A Phase 2, Randomized, Double-blind, Placebo-controlled Study of Cemdisiran in Adult Patients With IgA Nephropathy
Phase: PHASE2
Conditions: IgA Nephropathy (IgAN), Berger Disease, Glomerulonephritis, IgA
Sponsor: Alnylam Pharmaceuticals

 
 
Official Title:  
A Phase 2, Randomized, Double-blind, Placebo-controlled Study of 
Cemdisiran in Adult Patients With IgA Nephropathy   
 
NCT Number:   
NCT03841448 
 
Document Date:   
Protocol Amendment 4, 13 January 2021  

Clinical Study Protocol ALN-CC5-005 
cemdisiran 
Amendment 4, 19 January 2021 
Alnylam Pharmaceuticals 
Confidential 
1 
 
 
CLINICAL STUDY PROTOCOL 
ALN-CC5-005 
 
Protocol Title: 
A Phase 2, Randomized, Double-blind, 
Placebo-controlled Study of Cemdisiran in Adult 
Patients with IgA Nephropathy 
Short Title: 
A Phase 2 Study of Cemdisiran in Adult Patients 
with IgA Nephropathy 
Study Drug: 
Cemdisiran (ALN-CC5)  
EudraCT Number: 
2018-002716-27 
IND Number: 
140087 
Protocol Date: 
 
Original protocol 10 September 2018 
Amendment 1 [26 November 2018] 
Amendment 2 [20 September 2019] 
Amendment 3 [27 April 2020] 
Amendment 4 [19 January 2021] 
Sponsor: 
Alnylam Pharmaceuticals, Inc. 
300 Third Street 
Cambridge, MA  02142 USA 
Telephone:  
 
Sponsor Contact:   
 
 
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. 
 

Clinical Study Protocol ALN-CC5-005 
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Amendment 4, 19 January 2021 
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INVESTIGATOR’S AGREEMENT 
 
I have read the ALN-CC5-005 protocol and agree to conduct the study in accordance with the 
protocol and all applicable regulations.  I agree to maintain the confidentiality of all information 
received or developed in connection with this protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 

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• 
To evaluate the pharmacodynamic (PD) 
effect of cemdisiran ie, C5 level and 
CAP/CCP 
• 
To characterize the pharmacokinetics 
(PK) of cemdisiran and relevant 
metabolites in plasma and urine in adult 
patients with IgAN 
• 
To evaluate the effect of cemdisiran on 
serum and urine markers of complement 
activation, renal damage and 
inflammation 
• 
To assess the incidence of antidrug 
antibodies (ADA) 
• 
The slope of eGFR computed for the 
entire study period including the open 
label extension using all assessments 
during the study. 
• 
Change from baseline in creatinine 
clearance at Week 32 
• 
Percent of patients in full clinical 
remission (UP <0.3 g/24-hours) at 
Week 32  
• 
Change from baseline in 24-hour 
albuminuria at Week 32 
• 
Change from baseline in the urine 
albumin/creatinine ratio (UACR) as 
measured in 24-hour urine at Week 32 
• 
Change from baseline in C5 level over the 
course of the study 
• 
Change from baseline in complement 
activity (Complement Alternative 
Pathway [CAP]and Complement 
Classical Pathway [CCP]) over the course 
of the study 
• 
Evaluation of area under the curve 
(AUC), maximum plasma concentration 
(Cmax), time to maximum plasma 
concentration (Tmax), terminal half-life 
(t½), clearance (CL/F), volume of 
distribution (V/F), cumulative amount 
excreted unchanged in urine (Ae) and 
percent of dose excreted in the urine (fe) 
of cemdisiran (25-mer) and 23-mer 
• 
Evaluation of AUC, Cmax, Tmax, t½, CL/F, 
V/F, Ae and fe of 22-mer AS(N-1)3’ 
• 
Change from baseline in levels of renal 
damage, complement activation and 
inflammation markers over the course of 
the study 
• 
Incidence of antidrug antibodies (ADA) 
Study Design 
This is a multicenter, double-blind, placebo-controlled study comprised of three periods 
(Figure 1).  The first period of the study is an observational 14-week run-in period during which 
patients’ blood pressure, kidney function, degree of hematuria, and proteinuria will be measured.  
The standard of care is expected to remain unchanged during this run-in period.  Patients will not 
receive study drug (cemdisiran or placebo) during this time.  The second study period is a 
36-week treatment period (defined as the time the first dose of study drug is administered on 
Study Day 1 through completion of the Week 36 assessments) which will evaluate the efficacy 

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and safety of subcutaneous (SC) cemdisiran compared to SC placebo in combination with 
standard of care in patients with IgAN and persistent proteinuria.  The third period of the study is 
a 156-week optional open-label extension (OLE) period to further evaluate the long-term safety 
and clinical activity of cemdisiran.  During the OLE, all patients (including those initially on 
placebo) will be treated with cemdisiran in combination with standard of care. 
The study will include a Screening period of up to 120 days to determine eligibility of patients 
and to complete disease-related assessments.  The Investigator will notify the Sponsor before 
screening patients to allow an assessment of the ability of the site and new trial participants to 
comply with the protocol given limitations during the COVID-19 pandemic.  Patients will 
provide written informed consent and visit the study site approximately 2 weeks before starting 
the run-in period to complete the protocol screening assessments.  Following successful 
screening, the 14-week run-in period will commence, during which patients’ blood pressure, 
kidney function, degree of hematuria and proteinuria as well as treatment with standard of care 
will be documented by the Investigator.  The standard of care is expected to remain unchanged 
during this run-in period.  Patients whose proteinuria level remains ≥1 g/24-hours within 2 weeks 
of the end of the run-in period, and who meet blood pressure and estimated glomerular filtration 
rate (eGFR) criteria will be eligible to enroll in the 36-week treatment period.  Upon 
confirmation of eligibility followed by vaccination against meningococcal infections, patients 
will be randomized at a 2:1 ratio to receive 600 mg of cemdisiran or placebo every 4 weeks in 
combination with standard of care.  Approximately 30 patients are planned to be randomized in 
total, 20 in the cemdisiran arm and 10 in the placebo arm.  Patients excluded before 
randomization will be replaced at Screening.  
During the run-in period, patients will visit the study site 14, 8, and 2 weeks prior to 
randomization (Weeks 0, 6 and 12 of the run-in period).  If a run-in visit cannot proceed 
according to schedule, it may be delayed up to 28 days, with subsequent visits being rescheduled 
based on the new date.  Visit windows, as indicated in the Schedule of Assessments (Table 1), 
are applied to the rescheduled date.  Approval from the Medical Monitor is required prior to 
initiation of the treatment period.  If a subject cannot proceed to the treatment period as planned, 
the run-in period can be extended as needed.  If the final run-in visit will not be within 56 days of 
randomization, this visit will be repeated, and the new visit will serve as the Week -2 visit to 
determine eligibility for randomization.   
Study drug administration can be conducted at the study site or by a healthcare professional at a 
location other than the study site (eg, at home) from Week 4 of the treatment period for patients 
that have tolerated the study drug at the study site.  If the patient is unable to come to the study 
site, and a visit by a healthcare professional for patients at a location other than the study site (eg, 
at home) is not possible due to circumstances related to the COVID-19 pandemic, study drug 
may be administered by the patient or the caregiver under the oversight of the Investigator, and 
following consultation with the Medical Monitor, as allowed by applicable country and local 
regulations.  In such cases, the patient or the caregiver must receive appropriate training on 
cemdisiran administration prior to dosing.  This measure is intended to remain in effect only 
during periods of time when the COVID-19 pandemic impedes the ability of patients to travel to 
the study site or healthcare professionals to go to a location other than the study site (eg, at 
home) for dosing.  The primary endpoint will be assessed at the end of treatment at Week 32. 

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At the end of treatment (Week 32), patients in the two treatment arms may enter the optional 
OLE period where they will receive cemdisiran at a dose of 600 mg every 4 weeks in 
combination with standard of care for up to an additional 152 weeks (approximately 3 years).  If 
deemed necessary, the Investigator or Sponsor may shorten the time of the OLE period due to 
safety or administrative reasons.  For patients who do not enter the OLE period, an End of Study 
(EOS) visit will occur at Week 36 and the patient will then enter the 52-week safety follow-up 
period. 
The first study drug administration of the OLE will be administered at the study site at Week 36.  
From Week 40 onward in the OLE period (with the exception of the End of Treatment [EOT] 
and End of Study/Early Termination [EOS/ET] visits), study procedures (including cemdisiran 
administration) may be performed by a healthcare professional at a location other than the study 
site, at the discretion of the Investigator, with no more than 6 months between study site visits.  
If a visit by a healthcare professional at a location other than the study site (eg, at home) is not 
possible, study drug may be administered by the patient or caregiver under the oversight of the 
Investigator, and following consultation with the Medical Monitor, as allowed by applicable 
country and local regulations. 
An EOT visit will occur at Week 184 (OLE EOT) and an EOS/ET visit will be completed at 
Week 188 (OLE EOS/ET).  The EOT and EOS/ET visits will be performed at the study site.  For 
patients who complete the treatment period only and who do not consent to continue to 
participate in the study in the OLE period, the EOS/ET visit will be at Week 36. 
Patients will return to the clinical study site for safety follow-up visits approximately 13, 26, 39 
and 52 weeks after the EOS/ET visit (regardless if EOS/ET visit is at Week 36 or Week 188), 
unless enrolled in another study with cemdisiran.  Visits at a location other than the study site 
(eg, at home), where locally feasible, may be arranged during safety follow-up at 13 and 39 
weeks after the EOS/ET visit (regardless if EOS/ET visit is at Week 36 or Week 188).   
Regular reviews of safety and tolerability data will be performed by a Data Monitoring 
Committee (DMC) throughout the study with the primary purpose of protecting the safety of 
participating patients and the integrity of the study. 
Number of Planned Patients 
Approximately 30 patients are planned for randomization in this study. 
Diagnosis and Main Eligibility Criteria 
This study will include adults (≥18 years and ≤ 65 years of age) with a clinical diagnosis of 
primary immunoglobulin A (IgA) Nephropathy based on historical biopsy collected within 60 
months of Screening, treated for IgA Nephropathy with stable, optimal pharmacological therapy 
including maximum allowed or tolerated angiotensin converting enzyme (ACE) inhibitor or 
angiotensin II receptor blocker (ARB) for at least 3 months prior to the start of the run-in period.  
Eligible patients must have urine protein levels of ≥1 g/24-hour at Screening from a valid 24-
hour urine collection (see Section 6.4.1.1), and mean urine protein levels ≥1 g/24-hour from two 
valid 24-hour urine collections at the end of the run-in period (Week -2 visit), prior to 
randomization.  In addition, eligible patients must have hematuria defined by ≥10 red blood cells 
per high powered field (RBC/hpf) by microscopy or a positive urine dipstick (2+ [moderate] and 
above) measured by a central laboratory at Screening.  Eligible patients are required to have been 
previously vaccinated with meningococcal group ACWY conjugate vaccine and meningococcal 

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group B vaccine or be willing to receive these vaccinations as well as prophylactic antibiotic 
treatment, if required by local standard of care (see Section 5.3.2.1 and Section 5.3.2.2 for 
vaccination time windows).  In addition, patients not previously vaccinated against 
Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) must be willing to receive 
these vaccinations according to local guidelines. 
Patients will be excluded from the study if eGFR <30 mL/min/1.73 m2 2 weeks prior to 
randomization; treated with systemic steroids for more than 7 days or other immunosuppressant 
agents in the 6 months prior to randomization; treated with dual RAS blockade in the 3 months 
prior to entry into the run-in phase; have a diagnosis of rapidly progressive glomerulonephritis as 
measured by eGFR loss >30% over the duration of the run-in phase; sustained blood pressure 
>140/90 mmHg as defined by 2 or more readings during the run-in period measured in supine 
position after 10 minutes of rest; have received organ transplant (including hematologic 
transplant) or have secondary etiologies of IgAN (eg, inflammatory bowel disease, celiac 
disease).  
Study Drug, Dose, and Mode of Administration 
Cemdisiran is a synthetic small interfering RNA (siRNA) targeting complement component 5 
(C5) mRNA that is covalently linked to a triantennary N-acetylgalactosamine (Tri-GalNAc) 
ligand.  Cemdisiran will be supplied as a sterile solution for SC injection that contains 200 
mg/mL cemdisiran sodium (equivalent to 189 mg/mL of cemdisiran), formulated in water for 
injection (WFI) for SC administration.  Doses of 600 mg of cemdisiran will be administered 
every 4 weeks over a period of 32 weeks during the 36-week treatment period and the optional 
OLE period.  
Placebo (normal saline 0.9% for SC administration) will be packaged and administered 
identically to cemdisiran. 
Reference Treatment, Dose, and Mode of Administration 
Angiotensin converting enzyme inhibitors (ACE) or angiotensin II receptor blockers (ARB) per 
physician and manufacturer‘s instructions. 
Duration of Treatment and Study 
Subcutaneous doses of cemdisiran or matching placebo will be administered every 4 weeks over 
a period of 32 weeks during the 36-week treatment period and patients will receive SC doses of 
cemdisiran for up to an additional 152 weeks in the optional 156-week OLE.  The estimated total 
time on study, inclusive of Screening (120 days), run-in period (14 weeks), treatment period (36 
weeks), extension period (156 weeks) and safety follow-up (52 weeks), for patients is 
approximately 63 months or 5 years and 4 months. 
Statistical Methods 
The primary endpoint of the study is the percentage change from baseline in UPCR from a 24-
hour urine sample at Week 32.  Approximately 30 patients are planned to be randomized 2:1 
(cemdisiran:placebo) in this study based on the assumption that, in the placebo arm, the 
estimated geometric mean ratio of UPCR at Week 32 to baseline is 0.88 (log standard deviation 
[SD] 0.597), corresponding to a 12% reduction, while the geometric mean ratio is 0.5, or a 50% 
reduction for the cemdisiran arm.  Using these assumptions, sample size of 9 and 18 in the 
placebo and cemdisiran arms, respectively, will provide a width of 0.80 (± 0.4) for the 90% 

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confidence interval (CI) for treatment effect size estimate (cemdisiran – placebo) in log scale.  
The primary analysis will be performed using a restricted maximum likelihood (REML) based 
Mixed-Effect Model Repeated Measures (MMRM) approach.  
The analysis populations include: 
• The modified Intent-to-treat (mITT) population will include all patients who receive 
any amount of study drug and have at least one post baseline 24-hour proteinuria 
assessment.  Patients will be grouped by assigned treatments (ie, as randomized).  
• The Safety Analysis Set will include all patients who received any amount of study 
drug.  Patients who received any amount of cemdisiran will be included in the 
cemdisiran arm.  Patients in the Safety Analysis Set will be grouped by treatment 
received.  
• PK Analysis Set: All patients who receive a full dose of study drug and have at least 
one postdose blood or urine sample for PK concentration.  
• PD Analysis Set: All patients who receive a full dose of study drug and who have at 
least one postdose blood sample for the determination of plasma C5 level. 
The efficacy endpoints will be analyzed in the mITT population.  PK and PD parameters will be 
analyzed in the PK and PD analysis sets, respectively. 
Safety data will be summarized with descriptive statistics using the Safety Analysis Set.  
Figure 1: 
Study Design 
 
Abbreviations:  EOS=end of study; EOT=end of treatment; Q4W=once every 4 weeks. 
a Or at time of withdrawal from the study. 
 

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• 
If a patient is unable to complete a site visit due to the COVID-19 pandemic impacting activities at the study site or patient ability or willingness to 
access the site, study procedures, including cemdisiran administration, may occur at a location other than the study site (eg, at home) at the discretion of 
the Investigator, based on safety and tolerability.   
• 
In situations where a study visit cannot be completed at the study site or offsite by a healthcare professional at a location other than the study site (eg, at 
home) or the dose is missed, the study Investigator (or delegate) may verbally contact the patient within the study visit window to assess for any adverse 
events and concomitant medications 
a The 52-week safety follow-up period will follow the Week 36 EOS/ET visit only for those patients not continuing into the OLE period. 
b The Week 32 visit is the End of Treatment (EOT) visit for only those patients who do not continue into the OLE period.  
c The Week 36 visit is the End of Study/Early Termination (EOS/ET) visit for only those patients who do not continue into the OLE period. For patients who 
continue into the OLE period, the Week 36 visit will be the first administration of cemdisiran in the OLE period (see Table 2). 

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Table 5: 
Pharmacokinetic Time Points 
Phase 
Study Day 
Protocol Time Relative to 
Dosing 
(hh:mm)a 
PK Blood Pooled Urineb 
Treatment phase 
Day 1 
Predose (within 60 mins) 
X 
 
00:00 (dose) 
 
X 
01:00 (±5 mins) 
X 
02:00 (±15 mins) 
X 
04:00 (±15 mins) 
X 
06:00 (±15 mins) 
X 
08:00 (±30 mins) 
Xc 
X 
12:00 (±30 mins) 
 
24:00 (±120 mins) 
Xc 
X 
Abbreviations:  hh=hours; mm=minutes; mins=minutes; PK=pharmacokinetics. 
a The actual time of blood sample collection must be recorded. 
b The pooled urine 6-12 hours and 12-24 hours can be collected as outpatient. 
c Blood samples for PK assessment at these time points postdose may be collected if locally feasible. 

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TABLE OF CONTENTS 
SPONSOR PROTOCOL APPROVAL ...........................................................................................2 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
PROTOCOL SYNOPSIS ................................................................................................................4 
TABLE OF CONTENTS ...............................................................................................................28 
LIST OF TABLES .........................................................................................................................32 
LIST OF FIGURES .......................................................................................................................32 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................33 
1. 
INTRODUCTION ......................................................................................................36 
1.1. 
Disease Overview .......................................................................................................36 
1.2. 
Cemdisiran ..................................................................................................................38 
1.3. 
Study Design Rationale ..............................................................................................39 
1.4. 
Dose Rationale ............................................................................................................40 
1.5. 
Benefit-Risk Assessment ............................................................................................41 
2. 
OBJECTIVES AND ENDPOINTS ............................................................................43 
3. 
INVESTIGATIONAL PLAN .....................................................................................45 
3.1. 
Summary of Study Design ..........................................................................................45 
3.2. 
Duration of Treatment ................................................................................................46 
3.3. 
Duration of Study .......................................................................................................47 
3.3.1. 
Definition of End of Study for an Individual Patient .................................................47 
3.4. 
Number of Planned Patients .......................................................................................47 
3.5. 
Method of Assigning Patients to Treatment Groups ..................................................47 
3.6. 
Blinding ......................................................................................................................47 
3.6.1. 
Emergency Unblinding ...............................................................................................48 
3.7. 
Data Monitoring Committee .......................................................................................48 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................48 
4.1. 
Inclusion Criteria ........................................................................................................48 
4.2. 
Exclusion Criteria .......................................................................................................49 
4.3. 
Removal from Therapy or Assessment.......................................................................50 
4.3.1. 
Discontinuation of Study Drug or Declining Procedural Assessments ......................51 
4.3.2. 
Stopping a Patient’s Study Participation ....................................................................52 
4.3.2.1. 
Patient or Legal Guardian Stops Participation in the Study .......................................52 

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4.3.2.2. 
Withdrawal of Consent to Process the Patient’s Personal Data .................................52 
4.3.2.3. 
Investigator or Sponsor Stops Participation of a Patient in the Study ........................52 
4.3.2.4. 
Recording Reason for Stopping a Patient’s Study Participation ................................52 
4.3.3. 
Lost to Follow-Up.......................................................................................................53 
4.3.4. 
Replacement of Study Patients ...................................................................................53 
5. 
TREATMENTS AND OTHER REQUIREMENTS ..................................................53 
5.1. 
Treatments Administered ............................................................................................53 
5.2. 
Study Drug ..................................................................................................................53 
5.2.1. 
Description ..................................................................................................................53 
5.2.2. 
Dose and Administration ............................................................................................54 
5.2.3. 
Dose Modifications .....................................................................................................54 
5.2.3.1. 
LFT Criteria for Withholding, Monitoring and Stopping Cemdisiran Dosing ...........55 
5.2.4. 
Preparation, Handling, and Storage ............................................................................56 
5.2.5. 
Packaging and Labeling ..............................................................................................57 
5.2.6. 
Accountability .............................................................................................................57 
5.3. 
Concomitant Medications and Procedures .................................................................57 
5.3.1. 
Prohibited Concomitant Medications .........................................................................57 
5.3.2. 
Study-specific Vaccinations .......................................................................................58 
5.3.2.1. 
Meningococcal Vaccinations ......................................................................................58 
5.3.2.2. 
Pneumococcal and Hib Vaccinations .........................................................................58 
5.4. 
Treatment Compliance ................................................................................................59 
5.5. 
Other Requirements ....................................................................................................59 
5.5.1. 
Contraception ..............................................................................................................59 
5.5.2. 
Alcohol Restrictions ...................................................................................................60 
5.5.3. 
Antibiotic Compliance ................................................................................................60 
6. 
STUDY ASSESSMENTS ..........................................................................................60 
6.1. 
Screening Assessments ...............................................................................................60 
6.1.1. 
Rescreening .................................................................................................................61 
6.1.2. 
Retesting .....................................................................................................................61 
6.2. 
Run-in Period ..............................................................................................................61 
6.3. 
Baseline Assessments (Treatment Period) ..................................................................62 
6.4. 
Efficacy Assessments .................................................................................................62 
6.4.1. 
Urine Protein/Creatinine Ratio ...................................................................................62 

