will be 
managed as clinically indicated and asked to complete all safety assessments according to the 
protocol.  For patients with abnormal renal function consistent with their underlying disease at 
baseline, evidenced by elevated serum creatinine, the change in this parameter from baseline 
should be used in grading AEs, rather than laboratory normal values. 


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Table 8: 
Cohort Progression/Escalation and Suspension/Stopping Rules for 
Part B 
Adverse Event(s) 
Action 
If ≥1 patient in a 
cohort experiences a 
severe AE and/or 
SAE, judged to be 
possibly or definitely 
related to study drug 
Dosing within that cohort, and in any cohorts receiving a higher 
dose, will be suspended until SRC review.  Following data 
review, the SRC may permit continuation of any ongoing Part B 
cohort. 
Any further dose escalation in a subsequent cohort will be 
suspended.  Resumption of dose escalation will require a 
substantial amendment, approved by the regulatory authority and 
relevant ethics committee, if required by local regulations.  
However, de-escalation to a lower dose, or intermediate but 
lower dose, may be allowed by the SRC without a protocol 
amendment. 
If ≥1 patient in Part 
B experiences a 
Grade 4 or 5 AEa 
judged to be possibly 
or definitely related 
to study drug 
Dosing of all patients in Part B will be suspended until SRC 
review.  Resumption of the study will require a substantial 
amendment, approved by the regulatory authority and relevant 
ethics committee, if required by local regulations.   
Abbreviations:  AE=adverse event; SAE=serious adverse event; SRC=Safety Review Committee. 
a  Common Terminology Criteria for Adverse Events will be used to grade AEs. 
4.8. 
Adaptive Study Design Features 
The use of adaptive study design features will allow for the continuing development of the study 
as new data emerge; therefore, the study can be adjusted in accordance with the prespecified 
areas, features, and limits listed in Table 9. 
Table 9: 
Adaptive Study Design Areas, Features, and Limits 
Areas  
Features 
Limits 
A. Dosing 
regimen 
1. Dosing regimens may be 
determined or adapted in accordance 
with safety, tolerability, and 
available PD data collected up to the 
decision making time point. 
2. The term “dosing regimen”  
includes: (1) the dose level 
administered, (2) the frequency of 
dosing, and (3) the duration of 
dosing, ie, number of doses 
administered.  Accordingly, these 
can be adjusted individually or in 
combination. 
I. The starting dose for subjects in Part A will be 
0.3 mg/kg. 
II. The starting dose for subjects in Part B of the 
study will not exceed doses already evaluated 
and considered safe and tolerable in Part A. 
III. In Part A, provided no safety or tolerability 
concerns have occurred, the maximum single 
dose administered will be 6 mg/kg. 
IV. The interval between doses in Part B may be 
increased or decreased, but will not exceed 
3 doses over a 57 day period. 


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Table 9: 
Adaptive Study Design Areas, Features, and Limits 
Areas  
Features 
Limits 
V. Duration of dosing:  no more than 1 dose will 
be administered in Part A; dosing will not extend 
beyond 3 doses over a 57 day period in Part B. 
VI. The maximum dose level in Part B will not 
exceed a dose found to be safe and well-tolerated 
in Part A. 
B. Overlap 
1. Dosing regimens may overlap. 
I. Protocol-specific minimum study 
progression/escalation requirements for the SRC 
must be met before dose progression/escalation 
(Section 4.7). 
C. Cohort 
Sizes 
1. Withdrawn subjects (Part A) and 
patients (Part B) can be replaced at 
the discretion of the Sponsor and 
Investigator if not withdrawn for 
safety reasons (Section 5.3). 
2. Replacement subjects may be 
enrolled in an ongoing cohort, or 
dosed together as a group or 
separately. 
I. Protocol-specific minimum requirements must 
be met before dose escalation (Section 4.7). 
II. Provided suspension or stopping rules have 
not been met, the SRC may permit up to 
2 cohorts in Part B to be extended by up to 
4 additional patients per cohort receiving active 
treatment to further characterize the safety, 
tolerability, and PD of the study drug. 
D. Optional 
Cohorts 
1. Optional cohorts may be included 
to explore additional dosing 
regimens 
I. Up to 2 optional cohorts may be included in 
Part A. 
II. Up to 3 optional cohorts may be included in 
Part B. 
III. Cohort sizes will not exceed 8 subjects for 
each optional cohort in Part A, and 8 patients for 
each optional cohort in Part B. 
IV. To further explore safety, tolerability, PD, 
and/or PK, study drug dose level may be 
escalated or de-escalated to a lower and/or to 
intermediate dose levels.  Dose escalation in Part 
B will not exceed a dose level found to be safe 
and well-tolerated in Part A. 
V. Dosing in optional cohorts will follow the 
same randomization list as that in planned 
cohorts in the respective parts of the study. 
VI. The total number of study subjects/patients 
indicated in Section 4.3 cannot be exceeded. 
E. Samples 
and 
assessments 
1. If applicable, the inpatient period 
may be prolonged for 
subjects/patients in all dose levels in 
all cohorts if considered by the 
Investigator to be necessary for 
clinical reasons or for expeditious 
I. If applicable, a maximum extended inpatient 
period due to clinical concerns cannot be defined 
as the extension will be as long as necessary to 
ensure the safety of the subjects/patients. 
II. If applicable, an unplanned or extended 
inpatient stay because of a suspected adverse 


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Table 9: 
Adaptive Study Design Areas, Features, and Limits 
Areas  
Features 
Limits 
conduct of the study.  Prolonged 
inpatient periods will be 
recommended on a subject/patient, 
case-by-case basis and/or if the SRC 
considers it necessary for 
determining safety and tolerability 
for a future dose level cohort. 
event will constitute a serious adverse event and 
will be considered in the context of the study 
stopping rules (Section 4.7). 
2. Specialist referrals may be made if 
considered clinically necessary by 
the Investigator, delegate, Sponsor, 
or SRC for subjects/patients on a 
case-by-case basis. 
I. Specialist referrals for subjects/patients will be 
determined on a case-by-case basis, as necessary 
to ensure the safety of subjects/patients, so a 
maximum number of referrals cannot be defined. 
3. In Part A and B, timing of PK 
and/or PD samples (blood and/or 
urine) may be adjusted in accordance 
with evolving data and dosing 
schedule/regimen.  
4. In Part A and B, additional or 
fewer PK and/or PD samples (blood 
and/or urine) may be obtained in 
accordance with evolving data and 
dosing schedule. 
I. Maximum blood volume for any 
subject/patient is based on age and weight 
guidelines; the maximum blood volume will not 
be exceeded. (Section 7). 
II. Optional PK and/or PD analysis can be 
performed at any stage during or after the study 
to facilitate decision-making and/or to increase 
understanding of the compound (ie, samples will 
be obtained, but not necessarily analyzed; 
applicable to Features 3 and 4). 
III. The optional analysis is limited to the 
protocol-specified purpose (applicable to 
Features 3 and 4). 
Abbreviations:  PD=pharmacokinetic; PK=pharmacokinetic; SRC=Safety Review Committee. 
5. 
SELECTION AND WITHDRAWAL OF PATIENTS 
5.1. 
Inclusion Criteria 
Each subject/patient must meet all of the following inclusion criteria to be eligible for enrollment 
in the study. 
5.1.1. 
Inclusion Criteria for Parts A and B 
1. Male and female subjects aged 18 to 64 years (or age of legal consent, whichever is 
older), inclusive (Part A) and 6 to 64 years, inclusive (Part B).  
2. Women of child-bearing potential must have a negative pregnancy test, cannot be breast 
feeding, and must be willing to use a highly effective method of contraception 14 days 
before first dose, throughout study participation until the completion of the follow-up 
periods (see Section 6.4).  


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3. Willing to comply with protocol-required visit schedule and visit requirements; and able 
to provide written informed consent and assent in the case of patients under the age of 
legal consent. 
5.1.2. 
Additional Inclusion Criteria for Part A 
4. Body Mass Index (BMI) of 18-30 kg/m2, inclusive at screening and Day -1. 
5.1.3. 
Additional Inclusion Criteria for Part B 
5. Documentation or confirmation of PH1 as determined by genetic analysis and 
biochemical criteria and definite diagnosis based on the presence of AGXT mutations or 
reduced hepatic AGT enzyme activity that is considered evidence of the disease state 
(medical history) 
6. 24-hour urinary oxalate excretion of >0.7 mmol/1.73m2/day 
7. Estimated GFR of >45 mL/min/1.73m2 (calculation will be based on the MDRD formula 
for patients ≥18 years of age and the Schwartz Bedside Formula for patients <18 years of 
age; Section 11.2 in the Appendix) 
8. If taking Vitamin B6 (pyridoxine), must have been on stable regimen for at least 90 days 
before study entry, and willing to remain on this stable regimen for the study duration. 
5.2. 
Exclusion Criteria 
Each subject/patient must not meet any of the following exclusion criteria to be eligible for 
enrollment in the study. 
5.2.1. 
Exclusion Criteria for Parts A and B 
1. Any uncontrolled or serious disease, or any medical or surgical condition (with the 
exception of PH1 for patients in Part B) that may either interfere with participation in the 
clinical study, and/or put the subject significant risk (according to the Investigator’s 
judgment) if he/she participates in the clinical study 
2. An underlying known disease or surgical or medical condition (with the exception of 
PH1 for patients in Part B) that in the opinion of the investigator might interfere with the 
interpretation of the clinical study results 
3. Triplicate 12-lead ECG with clinically significant abnormalities 
4. Active serious mental illness or psychiatric disorder including, but not limited to, 
schizophrenia, bipolar disorder, or severe depression requiring concurrent pharmacologic 
intervention 
5. Clinically significant illness (with the exception of PH1 for patients in Part B) within 
7 days before the first dose of study drug 
6. Male and female subjects/patients aged 18 to 64 years (or age of legal consent, whichever 
is older), systolic blood pressure >140 mm Hg and/or a diastolic blood pressure 
>90 mmHg after 10 minutes of rest at screening 
7. Abnormal for AST/ALT and any other clinical safety laboratory result considered 
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8. Received an investigational agent within 90 days or 5 half-lives of the first dose of 
ALN-GO1 study drug, whichever is longer, or in the active follow-up phase of another 
clinical trial involving interventional treatment 
9. Clinical laboratory evidence or a clinical diagnosis of viral hepatitis or human 
immunodeficiency virus (HIV) infection 
10. Consume more than 14 (female) or 21 (male) units of alcohol per week (1 unit=1 glass of 
wine (125 mL), 1 measure of spirits or ½ pint of beer (subjects/patients above the age of 
legal consent).  Alcohol abuse is defined as regular weekly intake of more than 21 units 
for males and 14 units for females (using alcohol tracker at 
http://www.nhs.uk/Tools/Pages/NHSAlcoholtracker.aspx). 
11. History or clinical evidence of drug abuse, within the 12 months before screening.  Drug 
abuse is defined as compulsive, repetitive and/or chronic use of drugs or other substances 
with or without problems related to their use and/or where stopping or a reduction in dose 
will lead to withdrawal symptoms (subjects/patients above the age of legal consent). 
12. Positive for drugs of abuse at screening (subjects/patients above the age of legal consent) 
13. Heavy smokers and users of nicotine (defined as the equivalent of ≥10 cigarettes per 
day). 
14. Known history of allergic reaction to an oligonucleotide or GalNAc 
15. History of intolerance to SC injection or relevant abdominal scarring (eg, surgical, burns) 
16. Legal incapacity or limited legal capacity at screening of patient, parent, or legal guardian  
17. Any conditions which, in the opinion of the Investigator would make the subject/patient 
unsuitable for enrollment or could interfere with the subject’s/patient’s participation in, or 
completion of, the study. 
18. Donation of more than 500 mL of blood for adults (>18 years of age) within 90 days 
before the first dose of study drug (it is expected that children [6 to18 years of age] will 
not have donated blood). 
19. Women who are pregnant or breastfeeding 
5.2.2. 
Additional Exclusion Criteria for Part B 
20. Clinical evidence of systemic oxalosis, including but not limited to, myocardial 
dysfunction, bone marrow, bone, or eye infiltration with oxalate as determined by the 
Investigator 
21. For patients <18 years old, diastolic and/or systolic blood pressure equal to or greater 
than the 95th percentile for age, gender, and height (see Appendix 11.4 Table 14 and 
Table 15) after 10 minutes of rest at screening. 
22. Echocardiography (Echo) assessment of abnormal left ventricular systolic function, 
defined as left ventricular ejection fraction <55% at screening 
23. Troponin I greater than the upper limit of normal (ULN) at screening (abnormal results 
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5.3. 
Removal from Therapy or Assessment 
Subjects/Patients are free to discontinue treatment or withdraw from the study at any time and 
for any reason, without penalty to their continuing medical care.  Any discontinuation of 
treatment or withdrawal from the study must be fully documented in the electronic case report 
form (eCRF), and should be followed up by the Investigator.  The Investigator may withdraw a 
subject/patient at any time if this is considered to be in the subject’s/patient’s best interest. 
Discontinuation of study drug and withdrawal from the study are described in Section 5.3.1 and 
Section 5.3.2, respectively. 
5.3.1. 
Discontinuation of Study Drug 
The Investigator or designee may discontinue dosing in a subject/patient if the subject/patient: 
 Is in violation of the protocol 
 Experiences a serious or intolerable AE 
 Requires a prohibited medication 
 Becomes pregnant 
 Is found to be noncompliant with the protocol-requirements in a manner that is 
considered by the Investigator to compromise patient safety and/or the integrity of the 
study 
The Investigator will confer with the Sponsor, or Medical Monitor, before discontinuing dosing.  
Subjects/Patients who are pregnant will be discontinued from dosing immediately (see 
Section 7.5.7.6 for reporting and follow-up of pregnancy).  Subjects/patients who discontinue 
study drug may be replaced (see Section 5.3.3).  Subjects/patients who discontinue study drug 
dosing for any reason will be encouraged to complete the remaining assessments through the 
remaining scheduled study visits so that their experience is captured in the study analyses.  
Subjects/Patients who discontinue study drug but who agree to attend the remaining scheduled 
study visits will not be considered withdrawn from study.  Such subjects/patients may receive 
local standard of care treatment for their disease, as applicable. 
5.3.2. 
Withdrawal From Study 
A subject/patient may withdraw from the study at any time.  However, study integrity and 
interpretation is optimal if all randomized patients continue study assessments and follow-up.  
Subjects/Patients considering withdrawing from the study should be informed that they can 
alternatively discontinue study treatment and complete the remaining scheduled study visits or 
agree to alternative follow-up processes (as described in Section 5.3.1).   
If a subject/patient still chooses to withdraw consent/assent, every effort should be made to 
conduct the assessments performed at the EOT visit.  When a subject/patient withdraws from the 
study, the primary reason for withdrawal must be recorded in the appropriate section of the eCRF 
and all efforts will be made to complete and report the observations as thoroughly as possible. If 
a subject/patient withdraws due to a serious adverse event (SAE), the SAE should be followed as 
described in Section 7.5.7. 


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5.3.3. 
Replacement of Subjects or Patients 
Replacement subjects/patients may be enrolled to ensure that the minimum data requirements for 
SRC dose escalation decisions and study progression are met, as described in Section 4.6 and 
Section 4.7.  Subjects/patients who are discontinued from treatment for reasons other than 
experiencing an AE may be replaced following discussion between the Sponsor and Investigator.   
The replacement subject/patient will be assigned a unique study identification number and will 
receive the same study drug assignment and dose level as the subject/patient who is being 
replaced. 
6. 
TREATMENTS 
6.1. 
Treatments Administered 
The treatments administered in this study are ALN-GO1 and placebo.  ALN-GO1 is a synthetic, 
double-stranded small interfering RNA oligonucleotide directed against hydroxyacid oxidase 1 
mRNA that is covalently linked to a ligand containing 3 N-acetylgalactosamine residues. 
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 to a subject/patient and returned unused must not be re-dispensed to a different 
subject/patient. 
6.2. 
Investigational Study Drug 
Detailed information describing the preparation, administration, and storage of ALN-GO1 is 
provided in the Pharmacy Manual. 
6.2.1. 
Description 
ALN-GO1 Solution for Injection (SC use) is a clear, colorless to pale yellow solution essentially 
free of particulates.  ALN-GO1 will be supplied by the Sponsor as a sterile solution for SC 
injection at a targeted concentration of 200 mg/mL.  Placebo will be supplied by the clinical 
study center as a sterile, preservative-free normal saline 0.9% solution for SC injection. 
6.2.2. 
Dose and Administration 
Dose cohorts for this study are described in Section 4.7.1 (Part A) and Section 4.7.2 (Part B).  
Subjects/patients will be administered study drug by SC injection(s).  Study drug will be 
administered by qualified clinical study center staff under the supervision of the Investigator, or 
designee, and the injection site will be marked and mapped for later observation.  The preferred 
site of injection is the abdomen.  Optional additional sites are the upper arms and thighs.  If a 
local reaction around the injection site occurs, photographs may be obtained.  Detailed 
instructions for study drug administration are in the Pharmacy Manual. 
6.2.3. 
Dose Modifications 
The dose modifications permitted in this study are described in Section 4.7.3. 


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6.2.4. 
Preparation, Handling, and Storage 
Study drug may be dispensed only by the Investigator, by a staff member specifically authorized 
by the Investigator, or by pharmacy staff, as appropriate. 
Each clinical study center will be responsible for assembly and labeling of injection syringe(s) 
according to procedures detailed in the Pharmacy Manual.  The pharmacy staff will prepare the 
study drug using an aseptic technique.  The amount (in mg) of study drug to be administered will 
be determined based on the assigned dose level for the cohort and the Day -1 body weight for 
healthy subjects and patients with PH1.  On dosing days, the pharmacist, or designee, will 
withdraw the required amount of study drug into 1 or more syringes to be administered to the 
subject/patient on that day.  The procedure for preparing study drug and the volume to be loaded 
into each syringe is provided in the Pharmacy Manual. 
No special procedures for the safe handling of ALN-GO1 are required.  Study drug will be stored 
upright and refrigerated at approximately 2 to 8°C protected from light in the storage area of the 
clinical study center pharmacy, in a secure, temperature-controlled, locked environment with 
restricted access.  Any deviation from the recommended storage conditions should be reported to 
the Sponsor and use of the study drug halted until authorization for its continued use has been 
provided by the Sponsor or designee.  Additional storage details are provided in the Pharmacy 
Manual.   
A Sponsor representative or designee will be permitted, upon request, to audit the supplies, 
storage, dispensing procedures, and records. 
6.2.5. 
Packaging and Labeling 
ALN-GO1 (solution for SC injection) is packaged in 2-mL glass vials with a fill volume of no 
less than 0.55 mL to allow for complete withdrawal of 0.5 mL of drug product at the pharmacy.  
The container closure system consists of a Type I glass vial, a Teflon-faced 13-mm stopper, and 
a flip-off aluminum seal. 
6.2.6. 
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.   
Further instructions about drug accountability are detailed in the Pharmacy Manual. 
6.3. 
Concomitant Medications 
All concomitant medications must be recorded in the eCRF.  Concomitant medications will be 
coded using the WHO Drug Dictionary. 
Any concomitant medication that is required for the patient’s welfare may be administered by the 
Investigator.  However, it is the responsibility of the Investigator to ensure that details regarding 
the medication are recorded on the eCRF. 


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6.3.1. 
Permitted Concomitant Medications 
For Part A and Part B, the following medications/treatments are permitted: 
 hormone replacement therapy 
 oral contraceptives, injectable progesterone, and subdermal implants are permitted for 
contraception 
 acetaminophen (maximum 2 g daily) for treatment of AEs 
 at the discretion of the Investigator, prescription or nonprescription medications may 
be permitted when necessary to treat an AE; before the subject uses any prescription 
or nonprescription medications, the Investigator or delegate must be consulted and 
justify their use 
For Part B, the following medication/treatment is also permitted: 
 Vitamin B6 (pyridoxine):  If taking vitamin B6, must have been on stable regimen for 
at least 90 days before study entry, and willing to remain on this stable regimen for 
the study duration. 
 Sodium or potassium citrate 
6.3.2. 
Prohibited Concomitant Medications 
For Part A, the following medications/treatments are not permitted: 
 Any OTC medications, except routine vitamins from 7 days before the first dose of 
study drug, unless considered not clinically relevant by the Investigator and Sponsor 
 Prescription medications not specified in Section 6.3.1 from 14 days or 5 half-lives 
(whichever is longer) before the first dose of study drug. 
For Part B, there are no prohibited medications; however, all concomitant medications must be 
reviewed by the Investigator.  
6.4. 
Contraceptive Requirements 
Women of child-bearing potential (WOCBP) must be willing to use a highly effective method of 
contraception 14 days before first dose, and throughout study participation until the completion 
of the follow-up periods.  Highly effective methods of birth control result in a low failure rate 
(ie, less than 1% per year).  Birth control methods, which may be considered as highly effective, 
include: 
 Established use of oral (except low-dose gestagens [eg, lynestrenol and 
norethisterone]), implantable, injectable, or transdermal hormonal methods of 
conception 
 Placement of an intrauterine device  
 Placement of an intrauterine hormone-releasing system  
 Bilateral tubal occlusion 


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 Surgical sterilization of male partner (with the appropriate post-vasectomy 
documentation of the absence of sperm in the ejaculate; for female patients on the 
study, the vasectomized male partner should be the sole partner for that patient); 
 True sexual abstinence, when in line with the preferred and usual lifestyle of the 
patient (and for adolescents who are not sexually active).  Periodic abstinence (eg, 
calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception.  Abstinent subjects have to agree to use 1 of the 
abovementioned contraceptive methods, if they start sexual relationships during the 
study until the completion of the follow-up periods. 
WOCBP includes any female patient who has experienced menarche and who is not 
postmenopausal or permanently sterilized (eg, bilateral tubal occlusion, hysterectomy, or 
bilateral salpingectomy).  Postmenopausal state is defined as no menses for 12 months without 
an alternative medical cause, confirmed by follicle stimulating hormone (FSH) level within the 
postmenopausal range. 
No male contraception is considered to be required. 
6.5. 
Treatment Compliance 
All doses will be administered by qualified clinical study center personnel and any missed doses 
will be reported and recorded on the eCRF. 
7. 
STUDY ASSESSMENTS 
The schedules of assessments are provided in Table 1 for Part A; and in Table 2, Table 3, and 
Table 4 for Part B. 
7.1. 
Screening/Baseline Assessments 
Subject/patient demographic data and complete medical history (including documentation or 
confirmation of PH1) will be obtained at Screening.  Screening safety assessments are included 
in the Schedule of Assessments, with additional details provided in Section 7.5, as applicable. 
7.1.1. 
Renal Function in Part B  
7.1.1.1. 
Urinary Oxalate Excretion and Creatinine Clearance 
During the screening period, 24-hour urine collections will be completed at 2 separate time 
points.  The first screening 24-hour urine collection will be used to assess eligibility.  The second 
screening 24-hour urine collection will only be initiated after eligibility is confirmed.  Blood 
samples for serum creatinine will be obtained throughout the study as part of clinical laboratory 
assessments (see Section 7.5.6) for the calculation of creatinine clearance. 
Patients will be instructed to collect urine samples for the full 24-hour period; however, after 
confirming eligibility, for patients unable to collect urine samples for the full 24-hour period, 
urinary oxalate excretion may be calculated from samples collected over an 18 to 24 hour period. 


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Patients will have the option to bring the 24-hour urine collections to the clinical study center at 
specified follow-up visits, courier samples to the clinical study center or to the vendor 
performing analyses, or elect to have the 24-hour urine collected during an inpatient stay at the 
clinical study center for other assessments. 
7.1.1.2. 
Estimated Glomerular Filtration Rate 
eGFR (mL/min/1.73m2) will be calculated to confirm eligibility and to assess renal function 
during the study.  The calculation will be based on the Modification of Diet in Renal Disease 
(MDRD) formula for patients ≥18 years of age and the Schwartz Bedside Formula for patients 
<18 years of age (Appendix 11.2).[10, 11]  
7.2. 
Pharmacodynamic Assessments 
Urine and blood samples will be collected for assessment of PD parameters (oxalate and 
glycolate concentrations) at the time points in the Schedule of Assessments. 
In Part B, single, 24-hour urine collections 
 will be collected for the 
analysis of urinary glycolate and oxalate excretion, and creatinine clearance.  The 24-hour urine 
collection starting on Day -1 must conclude on Day 1 before administration of the first dose of 
study drug.  Blood samples will also be collected for the analysis of plasma glycolate 
concentration. 
Options for providing 24-hour urine collections to the clinical study center are in Section 7.1.1.1. 
Details regarding the processing and aliquoting of samples for storage and PD analyses will be 
provided in the Laboratory Manual. 
7.3. 
Pharmacokinetic Assessments 
Blood and urine samples will be collected for assessment of ALN-GO1 PK parameters in Part A 
and Part B of the study at the time points in the Schedule of Assessments.  In Part B, samples 
may also be analyzed for the 
  A detailed schedule of time points 
for the collection of blood and urine samples for PK analysis is in Table 10 for Part A and in 
Table 11 and Table 12 for Part B in Appendix 11.1. 
Options for providing urine collections to the clinical study center are in Section 7.1.1.1. 
The concentration of ALN-GO1 will be determined using a validated assay.  Details regarding 
the processing, shipping, and analysis of the samples will be provided in the Laboratory Manual. 
7.4. 
Exploratory Assessments 
Blood and urine samples will be collected for exploratory analyses of plasma oxalate 
concentration
 
 
 
 
 
 
  


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Details regarding the collection, processing, storage, and shipping of samples will be in the 
Laboratory Manual. 
7.5. 
Safety Assessments 
The assessment of safety during the course of the study will consist of the surveillance and 
recording of AEs, including serious adverse events (SAEs), recording of concomitant medication 
and measurements of vital signs, weight, physical examination and ECG findings, and clinical 
laboratory assessments; Echo assessments will also be evaluated in Part B only. 
Safety will be monitored over the course of the study by an SRC as described in Section 4.6. 
7.5.1. 
Vital Signs 
Vital sign measurements include blood pressure, heart rate, body temperature, and respiratory 
rate.  Vital signs will be measured in the supine position (should be consistent for each patient), 
after the subject/patient has rested comfortably for 10 minutes.  Body temperature will be 
measured using a tympanic or oral thermometer.  A patient’s body temperature should be 
measured using the same method throughout the course of the study. 
7.5.2. 
Weight and Height 
Body weight will be measured in kilograms.  Body mass index will be calculated from the height 
and weight.  For patients <18 years of age, height will be measured in centimeters, and in 
triplicate, to facilitate calculation of eGFR using the Schwartz Bedside Formula.  
7.5.3. 
Physical Examination 
A full physical examination will include general appearance, eyes, ears, nose and throat, 
chest/respiratory, heart/cardiovascular, gastrointestinal/liver, musculoskeletal/extremities, 
dermatological/skin, thyroid/neck, lymph nodes, and neurological/psychiatric assessments. 
A symptom-directed physical examination will include the evaluation of changes in symptoms, 
or the onset of new symptoms, since the last visit. 
7.5.4. 
Electrocardiogram 
Triplicate 12-lead ECGs will be measured approximately 5 minutes apart.  Recordings will be 
obtained after the subject/patient has rested comfortably in the supine position for approximately 
10 minutes.  Subjects/Patients should remain supine between ECGs.  ECGs should be performed 
at approximately the same time of day throughout the study.     
Additional ECGs may be collected at the discretion of the Investigator.  The electrophysiological 
parameters assessed will include, but are not limited to, rhythm, ventricular rate, PR interval, 
QRS duration, QT interval, ST and T waves, Bazett-corrected QT interval (QTcB) and Fridericia 
corrected QT interval (QTcF). 
The Investigator or designee is responsible for reviewing the ECGs to assess whether the results 
have changed since the Screening/Baseline visit and to determine the clinical significance of the 
results.  For any clinically significant changes from the Screening/Baseline visit (eg, ischemic 
ECG changes, wave/interval changes, or arrhythmia), the Investigator must contact the Medical 
Monitor to discuss continued participation of the subject/patient in the study. 