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6.4.1.1. 
24-Hour Urine Collection ...........................................................................................62 
6.4.1.2. 
Spot Urine Collection .................................................................................................63 
6.4.2. 
Hematuria ...................................................................................................................63 
6.4.3. 
Changes in Renal Function .........................................................................................63 
6.4.4. 
Markers of Complement Activation, Inflammation and Renal Injury .......................64 
6.5. 
Pharmacodynamic Assessments .................................................................................64 
6.6. 
Pharmacokinetic Assessments ....................................................................................64 
6.7. 
Safety Assessments .....................................................................................................64 
6.7.1. 
Vital Signs ..................................................................................................................65 
6.7.2. 
Weight and Height ......................................................................................................65 
6.7.3. 
Physical Examination .................................................................................................65 
6.7.4. 
Electrocardiogram .......................................................................................................65 
6.7.5. 
Clinical Laboratory Assessments ...............................................................................66 
6.7.5.1. 
Immunogenicity ..........................................................................................................68 
6.7.5.2. 
Pregnancy Testing ......................................................................................................68 
6.7.5.3. 
Additional Liver Function Assessments .....................................................................68 
6.7.6. 
Adverse Events ...........................................................................................................69 
6.7.6.1. 
Definitions ..................................................................................................................69 
6.7.6.2. 
Eliciting and Recording Adverse Events ....................................................................71 
6.7.6.3. 
Reporting Adverse Events of Clinical Interest to Sponsor/Designee .........................72 
6.7.6.4. 
Serious Adverse Events Require Immediate Reporting to Sponsor/Designee ...........72 
6.7.6.5. 
Sponsor Safety Reporting to Regulatory Authorities .................................................72 
6.7.6.6. 
Serious Adverse Event Notification to the Institutional Review 
Board/Independent Ethics Committee ........................................................................73 
6.7.6.7. 
Pregnancy Reporting ..................................................................................................73 
6.7.6.8. 
Overdose Reporting ....................................................................................................73 
6.7.7. 
COVID-19 Data Collection ........................................................................................73 
6.8. 
Biomarkers, DNA Genotyping, and Biospecimen Repository ...................................73 
7. 
STATISTICS ..............................................................................................................74 
7.1. 
Determination of Sample Size ....................................................................................74 
7.2. 
Statistical Methodology ..............................................................................................74 
7.2.1. 
Populations to be Analyzed ........................................................................................75 
7.2.2. 
Examination of Subgroups .........................................................................................75 

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7.2.3. 
Handling of Missing Data ...........................................................................................75 
7.2.4. 
Baseline Evaluations ...................................................................................................75 
7.2.5. 
Efficacy Analyses .......................................................................................................76 
7.2.5.1. 
Primary Endpoint ........................................................................................................76 
7.2.5.2. 
Secondary Efficacy Endpoints ....................................................................................76 
7.2.5.3. 
Exploratory Endpoints ................................................................................................76 
7.2.6. 
Pharmacodynamic Analysis........................................................................................76 
7.2.7. 
Pharmacokinetic Analysis ..........................................................................................77 
7.2.8. 
Safety Analyses ..........................................................................................................77 
7.2.9. 
Immunogenicity Analyses ..........................................................................................77 
7.2.10. 
Biomarker Analyses ....................................................................................................77 
7.2.11. 
Interim Analysis ..........................................................................................................78 
7.2.12. 
Optional Additional Research .....................................................................................78 
8. 
STUDY ADMINISTRATION ...................................................................................78 
8.1. 
Ethical and Regulatory Considerations ......................................................................78 
8.1.1. 
Informed Consent .......................................................................................................78 
8.1.2. 
Ethical Review ............................................................................................................78 
8.1.3. 
Serious Breach of Protocol .........................................................................................79 
8.1.4. 
Study Documentation, Confidentiality, and Records Retention .................................79 
8.1.5. 
End of Study ...............................................................................................................80 
8.1.6. 
Termination of the Clinical Study or Site Closure .....................................................80 
8.2. 
Data Quality Control and Quality Assurance .............................................................80 
8.2.1. 
Data Handling .............................................................................................................80 
8.2.2. 
Study Monitoring ........................................................................................................80 
8.2.3. 
Audits and Inspections ................................................................................................80 
8.3. 
Publication Policy .......................................................................................................81 
9. 
LIST OF REFERENCES ............................................................................................82 
10. 
APPENDICES ............................................................................................................85 
 

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LIST OF TABLES 
Table 1: 
Schedule of Assessments – Run-in and Treatment Periods (Screening 
through Week 36) including Safety Follow-up ..........................................................10 
Table 2: 
Schedule of Assessments – Open-Label Extension Period (Year 1) ..........................18 
Table 3: 
Schedule of Assessments – Open-Label Extension Period (Year 2) ..........................21 
Table 4: 
Schedule of Assessments – Open-Label Extension Period (Year 3) and 
Safety Follow-up ........................................................................................................24 
Table 5: 
Pharmacokinetic Time Points .....................................................................................27 
Table 6: 
Monitoring and Dosing Rules for Asymptomatic Patients with Confirmed 
Isolated Elevations of ALT and/or AST >3× ULN, with No Alternative 
Cause Identified ..........................................................................................................56 
Table 7: 
Clinical Laboratory Assessments ...............................................................................67 
Table 8: 
Hepatic Assessments in Patients Who Experience Elevated Transaminases .............69 
 
LIST OF FIGURES 
Figure 1: 
Study Design .................................................................................................................9 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation  
Definition 
ADA 
Antidrug antibodies 
ACE 
Angiotensin-converting enzyme 
AE 
Adverse event 
AECI 
Adverse event of clinical interest 
ALN-CC5 
Cemdisiran 
ALT 
Alanine transaminase 
ARB 
Angiotensin II receptor blocker 
AST 
Aspartate transaminase 
AUC 
Area under the concentration curve 
BMI 
Body mass index 
C3 
Complement component 3 
C3a 
Activated complement 3 
C5 
Complement component 5 
C5a 
Activated complement component 5 
CAP 
Complement alternative pathway 
CCP 
Complement classical pathway 
CFH 
Complement factor H 
CI 
Confidence interval 
CIC 
Circulating immune complexes 
CL/F 
Clearance 
Cmax 
Maximum concentration 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
ELISA 
Enzyme linked immunosorbent assay 
EOS 
End of study 
EOT 
End of treatment 
ESRD 
End-stage renal disease 
GalNAc 
N-acetylgalactosamine 
GCP 
Good Clinical Practice 

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Abbreviation  
Definition 
Gd-IgA1 
Galactose-deficient Immunoglobulin A 1 
GFR 
Glomerular filtration rate 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
Hib 
Haemophilus influenzae type b 
HIV 
Human immunodeficiency virus 
hpf 
High powered field 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonisation 
IEC 
Independent Ethics Committee 
IgA 
Immunoglobulin A 
IgG 
Immunoglobulin G 
IgAN 
IgA Nephropathy 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRS 
Interactive Response System 
ISR 
Injection site reaction 
IV 
Intravenous 
LFT 
Liver function test 
MAC 
Membrane attack complex 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified intent-to-treat 
mRNA 
Messenger RNA 
NHP 
Nonhuman primates 
O-GalNAc 
O-linked monosaccharide N-acetylgalactosamine 
OLE 
Open-label extension 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic(s) 
PNH 
Paroxysmal nocturnal hemoglobinuria 
RAS 
Renin-angiotensin system 
RBC 
Red blood cell 

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Abbreviation  
Definition 
RNAi 
RNA interference 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous(ly) 
siRNA 
Small interfering RNA 
SUSAR 
Suspected unexpected serious adverse reaction 
t½ 
Terminal half-life 
Tmax 
Time to maximum concentration 
TMF 
Trial Master File 
Tri-GalNAc 
Triantennary N-acetylgalactosamine 
UP 
Urine protein 
UACR 
Urine albumin/creatinine ratio 
ULN 
Upper limit of normal 
UPCR 
Urine protein/creatinine ratio 
V/F 
Volume of distribution 
 

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1. 
INTRODUCTION 
1.1. 
Disease Overview 
Globally, immunoglobulin A nephropathy (IgAN) is the most common primary 
glomerulonephritis that can progress to renal failure.[Lai 2016; Wyatt 1998]  While the exact 
pathogenesis of IgAN is incompletely understood, biochemical, genetic, and clinical data suggest 
IgAN is an autoimmune disease that may originate from overproduction of aberrantly 
O-glycosylated IgA1 and the presence of glycan-specific IgA and immunoglobulin G (IgG) 
autoantibodies that recognize the galactose-deficient IgA1 molecule (Gd-IgA1), resulting in the 
formation of pathogenic immune complexes.  Some of these circulating complexes may deposit 
in glomeruli and induce renal injury.[Knoppova 2016]  The lack of galactose exposes O-linked 
monosaccharide N-acetylgalactosamine (O-GalNAc) moieties in the hinge region of 
IgA1.[Novak 2018]  While the binding of autoantibodies to Gd-IgA1 is dependent on the 
presence of multiple O-GalNAc residues, the IgA1 protein backbone and the spatial arrangement 
of O-GalNAc moieties are also thought to play a role in the specificity of autoantibodies to 
Gd-IgA1.[Mestecky 2016; Suzuki 2009] 
Both the alternative and lectin complement pathways may be activated, leading to generation of 
the anaphylatoxins activated complement component 3 (C3a) and activated complement 
component 5 (C5a) and the membrane attack complex (MAC) C5b-9, with subsequent 
promotion of inflammatory mediators.[Maillard 2015]  Emerging data indicate that 
mesangial-derived mediators that are released following deposition of IgA1 may lead to 
podocyte and tubulointerstitial injury. 
Given that a biopsy specimen is required to diagnose IgAN, the clinical threshold for performing 
a biopsy will have a major impact on the prevalence of IgAN.  Persistent microscopic hematuria 
alone and/or mild proteinuria alone are not commonly used as a per cause indication for biopsy 
in the United States.  Thus, the prevalence of IgAN is modest in the United States (10 to 20% of 
primary glomerulonephritis), higher in some European countries (20 to 30%), and highest in 
developed countries in Asia (40 to 50%).[Woo 2010]  This considerable geographical variability 
can be explained by several factors, including the variation in access to primary care enabling 
early diagnosis and the differences in policies for performing renal biopsies as well as for early 
referrals.  For example, in some countries, urine screening tests are conducted in schools or for 
military service or ahead of employment, explaining the apparent high incidence.[Imai 2007; 
Wyatt 1998]  Ethnic differences can also contribute to the varying prevalence of IgAN.  
Genome-wide association studies have identified candidate genes as well as risk-associated and 
protective alleles, with the highest number of risk alleles present in individuals of East Asian 
origin and the lowest number in those from Africa.[Kiryluk 2014]  These genes are involved in 
antigen presentation, the mucosal defense system, and, notably, the alternative complement 
pathway (complement factor H [CFH]/CFHR locus).[Kiryluk 2014]  Finally, patients may 
present at any age with IgAN but there is a peak incidence in the second and third decades of 
life.  Most cases of IgAN occur in sporadic (90 to 95%) rather than in familial patterns (5 to 
10%).[Lai 2016] 
Routine screening for IgAN is not feasible given that no specific diagnostic laboratory tests are 
available.  The first indication for making a diagnosis comes after careful microscopic 
examination of a urine sample.  The presence of red blood cell (RBC) casts and dysmorphic 

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RBCs indicates glomerular bleeding.  Varying degrees of proteinuria are present in patients with 
IgAN.  Proteinuria can be quantified with a timed urine collection or a spot urine protein to 
creatinine ratio (UPCR) measurement.  Hence, IgAN can only be diagnosed definitively upon 
renal biopsy and study of kidney tissue using immunofluorescence.  The pathology of IgAN is 
characterized by deposition of pathogenic polymeric IgA1 immune complexes and C3 in the 
glomerular mesangium, proliferation of mesangial cells, increased synthesis of extracellular 
matrix, and variable infiltration of macrophages, monocytes, and T cells.  A consensus on the 
pathologic classification of IgAN has been developed by the International IgA Nephropathy 
Network in collaboration with the Renal Pathology Society (Oxford classification).[Lai 2016; 
Working Group of the International Ig 2009a; Working Group of the International Ig 2009b] 
The clinical presentation of patients with IgAN is highly variable, ranging from asymptomatic 
microscopic hematuria to a rapidly progressive form of glomerulonephritis which is often 
associated with severe hypertension, but between these extremes, most patients with IgAN 
pursue a chronic indolent course.[Lai 2016]  Some patients present with more severe proteinuria, 
hypertension, and renal progression over time, typically reaching end-stage renal disease (ESRD) 
over a span of 20 years.  Thus, the severity of proteinuria upon presentation has significant 
prognostic implications.  More importantly, the change in proteinuria over time is being regarded 
as the current best prognostic indicator:  those who had heavy time averaged proteinuria and 
achieved a partial remission of <1 g/24-hours had a similar course to those who had 
<1 g/24-hours throughout and fared far better than those who never achieved partial 
remission.[Reich 2007]  These observations support the notion that every effort should be made 
to reduce proteinuria in IgAN.  In addition to the degree of proteinuria, baseline renal function 
and the degree of histological injury are of prognostic value.  For example, patients with an 
estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 at the time of renal biopsy have 
worse outcomes than those with normal eGFR (90 to 120 mL/min/1.73 m2).  The rate of 
glomerular filtration rate (GFR) decline also correlates with glomerulosclerosis and tubular 
atrophy or interstitial fibrosis on biopsy as outlined by Oxford-MEST-C classification.  
Spontaneous full recovery in IgAN is rare in adults, especially if associated with significant 
proteinuria (>0.5 g/24-hour).[Knoop 2017] 
Patients with minor urine abnormalities, normal blood pressure, and normal GFR usually do well 
and require only monitoring.  For other patients, the therapeutic options are limited and include 
nonspecific treatment to reduce blood pressure and proteinuria by renin-angiotensin system 
(RAS) blockade.  Thus, no disease-specific therapies are currently available, and an unmet need 
persists for novel interventions, particularly in patients who are at risk of progressive disease that 
can result in end-stage renal failure.  The optimal role of immunosuppressive therapy is 
uncertain.  The available studies are not conclusive since most are relatively small and have 
limited follow-up.[Lai 2016]  STOP-IgAN, a German trial, randomly assigned adults with an 
eGFR of >30 mL/min/1.73 m2 and persistent proteinuria of >0.75 g/24-hour despite 6 months of 
supportive care with RAS inhibitors to receive supportive care alone or supportive care plus 
immunosuppression (prednisone alone for those with initial GFR >60 mL/min and prednisone 
combined with cyclophosphamide then azathioprine with initial GFR 30 to 59 mL/min).  This 
strategy did not significantly improve the renal outcome and was associated with increased 
adverse effects at 36 months.[Rauen 2015]  The TESTING trial demonstrated some GFR effect 
of steroids in Chinese patients, but had to be stopped due to large number of serious adverse 
events (SAEs) in the steroid arm.[Lv 2017]  The 2012 KDIGO guidelines recommend 

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corticosteroids, albeit at very low level of evidence.  Thus, steroids may be tried in some cases as 
rescue therapy if proteinuria markedly increases or GFR rapidly falls.  Further studies to address 
the role of steroids in IgAN are currently under way.  Finally, Rituximab seems to be ineffective 
in the treatment of patients with progressive IgAN.[Lafayette 2016] 
1.2. 
Cemdisiran 
Alnylam Pharmaceuticals, Inc. is developing cemdisiran (ALN-CC5), a synthetic RNA 
interference (RNAi) therapeutic designed to suppress liver production of C5 protein, for the 
treatment of IgAN.  Cemdisiran comprises a small interfering RNA (siRNA) targeting C5 
messenger RNA (mRNA) that is covalently linked to a triantennary N-acetylgalactosamine (Tri-
GalNAc) ligand.   
RNAi is a naturally occurring cellular mechanism for regulating gene expression that is mediated 
by siRNAs.  Synthetic siRNAs are short (19 to 25 base pairs), double-stranded oligonucleotides 
in a staggered duplex with an overhang at one or both 3-prime ends.  Such siRNAs can be 
designed to target the mRNA transcript of a given gene.  When formulated for tissue delivery 
and introduced into cells, the guide (or antisense) strand of the siRNA loads into an enzyme 
complex called the RNA-induced silencing complex.  This enzyme complex subsequently binds 
to its complementary mRNA sequence, mediating cleavage of the mRNA and the suppression of 
the target protein encoded by the mRNA.[Elbashir 2001]  Since unmodified siRNAs are rapidly 
eliminated and do not achieve significant tissue distribution upon systemic administration 
[Soutschek 2004], various formulations are currently used to target their distribution to tissues, 
and to facilitate uptake of siRNAs into the relevant cell type.  One approach that has been used 
successfully in vivo in animal models (including in rodents and nonhuman primates [NHP]) and 
humans employs intravenous (IV) delivery of siRNA in lipid nanoparticle 
formulations.[Soutschek 2004; Zimmermann 2006]  Another approach for liver-specific gene 
silencing is subcutaneously (SC) administered siRNA conjugated to an N-acetylgalactosamine 
(GalNAc) carbohydrate ligand.[Ashwell and Morell 1974]  Conjugation of a Tri-GalNAc ligand 
to an siRNA enables hepatocyte binding and subsequent cellular uptake via the 
asialoglycoprotein receptor, resulting in engagement of the RNAi pathway and downregulation 
of hepatic proteins. 
Cemdisiran (containing siRNA drug substance, ALN-62643, targeting C5 mRNA) is a synthetic 
investigational RNAi therapeutic designed to suppress liver production of C5 protein, when 
administered via SC injection.  C5 is encoded by a single gene and is expressed and secreted 
predominantly by hepatocytes.  Through the mechanism of RNAi, the cemdisiran siRNA enables 
the downregulation of C5 mRNA in the liver, thereby reducing levels of circulating C5 protein 
and resulting in inhibition of terminal complement pathway activity and prevention of MAC 
formation and C5a release.  This in turn would be expected to reduce mesangial cell proliferation 
and tissue injury in patients with IgAN resulting in renal function improvement.[Maillard 2015]  
Both lectin and alternative pathways of complement have been implicated in IgAN pathology.  
Cemdisiran-mediated silencing of C5 will inhibit MAC formation and C5a release regardless of 
the activating pathway and may be a superior approach in IgAN where the contribution of 
different pathways may be heterogenous between patients.[Medjeral-Thomas 2018] 
The safety of reducing C5 is supported by clinical precedence of C5 inhibition with eculizumab 
treatment and the absence of any phenotypic abnormalities, other than an increased susceptibility 

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to Neisserial infections, in subjects with known genetic C5 deficiencies.[Ross and Densen 1984]  
Subjects with known C5 deficiencies are generally healthy apart from an increased susceptibility 
to Neisserial infections.  These infections include invasive meningococcal disease, disseminated 
gonococcal infections as well as diseases caused by typically commensal Neisseria 
species.[Crew 2019a; Crew 2019b; McQuillen and Ram 2019; Ram 2010]  In addition, safety 
data on the treatment of healthy volunteers and patients with paroxysmal nocturnal 
hemoglobinuria (PNH) with cemdisiran in Study ALN-CC5-001 indicate that cemdisiran is 
generally well-tolerated; the maximum tolerated dose was 900 mg.  There were no SAEs or 
discontinuations due to adverse events (AEs) during this study, and most AEs were mild or 
moderate in severity.  In Study ALN-CC5-001, the frequency of anti-drug antibodies (ADA) was 
low.  Two of 48 healthy volunteers (1 cemdisiran-treated and 1 placebo-treated) were ADA 
positive during the study.  The cemdisiran-treated volunteer had transient ADA positivity, with a 
negative result later in the study and no impact on pharmacokinetics (PK) or pharmacodynamics 
(PD).  The placebo-treated volunteer was ADA positive at baseline (predose) and remained 
positive through Day 70.  
A detailed description of the chemistry, pharmacology, nonclinical PK and toxicology, as well as 
preliminary efficacy and safety of cemdisiran is provided in the current edition of the 
Investigator’s Brochure (IB). 
1.3. 
Study Design Rationale 
In contrast to the RBC lysis which characterizes the pathophysiology of PNH, which requires 
extremely high level of C5 inhibition for protection, mesangial cells are the cellular targets of 
dysregulated complement in IgAN.  These cells are nucleated cells which possess complement 
regulatory proteins as well as the ability to shed membrane associated MAC to defend against 
MAC-mediated damage, a key step in renal damage in IgAN.  It is therefore hypothesized that a 
lesser degree of cemdisiran-mediated C5 knockdown will be required for disease control in 
patients with IgAN than in patients with PNH.[Morgan 1989; Rosse 1973]  This hypothesis is 
supported by the observation that atypical hemolytic uremic syndrome patients who achieve C5 
inhibition maintain good disease control despite complement activity levels consistent with 
higher free C5 levels.[Cugno 2014]  Therefore, cemdisiran monotherapy may be a viable 
treatment option in patients with IgAN at levels of C5 silencing achieved in Study ALN-CC5-
001. 
This therapeutic hypothesis will be tested in a multicenter, multinational, double-blind, 
placebo-controlled study to evaluate the effect of multiple doses of cemdisiran given by SC 
injection in patients with IgAN with persistent proteinuria (≥1 g/24-hours) despite the standard 
of care (angiotensin converting enzyme inhibitors [ACE] or angiotensin II receptor blockers 
[ARB]) and additional medications if necessary for blood pressure control followed by a 
treatment extension to evaluate long-term safety and clinical activity.  The study population has 
been selected based on two major factors: 1) the severity of proteinuria upon presentation has 
significant prognostic implications.[Coppo and D'Amico 2005]  IgAN patients with heavy 
proteinuria ≥1 g/24-hours have a significantly worse renal outcome than those who have 
proteinuria <1 g/24-hours.[Reich 2007]  2) For patients with persistent proteinuria, despite the 
nonspecific treatment to reduce blood pressure and proteinuria by RAS blockade, no 
disease-specific therapies are currently available, and an unmet need persists for novel 

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interventions.  Since proteinuria can result both from active inflammation as well as irreversible 
scarring of renal tissue and in lieu of a protocol biopsy, the study will enrich our patients for 
presence of potentially reversible disease activity by requiring presence of hematuria and 
relatively preserved renal function with eGFR >30 mL/min.  To ensure the selection of patients 
who are truly at risk of progression of kidney disease despite standard of care, the first period of 
the study consists of a run-in period during which patients will not receive study drug 
(cemdisiran or placebo).  The run-in period will be an observational period during which 
patients’ treatment with standard of care, blood pressure, kidney function, degree of hematuria, 
and proteinuria will be documented.  The standard of care is expected to remain unchanged 
during this run-in period.  Only patients whose  
• proteinuria level remains ≥1 g/24-hours within 2 weeks before the end of the run-in 
period,  
• continue to meet blood pressure and eGFR criteria  
will be eligible to enroll in the 36-week treatment period (defined as the time the first dose of 
study drug is administered on Study Day 1 through completion of the Week 36 assessments) 
portion of the study. 
Randomization to cemdisiran or placebo will be performed in a 2:1 ratio so that more patients 
will receive cemdisiran.  This will allow a more precise estimation of the effect of cemdisiran 
with only marginal loss of power.  Inclusion of a placebo arm will allow better assessment of 
safety and interpretation of the efficacy of cemdisiran. 
The primary endpoint for the study is percent change from baseline in 24-hour UPCR at 
Week 32.  This is justified for a Phase 2 study given the slow progression of renal disease and 
the established role of proteinuria as a marker of disease progression. 
1.4. 
Dose Rationale 
In the Phase 1/2 Study (ALN-CC5-001), 32 healthy volunteers were treated with single SC doses 
of cemdisiran ranging from 50 mg to 900 mg, 24 healthy volunteers were treated with multiple 
doses of cemdisiran ranging from 100 mg to 600 mg (dosing weekly, every other week, or 
monthly), and 6 patients with PNH were treated with cemdisiran at cumulative doses of 3200 mg 
to 4200 mg (eculizumab-naïve patients) and 1200 mg to 2400 mg (patients on background 
eculizumab treatment).  Treatment with cemdisiran was generally well-tolerated in both healthy 
volunteers and patients with PNH.  There were no SAEs and no discontinuations due to AEs 
during this study, including at the highest doses administered.  Most AEs observed were mild or 
moderate in severity. 
Dose selection for the current study is based on the expected level of C5 and complement 
activity inhibition necessary for efficacy in patients with IgAN and the extent to which different 
doses of cemdisiran can inhibit production of C5.  C5 silencing is a novel approach for the 
treatment of IgAN and little clinical precedent exists for inhibiting the terminal complement 
pathway in this disease.  Since complement regulation is not impaired in IgAN like it is in PNH, 
and the kidney glomerular cells are nucleated cells, it is expected that the level of silencing 
needed for efficacy in IgAN is lower than that needed for PNH (see IB Section 2.4).  For this 
proof-of-concept study, a dose was selected that is expected to produce rapid and robust C5 
suppression and complement activity inhibition across the patient population, allowing an 

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unambiguous evaluation of whether C5 silencing results in proteinuria improvement in IgAN.  In 
Study ALN-CC5-001, a single dose of 600 mg cemdisiran achieved a C5 level of 
12.3±1.47 μg/mL by Day 14 and 2.3±0.76 μg/mL by Day 56, corresponding to 60.9% reduction 
in complement alternative pathway (CAP) activity and a 69.3% reduction in complement 
classical pathway (CCP) activity by Day 14 and 90.2% and 91.4% reduction in CAP and CCP 
activities, respectively, by Day 56.  Single and multiple biweekly doses of 600 mg were 
well-tolerated with an acceptable safety profile in healthy volunteers in Study ALN-CC5-001A.  
In this initial study, the cemdisiran dose of 600 mg that was safe and well-tolerated was chosen 
for evaluation.  This dose will yield robust C5 silencing and will have maximal opportunity to 
produce a meaningful clinical effect in patients with IgAN.  Since the relationship between C5 
levels and complement activity is non-linear, with small C5 fluctuations resulting in a larger 
increase in complement activity, a monthly dose regimen was selected to maintain a constant 
level of C5 silencing.  Additionally, a more consistent effect of cemdisiran on C5 protein and 
CCP level is predicted after monthly dosing when compared to quarterly dosing based on a 
modeling approach.   
During the open-label extension (OLE) period, patients treated with both cemdisiran and placebo 
will have the option to receive a 600 mg dose of cemdisiran every four weeks for up to an 
additional 152 weeks. 
IgAN can result in progressive renal impairment; however, patients with severe renal impairment 
(eGFR<30 mL/min/1.73 m2) who may have sustained irreversible damage to the kidney are not 
eligible for participation in this trial.  As the kidney is not the major elimination pathway for 
cemdisiran and based on available nonclinical and clinical data obtained with cemdisiran (with 
10.6 to 31.6% of the cemdisiran dose recovered in a 24-hour urine collection in the 
ALN-CC5-001 study), it is expected that moderate renal impairment 
(eGFR<60 mL/min/1.73 m2) will not affect the PK of cemdisiran to the extent that a dose 
adjustment would be required.  Therefore, patients with moderate renal impairment are eligible 
for study enrollment.  More information on urine PK can be found in the IB.   
1.5. 
Benefit-Risk Assessment 
To date, no medications have been approved specifically for the treatment of IgAN.  Therefore, 
there is a large unmet need for novel interventions, particularly in patients who are at risk of 
progressive renal disease such as those with persistent proteinuria despite treatment with RAS 
inhibitors.  Available data from studies on the role of immunosuppressive therapy in IgAN are 
not conclusive as most are relatively small and have limited follow-up.[Lai 2016]  Use of 
immunosuppressive drugs and high-dose steroids are also associated with increased AEs which 
is particularly common in patients with lower GFR.[Sarcina 2016] 
Given the biological target of cemdisiran, the available nonclinical and clinical data, and mode of 
administration, important potential risks for cemdisiran are infections, liver function test (LFT) 
abnormalities, and injection site reactions (ISRs).  C5 inhibition is associated with increased 
susceptibility for Neisserial infections (including disseminated gonococcal infections) and the 
potential risk of other infections, particularly those due to encapsulated bacteria including 
Streptococcus pneumoniae and Haemophilus influenzae type b (Hib), as well as Aspergillus in 
immunocompromised and neutropenic patients.  Therefore, prior immunization against N. 
meningitidis using meningococcal group ACWY conjugate vaccine and meningococcal group B 

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vaccine are required.  Patients will be instructed to contact the study site if any early signs of 
meningococcal infections are experienced.  In addition, patients with functional or anatomic 
asplenia will be excluded and only patients previously vaccinated or who agree to receive 
vaccination for Hib and Streptococcus pneumoniae according to current national/local 
vaccination guidelines at screening will be enrolled.  Investigators in Study ALN-CC5-005 
should educate patients on the risk of disseminated gonococcal infection and encourage safe sex 
practices.  All national/local screening recommendations for gonorrhea in the general population 
should also be followed.  Finally, given the reported evidence of a higher risk of disseminated 
gonococcal infections with treatment with eculizumab, Investigators are encouraged to evaluate 
any patient who has a Neisseria gonorrhoeae infection for the signs and symptoms of 
disseminated infection.[Crew 2019a; McQuillen and Ram 2019]  No cases of Neisserial infection 
or other infections due to encapsulated bacteria were observed in healthy volunteers or in 
patients with PNH (Study ALN-CC5-001). 
As cemdisiran is targeted for delivery to the liver, patients will be closely monitored for changes 
in LFTs and patients with a medical history or evidence of chronic liver disease or cirrhosis will 
be excluded.  Criteria for dose withholding and stopping of cemdisiran are provided in 
Section 5.2.3.1.  Patients will also be monitored for the development of ISRs and rotation of 
injection site is recommended during the study.   
Considering anti-glycan autoantibodies recognizing Gd-IgA1 are implicated in the pathogenesis 
of IgA nephropathy, exposure to the GalNAc moiety of cemdisiran may pose a theoretical risk of 
stimulating the production of pathogenic autoantibodies and immune complexes in patients with 
IgA nephropathy.  This could presumably occur when ADAs to cemdisiran’s Tri-GalNAc 
cross-react with Gd-IgA1.  The risk of developing these cross-reactive antibodies is likely low.  
This is based on the low incidence of ADA to cemdisiran in study ALN-CC5-001 (see 
Section 1.2) and the distinct difference in structure of the O-GalNAc moieties on a Gd-IgA1 
glycoprotein and the Tri-GalNAc moiety in cemdisiran.  This low risk is further mitigated by 
excluding patients with confirmed pre-existing IgG/IgM/IgA ADAs to total drug and real time 
monitoring for development of de novo IgG/IgM/IgA ADAs after dosing with cemdisiran.  
Patients with confirmed de novo ADAs will be discontinued from study drug but will continue to 
be monitored until the End of Study (EOS) visit and subsequent safety follow-up.  Patients who 
develop positive ADAs will be followed until ADA titers return to baseline.  Additional ADA 
samples will also be collected if any clinical evidence of progression of IgAN disease and/or 
relevant safety findings.  
Detailed information about the known and expected benefits and risks of cemdisiran and 
additional information on the clinical and nonclinical data may be found in the current version of 
the IB. 
Cumulatively, clinical data regarding the role of complement pathways in IgAN progression, 
robust nonclinical and clinical data with cemdisiran (see IB for more information), and prior and 
ongoing clinical experience with other RNAi therapeutics in humans suggest cemdisiran will 
have a favorable risk profile in the intended population and supports the initial clinical 
development of cemdisiran in IgAN.  In addition, cemdisiran may address the unmet medical 
need for the first efficacious and disease-specific treatment for patients with IgAN. 

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• 
To assess the incidence of antidrug 
antibodies (ADA) 
• Change from baseline in the urine 
albumin/creatinine ratio (UACR) as 
measured in 24-hour urine at Week 32 
• Change from baseline in C5 level over 
the course of the study 
• Change from baseline in complement 
activity (Complement Alternative 
Pathway [CAP] and Complement 
Classical Pathway [CCP]) over the 
course of the study 
• Evaluation of area under the curve 
(AUC), maximum plasma 
concentration (Cmax), time to 
maximum plasma concentration 
(Tmax), terminal half-life (t½), 
clearance (CL/F), volume of 
distribution (V/F), cumulative amount 
excreted unchanged in urine (Ae) and 
percent of dose excreted in the urine 
(fe) of cemdisiran (25-mer) and 23-
mer 
• Evaluation of AUC, Cmax, Tmax, t½, 
CL/F, V/F, Ae and fe of 22-mer 
AS(N-1)3’ 
• Change from baseline in levels of 
renal damage, complement activation 
and inflammation markers over the 
course of the study 
• 
Incidence of antidrug antibodies 
(ADA) 

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3. 
INVESTIGATIONAL PLAN 
3.1. 
Summary of Study Design 
This is a multicenter, double-blind, placebo-controlled study comprised of three periods 
(Figure 1).  The first period of the study is an observational 14-week run-in period during which 
patients’ blood pressure, kidney function, degree of hematuria, and proteinuria will be measured.  
Patients will not receive study drug (cemdisiran or placebo) during this time.  The standard of 
care is expected to remain unchanged during this run-in period.  The second study period is a 
36-week treatment period which will evaluate the efficacy and safety of SC cemdisiran 
compared to SC placebo in combination with standard of care in patients with IgAN and 
persistent proteinuria.  The third period of the study is a 156-week optional OLE period to 
further evaluate the long-term safety and clinical activity of cemdisiran.  During the OLE, all 
patients (including those initially on placebo) will be treated with cemdisiran in combination 
with standard of care. 
The study will include a Screening period of up to 120 days to determine eligibility of patients 
and to complete disease-related assessments.  The Investigator will notify the Sponsor before 
screening patients to allow an assessment of the ability of the site and new trial participants to 
comply with the protocol given limitations during the COVID-19 pandemic.  Patients will 
provide written informed consent and visit the study site approximately 2 weeks before starting 
the run-in period to complete the protocol screening assessments.  Following successful 
screening, the 14-week run-in period will commence, during which patients’ blood pressure, 
kidney function, degree of hematuria, and proteinuria as well as treatment with standard of care 
will be documented by the Investigator.  The standard of care is expected to remain unchanged 
during this run-in period.  Patients whose proteinuria level remains ≥1 g/24-hours within 2 weeks 
of the end of the run-in period, and who meet blood pressure and eGFR criteria will be eligible to 
enroll in the 36-week treatment period.  Upon confirmation of eligibility followed by vaccination 
against meningococcal infections, patients will be randomized at a 2:1 ratio to receive 600 mg of 
cemdisiran or placebo every 4 weeks in combination with standard of care.  Approximately 
30 patients are planned to be randomized in total, 20 in the cemdisiran arm and 10 in the placebo 
arm.  Patients excluded before randomization will be replaced at screening.  
During the run-in period, patients will visit the study site 14, 8, and 2 weeks prior to 
randomization (Weeks 0, 6, and 12 of the run-in period).  If a run-in visit cannot proceed 
according to schedule, it may be delayed up to 28 days, with subsequent visits being rescheduled 
based on the new date.  Visit windows, as indicated in the Schedule of Assessments (Table 1), 
are applied to the rescheduled date.  Approval from the Medical Monitor is required prior to 
initiation of the treatment period.  If a patient cannot proceed to the treatment period as planned, 
the run-in period can be extended as needed.  If the final run-in visit will not be within 56 days of 
randomization, this visit will be repeated, and the new visit will serve as the Week -2 visit to 
determine eligibility for randomization.   
Study drug administration can be conducted at the study site or by a healthcare professional at a 
location other than the study site (eg, at home) from Week 4 of the treatment period for patients 
that have tolerated the study drug at the study site.  If the patient is unable to come to the study 
site, and a visit by a healthcare professional for patients at a location other than the study site (eg, 
at home) is not possible due to circumstances related to the COVID-19 pandemic, study drug 

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may be administered by the patient or caregiver under the oversight of the Investigator, and in 
consultation with the Medical Monitor, as allowed by applicable country and local regulations.  
In such cases, the patient or the caregiver must receive appropriate training on study drug 
administration prior to dosing.  This measure is intended to remain in effect only during periods 
of time when the COVID-19 pandemic impedes the ability of patients to travel to the study site 
or healthcare professionals to go to a location other than the study site (eg, at home) for dosing.  
The primary endpoint will be assessed at the end of treatment at Week 32. 
At the end of treatment (Week 32), patients in the two treatment arms may enter the optional 
OLE period where they will receive cemdisiran at a dose of 600 mg every 4 weeks in 
combination with standard of care for up to an additional 152 weeks (approximately 3 years).  If 
deemed necessary, the Investigator or Sponsor may shorten the time of the OLE period due to 
safety or administrative reasons.  For patients who do not enter the OLE period, an End of Study 
(EOS) visit will occur at Week 36 and the patient will then enter the 52-week safety follow-up 
period (Table 1). 
The first study drug administration of the OLE will be administered at the study site at Week 36.  
From Week 40 onward in the OLE period (with the exception of the End of Treatment [EOT] 
and End of Study/Early Termination [EOS/ET] visits), study procedures (including cemdisiran 
administration) may be performed by a healthcare provider at a location other than the study site, 
at the discretion of the Investigator, with no more than 6 months between study site visits 
(Table 2, Table 3, and Table 4).  Patients may be required to visit the study site more frequently, 
as judged necessary by the Investigator or if visits at a location other than the study site (eg, at 
home) cannot be arranged.  If a visit by a healthcare professional for patients at a location other 
than the study site (eg, at home) is not possible, study drug may be administered by the patient or 
caregiver under the oversight of the Investigator, and following consultation with the Medical 
Monitor, as allowed by applicable country and local regulations.   
An EOT visit will occur at Week 184 (OLE EOT) and an EOS or Early Termination (ET) visit 
will be completed at Week 188 (OLE EOS/ET).  The EOT and EOS/ET visits will be performed 
at the study site.  For patients who complete the treatment period only who do not consent to 
continue to participate in the study in the OLE period, the EOS/ET visit will be at Week 36. 
Patients will return to the clinical study site for safety follow-up visits approximately 13, 26, 39, 
and 52 weeks after the EOS/ET visit (regardless if EOS/ET visit is at Week 36 or Week 188), 
unless enrolled in another study with cemdisiran.  Visits at a location other than the study site 
(eg, at home), where locally feasible, may be arranged during safety follow-up at 13 and 39 
weeks after the EOS/ET visit (regardless if EOS/ET visit is at Week 36 or Week 188). 
Regular reviews of safety and tolerability data will be performed by an independent data 
monitoring committee (DMC) throughout the study with the primary purpose of protecting the 
safety of participating patients and the integrity of the study. 
3.2. 
Duration of Treatment  
Subcutaneous doses of cemdisiran or matching placebo will be administered every 4 weeks over 
a period of 32 weeks during the 36-week treatment period and patients will receive 600 mg SC 
doses of cemdisiran for up to 152 additional weeks in the optional 156-week OLE.  

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3.3. 
Duration of Study 
The maximum estimated total time on study, inclusive of screening (maximum of 120 days), 
run-in period (14 weeks), treatment period (36 weeks), optional OLE period (156 weeks) and 
safety follow-up (52 weeks), is approximately 63 months or 5 years and 4 months. 
3.3.1. 
Definition of End of Study for an Individual Patient 
A patient is considered to have reached the end of the study if the patient has completed the EOS 
visit (Week 36 for those patients who do not consent to continue to participate in the study in the 
OLE period and Week 188 for patients who enter the OLE period).  Upon study completion 
(regardless if EOS visit is at Week 36 or Week 188) patients will enter a safety follow-up period 
with visits scheduled at intervals of 13 weeks. 
For patients withdrawing from the study after receiving one dose of cemdisiran at a minimum 
(ET), all efforts should be made to conduct the EOS/ET assessments.  Patients should then be 
encouraged to enter the safety follow-up period. 
3.4. 
Number of Planned Patients 
Approximately 30 patients are planned for randomization in this study. 
3.5. 
Method of Assigning Patients to Treatment Groups 
Using the Interactive Response System (IRS), patients will be randomized 2:1 to the cemdisiran 
or placebo arms.  Randomization will be stratified by baseline urine proteinuria levels (≥1 g/24h 
and <2 g/24h versus ≥2 g/24h). 
Each patient will be uniquely identified in the study by a combination of the site number and 
patient identification number.  Upon signing the informed consent form (ICF), the patient will be 
assigned a patient identification number by the IRS.  The Investigator or his/her designee will 
contact the IRS after confirming that the patient fulfills all the inclusion criteria and none of the 
exclusion criteria at Screening and prior to randomization.  
3.6. 
Blinding 
All site personnel including sponsor delegated clinical research associates, data management 
Contract Research Organization, and patients will be blinded to study drug treatment during the 
efficacy period (up to Week 36).  Sponsor personnel will not be blinded to study treatment.  
Cemdisiran and placebo will be packaged identically.  The study drug will be administered under 
the supervision of the Investigator or at a location other than the study site (eg, at home) by a 
healthcare professional (see Section 5.2.2).  If the patient is unable to come to the study site, and 
a visit by a healthcare professional for patients at a location other than the study site (eg, at 
home) is not possible, study drug may be administered by the patient or the caregiver under the 
oversight of the Investigator, and following consultation with the Medical Monitor, as allowed 
by applicable country and local regulations.  In such cases, the patient or the caregiver must 
receive appropriate training on study drug administration prior to dosing.  Since cemdisiran may 
be visually distinguishable from placebo, the syringe will be masked by the healthcare 
professional.  Syringe masking is not required if study drug is being administered at home by the 
patient or caregiver, as it is not considered a significant risk to unblinding.  See the Pharmacy 