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7.5.5. 
Echocardiography (Part B only) 
Echo assessments will be performed according to instructions provided in a study manual.  The 
Investigator or designee is responsible for reviewing the Echos to assess whether the results have 
changed since the Screening/Baseline visit and to determine the clinical significance of the 
results.  For any clinically significant changes from the Screening/Baseline visit, the Investigator 
must contact the Medical Monitor. 
7.5.6. 
Clinical Laboratory Assessments 
Clinical laboratory tests will be evaluated as noted in the Schedule of Assessments.  In the event 
of an unexplained clinically relevant abnormal laboratory test occurring after study drug 
administration, the test should be repeated and followed up at the discretion of the Investigator 
until it has returned to the normal range or stabilized, and/or a diagnosis is made to adequately 
explain the abnormality. 
Hematology 
Complete blood count with differential 
 
Serum Chemistry 
Sodium 
Potassium 
BUN 
Phosphate 
Creatinine and eGFR calculation (using the MDRD 
or Schwartz formula depending on age) 
Albumin 
Uric acid 
Calcium 
Total protein 
Carbon dioxide/bicarbonate 
Glucose 
Chloride 
Cardiac Enzyme 
 
Troponin I 
 
Liver Function Tests 
 
AST 
ALP 
ALT 
Bilirubin (total and direct) 
Coagulation Panel 
 
Prothrombin time 
International Normalized Ratio 
Activated partial thromboplastin time 
 


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Urinalysis 
Visual inspection for appearance and color 
Bilirubin 
pH (dipstick) 
Nitrite 
Specific gravity 
RBCs 
Ketones 
Urobilinogen 
Albumin (optional) 
Leukocytes 
Glucose 
Microscopy (if clinically indicated) 
Protein 
 
Immunogenicity 
Antidrug Antibodies 
Pregnancy Testing (WOCBP only) 
β-human chorionic gonadotropin 
Abbreviations:  AST=aspartate transaminase; ALP=alkaline phosphatase; ALT=alanine transaminase; BUN=blood 
urea nitrogen; eGFR=estimated glomerular filtration rate; MDRD=modification of diet in renal disease; 
WOCBP=women of child bearing potential. 
7.5.6.1. 
Immunogenicity 
Blood samples will be collected to evaluate antidrug antibodies (ADA).  Blood samples for ADA 
testing that are collected on the day of dosing must be collected before study drug administration.  
Blood samples to evaluate ADAs will be collected throughout the treatment and follow-up 
periods as detailed in the Schedule of Assessments. Confirmed positive ADA samples will be 
tested for cross-reactivity with DNA and nucleic acids. 
Details regarding the processing, shipping, and analysis of the samples will be provided in the 
Laboratory Manual. 
7.5.6.2. 
Pregnancy Testing 
A pregnancy test will be performed for WOCBP only.  A serum pregnancy test will be 
performed at Screening or after the onset of menarche if the patient was not of childbearing 
potential at screening, and urine pregnancy tests will be performed thereafter per the Schedule of 
Assessments and any time pregnancy is suspected.  The results of the pregnancy test must be 
known before study drug administration.  Women who are pregnant are not eligible for study 
participation.  Any woman with a positive pregnancy test during the study will be discontinued 
from study drug, but will continue to be followed for safety.  Women determined to be pregnant 
while on study will be followed until the pregnancy outcome is known (see Section 7.5.7.6 for 
follow-up instructions). 
7.5.6.3. 
Drugs of Abuse 
At Screening, urine will be tested for the following drugs of abuse: amphetamines, barbiturates, 
benzodiazepines, cannabinoids, opiates, cocaine, and methadone.  If a subject/patient fails the 
screening, they will be excluded from the study, unless, in Part B only, the positive result is due 
to prescribed medications for patients.  A repeat drug screen may only be performed when 


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methodological reasons are believed to have led to a false positive.  Borderline positive results, 
unless covered by the preceding condition, are to be considered as positive and the 
subject/patient will be excluded from the study.  If subjects/patients are found to be positive due 
to short term medication use, eg, antitussives medication, they may undergo a repeat drug screen 
to determine if they continue to meet study requirements.  
All subjects/patients should refrain from consuming poppy seeds 48 hours before screening and 
then from 48 hours before study drug administration until follow-up has been completed.  Poppy 
seed ingestion may cause a positive result for opiates in urine drug screen. 
7.5.6.4. 
Maximum Blood Volume 
The maximum blood volume for subjects in Part A will not exceed 500 mL over the course of 
the study.   
In Part B, 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 13 from the Feinstein Institute for Medical Research Human Subject Protection Program 
Guidance Document (Section 11.3 in the Appendix).[12]  The maximum blood volume for adult 
and pediatric patients initially randomized to ALN-GO1 is not expected to exceed 400 mL over 
the course of the study.  The maximum blood volume for adult and pediatric patients initially 
randomized to placebo is not expected to exceed 450 mL over the course of the study.  The blood 
volume limits for patients in Part B are based on those for 6 year old girls in the 5th percentile for 
weight, the smallest patients who may be enrolled in the study. 
7.5.7. 
Adverse Events 
7.5.7.1. 
Definitions 
Adverse Event 
According to the International Conference on Harmonization (ICH) E2A guideline Definitions 
and Standards for Expedited Reporting, and 21 CFR 312.32, IND Safety Reporting, an AE is any 
untoward medical occurrence in a patient or clinical investigational subject administered a 
medicinal product and which does not necessarily have a causal relationship with this treatment. 
Serious Adverse Event 
A serious adverse event (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 in-patient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability or incapacity 
 Is a congenital anomaly or birth defect 


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 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 1 of the other outcomes listed in the definition above (eg, 
events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias, convulsions, or the development of drug 
dependency or abuse). 
Adverse Event Severity 
AE severity should be graded using the Common Terminology Criteria for Adverse Events 
(CTCAE).  Refer to CTCAE for unique clinical descriptions of severity (Grades I through IV) 
for each AE based on the following general guideline: 
Grade I: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated 
Grade II: 
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age appropriate instrumental activity of daily living (eg, preparing meals, 
shopping for groceries or clothes, using the telephone, managing money) 
Grade III: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care activity of daily living (ie, bathing, dressing and 
undressing, feeding self, using the toilet, taking medications, and not 
bedridden) 
Grade IV: 
Life-threatening consequences; urgent intervention indicated 
Grade V: 
Death related to an adverse event 
Changes in severity should be documented in the medical record to allow assessment of the 
duration of the event at each level of severity.  Adverse events characterized as intermittent 
require documentation of the start and stop of each incidence.  When changes in the severity of 
an AE occur more frequently than once a day, the maximum severity for the experience that day 
should be noted.  If the severity category changes over a number of days, then those changes 
should be recorded separately (with distinct onset dates). 
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 Serious Adverse Event). 
Relationship of the Adverse Event to Study Treatment 
The relationship of each AE to study treatment should be evaluated by the Investigator using the 
following criteria:  
Definitely related: 
A clinical event, including laboratory test abnormality, occurring in a plausible 
time relationship to the medication administration, and which cannot be 
explained by concurrent disease or other drugs or chemicals.  The response to 
withdrawal of the drug should be clinically plausible. 


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Possibly related: 
A clinical event, including laboratory test abnormality, with a reasonable time 
sequence to the medication administration, but which could also be explained 
by concurrent disease or other drugs or chemicals.  Information on the drug 
withdrawal may be lacking or unclear. 
Unlikely related: 
A clinical event, including laboratory test abnormality, with little or no 
temporal relationship to medication administration, and which other drugs, 
chemicals, or underlying disease provide plausible explanations. 
Not related: 
A clinical event, including laboratory test abnormality that has no temporal 
relationship to the medication or has more likely alternative etiology. 
7.5.7.2. 
Eliciting and Recording Adverse Events 
Eliciting Adverse Events 
The patient should be asked about medically relevant changes in his/her health since the last 
visit.  The patient should also be asked if he/she has been hospitalized, had any accidents, used 
any new medications, or changed concomitant medication routines (both prescription and OTC).  
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. 
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 investigational drug, 
action taken, and outcome (including time and date of resolution, if applicable). 
For purposes of this study, ISRs are considered to be Adverse Events of Clinical Interest.  These 
AEs will be recorded both on a supplemental eCRF and on an Adverse Event of Clinical Interest 
form.  Refer to the eCRF completion guidelines for details on these forms. 
For SAEs, record the event(s) in the eCRF.  If the EDC system is unavailable, complete the 
back-up SAE form. 
7.5.7.3. 
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 7.5.7.1 must be reported to the 
Sponsor or designee within 24 hours from the time that clinical study center staff first learns of 
the event.  All SAEs must be reported regardless of the relationship to study drug. 


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The initial report should include at least the following information: 
 Subject/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.  If the EDC system is unavailable, complete the back-up 
SAE form.  Within 24 hours of receipt of follow-up information, the Investigator must update the 
SAE form.  SAEs must be reported using the contact information provided in the Study 
Reference Guide. 
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. 
7.5.7.4. 
Sponsor Safety Reporting to Regulatory Authorities 
The Sponsor or its representative is required to 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. 
The following describes the safety reporting timeline requirements for suspected unexpected 
serious adverse reactions (SUSARs) and other reportable events: 
Immediately and within 7 calendar days 
 Any suspected adverse reaction that is associated with the use of the study drug, 
unexpected, and fatal or life threatening.  Follow-up information must be reported in 
the following 8 days. 
Immediately and within 15 calendar days 
 Any suspected adverse reaction that is associated with the use of the study drug, 
unexpected, and serious, but not fatal or life threatening, and there is evidence to 
suggest a causal relationship between the study drug and the reaction. 
 Any finding from tests in laboratory animals that suggest a significant risk for human 
patients including reports of mutagenicity, teratogenicity, or carcinogenicity. 
 Any event in connection with the conduct of the study or the development of the 
study drug that may affect the safety of the trial patients. 
In addition, periodic safety reporting to regulatory authorities will be performed by the Sponsor 
or its representative according to national and local regulations. 


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7.5.7.5. 
Serious Adverse Event Notification to the Institutional Review 
Board/Independent Ethics Committee 
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.
7.5.7.6. 
Pregnancy Reporting 
If a female patient becomes pregnant during the course of this study, the Investigator must report 
the pregnancy to the Sponsor or designee within 24 hours of being notified of the pregnancy.  
Details of the pregnancy will be recorded on the pregnancy reporting form.  The patient should 
receive any necessary counseling regarding the risks of continuing the pregnancy and the 
possible effects on the fetus. 
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 7.5.7.3. 
7.5.7.7. 
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.  It is up to the investigator to decide whether a dose is to be considered an overdose, in 
consultation with the Sponsor.  Overdose 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.   
8. 
STATISTICS 
This is a randomized, single-blind, placebo-controlled study of ALN-GO1 administered 
subcutaneously to healthy adult subjects (Part A) and to adult and pediatric patients with PH1 
disease (Part B).  The study is designed to evaluate the safety, tolerability, PK, and PD of 
single- and multiple-ascending doses of ALN-GO1. 
8.1. 
Determination of Sample Size 
The sample size was based on clinical considerations rather than power calculations.  Up to 
64 participants (40 subjects and 24 patients) are planned to be enrolled in this study, including 
optional and expansion cohorts (see Table 9 ). 
8.2. 
Statistical Methodology 
A Statistical Analysis Plan (SAP) will be finalized before database lock.  The plan will detail the 
implementation of all planned statistical analyses in accordance with the principal features stated 


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in the protocol.  Any changes to the methods described in the final SAP will be described and 
justified as needed in the clinical study report. 
Statistical analyses will be primarily descriptive.  Analyses will be performed using SAS® 
(Version 9.2, or higher).  Data from Parts A and B will be analyzed separately.  Tabular 
summaries will be generated by dose level and dosing regimen of ALN-GO1 and placebo 
(pooled across all cohorts) for Part A and Part B (through Day 85).   
Safety and PD data will be summarized by dose level and dosing regimen of ALN-GO1 
compared to placebo for data collected up to, and including, study Day 85.  Data from placebo 
patients from all cohorts will be combined.  Data collected after Day 85 will be summarized 
separately for patients in quarterly dosing cohorts who receive a second dose of ALN-GO1 on 
Day 85.  Additionally, all safety and PD data collected from all patients in Part B during the 
ALN-GO1 dosing period, regardless of treatment sequence, will be combined and summarized 
by ALN-GO1 dose level and regimen. 
Data collected beyond the designated dosing period will be summarized or presented in data 
listings.  
Descriptive statistics will be presented for continuous variables.  Frequencies and percentages 
will be presented for categorical and ordinal variables.  Percentages will be based on the number 
of non-missing values in a dose group. 
8.2.1. 
Populations to be Analyzed 
The populations (analysis sets) are defined as follows:  
 Safety Analysis Set:  All subjects/patients who receive at least 1 dose of study drug.  
 PK Analysis Set:  All subjects/patients who receive at least 1 dose of study drug and 
have at least 1 postdose sample for PK parameters and who have evaluable PK data. 
 PD Analysis Set:  All subjects/patients who receive at least 1 dose of study drug and 
who have at least 1 postdose blood and/or urine sample evaluable for PD parameters. 
8.2.2. 
Examination of Subgroups 
Subgroup analyses may be conducted for selected endpoints.  Detailed methodology will be 
provided in the SAP. 
8.2.3. 
Handling of Missing Data 
Unrecorded values will be treated as missing.  The appropriateness of the method(s) described 
for handling missing data may be reassessed and documented in the SAP prior to database lock.  
Depending on the extent of missing values, further investigation may be made into the sensitivity 
of the analysis results to the method(s) specified. 
8.2.4. 
Baseline Evaluations 
Demographics and other baseline characteristics will be summarized using the Safety Analysis 
Set by dose level groups and placebo.  If the PK and PD Analysis Sets contain a different set of 
subjects/patients compared to those included in the Safety Analysis Set, then demographic 
information will be summarized separately for those analysis sets.  Descriptive statistics for age, 


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race, ethnicity, gender, height, weight, and BMI will be provided.  Demographic information for 
patients in Part B may include additional disease-specific information collected at baseline. 
8.2.5. 
Pharmacodynamic Analyses 
For Part A, PD analysis will be the comparison of change from baseline in plasma glycolate 
concentration for each subject in ALN-GO1 dose groups and placebo.   
For Part B, PD analysis will be the comparison of the change from baseline in urinary oxalate 
excretion (oxalate concentration in 24-hour urine collection), with additional analyses of the 
change from baseline in urinary glycolate excretion (glycolate concentration in 24-hour urine 
collection), plasma glycolate concentration, and calculated creatinine clearance, for each patient 
in active dose groups and placebo. 
The PD parameters will be summarized using descriptive statistics for actual results and relative 
to baseline for each follow-up time points. 
8.2.6. 
Pharmacokinetic Analyses 
Pharmacokinetic analyses will be conducted using noncompartmental methods.   
Pharmacokinetic parameters include, but are not limited to, Cmax, tmax, AUC, t½, fe/F, and CLR.  
Other parameters may be calculated, if necessary.  
8.2.7. 
Safety Analyses 
The primary safety parameter is the incidence of AEs.  Safety will also be evaluated through 
vital signs, ECGs, clinical laboratory assessments, and physical examinations; Echo assessments 
will be evaluated in Part B only.  ADAs will also be analyzed. 
AEs will be summarized by the MedDRA System Organ Class and Preferred Term (Version 16, 
or higher).  Prior and concomitant medications will be classified according to the World Health 
Organization (WHO) drug dictionary. 
Separate tabulations of the incidence of treatment emergent adverse events (TEAEs), TEAEs by 
maximum severity, treatment-related AEs, SAEs, and discontinuation due to AEs will be 
provided.  By-subject listings will also be provided for any deaths, SAEs and AEs leading to 
discontinuation.  
Descriptive statistics will be provided for clinical laboratory data and vital signs data, presented 
as both actual values and changes from baseline over time.  Clinical laboratory assessment shift 
tables from baseline to worst post-values will be presented.  Abnormal physical examination 
findings, ECG, and Echo (Part B only) data will be presented in a by-patient data listing. 
Descriptive statistics will be provided for ECG interval data and presented as both actual values 
and changes from baseline relative to each on-study evaluation and to the last evaluation on 
study.  Details of any abnormalities will be included in patient listings. 
ADA results will be provided in a by-patient data listing. 
8.2.8. 
Interim Analysis 
There is no formal interim analysis planned for this study. 


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9. 
STUDY ADMINISTRATION 
9.1. 
Ethical and Regulatory Considerations 
This study will be conducted in accordance with the protocol, all applicable regulatory 
requirements, and the guidelines of Good Clinical Practice (GCP).  Compliance with GCP 
provides public assurance that the rights, safety, and well-being of study subjects/patients are 
protected consistent with the principles that have their origin in the Declaration of Helsinki. 
9.1.1. 
Informed Consent 
The Investigator will ensure that the subject/patient/legal guardian is given full and adequate oral 
and written information about the nature, purpose, possible risk and benefit of the study.  
Subjects/Patients/Legal guardians must also be notified that they are free to discontinue from the 
study at any time.  The subject/patient/legal guardian should be given the opportunity to ask 
questions and allowed time to consider the information provided.  In the case of patients under 
the age of legal consent, legal guardian(s) must provide informed consent and the patient should 
provide assent per local regulations and institutional standards. 
The subject’s/patient’s/legal guardian’s signed and dated informed consent (or assent, if 
applicable) must be obtained before conducting any study procedures. 
The Investigator must maintain the original, signed Informed Consent Form (or assent, if 
applicable).  A copy of the signed Informed Consent Form (or assent, if applicable) must be 
given to the subject/patient/legal guardian. 
9.1.2. 
Ethical Review 
The final study protocol, including the final version of the ICF, must be approved or given a 
favorable opinion in writing by an IRB or IEC, as appropriate.  The Investigator must submit 
written approval before he or she can enroll any subject/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 advertising 
used to recruit subjects/patients for the study.  The protocol must be reapproved by the IRB or 
IEC upon receipt of amendments and annually, as local regulations require. 
Initial IRB approval of the protocol, and all materials approved by the IRB for this study 
including the subject/patient consent form (and 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 7.5.7.  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 in regard to inspections, other studies that impact 
this protocol or the qualifications of study personnel should be promptly reported to the Sponsor 
or its designee. 


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The Investigator is also responsible for providing the IRB with reports of any reportable serious 
adverse drug reactions from any other study conducted with the investigational 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 subject/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 subjects/patients are 
enrolled under the amended protocol. 
9.1.3. 
Study Documentation, Confidentiality, and Records Retention 
All documentation relating to the study should be retained for the period of time required by 
applicable local law.  If it becomes necessary for the Sponsor, the Sponsor’s designee, applicable 
IRB/IEC, or applicable regulatory authorities to review or audit any documentation relating to 
the study, the Investigator must permit direct access to all source documents/data.  Records will 
not be destroyed without informing the Sponsor in writing and giving the Sponsor the 
opportunity to store the records for a longer period of time at the Sponsor’s expense.   
The Investigator must ensure that the subject’s/patients’ anonymity will be maintained.  On the 
eCRFs or other documents submitted to the Sponsor or designees, subjects/patients should not be 
identified by their names, but by the assigned subjects/patient number and initials.  If 
subjects/patient names are included on copies of documents submitted to the Sponsor or 
designees, the names (except for initials) will be obliterated and the assigned subjects/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. 
In compliance 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. 
9.1.4. 
End of the Study 
The end of the study is defined as last patient last visit. 
9.1.5. 
Discontinuation of the Clinical Study 
The Sponsor reserves the right to discontinue the study for clinical or administrative reasons at 
any time.  If the site does not recruit at a reasonable rate, the study may be discontinued at that 
site.  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, IEC/IRB and Regulatory Authorities will be promptly 
informed of the termination and the reason for the decision.  The Investigator should promptly 
inform the subjects/patients and assure appropriate therapy and follow-up.  Subjects/Patients 
should then be withdrawn from the study.   


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9.2. 
Data Quality Control and Quality Assurance 
9.2.1. 
Data Handling 
Study data must be recorded on case report forms (paper and/or electronic) provided by the 
Sponsor or designee on behalf of the Sponsor.  Case report forms must be completed only by 
persons designated by the Investigator.  If eCRFs are used, study data must be entered by trained 
site personnel with access to a valid and secure eCRF system.  All data entered into the eCRF 
must also be available in the source documents.  Corrections on paper CRFs must be made so as 
to not obliterate the original data and must be initialed and dated by the person who made the 
correction. 
9.2.2. 
Study Monitoring 
The clinical 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, subject/patient charts and study source documents, and other records 
relative to study conduct. 
9.2.3. 
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, or its designee, immediately if 
contacted by a regulatory agency about an inspection. 
9.3. 
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 manuscript 
must be provided and confirmed received at the Sponsor at least 30 days before its submission, 
and according to any additional publication details in the Investigator Agreement. 


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10. 
LIST OF REFERENCES 
1. 
Cochat, P. and G. Rumsby, Primary hyperoxaluria. N Engl J Med, 2013. 369(7): p. 649-
58. 
2. 
Hopp, K., et al., Phenotype-Genotype Correlations and Estimated Carrier Frequencies of 
Primary Hyperoxaluria. J Am Soc Nephrol, 2015. 
3. 
Hoppe, B., Evidence of true genotype-phenotype correlation in primary hyperoxaluria 
type 1. Kidney Int, 2010. 77(5): p. 383-5. 
4. 
Al-Eisa, A.A., M. Samhan, and M. Naseef, End-stage renal disease in Kuwaiti children: 
an 8-year experience. Transplant Proc, 2004. 36(6): p. 1788-91. 
5. 
Kamoun, A. and R. Lakhoua, End-stage renal disease of the Tunisian child: 
epidemiology, etiologies, and outcome. Pediatr Nephrol, 1996. 10(4): p. 479-82. 
6. 
Cochat, P., et al., Primary hyperoxaluria Type 1: indications for screening and guidance 
for diagnosis and treatment. Nephrol Dial Transplant, 2012. 27(5): p. 1729-36. 
7. 
ICH Harmonized Tripartite Guideline on Genotoxicity Testing and Data Interpretation 
for Pharmaceuticals Intended for Human Use S2(R1). 
8. 
Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical 
Trials for Therapeutics in Adult Healthy Volunteers. U.S. Department of Health and 
Human Services Food and Drug Administration Center for Drug Evaluation and 
Research (CDER) July 2005. 
9. 
Frishberg, Y., et al., Mutations in HAO1 encoding glycolate oxidase cause isolated 
glycolic aciduria. J Med Genet, 2014. 51(8): p. 526-9. 
10. 
Levey, A.S., et al., A new equation to estimate glomerular filtration rate. Ann Intern 
Med, 2009. 150(9): p. 604-12. 
11. 
Schwartz, G.J., et al., New equations to estimate GFR in children with CKD. J Am Soc 
Nephrol, 2009. 20(3): p. 629-37. 
12. 
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. 
13. 
Flynn, J.T., et al., Clinical Practice Guideline for Screening and Management of High 
Blood Pressure in Children and Adolescents. Pediatrics, 2017. 140(3). 
 