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Manual for additional details.  Further details on blinding and unblinding arrangements will be 
documented in a Randomization and Blinding Plan document. 
3.6.1. 
Emergency Unblinding 
If the treating physician determines that the clinical management of the patient requires 
knowledge of the study drug assignment, the Investigator may break the blind, as necessary.  If 
time permits, clinical study site personnel should contact the Medical Monitor before unblinding 
to discuss the need to unblind the patient but must do so within 1 working day after the 
unblinding event.  A record of when the blind was broken, who was unblinded, who broke the 
blind, and why it was broken, will be maintained in the Trial Master File (TMF). 
Further details on blinding and unblinding arrangements will be documented in a Randomization 
and Blinding Plan document. 
3.7. 
Data Monitoring Committee 
An independent DMC will perform regular reviews of safety, tolerability, and immunogenicity 
data throughout the study with the primary purpose of protecting the safety of participating 
patients and the integrity of the study.  The DMC will operate under the rules of a Charter that 
will be reviewed and approved at the organizational meeting of the DMC.  The DMC will 
perform periodic reviews of unblinded data (safety, tolerability, PD, ADA, circulating immune 
complexes [CIC] and efficacy of cemdisiran) during the clinical trial, and on an ad hoc basis 
review emergent safety data.  Details are provided in the DMC Charter. 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS 
4.1. 
Inclusion Criteria 
Patients are eligible to be included in the study if all the following criteria apply: 
Age and Sex 
1. Male or female ≥18 years and ≤65 years of age at the time of informed consent 
Patient and Disease Characteristics 
2. Clinical diagnosis of primary IgAN as demonstrated by historical biopsy collected within 
60 months of screening 
3. Treated for IgAN with stable, optimal pharmacological therapy.  In general, stable and 
optimal treatment will include maximum allowed or tolerated ACE inhibitor or an ARB 
for at least 3 months prior to start of run-in period. 
4. Urine protein ≥1 g/24-hour at Screening from a valid 24-hour urine collection (see 
Section 6.4.1.1), and mean urine UP ≥1 g/24-hour from two valid 24-hour urine 
collections at the end of the run-in period, prior to randomization  
5. Hematuria as defined by ≥10 RBCs per high powered field (RBC/hpf) by microscopy or 
a positive urine dipstick (2+ [moderate] and above) measured by a central laboratory at 
screening 

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6. Females 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, and for 90 days after last dose 
administration  
7. Previously vaccinated with meningococcal group ACWY conjugate vaccine and 
meningococcal group B vaccine or willingness to receive these vaccinations as well as 
prophylactic antibiotic treatment, if required by local standard of care 
8. Previously vaccinated or willingness to receive vaccinations for Hib and Streptococcus 
pneumoniae according to current national/local vaccination guidelines for vaccination use 
Informed Consent 
9. Patient is willing and able to provide written informed consent and to comply with the 
study requirements 
4.2. 
Exclusion Criteria 
Patients are excluded from the study if any of the following criteria apply: 
Disease-specific Conditions 
1. Concomitant significant renal disease other than IgAN 
2. A diagnosis of rapidly progressive glomerulonephritis as measured by eGFR loss >30% 
over the duration of the run-in phase 
3. Secondary etiologies of IgAN (eg, inflammatory bowel disease, celiac disease) 
4. Diagnosis of Henoch-Schonlein Purpura (IgA Vasculitis) 
5.  eGFR <30 mL/min/1.73 m2 2 weeks prior to randomization (local results may be used 
for assessment of eligibility) 
Laboratory Assessments 
6. Has any of the following laboratory parameter assessments:  
a. Alanine transaminase (ALT) >1.5×upper limit of normal (ULN), International 
Normalized Ratio (INR) >2 (or >3.5 if on anticoagulants), or total bilirubin 
>1.5×ULN (unless bilirubin elevation is due to Gilbert’s syndrome)  
7. Confirmed positive IgG/IgM/IgA ADAs to cemdisiran at screening 
8. Clinical laboratory test results considered clinically relevant and unacceptable in the 
opinion of the Investigator 
9. Positive hepatitis B virus (HBV) surface antigen, HBV core antibody, hepatitis C virus 
(HCV) antibody (unless HCV viral load demonstrated negative) 
Prior/Concomitant Therapy 
10. Treatment with systemic steroids for more than 7 days or other immunosuppressant 
agents in the 6 months prior to randomization 
11. Treatment with dual RAS blockade in the 3 months prior to entry into the run-in phase 

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12. Received an investigational agent within the last 30 days or 5 half-lives, whichever is 
longer, prior to the first dose of study drug, or are in follow-up of another clinical study 
prior to study enrollment 
Medical Conditions 
13. Known human immunodeficiency virus (HIV) infection, HCV infection, or HBV 
infection 
14. Malignancy (except for non-melanoma skin cancers, cervical in situ carcinoma, breast 
ductal carcinoma in situ, or stage 1 prostate cancer) within the last 5 years 
15. Active psychiatric disorder, including, but not limited to schizophrenia, bipolar disorder, 
or severe depression despite current pharmacological intervention 
16. Known medical history or evidence of chronic liver disease or cirrhosis 
17. Has other medical conditions or comorbidities which, in the opinion of the Investigator, 
would interfere with study compliance or data interpretation 
18. History of multiple drug allergies or history of allergic reaction to an oligonucleotide or 
GalNAc 
19. History of intolerance to SC injection(s) or significant abdominal scarring that could 
potentially hinder study drug administration or evaluation of local tolerability 
20. Known contraindication to meningococcal vaccines (group ACWY conjugate and group 
B vaccines) required for this study.  Refer to the most recent local product information 
for each vaccine for the current list of contraindications 
21. Unable to take antibiotics for meningococcal prophylaxis, if required by local standard of 
care 
22. Sustained blood pressure >140/90 mmHg as defined by 2 or more readings during the 
run-in period, measured in supine position after 10 minutes of rest 
23. Receipt of an organ transplant (including hematologic transplant) 
24. History of meningococcal infection within 12 months before Screening 
25.  Patients with systemic bacterial or fungal infections that require systemic treatment with 
antibiotics or antifungals  
26. Patients with functional or anatomic asplenia 
Alcohol Use 
27. Patients who consume more than 14 units of alcohol a week (unit 1 glass of wine 
[125 mL] = 1 measure of spirits [approximately 1 fluid ounce] = ½ pint of beer 
[approximately 284 mL])  
4.3. 
Removal from Therapy or Assessment 
Patients or their legal guardians are free to discontinue study drug and/or stop participation in the 
study at any time and for any reason, without penalty to their continuing medical care.  The 
Investigator or the Sponsor may stop a patient’s participation in the study at any time if this is 

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considered to be in the patient’s best interest.  Any discontinuation of treatment or the stopping 
of the patient’s participation in the study must be fully documented in the electronic case report 
form (eCRF) and should be followed up by the Investigator.   
Discontinuation of study drug is described in Section 4.3.1, while the stopping of a patient’s 
participation in the study is detailed in Section 4.3.2. 
4.3.1. 
Discontinuation of Study Drug or Declining Procedural Assessments 
Reasons for discontinuation of study drug include any of the following: 
• Significant violation of the protocol 
• Adverse event  
• Non-adherence to treatment regimen 
• Pregnancy 
• Lost to follow-up 
• Other reason (non-AE), including confirmed positive test for ADA to cemdisiran 
• Or, study is terminated by the Sponsor 
Patients who are pregnant will be discontinued from study drug dosing immediately (see 
Section 6.7.5.2 for reporting and follow-up of pregnancy).  A positive urine pregnancy test 
should be confirmed by a serum pregnancy test prior to discontinuing study drug. 
Patients who discontinue study drug and/or decline procedural assessments should not be 
automatically removed from study.  In general, patients who discontinue study drug dosing for 
any reason will be encouraged to remain on the study to complete the remaining assessments 
through the Week 36/EOS or Week 188/OLE EOS visit and safety follow-up so that their 
experience is captured in the final analyses.  
If this occurs, the Investigator is to discuss with the patient the appropriate processes for 
discontinuation from study drug and must discuss with the patient the options for continuation of 
the Schedule of Assessments (Table 2, Table 3, and Table 4), including different options for 
follow-up and collection of data (eg, in person, by phone, by mail, through family or friends, or 
from options not involving patient contact, such as communication with other treating physicians 
or from review of medical records), including endpoints and AEs, and must document this 
decision in the patient’s medical records.  
If a patient discontinues dosing due to an AE, including SAEs, the event should be followed as 
described in Section 6.7.6.  When a patient discontinues study drug dosing, the primary reason 
must be recorded in the eCRF.  Patients who discontinue study drug and remain on study may 
receive treatment consistent with local standard practice for their disease per Investigator 
judgement, as applicable.  
Patients who discontinue from study drug during the 36-week treatment period will be 
encouraged to remain on the study and complete assessments through Week 36; they will also be 
asked to complete safety follow-up visits 13, 26, 39 and 52 weeks thereafter (see Table 1).  

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Patients who discontinue study drug during the OLE period will be asked to return for their next 
scheduled visit to complete the OLE EOS/ET assessments; they will also be asked to complete 
safety follow-up visits 13, 26, 39 and 52 weeks thereafter (see Table 4). 
4.3.2. 
Stopping a Patient’s Study Participation 
4.3.2.1. 
Patient or Legal Guardian Stops Participation in the Study 
A patient or their legal guardian may stop participation in the study at any time.  A patient/legal 
guardian considering stopping participation in the study should be informed that they can 
discontinue study drug and/or decline procedural assessments and remain in the study to 
complete their study assessments through the Week 36 visit and the 52-week safety follow-up.  If 
a patient/legal guardian still chooses to discontinue study drug and stop participation in all 
follow-up prior to the completion of the 36-week treatment period, every effort should be made 
to conduct the assessments scheduled to be performed at the Week 36 EOS/ET visit (see Table 
1).   
If the patient does not wish to or is unable to continue further study participation, the Investigator 
is to discuss with the patient appropriate procedures for stopping participation in the study.  Data 
collected from the patient can continue to be used. 
In addition, in the countries where the collection and processing of the patient data is based on 
the patient consent, if a patient withdraws consent to collect and process his/her data (see 
Section 4.3.2.2), as applicable, patient data up to the withdrawal of consent will be included in 
the analysis of the study.  In addition, where permitted, publicly available data (such as 
appropriate national or regional vital status registry or other relevant databases) can be included 
after withdrawal of consent, where available and allowable by local law. 
4.3.2.2. 
Withdrawal of Consent to Process the Patient’s Personal Data  
Where allowed by local law, the patient may decide to withdraw consent to collect, store, and 
use biological samples and, as applicable, other personal data, informing the study doctor at any 
time in writing or in any other form that may be locally required.  The Sponsor will continue to 
keep and use the patient’s study information (including any data resulting from the analysis of 
patient’s biological samples until the time of withdrawal) according to applicable law.  The 
process for the storage and, as applicable, further use of remaining samples will be followed per 
local requirements. 
4.3.2.3. 
Investigator or Sponsor Stops Participation of a Patient in the Study 
The Investigator or Sponsor may stop the participation of a patient in the study at any time if this 
is considered to be in the patient’s best interest.  However, study integrity and interpretation are 
best maintained if all enrolled patients continue study assessments and follow-up even if study 
drug is discontinued. 
Termination of the clinical study and site closure are described in Section 8.1.6. 
4.3.2.4. 
Recording Reason for Stopping a Patient’s Study Participation 
The primary reason that a patient’s study participation is stopped must be recorded in the 
appropriate section of the eCRF and all efforts will be made to complete and report the 

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observations as thoroughly as possible.  If a patient’s study participation is stopped due to an AE, 
including SAEs, the event should be followed as described in Section 6.7.6. 
4.3.3. 
Lost to Follow-Up 
A patient will be considered lost to follow-up if the patient repeatedly fails to return for 
scheduled visits and is unable to be contacted by the clinical study site.  The following actions 
must be taken if a patient misses a required study visit: 
• The site must attempt to contact the patient or legal guardian and reschedule the 
missed visit as soon as possible and counsel the patient or legal guardian on the 
importance of maintaining the assigned visit schedule and ascertain if the patient or 
legal guardian wishes to continue in the study, and/or should continue in the study.  
• Before a patient is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the patient or legal guardian (where possible, 3 
telephone calls and, if necessary, a certified letter to the patient’s last known mailing 
address or local equivalent methods).  These contact attempts should be documented 
in the patient’s medical record. 
• Should the patient or legal guardian continue to be unreachable, the patient will be 
considered to have stopped participation in the study. 
• For patients who are lost to follow-up, the Investigator can search publicly available 
records (where permitted and allowed by local law) to ascertain survival status.  This 
ensures that the outcome of the study is as comprehensive as possible. 
4.3.4. 
Replacement of Study Patients  
Patients who discontinue the study drug or stop participation in the study during the 36-week 
treatment period or the OLE will not be replaced. 
5. 
TREATMENTS AND OTHER REQUIREMENTS 
5.1. 
Treatments Administered 
Study drug supplied for this study must not be used for any purpose other than the present study 
and must not be administered to any person not enrolled in the study.  Study drug that has been 
dispensed to a patient and returned unused must not be re-dispensed to a different patient. 
5.2. 
Study Drug 
Detailed information describing the preparation, administration, and storage of cemdisiran and 
placebo is provided in the Pharmacy Manual. 
5.2.1. 
Description  
Cemdisiran will be supplied as a sterile solution for SC injection that contains 200 mg/mL 
cemdisiran sodium (equivalent to 189 mg/mL of cemdisiran), formulated in water for injection 

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(WFI) for SC administration.  See the Pharmacy Manual for further details of solution 
concentration and fill volume. 
The control drug for this study will be a placebo (sodium chloride 0.9% w/v for SC 
administration).  Placebo will be provided by the Sponsor; it will be packaged identically to 
cemdisiran. 
5.2.2. 
Dose and Administration 
Patients will be administered cemdisiran (600 mg) or placebo (at the same volume as the active 
drug) as an SC injection once every 4 weeks in combination with standard of care in the 32-week 
period of the 36-week treatment period.  During the OLE period, patients will be administered 
cemdisiran at a dose of 600 mg every 4 weeks in combination with standard of care. 
Study drug injections will be administered under the supervision of the Investigator or a 
healthcare professional.  For patients that have tolerated the study drug at the study site, study 
drug administration may be conducted by a healthcare professional at a location other than the 
study site (eg, at home) from Week 4 of the treatment period (with the exceptions of the EOT 
and EOS/ET visits, which must be performed at the study site).  If the patient is unable to come 
to the study site, and a visit by a healthcare professional for patients at a location other than the 
study site (eg, at home) is not possible due to circumstances related to the COVID-19 pandemic, 
study drug may be administered by the patient or the caregiver under the oversight of the 
Investigator, and following consultation with the Medical Monitor, as allowed by applicable 
country and local regulations.  In such cases, the patient or the caregiver must receive 
appropriate training on study drug administration prior to dosing.  This measure is intended to 
remain in effect only during periods of time when the COVID-19 pandemic impedes the ability 
of patients to travel to the study site or healthcare professionals to go to a location other than the 
study site (eg, at home) for dosing.   
From Week 40 onward in the OLE, except for the EOT and EOS/ET visits, study procedures, 
including cemdisiran administration, may occur at a location other than the study site (eg, at 
home) at the discretion of the Investigator, based on safety and tolerability, with no more than 
6 months between study site visits.  If the patient is unable to come to the study site, and a visit 
by a healthcare professional for patients at a location other than the study site (eg, at home) is not 
possible, study drug may be administered by the patient or the caregiver under the oversight of 
the Investigator, and following consultation with the Medical Monitor, as allowed by applicable 
country and local regulations.  In such cases, the patient or the caregiver must receive 
appropriate training on study drug administration prior to dosing.   
The injection site may 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, if permitted.  Detailed 
instructions for study drug administration are found in the Pharmacy Manual.  In addition, 
instructions and procedures related to administration of study drug by a patient or caregiver will 
be provided in the Patient/Caregiver Storage and Administration Instructions. 
5.2.3. 
Dose Modifications 
Dose modifications are not permitted. 

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The visit window for the treatment and OLE periods is ±14 days, but the interval between 
2 doses may not be shorter than 14 days.  If a dose is not administered within 14 days of the date 
determined by the Schedule of Assessments (see Table 1, Table 2, Table 3, and Table 4), then 
the dose is considered missed and should not be given. 
If a study drug-related AE occurs in a patient that the Investigator judges as presenting a 
potential risk to the patient for further dosing, the study drug dose may be held at the discretion 
of the Investigator and the Medical Monitor should be contacted.  In situations where study drug 
is administered at a location other than the study site (eg, at home), or the dose is missed, the 
Investigator (or delegate) will verbally contact the patient to assess any AEs and concomitant 
medications. 
5.2.3.1. 
LFT Criteria for Withholding, Monitoring and Stopping Cemdisiran Dosing   
1. LFT results (Table 7) from the previous collection should be reviewed prior to dosing.  
Central laboratory results are preferable.  If not available, local laboratory results may be 
used; however, if a local assessment is drawn, a serum chemistry sample must also be 
drawn for analysis at the central laboratory.  
2. For any ALT or AST elevation >3×ULN, central laboratory results should be used to 
guide subsequent monitoring as detailed in Table 6.  
a. Confirm using central laboratory, as soon as possible, ideally within 2 to 3 days, but 
no later than 7 days. 
b. Perform assessments per Table 6 and Table 8. 
c. If an alternative cause is found, provide appropriate care. 
3. For any ALT or AST elevation >3×ULN without alternative cause that is accompanied 
by clinical symptoms consistent with liver injury (eg, nausea, right upper quadrant 
abdominal pain, jaundice) or elevated bilirubin to ≥2×ULN or INR ≥1.5, permanently 
discontinue dosing. 
4. For confirmed ALT or AST elevations >3×ULN without alternative cause and not 
accompanied by symptoms or elevated bilirubin ≥2×ULN or INR ≥1.5, see Table 6. 

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Table 6: 
Monitoring and Dosing Rules for Asymptomatic Patients with Confirmed 
Isolated Elevations of ALT and/or AST >3× ULN, with No Alternative Cause 
Identified 
Transaminase Level 
Action 
>3× to 5× ULN 
• 
May continue dosing   
• 
Evaluate the initial elevation in LFT per the following assessments: 
• 
Table 8 (all assessments to be performed once) 
• 
Hematology, serum chemistry, LFT, and coagulation per Table 7 
• 
Monitor at least every two weeks: LFT and coagulation per Table 7 
• 
If elevation persists for ≥2 months, must discuss with the Medical Monitor 
before continuing dosing 
>5× to 8× ULN 
• 
Hold cemdisiran dosing until recovery to ≤1.5×ULN; may resume dosing 
after discussion with the Medical Monitor 
• 
Evaluate the initial elevation in LFT per the following assessments 
• 
Table 8 (all assessments to be performed once) 
• 
Hematology, serum chemistry, LFT, and coagulation per Table 7 
• 
Monitor at least weekly: LFT and coagulation per Table 7 until ALT and/or 
AST is declining on 2 consecutive draws, then may decrease monitoring to 
biweekly 
• 
If ALT or AST rises to >5×ULN following resumption of dosing, 
permanently discontinue dosing 
>8× ULN 
Permanently discontinue dosing after confirmation of the transaminase value 
Abbreviations: ALT=alanine transaminase; AST=aspartate transaminase; LFT=liver function test(s); ULN=upper 
limit of normal. 
Notes:  In addition to these criteria, other assessments or evaluations may be performed per Investigator discretion, 
as appropriate. 
5.2.4. 
Preparation, Handling, and Storage 
Staff at each clinical study site or the healthcare professional performing administration at a 
location other than the study site (eg, at home) will be responsible for preparation of study drug 
doses, according to procedures detailed in the Pharmacy Manual.  In cases where study drug is 
administered at a location other than the study site (eg, at home) by a patient/caregiver, dosing 
may be prepared and administered by the patient/caregiver according to procedures detailed in 
the Patient/Caregiver Storage and Administration Instructions.  No special procedures for the 
safe handling of study drug are required. 
Study drug will be stored upright and refrigerated at approximately 2 to 8°C.  The vial should be 
stored in the carton until ready for use in the storage area of the clinical study site pharmacy, in a 
secure, temperature-controlled, locked environment with restricted access. 
A Sponsor representative or designee will be permitted, upon request, to audit the supplies, 
storage, dispensing procedures, and records. 
Instructions specific to unused study drug and additional storage will be provided in the 
Pharmacy Manual and Patient/Caregiver Storage and Administration Instructions. 

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5.2.5. 
Packaging and Labeling 
All packaging, labeling, and production of study drug will be in compliance with current Good 
Manufacturing Practice specifications, as well as applicable local regulations.  Study drug labels 
and external packaging will include all appropriate information as per local labeling 
requirements.  
Cemdisiran (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. 
Additional details will be available in the Pharmacy Manual. 
5.2.6. 
Accountability 
The Investigator or designee will maintain accurate records of receipt and the condition of the 
study drug supplied for this study, including dates of receipt.  In addition, accurate records will 
be kept of when and how much study drug is dispensed and administered to each patient in the 
study.  Any reasons for departure from the protocol dispensing regimen must also be recorded. 
At the completion of the study, there will be a final reconciliation of all study drugs.  Used, 
partially used, and unused study drug will be returned to the Sponsor (or designee) or destroyed 
at the clinical study site according to applicable regulations. 
Further instructions about drug accountability will be detailed in the Pharmacy Manual. 
5.3. 
Concomitant Medications and Procedures 
The standard of care treatment should be held stable throughout the run-in and treatment periods.  
Use of concomitant medications and procedures will be recorded on the patient’s eCRF as 
specified in the Schedule of Assessments (see Table 1, Table 2, Table 3, and Table 4).  This 
includes all prescription medications, herbal preparations, over the counter medications, 
vitamins, and minerals.  Any changes in medications during the study will also be recorded on 
the eCRF. 
If patients use nonsteroidal anti-inflammatory drugs intermittently or chronically, they must have 
been able to tolerate them with no previous side effects (eg, gastric distress or bleeding).   
Standard vitamins and topical medications are permitted.  However, topical steroids must not be 
applied anywhere near the injection site(s) unless medically indicated.   
For other permitted concomitant medications administered SC, do not administer in same 
injection site area as the study drug, for 7 days after the last dose of study drug.  
Any concomitant medication that is required for the patient’s welfare may be administered by the 
Investigator.  However, it is the responsibility of the Investigator to ensure that details regarding 
the medication are recorded on the eCRF.  Concomitant medication will be coded using an 
internationally recognized and accepted coding dictionary. 
5.3.1. 
Prohibited Concomitant Medications 
The following concomitant medications are prohibited during the study:  

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• Systemic steroids (short-term steroid course for <7 days for common conditions not 
related to IgAN (i.e. asthma, gout) is permitted) 
• Immunosuppressive agents 
• Fish oil supplements (if started prior to Screening, then may continue during the study 
at the same dose) 
• Hydroxychloroquine 
• Creatine supplements 
5.3.2. 
Study-specific Vaccinations 
5.3.2.1. 
Meningococcal Vaccinations 
All patients taking part in this study must be vaccinated against meningitis types A, C, W135, Y 
and B, at least 14 days prior to randomization to cemdisiran or placebo, as per the Schedule of 
Assessments.  Meningococcal group ACWY conjugate vaccine and meningococcal group B 
vaccine will be administered in accordance with the manufacturer’s instructions and according to 
the Advisory Committee on Immunization Practices (ACIP) or other locally applicable 
recommendations for patients with complement deficiencies.  On days of vaccination, urinary 
samples should be collected prior to administration of vaccines.  Revaccination should be 
assessed in accordance with local guidelines throughout the OLE period. 
Patients will be immunized against Neisseria meningitidis according to the following 
specifications: 
• Patients who have previously completed the recommended series of meningococcal 
vaccinations (meningococcal group ACWY conjugate vaccine and meningococcal 
group B vaccine) at least 14 days but no more than 3 years from randomization can 
start study assessments after confirming eligibility.  Documented vaccine history 
must be available to, and verified by, study site staff at the time of Screening. 
• Patients who were previously vaccinated with polysaccharide type vaccines within 
3 years of study entry will be revaccinated using conjugate vaccines per the Schedule 
of Assessments.   
• Patients who have not been previously vaccinated against Neisseria meningitidis, 
those without documentation of vaccination history, or those vaccinated more than 
3 years from study randomization will commence the vaccination series with the 
recommended meningococcal vaccines (meningococcal group ACWY conjugate 
vaccine and meningococcal group B vaccine) per the Schedule of Assessments.   
• If required locally, patients will receive prophylactic antibiotics according to the local 
standard of care after randomization to cemdisiran or placebo. 
5.3.2.2. 
Pneumococcal and Hib Vaccinations 
Patients will receive vaccinations for Hib and Streptococcus pneumoniae, if not previously 
vaccinated, according to current national/local vaccination guidelines for vaccination use.  Hib 
and pneumococcal vaccinations, if required at Screening per national/local guidelines, should be 

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administered at least 14 days prior to randomization.  At Screening, patient vaccination records 
will be checked for compliance with local recommendations for the use of these vaccines. 
Revaccination should be assessed in accordance with local guidelines throughout the OLE 
period. 
5.4. 
Treatment Compliance 
Compliance with study drug administration will be verified through observation by study staff or 
trained healthcare professionals at a location other than the study site (eg, at home). 
5.5. 
Other Requirements 
5.5.1. 
Contraception 
Females of child-bearing potential must be willing to use a highly effective method of 
contraception from 14 days before first dose, throughout study participation, and for 90 days 
after last dose administration or until study completion.   
Birth control methods which are considered highly effective include: 
• Placement of an intrauterine device. 
• Placement of an intrauterine hormone-releasing system.  
• Bilateral tubal occlusion. 
• Surgical sterilization of male partner (with the appropriate post-vasectomy 
documentation of the absence of sperm in the ejaculate; for female patients on the 
study, the vasectomized male partner should be the sole partner for that patient). 
• Established use of oral (except low-dose gestagens), implantable, injectable, or 
transdermal hormonal methods of contraception.  Females of child-bearing potential 
who use hormonal contraceptives as a method of contraception must also use a barrier 
method (condom or occlusive cap [diaphragm or cervical/vault cap] in conjunction 
with spermicide [eg, foam, gel, film, cream, or suppository]).   
• True sexual abstinence, when in line with the preferred and usual lifestyle of the 
patient.  Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception.  Abstinent 
patients must agree to use one of the above-mentioned contraceptive methods if they 
start sexual relationships during the study and for up to 90 days after the last dose of 
study drug. 
Investigators should advise females of child-bearing potential of the most appropriate birth 
control method available within their country taking into account local medical practice. 
Females of child-bearing potential include female patients who have experienced menarche (or 
begin menarche over the course of the study) and who are not postmenopausal or permanently 
sterilized (eg, bilateral tubal occlusion, hysterectomy, or bilateral salpingectomy).  A 
postmenopausal state is defined as the absence of menses for 12 months without an alternative 
medical cause, confirmed by follicle stimulating hormone level within the postmenopausal 
range.  

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For male patients, no contraception is required.  However, use by males of contraception 
(condom) may be required in some countries e.g.  France, in order to comply with local 
requirements as described in the corresponding patient consent forms. 
Compliance with contraception requirements will be assessed on a regular basis by the 
Investigator throughout the course of the study (see Section 6.7.5.2). 
5.5.2. 
Alcohol Restrictions 
Patients will limit alcohol consumption throughout the course of the study.  Alcohol is limited to 
no more than 2 units per day (unit:  1 glass of wine [approximately 125 mL] = 1 measure of 
spirits [approximately 1 fluid ounce] = ½ pint of beer [approximately 284 mL]) for the duration 
of the study. 
5.5.3. 
Antibiotic Compliance 
Patients who require prophylactic antibiotics after randomization to cemdisiran or placebo (see 
Section 5.3.2.1) per local standard of care will undergo antibiotic compliance checks.  Antibiotic 
compliance checks will be performed at the time points in the Schedule of Assessments.  
Antibiotic dose adjustments will be permitted in the case of renal impairment.  All dose 
adjustments must comply with the manufacturer’s instructions. 
6. 
STUDY ASSESSMENTS 
The Schedule of Assessments are provided in Table 1, Table 2, Table 3, and Table 4 .  If a 
patient is unable to complete a site visit, routine physical examination/body system assessment, 
height, weight, body mass index (BMI), vital signs and collection of blood and urine samples for 
efficacy, safety, PD, PK, and exploratory assessments may be conducted at a location other than 
the study site (eg, at home) by a trained healthcare professional as locally feasible (refer to 
instructions for home nurses in the Laboratory Manual). 
6.1. 
Screening Assessments 
An ICF approved by the appropriate Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) must be signed by the patient (or legal guardian) before the Screening 
procedures are initiated.  All patients (or their legal guardians) will be given a copy of the signed 
and dated ICF.  
The Investigator will notify the Sponsor before screening patients to allow an assessment of the 
ability of the site and any new trial participant to comply with the protocol given limitations 
during the COVID-19 pandemic. 
Patients will be screened to ensure that they meet all the inclusion criteria and none of the 
exclusion criteria.  Rescreening of patients is permitted with consultation of the Medical 
Monitor; see Section 6.1.1.  
Patient demographic data and medical history/disease history will be obtained.  In particular, the 
MEST-C score and degree of IgG, IgA, IgM, C3, C1q, C4d and C5b-9 stains will be obtained 
from pathology reports, if available, and documented.  Any changes to medical history occurring 
between the Screening assessment and Day 1 will be updated prior to study drug administration.  

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Additional screening assessments include a full physical examination (with emphasis on 
presence/degree of edema), collection of vital signs, height, weight and BMI, 12-lead 
electrocardiogram (ECG), clinical laboratory assessments, pregnancy, 24-hours urine proteinuria 
assessment (from a single valid collection; see Section 6.4.1.1), eGFR, urinalysis, spot urine 
assessments, ADA, and CIC assessments.  Vaccination records will also be checked for 
compliance with national/local guidelines for pneumococcal and Hib vaccinations. 
6.1.1. 
Rescreening 
A patient who does not meet all study eligibility criteria due to a transient condition observed at 
screening (eg, prohibited medications that were subsequently discontinued) will be allowed to 
return for rescreening (once only).  A patient who is unable to complete screening and run-in 
visits due to COVID-19 associated delays may be rescreened with approval of the Sponsor.  A 
patient will be re-consented if rescreening occurs outside of the 120-day screening window.  In 
this case, all screening procedures must be repeated.  
6.1.2. 
Retesting 
If in the Investigator’s judgement, the laboratory abnormalities at screening or in the run-in 
period are likely to be transient, then laboratory tests may be repeated.  The Investigator’s 
rationale is to be documented.  Laboratory values can be retested once during screening or the 
run-in period as long as the patient can be evaluated for eligibility and randomized within the 
allowed Screening or run-in period.  Two retests will be permitted for hematuria during 
Screening, if the first test is negative.   
6.2. 
Run-in Period 
During the 14-week run-in period, the following will be performed at time points specified in the 
Schedule of Assessments (Table 1): Hib and pneumococcal vaccinations (if required at 
Screening per national/local guidelines; vaccination should occur at least 14 days prior to 
randomization), vital signs, clinical laboratory assessments, pregnancy test, 24-hour urine 
proteinuria assessment (from 2 single valid collections; see Section 6.4.1.1), urinalysis for 
hematuria, spot urine assessments, and eGFR.  Clinical laboratory tests will be performed 
centrally; however, eGFR may also be assessed locally at the end of the run-in period (Week -2) 
to facilitate assessment of patient eligibility and administer meningococcal vaccination on the 
same day.  Meningococcal vaccines should be administered only if patient eligibility for 
randomization is confirmed and after urine collections are completed.  
If a run-in visit cannot proceed according to schedule, it may be delayed up to 28 days, with 
subsequent visits being rescheduled based on the new date.  Visit windows, as indicated in the 
Schedule of Assessments (Table 1), are applied to the rescheduled date.  Approval from the 
Medical Monitor is required prior to initiation of the treatment period.  If a patient cannot 
proceed to the treatment period as planned, the run-in period can be extended as needed.  If the 
final run-in visit will not be within 56 days of randomization, this visit will be repeated, and the 
new visit will serve as the Week -2 visit to determine eligibility for randomization. 
Sites are encouraged to discuss study information with the patients again at the end of the run-in 
period and to check key inclusion and exclusion criteria when run-in visits are delayed. 

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6.3. 
Baseline Assessments (Treatment Period) 
Prior to dosing on Day 1, patients will be reassessed for eligibility, and blood and urine samples 
for clinical laboratory assessments and exploratory analyses collected, including blood samples 
for complement activity tests (CAP/CCP), C5 analysis, PK, ADA, CIC, and anti-Gd-IgA1 
antibodies.  
In addition, prior to administration of study drug, the following assessments will be performed:  
full physical examination, body weight and height, vital signs, ECG, urine pregnancy test, eGFR 
assessment, spot urine, and urinalysis.  
Collection of blood and urine samples for PK analysis on Day 1 will be performed as outlined in 
Table 5.   
6.4. 
Efficacy Assessments 
6.4.1. 
Urine Protein/Creatinine Ratio 
Primary efficacy will be assessed by determining the percent change from baseline in UPCR 
from a 24-hour urine sample after 32 weeks of treatment. 24-hour urine samples for 
determination of UPCR will be collected throughout the study as outlined in the Schedules of 
Assessments and will be analyzed by a central laboratory. 
6.4.1.1. 
24-Hour Urine Collection 
Patients will be required to provide two separate valid 24-hour urine collections 2 weeks prior to 
randomization (to assess eligibility after the run-in period), at Week 32 (to assess the primary 
endpoint), and at the EOS/ET visit.  Patients will also be asked to provide a single valid 24-hour 
urine sample for other 24-hour urinary assessments outlined in the Schedule of Assessments 
(Table 1, Table 2, Table 3, and Table 4).  Both UPCR as well as UACR will be calculated in an 
aliquot of each 24-hour urine collection.  Rigorous exercise and significant change in diet (in 
particular salt intake) should be avoided within 48 hours before collection of 24-hour urine 
samples, whenever possible.  The two valid 24-hour urine samples may be collected within 2 
weeks before assessment is due while the one valid 24-hour urine sample may be collected 
within one week before the assessment takes place.  If any of the collections do not meet validity 
criteria outlined below, then repeat collections must be scheduled within the time frames outlined 
above to assure the minimum number of valid collections required for each of the study time 
points.  The duration of collection and volume of urine in the collection will be recorded in the 
eCRF.  In addition to protein, albumin, sodium and creatinine will also be quantified in each of 
the 24-hour urine samples.  
A 24-hour urine collection will only be considered valid if the following criteria are met, 
otherwise a repeat urine collection will be required: 
• The collection is between 22-26 hours in duration between the initial discarded void 
and the last void or attempt to void. 
• No voids are missed between the start and end time of the collection as indicated by 
the patient’s urine collection diary. 

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Primary efficacy will be evaluated by comparing the percent change from baseline in 24-hour 
UPCR at Week 32 in patients treated with cemdisiran versus those treated with placebo.  
Secondary and exploratory efficacy assessments include comparisons of the proportion of 
patients with partial or complete clinical remission, respectively, as measured by the amount of 
total protein in a 24-hour urine sample.  Partial clinical remission is defined as having UP 
<1 g/24-hours and complete clinical remission is defined as UP <0.3 g/24-hours.  Each will be 
assessed at Week 32. 
Additionally, using 24-hour samples, the percent change from baseline in total protein will be 
evaluated as a secondary endpoint and the change from baseline in urine UACR at Week 32 as 
an exploratory endpoint. 
6.4.1.2. 
Spot Urine Collection 
Urinary protein, albumin and creatinine levels from spot urine collections prior to dosing will 
also be measured to assess the effect of cemdisiran on UPCR and UACR as outlined in the 
Schedule of Assessments. 
The change from baseline in UPCR at Week 32 will be evaluated in spot urine samples as a 
secondary efficacy assessment.  Spot urine samples will be collected at the time points outlined 
in the Schedule of Assessments (Table 1).   
6.4.2. 
Hematuria 
Hematuria from spot urine collections will also be evaluated to assess the effect of cemdisiran on 
disease course in patients with IgAN.  The degree of hematuria will be assessed by microscopic 
examination of the spun urine sediment (RBC/hpf) and by urine dipstick.  Single void collections 
for random urine sample for hematuria evaluation should be collected.  If the investigator 
determines that the hematuria is transient due to menses in women or exercise, the sample may 
need to be repeated. 
Random spot urine samples for hematuria measurement will be collected throughout the study as 
outlined in the Schedule of Assessments (Table 1, Table 2, Table 3, and Table 4) and will be 
analyzed by a central laboratory.  On dosing days, samples should be collected prior to study 
drug administration, if applicable. 
6.4.3. 
Changes in Renal Function 
Changes in renal function will be monitored using measurements of serum creatinine and eGFR 
(mL/min/1.73m2) as outlined in the Schedule of Assessments (Table 1, Table 2, Table 3, and 
Table 4).  The calculation will be based on the Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) formula for all patients.  For assessment of eligibility at the last visit of 
run-in period, 2 weeks prior to randomization, local lab can be utilized.  This will allow 
evaluation for eligibility on the same day.  A sample will also be sent to central lab. 
Renal function will also be estimated as creatinine clearance based on the 24-hour urine 
collection.  The creatinine clearance is a widely used test to estimate the GFR using the 
following formula: 
GFR  =  [UCr  x  V] / SCr 

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SCr is the serum creatinine concentration and the value assessed closest to collection of 24-hour 
urine collection will be utilized for purpose of above calculation.  UCr is the urine creatinine 
concentration and V is the urine flow rate or volume. 
Blood and urine samples for renal function assessments will be collected prior to administration 
of study drug on dosing days, if applicable. 
The change from baseline in eGFR will be measured throughout the course of the study.  In 
addition, the slope of eGFR will be computed for the treatment period and the entire study period 
(including the OLE).  
6.4.4. 
Markers of Complement Activation, Inflammation and Renal Injury 
Samples for measurement of markers of complement activation, inflammation and renal injury 
will be collected at the time points outlined in the Schedule of Assessments (Table 1, Table 2, 
Table 3, and Table 4) and analyzed by central laboratories.  On dosing days, blood samples will 
be collected predose. 
6.5. 
Pharmacodynamic Assessments 
Blood samples for PD analysis will be collected at the time points outlined in the Schedule of 
Assessments (Table 1, Table 2, Table 3, and Table 4).  Samples will be collected prior to 
administration of cemdisiran or placebo on dosing days. 
Analysis of PD will include the impact of cemdisiran administration on plasma C5 protein levels 
(assessed by a mass spectrometry-based method) and serum complement activity (assessed by 
CAP enzyme linked immunosorbent assay [ELISA] and CCP ELISA).  Samples will be analyzed 
at central laboratories.  Details regarding the collection, processing, shipping, and storage of the 
samples will be provided in the Laboratory Manual. 
6.6. 
Pharmacokinetic Assessments 
Blood samples and urine samples will be collected for assessment of cemdisiran PK parameters 
and possible metabolite analysis at the time points in the Schedule of Assessments.  A detailed 
schedule of time points for the collection of blood samples and urine samples for PK analysis is 
in Table 5. 
The concentration of cemdisiran will be determined using a validated assay.  Details regarding 
sample volumes to be collected, and the processing, shipping, and analysis of the samples will be 
provided in the Laboratory Manual. 
6.7. 
Safety Assessments 
The assessment of safety during the study will consist of the surveillance and recording of the 
frequency of AEs including SAEs, recording of concomitant medication and measurements of 
vital signs, weight and height, physical examination, and ECG findings and laboratory tests, 
including assessment of IgG/IgM/IgA ADA, CIC, and anti-Gd-IgA1 antibodies.  Clinically 
significant abnormalities observed during the physical examination are recorded.   
Safety will be monitored over the course of the study by a DMC as described in Section 3.7. 

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6.7.1. 
Vital Signs 
Vital signs will be measured as specified in the Schedule of Assessments (Table 1, Table 2, 
Table 3, and Table 4) and include blood pressure, heart rate, body temperature, and respiratory 
rate.  Vital signs will be measured in the seated or supine position, after the patient has rested 
comfortably for at least 10 minutes.  On Day 1, vital signs will be collected predose (no more 
than 4 hours prior to dosing) and 4 hours (±30 minutes) postdose.  On all other dosing days, vital 
signs will be collected predose.  
Blood pressure should be taken using the same arm throughout the study.  Body temperature in 
degrees Celsius will be obtained via oral or tympanic method.  Heart rate will be counted for a 
full minute and recorded in beats per minute, and respiration rate will be counted for a full 
minute and recorded in breaths per minute. 
Additional vital sign assessments, as medically indicated, may be added at the discretion of the 
Investigator, or as per DMC advice. 
Vital signs results will be recorded in the eCRF. 
6.7.2. 
Weight and Height 
Height will be measured in centimeters.  Body weight will be measured in kilograms.  Height 
and body weight measurements will be collected as specified in the Schedule of Assessments 
(Table 1, Table 2, Table 3, and Table 4; height at screening only and dosing weight during the 
clinical study site visits) and will be recorded in the eCRF. 
6.7.3. 
Physical Examination 
Routine physical examinations will be conducted according to the Schedule of Assessments 
(Table 1, Table 2, Table 3, and Table 4); if a physical examination is scheduled for a dosing visit, 
it should be conducted prior to dosing.   
At screening and Day 1 predose, a full physical examination will be performed.  At all other time 
points, including Day 1 at 4 hours (±30 minutes) postdose, a directed physical examination will 
be performed. 
Full physical examinations will include the examination of the following:  general appearance; 
head, eyes, ears, nose and throat; respiratory, cardiovascular, gastrointestinal, musculoskeletal, 
and dermatological systems; thyroid; lymph nodes; and neurological status. 
Directed physical examinations will include examination of the following:  respiratory, 
cardiovascular, dermatological, gastrointestinal, and musculoskeletal systems. 
Clinically significant abnormalities observed during the physical examination are recorded on 
the medical history or AE eCRF. 
6.7.4. 
Electrocardiogram 
Twelve-lead ECGs reporting rhythm, ventricular rate, RR interval, PR interval, QRS duration, 
and QT interval and Fridericia-corrected QT interval will be obtained, as specified in the 
Schedule of Assessments (Table 1, Table 2, Table 3, and Table 4).  Patients should be supine for 
at least 5 minutes before each ECG is obtained.  A single 12-lead ECG will be performed at 
Screening.  At all other time points, 12-lead ECGs will be performed in triplicate, with readings 

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1 minute apart. 12-lead ECGs will be performed predose (on the same day as dosing); 60 
minutes (±15 minutes) postdose; and 4 hours (±30 minutes) postdose in relation to the Day 1 and 
Week 32 cemdisiran or placebo doses. 
When ECG and blood sample collection occur at the same time, ECGs should be performed 
before blood samples are drawn. 
The Investigator or qualified designee will review all ECGs to assess whether the results have 
changed since the Baseline visit and to determine the clinical significance of the results.  These 
assessments will be recorded on the eCRF.  Additional ECGs may be collected at the discretion 
of the Investigator, or as per DMC advice.   
6.7.5. 
Clinical Laboratory Assessments 
The following clinical laboratory tests will be evaluated by a central laboratory.  However, to 
assess patient eligibility at the end of the run-in period, eGFR will also be assessed locally.  
Specific instructions for transaminase elevations are provided in Section 5.2.3.1.  For any other 
unexplained clinically relevant abnormal laboratory test occurring after study drug 
administration, the test should be repeated and followed up at the discretion of the Investigator, 
or as per DMC advice, until it has returned to the normal range or stabilized, and/or a diagnosis 
is made to adequately explain the abnormality.  Additional safety laboratories and assessments as 
indicated by the clinical situation may be requested.  Clinical laboratory assessments are listed in 
Table 7 and include: hematology, serum chemistry and urinalysis parameters.  Parameters will be 
assessed as specified in the Schedule of Assessments (Table 1, Table 2, Table 3, and Table 4).  
While local laboratory results may be used for urgent clinical and dosing decisions, on the day of 
the clinic visit assessments, all laboratory assessments specified in Table 7 which are measured 
locally should also be sent in parallel to the central laboratory.  In the case of discrepant local 
and central laboratory results on samples drawn on the same day, central laboratory results will 
be relied upon for clinical and dosing decisions.  If central laboratory tests are not feasible due to 
COVID-19 restrictions, local laboratory tests for safety monitoring can be performed with 
approval from the Sponsor. 
Clinical laboratory assessments may be collected at the clinical study site or at a location other 
than the study site (eg, at home) by a trained healthcare professional.  On dosing days blood 
samples will be collected predose. 
For any safety event or laboratory abnormality, additional laboratory assessments, imaging, and 
consultation may be performed for clinical evaluation and/or in consultation with the Medical 
Monitor; results may be collected and should be included in the clinical database. 