 
 
 


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11. 
APPENDICES 
11.1. 
Pharmacokinetic Assessment Time Points 
Table 10 contains a detailed schedule for the collection of blood and urine samples for PK 
analysis for Part A. 
Table 10: 
Pharmacokinetic Time Points for Single-ascending Dose Cohorts in 
Healthy Subjects (Part A) 
Study Day 
Protocol Time 
(hh:mm) 
Blood PK 
Urine PK 
Pooled Urine 
Day 1 
Predose (within 1 hour of 
dosing) 
X 
X 
 
00:00 (dose) 
 
 
X 
(00:00-04:00) 
00:30 (±2 min) 
X 
 
01:00 (±5 min) 
X 
 
02:00 (±5 min) 
X 
 
04:00 (±10 min) 
X 
 
04:01 (±10 min) 
 
 
X 
(04:01-08:00) 
06:00 (±15 min) 
X 
 
08:00 (±15 min) 
X 
 
08:01 (±15 min) 
 
 
X 
(08:01-24:00) 
Day 2 
24:00 (±30 min) 
X 
 


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Table 11 contains a detailed schedule for the collection of blood and urine samples for PK 
analysis for patients dosed monthly in Part B. 
Table 11: 
Pharmacokinetic Time Points for Multiple-ascending Dose Cohorts in 
Patients with PH1 (Part B – Monthly Dosing) 
Study Day 
Protocol Time 
(hh:mm) 
Blood PK 
Urine PK 
Pooled Urine 
Day 1 
Predose (within 2 hours of 
dosing) 
X 
X 
 
00:00 (dose) 
 
 
X 
(00:00-04:00) 
00:30 (±2 min) 
X 
 
02:00 (±5 min) 
X 
 
04:00 (±10 min) 
X 
 
04:01 (±10 min) 
 
 
X 
(04:01-08:00) 
06:00 (±15 min) 
X 
 
08:00 (±15 min) 
X 
 
08:01 (±15 min) 
 
 
X 
(08:01-12:00) 
12:00 (±15 min) 
X 
 
12:01 (±15 min) 
 
 
X 
(12:01-24:00) 
Day 2 
24:00 (±30 min) 
X 
 
Day 3 
48:00 (±30 min) 
X 
 
 
Day 15 
Anytime during visit 
X 
 
 
Day 29 
Predose (within 2 hours of 
dosing) 
X 
X 
 
00:00 (dose) 
 
 
 
02:00 (±5 min) 
X 
 
 
Day 57 
Predose (within 2 hours of 
dosing) 
X 
X 
 
00:00 (dose) 
 
 
X 
(00:00-04:00) 
00:30 (±2 min) 
X 
 
02:00 (±5 min) 
X 
 
04:00 (±10 min) 
X 
 
04:01 (±10 min) 
 
 
X 
(04:01-08:00) 
06:00 (±15 min) 
X 
 
08:00 (±15 min) 
X 
 
08:01 (±15 min) 
 
 
X 
(08:01-12:00) 
12:00 (±15 min) 
X 
 


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Table 11: 
Pharmacokinetic Time Points for Multiple-ascending Dose Cohorts in 
Patients with PH1 (Part B – Monthly Dosing) 
Study Day 
Protocol Time 
(hh:mm) 
Blood PK 
Urine PK 
Pooled Urine 
12:01 (±15 min) 
 
 
X 
(12:01-24:00) 
Day 58 
24:00 (±30 min) 
X 
 
Day 59 
48:00 (±30 min) 
X 
 
 
Day 85a 
Anytime during visit 
X 
 
 
Day 85b 
Predose (within 2 hours of 
dosing) 
X 
X 
 
00:00 (dose) 
 
 
X 
(00:00-04:00) 
00:30 (±2 min) 
X 
 
02:00 (±5 min) 
X 
 
04:00 (±10 min) 
X 
 
04:01 (±10 min) 
 
 
X 
(04:01-08:00) 
06:00 (±15 min) 
X 
 
08:00 (±15 min) 
X 
 
08:01 (±15 min) 
 
 
X 
(08:01-12:00) 
12:00 (±15 min) 
X 
 
12:01 (±15 min) 
 
 
X 
(12:01-24:00) 
Day 86b 
24:00 (±30 min) 
X 
 
Day 87b 
48:00 (±30 min) 
X 
 
 
Day 99b 
Anytime during visit 
X 
 
 
Day 113b 
Predose (within 2 hours of 
dosing) 
X 
X 
 
00:00 (dose) 
 
 
 
02:00 (±5 min) 
X 
 
 
Day 141b 
Predose (within 2 hours of 
dosing) 
X 
X 
 
00:00 (dose) 
 
 
X 
(00:00-04:00) 
00:30 (±2 min) 
X 
 
02:00 (±5 min) 
X 
 
04:00 (±10 min) 
X 
 
04:01 (±10 min) 
 
 
X 
(04:01-08:00) 
06:00 (±15 min) 
X 
 
08:00 (±15 min) 
X 
 


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Table 11: 
Pharmacokinetic Time Points for Multiple-ascending Dose Cohorts in 
Patients with PH1 (Part B – Monthly Dosing) 
Study Day 
Protocol Time 
(hh:mm) 
Blood PK 
Urine PK 
Pooled Urine 
08:01 (±15 min) 
 
 
X 
(08:01-12:00) 
12:00 (±15 min) 
X 
 
12:01 (±15 min) 
 
 
X 
(12:01-24:00) 
Day 142b 
24:00 (±30 min) 
X 
 
Day 143b 
48:00 (±30 min) 
X 
 
 
Day 169b 
Anytime during visit 
X 
 
 
a.  For subjects initially randomized to ALN-GO1 
b. Collect blood and urine samples from patients who previously received placebo and continue on-study to 
receive open-label ALN-GO1. 


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Table 12 contains a detailed schedule for the collection of blood and urine samples for PK 
analysis for patients dosed quarterly in Part B. 
 
Table 12: 
Pharmacokinetic Time Points for Patients with PH1 (Part B – Quarterly 
Dosing) 
Study Day 
Protocol Time 
(hh:mm) 
Blood PK 
Urine PK 
Pooled Urine 
Day 1 
Predose (within 2 hours of 
dosing) 
X 
X 
 
00:00 (dose) 
 
 
X 
(00:00-04:00) 
00:30 (±2 min) 
X 
 
02:00 (±5 min) 
X 
 
04:00 (±10 min) 
X 
 
04:01 (±10 min) 
 
 
X 
(04:01-08:00) 
06:00 (±15 min) 
X 
 
08:00 (±15 min) 
X 
 
08:01 (±15 min) 
 
 
X 
(08:01-12:00) 
12:00 (±15 min) 
X 
 
12:01 (±15 min) 
 
 
X 
(12:01-24:00) 
Day 2 
24:00 (±30 min) 
X 
 
Day 3 
48:00 (±30 min) 
X 
 
 
Day 15 
Anytime during visit 
X 
 
 
Day 85 
Predose (within 2 hours of 
dosing) 
X 
X 
 
00:00 (dose) 
 
 
X 
(00:00-04:00) 
00:30 (±2 min) 
X 
 
02:00 (±5 min) 
X 
 
04:00 (±10 min) 
X 
 
04:01 (±10 min) 
 
 
X 
(04:01-08:00) 
06:00 (±15 min) 
X 
 
08:00 (±15 min) 
X 
 
08:01 (±15 min) 
 
 
X 
(08:01-12:00) 
12:00 (±15 min) 
X 
 
12:01 (±15 min) 
 
 
X 
(12:01-24:00) 
Day 86 
24:00 (±30 min) 
X 
 
Day 87 
48:00 (±30 min) 
X 
 
 


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Table 12: 
Pharmacokinetic Time Points for Patients with PH1 (Part B – Quarterly 
Dosing) 
Study Day 
Protocol Time 
(hh:mm) 
Blood PK 
Urine PK 
Pooled Urine 
Day 99 
Anytime during visit 
X 
 
 
Day 113 
Anytime during visit 
X 
 
 
 
 
 


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11.2. 
Formulae for Estimated Glomerular Filtration Rate Calculation 
Estimated glomerular filtration rate (eGFR; in mL/min/1.73m2) will be calculated from serum 
creatinine (SCr) based on the Modification of Diet in Renal Disease formula for patients 
≥18 years of age and the Schwartz Bedside Formula for patients <18 years of age. 
 
Modification of Diet in Renal Disease Formula [10] 
 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) 
 
Schwartz Bedside Formula [11] 
 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) 
 
 
 
 
 
 


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11.3. 
Blood Volume Limits in Pediatric Patients (Part B) 
The maximum blood volume, which will be collected from pediatric patients in Part B over the 
course of the study, will be based on age and weight and will not exceed those specified in 
Table 13, which was adapted from the Human Subject Protection Program Guidance Document. 
Table 13: 
Maximum Allowable Total Blood Collection Volumes Chart (Part B) 
Body 
Weight  
Body 
Weight  
Total blood 
volume  
Maximum allowable 
volume in a 24 hour 
period 
Total volume collected 
in a 30-day period 
2.5% of 
total blood 
volume 
3% of total 
blood 
volume  
5% of 
total blood 
volume  
10% of 
total blood 
volume  
(kg) 
(lbs) 
(mL) 
(mL) 
(mL) 
(mL) 
(mL) 
1 
2.2 
100 
2.5 
3 
5 
10 
2 
4.4 
200 
5 
6 
10 
20 
3 
6.6 
240 
6 
7.2 
12 
24 
4 
8.8 
320 
8 
9.6 
16 
32 
5 
11 
400 
10 
12 
20 
40 
6 
13.2 
480 
12 
14.4 
24 
48 
7 
15.4 
560 
14 
16.8 
28 
56 
8 
17.6 
640 
16 
19.2 
32 
64 
9 
19.8 
720 
18 
21.6 
36 
72 
10 
22 
800 
20 
24 
40 
80 
11-15 
24-33 
880-1200 
22-30 
26.4-36 
44-60 
88-120 
16-20 
35-44 
1280-1600 
32-40 
38.4-48 
64-80 
128-160 
21-25 
46-55 
1680-2000 
42-50 
50.4-60 
64-100 
168-200 
26-30 
57-66 
2080-2400 
52-60 
62.4-72 
104-120 
208-240 
31-35 
68-77 
2480-2800 
62-70 
74.4-84 
124-140 
248-280 
36-40 
79-88 
2880-3200 
72-80 
86.4-96 
144-160 
288-320 
41-45 
90-99 
3280-3600 
82-90 
98.4-108 
164-180 
328-3600 
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/2013/03/Recruitment-Methods-for-
Clinical-Research-Studies.pdf.[12] 
 
 


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11.4. 
Normative Pediatric Blood Pressure Tables 
For pediatric patients <18 years old, study entry criteria for blood pressure will be determined 
according to normative blood pressure tables based on normal-weight children included in 
published guidelines issued by the American Academy of Pediatrics [13] (see Table 14 and 
Table 15).  Patients will be excluded if diastolic and/or systolic blood pressure is equal to or 
greater than the 95th percentile for sex, age, and height (mean of screening height measurements). 
 


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Table 14: 
Blood Pressure Levels for Girls by Age and Height Percentile 
 


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Adapted from Flynn et al. 2017 [13] 
 


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Table 15: 
Blood Pressure Levels for Boys by Age and Height Percentile 
 


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Adapted from Flynn et al. 2017 [13] 
 
 


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ALN-GO1-001 Protocol Amendment 1 
Summary of Changes dated 01 July 2016 
Compared to the Original Protocol dated 18 December 2015 
A Phase 1/2, Single-Blind, Placebo-Controlled, Single- and Multiple-Ascending Dose 
Safety, Tolerability, Pharmacokinetic and Pharmacodynamics Study of Subcutaneously 
Administered ALN-GO1 in Healthy Adult Subjects, and Patients with Primary 
Hyperoxaluria Type 1 
Rationale for Protocol Amendment 
The primary purpose of this amendment is to provide the starting dose of ALN-GO1 for 
administration to patients with primary hyperoxaluria type 1 in Part B of the study, which is 
based on preliminary data from Part A of the study in healthy subjects.  The Part B starting dose 
is 1.0 mg/kg, administered every 28 days, the lowest dose determined to have a pharmacological 
effect in healthy subjects in Part A that was also considered well-tolerated. 
Further, in response to feedback from Regulatory Agencies, study cohort progression/escalation 
and suspension/stopping rules have been included for Part B.  These rules apply to adverse 
events (AEs) considered likely to be related to the underlying disease and for AEs considered 
possibly or definitely related to study drug.  Common Terminology Criteria for Adverse Events 
criteria will continue to be used to grade AEs.  The revised dose escalation rules will be specified 
to take into consideration the severity of the AEs observed and the frequency of the occurrence 
of these toxicities within a given cohort in order to authorize dosing in the next cohort (as 
outlined in Table 1 below).  These rules will guide Part B dose escalation and stopping decisions 
for the cohort by the Safety Review Committee. 
The following changes have been made in Part B to streamline and simplify blood sample 
collections and study evaluations: 
 Clarified that the exploratory endpoint 
 
 
 Clarified symptom-directed exam specifications and that symptom-directed physical 
examinations occur during the study, except during Screening and on the last 
postdose follow-up visit when a full physical examination occurs 
 
 
 
 clarified that eligibility requires a 24-hour 
urine sample collection 
 
 Removed requirement for an inpatient stay at the clinical study center for 24-hour 
urine sample collection, added a 6 hour window for sample collection after study 
eligibility is confirmed, and clarified the start day for sample collections 
 Removed blood and urine sample collection for pharmacokinetic (PK) analyses on 
Day 141 for patients initially randomized to ALN-GO1 as it is not expected that there 
will be measureable drug concentrations at this time point postdose 


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 Removed the Day 2 blood sample collection for pharmacodynamic (PD) analyses as 
it is not expected that there will be an evident PD effect this soon postdosing 
 Added blood and urine sample collections for exploratory 
 
 for patients initially randomized to placebo 
 Changed the day on which patients will be unblinded to Day 78, rather than Day 85, 
in order for patients and their families to be better prepared for the transition to 
receive ALN-GO1 if initially randomized to placebo 
 Specified the screening blood pressure criteria for eligibility for patients 6 to18 years, 
inclusive, accounting for blood pressure cut-off values for hypertension in children 
 Specified that clinical laboratory assessments of liver function tests and serum 
creatinine will be reviewed locally before study drug administration 
 Specified that on days when a blood sample for vitamin B6 should be collected, 
patients should be instructed to not take vitamin B6 before the blood sample is 
collected and the study drug is administered 
 Removed the 28 day window for the Day 85 study visit indicating that this visit must 
occur on the scheduled day 
 Clarified that additional cohorts may be enrolled at higher, lower, or intermediate 
dose levels, but will not exceed the maximum administered dose of 6.0 mg/kg 
 Updated the procedure for recording serious adverse events (SAEs) in the case report 
form, with an SAE form as back-up 
The following changes have been applied to Part A and Part B to simplify the study: 
 Specified that plasma samples, in addition to urine samples, will be collected for 
assessment of PD parameters 
 Increased the overall study duration from 1 year and 8 months to 2 years 
 Clarified that the relationship of AEs to study drug will be classified as definitely, 
possible, unlikely, or not related to study drug; AEs will not be classified as probably 
related  
Additional administrative changes include the following:  aligned footnotes in the Schedules of 
Assessments for Part B (Table 2 and Table 3); moved the blood sample for antidrug antibody 
analysis from Day -1 to Day 1, and added a blood sample for antidrug antibody analysis at 
Day 57, for consistency with Part A; added windows for postdose electrocardiograms in Part B; 
and corrected the time range for pooled urine sample collection for PK analysis on Day 113 and 
Day 141 from 4-6 hours to 0-4 hours in Part B. 
A detailed summary of changes is provided in Table 1.  Corrections to typographical errors, 
punctuation, grammar, abbreviations, and formatting are not detailed.  Additionally, updates to 
the protocol as described in administrative change letters, dated 05 May 2016; 22 February 2016; 
and 24 February 2016, are not detailed.


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Table 1: 
Protocol Amendment 1 Detailed Summary of Changes 
The primary section(s) of the protocol affected by the changes in the amendment are indicated.  The corresponding text has been 
revised throughout the protocol.  Deleted text is indicated by strikeout; added text is indicated by bold font. 
Purpose:  Provided the starting dose of ALN-GO1 with dose rationale for Part B of the study and that additional cohorts may be enrolled at 
higher, lower, or intermediate dose levels, but will not exceed the maximum administered dose of 6.0 mg/kg 
The primary change occurs in Section 1.4 Dose Rationale 
Added: 
Preliminary data from Part A suggest that ALN-GO1 is well-tolerated and support selection of the starting dose 
for the first cohort of Part B of study ALN-GO1-001.  The Part B starting dose is 1.0 mg/kg, administered every 
28 days, the lowest dose determined to have a pharmacological effect in healthy subjects in Part A that was also 
considered well-tolerated.  The starting dose in Part B is based on data derived from Part A and recommended by 
the Safety Review Committee (SRC).  Additional cohorts may be enrolled at higher, lower, or intermediate dose 
levels, but will not exceed the maximum administered dose of 6 mg/kg, and will follow the protocol-specified dose 
escalation criteria. 
Section(s) also containing this change:  
 
Synopsis 
 
Section 4.7.2 Study Drug Dosing, Study Progression, and Dose Escalation in Part B 
Purpose:  Specified that plasma samples, in addition to urine samples, will be collected for assessment of PD parameters 
The primary change occurs in Section 3.2, Secondary Endpoints 
Now reads: 
• 
Plasma and urine glycolate concentration 
Section(s) also containing this change:  
 
Synopsis 
 
Section 1.3, Study Design Rationale 
 
Section 7.2,  Pharmacodynamic Assessments 
Purpose:  Clarified that the exploratory endpoint 
 
 
 
 
 
 


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Section(s) also containing this change:  
 
Synopsis 
 
Section 7.2, Pharmacodynamic Assessments 
Purpose:  Increased the overall study duration from 1 year and 8 months to 2 years 
The primary change occurs in Section 4.2, Duration of Treatment and Overall Duration of Study 
Now reads: 
The overall duration of the study is estimated to be 1 year and 8 months 2 years, including enrollment. 
Section(s) also containing this change:  
 
Synopsis 
Purpose:  Changed the day on which patients will be unblinded to Day 78 (from Day 85) 
The primary change occurs in Section 4.5 Blinding 
Now reads: 
This is a single-blind, placebo-controlled study; therefore, only the study subjects/patients will be blinded to treatment 
assignment (up to Day 85 for Part B).  Patients in Part B will be unblinded on or after Day 78 in order for patients 
and their families to be better prepared for the transition to receive ALN-GO1 if initially randomized to placebo.   
Section(s) also containing this change:  
 
Synopsis 
 
Table 2:  Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria Type 1 (Part B) 
 
Section 4.1.2 Multiple-ascending Dose Part in Patients with Primary Hyperoxaluria Type 1 (Part B) 
Purpose:  Clarified that the relationship of AEs to study drug will be classified as definitely, possible, unlikely, or not related to study drug 
The primary change occurs in Section 4.7.3.1 Cohort Progression/Escalation and Suspension/Stopping Rules in Part A  
Now reads: 
Study cohort progression/escalation and suspension/stopping rules for AEs considered possibly, probably, or definitely 
related to study drug for Part A are described in Table 5.  If a subject meets a stopping rule, the subject will be managed 
as clinically indicated and asked to complete all safety assessments according to the protocol. 
Section(s) also containing this change:  
 
Section 4.7.3.2  Individual Patient Progression/Escalation and Suspension/Stopping Rules in Part B 


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Purpose:  Provided study cohort progression/escalation and suspension/stopping rules for Part B have been included in response to feedback 
from Regulatory Agencies 
The primary change occurs in Section 4.7.3.3 Cohort Progression/Escalation and Suspension/Stopping Rules in Part B 
Added: 
Study cohort progression/escalation and suspension/stopping rules for AEs considered likely to be related to the 
underlying disease and for AEs considered possibly or definitely related to study drug for Part B are described in 
Table 7.  If a patient meets a stopping rule, the patient will be managed as clinically indicated and asked to 
complete all safety assessments according to the protocol.  For patients with abnormal renal function consistent 
with their underlying disease at baseline, evidenced by elevated serum creatinine, the change in this parameter 
from baseline should be used in grading AEs, rather than laboratory normal values. 
Table 7: 
Cohort  Progression/Escalation and Suspension/Stopping Rules for Part B 
Adverse Event(s) 
Action 
If ≥1 patient in a cohort 
experiences a severe AE 
and/or SAE, judged to be 
possibly or definitely related 
to study drug 
Dosing within that cohort, and in any cohorts receiving a higher dose, will be 
suspended until SRC review.  Following data review, the SRC may permit 
continuation of any ongoing Part B cohort. 
 
Any further dose escalation in a subsequent cohort will be suspended.  Resumption of 
dose escalation will require a substantial amendment, approved by the regulatory 
authority and relevant ethics committee.  However, de-escalation to a lower dose, or 
intermediate but lower dose, may be allowed by the SRC without a protocol 
amendment. 
If ≥1 patient in Part B 
experiences a Grade 4 or 
5 AEa judged to be 
possibly or definitely 
related to study drug 
Dosing of all patients in Part B will be suspended until SRC review.  
Resumption of the study will require a substantial amendment, approved by 
the regulatory authority and relevant ethics committee.   
Abbreviations:  AE=adverse event; SAE=serious adverse event; SRC=Safety Review Committee. 
a Common Terminology Criteria for Adverse Events will be used to grade AEs. 
 
Purpose:  Specified the screening blood pressure criteria for eligibility for patients 6 to17 years, inclusive 
The primary change occurs in Section 5.2.2 Additional Exclusion Criteria for Part B  
Added: 
For patients aged 6 to 11 years, inclusive, males with systolic blood pressure >115 mmHg and/or a diastolic blood 
pressure >75 mmHg and females with systolic blood pressure >110 mmHg and/or a diastolic blood pressure >75 
mmHg after 10 minutes of rest at screening.  For male and female patients aged 12 to 17 years, inclusive, systolic 
blood pressure >120 mmHg and/or a diastolic blood pressure >80 mmHg after 10 minutes of rest at screening. 


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Section(s) also containing this change:   
 
Section 5.2.1 Exclusion Criteria for Parts A and B 
Purpose:  
 
 clarified that eligibility requires a 24-hour urine sample collection 
 
   
The primary change occurs in Section 7.1.1.1, Urinary Oxalate Excretion and Creatinine Clearance 
Now reads: 
Urinary oxalate excretion and creatinine clearance will be measured over a 24-hour urine collection period.  During the 
screening period only, 24-hour urine collections will be completed in triplicate to assess baseline urinary oxalate excretion 
and creatinine clearance.  The first 2 urine collections may be completed over 2 consecutive 24-hour periods, or separated 
in time for the convenience of patients.  The excretion of oxalate in at 2 separate time points.  The first screening 24-
hour urine collection will be used to assess eligibility.  Patients will be admitted to the clinical study center on the 
evening of Day -2 to permit the third,The second screening 24-hour urine collection of the screening period, which will 
be completed before dosing on Day 1.Evaluation of oxalate excretion is generally performed on a 24-hour urine 
collection; however, for patients unable to provide 24-hour urine collection 
 may be used to 
calculatewill only be initiated after eligibility is confirmed.  A blood sample for serum creatinine must be obtained 
after each 24-hour urine collection for PD analysis for the calculation of creatinine clearance. 
Patients will be instructed to collect urine samples for the full 24-hour period; however, after confirming eligibility, 
for patients unable to collect urine samples for the full 24-hour period, urinary oxalate excretion may be calculated 
from samples collected over an 18 to 24 hour period. 
After the screening period, assessments are single, 24-hour urine collections (Section Section 7.2)Patients will have the 
option to bring the 24-hour urine collections to the clinical study center at specified follow-up visits, courier 
samples to the clinical study center or to the vendor performing analyses, or elect to have the 24-hour urine 
collected during an inpatient stay at the clinical study center for other assessments. 
Purpose:  Removed requirement for an inpatient stay at the clinical study center for 24-hour urine sample collection, added a 6-hour window for 
sample collection after study eligibility is confirmed, and clarified the start day for sample collections 
The primary change occurs in Section 7.2 Pharmacodynamic Assessments 
Now reads: 
In Part B, single, 24-hour urine collections 
 will be collected for the analysis of urinary glycolate 
and oxalate excretion, and creatinine clearance.  The 24-hour urine collection starting on Day -1 must conclude on 
Day 1 before administration of the first dose of study drug.  Blood samples will also be collected for the analysis of 


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plasma glycolate concentration. 
Options for theproviding 24-hour urine collections, patients will have the option to bring the urine collection to the 
clinical study center at specified PD follow-up visits, courier samples to the clinical study center or vendor performing 
analyses, or have the 24-hour urine collected during an inpatient stay at the clinical study center for other assessments.  
are in Section 7.1.1.1. 
Section(s) also containing this change:   
 
Table 2:  Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria Type 1 (Part B) 
 
Table 3:  Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria Type 1 (Part B) who 
Previously Received Placebo and Will Receive Open-Label ALN-GO1 
 
Table 8:  Adaptive Study Design Areas, Features, and Limits 
Purpose:  Clarified symptom-directed exam specifications and that symptom directed physical examinations occur during the study, except during 
Screening and on the last postdose follow-up visit when a full physical examination occurs 
The primary change occurs in Section 7.5.3, Physical Examination 
Now reads: 
A symptom-directed physical examination will include chest/respiratory, heart/cardiovascular, dermatological/skin, 
gastrointestinal/liver, and musculoskeletal/extremities assessmentsthe evaluation of changes in symptoms, or the onset 
of new symptoms, since the last visit. 
Section(s) also containing this change:   
 
Table 2:  Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria Type 1 (Part B) 
 
Table 3:  Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria Type 1 (Part B) who 
Previously Received Placebo and Will Receive Open-Label ALN-GO1 
Purpose: Removed requirement for an alcohol screening (protocol administrative change letter, dated 24 February 2016) 
The primary change occurs in Section 7.5.5.3, Drugs of Abuse and Alcohol Screening 
Now reads: 
An alcohol test (urine and/or breathalyzer) will be performed according to local clinical study center policy at the time 
points listed in the Schedule of Assessments.  If a subject/patient tests positive, they will be excluded from the study. 
Purpose:  Updated the procedure for recording serious adverse events in the case report form, with an SAE form as back-up 
The primary change occurs in Section 7.5.6.3  Serious Adverse Events Require Immediate Reporting to Sponsor/Designee 
Now reads: 
To report the SAE, complete the eCRF.  If the EDC system is unavailable, complete the back-up SAE form.  Within 
24 hours of receipt of follow-up information, the Investigator must update the SAE form.  SAEs must be reported using 


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the contact information provided in the Study Manual 
Section(s) also containing this change:   
 
Section 7.5.6.2, Eliciting and Recording Adverse Events 
Purpose:  Removed blood and urine sample collection for pharmacokinetic analyses on Day 141 for patients initially randomized to ALN-GO1  
The primary change occurs in Table 2:  Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria 
Type 1 (Part B) 
Removed: 
The “X” from the Day 141 column for the row titled “Blood and urine samples for PK analyses” was deleted. 
Purpose:  Removed the Day 2 blood sample collection for pharmacodynamic analyses 
The primary change occurs in Table 2:  Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria 
Type 1 (Part B) 
Removed: 
The “X” from the Day 2 column for the row titled “Blood sample for PD analyses” was deleted. 
Section(s) also containing this change:   
 
Table 3:  Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria Type 1 (Part B) who 
Previously Received Placebo and Will Receive Open-Label ALN-GO1 
Purpose:  Specified that clinical laboratory assessments of liver function tests and serum creatinine will be reviewed locally before study drug 
administration 
The primary change occurs in Table 2:  Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria 
Type 1 (Part B) 
Now reads: 
Biochemistry, hematology, coagulation, LFTs, and urinalysis parameters are described in Section 7.5.5.  Day -1On Day -
1, and on days when study drug is administered, clinical laboratory tests will be analyzed by a local laboratory and 
confirmed by a central laboratory.  Local clinical laboratory assessment results for LFT measurements must be 
available and reviewed by the Investigator before study drug administration.  On all other days, clinical laboratory 
tests will be analyzed by a central laboratory.  A blood sample for serum creatinine must be obtained after the third 
24-hour urine collection for PD analysis on Day 1; and after each 24-each 24-hour urine collection for PD analysis for the 
calculation of creatinine clearance.  Clinical laboratory tests will be evaluated by a central laboratory, except for tests 
performed on Day -1, and all predose LFT and creatinine measurements, which will be locally analyzed and centrally 
confirmed. (and before study drug administration, as applicable) 
Section(s) also containing this change:   
 
Table 3:  Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria Type 1 (Part B) who 
Previously Received Placebo and Will Receive Open-Label ALN-GO1 


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Purpose:  Specified that on days when a blood sample for vitamin B6 should be collected, patients should be instructed to not take vitamin B6 
before the blood sample is collected and the study drug is administered 
The primary change occurs in Table 2:  Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria 
Type 1 (Part B) 
Now reads: 
On days when a blood sample for pyridoxine (vitamin B6) will be collected, patients should be instructed not to 
take vitamin B6 before the blood sample is collected and study drug is administered. 
Section(s) also containing this change:   
 
Table 3:  Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria Type 1 (Part B) who 
Previously Received Placebo and Will Receive Open-Label ALN-GO1 
Purpose:  Removed the 28-day window for the Day 85 study visit 
The primary change occurs in Table 3:  Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria 
Type 1 (Part B) who Previously Received Placebo and Will Receive Open-Label ALN-GO1 
Removed: 
The “28-day window” from the Day 85 column for the row titled “Visit Window (D)” was deleted. 
Purpose:  Added blood and urine sample collections for exploratory 
for patients initially randomized to placebo 
The primary change occurs in Table 3:  Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria 
Type 1 (Part B) who Previously Received Placebo and Will Receive Open-Label ALN-GO1 
Added: 
An “X” was added to the row titled 
 
Purpose:  Corrected typographical errors, punctuation, grammar, abbreviations, and formatting, and incorporated administrative change letters 
These changes are not listed individually. 
 