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Table 7: 
Clinical Laboratory Assessments 
Hematology 
Complete blood count with differential 
 
Serum Chemistry 
Sodium 
Potassium 
BUN 
Phosphate 
Creatinine and eGFR (using the CKD-EPI formula)  
Albumin 
Uric acid 
Calcium 
Total protein 
Carbon dioxide 
Glucose 
Chloride 
Liver Function Tests 
 
AST 
ALP 
ALT 
Bilirubin (total and direct) 
GGT  
 
Urinalysis 
Visual inspection for appearance and color 
Bilirubin 
pH 
Nitrite 
Specific gravity 
Blood 
Ketones 
Urobilinogen 
Albumin 
Leukocytes 
Glucose 
Microscopy 
Protein 
 
Coagulation  
Prothrombin time 
International Normalized Ratio 
Partial Thromboplastin Time 
 
Immunogenicity (see Section 6.7.5.1) 
Antidrug antibodies 
Hepatic Tests (Screening Only)  
Hepatitis C, including:  
HCV RNA PCR – qualitative and quantitative 
assays 
Hepatitis B, including:  
HBs Ag, HBc antibody IgM and IgG 
Pregnancy Testing (Females of Child-bearing Potential Only) (see Section 6.7.5.2) 
β-human chorionic gonadotropin 
Abbreviations:  ALP=alkaline phosphatase; ALT=alanine transaminase; AST=aspartate transaminase; BUN=blood 
urea nitrogen; CKD-EPI=Chronic Kidney Disease Epidemiology Collaboration; eGFR=estimated glomerular 
filtration rate; GGT=gamma glutamyl transferase; HBsAg=hepatitis B virus surface antigen; HBc=hepatitis B virus 

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core; HCV=hepatitis C virus; IgG= IgG=immunoglobulin G antibody; IgM=immunoglobulin M antibody; 
PCR=polymerase chain reaction; RNA=ribonucleic acid. 
6.7.5.1. 
Immunogenicity 
Blood samples will be collected to evaluate ADA and CIC.  IgG/IgM/IgA ADAs to total drug 
will be assessed at screening and during the study.  ADA samples will be tested in real time.  
Clinical study decision will be based on confirmed positive ADA results from the IgG/IgM/IgA 
assay.  Confirmed positive ADA samples will be further characterized for cemdisiran domain 
specificity against the Tri-GalNAc component if a reliable method is established.  Blood samples 
for ADA and CIC testing must be collected before study drug administration as specified in the 
Schedule of Assessments.  Blood samples to evaluate ADAs will be collected at screening to 
assess study eligibility and at the ET visit, if applicable.  ADA and CIC will be routinely 
monitored during the treatment period and throughout the OLE period and safety follow-up 
(ADA only), as indicated in the Schedule of Assessments (Table 1, Table 2, Table 3, and 
Table 4).  Finally, ADA and CIC samples will also be collected and analyses will be performed 
and prioritized if any clinical evidence of progression of IgAN disease and/or relevant safety 
findings.  Patients who are confirmed positive for IgG/IgM/IgA ADAs at baseline will be 
excluded from study treatment.  In addition, patients who develop de novo ADAs will be 
discontinued from study drug but will be followed until EOS visit and during safety follow-up.  
These patients will also be monitored until ADA levels return to baseline. 
Exploratory analysis of anti-Gd-IgA1 antibody levels will be conducted; serum samples for these 
analyses will be drawn when CIC samples are collected. 
Details regarding the processing, shipping, and analysis of the samples will be provided in the 
Laboratory Manual. 
6.7.5.2. 
Pregnancy Testing 
A pregnancy test will be performed for females of child-bearing potential.  A serum pregnancy 
test will be performed at screening and urine pregnancy tests will be performed thereafter per the 
Schedule of Assessments (Table 1, Table 2, Table 3, and Table 4) and any time pregnancy is 
suspected.  The results of the pregnancy test must be known before study drug administration.  
Patients 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.  Patients determined to be pregnant while on study will be followed until the 
pregnancy outcome is known (see Section 6.7.6.7 for follow-up instructions).  
6.7.5.3. 
Additional Liver Function Assessments 
Additional laboratory assessments will be performed in patients who experience any LFT 
abnormalities.  Following the occurrence of elevated liver transaminases or other LFT 
abnormalities per central laboratory, all assessments in Table 8 will be performed one time, as 
well as hematology, serum chemistry, LFT, and coagulation assessments from Table 7, and other 
assessments or evaluations per Investigator discretion, as appropriate. 

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Table 8: 
Hepatic Assessments in Patients Who Experience Elevated Transaminases 
Extended Hepatic Panel 
Herpes Simplex Virus 1 and 2 antibody IgM, IgG 
HHV-6 
Cytomegalovirus antibodies, IgM, IgG  
HBs Ag, HBc antibody IgM and IgG 
Anti-nuclear antibodies 
Epstein-Barr Virus antibodies, IgM and IgG 
Anti-smooth muscle antibodies 
Anti-mitochondrial antibodies 
HCV antibody 
HAV antibody IgM 
HCV RNA PCR – qualitative and quantitative 
HEV antibody IgM 
Herpes Zoster Virus IgM, IgG 
 
Imaging 
Abdominal ultrasound with Doppler flow (or CT or MRI) including right upper quadrant 
Focused Medical and Travel History 
Use of any potentially hepatotoxic concomitant 
medications, including over the counter medications 
and herbal remedies 
Alcohol consumption  
Other potentially hepatotoxic agents including any 
work-related exposures 
Recent travels to areas where hepatitis A or E 
is endemic 
Abbreviations:  CT=computed tomography; HAV=hepatitis A virus; HBc=hepatitis B core; HBsAg=hepatitis B 
virus surface antigen; HCV=hepatitis C virus; HEV=hepatitis E virus; HHV-6=human herpesvirus 6; 
IgG=immunoglobulin G antibody; IgM=immunoglobulin M antibody; MRI=magnetic resonance imagery; 
PCR=polymerase chain reaction; RNA=ribonucleic acid. 
Note: 
• 
All assessments will be measured in central laboratory.  The full panel of assessments should only be 
performed once; individual assessments may be repeated, as needed. 
6.7.6. 
Adverse Events 
6.7.6.1. 
Definitions 
Adverse Event  
According to the International Council on Harmonisation (ICH) E2A guideline Definitions and 
Standards for Expedited Reporting, and 21 CFR 312.32, investigational new drug (IND) Safety 
Reporting, an AE is any untoward medical occurrence in a patient or clinical investigational 
subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening (an event which places the patient at immediate risk of death from 
the event as it occurred.  It does not include an event that had it occurred in a more 
severe form might have caused death) 

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• Requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly or birth defect 
• Is an important medical event that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient and may require 
intervention to prevent one of the other outcomes listed in the definition above (eg, 
events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at a location other than the study site (eg, at home), blood dyscrasias, 
convulsions, or the development of drug dependency or abuse). 
Adverse Events of Clinical Interest 
Based on the biological target and the available nonclinical and clinical data, AEs of Clinical 
Interest (AECI) for this study are: 
• Severe infections as judged by the Investigator  
• ALT or AST >3×ULN 
• Severe or serious ISRs; ISRs that are associated with a recall phenomenon (reaction 
at the site of a prior injection with subsequent injections), or those that lead to 
temporary dose interruption or permanent discontinuation of cemdisiran. 
An ISR is defined as a local reaction at or near the site of injection.  “At or near” the 
injection site includes reactions at the injection site, adjacent to the injection site, or a 
reaction which may shift slightly away from the injection site due to gravity (eg, as 
may occur with swelling or hematoma).  A systemic reaction which includes the 
injection site (eg, generalized urticaria, other distinct entities or conditions like 
lymphadenopathy that may be near the injection site) is not considered an ISR.  
For information on recording and reporting of AECIs, see Section 6.7.6.2 and Section 6.7.6.3 , 
respectively. 
Adverse Event Severity 
AEs are to be graded according to the categories detailed below: 
Mild: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Moderate: 
Moderate; minimal, local or noninvasive intervention indicated; limiting age 
appropriate instrumental activities of daily living (eg, preparing meals, 
shopping for groceries or clothes, using the telephone, managing money). 
Severe: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care activities of daily living (ie, bathing, dressing and undressing, feeding 
self, using the toilet, taking medications, and not bedridden); OR life-
threatening consequences; urgent intervention indicated; OR death related to 
an adverse event. 

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Changes in severity should be documented in the medical record to allow assessment of the 
duration of the event at each level of severity.  AEs characterized as intermittent require 
documentation of the start and stop of each incidence.  When changes in the severity of an AE 
occur more frequently than once a day, the maximum severity for the experience that day should 
be noted.  If the severity category changes over a number of days, then those changes should be 
recorded separately (with distinct onset dates). 
AE severity and seriousness are assessed independently.  ‘Severity’ characterizes the intensity of 
an AE.  ‘Serious’ is a regulatory definition and serves as a guide to the Sponsor for defining 
regulatory reporting obligations (see definition for SAE). 
Relationship of the Adverse Event to Study Drug 
The relationship of each AE to study drug should be evaluated by the Investigator by a “yes” or 
“no” response to the question: “Is there a reasonable possibility that the event may have been 
caused by the study drug?” 
6.7.6.2. 
Eliciting and Recording Adverse Events 
Eliciting Adverse Events 
The patient and legal guardian, if applicable, should be asked about medically relevant changes 
in the patient’s health since the last visit.  The patient and legal guardian, if applicable, should 
also be asked if the patient has been hospitalized, had any accidents, used any new medications, 
or changed concomitant medication routines (both prescription and over-the-counter).  In 
addition to patient observations, AEs will be documented from any clinically relevant laboratory 
findings, physical examination findings, ECG changes, or other findings that are relevant to 
patient safety. 
Recording Adverse Events 
The Investigator is responsible for recording all SAEs and only AEs related to study procedures 
that are observed or reported by the patient during the run-in period (before the administration of 
the first dose of study drug) regardless of their relationship to study drug through the end of 
study.  All AEs, including non-serious AEs, occurring after signing of the ICF and before study 
drug administration will be captured as medical history (see Section 6.1).  All AEs will be 
collected starting after administration of the first dose through the end of the safety follow-up 
period.  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 site and in the eCRF for the 
patient, whether or not they are considered to be drug-related.  Each AE must be described in 
detail:  onset time and date, description of event, severity, relationship to study drug, action 
taken, and outcome (including time and date of resolution, if applicable). 
For SAEs, record the event(s) on both the eCRF and the SAE form.  

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For AEs that are considered AEs of clinical interest (Section 6.7.6.1), the supplemental AEs of 
Clinical Interest eCRF should be completed.  Additional clinical and laboratory information may 
be collected.  Refer to CRF completion guidelines for details on reporting events in the 
supplemental AEs of Clinical Interest eCRF.   
For all ISRs, the Investigator, or delegate, should submit a supplemental ISR eCRF, recording 
additional information (eg, descriptions, onset and resolution date, severity, treatment given, 
event outcome). 
6.7.6.3. 
Reporting Adverse Events of Clinical Interest to Sponsor/Designee 
For AEs that are considered AECIs (Section 6.7.6.1), the Sponsor or its designee should be 
notified within 24 hours using a supplemental AEs of Clinical Interest eCRF. 
6.7.6.4. 
Serious Adverse Events Require Immediate Reporting to Sponsor/Designee 
An assessment of the seriousness of each AE will be made by the Investigator.  Any AE and 
laboratory abnormality that meets the SAE criteria in Section 6.7.6.1 must be reported to the 
Sponsor or designee within 24 hours from the time that clinical study site staff first learns of the 
event.  All SAEs must be reported regardless of the relationship to study drug. 
The initial report should include at least the following information: 
• Patient’s study number 
• Description and date of onset of the event 
• Criterion for serious 
• Preliminary assignment of relationship to study drug, and 
• Investigator/site information 
To report the SAE, complete the 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 Investigator Site File. 
Appropriate remedial measures should be taken by the Investigator using his/her best medical 
judgment to treat the SAE.  These measures and the patient’s response to these measures should 
be recorded.  All SAEs, regardless of relationship to study drug, will be followed by the 
Investigator until satisfactory resolution or the Investigator deems the SAE to be chronic or 
stable.  Clinical, laboratory, and diagnostic measures should be employed by the Investigator as 
needed to adequately determine the etiology of the event. 
6.7.6.5. 
Sponsor Safety Reporting to Regulatory Authorities 
The Sponsor or its representative will report certain study events in an expedited manner to the 
Food and Drug Administration, the European Medicines Agency’s EudraVigilance electronic 
system according to Directive 2001/20/EC, and to all country Regulatory Authorities where the 
study is being conducted, according to local applicable regulations. 

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6.7.6.6. 
Serious Adverse Event Notification to the Institutional Review 
Board/Independent Ethics Committee 
Suspected unexpected serious adverse reactions (SUSARs) will be reported to the IRB/IEC per 
their institutional policy by the Investigator or Sponsor (or Sponsor designee) according to 
country requirements.  Copies of each report and documentation of IRB/IEC notification and 
acknowledgement of receipt will be kept in the Investigator’s Site File. 
6.7.6.7. 
Pregnancy Reporting 
If a female patient becomes pregnant during the study through 90 days following the last dose of 
study drug, the Investigator must report the pregnancy to the Sponsor or designee within 
24 hours of being notified of the pregnancy.  Details of the pregnancy will be recorded on the 
pregnancy reporting form.  The patient should receive any necessary counseling regarding the 
risks of continuing the pregnancy 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 6.7.6.4. 
6.7.6.8. 
Overdose Reporting 
An overdose is defined as any dose administered to or taken by a patient (accidentally or 
intentionally) that exceeds the highest daily dose, or is at a higher frequency, than included in the 
protocol.  The Investigator will decide whether a dose is to be considered an overdose, in 
consultation with the Sponsor.  In the event of an overdose, the actual dose administered must be 
recorded in the eCRF. 
All reports of overdose (with or without an AE) must be reported within 24 hours to the Sponsor 
or designee. 
6.7.7. 
COVID-19 Data Collection 
Information on the COVID-19 infection status of the patient, if known, and other information on 
the impact of the COVID-19 pandemic on the patient's participation in the study will be 
collected, where permitted by local regulations. 
6.8. 
Biomarkers, DNA Genotyping, and Biospecimen Repository 
Alnylam’s RNAi therapeutics platform permits the highly specific targeting of investigational 
therapies based on genetic sequence.  It is possible that variations in the target genetic sequence 
will result in variations in drug effect. 
More generally, genetic variations may account for the well-described heterogeneous 
manifestations of disease in patients with IgAN, as well as their responses to treatment. 
To permit exploratory investigations and the application of novel approaches to bioanalyses that 
may further elucidate the outcomes of this study, or potentially advance understanding of the 

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safety, mechanism of action, and/or efficacy of cemdisiran, a set of biological specimens will be 
collected at the intervals indicated in the Schedule of Assessments. 
The biospecimen repository will also include residual material from routine samples (safety 
laboratory samples, PK samples, etc.) that are obtained during the study. 
These specimens will be securely stored in a central biorepository for up to 10 years following 
the completion of this clinical study (ie, last patient last visit), or as per local regulations.  After 
10 years have elapsed, samples will be destroyed. 
Where allowed per local regulations, ethics committee (IRB/IEC) approval, and patient consent, 
the samples will be collected as part of this study.  Examples of potential exploratory 
investigations would include DNA, RNA, protein, or biochemical metabolite assessments as they 
relate to disease progression, efficacy or safety.  
Details regarding the collection, processing, storage, and shipping of the samples will be 
provided in the Laboratory Manual. 
Exploratory analysis of these biospecimens will be performed by Alnylam Pharmaceuticals or its 
designees. 
When biobanking is permitted by local regulation, study participants will be advised during the 
informed consent process of these biobanking details and the potential for exploratory 
investigation of their samples. 
7. 
STATISTICS 
A Statistical Analysis Plan (SAP) will be finalized before database lock.  The plan will detail the 
implementation of the statistical analyses in accordance with the principle features stated in the 
protocol. 
7.1. 
Determination of Sample Size 
The sample size of the study was determined based on the precision of the estimate of the 
treatment effect for the primary endpoint – the percent change from baseline in UPCR from a 
24-hour urine sample at Week 32.  It should be noted that geometric mean ratio of UPCR at 
Week 32 to baseline is statistically equivalent to mean of the change from baseline in logarithm 
of UPCR.  Therefore, the effect size of the study is defined as the difference of change from 
baseline between cemdisiran and placebo in the logarithm of UPCR.  
Based on the [Fellstrom 2017] study, we assume that in the placebo arm the geometric mean 
ratio of UPCR at Week 32 to baseline is 0.88 (log standard deviation [SD] 0.597), corresponding 
to a 12% reduction, while the geometric mean ratio is 0.5, or a 50% reduction for the cemdisiran 
arm.  Using these assumptions, sample size of 9 and 18 in the placebo and cemdisiran arms will 
provide a width of 0.80 (± 0.4) for the 90% confidence interval (CI) for treatment effect size 
estimate (cemdisiran – placebo) in log scale. 
7.2. 
Statistical Methodology 
The statistical and analytical plans presented below are brief summaries of planned analyses.  
More complete plans will be detailed in the statistical analysis plan (SAP).  Changes to the 

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methods described in the final SAP will be described and justified as needed in the clinical study 
report.  For information on study endpoints, see Section 2. 
Descriptive statistics including the number of patients, mean, median, standard deviation (SD), 
interquartile range (Q1, Q3), minimum, and maximum values will be presented for continuous 
variables.  Frequencies and percentages will be presented for categorical and ordinal variables. 
Additional data summaries to help understand any impact of COVID-19 on PK/PD, efficacy and 
safety assessments will be outlined in the SAP. 
7.2.1. 
Populations to be Analyzed 
The following populations will be analyzed: 
• Modified Intent-to-treat (mITT): All patients who receive any amount of study drug 
and have at least one post baseline assessment in proteinuria.  Patients will be 
grouped by assigned treatments (ie, as randomized). 
• Safety Analysis Set: All patients who received any amount of study drug.  Patients 
who received any amount of cemdisiran will be included in the cemdisiran arm.  
Patients in the Safety Analysis Set will be grouped by treatment received. 
• PK Analysis Set: All patients who receive a full dose of study drug and have at least 
one postdose blood or urine sample for PK concentration. 
• PD Analysis Set: All patients who receive a full dose of study drug and who have at 
least one postdose blood sample for the determination of plasma C5 level. 
The primary population used to evaluate efficacy will be the mITT Population.  Safety will be 
analyzed using the Safety Analysis Set.  The PK and PD Analysis Sets will be used to conduct 
PK and PD analyses, respectively.  
7.2.2. 
Examination of Subgroups 
Subgroup analyses may be conducted for selected endpoints.  Detailed methodology will be 
provided in the SAP. 
7.2.3. 
Handling of Missing Data 
Handling of missing data will be described in the SAP. 
7.2.4. 
Baseline Evaluations 
Demographics and other baseline characteristics, including disease-specific information, will be 
summarized descriptively by treatment arm and overall for the mITT and Safety Analysis Set. 
Baseline value for 24-hour UPCR will be calculated as the average of two valid 24-hour urine 
assessments before randomization (at the Week -2 visit). 

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7.2.5. 
Efficacy Analyses 
7.2.5.1. 
Primary Endpoint 
The primary endpoint of the study is the percentage change from baseline in 24-hour UPCR at 
Week 32.  The 24-hour UPCR will be log transformed for analyses.  The primary analysis will 
be performed using a restricted maximum likelihood (REML) based Mixed-Effect Model 
Repeated Measures (MMRM) approach.  The outcome variable is change from baseline in 24-
hour UPCR in log-scale at the Week 16 and Week 32 visits.  Analysis will include fixed effects 
of treatment (cemdisiran vs. placebo), scheduled visits (Week 16 and Week 32), interaction term 
of treatment and scheduled visits, baseline 24-hour UPCR in log-scale (continuous), and patient 
as a random effect.  The least square mean difference and its 90% confidence interval will be 
estimated .  In addition, placebo-adjusted geometric mean percent change at the Week 32 visit 
and its 90% CI will be presented. 
A sensitivity analysis for the impact of missing data and the normality assumptions on the log-
transformed UPCR data will be performed.  Details will be provided in the SAP. 
7.2.5.2. 
Secondary Efficacy Endpoints  
The secondary efficacy endpoints include percent change from baseline in 24-hour proteinuria 
(g/24 hours) at Week 32, percent of patients with partial clinical remission (UP <1.0 g/24-hours), 
percent of patients with >50% reduction in 24-hour proteinuria, change from baseline in UPCR 
as measured in a spot urine at Week 32 and change from baseline in hematuria at Week 32. 
The percentage of patients with partial clinical remission or with >50% reduction in 24-hour 
proteinuria for each treatment arm and the difference between treatment arms will be presented 
together with an approximate 90% confidence interval based on Wilson score method.  
Change from baseline in UP in 24-hour urine assessments and UPCR by spot urine at Week 32 
will be analyzed similarly to the analysis of the primary variable as appropriate.  The descriptive 
statistics for change from baseline in hematuria (urine dipstick) at Week 32 will be provided.  
7.2.5.3. 
Exploratory Endpoints  
Change from baseline in exploratory efficacy variables will be summarized.  Percent of patients 
in full clinical remission and incidence of ADA will be tabulated by treatments.  
The slope of eGFR for the double-blind period will be estimated for each treatment and the slope 
of eGFR for the entire study period including the OLE will be analyzed.  Other inferential 
statistics for exploratory efficacy variables may be presented as needed.  Details will be 
described in the SAP.  
7.2.6. 
Pharmacodynamic Analysis 
Assessment of the PD effect of the treatment will be performed descriptively, including plotting 
graphically levels of serum C5 protein and CAP/CCP over time and relative to baseline levels.  
Inferential statistics may be generated as deemed necessary. 

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7.2.7. 
Pharmacokinetic Analysis 
Pharmacokinetic analyses will be conducted using noncompartmental methods.  Pharmacokinetic 
parameters include, but will not be limited to:  AUC, Cmax, Tmax, t½, CL/F, V/F, cumulative 
amount excreted unchanged in urine (Ae), and percent of dose excreted (fe) in the urine of 
cemdisiran (25-mer) and 23-mer.  
Other parameters may be calculated, if deemed necessary.  Summary statistics and figures will 
be presented.  Inferential statistics may be generated when deemed necessary. 
7.2.8. 
Safety Analyses 
The primary parameter is the frequency of treatment-emergent AEs (hereafter referred to simply 
as AEs).  Safety parameters also include vital signs, ECGs, clinical laboratory assessments, and 
physical exams.  The extent of exposure will be summarized by treatment arm and overall. 
AEs will be classified according to the Medical Dictionary for Regulatory Activities (MedDRA) 
System Organ Class and Preferred Term.  Prior and concomitant medications will be classified 
according to the World Health Organization (WHO) drug dictionary.  All SAEs occurring before 
the first dose of study drug and AEs related to study procedures will be listed.  The number and 
percentage of patients experiencing AEs after the first dose of the study drug or events that 
worsened in severity after dosing will be summarized.  AEs will be presented by maximum 
severity and relationship to study medication.  SAEs and AEs leading to discontinuation of 
treatment will also be tabulated. 
By-subject listings will be provided for deaths, SAEs, and AEs leading to study discontinuation. 
Frequency of AEs of clinical interest will also be summarized and by-subject listings will be 
provided. 
Descriptive statistics will be provided for clinical laboratory data, 12-lead ECG interval data and 
vital signs data, presented as both actual values and changes from baseline over time.  
Laboratory shift tables from baseline to worst values will be presented.  Baseline will be defined 
as the last observation on or prior to Study Day 1.  
Abnormal physical examination findings and 12-lead ECG data will be presented in a by-patient 
data listing.  Details of any abnormalities will be included in patient listings. 
Other safety summaries will be presented as appropriate.  Further details will be specified in the 
SAP. 
All safety analyses will be conducted using the Safety Analysis Set. 
Additional data summaries to help understand any impact of COVID-19 on safety assessments 
will be outlined in the SAP. 
7.2.9. 
Immunogenicity Analyses 
Antidrug antibody, CIC and anti-Gd-IgA1 antibody results will be summarized descriptively.   
7.2.10. 
Biomarker Analyses 
Urine and serum complement activation products, inflammation and renal injury markers will be 
summarized descriptively.  

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7.2.11. 
Interim Analysis 
No formal interim analysis is planned. 
7.2.12. 
Optional Additional Research 
Optional additional research may be conducted in the future on the biological samples and/or 
data collected during the study in accordance with the strict terms of the ICF (see Section 4.3.2). 
8. 
STUDY ADMINISTRATION 
8.1. 
Ethical and Regulatory Considerations 
This study will be conducted in accordance with the protocol, all applicable regulatory 
requirements, and the current guidelines of Good Clinical Practice (GCP).  Compliance with 
GCP provides public assurance that the rights, safety, and well-being of study patients are 
protected consistent with the principles that have their origin in the Declaration of Helsinki. 
8.1.1. 
Informed Consent 
The Investigator will ensure that the patient/legal guardian is given full and adequate oral and 
written information about the nature, purpose, possible risk and benefit of the study.  
Patients/legal guardians must also be notified that they are free to discontinue from the study at 
any time.  The patient/legal guardian should be given the opportunity to ask questions and 
allowed time to consider the information provided.   
The patient’s/legal guardian’s signed and dated informed consent must be obtained before 
conducting any study tests or procedures that are not part of routine care.   
The Investigator must maintain the original, signed ICF.  A copy of the signed ICF must be 
given to the patient/legal guardian. 
The Investigator will inform the patient/legal guardian if new information becomes available that 
may be relevant to the patient’s/legal guardian’s willingness to continue participation in the 
study.  Communication of this information should be documented. 
8.1.2. 
Ethical Review 
The study protocol, including the ICF, must be approved or given a favorable opinion in writing 
by an IRB or IEC, as appropriate.  The Investigator must submit written approval before he or 
she can enroll any patient into the study. 
The Investigator is responsible for informing the IRB or IEC of any amendment to the protocol 
in accordance with local requirements.  In addition, the IRB or IEC must approve all patient 
materials for the study (except those that support the need to remove an apparent immediate 
hazard to the patient).  The protocol must be reapproved by the IRB or IEC upon receipt of 
amendments and annually, as local regulations require. 
Initial IRB approval of the protocol, and all materials approved by the IRB for this study 
including the ICF and recruitment materials must be maintained by the Investigator and made 
available for inspection. 

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The Investigator will submit reports of SAEs as outlined in Section 6.7.6.  In addition, the 
Investigator agrees to submit progress reports to the IRB or IEC per their local reporting 
requirements, or at least annually and at the conclusion of the study.  The reports will be made 
available to the Sponsor or designee. 
Any communications from regulatory agencies, IRBs, or IECs in regard to inspections, other 
studies that impact this protocol or the qualifications of study personnel should be promptly 
reported to the Sponsor or its designee. 
The Investigator is also responsible for providing the IRB with reports of any reportable serious 
adverse drug reactions from any other study conducted with the study drug.  The Sponsor or 
designee will provide this information to the Investigator. 
Major changes in this research activity, except those to remove an apparent immediate hazard to 
the patient, must be reviewed and approved by the Sponsor and the IRB or IEC that approved the 
study.  Amendments to the protocol must be submitted in writing to the Investigator’s IRB or 
IEC and the Regulatory Authority for approval before patients are randomized under the 
amended protocol, and patients must be re-consented to the most current version of the ICF. 
8.1.3. 
Serious Breach of Protocol 
Investigators must notify the Medical Monitor within 24 hours of becoming aware of a serious 
breach of the protocol.  A serious breach is a breach that is likely to affect to a significant degree 
the safety and rights of a study participant or the reliability and robustness of the data generated 
in the clinical trial. 
8.1.4. 
Study Documentation, Confidentiality, and Records Retention 
All documentation relating to the study should be retained for 2 years after the last approval in an 
ICH territory or as locally required, whichever is longer.  If it becomes necessary for the 
Sponsor, the Sponsor’s designee, applicable IRB/IEC, or applicable regulatory authorities to 
review or audit any documentation relating to the study, the Investigator must permit direct 
access to all source documents/data.  Records will not be destroyed without informing the 
Sponsor in writing and giving the Sponsor the opportunity to store the records for a longer period 
of time at the Sponsor’s expense.   
The Investigator must ensure that the patients’ confidentiality will be maintained.  On the eCRFs 
or other documents submitted to the Sponsor or designees, patients should not be identified by 
their names, but by the assigned patient number or code.  If patient names are included on copies 
of documents submitted to the Sponsor or designees, the names will be obliterated, and the 
assigned patient number added to the document.  Documents not for submission to the Sponsor 
(eg, signed ICFs) should be maintained by the Investigator in strict confidence. 
The Investigator must treat all information related to the study and the compiled data as 
confidential, whose use is for the purpose of conducting the study.  The Sponsor must approve 
any transfer of information not directly involved in the study. 
To comply with local and/or regional regulations, this clinical study may be registered, and study 
results may be posted on public registries, such as ClinicalTrials.gov. 

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8.1.5. 
End of Study 
The end of study is defined as the last patient last visit. 
8.1.6. 
Termination of the Clinical Study or Site Closure 
The Sponsor reserves the right to terminate the study for clinical or administrative reasons at any 
time.  If the site does not recruit at a reasonable rate, or if there is insufficient adherence to the 
protocol requirements, the study may be closed 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, IRB/IEC and 
Regulatory Authorities will be promptly informed of the termination and the reason for the 
decision.  The Investigator should promptly inform the patients and assure appropriate therapy 
and follow-up. 
8.2. 
Data Quality Control and Quality Assurance 
8.2.1. 
Data Handling 
Study data must be recorded on CRFs (paper and/or electronic) provided by the Sponsor or 
designee on behalf of the Sponsor.  Case report forms must be completed only by persons 
designated by the Investigator.  If eCRFs are used, study data must be entered by trained site 
personnel with access to a valid and secure eCRF system.  All data entered into the eCRF must 
also be available in the source documents.  Corrections on paper CRFs must be made so as to not 
obliterate the original data and must be initialed and dated by the person who made the 
correction. 
8.2.2. 
Study Monitoring 
The Monitor, as a representative of the Sponsor, has an obligation to closely follow the study 
conduct at the site.  The Monitor will visit the Investigator and clinical study site periodically 
and will maintain frequent telephone and written contact.  The Monitor will maintain current 
personal knowledge of the study through observation, review of study records and source 
documentation, and discussion of the conduct of the study with the Investigator and staff. 
The Monitor will review source documents, systems and CRFs to ensure overall quality and 
completeness of the data and to confirm study procedures are complied with the requirements in 
the study protocol accurately.  The Sponsor, or its designee, will be allowed to conduct site visits 
to the investigation facilities for the purpose of monitoring any aspect of the study.  The 
Investigator agrees to allow the Monitor to inspect the drug storage area, study drug stocks, drug 
accountability records, patient charts and study source documents, site standard operating 
procedures and training records, and other records relative to study conduct. 
8.2.3. 
Audits and Inspections 
Periodically, the Sponsor or its authorized representatives audit clinical investigative sites as an 
independent review of core trial processes and documents to determine whether these activities 
were conducted, and data were recorded, analyzed, and accurately reported according to the 
protocol, GCP guidelines of the ICH, and any applicable regulatory requirements.  A regulatory 
authority, an IRB/IEC may visit the site to perform audits or inspections, including source data 

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verification.  The Investigator should contact the Sponsor and designee, immediately if contacted 
by a regulatory agency or an IRB/IEC about an inspection. 
8.3. 
Publication Policy 
It is intended that after completion of the study, the data are to be submitted for publication in a 
scientific journal and/or for reporting at a scientific meeting.  A separate publication by 
Institution or Investigator may not be submitted for publication until after this primary 
manuscript is published or following the period of 18 months after completion of the study at all 
sites.  A copy of any proposed publication (eg, manuscript, abstracts, oral/slide presentations, 
book chapters) based on this study, must be provided and confirmed received at the Sponsor at 
least 30 days before its submission.  The Clinical Trial Agreement among the institution, 
Investigator, and Alnylam will detail the procedures for Alnylam’s review of publications. 
Authorship of any publications resulting from this study will be determined on the basis of the 
Uniform Requirement for Manuscripts Submitted to Biomedical Journals (International 
Committee of Medical Journal Editors). 
 

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9. 
LIST OF REFERENCES 
Ashwell G,Morell AG. The role of surface carbohydrates in the hepatic recognition and transport 
of circulating glycoproteins. Adv Enzymol Relat Areas Mol Biol. 1974;41(0):99-128. 
Coppo R,D'Amico G. Factors predicting progression of IgA nephropathies. J Nephrol. 2005 Sep-
Oct;18(5):503-12. 
Crew PE, Abara WE, McCulley L, Waldron PE, Kirkcaldy RD, Weston EJ, et al. Disseminated 
Gonococcal Infections in Patients Receiving Eculizumab: A Case Series. Clin Infect Dis. 2019a 
Aug 1;69(4):596-600. 
Crew PE, McNamara L, Waldron PE, McCulley L, Jones SC,Bersoff-Matcha SJ. Unusual 
Neisseria species as a cause of infection in patients taking eculizumab. J Infect. 2019b 
Feb;78(2):113-8. 
Cugno M, Gualtierotti R, Possenti I, Testa S, Tel F, Griffini S, et al. Complement functional tests 
for monitoring eculizumab treatment in patients with atypical hemolytic uremic syndrome. J 
Thromb Haemost. 2014 Sep;12(9):1440-8. 
Elbashir SM, Lendeckel W,Tuschl T. RNA interference is mediated by 21- and 22-nucleotide 
RNAs. Genes Dev. 2001 Jan 15;15(2):188-200. 
Fellstrom BC, Barratt J, Cook H, Coppo R, Feehally J, de Fijter JW, et al. Targeted-release 
budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, 
randomised, placebo-controlled phase 2b trial. Lancet. 2017 May 27;389(10084):2117-27. 
Imai E, Yamagata K, Iseki K, Iso H, Horio M, Mkino H, et al. Kidney disease screening program 
in Japan: history, outcome, and perspectives. Clinical journal of the American Society of 
Nephrology. 2007;2(6):1360-6. 
Kiryluk K, Li Y, Scolari F, Sanna-Cherchi S, Choi M, Verbitsky M, et al. Discovery of new risk 
loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens. 
Nat Genet. 2014 Nov;46(11):1187-96. 
Knoop T, Vikse BE, Mwakimonga A, Leh S,Bjorneklett R. Long-term outcome in 145 patients 
with assumed benign immunoglobulin A nephropathy. Nephrol Dial Transplant. 2017 Nov 
1;32(11):1841-50. 
Knoppova B, Reily C, Maillard N, Rizk DV, Moldoveanu Z, Mestecky J, et al. The Origin and 
Activities of IgA1-Containing Immune Complexes in IgA Nephropathy. Front Immunol. 
2016;7:117. 
Lafayette RA, Canetta PA, Rovin BH, Appel GB, Novak J, Nath KA, et al. A randomized, 
controlled trial of rituximab in IgA nephropathy with proteinuria and renal dysfunction. Journal 
of the American Society of Nephrology. 2016:ASN. 2016060640. 
Lai KN, Tang SC, Schena FP, Novak J, Tomino Y, Fogo AB, et al. IgA nephropathy. Nat Rev 
Dis Primers. 2016 Feb 11;2:16001. 
Lv J, Zhang H, Wong MG, Jardine MJ, Hladunewich M, Jha V, et al. Effect of Oral 
Methylprednisolone on Clinical Outcomes in Patients With IgA Nephropathy: The TESTING 
Randomized Clinical Trial. JAMA. 2017 Aug 1;318(5):432-42. 

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Maillard N, Wyatt RJ, Julian BA, Kiryluk K, Gharavi A, Fremeaux-Bacchi V, et al. Current 
Understanding of the Role of Complement in IgA Nephropathy. J Am Soc Nephrol. 2015 
Jul;26(7):1503-12. 
McQuillen DP,Ram S. No Good Deed Goes Unpunished: Eculizumab and Invasive Neisserial 
Infections. Clin Infect Dis. 2019 Aug 1;69(4):601-3. 
Medjeral-Thomas NR, Troldborg A, Constantinou N, Lomax-Browne HJ, Hansen AG, 
Willicombe M, et al. Progressive IgA Nephropathy Is Associated With Low Circulating 
Mannan-Binding Lectin–Associated Serine Protease-3 (MASP-3) and Increased Glomerular 
Factor H–Related Protein-5 (FHR5) Deposition. Kidney Intl Rep. 2018;3(2):426-38. 
Mestecky J, Novak J, Moldoveanu Z,Raska M. IgA nephropathy enigma. Clinical Immunology. 
2016;172:72-7. 
Morgan BP. Complement membrane attack on nucleated cells: resistance, recovery and non-
lethal effects. Biochem J. 1989 Nov 15;264(1):1-14. 
Novak J, Barratt J, Julian BA,Renfrow MB, editors. Aberrant Glycosylation of the IgA1 
Molecule in IgA Nephropathy. Seminars in nephrology; 2018: Elsevier. 
Ram S, Lewis SA,Rice PA. Infections of people with complement deficiencies and patients who 
have undergone splenectomy. Clin Microbiol Rev. 2010;23(4):740-80. 
Rauen T, Eitner F, Fitzner C, Sommerer C, Zeier M, Otte B, et al. Intensive Supportive Care plus 
Immunosuppression in IgA Nephropathy. N Engl J Med. 2015 Dec 3;373(23):2225-36. 
Reich HN, Troyanov S, Scholey JW,Cattran DC. Remission of proteinuria improves prognosis in 
IgA nephropathy. Journal of the American Society of Nephrology. 2007;18(12):3177-83. 
Ross SC,Densen P. Complement deficiency states and infection: epidemiology, pathogenesis and 
consequences of neisserial and other infections in an immune deficiency. Medicine (Baltimore). 
1984 Sep;63(5):243-73. 
Rosse WF. Variations in the red cells in paroxysmal nocturnal haemoglobinuria. Br J Haematol. 
1973 Mar;24(3):327-42. 
Sarcina C, Tinelli C, Ferrario F, Pani A, De Silvestri A, Scaini P, et al. Changes in Proteinuria 
and Side Effects of Corticosteroids Alone or in Combination with Azathioprine at Different 
Stages of IgA Nephropathy. Clin J Am Soc Nephrol. 2016 Jun 6;11(6):973-81. 
Soutschek J, Akinc A, Bramlage B, Charisse K, Constien R, Donoghue M, et al. Therapeutic 
silencing of an endogenous gene by systemic administration of modified siRNAs. Nature. 2004 
Nov 11;432(7014):173-8. 
Suzuki H, Fan R, Zhang Z, Brown R, Hall S, Julian BA, et al. Aberrantly glycosylated IgA1 in 
IgA nephropathy patients is recognized by IgG antibodies with restricted heterogeneity. J Clin 
Invest. 2009 Jun;119(6):1668-77. 
Woo KT, Chan CM, Chin YM, Choong HL, Tan HK, Foo M, et al. Global evolutionary trend of 
the prevalence of primary glomerulonephritis over the past three decades. Nephron Clin Pract. 
2010;116(4):c337-46. 

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Working Group of the International Ig ANN, the Renal Pathology S, Cattran DC, Coppo R, 
Cook HT, Feehally J, et al. The Oxford classification of IgA nephropathy: rationale, 
clinicopathological correlations, and classification. Kidney Int. 2009a Sep;76(5):534-45. 
Working Group of the International Ig ANN, the Renal Pathology S, Roberts IS, Cook HT, 
Troyanov S, Alpers CE, et al. The Oxford classification of IgA nephropathy: pathology 
definitions, correlations, and reproducibility. Kidney Int. 2009b Sep;76(5):546-56. 
Wyatt RJ, Julian BA, Baehler RW, Stafford CC, McMorrow RG, Ferguson T, et al. 
Epidemiology of IgA nephropathy in central and eastern Kentucky for the period 1975 through 
1994. Central Kentucky Region of the Southeastern United States IgA Nephropathy 
DATABANK Project. J Am Soc Nephrol. 1998 May;9(5):853-8. 
Zimmermann TS, Lee AC, Akinc A, Bramlage B, Bumcrot D, Fedoruk MN, et al. RNAi-
mediated gene silencing in non-human primates. Nature. 2006 May 04;441(7089):111-4. 
 

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10. 
APPENDICES 
None. 