 


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ALN-GO1-001 Protocol Amendment 2 
Summary of Changes (dated 21 September 2016) compared to  
Protocol Amendment 1 (dated 01 July 2016) 
 
A Phase 1/2, Single-Blind, Placebo-Controlled, Single and Multiple Ascending Dose Safety, 
Tolerability, Pharmacokinetic and Pharmacodynamics Study of Subcutaneously 
Administered ALN-GO1 in Healthy Adult Subjects, and Patients with Primary 
Hyperoxaluria Type 1 
 
Rationale for Protocol Amendment 
This purpose of this protocol amendment is to address feedback from Regulatory Agencies.  
Additionally, preliminary nonclinical embryofetal toxicity results (as described in a nonclinical 
safety report) were recently received, which will be further elucidated in a planned definitive 
study. These data showed a low incidence of cardiac malformation in low- and mid-dose treated 
groups but not in high-dose or control groups. Based on the lack of dose response and absence of 
drug exposure in any fetal tissues, the relationship to test article is uncertain.  However, the 
possibility of a pharmacologically-mediated effect cannot be ruled out, and thus, we have 
extended the follow-up period and contraception requirements.  
Based on these considerations, the following changes are being implemented:  
 All patients/subjects will be followed until pharmacodynamic recovery occurs; there 
will no longer be a maximum follow-up of 180 days.  Contraceptive requirements 
mirror this change such that women of childbearing potential are required to use 
approved methods of contraception through the end of the follow-up periods until PD 
recovery occurs. As a result of the extended follow-up periods, estimates of total time 
on study and overall duration of study have been updated. 
 For Part B, blood samples for anti-drug antibody analysis have been added at the final 
dosing visit/end of treatment visit, at 28 days after the final dose of ALN-GO1, and 
every 56 days for the remainder of the follow-up periods. 
 Language has been added to indicate that confirmed positive ADA samples will be 
tested for cross-reactivity with DNA and nucleic acids. 
 For Part B, pharmacokinetic (PK) sampling times have been added to ensure capture 
of the full PK profile.  In order to reduce burden on patients and reduce total amount 
of blood sampled, several PK time points have been removed, specifically: 
 Following the first ALN-GO1 dose, the 1-hr time point has been removed and 
12-hour, 48-hour, and 15-day time points have been added for blood PK.  
 Following the second ALN-GO1 dose, 24-hour pooled urine will no longer be 
collected, and all blood PK time points have been removed except for predose and 
2-hour postdose. 


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 Following the third/final ALN-GO1 dose, the 1 hr time point has been removed 
and 12-hour, 24-hour, 48-hour, and 15-day time points have been added for blood 
PK. Pooled urine following the third/final ALN-GO1 dose has been extended 
such that it will be collected over a 24-hour (rather than 8 hour) period. 
 In order to accommodate the additional time points for blood and urine PK in Part B, 
clinic visits have been added at Day 3, Day 58 and Day 59.  For subjects initially 
receiving placebo, clinic visits have also been added at Day 87, Day 142, and Day 
143. 
 Text has been modified to clarify that prior to the administration of each dose LFTs 
(rather than all clinical laboratory tests) will be reviewed locally prior to central 
laboratory confirmation. 
 Text has been added to clarify that patients should begin pregnancy tests after the 
onset of menarche, if menarche occurs after the screening period during the course of 
the study. 
 An erroneous reference to antiviral efficacy data has been removed. 
A detailed summary of changes is provided in Table 1. Corrections to typographical errors, 
punctuation, grammar, abbreviations, and formatting are not detailed, nor are updates to the 
protocol described in administrative change letters dated 15 July 2016, 04 August 2016, and 
19 September 2016.


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Table 1: 
Protocol Amendment 2 Detailed Summary of Changes 
The primary section(s) of the protocol affected by the changes in the protocol amendment are indicated.  The corresponding text has 
been revised throughout the protocol.  Deleted text is indicated by strikeout; added text is indicated by bold font. 
Purpose:  Follow-up periods have been extended to continue until pharmacodynamic recovery occurs. 
The primary change occurs in Table 2 (Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria 
Type 1 (Part B)), footnote a 
Now reads:  
Safety and PD follow-up will continue for until recovery of both plasma glycolate and urinary oxalate occurs. 
Plasma glycolate must decrease to a level that is no more than 20% above baseline or to below the upper 
limit of normal (14 nmol/mL).  Urinary oxalate must increase to a level that is above 80% of baseline.up to 
180 days after administration of the last dose of ALN–GO1 or placebo (study drug), or until plasma glycolate is 
within 20% of baseline, whichever duration is shorter. 
Section(s) also containing this change: 
 
Synopsis, Duration of Treatment and Overall Duration of Study 
 
Table 1, footnote a  
 
Table 2, footnote a 
 
Table 3, footnote a 
 
Section 4.1.1 Single-ascending Dose Part in Healthy Adult Subjects (Part A) 
 
Section 4.1.2 Multiple-ascending Dose Part in Patients with Primary Hyperoxaluria Type 1 (Part B) 
 
Section 4.2 Duration of Treatment and Overall Duration of Study 
Purpose:  Contraception requirements have been extended to continue through the entire study period. 
The primary change occurs in Section 5.1.1 Inclusion Criteria for Parts A and B 
Now reads:  
Women of child-bearing potential must have a negative pregnancy test, cannot be breast feeding, and must be 
willing to use a highly effective method of contraception 14 days before first dose, and throughout study 
participation, and for 90 days after last dose administration until the completion of the follow-up periods. 
Section(s) also containing this change: 
 
Section 6.4 Contraceptive Requirements 
 
Section 7.5.6.6 Pregnancy Reporting 
Purpose:  ADA collection time points have been added at the final dosing visit/end of treatment visit and during the follow-up period. 


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The primary change occurs in Table 2 (Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria 
Type 1 (Part B)) 
Now reads:  
Adjustments to Table 2 and 3 have been made to indicate that blood samples for ADA analysis will occur at the 
final dosing visit/end of treatment visit, at 28 days after the final dose of ALN-GO1, and every 56 days for the 
remainder of the follow-up periods. 
Section(s) also containing this change: 
 
Table 2 footnote t 
 
Table 3 footnote q 
 
Section 7.5.5.1 Immunogenicity 
Purpose:  To clarify the pregnancy test schedule for patients experiencing menarche after the screening period 
The primary change occurs in Table 2 (Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria 
Type 1 (Part B)), footnote i 
Added text:  
Pregnancy tests will be performed for women of childbearing potential only.  A serum pregnancy test will be 
performed at Screening or after the onset of menarche if the patient was not of childbearing potential at 
screening, and urine pregnancy tests will be performed thereafter per the Schedule of Assessments and any time 
pregnancy is suspected.  The results of the pregnancy test must be known before study drug administration.  FSH 
will be measured at Screening only to confirm post-menopausal status. 
Section(s) also containing this change: 
 
Table 3, footnote h 
 
Section 7.5.5.2 Pregnancy Testing 
Purpose:  Addition has been made to indicate that cross-reactivity testing will occur for confirmed positive ADA samples 
The primary change occurs in Section 7.5.5.1 Immunogenicity 
Added text:  
Confirmed positive ADA samples will be tested for cross-reactivity with DNA and nucleic acids. 
Purpose:  Changed time points for blood and urine PK sampling in Part B 
The primary change occurs in Table 10 (Pharmacokinetic Time Points for Multiple-ascending Dose Cohorts in Patients with PH1 (Part B)) 
Now reads:  
Adjustments to Table 10 have been made to reflect modifications to blood and urine PK time points.  
Section(s) also containing this change: 


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 
Table 2 
 
Table 3 
 
Section 7.3 Pharmacokinetic Assessments 
Purpose:  Added clinic visits in Part B to accommodate additional blood and urine PK sampling 
The primary change occurs in Table 2 (Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria 
Type 1 (Part B)) and Table 3 (Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria Type 1 (Part 
B) who Previously Received Placebo and will Receive Open-Label ALN-GO1) 
Added text:  
Columns have been added to Table 2 and Table 3 indicating clinic visits will occur on Day 3, Day 58, Day 59, 
Day 87, Day 142, and Day 143. “X”s are included in these columns corresponding to the following assessments: 
symptom-directed physical examination, vital signs, and blood and urine samples for PK analyses. 
Section(s) also containing this change: 
 
Section 4.1.2  Multiple-ascending Dose Part in Patients with Primary Hyperoxaluria Type 1 (Part B) 
Purpose:  Updated maximum blood volume estimates for Part B to accommodate additional PK and ADA sampling, and extended follow-up 
period 
The primary change occurs in Section 7.5.5.4 Maximum Blood Volume 
Now reads:  
The maximum blood volume for adult and pediatric patients initially randomized to ALN-GO1 will is not 
expected to exceed 250 260 mL over the 6 month course of the study.  The maximum blood volume for adult and 
pediatric patients initially randomized to placebo will notis not expected to exceed 350 375 mL over the 9 month 
course of the study. 
Purpose:  The end of study definition has been added. 
Section 9.1.4 End of Study has been added to the protocol.  Subsequent sections under 9.1 have been consequently renumbered. 
Added text: 
9.1.4. End of the Study  
The end of the study is defined as last patient last visit. 
Purpose: Clarified that prior to the administration of each dose, LFTs (rather than all clinical laboratory tests) will be reviewed locally prior to 
central laboratory confirmation. 
The primary change occurs in Footnote j of Table 2 (Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary 
Hyperoxaluria Type 1 (Part B))  
Now reads:  
Biochemistry, hematology, coagulation, LFTs, and urinalysis parameters are described in Section 7.5.5.  Clinical 
laboratory tests will be performed by a central laboratory. On Day -1, Day 29, and Day 57, and on days 


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when study drug is administered, clinical laboratory tests LFTs will be analyzed by a local laboratory and 
confirmed by athe central laboratory.  Local clinical laboratory assessment results for LFT measurements must be 
available and reviewed by the Investigator before study drug administration. On all other days, clinical laboratory 
tests will be analyzed by a central laboratory.  
Section(s) also containing this change: 
 
Footnote i of Table 3 
Purpose: Removed erroneous reference to antiviral efficacy data. 
The primary change occurs in Section 4.7 Study Drug Dosing, Study Progression, and Dose Escalation  
Now reads:  
The decision to enroll an optional cohort, extend an existing cohort, and (in the US) to enroll patients under 12 
years of age, will be made by the SRC based on available safety, tolerability, and antiviral efficacy PD data, if 
further elucidation of dose response is considered necessary to better understand dose response and/or safety and 
tolerability. 
Purpose:  Correct typographical errors, punctuation, grammar, abbreviations, and formatting, and incorporated administrative change letters.  
These changes are not listed individually. 
 


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ALN-GO1-001 Protocol Amendment 3  
Summary of Changes dated 09 December 2016 
 
A Phase 1/2, Single-Blind, Placebo-Controlled, Single  and Multiple Ascending Dose Safety, 
Tolerability, Pharmacokinetic and Pharmacodynamics Study of Subcutaneously 
Administered ALN GO1 in Healthy Adult Subjects, and Patients with Primary 
Hyperoxaluria Type 1 
 
Rationale for Protocol Amendment 
The primary purpose of this amendment is to further define the cardiac function requirements 
and monitoring for adult and pediatric patient population being considered for the 
multiple-ascending dose part (Part B) of study ALN-GO1-001.  These updates are based on 
recommendations from the Safety Review Committee (SRC) and further discussion with primary 
hyperoxaluria type 1 (PH1) experts on the cardiovascular manifestations of this disease, in 
particular in patients with severe disease.  Preliminary data from the single-ascending dose part 
(Part A) of this study in healthy adult subjects suggest that ALN-GO1 is well-tolerated at all 
doses tested; no signs or symptoms of cardiac abnormalities have been reported.  The benefit:risk 
profile for ALN-GO1 remains unchanged. 
Alnylam Pharmaceuticals is developing RNA interference (RNAi) therapeutics for multiple 
clinical indications.  Recently, ENDEAVOUR, a Phase 3 study with revusiran, an RNAi 
therapeutic for the treatment of amyloidosis-related cardiomyopathy in hereditary 
transthyretin-mediated amyloidosis, was stopped due to an imbalance in mortality between the 
treatment arm relative to the placebo arm.  The cause of death in this study was primarily cardiac 
in origin, which is consistent with the underlying natural history in this patient population with 
advanced heart failure (New York Heart Association Class II and III).  The root cause of this 
mortality imbalance remains under investigation. 
Following discontinuation of the revusiran program, the SRC for ALN-GO1-001 was 
convened.  The SRC noted that patients with PH1 with systemic oxalosis can also develop 
infiltrative cardiomyopathy in later stages of the disease process.  Since this initial study with 
ALN-GO1 is restricted to patients without evidence of systemic oxalosis, patients are not 
expected to have decreased ejection fraction; however, the SRC recommended a cautious 
approach by adding screening cardiac assessments to exclude patients with compromised cardiac 
function.  The SRC also recommended additional cardiac monitoring for patients enrolled in this 
study. 
The following changes are being implemented in Part B as outlined below: 
 Added exclusion criteria for ECHO assessment of left ventricular ejection fraction 
(LVEF) <55% and troponin I greater than the upper limit of normal (ULN) at 
screening 
 Added ECHO and troponin I assessments 
 Specified that electrocardiograms (ECGs) will be read using centralized equipment 


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 Increased maximum blood volume to align with cardiac monitoring evaluations 
 Aligned wording describing the resumption of dosing requirements after a dose 
suspension rule has been met 
A detailed summary of changes is provided in Table 1.  Corrections to typographical errors, 
punctuation, grammar, abbreviations, and formatting are not detailed. 


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Amendment 3 Summary of Changes_09 December 2016 
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Table 1: 
Protocol Amendment 3 Detailed Summary of Changes 
The primary section(s) of the protocol affected by the changes in the protocol amendment are indicated.  The corresponding text has 
been revised throughout the protocol.  Deleted text is indicated by strikeout; added text is indicated by bold font. 
Purpose:  Added ECHO assessments 
The primary change occurs in Table 2:  Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria 
Type 1 (Part B) 
Added text: 
Added a row for ECHO assessments in the table with ‘X’ at Screening, Day 85 during the Postdose Follow-up Period, and 
approximately every 168 days during Safety and PD Follow-up 
Section(s) also containing this change: 
 
Footnote ‘i’ in Table 2:  Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria Type 1 
(Part B) 
 
Table 3:  Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria Type 1 (Part B) who 
Previously Received Placebo and will Receive Open-Label ALN-GO1 
 
Footnote ‘h’ in Table 3:  Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria Type 1 
(Part B) who Previously Received Placebo and will Receive Open-Label ALN-GO1 
 
Section 7.5, Safety Assessments 
 
Section 7.5.5, Echocardiography (Part B only) 
 
Section 8.2.7, Safety Analyses 
Purpose:  Added troponin I assessments 
The primary change occurs in Table 2:  Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria 
Type 1 (Part B) 
Added text: 
Added a row for troponin I assessments in the table with ‘X’ at Screening, Day -1, 29, and 57/EOT during the Dosing Period, and 
Day 85 during the Postdose Follow-up Period, and approximately every 168 days during Safety and PD Follow-up 
Section(s) also containing this change: 
 
Footnote ‘l’ in Table 2:  Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria Type 1 
(Part B) 
 
Table 3:  Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria Type 1 (Part B) who 
Previously Received Placebo and will Receive Open-Label ALN-GO1 
 
Footnote ‘h’ in Table 3 


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 
Section 7.5.6, Clinical Laboratory Assessments 
Purpose:  Specified that ECGs will be read using centralized equipment 
The primary change occurs in Table 2:  Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria 
Type 1 (Part B) 
Added text: 
h. All 12-lead ECGs are triplicate, using centralized equipment.  Triplicate 12-lead ECGs will be measured 5 minutes apart.  Recordings 
will be obtained after the patient has rested comfortably in the supine position for approximately 10 minutes.  Patients should remain supine 
between ECGs.  On dosing days, ECGs will be measured within 1 hour predose; and at 1 hour (±20 minutes), 2 hours (±20 minutes), and 
4 hours (±20 minutes) postdose.  On all other days, ECGs should be collected at approximately the same time of day corresponding to the 
predose collection (±1 hour). 
Section(s) also containing this change: 
 
Table 3:  Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria Type 1 (Part B) who 
Previously Received Placebo and will Receive Open-Label ALN-GO1 
 
Footnote ‘g’ in Table 3 
 
Section 7.5.4, Electrocardiogram 
Purpose:  Aligned wording describing the resumption of dosing requirements after a dose suspension rule has been met 
The primary change occurs in Section 4.7.3, Dose Suspension and Stopping Rules 
Now reads: 
For the purpose of this study, dose suspension and stopping rules are based on toxicity.  Standard toxicity grading 
according to the CTCAE will be used to grade AEs.  The term ‘suspension’ means that no further study drug will be 
administered at the dose level and that further dose escalation/progression will be suspended.  If a suspension/stopping 
rule is met, there will be no further enrollment or dosing in the current cohort, or escalation to another cohort, in that 
part of the study and an ad hoc SRC meeting will be held.  Following SRC review, dosing may be resumed at the same 
or higher dose level following approval from the concerned Regulatory Authority and the independent ethics 
committee (IEC)/institutional review board (IRB) in accordance with applicable requirements, if required by local 
regulations.  However, de-escalation to a lower dose, or intermediate may be allowed without prior Regulatory 
Authority or IEC/IRB approval. 
Section(s) also containing this change: 
 
Table 7:  Cohort Progression/Escalation and Suspension/Stopping Rules for Part B 


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Purpose:  Added exclusion criteria for ECHO assessment of LVEF and troponin I at screening 
The primary change occurs in Section 5.2.2, Additional Exclusion Criteria for Part B 
Added text: 
22. Echocardiography (ECHO) assessment of abnormal left ventricular systolic function, defined as left ventricular 
ejection fraction <55% at screening 
23. Troponin I greater than the upper limit of normal (ULN) at screening (abnormal results should be repeated) 
Purpose:  Increased maximum blood volume to align with additional cardiac monitoring evaluations 
The primary change occurs in Section 7.5.6.4, Maximum Blood Volume 
Added text: 
In Part B, 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 11 from the Feinstein Institute for Medical Research Human 
Subject Protection Program Guidance Document (Section 11.3 in the Appendix).[13]  The maximum blood volume for adult and 
pediatric patients initially randomized to ALN-GO1 is not expected to exceed 260 mL 350 mL over the course of the study.  The 
maximum blood volume for adult and pediatric patients initially randomized to placebo is not expected to exceed 375 mL 450 mL 
over the course of the study.  The blood volume limits for patients in Part B are based on those for 6 year old girls in the 5th 
percentile for weight, the smallest patients who may be enrolled in the study. 
Purpose:  Correct typographical errors, punctuation, grammar, abbreviations, and formatting 
These changes are not listed individually. 
 


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ALN-GO1-001 Protocol Amendment 4 
Summary of Changes (dated 27 June 2017) compared to 
Protocol Amendment 3 (dated 09 December 2016) 
 
A Phase 1/2, Single-Blind, Placebo-Controlled, Single- and Multiple-Ascending Dose 
Safety, Tolerability, Pharmacokinetic and Pharmacodynamics Study of Subcutaneously 
Administered ALN-GO1 in Healthy Adult Subjects, and Patients with Primary 
Hyperoxaluria Type 1 
 
Rationale for Protocol Amendment 
The protocol is being amended to revise the study follow-up period for Part B.  In Part B of this 
study, adults or pediatric patients are randomized to receive multiple doses of ALN-GO1 or 
placebo.  Prior to this amendment, the protocol required that following completion of dosing, 
patients continue safety and pharmacodynamic (PD) follow-up until urinary oxalate is >80% of 
baseline and plasma glycolate is <20% above baseline or to below the upper limit of normal.   
To allow patients the opportunity to continue to receive potentially beneficial treatment for PH1, 
a chronic disease with no approved therapies, we are amending the protocol to potentially 
shorten the duration of follow-up to allow patients in Part B to transition to an open-label 
extension study earlier, provided that urinary oxalate is above the upper limit of normal and 
patients meet at least 1 of the following criteria: 
 One 24 hour urinary oxalate value is >80% of baseline. 
 Two 24 hour urinary oxalate values are above the midpoint between their baseline and 
nadir 24 hour urinary oxalate values.  The nadir must be from a valid collection after all 
doses are administered. 
 At least 12 months have elapsed from time of final dose administration.  
Relaxing the threshold for oxalate recovery and capping the duration of safety and PD follow-up 
potentially avoids a long lapse in treatment administration for patients who wish to continue to 
receive ALN-GO1 in an open-label extension study.  Glycolate recovery is not considered to be 
required for patients who enroll in the open-label extension study since plasma glycolate and 
safety data will continue to be monitored in the extension study. 
Other changes being introduced in this amendment include an increase in the number of optional 
cohorts and sample size in Part B in order to allow for further exploration of the optimal dose 
and dosage regimen to support later stage clinical development.  The current protocol allows the 
option to enroll 2 additional cohorts or to expand a cohort by up to 4 additional patients in 
Part B.  The protocol is being amended to allow for up to 3 optional cohorts in Part B.  In 
addition, this amendment allows the Safety Review Committee (SRC) to permit up to 2 cohorts 
in Part B to be extended by up to 4 additional patients.  The total number of patients in Part B has 
been increased to up to 24 patients. 


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A Schedule of Assessments for quarterly dosing in Part B has also been added in this 
amendment. The current protocol allows the dosing regimen to be determined or adapted in 
accordance with safety, tolerability and PD data; however, the only schedules of assessments 
included were for monthly dosing.  Preliminary data from Part A in healthy subjects informed 
the potential option for quarterly dosing in Part B.  This amendment specifies the schedule and 
planned procedures for quarterly dosing in Part B, if implemented. 
In addition to these changes, the following has been updated for this study: 
 The information in the Benefit-Risk Assessment, which remains positive, was updated to 
align with the information in the Investigator’s Brochure (Edition 2). 
 The Statistical Methods section has been updated to account for a quarterly dosing 
regimen, if implemented. 
 Section 4.6 Safety Review Committee was amended to align with recent changes to the 
SRC charter regarding the frequency of safety data reviews during the study.  The SRC 
charter stipulates that after initiation of dosing in Part B, the SRC will review data 
approximately every 4 weeks during the dosing and post-dose follow-up periods, or as 
further decided by the SRC until all subjects and patients have completed their 
participation in the study as per protocol. 
 Clarified that the PK population (analysis set) includes subjects/patients with any 
evaluable postdose PK data. 
 Clarified that Part B is expected to take place at approximately 12 clinical study centers 
worldwide. 
 Clarified that for certain study visits, blood sample collection for exploratory 
 
is optional for pediatric patients who exceed the maximum blood volume collection limits. 
A detailed summary of changes is provided in Table 1.  Corrections to typographical errors, 
punctuation, grammar, abbreviations, and formatting (including administrative changes noted in 
Protocol Administrative Change #8 (dated 26 April 2017) are not detailed. 
 


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Table 1: 
Protocol Amendment 4 Detailed Summary of Changes 
The primary section(s) of the protocol affected by the changes in the protocol amendment are indicated.  The corresponding text has 
been revised throughout the protocol.  Deleted text is indicated by strikeout; added text is indicated by bold font. 
Purpose:  Add Schedule of Assessments for Quarterly Dosing and associated Pharmocokinetic Time Points table 
The primary change occurs in Table 4: Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria 
Type 1 (Part B) – Quarterly Dosing, Appendix 11.1 text, and Table 12: Pharmacokinetic Time Points for Patients with PH1 (Part B – Quarterly 
Dosing) 
Section(s) also containing this change: 
 
Section 7 Study Assessments 
 
Section 7.3 Pharmacokinetic Assessments 
Purpose:  Update table titles to clarify monthly vs quarterly dosing schedules 
Now reads: 
 
 
Table 2: 
Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria Type 1 (Part B  – 
Monthly Dosing) (PartB) 
 
Table 3: 
Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria Type 1 (Part B) who 
Previously Received Placebo and will Receive Open-Label ALN-GO1 – Monthly Dosing 
 
Table 11: 
Pharmacokinetic Time Points for Multiple-ascending Dose Cohorts in Patients with PH1 (Part B – Monthly Dosing) 


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Purpose:  Amend study design to describe quarterly dosing procedures 
The primary change occurs in Section 4.1.2. Multiple-ascending Dose Part in Patients with Primary Hyperoxaluria Type 1 (Part B) 
Now reads: 
Patients will be randomized on between Day -1 and Day 1 and will receive the first dose of ALN-GO1 or placebo on Day 1.  The 
24- and 48-hour postdose follow up assessments will take place on Day 2 and Day 3.  Patients who receive study drug monthly 
will return to the clinical study center on an outpatient basis for safety, tolerability, PK, and PD monitoring at time points 
specified in the Schedule of Assessments (Table 2) for the remaining 2 single-blind doses of study drug (through Day 57).  After 
completion of the blinded portion of the study, patients dosed monthly will be unblinded (on or after Day 78).  Patients who 
initially received placebo will then receive ALN-GO1 at the same dose administered to the cohort into which they were initially 
randomized and will follow the same assessment schedule with the first dose administered on the new Day 1 (corresponding to 
study Day 85) as indicated in Table 3. 
Patients who receive study drug quarterly will return to the clinical study center for safety, tolerability, PK, and PD 
monitoring at time points specified in the Schedule of Assessments (Table 4) and will receive a 2nd dose of study drug at 
Day 85.  Patients who initially received placebo will receive a single dose of ALN-GO1 on Day 85 at the same dose 
administered to the cohort into which they were initially randomized.  Patients dosed quarterly will be unblinded to initial 
treatment assignment following completion of the postdose follow-up period 
Section(s) also containing this change: 
 
Synopsis 
Purpose:  Clarify blinding plan for quarterly dosing cohort(s), if enrolled 
The primary change occurs in Section 4.5 Blinding 
Added text: 
This is a single-blind, placebo-controlled study; therefore, only the study subjects/patients will be blinded to treatment 
assignment.  Patients in Part B dosed monthly will be unblinded on or after Day 78 in order for patients and their families to be 
better prepared for the transition to receive ALN-GO1 if initially randomized to placebo.  Patients dosed quarterly will be 
unblinded to initial treatment assignment following completion of the postdose follow-up period.  The Investigators, Medical 
Monitors at the Sponsor and CRO, clinical study center personnel, pharmacokineticist, and members of the SRC will have 
knowledge of the treatment assignment.  The clinical study center pharmacy staff will maintain the single-blind according to 
clinical study center-specific procedures and the Pharmacy Manual.  Syringes containing dispensed study drug will be masked in 
the pharmacy before transfer to the clinic. 
Purpose:  Update Benefit-Risk Assessment to align with the Investigator’s Brochure 
The primary change occurs in Section 1.5 Benefit-Risk Assessment 
Now reads: 
Non-specific potential risks Important potential risks to healthy subjects and patients include injection site reactions (ISRs).  
Other potential risks include:  embryofetal risk toxicity, coagulation abnormalities, and liver function test abnormalities.  


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These potential risks have been reduced by the specific inclusion and exclusion criteria incorporated into the selection of healthy 
subjects as well as for patients with PH1 in this clinical study.   
No data are available on the use of ALN-GO1 in pregnancy; however, there is no suspicion of human teratogenicity based on 
class effects or genotoxic potential mutagenicity is not suggested based on the available nonclinical data (see Investigator’s 
Brochure for further information).  Embryofetal risk is limited by requiring that women of childbearing potential (WOCBP) 
must have a negative pregnancy test, cannot be breast feeding, and must be willing to use a highly effective method of 
contraception as specified in the protocol.  Male subjects/patients are not required to use the contraception measures required for 
female study subjects/patients.  No male contraception is considered to be required.   
The occurrence of ISRs will be carefully monitored. 
Nonclinical studies in rats showed mild to moderate decreases in fibrinogen and occasionally minimal prolonged 
prothrombin time without accompanying clinical or microscopic evidence of hemorrhage.  This effect is likely species-
specific as it was not observed in NHPs and will be monitored via clinical laboratory safety assessments. 
Purpose:  Increase the number of patients in the study due to the option to enroll up to 1 additional optional cohort or to expand a cohort in 
Part B 
The primary change occurs in Section 8.1 Determination of Sample Size 
Now reads: 
The sample size was based on clinical considerations rather than power calculations.  Up to 604 participants (40 subjects and 204 
patients) are planned to be enrolled in this study, including optional and expansion cohorts (see Table 9). 
Section(s) also containing this change: 
 
Synopsis 
 
Section 4.3 Number of Subjects and Patients 


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Purpose:  Specify criteria for patients who wish to enroll in an open-label extension study following completion of the postdose follow-up period 
and clarified duration of safety and PD follow up for patients who do not enroll in an open-label extension study. 
The primary change occurs in Section 4.1.2. Multiple-ascending Dose Part in Patients with Primary Hyperoxaluria Type 1 (Part B) 
Added text: 
After the dosing period, patients will return to the clinical study center for continued safety, tolerability, PK, and PD monitoring 
through the last postdose follow-up visit.  Following completion of the postdose follow-up period, patients will be invited to 
participate in an open-label extension study provided that: 
 
Urinary oxalate is above the ULN and patients meet at least 1 of the following criteria: 
o One 24-hour urinary oxalate value is >80% of baseline. 
o Two 24-hour urinary oxalate values are above the midpoint between their baseline and nadir 24-hour 
urinary oxalate values.  The nadir must be from a valid collection after all doses are administered. 
o At least 12 months have elapsed from time of final dose administration.  
For patients who do not enroll in the open-label extension study, safety and PD follow up will continue until: 
 
24-hour urinary oxalate is >80% of baseline, AND 
 
Plasma glycolate is <20% above baseline or ≤ the ULN. 
Section(s) also containing this change: 
 
Synopsis 
 
Table 2: Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria Type 1 (Part B) – 
Monthly Dosing 
 
Table 3: Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria Type 1 (Part B) who 
Previously Received Placebo and will Receive Open-Label ALN-GO1 – Monthly Dosing 


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Purpose:  Increase the number of optional cohorts and expansion cohorts in Part B to allow for further exploration of the optimal dose or dosing 
regimen. 
The primary change occurs in Section 4.1.2 Multiple-ascending Dose Part in Patients with Primary Hyperoxaluria Type 1 (Part B) 
Now reads: 
Part B is the multiple-ascending dose part of the study in up to 24 adult and pediatric patients with PH1 with relatively 
well-preserved renal function.  Patients will be enrolled in 1 of 2 ascending dose cohorts. Two ascending dose cohorts will be 
enrolled, with the possibility to also enroll up to 3 Two additional optional cohorts may also be enrolled to further explore the 
optimal dose or regimen.  Each cohort will be comprised of 4 patients, randomized 3:1 to ALN-GO1 or placebo.  Expansion of a 
cohort in Part B by up to 4 additional patients may also occur Up to 2 cohorts in Part B may be expanded by up to 4 additional 
patients (these patients will all receive ALN-GO1, not placebo). 
Section(s) also containing this change: 
 
Table 9: Adaptive Study Design Areas, Features, and Limits 
 
Section 4.7.2 Study Drug Dosing, Study Progression, and Dose Escalation in Part B 
Purpose:  Differentiate monthly vs quarterly drug dosing procedures 
The primary change occurs in 4.7.2 Study Drug Dosing, Study Progression, and Dose Escalation in Part B 
Now reads: 
In Part B, all subjects patients in a cohort dosed monthly will receive the same dose for each of the 3 study drug doses.  Subjects 
Patients initially receiving 3 doses of placebo will receive 3 doses of ALN-GO1, with all 3 doses being the same for each of the 3 
administrations of ALN-GO1.  Patients in a cohort dosed quarterly who are randomized to ALN-GO1 will receive the same 
dose for each of the 2 study drug doses.  Patients initially receiving 1 dose of placebo on Day 1 will receive 1 dose of ALN-
GO1 on study Day 85.  The maximum dose administered will not exceed 6.0 mg/kg. 
Dose levels and/or dosing regimen in each cohort in Part B may be modified by the SRC.  The next higher dose cohort can be 
enrolled after at least 3 patients in the previous cohort receive their first and second dose and have been followed for at least 
14 days following the second dose of study drug.  The SRC must review accumulating safety data from both single- and multiple-
ascending dose cohorts to confirm the dose level and permit dosing in the next MAD cohort.  In Part B, after unblinding, patients 
randomized to placebo will be administered active ALN-GO1 in an open-label manner according to the same dose and assessment 
schedule for the cohort to which they were initially assigned. 


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Purpose:  Revise statistical methods to account for quarterly dosing, if implemented 
The primary change occurs in Section 8.2 Statistical Methodology  
Now reads: 
Data from Parts A and B will be analyzed separately.  Tabular summaries will be generated by dose level and dosing regimen of 
ALN-GO1 and placebo (pooled across all cohorts) for Part A and Part B (through Day 85).   
For the blinded portion of Part B, sSafety and PD data will be summarized for each cohort by dose level and dosing regimen of 
ALN-GO1 compared to placebo for data collected up to, and including, study Day 85.  After receiving 3 single-blind doses of 
study drug (and completing assessments for that portion of the study), patients initially randomized to placebo will be unblinded 
and administered 3 doses of active ALN-GO1 in an open-label manner according to the same dose and assessment schedule.  Data 
from the blinded and open-label portion of the study will also be combined to summarize the safety and PD effect of ALN-GO1 at 
each dose level.  Data from placebo patients from all cohorts will be combined.  Data collected after Day 85 will be 
summarized separately for patients in quarterly dosing cohorts who receive a second dose of ALN-GO1 on Day 85.  
Additionally, all safety and PD data collected from all patients in Part B during the ALN-GO1 dosing period, regardless of 
treatment sequence, will be combined and summarized by ALN-GO1 dose level and regimen.  
Data collected beyond the designated dosing period will be summarized or presented in data listings.  
Section(s) also containing this change: 
 
Synopsis 
Purpose:  Clarify the PK population (analysis set) includes patients/subjects with any evaluable postdose PK data. 
The primary change occurs in Section 8.2.1. Populations to be Analyzed  
Now reads: 
PK Analysis Set:  All subjects/patients who receive at least 1 dose of study drug and have at least 1 postdose blood sample for PK 
parameters and who have evaluable for PK parameters data. 
Purpose:  Clarify that Part B is expected to take place at approximately 12 clinical study center worldwide 
The primary change occurs in Section 4.1 Summary of Study Design  
Now reads: 
Part B is expected to take place at up to approximately 12 clinical study centers worldwide.  


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Purpose:  Update treatment duration and overall study duration to account for the option for quarterly dosing Part B and also to account for the 
option to include an additional optional cohort or expansion cohort in PartB. 
The primary change occurs in Section 4.2 Duration of Treatment and Overall Duration of Study 
Now reads: 
The duration of treatment is as follows: 
 
Part A:  The estimated total time on study, inclusive of screening, for each subject is up to 405 days.  The duration of 
treatment is a single dose. 
 
Part B:  The estimated total time on study, inclusive of screening and safety and PD follow-up, for each patient 
initially randomized to receive active study drug is 462 days.  The duration of treatment is 57 days.  Additionally, the 
estimated total time on study, inclusive of screening and safety and PD follow-up, for each patient initially 
randomized to receive placebo, then active study drug, is 546 days.  The duration of treatment is 141 days 
 
For patients dosed monthly:  The duration of treatment for patients initially randomized to receive active 
study drug is 57 days.  The estimated total time on study, inclusive of screening, for each patient is up to 
462 days.  Additionally, the duration of treatment for patients initially randomized to receive placebo is 141 
days.  The estimated total time on study, inclusive of screening, for each patient initially randomized to 
receive placebo, then active study drug, is up to 546 days.  
 For patients dosed quarterly: The duration of treatment is 85 days for patients randomized to placebo and 
active study drug.  The estimated total time on study, inclusive of screening, is up to 490 days.  
The overall duration of the study is estimated to be 34 years, including enrollment. 
Section(s) also containing this change: 
 
Synopsis 
 
 


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Purpose:  Clarify that triplicate12-lead ECGs will be measured approximately 5 minutes apart. 
The primary change occurs in Section 7.5.4 Electrocardiogram 
Added text: 
Triplicate 12-lead ECGs will be measured approximately 5 minutes apart. 
Section(s) also containing this change: 
 
Table 1: Schedule of Assessments for Single-ascending Dose Cohorts in Healthy Subjects (Part A) 
 
Table 2: Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria Type 1 (Part B – Monthly 
Dosing) 
 
Table 3: Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria Type 1 (Part B) who 
Previously Received Placebo and will Receive Open-Label ALN-GO1 – Monthly Dosing 
Purpose:  Delete text in Schedule of Assessment footnotes providing examples of days when echocardiograms are performed and days when 
troponin I is measured. 
The primary change occurs in footnote i (echocardiogram) and footnote l (troponin I) in Table 2 Schedule of Assessments for Multiple-ascending 
Dose Cohorts in Patients with Primary Hyperoxaluria Type 1 (Part B) 
Now reads: 
i. 
Echo will be performed during the first visit of the Safety and PD Follow-up Period (Day 169), and thereafter, approximately 
every 168 days corresponding with visits to the clinical study center (eg, Day 337, Day 505, Day 673) for the duration of the 
study. 
l. 
During Screening and throughout the Dosing Period, abnormal results for troponin I tests should be repeated.  During the 
Dosing Period only, local clinical laboratory results must be drawn within 4 days prior to dosing and available and reviewed by 
the Investigator before study drug administration.  Troponin I levels will be measured on the first day of the Safety and PD 
Follow-up Period (Day 169), and thereafter, approximately every 168 days (eg, Day 337, Day 505, Day 673) for the duration of 
the study. 
Section(s) also containing this change: 
 
Table 3:  Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria Type 1 (Part B) who 
Previously Received Placebo and will Receive Open-Label ALN-GO1 footnote h (echocardiogram) and footnote k (troponin I) 


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Purpose:  Clarify that for certain visits, blood samples for exploratory 
 are optional for pediatric patients who exceed the maximum 
blood volume collection limits. 
The primary change occurs in Table 2 Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria 
Type 1 (Part B) and Table 3: Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria Type 1 (Part 
B) who Previously Received Placebo and will Receive Open-Label ALN-GO1 
Added text: 
Footnote v. (Table 2)  Blood samples for exploratory
 on Day 57 are optional for pediatric patients who exceed 
the maximum blood volume collection limits listed in Table 13. 
Footnote r. (Table 3)  Blood samples for exploratory
s on Day 85 are optional for pediatric patients who exceed 
the maximum blood volume collection limits listed in Table 13. 
Purpose:  Amend text describing the frequency of SRC data reviews to align with recent changes to the SRC charter.  
The primary change occurs in Section 4.6 Safety Review Committee  
Now reads 
The SRC will undertake safety data review before initiation of dosing in a new cohort in Part A and Part B, and before initiation 
of dosing in Part B.  After initiation of dosing in Part B, the SRC will review data approximately every 4 weeks after 
administration of the last dose of ALN-GO1 until recovery of both plasma glycolate and urinary oxalate occurs safety reviews 
will be conducted in accordance with the SRC charter at a minimum of every 3 months for the duration of the study. 
Purpose:  Increase the maximum blood volume over the course of the study in patients initially randomized to ALN-GO1 to account for the 
quarterly dosing schedule, if implemented 
The primary change occurs in Section 7.5.6.4 Maximum Blood Volume  
Now reads: 
The maximum blood volume for adult and pediatric patients initially randomized to ALN-GO1 is not expected to exceed 350 
400 mL over the course of the study. 
Purpose:  Remove reference to outpatient visits in Part B since outpatient visits are not required (sites have the option to admit patients) 
The primary change occurs in Section 4.1.2 Multiple-ascending Dose Part in Patients with Primary Hyperoxaluria Type 1 (Part B) 
Now reads 
Patients will return to the clinical study center on an outpatient basis for safety, tolerability, PK, and PD monitoring at time points 
specified in the Schedule of Assessments for the remaining 2 single-blind doses of study drug (through Day 57). 
After the dosing period, patients will return to the clinical study center on an outpatient basis for continued safety, tolerability, PK, 
and PD monitoring through the last postdose follow-up visit. 


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Section(s) also containing this change: 
 
Synopsis 
Purpose:  Clarify in Table 3 that the calculation of the ALN–GO1 dose to be administered during the open label portion of the study will be based 
on the body weight obtained on Day 57, not Day 85 
The primary change occurs in Table 3:  Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria 
Type 1 (Part B) who Previously Received Placebo and will Receive Open-Label ALN-GO1 footnote e 
Now reads: 
e. The Day 85 57 body weight will be used for calculation of the ALN–GO1 dose to be administered during this portion of the 
study.  
Purpose:  Simplify text describing study design period 
The primary change occurs in Section 4.1.2. Multiple-ascending Dose Part in Patients with Primary Hyperoxaluria Type 1 (Part B) 
Now reads: 
Patients will be screened within from -45 to -2 days before prior to study drug administration.  Baseline urinary oxalate excretion 
and creatinine clearance will be assessed through 24-hour urine collections.  The remaining screening and predose assessments 
will take place on Day -1. 
Purpose:  Add footnote to Figure 1 to indicate that patients in Part B will be invited to participate in an open-label extension study following the 
postdose follow-up period 
The primary change occurs in Figure 1: Study Design 
Added text: 
a Patients in Part B will be invited to participate in an open-label extension study provided they meet the criteria described 
in Section 4.1.2.  
Purpose:  Correct typographical errors, punctuation, grammar, abbreviations, and formatting 
These changes are not listed individually. 
 


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ALN-GO1-001 Protocol Amendment 5  
Summary of Changes (dated 14 February 2018) compared to 
Protocol Amendment 4 (dated 27 June 2017) 
 
A Phase 1/2, Single-Blind, Placebo-Controlled, Single- and Multiple-Ascending Dose 
Safety, Tolerability, Pharmacokinetic and Pharmacodynamics Study of Subcutaneously 
Administered ALN-GO1 in Healthy Adult Subjects, and Patients with Primary 
Hyperoxaluria Type 1 
 
Rationale for Protocol Amendment 
The protocol is being amended to allow patients with primary hyperoxaluria type 1 (PH1) in 
Part B to more rapidly rollover to an open-label extension study to continue to receive 
ALN-GO1.  This amendment shortens the required follow-up period from up to 1 year to 
12 weeks after their last dose of ALN-GO1,  without requiring the protocol-defined thresholds 
for urinary oxalate levels.  Data to date indicate that ALN-GO1 has a favorable impact on 
suppressing urinary oxalate production, the cause of morbidity and mortality in patients with 
PH1.  In addition, the available data have not identified a safety concern of ALN-GO1 nor 
ALN-GO1-mediated GO1 knockdown.  Patients who rollover to the open-label extension study 
will continue to be monitored for safety and ongoing reviews of safety, tolerability and available 
study data will be performed by the same Safety Review Committee (SRC) used in this study.  
This amendment will also permit the investigator to discontinue safety and pharmacodynamic 
(PD) follow up for patients who do not enroll in the open-label extension study, and who have 
not yet met the protocol-specified recovery criteria. This decision must not be made until 
completion of the required 12-week follow-up period and must be endorsed by the SRC based 
upon the patient's pharmacodynamic and safety data, as well as emerging data on the safety of 
ALN-GO1 knockdown.  This change will potentially reduce the total burden of study follow-up 
for some patients while ensuring patient safety. 
Another change being introduced in this amendment includes revision of the blood pressure 
exclusion criteria for pediatric patients in Part B. The definition for uncontrolled hypertension in 
patients <18 years of age is being redefined from a set cutoff by age to using the American 
Academy of Pediatric guidelines which account for age, gender and height.  This will prevent 
pediatric patients who are normotensive by these accepted guidelines from being excluded from 
the study. 
In addition to these changes, the following has been updated for this study: 
 Extended the allowable time window (from 1 to 2 hours) to conduct predose assessments 
(ie, vital signs, 12-lead ECGs, physical examinations, blood and urine sample collections) 
when scheduled at the same time points for Part B. 
 Clarified that blood samples for pyridoxine (vitamin B6) are required only for patients 
receiving therapeutic pyridoxine since they are being measured to monitor adherence to 
the baseline regimen.  


ALN-GO1  
 
Clinical Study Protocol ALN-GO1-001 
Amendment 5 Summary of Changes_14 February 2018 
 
Alnylam Pharmaceuticals 
Confidential 
2 
A detailed summary of changes is provided in Table 1.  Corrections to typographical errors, 
punctuation, grammar, abbreviations, and formatting are not detailed. 
 


ALN-GO1-001 
Clinical Study Protocol ALN-GO1-001 
 
Amendment 5 Summary of Changes_14 February 2018 
Alnylam Pharmaceuticals 
Confidential 
3 
Table 1: 
Protocol Amendment 5 Detailed Summary of Changes 
The primary section(s) of the protocol affected by the changes in the protocol amendment are indicated.  The corresponding text has 
been revised throughout the protocol.  Deleted text is indicated by strikeout; added text is indicated by bold font. 
Purpose:  Clarify that blood samples for pyridoxine (vitamin B6) are required only for patients receiving therapeutic pyridoxine. 
The primary change occurs in Table 2: Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria 
Type 1 (Part B – Monthly Dosing  
Now reads: 
Blood sample for pyridoxine (vitamin B6) is required only for patients receiving therapeutic pyridoxine.  On days when a 
blood sample for pyridoxine vitamin B6 will be collected, patients should be instructed not to take vitamin B6 before the blood 
sample is collected and study drug is administered. 
Section(s) also containing this change: 
 
Table 3:  Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria Type 1 (Part B) who 
Previously Received Placebo and will Receive Open-Label ALN-GO1 – Monthly Dosing, footnote s 
 
Table 4:  Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria Type 1 (Part B – 
Quarterly Dosing), footnote w 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


ALN-GO1-001 
Clinical Study Protocol ALN-GO1-001 
 
Amendment 5 Summary of Changes_14 February 2018 
Alnylam Pharmaceuticals 
Confidential 
4 
Purpose:  Shorten the study follow up criteria for patients in Part B who wish to enroll in an open-label extension study. 
The primary change occurs in Section 4.1.2  Multiple-ascending Dose Part in Patients with Primary Hyperoxaluria Type 1 (Part B) 
Now reads: 
After the dosing period, patients will return to the clinical study center for continued safety, tolerability, PK, and PD 
monitoring through for at least 12 weeks (84 days) following the last postdose follow-up visit dose of study drug.  
Following completion of the 12-week postdose follow-up period, patients will be invited to participate in an open-label 
extension study provided that: 
Urinary oxalate is above the ULN and patients meet at least 1 of the following criteria: 
 One 24-hour urinary oxalate value is >80% of baseline. 
 Two 24-hour urinary oxalate values are above the midpoint between their baseline and nadir 24-hour 
urinary oxalate values.  The nadir must be from a valid collection after all doses are administered. 
 At least 12 months have elapsed from time of final dose administration. 
 
Section(s) also containing this change: 
 
Synopsis 
Purpose:  Clarify that up to 2 cohorts in Part B may be extended by up to 4 patients per cohort. 
The primary change occurs in Section 4.1.2 Multiple-ascending Dose Part in Patients with Primary Hyperoxaluria Type 1 (PartB) 
Now reads: 
Based on SRC review of accumulated safety, tolerability, and available PD data, up to 2 cohorts in Part B may be 
extended by up to 4 additional patients per cohort (these patients will all receive active drug, not placebo). 
 
Section(s) also containing this change: 
 
4.7.2 Study Drug Dosing, Study Progression, and Dose Escalation in Part B 
 
Table 9: 
Adaptive Study Design Areas, Features, and Limits 


ALN-GO1-001 
Clinical Study Protocol ALN-GO1-001 
 
Amendment 5 Summary of Changes_14 February 2018 
Alnylam Pharmaceuticals 
Confidential 
5 
Purpose: Clarify the duration of screening and minimum duration of postdose follow up 
The primary change occurs in Section 4.2 Duration of Treatment and Overall Duration of Study 
Now reads: 
 Part A:  The estimated total time on study, inclusive of screening, for each subject is up to 405 days.  The duration of 
treatment is a single dose. 
 
Part B:  For all patients, the duration of screening is up to 45 days and the minimum duration of postdose 
follow-up is 84 days. The duration of treatment and estimated total time on study, inclusive of screening, for 
each patient is as follows: 
 
For patients dosed monthly:  The duration of treatment for patients initially randomized to receive active study 
drug is 57 days.  The estimated total time on study, inclusive of screening for each patient is up to 462 days.  
Additionally, the duration of treatment for patients initially randomized to receive placebo is 141 days.  The 
estimated total time on study, inclusive of screening, for each patient initially randomized to receive placebo, then 
active study drug, is up to 546 days. 
 
For patients dosed quarterly: The duration of treatment is 85 days for patients randomized to placebo and active 
study drug.  The estimated total time on study, inclusive of screening, is up to 490 days. 
Section(s) also containing this chage: 
 Synopsis 
Purpose:  Add an alternative threshold for discontinuation from study follow-up for patients in Part B who do not wish to enroll in an open-label 
extension study. 
The primary change occurs in Section 4.1.2 Multiple-ascending Dose Part in Patients with Primary Hyperoxaluria Type 1 (Part B) 
Now reads: 
For patients who do not enroll in the open-label extension study, safety and PD follow up will continue until 24-hour 
urinary oxalate is >80% of baseline, and AND P plasma glycolate is <20% above baseline or ≤ the ULN.  If an 
investigator wishes to discontinue follow up after completion of the postdose follow-up period and prior to 
oxalate and glycolate recovery, the SRC must agree based upon consideration of emerging data on the safety of 
ALN-GO1 knockdown and the individual patient’s safety and PD data.  
Section(s) also containing this change: 
 
Synopsis 
 
Section 4.6 Safety Review Committee 


ALN-GO1-001 
Clinical Study Protocol ALN-GO1-001 
 
Amendment 5 Summary of Changes_14 February 2018 
Alnylam Pharmaceuticals 
Confidential 
6 
Purpose:  Revise blood pressure eligibility criteria for pediatric patients in Part B and provide corresponding age and weight-based blood 
pressure tables  
The primary change occurs in 5.2.2 Additional Exclusion Criteria for Part B   
Revised text: 
21. For patients <18 years old, aged 6 to 11 years, inclusive, males with systolic blood pressure >115 mmHg and/or a 
diastolic blood pressure >75 mmHg and females with systolic blood pressure >110 mmHg and/or a diastolic blood 
pressure >75 mmHg after 10 minutes of rest at screening.  For male and female patients aged 12 to 17 years, inclusive, 
systolic blood pressure >120 mmHg and/or a diastolic blood pressure >80 mmHg diastolic and/or systolic blood 
pressure equal to or greater than the 95th percentile for age, gender, and height (see Appendix 11.4 Table 14 and 
Table 15) after 10 minutes of rest at screening. 
Purpose:  Add Appendix to include normative pediatric blood pressure tables and corresponding reference  
The primary change occurs in Appendix 11.4 Nortmative Pediatric Blood Pressure Tables   
Added text: For pediatric patients <18 years old, study entry criteria for blood pressure will be determined according to normative blood      
pressure tables based on normal-weight children included in published guidelines issued by the American Academy of 
Pediatrics [13] (see Table 14 and Table 15).  Patients will be excluded if diastolic and/or systolic blood pressure is equal to or 
greater than the 95th percentile for sex, age, and height (mean of screening height measurements).    
Added tables:  
 Table 14: Blood Pressure Levels for Girls by Age and Height Percentile 
 Table 15: Blood Pressure Levels for Boys by Age and Height Percentile 
Section(s) also containing this change: 
 References: Flynn, J.T., et al., Clinical Practice Guideline for Screening and Management of High Blood Pressure in 
Children and Adolescents. Pediatrics, 2017. 140(3). 
 
 


ALN-GO1-001 
Clinical Study Protocol ALN-GO1-001 
 
Amendment 5 Summary of Changes_14 February 2018 
Alnylam Pharmaceuticals 
Confidential 
7 
Purpose:   Extend the allowable time window to conduct predose assessments (ie, vital signs, 12-lead ECGs, physical examinations, blood and 
urine sample collections) when scheduled at the same time points for Part B 
The primary change occurs in footnote g (vital signs), footnote h (ECG), footnote q (blood sample for PD analysis)  in Table 2 Schedule of 
Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria Type 1 (Part B) 
Now reads: 
g. Vital signs (blood pressure, pulse rate, body temperature, and respiration rate) will be measured in the supine position 
after the patient has rested comfortably for 10 minutes.  On Day 1 only, vital signs will be measured within 21 hours 
predose; and 30 (±5 minutes) and 4 hours (±15 minutes) postdose.  
h. All 12-lead ECGs are triplicate, using centralized equipment.  ECGs will be measured approximately 5 minutes apart.  
Recordings will be obtained after the patient has rested comfortably in the supine position for approximately 10 minutes.  
Patients should remain supine between ECGs.  On dosing days, ECGs will be measured within 21 hours predose; and at 1 
hour (±20 minutes), 2 hours (±20 minutes), and 4 hours (±20 minutes) postdose.  On all other days, ECGs should be 
collected at approximately the same time of day corresponding to the predose collection (±1 hour). 
q. On Day 1, the blood sample for PD analysis must be collected within 21 hours predose.  The remaining PD samples 
should be collected at approximately the same time of day corresponding to the predose collection (±1 hour), as 
applicable. 
Section(s) also containing this change: 
 
Table 3: 
Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria Type 1 (Part B) who 
Previously Received Placebo and will Receive Open-Label ALN-GO1 – Monthly Dosing, footnote f (vital signs), footnote g (ECG), and 
footnote n (blood sample for PD analysis) 
 
Table 4: 
Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria Type 1 (Part B – 
Quarterly Dosing), footnote g (vital signs), footnote h (ECG), and footnote q (blood sample for PD analysis) 
 
Table 11: 
Pharmacokinetic Time Points for Multiple-ascending Dose Cohorts in Patients with PH1 (Part B – Monthly Dosing), Day 1 
Predose, Day 29 Predose, Day 57 Predose, Day 85 Predose, Day 113 Predose, and Day 141 Predose 
 
Table 12: 
Pharmacokinetic Time Points for Patients with PH1 (Part B – Quarterly Dosing), Day 1 Predose and Day 85 Predose 
Purpose: Clarify that patients in Part B are enrolled in sequential dose cohorts and align study design language between the body of the protocol 
and synopsis 
The primary change occurs in the synopsis 


ALN-GO1-001 
Clinical Study Protocol ALN-GO1-001 
 
Amendment 5 Summary of Changes_14 February 2018 
Alnylam Pharmaceuticals 
Confidential 
8 
Now reads: 
In Part B, patients will be enrolled in up to 6 sequential dose cohorts randomized to receive ALN-GO1 or placebo monthly or 
quarterly.  Patients dosed monthly will receive 3 doses of ALN-GO1 or placebo in a blinded fashion.  After completion of the 
blinded portion of the study, patients dosed monthly will be unblinded on or after Day 78.  Patients who initially received placebo 
will then receive 3 doses of open-label ALN-GO1 dosed monthly at the same dose administered to the cohort into which they 
were initially randomized and will follow the same assessment schedule.  Patients dosed quarterly will receive either ALN-GO1 
or placebo on Day 1.  All patients in quarterly dosing cohorts, including those initially randomized to placebo, will receive 
open-label ALN-GO1 on Day 85 at the same dose administered to the cohort into which they were initially randomized.  Up to 2 
expansion cohorts in Part B may be enrolled based on available safety and PD data; these patients will all receive open-
label ALN-GO1, not placebo. 
Purpose:  Modify footnotes in Schedule of Assessments and Figure 1 to indicate the shortened duration of study follow-up in patients who enroll in 
the open-label extension study and added an alternative threshold for discontinuation from study follow-up for patients in Part B who do not wish 
to enroll in an open-label extension study. 
The primary change occurs in Figure 1: Study Design 
Revised text: 
a Patients in Part B will be invited to participate in an open-label extension study once they complete the postdose follow-up 
period.  For patients who do not enter the open-label extension study, safety and PD follow-up will continue until they 
meet the criteria provided they meet the criteria described in Section Error! Reference source not found., or until the SRC 
makes a decision per investigator request to discontinue follow-up on a case-by-case basis. The decision cannot be made 
until after completion of the last postdose follow-up visit (84 days after last dose). 
Section(s) also containing this change: 
 
Table 2: Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria Type 1 (Part B) 
– Monthly Dosing, footnote a 
 
Table 3:  Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria Type 1 (Part B) 
who Previously Received Placebo and will Receive Open-Label ALN-GO1 – Monthly Dosing, footnote a 
 
Table 4:  Schedule of Assessments for Multiple-ascending Dose Cohorts in Patients with Primary Hyperoxaluria Type 1 (Part B 
– Quarterly Dosing), footnote a 
 
Purpose:  Correct typographical errors, punctuation, grammar, abbreviations, and formatting 
These changes are not listed individually. 
 

SAP_000.pdf: 
 
 
Official Title:  
A Phase 1/2, Single‐Blind, Placebo‐Controlled, Single and Multiple 
Ascending Dose Safety, Tolerability, Pharmacokinetic and 
Pharmacodynamics Study of Subcutaneously Administered ALN‐GO1 in 
Healthy Adult Subjects, and Patients With Primary Hyperoxaluria Type 1  
 
NCT Number:    
NCT02706886 
 
Document Date:   
Statistical Analysis Plan, 01 November 2017 


ALN-GO1 
 
Statistical Analysis Plan ALN-GO1-001 
 
 
 01 November 2017 
 
Alnylam Pharmaceuticals 
Confidential 
1 
 
STATISTICAL ANALYSIS PLAN 
(SAP) 
 
 
 
A Phase 1/2, Single-Blind, Placebo-Controlled, Single- and Multiple-
Ascending Dose Safety, Tolerability, Pharmacokinetics, and 
Pharmacodynamics Study of Subcutaneously Administered ALN-GO1 in 
Healthy Adult Subjects, and Patients with Primary Hyperoxaluria Type 1 
 
Investigational Product: 
ALN-GO1 
Protocol Number: 
ALN-GO1-001 
Development Phase: 
1/2 
Sponsor: 
Alnylam Pharmaceuticals, Inc. 
300 Third Street 
Cambridge, MA 02142 USA 
Tel: 1-617-551-8200 
Protocol Version Number and Date: 
Original Protocol, 18 December 2015 
Amendment 1, 01 July 2016 
Amendment 2, 21 September 2016 
Amendment 3, 09 December 2016 
Amendment 4, 27 June 2017 
 
 
 
SAP Version: 
Original  
SAP Date: 
01 November 2017 
 
 
 
 
 
Confidentiality Statement 
The concepts and information contained in this document or generated during the study are considered proprietary 
and may not be disclosed in whole or in part without expressed written authorization of Alnylam Pharmaceuticals, 
Inc. 
 
 


ALN-GOl 
Statistical Analysis Plan ALN-GOl-001 
01November2017 
A Phase 112, Single-Blind, Placebo-Controlled, Single- and Multiple-
Ascending Dose Safety, Tolerability, Pharmacokinetics, and 
Pharmacodynamics Study of Subcutaneously Administered ALN-GOl in 
Healthy Adult Subjects, and Patients with Primary Hyperoxaluria Type 1 
Protocol Number: 
Original Protocol: 
Amendment 1 
Amendment2 
Amendment3 
Amendment4 
SAP Version: 
ALN-GO 1-001 
18 December 2015 
01July2016 
21 September 2016 
09 December 2016 
27 June 2017 
Original, 1November2017 
This Statistical Analysis Plan has been reviewed and approved by: 
Alnylam Pharmaceuticals, Inc. 
300 Third Street, Cambridge, MA 02142 
 PhD. 
Alnylam Pharmaceuticals, Inc. 
300 Third Street, Cambridge, MA 02142 
Alnylam Pharmaceuticals 
Confidential 
Date 
o/ vuo v ·'Lz>t7 
Date 
2 


ALN-GO1 
 
Statistical Analysis Plan ALN-GO1-001 
 
 
 01 November 2017 
 
Alnylam Pharmaceuticals 
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 TABLE OF CONTENTS 
1 
Introduction .............................................................................................................. 7 
2 
Study Objectives ....................................................................................................... 7 
2.1 
Primary Objective ............................................................................................................ 7 
2.2 
Secondary Objectives ....................................................................................................... 7 
2.3 
Exploratory Objectives ..................................................................................................... 7 
3 
Study Overview ........................................................................................................ 7 
3.1 
Summary of Study Design ............................................................................................... 7 
3.1.1 
Single-ascending Dose Part in Healthy Adult Subjects (Part A) .............................. 8 
3.1.2 
Multiple-ascending Dose Part in Patients with Primary Hyperoxaluria Type 1 (Part 
B) .............................................................................................................................. 8 
3.2 
Study Assessments ................................................................................................9 
3.3 
Duration of Treatment and Overall Duration of Study .................................................. 10 
3.4 
Study Populations ........................................................................................................... 10 
3.5 
Study Centers ................................................................................................................. 10 
3.6 
Randomization and Blinding .......................................................................................... 10 
4 
Statistical Methodology .......................................................................................... 11 
4.1 
Sample Size Determination ............................................................................................ 12 
4.2 
Analysis Populations ...................................................................................................... 12 
4.2.1 
Safety Analysis Set ................................................................................................. 12 
4.2.2 
Pharmacokinetic Analysis Set................................................................................. 12 
4.2.3 
Pharmacodynamic Analysis Set .............................................................................. 12 
4.3 
General Statistical Considerations ................................................................................. 12 
4.3.1 
Baseline Definition ................................................................................................. 13 
4.3.2 
Multicenter Studies ................................................................................................. 13 
4.3.3 
Multiple Comparisons ............................................................................................. 13 
4.3.4 
Missing Data ........................................................................................................... 13 
4.3.5 
Examination of Subgroups ...................................................................................... 14 
4.3.6 
Interim Analysis ...................................................................................................... 14 
5 
Study Endpoints ..................................................................................................... 14 
6 
Study Assessments ................................................................................................. 15 
6.1 
Safety Assessments ........................................................................................................ 15 
6.1.1 
Adverse Events ....................................................................................................... 15 
6.1.2 
Vital Signs ............................................................................................................... 15 


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6.1.3 
Weight and Height .................................................................................................. 16 
6.1.4 
Physical Examinations ............................................................................................ 16 
6.1.5 
Electrocardiograms (ECGs) .................................................................................... 16 
6.1.6 
Echocardiograms (Part B Only) .............................................................................. 17 
6.1.7 
Clinical Laboratory Assessments ............................................................................ 17 
6.1.8 
Other Safety Variables ............................................................................................ 18 
6.2 
Pharmacokinetics Assessments ...................................................................................... 18 
6.2.1 
Sample Collections for Pharmacokinetic Analysis ................................................. 18 
6.2.2 
PK Parameters ......................................................................................................... 18 
6.2.3 
Pharmacokinetic Parameter Calculation ................................................................. 20 
6.2.4 
Handling of Missing or Non-Quantifiable PK Data ............................................... 20 
6.3 
Pharmacodynamics Assessments ................................................................................... 21 
6.4 
Exploratory Assessments ............................................................................................... 22 
6.5 
Immunogenicity ............................................................................................................. 23 
7 
Statistical Analysis ................................................................................................. 23 
7.1 
Analysis Periods in Part A ............................................................................................. 23 
7.2 
Analysis Periods and By-visit Data Presentation in Part B ............................................ 23 
7.2.1 
Single-Blind Dosing Period .................................................................................... 23 
7.2.2 
ALN-GO1 Dosing Period and Follow-up Periods .................................................. 24 
7.2.3 
By-visit Data Presentation ...................................................................................... 25 
7.3 
Study Population Data .................................................................................................... 26 
7.3.1 
Subject and Patient Disposition .............................................................................. 26 
7.3.2 
Protocol Deviations ................................................................................................. 27 
7.3.3 
Demographic and Baseline Characteristics ............................................................ 27 
7.3.4 
Medical History ...................................................................................................... 28 
7.3.5 
Prior and Concomitant Medications ....................................................................... 28 
7.4 
Safety Analysis ............................................................................................................... 28 
7.4.1 
Adverse Events ....................................................................................................... 29 
7.4.2 
Dosing and Extent of Exposure .............................................................................. 30 
7.4.3 
Clinical Laboratory Assessments ............................................................................ 31 
7.4.4 
Vital Signs ............................................................................................................... 32 
7.4.5 
Physical Examinations ............................................................................................ 32 
7.4.6 
ECGs ....................................................................................................................... 32 
7.4.7 
Echocardiograms (Part B Only) .............................................................................. 33 


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7.4.8 
Analysis of Other Safety Variables......................................................................... 33 
7.5 
Pharmacokinetic Analyses ............................................................................................. 33 
7.6 
Pharmacodynamic and Exploratory Analyses................................................................ 34 
7.7 
Immunogenicity Analysis .............................................................................................. 35 
8 
General Information ............................................................................................... 35 
8.1 
Statistical Software ......................................................................................................... 35 
8.2 
Format of Tables, Listings, and Figures ......................................................................... 35 
9 
Changes from the protocol specified statistical analysis ........................................ 35 
10 
References .............................................................................................................. 35 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
ABBREVIATION 
DEFINITION 
ADA 
anti-drug antibody 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
AST 
aspartate transaminase 
ATC 
anatomical therapeutic chemical 
AUC 
area under curve 
BMI 
body mass index 
BUN 
blood urea nitrogen 
CRF 
case report form 
CRO 
contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
ECG 
electrocardiogram 
eGFR 
estimated glomerular filtration rate 
EOT 
End of Treatment 
HLT 
high level term 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
LLOQ 
lower level of quantitation 
MAD 
multiple-ascending dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
MDRD 
modification of diet in renal disease 
NQ 
non-quantifiable 
PD 
pharmacodynamics 
PH1 
Primary Hyperoxaluria Type 1 
PK 
Pharmacokinetics 
QTcB 
Bazett-corrected QT interval 
QTcF 
Fridericia-corrected QT interval 
SAD 
single-ascending dose 
SAP 
statistical analysis plan 
SC 
subcutaneous(ly) 
SCR 
serum creatinine 
SD 
standard deviation 
SE 
standard error 
SAE 
serious adverse advent 
SAP 
statistical analysis plan 
SOC 
system organ class 
SRC 
safety review committee 
WHO 
World Health Organization 


ALN-GO1 
 
Statistical Analysis Plan ALN-GO1-001 
 
 
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1 
INTRODUCTION 
This Statistical Analysis Plan (SAP) describes the statistical methodology and analysis to be 
performed based on Alnylam Pharmaceuticals, Inc., Protocol ALN-GO1-001 (Original, 18 
December 2015; Amendment 1, 01 July 2016; Amendment 2, 21 September 2016; Amendment 
3, 09 December 2016; and Amendment 4, 27 June 2017).  Any deviations from this analysis plan 
will be substantiated by sound statistical rationale and will be documented in the final clinical 
study report. 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
 Evaluate the safety and tolerability of single- and multiple-ascending doses of ALN-
GO1, respectively, in healthy adult subjects and in patients with Primary hyperoxaluria 
type 1 (PH1)   
2.2 
Secondary Objectives 
 Characterize the pharmacokinetics (PK) of ALN-GO1  
 Evaluate the pharmacodynamics (PD) of ALN-GO1  
2.3 
Exploratory Objectives 
 
  
 
 
3 
STUDY OVERVIEW 
3.1 
Summary of Study Design  
This is a randomized, single-blind, placebo-controlled study of subcutaneously administered 
ALN-GO1. The study is designed to evaluate the safety, tolerability, PK, and PD of single- and 
multiple-ascending doses of ALN-GO1 and will be conducted in 2 parts:  
 Part A: single-ascending dose (SAD) part in healthy adult subjects, followed by 
 Part B: multiple-ascending dose (MAD) part in adult and pediatric patients with PH1  
The study will be conducted in a single-blind manner, with the Investigators, SRC, and Sponsor 
unblinded to permit ongoing unblinded review of safety, tolerability, PK, and PD data.  
Part A will be conducted at 1 clinical study center in the UK. Part B is expected to take place at 
approximately 12 clinical study centers worldwide.  
The study design is summarized in Figure 1. 


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a Patients in Part B will be invited to participate in an open-label extension study provided they meet the criteria 
described in Protocol ALN-GO1-001 Section 4.1.2 (Amendment 4; 27 June 2017). 
3.1.1 
Single-ascending Dose Part in Healthy Adult Subjects (Part A) 
Part A is the single-ascending dose part of the study in healthy adult subjects. Subjects will be 
enrolled in 1 of 3 ascending dose cohorts, with the possibility for 2 additional optional cohorts. 
Each cohort will be comprised of 8 subjects randomized 3:1 to ALN-GO1 or placebo (study 
drug).  
Subjects will be screened from -45 to -2 days before study drug administration. Subjects will be 
admitted to the clinical study center on Day -1 to determine continued eligibility and for predose 
assessments. Subjects in each cohort will be randomized on Day 1 and will receive 1 SC dose of 
study drug. Subjects will be discharged from the clinical study center on Day 2 after completing 
the 24-hour postdose follow-up assessments. 
Subjects will return to the clinical study center on an outpatient basis for safety, tolerability, PK, 
and PD monitoring at time points specified in the Schedule of Assessments through the last 
postdose follow-up visit (Day 57). Safety and PD follow-up will continue: 1) for at least 57 days, 
and 2) until plasma glycolate decreases to a level that is no more than 20% above of baseline or 
until plasma glycolate is below the upper limit of normal (≤14 nmol/mL). 
3.1.2 
Multiple-ascending Dose Part in Patients with Primary Hyperoxaluria Type 1 
(Part B) 
Part B is the multiple-ascending dose part of the study in up to 24 adult and pediatric patients 
with PH1 with relatively well-preserved renal function. The overall allowable age range of the 
patients in Part B will be 6-64 years.  


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Two mandatory ascending dose cohorts will be enrolled, with the possibility to also enroll up to 
3 additional optional cohorts to further explore the optimal dose or regimen. Each cohort will be 
comprised of 4 patients, randomized 3:1 to ALN-GO1 or placebo. Up to 2 cohorts in Part B may 
be expanded by up to 4 additional patients (these patients will all receive ALN-GO1, not 
placebo).  
Patients will be screened within 45 days prior to study drug administration. Baseline urinary 
oxalate excretion and creatinine clearance will be assessed through 24-hour urine collections. 
Patients will be randomized between Day -1 and Day 1 and will receive the first dose of ALN-
GO1 or placebo on Day 1. The 24- and 48-hour postdose follow up assessments will take place 
on Day 2 and Day 3. Patients who receive study drug monthly will return to the clinical study 
center for safety, tolerability, PK, and PD monitoring at time points specified in the Schedule of 
Assessments (Protocol ALN-GO1-001 Table 2; Amendment 4, 27 June 2017) for the remaining 
2 single-blind doses of study drug (through Day 57). After completion of the blinded portion of 
the study, patients dosed monthly will be unblinded (on or after Day 78). Patients who initially 
received placebo will then receive ALN-GO1 at the same dose administered to the cohort into 
which they were initially randomized and will follow the assessment schedule as indicated 
(Protocol ALN-GO1-001 Table 3; Amendment 4, 27 June 2017). 
After the dosing period, patients will return to the clinical study center for continued safety, 
tolerability, PK, and PD monitoring through the last postdose follow-up visit. Following 
completion of the postdose follow-up period, patients will be invited to participate in an open-
label extension study provided that: 
 Urinary oxalate is above the ULN and patients meet at least 1 of the following criteria:  
- 
One 24-hour urinary oxalate value is >80% of baseline. 
- 
Two 24-hour urinary oxalate values are above the midpoint between their baseline 
and nadir 24-hour urinary oxalate values. The nadir must be from a valid 
collection after all doses are administered.  
- 
At least 12 months have elapsed from time of final dose administration. 
For patients who do not enroll in the open-label extension study, safety and PD follow up will 
continue until: 
 24-hour urinary oxalate is >80% of baseline, AND  
 Plasma glycolate is <20% above baseline or ≤ the ULN 
 
3.2 
Study Assessments 
The complete Schedule of Assessments is found in Table 1 (Single-ascending Dose Cohorts in 
Healthy Subjects (Part A)), Table 2 (Multiple-ascending Dose Cohorts in Patients with Primary 
Hyperoxaluria Type 1 (Part B – Monthly Dosing)), Table 3 (Multiple-ascending Dose Cohorts in 
Patients with Primary Hyperoxaluria Type 1 (Part B) who Previously Received Placebo and will 
Receive Open-Label ALN-GO1 – Monthly Dosing), and Table 4 (Multiple-ascending Dose 


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Cohorts in Patients with Primary Hyperoxaluria Type 1 (Part B – Quarterly Dosing)) of Protocol 
ALN-GO1-001 (Amendment 4; 27 June 2017). 
3.3 
Duration of Treatment and Overall Duration of Study 
The duration of the study is as follows:  
 Part A: The estimated total time on study, inclusive of screening, for each subject is up to 
405 days. The duration of treatment is a single dose. 
 Part B:  
- 
For patients dosed monthly: The duration of treatment for patients initially 
randomized to receive active study drug is 57 days. The estimated total time on 
study, inclusive of screening, for each patient is up to 462 days. Additionally, the 
duration of treatment for patients initially randomized to receive placebo is 141 
days. The estimated total time on study, inclusive of screening, for each patient 
initially randomized to receive placebo, then active study drug, is up to 546 days. 
- 
For patients dosed quarterly: The duration of treatment is 85 days for patients 
randomized to placebo and active study drug. The estimated total time on study, 
inclusive of screening, is up to 490 days.  
The overall duration of the study is estimated to be 4 years, including enrollment.  
3.4 
Study Populations 
In Part A, the study population will consist of healthy adult volunteers ages 18 years and older.  
In Part B, the study population will consist of pediatric and adult patients (ages 6 years - 64 years 
inclusive) that have a confirmed diagnosis of PH1.  
Additional information regarding specific inclusion and exclusion criteria are listed in Protocol 
ALN-GO1-001 Section 5.1 and 5.2 (Amendment 4; 27 June 2017). 
3.5 
Study Centers 
The single-ascending dose (SAD) part in healthy adult subjects (Part A) will be conducted at 1 
clinical study center in the United Kingdom. The multiple-ascending dose (MAD) part in 
patients with PH1 (Part B) is expected to take place at approximately 12 clinical study centers 
worldwide.  
3.6 
Randomization and Blinding 
This is a randomized, single blind, placebo-controlled study; therefore, only the study 
subjects/patients will be blinded to treatment assignment. In Parts A and B, after confirmation of 
eligibility, during screening, and upon admission the clinical study center, subjects/patients will 


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be assigned to a dose cohort and randomized in a 3:1 ratio (ALN-GO1:placebo). No 
subject/patient will be a member of more than 1 cohort. A unique subject/patient identification 
number, incorporating the clinical study center number, will be assigned sequentially to the 
subject/patient.  
The clinical study center pharmacy staff will randomize the subject/patient in accordance to a 
cohort-specific randomization list generated by the biostatistician at the Contract Research 
Organization (CRO) for appropriate dispensation of the study drug.  
Patients in Part B dosed monthly will be unblinded on or after Day 78 in order for patients and 
their families to be better prepared for the transition to receive ALN-GO1 if initially randomized 
to placebo. Patients dosed quarterly will be unblinded to initial treatment assignment following 
completion of the postdose follow-up period. The Investigators, Medical Monitors at the Sponsor 
and CRO, clinical study center personnel, pharmacokineticist, and members of the SRC will 
have knowledge of the treatment assignment. The clinical study center pharmacy staff will 
maintain the single-blind according to clinical study center-specific procedures and the 
Pharmacy Manual. Syringes containing dispensed study drug will be masked in the pharmacy 
before transfer to the clinic. 
During the blinded period, if the subject/patient becomes seriously ill during the study, and the 
treating physician determines that the clinical management of the subject requires that the subject 
know the study drug assignment, the Investigator may break the blind, as necessary.  
Based on SRC review of accumulated safety, tolerability, and PD data, 3 additional cohorts may 
be enrolled and dosed according to the same eligibility criteria in Part B to better define safety or 
PD effects. Additional cohorts may be enrolled at higher, lower, or intermediate dose levels, but 
will not exceed the maximum administered dose of 6 mg/kg, and will follow the protocol-
specified dose escalation criteria.  
Based on SRC review of accumulated safety, tolerability, and available PD data, up to 2 cohorts 
in Part B may be extended by up to 4 additional patients based on study progression and stopping 
rules. These patients will all receive active drug, not placebo. 
4 
STATISTICAL METHODOLOGY 
Unless stated otherwise, the methodology described in this section will apply to both Part A and 
Part B of this study. Data from Part A and Part B will be analyzed separately.  
Summary analyses will be presented as follows. The primary analyses will be presented in order 
of ascending ALN-GO1 dose with the placebo group presented first. Patients randomized to 
placebo will be pooled across enrollment cohorts for all analyses where applicable.  


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4.1 
Sample Size Determination 
The sample size was determined on the basis of clinical considerations rather than power 
calculations. Up to a total of 64 participants (40 subjects in Part A, 24 patients in Part B) are 
planned to be enrolled in this study, including optional and expansion cohorts.  
4.2 
Analysis Populations 
The following analysis populations will be considered for the purposes of data analysis.  
4.2.1 
Safety Analysis Set 
For both Part A and Part B, the Safety Analysis Set will include all subjects who received at least 
1 dose of study drug (placebo or ALN-GO1).  
The Safety Analysis Set will be used for safety analyses. Subjects will be summarized according 
to the treatment actually administered. 
4.2.2 
Pharmacokinetic Analysis Set 
The PK Analysis Set will include all subjects/patients who receive at least 1 dose of study drug 
and have at least 1 postdose sample for PK parameters and who have evaluable PK data.   
The PK analysis will be based on the PK Analysis Set. 
4.2.3 
Pharmacodynamic Analysis Set 
The PD Analysis Set will include all subjects/patients who receive at least 1 dose of study drug 
and who have at least 1 postdose blood and/or urine sample evaluable for PD parameters.    
PD summaries will be based on the PD Analysis Set.  
4.3 
General Statistical Considerations 
The primary goal of the study is to evaluate the safety and tolerability of ALN-GO1 in healthy 
adult subjects and patients diagnosed with PH1. The data cutoff date for the primary analysis will 
occur after all subjects have either discontinued the study or completed all safety follow-up 
assessments (as in Section 3.2).    
Continuous data will be described using descriptive statistics including the number of 
observations (n), mean, standard deviation, median, minimum, and maximum. Categorical and 
ordinal data will be described using the subject/patient count and percentage in each category. 
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. Mean, median, and 
standard deviation will be displayed to one level of precision greater than the data collected. 
Summary tables will present results by cohort for each ALN-GO1 dose in ascending dose order, 
total (all subjects receiving ALN-GO1), and placebo, where the placebo subjects/patients will be 


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combined across dose cohorts. Data will be displayed in all listings sorted by study part and 
cohorts with placebo ordered last.  
Subjects/patients will be identified in the listings by the subject/patient identification number 
concatenated with the investigator number.  
When count data are presented, the percentage will not be presented when the count is zero in 
order to draw attention to non-zero counts. A row denoted “Missing” will be included in 
tabulations where specified on the shells to account for dropouts and missing values. The 
denominator for all percentages will be the number of non-missing values in that 
cohort/treatment, unless otherwise specified.  
If the assessment date is after the date of first study drug dose The study day will be calculated 
as: 
Study day = Date of assessment – date of first dose of study drug + 1, 
otherwise if assessment date is before the date of the first dose of study drug then study day will 
be calculated as:  
Study day = Date of assessment – date of first study drug dose.  
4.3.1 
Baseline Definition 
The baseline value is defined as the last non-missing value before the first dose of the 
randomized study drug, unless otherwise specified.  
In Part B, for patients who are randomized initially to placebo, the baseline value for the placebo 
dosing period is defined as the last non-missing value before the first dose of placebo.  For these 
patients, their baseline value for the open-label ALN-GO1 period is defined as the last non-
missing value before the first dose of ALN-GO1.  
4.3.2 
Multicenter Studies 
Part A will take place at a single study center.  
Part B will take place at multiple centers but the center effect will not be considered for the 
planned descriptive analysis. Data will not be stratified by study center for reporting of 
descriptive statistics.  
4.3.3 
Multiple Comparisons 
No adjustments for multiple comparisons will be made for the planned descriptive analysis.  
4.3.4 
Missing Data 
Unrecorded data values will be recorded as missing. Only recorded (i.e. non-missing) data values 
will be used for reporting of descriptive statistics unless otherwise stated.  


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4.3.5 
Examination of Subgroups 
No subgroup-specific analysis is planned.  
4.3.6 
Interim Analysis 
No formal interim statistical analysis is planned for this study. The Safety Review Committee 
(SRC) will perform ongoing reviews of safety, tolerability, and available PD data, with the 
primary purpose of protecting the safety of subjects/patients participating in this clinical study.   
5 
STUDY ENDPOINTS 
Primary Endpoint 
 The primary endpoint is the incidence of adverse events (AEs). Safety will also be 
evaluated through vital signs, electrocardiograms (ECGs), clinical laboratory 
assessments, and physical examinations. 
Secondary Endpoints 
For Part A, the secondary endpoints are: 
 PK parameters including, but not limited to, maximum plasma concentration [Cmax], time 
to reach maximum plasma concentration [tmax], area under the plasma concentration 
versus time curve [AUC], apparent terminal elimination half-life [t½], fraction eliminated 
in urine [fe/F], and renal clearance [CLR] 
 Plasma and urine glycolate concentration 
For Part B, the secondary endpoints are: 
 First dose and steady state PK parameters including, but not limited to, Cmax, tmax, AUC, 
t½, fe/F, and CLR 
 Urinary oxalate excretion (oxalate content in 24-hour urine collection) 
 Urinary glycolate excretion (glycolate content in 24-hour urine collection) 
 Plasma glycolate concentration 
 Calculated creatinine clearance 
Exploratory Endpoints 
The exploratory endpoints are: 
 Plasma oxalate concentration 
 
 
Additional exploratory endpoints for Part B only are: 


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 
 
 
 
 
 
6 
STUDY ASSESSMENTS 
For both Part A and Part B, the assessments described in this section will be collected at 
assessment times throughout the course of the study. The exact frequency and timing of 
collection may be found in the Schedule of Assessments in Protocol ALN-GO1-001 
(Amendment 4; 27 June 2017) for Safety and PD variables: Table 1 for Part A; Tables 2 and 3 
for Part B monthly dosing, and Table 4 for Part B quarterly dosing. A detailed schedule of time 
points for the collection of blood and urine samples for PK analysis is in Protocol ALN-GO1-
001 (Amendment 4; 27 June 2017) Table 10 for Part A and in Tables 11 and 12 for Part B. 
Detailed assessments will not be repeated in this document and it will be referred to herein as the 
Schedule of Assessments.  
6.1 
Safety Assessments 
6.1.1 
Adverse Events 
An Adverse Event (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. AEs will be graded according to the CTCAE criteria 
(Version 4.0 or higher). Refer to CTCAE for unique clinical descriptions and additional 
information regarding grading of severity for specific AEs.  
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. 
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 AE is stable, as 
appropriate.  
6.1.2 
Vital Signs 
Vital sign measurements include:  
 Systolic and diastolic blood pressure (mmHg) 
 Heart rate/Pulse rate (beats/min) 


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 Body temperature (ºC) 
 Respiratory rate (breaths/min) 
6.1.3 
Weight and Height 
For all participants, height will be measured in centimeters. For Part B patients who are <18 
years, height will be measured in triplicate and the mean value will be used to calculate the 
estimated glomerular filtration rate (eGFR) using the Schwartz Bedside Formula.  
The variables recorded will include:  
 Height (centimeters) 
 Weight (kilograms) 
 Body Mass Index (BMI) (kg/m2) which will be calculated from the height and weight 
measurement.  
The baseline value for height for subjects in Part A and patients in Part B who are 18 years and 
older is defined as the last non-missing value before first dose of study drug; and for patients in 
Part B who are younger than 18 years old is defined as the mean of the last triplicate before first 
dose of study drug.  
6.1.4 
Physical Examinations 
A full physical examination or a symptom-directed physical examination will be performed at 
selected time points, as described in the Schedule of Assessments.  
A symptom-directed physical examination will include the evaluation of changes in symptoms or 
onset of new symptoms since the last visit. 
6.1.5 
Electrocardiograms (ECGs)  
For both parts A and B, triplicate 12-lead ECGs will be measured 5 minutes apart at times 
indicated in the Schedule of Assessments. Recording will be obtained after the subject has rested 
comfortably in the supine position for approximately 10 minutes. ECGs should be performed at 
approximately the same time of day throughout the study. The Investigator (or designee) is 
responsible for reviewing ECGs and to determine the clinical significance of the results. The 
overall interpretation of the ECG will be recorded and any abnormality specified. The 
Investigator will provide a determination regarding the change from baseline ECG and 
specification of the change. The electrophysiological parameters assessed will include  
 Rhythm  
 Ventricular rate 
 PR interval 


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 QRS duration 
 QT interval 
 ST and T waves 
 Bazett-corrected QT interval (QTcB)  
 Fridericia-corrected QT interval (QTcF)  
All triplicate ECG measurements at a particular time point will be averaged prior to analysis and 
summarization. 
6.1.6 
Echocardiograms (Part B Only)  
ECHO assessments will be performed according to instructions provided in a study manual at 
select time points outlined in the Schedule of Assessments. The Investigator or designee is 
responsible for reviewing the ECHOs to assess whether the results have changed since the 
Screening/Baseline visit and to determine the clinical significance of the results. 
6.1.7 
Clinical Laboratory Assessments 
For both Part A and Part B, clinical laboratory tests will be evaluated at the times indicated in the 
Schedule of Assessments. Laboratory tests to be collected include:  
 Hematology: Complete blood count with differential 
 Serum Chemistry: Sodium, blood urea nitrogen (BUN), Creatinine and estimated 
glomerular filtration rate (eGFR) calculation (using the modification of diet in renal 
disease or Schwartz formula depending on age), uric acid, total protein, glucose, 
potassium, phosphate, albumin, calcium, carbon dioxide/bicarbonate, chloride 
 Cardiac Enzyme: Troponin I 
 Liver Function Tests: aspartate transaminase (AST), alkaline phosphatase (ALT), 
alkaline phosphatase (ALP), total and direct bilirubin 
 Coagulation Panel: Prothrombin Time, Activated partial thromboplastin time, 
International Normalized Ratio 
 Urinalysis: Visual inspection of appearance and color, pH (dipstick), specific gravity, 
Ketones, Albumin (optional), Glucose, Protein, Bilirubin, Nitrite, RBCs, Urobilinogen, 
Leukocytes, Microscopy (if clinically indicated)  
 Immunogenicity: Anti-drug antibodies 
 Pregnancy Testing: β-human chorionic gonadotropin (women of child bearing potential 
only). Serum testing will be performed at screening or menarche, and urinary screening 
thereafter.  


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The eGFR (in mL/min/1.73m2) will be calculated from serum creatinine (SCr) based on the 
Modification of Diet in Renal Disease (MDRD) formula for patients ≥ 18 years of age and the 
Schwartz Bedside Formula for subjects <18 years of age at enrollment.  
MDRD Formula 
 Conventional units: 
eGFR (mL/min/1.73m2) = 175 × (SCr [mg/dL])-1.154 × (age)-0.203 × (0.742, if 
female), or × (1.212, if African American) 
 SI units 
eGFR (mL/min/1.73m2) = 175 × (SCr [µmol/dL]/88.4)-1.154 × (age)-0.203 × (0.742, if 
female), or × (1.212, if African American) 
Schwartz Bedside Formula 
 Conventional units: 
eGFR (mL/min/1.73m2) = (.413 × height [cm])/ SCr (mg/dL) 
 SI units: 
eGFR (mL/min/1.73m2)= (36.2 × height [cm])/ SCr (µmol /dL) 
All triplicate height measurements at a particular time point will be averaged and the mean will 
be used in the calculation of the eGFR.  
6.1.8 
Other Safety Variables 
In Part A and Part B, testing for drugs of abuse will be conducted and judged at screening for 
participants ≥18 years of age.  
6.2 
Pharmacokinetics Assessments 
6.2.1 
Sample Collections for Pharmacokinetic Analysis 
Blood and urine samples will be collected for PK analysis at scheduled time points listed in 
Protocol ALN-GO1-001 (Amendment 4; 27 June 2017) Table 10 for Part A and in Table 11 and 
Table 12 for Part B. 
6.2.2 
PK Parameters 
In Part A, PK parameters following single dose of ALN-GO1 (Day 1) will be characterized. In 
Part B, PK parameters following single and multiple doses (Day 1 and Day 57 for monthly 
dosing cohorts; Day 1 and Day 85 for quarterly dose cohorts) of ALN-GO1 will be calculated. 
 
 


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The following PK parameters will be calculated from the individual plasma concentration 
profiles ALN-GO1 by standard non-compartmental methods: 
Parameters 
Units 
Description 
Cmax 
ng/mL 
Maximum observed plasma concentration  
tmax 
 h 
The time to reach the maximum observed concentration  
AUC0-24 
ngh/mL  
The area under the plasma concentration versus time curve, from 
time 0 to the 24 hour concentration (C24h), as calculated by the 
linear trapezoidal method 
AUC0-last 
ngh/mL 
The area under the plasma concentration versus time curve, from 
time 0 to tlast (time of last quantifiable concentration) as 
calculated by the linear trapezoidal method.  
AUC0-inf 
ngh/mL 
The area under the plasma concentration versus time curve, from 
time 0 extrapolated to infinity, calculated as: AUC0-inf = 
AUC0-last + Clast/λz (Reported for Part A only) 
AUCtau,ss 
ngh/mL 
Steady state area under the plasma concentration versus time 
curve, over the dosing interval at steady state (Reported for Part 
B only) 
Lambda z (λZ) 
h-1 
Apparent terminal elimination rate constant calculated by linear 
regression of the terminal linear portion of the log concentration 
versus time curve 
t½ 
 h 
Apparent terminal elimination half-life, calculated as: ln(2)/λZ 
CL/F 
L/h 
Total apparent body clearance after extravascular administration, 
calculated as: Dose/AUC0-inf 
CL/Fss 
L/h 
Total apparent body clearance at steady-state after extravascular 
administration, calculated as: Dose/AUC0-tau  (Reported for Part 
A only) 
VZ/F 
L 
Apparent volume of distribution based on the terminal 
elimination phase, calculated as: Dose/(AUC0-inf × λZ) (for Part 
A) or Dose/(AUC0-tau × λZ) (for Part B) 
 
The following urine PK parameters will also be calculated: 
Parameters 
Units 
Description 
Ae(0-24) 
mg 
Cumulative amount of drug excreted in urine after dosing, 
calculated as the sum of (Cur × Vur), where Cur is the concentration 
in urine and Vur is the volume of urine collected. 
fe/F 
% 
Fraction eliminated in the urine, calculated as (Ae(0-24)/Dose) × 
100 
CLR 
 L/h 
Renal clearance, calculated as Ae(0-24)/AUC0-24 
In addition, Part B samples may also be used to characterize the
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6.2.3 
Pharmacokinetic Parameter Calculation 
Actual sampling times, rather than scheduled sampling times, will be used in all computations 
involving sampling times.   
The PK parameters λz, t½, AUC0-inf, CL/F, and Vz/F will not be presented for those subjects who 
do not exhibit a terminal elimination phase in their concentration versus time profiles. In order to 
estimate the apparent first-order terminal elimination rate constant, λz, linear regression of 
concentration in logarithm scale vs. time will be performed using at least 3 data points. Uniform 
weighting will be selected to perform the regression analysis to estimate λz. The constant λz will 
not be assigned if:  
 The terminal elimination rate constant indicates a positive slope (λz < 0)  
 Tmax is one of the last 3 data points  
 The adjusted regression coefficient (R2) is less than 0.8  
 t1/2 is more than half the total sampling interval 
In cases where the λz interval is not assigned, the values of the associated parameters (λz, t½, 
AUC0-inf, CL/F, Vz/F, and possibly AUC0-24h) will not be reported.  
The linear trapezoidal method will be used in the computation of all AUC values. AUC0-inf will 
be calculated as AUC0-last + Clast,observed/λz, where Clast,observed is the last observed evaluable plasma 
concentration. 
6.2.4 
Handling of Missing or Non-Quantifiable PK Data 
For the calculation of individual pharmacokinetic profiles, missing or non-quantifiable (NQ) data 
will be handled based on the current knowledge of drug pharmacokinetics measures. The 
methods for missing data imputation will be as follows: 
 Missing values will generally be omitted (set to missing) in the derivation of PK 
parameters and from the individual subject plots.  
 A non-quantifiable (NQ) value, and all subsequent NQ values before the first measurable 
concentration will be set to zero in the derivation of PK parameters, statistical analyses, 
and the individual subject plots.  
 If a single NQ value occurs between measurable concentrations in a profile, the NQ 
should generally be omitted (set to missing) in the derivation of PK parameters, statistical 
analysis, and the individual subject plots. 
 NQs which occur after the last measurable concentration will be omitted (set to missing) 
in the derivation of PK parameters, statistical analysis,  and from the individual subject 
plots. 


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For linear plots, zero concentration value(s) before the first measurable concentration will be 
included in the plot. For log-linear plots, zero concentration value(s) before the first measurable 
concentration will be assigned a missing value. Concentration values that are less than lower 
limit of quantitation (LLOQ) will be indicated on appropriate listings without imputation. 
For urine PK parameters, if urine concentration values or volumes are missing, Ae(0-24), fe, and 
CLR will not be estimated and will be listed as NA. 
6.3 
Pharmacodynamics Assessments 
Urine and blood samples will be collected for assessment of PD parameters (oxalate and 
glycolate concentrations) at the time points in the Schedule of Assessments for Part A and Part 
B.  
In Part B, 24-hour urine collections will be analyzed for glycolate, oxalate, and creatinine 
excretion. The 24-hour urine collection starting on Day -1 must conclude on Day 1 before 
administration of the first dose of study drug. PD blood samples will also be collected prior to 
dosing for the analysis of plasma glycolate and oxalate concentration.  
For Part A, baseline for PD parameters is defined as the last non-missing measurement prior to 
the first dose of randomized study drug.  
For Part B, baseline is defined as the median for 24-hour urine PD parameters of the 
measurements and as the mean for all other PD parameters of the measurements during the 
screening period prior to the first dose date/time of study drug in the study. Patients randomized 
to placebo will receive open-label ALN-GO1 after their single-blind placebo dosing period. 
Baseline for the open-label ALN-GO1 dosing period for these patients will be the median or 
mean of all assessments after the single-blind placebo first dose date/time and prior to the open-
label ALN-GO1 first dose date/time for 24-hour urine PD parameters or all other PD parameters, 
respectively.  
The following PD parameters will be assessed in Part A: 
 Plasma glycolate concentration 
 Urine glycolate concentration 
 
 
 
 
The following PD parameters will be assessed in Part B: 
 Plasma glycolate concentration  
 Urine glycolate concentration 
 Plasma oxalate concentration 


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 Urine oxalate concentration 
 24-hour urine oxalate content corrected for BSA 
 24-hour urine creatinine content  
 24-hour urine oxalate/creatinine ratio 
 24-hour urine glycolate content 
6.4 
Exploratory Assessments 
 
 
 
 
  
:  
  
 
 
 
 
 
: 
 
  
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 


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6.5 
Immunogenicity 
Blood samples will be collected to evaluate antidrug antibodies (ADA). Blood samples for ADA 
testing that are collected on the day of dosing must be collected before study drug administration. 
Blood samples to evaluate ADAs will be collected throughout the treatment and follow-up 
periods as detailed in the Schedule of Assessment. Confirmed positive ADA samples will be 
tested for cross-reactivity with DNA and nucleic acids.  
7 
STATISTICAL ANALYSIS 
This study is designed to evaluate the safety, tolerability, PK, and PD of single- and multiple- 
ascending doses of ALN-GO1. The described analyses will be carried out separately for Part A 
and Part B of this study.  
Statistical analyses will be primarily descriptive and no formal hypothesis testing will be 
performed in this study. Assessments of change from baseline to post-treatment will be 
computed only for those subjects with both baseline and post-treatment measurements.  
7.1 
Analysis Periods in Part A 
Part A is the single ascending dose study part. Subjects will be randomized in a 3:1 ratio (ALN-
GO1: placebo) to receive 1 dose of a single-blind study drug and followed until Day 57/End of 
Treatment (EOT). If additional follow-up beyond Day 57 (End of Treatment) is required, this 
will be defined as the safety and PD follow-up period.   
In Part A, summary statistics for Safety and PD data will be presented by ascending dose level of 
ALN-GO1 and the pooled placebo group with pooled placebo presented first. The pooled 
placebo group includes subjects receiving placebo across all cohorts.  
7.2 
Analysis Periods and By-visit Data Presentation in Part B 
Part B is the multiple ascending dose study part including monthly and quarterly dosing 
regimens with ALN-GO1 or placebo. Analysis periods and treatment groups will be defined in 
Section 7.2.1 and Section 7.2.2.  
All data listings will be presented with corresponding treatment, study day relative to first dose 
date of study drug, and study day relative to first dose of ALN-GO1.  
7.2.1 
Single-Blind Dosing Period 
In Part B, Safety and PD data during the single-blind period will be summarized for the period 
starting from the first single-blind study drug date/time up to, and including, Study Day 85 for 
patients randomized to ALN-GO1, or prior to the first dose of ALN-GO1 for patients 
randomized to placebo. Patients receiving placebo in all regimen and dose cohorts will be pooled 
together.  


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7.2.2 
ALN-GO1 Dosing Period and Follow-up Periods 
In monthly dosing regimen cohorts, after receiving 3 single-blind doses of study drug (and 
completing the corresponding assessments in the Schedule of Assessments), patients initially 
randomized to placebo will be unblinded and administered 3 doses of active ALN-GO1 (at the 
dose level of the cohort) in an open-label manner and will follow a parallel assessment schedule, 
as in the Schedule of Assessments (Protocol ALN-GO1-001 Table 3; Amendment 4, 27 June 
2017).  
In quarterly dosing regimen cohorts, after the single-blind dosing period, all patients will receive 
an open-label dose of ALN-GO1 (at the dose level of the cohort) following the Schedule of 
Assessments (Protocol ALN-GO1-001 Table 4; Amendment 4, 27 June 2017).  
Safety and PD data collected during the ALN-GO1 open-label period from these patients who 
received placebo initially will be realigned in terms of Study Day on ALN-GO1with data 
collected during the single-blind period from patients who were initially randomized to ALN-
GO1. This data may be used for a separate Safety and PD analysis through Day 85 relative to 
ALN-GO1 dosing, inclusive.   
The Study Day relative to the first dose of ALN-GO1 will be defined as: 
 Study Day relative to the first dose of ALN-GO1= Date of assessment – Date of first dose 
of ALN-GO1 + 1. 
The ALN-GO1 dosing period and follow-up periods are defined in the table below.  
ALN-GO1 Dosing Period and Follow-up Periods  
Dosing 
Regimen 
ALN-GO1 Dosinga  
Postdose Follow-upb 
Safety and PD Follow-
upc 
Monthly 
Day 1 to 85 relative to the first dose 
of ALN-GO1 
Day 85+ to 169 relative 
to the first dose of 
ALN-GO1  
Day 169+ relative to the 
first dose of ALN-GO1  
Quarterly 
Day 1 to 85 relative to the first dose 
of ALN-GO1 for patients randomized 
to placebo 
Day 1 to 169 for patients randomized 
to ALN-GO1 
 
Day 86+ relative to the 
first dose of ALN-GO1 
for patients randomized 
to placebo 
Day 169+ for patients 
randomized to ALN-GO1 
a: Patients receiving ALN-GO1 in single-blind or open-label manner and in any sequence  
b: Patients in monthly dosing cohorts 
c: Patients in all regimen and dosing cohorts 


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7.2.3 
By-visit Data Presentation  
In Part B, the by-visit PD and safety summaries will be presented according to the specifications 
below. 
 
 
 
Monthly Dosing Regimen: Part B 
Timepointa 
Placebob 
(N=4) 
Monthly 
ALN-GO1 
Single-blindc 
Dose1 
(N=3) 
Monthly 
ALN-GO1 
Comb.d  
Dose1 
(N=4 or 8) 
Monthly 
ALN-GO1 
Single-blindc 
Dose2 
(N=3) 
Monthly 
ALN-GO1 
Comb.d 
Dose2 
(N=4 or 8) 
Monthly 
ALN-GO1 
Single-blindc 
Total 
(N=6) 
Monthly 
ALN-GO1 
Comb.d  
Total 
(N=8 or 16) 
Baselinee  
 
 
 
 
 
 
 
Day 29  
 
 
 
 
 
 
 
Day 57 
 
 
 
 
 
 
 
Day 85f 
 
 
 
 
 
 
 
Day 113 
NA 
 
 
 
 
 
 
Day 141 
NA 
 
 
 
 
 
 
Day 169g 
NA 
 
 
 
 
 
 
Day 197h 
NA 
 
 
 
 
 
 
Day 225 
NA 
 
 
 
 
 
 
Day 253 
NA 
 
 
 
 
 
 
Day 281 
NA 
 
 
 
 
 
 
Day 309 
NA 
 
 
 
 
 
 
a: In monthly dosing regimen, patients randomized to ALN-GO1 will be summarized by study day 1 to 85 during the single-
blind monthly treatment period, then by post dosing follow-up period after Day 85 and up to Day 169, followed by Safety 
and PD follow-up after Day 169.  Patients randomized to Placebo will be summarized by study day 1 to 85 relative to 
placebo dosing date during the single-blind treatment period. Data collected after the first dose of ALN-GO1 will be 
summarized separately by days relative to the first open-label ALN-GO1 dose with all visits for the rest of the study 
mirrored to the patients randomized to the single-blind ALN-GO1. These data will be summarized in combination with 
data from patients randomized to ALN-GO1 at each corresponding visit. 
b: Patients from all monthly and quarterly dosing cohorts randomized to placebo at study start 
c: Patients randomized to ALN-GO1 at study start receiving ALN-GO1 in single-blind manner 
d: Patients receiving ALN-GO1 in single-blind or open-label manner and in any sequence combined 
e: Baseline is defined as ….. before first dose date/time of each treatment, placebo or ALN-GO1 
f: Day 85 is the end of treatment period 
g: Day 169 is the end of post-treatment follow-up period 
h: Day 197 and later visits are Safety and PD follow-up visits 


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Quarterly Dosing Regimen: Part B 
Timepointa 
Placebob 
(N=4) 
Quarterly 
2-dosesc 
ALN-GO1 
Dose1 
(N=3) 
Quarterly  
1-dosed 
ALN-GO1 
Dose1 
(N=1) 
Quarterly 
Comb.e 
ALN-GO1 
Dose1 
(N=4) 
Quarterly  
2-dosesc 
ALN-GO1 
Dose2 
(N=3) 
Quarterly  
1-dosed 
ALN-GO1 
Dose2 
(N=1) 
Quarterly 
Comb.e 
ALN-GO1 
Dose2 
(N=4) 
Quarterly 
2-dosesc 
ALN-GO1 
Total  
 (N=6) 
Quarterly 
1-dosed 
ALN-GO1  
Total 
(N=2) 
Quarterly 
Comb.e 
ALN-GO1 
Total 
(N=8) 
Baselinef  
 
 
 
 
 
 
 
 
 
 
Day 29  
 
 
 
 
 
 
 
 
 
 
Day 57 
 
 
 
 
 
 
 
 
 
 
Day 85g 
 
 
 
 
 
 
 
 
 
 
Day 113h 
NA 
 
 
NA 
 
 
NA 
 
 
NA 
Day 141 
NA 
 
 
NA 
 
 
NA 
 
 
NA 
Day 169i 
NA 
 
 
NA 
 
 
NA 
 
 
NA 
Day 197j 
NA 
 
 
NA 
 
 
NA 
 
 
NA 
Day 225 
NA 
 
 
NA 
 
 
NA 
 
 
NA 
Day 253 
NA 
 
 
NA 
 
 
NA 
 
 
NA 
Day 281 
NA 
 
 
NA 
 
 
NA 
 
 
NA 
Day 309 
NA 
 
 
NA 
 
 
NA 
 
 
NA 
a:  In quarterly dosing regimen, patients randomized to ALN-GO1 will be summarized during the treatment period by study days with 
ALN-GO1 dosing on Day 1 (single-blind) and 85 (open-label) followed by the Safety and PD follow-up period after Day 169. Patient 
randomized to Placebo will be summarized by days relative to placebo dosing date for the placebo period (Study Days 1-85), and 
separately by days relative to the open-label ALN-GO1 dosing date for the treatment period (Days 85-169 post placebo dose; Days 1-
85 post ALN-GO1 dose), followed by the Safety and PD follow up period after Day 169. 
b:  Patients from all monthly and quarterly dosing cohorts randomized to placebo at study start 
c:  Patients randomized to ALN-GO1 at study start. First quarterly GO1 dose is in single-blind manner and the second quarterly GO1 
dose is in open-label manner 
d:  Patients randomized to placebo at study start and received one dose of open-label ALN-GO1 on Day 85, and Days are relative to the 
open label ALN-GO1 dose.  
e:  Patients receiving ALN-GO1 in single-blind or open-label manner and in any sequence combined.  
f:  Baseline is defined as xxxx before first dose date/time of each treatment, placebo or ALN-GO1 
g:  Day 85 is the end of single-blind treatment period for placebo and 2-doses ALN-GO1 patients, and the end of open-label ALN-GO1 
treatment period for 1-dose ALN-GO1 patients 
h:  Day 113 and later visits are Safety and PD follow-up period for 1-dose ALN-GO1 patients 
i:   Day 169 is the end of open-label treatment period for 2-doses ALN-GO1 patients 
j:   Day 197 and later visits are Safety and PD follow-up period for 2-doses ALN-GO1 patients 
7.3 
Study Population Data 
7.3.1 
Subject and Patient Disposition 
For Part A, the following subject disposition categories will be summarized, if applicable: 
 Subjects who were randomized, 
 Subjects who were randomized but not treated, 
 Subjects who were randomized and treated, 
 Subjects who completed/did not complete the single-blind treatment, and 
 Subjects who completed/did not complete the study.  
Patient disposition will be summarized by initial ALN-GO1 dose level and regimen and in total 
for all subjects in Part B. Patients in randomized cohorts 
For Part B, the following patient disposition categories will be summarized, if applicable: 


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 Patients who were enrolled, 
 Patients who were enrolled but not treated, 
 Patients who were enrolled and treated, 
 Patients who completed/did not complete the initial/all treatment,  
 Patients who completed/did not complete the study.  
Patients that signed the informed consent form and met applicable eligibility criteria will be 
considered as enrolled. For those who did not complete study treatment per protocol and/or did 
not complete the study, the primary reason for withdrawal will be summarized. 
The number and percentage of subjects in each defined analysis population will be tabulated and 
presented.  
All subject disposition data will be presented in a data listing for both Part A and Part B. 
7.3.2 
Protocol Deviations 
All major protocol deviations will be presented in a data listing.  
7.3.3 
Demographic and Baseline Characteristics 
In Part A and Part B, demographic and baseline characteristics will be summarized by regimen 
(as applicable in Part B) and ascending dose level groups, placebo, and in total for the Safety 
Analysis Sets. If the PK and PD Analysis Sets contain a different set of subjects/patients 
compared to those included in the Safety Analysis Set, then demographic information will be 
summarized separately for those analysis sets. 
The following variables will be considered based on their collection at screening. Gender, race, 
and ethnicity will be summarized with contingency tables. Age at screening (years), height, 
weight, and body mass index (BMI) at baseline will be presented with appropriate summary 
statistics (n, mean, median, SD, minimum, maximum). See Section 6.1.3 for height and weight 
baseline definition. Patients <18 years of age at screening Part B will have the modified z-score 
calculated for their height, weight, and BMI according to the Centers for Disease Control growth 
chart [1] and will be presented with summary statistics.  
For Part B patients, the 24-hour urinary oxalate excretion (mmol/24 hours/1.73m2) and eGFR at 
baseline will be summarized descriptively by dose level groups, placebo, and in total. Separate 
analyses will be provided for patients less than 18 years of age and patients 18 years or older at 
informed consent.  
The number and percentage of subject who took vitamin B6 within 90 days of informed consent 
and/or during the study will be tabulated. 


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Summary tables will be presented by ascending ALN-GO1 dose level with subjects/patients 
receiving placebo pooled across enrollment cohort and in total. 
By-subject data listings of demographic information will be presented for Part A and Part B. 
7.3.4 
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 19.1 or Higher).  
Medical and surgical history will be summarized for the Safety Analysis Sets for Part A and Part 
B by system organ class and preferred term for each dose level groups and placebo and overall. 
For Part A and Part B, all medical/surgical history will be presented in by-subject listings for all 
randomized subjects.  
7.3.5 
Prior and Concomitant Medications  
Prior and concomitant medications will be coded using the World Health Organization (WHO) 
Drug Dictionary (October 2016 or later). Prior medications are defined as medications that were 
taken prior to and stopped before the first dose of the study medication. Concomitant 
medications are defined as medications that were taken on or after the first dose date of the study 
medication. 
The number and percentage of subjects taking concomitant medications will be summarized by 
anatomic therapeutic class (ATC) and preferred term. Data will be presented by dose level and 
placebo for the Safety Analysis Sets in Part A and Part B.  In addition, for Part B, concomitant 
medications will also be summarized in the same manner by dose level of ALN-GO1 using 
combined data from both the blinded portion and the open-label portion. 
For Part A and Part B, prior and concomitant medications will be presented in by-subject 
listings.    
7.4 
Safety Analysis 
The primary objective of the study is to assess the safety and tolerability of ALN-GO1 in healthy 
adult subjects and patients with a confirmed diagnosis of PH1. Safety analyses will include the 
summarization of Adverse Events (including Serious Adverse Events and Treatment-Emergent 
Adverse Events), exposure to study drug, vital signs, physical examination findings, ECG 
parameters, echocardiograms (Part B only), clinical laboratory assessments, and other safety 
variables. All safety analyses will be based on the Safety Analysis Sets.  


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7.4.1 
Adverse Events 
In Part A, summary tables for AEs will be presented by ascending ALN-GO1 dose level, in total 
with all subjects receiving ALN-GO1, and placebo with subjects/patients receiving placebo 
pooled across enrollment cohorts presented first. AEs will be summarized separately for the 
single-blind dosing period and the study. 
In Part B, for patients who were randomized to placebo, an AE during the single-blind period is 
defined as an AE with onset date/time on and after the first dose date/time of placebo and prior to 
the first dose date/time of open-label ALN-GO1. For patients who were initially randomized to 
ALN-GO1 a AE during the single-blind period is defined as an AE with onset date/time on or 
after the first dose date/time of ALN-GO1 and up to, and including, Study Day 85. AEs for 
single-blind period will be summarized by regimen and ascending dose level of ALN-GO1 and 
pooled placebo across regimen and dose being presented first. Sub-total for each regimen and 
overall will also be presented. 
In Part B, a summary of AEs for the single-blind period will be provided by regimen and 
ascending dose level of ALN-GO1 and pooled placebo presented first. Total for each regimen 
and overall of ALN-GO1 will also be provided. 
In Part B, for all patients receiving ALN-GO1, either as single-blind or open-label 
administration, and in any sequence, a AE is defined as an AE with onset date/time on or after 
the first dose date/time of ALN-GO1 and up to the end of study. All AEs under ALN-GO1 will 
be summarized by regimen and ascending dose, sub-total for each regimen, and for overall. At 
each dose level and for the sub-total and overall, AEs with be summarized for patients with 
single-blind administration only and then for single-blind and open-label administration 
combined. 
In each analysis above, an overview of adverse events will be provided which summarizes 
subject-level incidence (frequency) of all AEs, drug-related AEs, grade 3/4/5 AEs, drug-related 
grade 3/4/5 AEs, treatment-emergent SAEs, drug-related treatment-emergent SAEs, and AEs 
leading to discontinuation of study drug and/or deaths.  
The number and percentage of subjects with AEs will be summarized by system organ class and 
preferred term. Drug-related AEs, grade 3/4/5 AEs, drug-related grade 3/4/5 AEs, treatment-
emergent SAEs, drug-related treatment-emergent SAEs, AEs leading to discontinuation of study 
drug, AEs leading to study drug dose interruption and drug-related AEs leading to 
discontinuation of study drug will be summarized by system organ class and preferred term. For 
these summaries, subjects with multiple adverse events will be counted only once per SOC and 
preferred term. Summaries of AEs leading to discontinuation of study drug and leading to study 
drug dose interruption will be presented as applicable for the single-blind period, ALN-GO1 
dosing period, and ALN-GO1 quarterly dosing period. Other summaries will be presented 
separately for the time periods in Sections 7.2.1 and 7.2.2.  


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In addition, summaries will be provided by the worst NCI-CTCAE grade, system organ class and 
preferred term for the number and percentage of subjects with AEs and drug-related AEs. 
Listings will be provided for AEs leading to deaths, SAEs, and AEs leading to discontinuation of 
study drug or dose interruption. 
By-subject AE data listings which will include at a minimum, subject/patient identifier, study 
drug taken prior to or on an AE onset date/time, verbatim term, preferred term, system organ 
class, NCI-CTCAE grade, relationship to study drug, action taken with study drug, SAE 
classification (Yes/No) and AE onset and end date/time. In addition, for Part A, AE and study 
day will also be included. In Part B, classification (yes/no) as a AE during the single-blind 
dosing period and the ALN-GO1 dosing period will be included. In Part B, study day and day 
relative to ALN-GO1 dosing will be included.  
By-subject AE listings will be provided for Part A and Part B separately.  
7.4.2 
Dosing and Extent of Exposure 
The actual dose administered and the number of injections will be summarized descriptively by 
dose level (or placebo) and overall for the Safety Analysis Set in Part A. Compliance with study 
drug administration is not relevant as all doses will be administered by qualified clinical study 
site personnel and recorded on the electronic Case Report Form. 
Part B consists of three doses of study drug on Days 1, 29, and 57 for monthly dosing cohorts. 
For patients who randomized to placebo and crossed over to ALN-GO1 during the open label 
portion, study drug will be administered on Days 85, 113, and 141. Patients who randomized to 
receive ALN-GO1 will receive study treatment in a single-blind manner while patients enrolled 
in expansion cohorts will receive ALN-GO1 in an open-label manner.  
In Part B for quarterly dosing cohorts, patients will receive either ALN-GO1 or placebo 
according to the randomized treatment assignment on Day 1. All patients in quarterly dosing 
cohorts, including those randomized to placebo, will receive open-label ALN-GO1 on Day 85 at 
the same dose administered to the cohort into which they were initially randomized.  
Treatment duration of study drug in Part B is defined as: 
 For patients randomized to placebo in monthly or quarterly cohorts, treatment duration of 
placebo is min (first dose date of open-label ALN-GO1 or visit date of Day 85 visit) – 
first dose date of placebo +1 
 For patients in monthly dosing regimen, treatment duration of ALN-GO1 is the visit date 
of Day 85 relative to first dose of ALN-GO1 – first dose date of ALN-GO1 +1   
 For patients randomized to placebo in quarterly dosing cohorts, their treatment duration 
of open-label ALN-GO1 is the same as for monthly dosing regimen.  


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 For patients randomized to ALN-GO1 in quarterly dosing cohorts, the single-blind 
treatment duration is Day 85 visit date – first dosed date of ALN-GO1 +1 and the total 
ALN-GO1 treatment duration is Day 169 visit date – first dose date of ALN-GO1 +1. 
Treatment duration of study drug will be summarized using descriptive statistics by regimen, 
ascending dose level of ALN-GO1, pooled placebo, and in total for the single-blind time period 
and total ALN-GO1 dosing period.  
In Part B, dosing status will be tabulated by regimen and dose level (including placebo during 
the summary for the single-blind study period). The following categories will be summarized: 
 Subjects with a missed dose,  
 Subjects with a dose interruption 
The above summary will be provided in Part B for the single-blind dosing period by pooled 
placebo, regimen, and ascending ALN-GO1 dose. The above summary will be provided 
separately for the ALN-GO1 dosing period (by regimen and ascending ALN-GO1 dose, 
regardless of treatment sequence) and ALN-GO1 quarterly open-label dosing period.  
In Part A and Part B, all study drug administration information will be listed.  
7.4.3 
Clinical Laboratory Assessments 
Where applicable, abnormal laboratory results will be graded according to NCI CTCAE v4.0. A 
shift table, presenting the 2-way frequency tabulation for baseline and the worst post-baseline 
value according to the NCI CTCAE grade, will be provided for selected clinical laboratory tests. 
Both scheduled and unscheduled post-baseline values will be considered. 
For Part A, descriptive statistics will be provided for clinical laboratory data for actual results, 
changes from baseline, and relative to the upper limit of normal range (ULN) over time by 
pooled placebo and ascending ALN-GO1 dose.  
For Part B, descriptive statistics will be provided for clinical laboratory data for actual results, 
changes from baseline and relative to the upper limit of normal range over time according to the 
data display specification in Section 7.2.  
Clinical laboratory tests with normal ranges will be classified as Low, Normal, and High. For 
these tests, abnormal values will be flagged in the listings with H when the value is higher than 
the upper limit of the reference ranges and with L when the value is lower than the lower limit of 
the reference ranges.  
This categorical data will also be summarized in shift tables comparing the worst value post-
baseline with those at the baseline visit. When there are both high and low abnormal values for a 
subject for a particular laboratory variable, the worst value will be taken (the value furthest 
outside of the normal ranges, or the first value experienced, if this value is the same). In Part A, 
frequencies and percentages will be presented by dose group. In Part B, shift table will be 


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summarized by pooled placebo and ascending single-blind ALN-GO1 dose and by ALN-GO1 
dose in single-blind and open-label combined. 
All clinical laboratory data in Part A and Part B will be listed.    
7.4.4 
Vital Signs 
For Part A and B, systolic blood pressure, diastolic blood pressure, pulse rate, body temperature, 
respiratory rate, height (Part B only), and body weight will be summarized as actual values and 
changes from baseline in the same way as described in Sections 7.1 (Part A) and Section 7.2.1-2 
(Part B). Patients<18 years of age in Part B at enrollment will have the modified z-score 
calculated for their height, weight, and BMI according to CDC growth chart [1].   
Separate summaries will be provided in Part B for the single-blind dosing period (by pooled 
placebo, regimen, and ascending ALN-GO1 dose), the ALN-GO1 dosing period (by regimen and 
ascending ALN-GO1 dose, regardless of treatment sequence), and the post-dose, safety, and PD 
follow-up period (by regimen and ascending ALN-GO1 dose, regardless of treatment sequence) 
as described in Sections 7.2.1-7.2.2.  
All vital signs data in Part A and Part B will be listed. 
7.4.5 
Physical Examinations 
For both Part A and Part B, physical examination findings, including any abnormal findings, will 
be listed. All data from symptom-directed physical examinations will be listed.  
For Part B, all data from symptom-related physical examinations will be listed. 
7.4.6 
ECGs 
Analyses of ECGs for both Part A and Part B and will be based on the Safety Analysis Sets.  
In Part A, analyses will be presented separately for the single-blind dosing period and safety and 
PD follow-up period. In Part B, analyses will be presented separately for the single-blind dosing 
period (by pooled placebo, regimen, and ascending ALN-GO1 dose), ALN-GO1 dosing period 
(by regimen and ascending ALN-GO1 dose, regardless of treatment sequence), quarterly open-
label ALN-GO1 dosing period (by ascending ALN-GO1 dose), postdose follow-up period (by 
ascending ALN-GO1 dose), and Safety and PD follow-up period (by regimen and ascending 
ALN-GO1 dose, regardless of treatment sequence).  
Subjects with the following diagnoses or abnormal ECG findings will be excluded from the ECG 
analysis: artificial pacemaker (recorded as presence of atrial pacing, ventricular pacing, and/or 
atrial ventricular pacing), atrial fibrillation (or flutter), left bundle branch block (complete or 
incomplete), and right bundle branch block (complete or incomplete).     
The number and percentage of patients with normal, abnormal, and clinically significant 
abnormal results at baseline and each timepoint will be summarized.  


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For both Part A and Part B, electrocardiogram parameters (ventricular rate, PR, QRS, QT, QTcB, 
and QTcF) will be summarized using descriptive statistics for actual values and for changes from 
baseline by scheduled time of evaluation (given in the Schedule of Assessments). These 
summaries will be presented separately for the time periods in Sections 7.1 (Part A) and Sections 
7.2.1-2 (Part B).  
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 QT, QTcF, and QTcB intervals (<=450, > 450, 
> 480, and > 500 ms) over all post-treatment evaluations, as well as in QT, QTcF, and QTcB 
maximum changes from baseline (> 30 and > 60 ms) over all post-treatment evaluations will be 
summarized by dose level of ALN-GO1, pooled placebo, and overall for all subjects receiving 
ALN-GO1 in Part A. In Part B, the summary will be presented by regimen and ascending ALN-
GO1 dose level, regardless of treatment sequence.  
Scatterplots of QT Interval by RR Interval, QTcF Interval by RR Interval, and QTcB Interval by 
RR Interval will be presented for the pooled placebo and by regimen and by dose groups.  For 
each QTcF Interval that has a time-matched pharmacokinetic concentration, a scatterplot of 
change from baseline QTcF Interval by concentration will be presented for the pooled placebo 
and by regimen and by dose groups.  The line produced from simple linear regression will be 
used as a line of reverence. 
A listing of all ECG data will be provided. 
7.4.7 
Echocardiograms (Part B Only)  
Summary statistics (n, mean, median, SD, minimum, maximum) will be presented for the 
baseline measurement of Left Ventricular Ejection Fraction.  
The number of patients with clinically significant changes in systolic function will be tabulated 
for each on-study assessment separately by ascending ALN-GO1 dose level and regimen and 
placebo for the single-blind dosing period.  
All ECHO assessments will be listed by subject in the order of ascending ALN-GO1 dose and 
placebo. 
7.4.8 
Analysis of Other Safety Variables 
For both Part A and Part B, all other safety data will be listed. 
7.5 
Pharmacokinetic Analyses 
PK analyses will be performed based on the PK Analysis Set. All PK summaries will be 
presented by dose level of ALN-GO1.  For Part B, the PK data of ALN-GO1 from both the 
blinded and open-label portion will be combined at each dose level. 


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Plasma and urine PK concentration data of ALN-GO1 will be summarized at each scheduled 
time point by dose level using descriptive statistics (n, mean, standard deviation [SD], standard 
error [SE], minimum, maximum, median, and percent coefficient of variation [%CV]). Mean 
plasma concentrations of ALN-GO1 versus nominal time will be plotted by dose level and study 
day on both linear scale and semi-logarithm scale. Individual plasma concentration versus actual 
time plots will also be provided. Individual and mean plasma concentrations of ALN-GO1 versus 
nominal time will also be plotted by dose level, study day and ADA status on both linear scale 
and semi-logarithm scale.  
The plasma PK parameters and urine PK parameters of ALN-GO1 following single dose on Day 
1 in Part A, single dose on Day 1 relative to ALN-GO1 dosing (Part B monthly and quarterly 
cohorts), multiple doses on Day 57 relative to ALN-GO1 dosing (Part B monthly cohorts only), 
and multiple doses on Day 85 relative to ALN-GO1 dosing (Part B quarterly cohorts only) will 
be summarized by regimen and ascending dose level. Geometric mean and geometric coefficient 
of variation will be added to the descriptive statistics for calculated PK parameters.  
All individual subject plasma and urine concentrations data and actual sampling times will be 
listed. All PK parameters will be listed by subject, dose level, study day and ADA status. 
7.6 
Pharmacodynamic and Exploratory Analyses 
Pharmacodynamic parameters will be measured from blood and urine samples collected at times 
outlined in the Schedule of Assessments in both Part A and Part B. PD analyses will be based on 
the Pharmacodynamic Analysis Sets. 
24-hour urine oxalate content corrected for BSA will be calculated as: 
[24-hour urine oxalate in mmol/L]*[24-hour urine volume recorded in CRF in ml] 
  /(1000 ml per L)*24hours/[actual collection time calculated from CRF in hours] 
  *1.73/[patient BSA] 
Where patient BSA will be calculated as: 
Patient BSA = sqrt([mean height in cm] *[weight in kg] /3600).  
24-hour urine creatinine clearance corrected for BSA will be calculated as: 
[24-hour urine creatinine concentration in mg/dl]*[24-hour urine volume recorded in 
CRF in ml] 
  /[Plasma creatinine in mg/dl]/[actual collection time calculated from CRF in minutes] 
  *1.73/[patient BSA]24-hour urine oxalate/creatinine ratio will be calculated as:  
24-hour urine oxalate concentration (mg/L) /24-hour urine creatinine concentration 
(mg/dL)/10. 
For Part A and Part B, the mean and standard error of actual values and changes from baseline in 
plasma and urine glycolate will be plotted over time by ALN-GO1 dose level and placebo. In 


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addition, plots will be provided for plasma and urine glycolate of individual subjects by dose 
level of ALN-GO1 and placebo.  
For Part B, the mean and standard error of actual values and changes from baseline in urinary 
oxalate per 24-hour urine collection and urinary creatinine per 24-hour urine collection will be 
plotted over time. In addition, the plots will be presented separately by ADA status. Plasma 
glycolate concentration and oxalate/creatinine ratio will be plotted in the same manner. For 
patients randomized to placebo, figures will include PD measurements up to the first dose of 
open-label study drug.  
For other PD variables in Part A and B, descriptive statistics will be provided for actual results, 
change from baseline, and percent change from baseline. For Part B, the PD summaries will be 
presented according to the data display specification in Section 7.2.3.For Part A and Part B, 
Cmax and AUCt of plasma glycolate will be presented with descriptive statistics and percent 
coefficient of variation [%CV]) by regimen and ascending dose level and placebo presented first.   
In Part A and Part B, all PD data will be listed by regimen, dose, ADA status (Part B only) and 
subject/patient.  
7.7 
Immunogenicity Analysis 
For Part A and Part B, results from tests for antidrug antibodies will be listed by subject in the 
order of ascending ALN-GO1 dose and placebo for the Safety Analysis Sets.    
8 
GENERAL INFORMATION 
8.1 
Statistical Software 
The creation of analysis datasets and statistical analyses will be done using SAS® version 9.3 or 
higher.  The Medpace standard operating procedures (Medpace documents
 
) will be followed for the validation of all SAS programs and outputs. 
Pharmacokinetic parameters will be derived at Alnylam Pharmaceuticals using Phoenix 
WinNonlin software Version 7.0 or higher. 
8.2 
Format of Tables, Listings, and Figures 
The format of tables, listings, and figures will be described in a stand-alone programming 
specifications document and will be finalized before database lock for the study.  
9 
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSIS 
No changes have been issued or planned.  
10 
REFERENCES 


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References are provided in the study Protocol.   
[1] CDC Growth Chart https://www.cdc.gov/nccdphp/dnpao/growthcharts/resources/sas.htm