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ALN-CC5-005 PROTOCOL AMENDMENT 4 
SUMMARY OF CHANGES DATED 19 JANUARY 2021  
COMPARED TO PROTOCOL AMENDMENT 3 DATED 27 APRIL 2020 
A Phase 2, Randomized, Double-blind, Placebo-controlled Study of Cemdisiran in Adult 
Patients with IgA Nephropathy 
1.
RATIONALE FOR PROTOCOL AMENDMENT
The primary purpose for this protocol amendment is to extend the open-label extension (OLE) 
period by an additional 2 years.  This will allow patients who are nearing the end of the current 
1-year OLE period to continue to receive cemdisiran on-study and will allow for collection of
additional data on long-term treatment with cemdisiran.
Several additional changes are being implemented as outlined below. 
•
Clarification that off-site visit flexibility applies from Week 40 of the OLE period, as
described in Protocol Administrative Letter 3
•
Clarification that masking of the study drug syringe is not required during home
administration by a patient/caregiver as it is not considered a significant risk to
unblinding
•
Addition of creatine supplementation to list of prohibited concomitant medications, as
these supplements may increase plasma and urine creatinine and may, therefore,
confound study assessments
•
Clarification that electrocardiogram (ECG) readings are to be recorded one minute
apart
•
Specification that only patients who receive a full dose of study drug and have
1 relevant postdose sample will be analyzed in the pharmacokinetic (PK) and
pharmacodynamic (PD) analysis sets.
A detailed summary of changes is provided in Section 2.  The following changes are not 
detailed:  administrative changes, changes associated with administrative letters (between 
protocol amendments 3 and 4), and corrections to typographical errors, punctuation, grammar, 
abbreviations, and formatting.  
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2. 
PROTOCOL AMENDMENT 4 DETAILED SUMMARY OF CHANGES 
The primary section(s) of the protocol affected by the changes in Protocol Amendment 4 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:  To extend the open-label extension period from 1 year (52 weeks) to 3 years (156 weeks) 
The primary change occurs in Table 2 (Schedule of Assessments – Open Label Extension Period and Safety Follow-up) 
Revised text: Assessment timing during Year 1 of the OLE period was updated and Table 3 (Schedule of Assessments – Year 2) and 
Table 4 (Schedule of Assessments- Year 3 and Safety Follow-up) were added.  The End of Treatment visit will be at Week 184 and 
the End of Study/Early Termination visit will be at Week 188. 
Section(s) also reflecting this change:   
• Synopsis 
• Figure 1, Study Design 
• Section 1.4, Dose Rationale 
• Section 3.1, Summary of Study Design 
• Section 3.2, Duration of Treatment 
• Section 3.3, Duration of Study 
• Section 4.3.1, Discontinuation of Study Drug or Declining Procedural Assessments 
• Section 5.2.2, Dose and Administration 
• Section 5.3.2, Study-specific Vaccinations 
• Section 6.4, Efficacy Assessments 
• Section 6.5, Pharmacodynamic Assessments 
• Section 6.7, Safety Assessments 
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Purpose:  To clarify that study drug syringe masking is not required when study drug is administered at home by the 
patient/caregiver. 
The primary change occurs in Section 3.6, Blinding 
Revised text:  Since cemdisiran may be visually distinguishable from placebo, the syringe will be masked by a site pharmacist prior to 
administration by a the healthcare professional or a patient/caregiver.  Syringe masking is not required if study drug is being 
administered at home by the patient or caregiver as it is not considered a significant risk to unblinding. 
Section(s) also reflecting this change:  None. 
Purpose:  To state that creatine supplements should be avoided during the study. 
The primary change occurs in Section 5.3.1, Prohibited Concomitant Medications 
Added text: The following concomitant medications are prohibited during the study:  
• Systemic steroids (short-term steroid course for <7 days for common conditions not related to IgAN (i.e. asthma, gout) is 
permitted) 
• Immunosuppressive agents 
• Fish oil supplements (if started prior to Screening, then may continue during the study at the same dose) 
• Hydroxychloroquine 
• Creatine supplements 
Section(s) also reflecting this change:  None. 
Purpose:  To clarify that ECG readings are to be recorded 1 minute apart. 
The primary change occurs in Section 6.7.4, Electrocardiogram 
Revised text:  A single 12-lead ECG will be performed at screening.  At all other time points, 12-lead ECGs will be performed in 
triplicate, with readings approximately 1 minute apart. 
Section(s) also reflecting this change:  None. 
Purpose:  To specify that only patients who receive a full dose of study drug and have at least 1 relevant postdose sample will be 
analyzed in the PK and PD analysis sets. 
The primary change occurs in Section 7.2.1, Populations to be Analyzed 
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Revised text:  The following populations will be analyzed: 
• Modified Intent-to-treat (mITT): All patients who receive any amount of study drug and have at least one post baseline 
assessment in proteinuria.  Patients will be grouped by assigned treatments (ie, as randomized). 
• Safety Analysis Set: All patients who received any amount of study drug.  Patients who received any amount of cemdisiran 
will be included in the cemdisiran arm.  Patients in the Safety Analysis Set will be grouped by treatment received. 
• PK Analysis Set: All patients who receive any amount a full dose of study drug and have at least one postdose blood or 
urine sample for PK concentration. 
• PD Analysis Set: All patients who receive any amount a full dose of study drug and who have at least one postdose blood 
sample for the determination of plasma C5 level. 
Section(s) also reflecting this change:  Synopsis. 
Purpose:  Administrative changes, changes associated with administrative letters (between protocol amendments 3 and 4), and 
corrections to typographical errors, punctuation, grammar, abbreviations, and formatting.  
These changes are not listed individually. 
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CLINICAL STUDY PROTOCOL 
ALN-CC5-005 
 
Protocol Title: 
A Phase 2, Randomized, Double-blind, 
Placebo-controlled Study of Cemdisiran in Adult 
Patients with IgA Nephropathy 
Short Title: 
A Phase 2 Study of Cemdisiran in Adult Patients 
with IgA Nephropathy 
Study Drug: 
Cemdisiran (ALN-CC5)  
EudraCT Number: 
2018-002716-27 
IND Number: 
140087 
Protocol Date: 
 
Original protocol 10 September 2018 
Amendment 1 [26 November 2018] 
Amendment 2 [20 September 2019] 
Amendment 3 [27 April 2020] 
Sponsor: 
Alnylam Pharmaceuticals, Inc. 
300 Third Street 
Cambridge, MA  02142 USA 
Telephone:  
 
Sponsor Contact:   
 
 
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. 
 
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INVESTIGATOR’S AGREEMENT 
 
I have read the ALN-CC5-005 protocol and agree to conduct the study in accordance with the 
protocol and all applicable regulations.  I agree to maintain the confidentiality of all information 
received or developed in connection with this protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 
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• 
To evaluate the pharmacodynamic (PD) 
effect of cemdisiran ie, C5 level and 
CAP/CCP 
• 
To characterize the pharmacokinetics 
(PK) of cemdisiran and relevant 
metabolites in plasma and urine in adult 
patients with IgAN 
• 
To evaluate the effect of cemdisiran on 
serum and urine markers of complement 
activation, renal damage and 
inflammation 
• 
To assess the incidence of antidrug 
antibodies (ADA) 
• 
The slope of eGFR computed for the 
entire study period including the open 
label extension using all assessments 
during the study. 
• 
Change from baseline in creatinine 
clearance at Week 32 
• 
Percent of patients in full clinical 
remission (UP <0.3 g/24-hours) at 
Week 32  
• 
Change from baseline in 24-hour 
albuminuria at Week 32 
• 
Change from baseline in the urine 
albumin/creatinine ratio (UACR) as 
measured in 24-hour urine at Week 32 
• 
Change from baseline in C5 level over the 
course of the study 
• 
Change from baseline in complement 
activity (Complement Alternative 
Pathway [CAP]and Complement 
Classical Pathway [CCP]) over the course 
of the study 
• 
Evaluation of area under the curve 
(AUC), maximum plasma concentration 
(Cmax), time to maximum plasma 
concentration (Tmax), terminal half-life 
(t½), clearance (CL/F), volume of 
distribution (V/F), cumulative amount 
excreted unchanged in urine (Ae) and 
percent of dose excreted in the urine (fe) 
of cemdisiran (25-mer) and 23-mer 
• 
Evaluation of AUC, Cmax, Tmax, t½, CL/F, 
V/F, Ae and fe of 22-mer AS(N-1)3’ 
• 
Change from baseline in levels of renal 
damage, complement activation and 
inflammation markers over the course of 
the study 
• 
Incidence of antidrug antibodies (ADA) 
Study Design 
This is a multicenter, double-blind, placebo-controlled study comprised of three periods Figure 1.  The 
first period of the study is an observational 14-week run-in period during which patients’ blood pressure, 
kidney function, degree of hematuria, and proteinuria will be measured.  The standard of care is expected 
to remain unchanged during this run-in period.  Patients will not receive study drug (cemdisiran or 
placebo) during this time.  The second study period is a 36-week treatment period (defined as the time the 
first dose of study drug is administered on Study Day 1 through completion of the Week 36 assessments) 
which will evaluate the efficacy and safety of subcutaneous (SC) cemdisiran compared to SC placebo in 
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combination with standard of care in patients with IgAN and persistent proteinuria.  The third period of 
the study is a 52-week optional open-label extension (OLE) period to further evaluate the long-term 
safety and clinical activity of cemdisiran.  During the OLE, all patients (including those initially on 
placebo) will be treated with cemdisiran in combination with standard of care. 
The study will include Screening of up to 120 days to determine eligibility of patients and to complete 
disease-related assessments.  The Investigator will notify the Sponsor before screening patients to allow 
an assessment of the ability of the site and new trial participants to comply with the protocol given 
limitations during the COVID-19 pandemic.  Patients will provide written informed consent and visit the 
study site approximately 2 weeks before starting the run-in period to complete the protocol screening 
assessments.  Following successful screening, the 14-week run-in period will commence, during which 
patients’ blood pressure, kidney function, degree of hematuria and proteinuria as well as treatment with 
standard of care will be documented by the Investigator.  The standard of care is expected to remain 
unchanged during this run-in period.  Patients whose proteinuria level remains ≥1 g/24-hours within 2 
weeks of the end of the run-in period, and who meet blood pressure and estimated glomerular filtration 
rate (eGFR) criteria will be eligible to enroll in the 36-week treatment period.  Upon confirmation of 
eligibility followed by vaccination against meningococcal infections, patients will be randomized at a 2:1 
ratio to receive 600 mg of cemdisiran or placebo every 4 weeks in combination with standard of care.  
Approximately 30 patients are planned to be randomized in total, 20 in the cemdisiran arm and 10 in the 
placebo arm.  Patients excluded before randomization will be replaced at Screening.  
During the run-in period, patients will visit the study site 14, 8, and 2 weeks prior to randomization 
(Weeks 0, 6 and 12 of the run-in period).  If a run-in visit cannot proceed according to schedule, it may be 
delayed up to 28 days, with subsequent visits being rescheduled based on the new date.  Visit windows, as 
indicated in the Schedule of Assessments (Table 1), are applied to the rescheduled date.  Approval from 
the Medical Monitor is required prior to initiation of the treatment period.  If a subject cannot proceed to 
the treatment period as planned, the run-in period can be extended as needed.  If the final run-in visit will 
not be within 56 days of randomization, this visit will be repeated, and the new visit will serve as the 
Week -2 visit to determine eligibility for randomization.   
Study drug administration may be conducted by a healthcare professional at a location other than the 
study site (eg, at home) from Week 4 of the treatment period for patients that have demonstrated the 
ability to tolerate the study drug at the study site.  If the patient is unable to come to the study site, and a 
visit by a healthcare professional for patients at a location other than the study site (eg, at home) is not 
possible due to circumstances related to the COVID-19 pandemic, cemdisiran may be administered by the 
patient or the caregiver under the oversight of the Investigator, and following consultation with the 
Medical Monitor, as allowed by applicable country and local regulations.  In such cases, the patient or the 
caregiver must receive appropriate training on cemdisiran administration prior to dosing.  This measure is 
intended to remain in effect only during periods of time when the COVID-19 pandemic impedes the 
ability of patients to travel to the study site or healthcare professionals to go to a location other than the 
study site (eg, at home) for dosing.  The primary endpoint will be assessed at the end of treatment at 
Week 32. 
At the end of treatment (Week 32), patients in the two treatment arms will enter the optional OLE period 
where they will receive cemdisiran at a dose of 600 mg every 4 weeks in combination with standard of 
care for 52 weeks.  The first study drug administration of the OLE will be administered at Week 36.  
Patients will return to the study site at Week 40 and every 8 weeks thereafter during the OLE.  Visits at a 
location other than the study site (eg, at home), where locally feasible, may be arranged for cemdisiran 
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administration in between 8-weekly study site visits (Weeks 44, 52, 60, 68 and 76), unless patients are 
required to visit the study site as judged necessary by the Investigator, or if visits at a location other than 
the study site (eg, at home) cannot be arranged.  An end of treatment (EOT) visit will occur at Week 80 
(OLE EOT) and an end of study (EOS) or early termination (ET) visit will be completed at Week 84 
(OLE EOS/ET).  For patients who complete the treatment period only and who do not consent to continue 
to participate in the study in the OLE period, the EOS/ET visit will be at Week 36. 
Patients will return to the clinical study site for safety follow-up visits approximately 13, 26, 39 and 52 
weeks after the EOS/ET visit (regardless if EOS/ET visit is at Week 36 or Week 84), unless enrolled in 
another study with cemdisiran.  Visits at a location other than the study site (eg, at home), where locally 
feasible, may be arranged during safety follow-up at 13 and 39 weeks after the EOS/ET visit (regardless if 
EOS/ET visit is at Week 36 or Week 84).   
Regular reviews of safety and tolerability data will be performed by a Data Monitoring Committee 
(DMC) throughout the study with the primary purpose of protecting the safety of participating patients 
and the integrity of the study. 
Number of Planned Patients 
Approximately 30 patients are planned for randomization in this study. 
Diagnosis and Main Eligibility Criteria 
This study will include adults (≥18 years and ≤ 65 years of age) with a clinical diagnosis of primary 
immunoglobulin A (IgA) Nephropathy based on historical biopsy collected within 60 months of 
Screening, treated for IgA Nephropathy with stable, optimal pharmacological therapy including 
maximum allowed or tolerated angiotensin converting enzyme (ACE) inhibitor or angiotensin II receptor 
blocker (ARB) for at least 3 months prior to the start of the run-in period.  Eligible patients must have 
urine protein levels of ≥1 g/24-hour at Screening from a valid 24-hour urine collection (see 
Section 6.4.1.1), and mean urine protein levels ≥1 g/24-hour from two valid 24-hour urine collections at 
the end of the run-in period (Week -2 visit), prior to randomization.  In addition, eligible patients must 
have hematuria defined by ≥10 red blood cells per high powered field (RBC/hpf) by microscopy or a 
positive urine dipstick (2+ [moderate] and above) measured by a central laboratory at Screening.  Eligible 
patients are required to have been previously vaccinated with meningococcal group ACWY conjugate 
vaccine and meningococcal group B vaccine or be willing to receive these vaccinations as well as 
prophylactic antibiotic treatment, if required by local standard of care (see Section 5.3.2.1 and 
Section 5.3.2.2 for vaccination time windows).  In addition, patients not previously vaccinated against 
Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) must be willing to receive these 
vaccinations according to local guidelines. 
Patients will be excluded from the study if eGFR <30 mL/min/1.73 m2 2 weeks prior to randomization; 
treated with systemic steroids for more than 7 days or other immunosuppressant agents in the 6 months 
prior to randomization; treated with dual RAS blockade in the 3 months prior to entry into the run-in 
phase; have a diagnosis of rapidly progressive glomerulonephritis as measured by eGFR loss >30% over 
the duration of the run-in phase; sustained blood pressure >140/90 mmHg as defined by 2 or more 
readings during the run-in period measured in supine position after 10 minutes of rest; have received 
organ transplant (including hematologic transplant) or have secondary etiologies of IgAN (eg, 
inflammatory bowel disease, celiac disease).  
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Study Drug, Dose, and Mode of Administration 
Cemdisiran is a synthetic small interfering RNA (siRNA) targeting complement component 5 (C5) 
mRNA that is covalently linked to a triantennary N-acetylgalactosamine (Tri-GalNAc) ligand.  
Cemdisiran will be supplied as a sterile solution for SC injection that contains 200 mg/mL cemdisiran 
sodium (equivalent to 189 mg/mL of cemdisiran), formulated in water for injection (WFI) for SC 
administration.  Doses of 600 mg of cemdisiran will be administered every 4 weeks over a period of 32 
weeks during the 36-week treatment period and the optional OLE period.  
Placebo (normal saline 0.9% for SC administration) will be packaged and administered identically to 
cemdisiran. 
Reference Treatment, Dose, and Mode of Administration 
Angiotensin converting enzyme inhibitors (ACE) or angiotensin II receptor blockers (ARB) per physician 
and manufacturer‘s instructions. 
Duration of Treatment and Study 
Subcutaneous doses of cemdisiran or matching placebo will be administered every 4 weeks over a period 
of 32 weeks during the 36-week treatment period and patients will receive SC doses of cemdisiran for a 
further 52 weeks in the optional OLE.  The estimated total time on study, inclusive of Screening (120 
days), run-in period (14 weeks), treatment period (36 weeks), extension period (52 weeks) and safety 
follow-up (52 weeks), for patients is approximately 43 months or 3 years and 7 months. 
Statistical Methods 
The primary endpoint of the study is the percentage change from baseline in UPCR from a 24-hour urine 
sample at Week 32.  Approximately 30 patients are planned to be randomized 2:1 (cemdisiran:placebo) in 
this study based on the assumption that, in the placebo arm, the estimated geometric mean ratio of UPCR 
at Week 32 to baseline is 0.88 (log standard deviation [SD] 0.597), corresponding to a 12% reduction, 
while the geometric mean ratio is 0.5, or a 50% reduction for the cemdisiran arm.  Using these 
assumptions, sample size of 9 and 18 in the placebo and cemdisiran arms, respectively, will provide a 
width of 0.80 (± 0.4) for the 90% confidence interval (CI) for treatment effect size estimate (cemdisiran – 
placebo) in log scale.  The primary analysis will be performed using a restricted maximum likelihood 
(REML) based Mixed-Effect Model Repeated Measures (MMRM) approach.  
The analysis populations include: 
• 
The modified Intent-to-treat (mITT) population will include all patients who receive any 
amount of study drug and have at least one post baseline 24-hour proteinuria assessment.  
Patients will be grouped by assigned treatments (ie, as randomized).  
• 
The Safety Analysis Set will include all patients who received any amount of study drug.  
Patients who received any amount of cemdisiran will be included in the cemdisiran arm.  
Patients in the Safety Analysis Set will be grouped by treatment received.  
• 
PK Analysis Set: All patients who receive any amount of study drug and have at least one 
postdose blood or urine sample for PK concentration.  
• 
PD Analysis Set: All patients who receive any amount of study drug and who have at least 
one postdose blood sample for the determination of plasma C5 level. 
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The efficacy endpoints will be analyzed in the mITT population.  PK and PD parameters will be analyzed 
in the PK and PD analysis sets, respectively. 
Safety data will be summarized with descriptive statistics using the Safety Analysis Set.  
Figure 1: 
Study Design  
 
Abbreviations:  Q4W=once every 4 weeks; EOS=end of study; EOT=end of treatment 
 
 
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Table 3: 
Pharmacokinetic Time Points 
Phase 
Study Day 
Protocol Time Relative to 
Dosing 
(hh:mm)a 
PK Blood Pooled Urineb 
Treatment phase 
Day 1 
Predose (within 60 mins) 
X 
 
00:00 (dose) 
 
X 
01:00 (±5 mins) 
X 
02:00 (±15 mins) 
X 
04:00 (±15 mins) 
X 
06:00 (±15 mins) 
X 
08:00 (±30 mins) 
Xc 
X 
12:00 (±30 mins) 
 
24:00 (±120 mins) 
Xc 
X 
Abbreviations:   hh=hours; mm=minutes; mins=minutes; PK=pharmacokinetics. 
a The actual time of blood sample collection must be recorded. 
b The pooled urine 6-12 hours and 12-24 hours can be collected as outpatient. 
c Blood samples for PK assessment at these time points postdose may be collected if locally feasible. 
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TABLE OF CONTENTS 
SPONSOR PROTOCOL APPROVAL ...........................................................................................2 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
PROTOCOL SYNOPSIS ................................................................................................................4 
TABLE OF CONTENTS ...............................................................................................................21 
LIST OF TABLES .........................................................................................................................25 
LIST OF FIGURES .......................................................................................................................25 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................26 
1. 
INTRODUCTION ......................................................................................................29 
1.1. 
Disease Overview .......................................................................................................29 
1.2. 
Cemdisiran ..................................................................................................................31 
1.3. 
Study Design Rationale ..............................................................................................32 
1.4. 
Dose Rationale ............................................................................................................33 
1.5. 
Benefit-Risk Assessment ............................................................................................34 
2. 
OBJECTIVES AND ENDPOINTS ............................................................................36 
3. 
INVESTIGATIONAL PLAN .....................................................................................38 
3.1. 
Summary of Study Design ..........................................................................................38 
3.2. 
Duration of Treatment ................................................................................................39 
3.3. 
Duration of Study .......................................................................................................39 
3.3.1. 
Definition of End of Study for an Individual Patient .................................................39 
3.4. 
Number of Planned Patients .......................................................................................40 
3.5. 
Method of Assigning Patients to Treatment Groups ..................................................40 
3.6. 
Blinding ......................................................................................................................40 
3.6.1. 
Emergency Unblinding ...............................................................................................40 
3.7. 
Data Monitoring Committee .......................................................................................41 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................41 
4.1. 
Inclusion Criteria ........................................................................................................41 
4.2. 
Exclusion Criteria .......................................................................................................42 
4.3. 
Removal from Therapy or Assessment.......................................................................43 
4.3.1. 
Discontinuation of Study Drug or Declining Procedural Assessments ......................44 
4.3.2. 
Stopping a Patient’s Study Participation ....................................................................45 
4.3.2.1. 
Patient or Legal Guardian Stops Participation in the Study .......................................45 
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4.3.2.2. 
Withdrawal of Consent to Process the Patient’s Personal Data .................................45 
4.3.2.3. 
Investigator or Sponsor Stops Participation of a Patient in the Study ........................45 
4.3.2.4. 
Recording Reason for Stopping a Patient’s Study Participation ................................45 
4.3.3. 
Lost to Follow-Up.......................................................................................................46 
4.3.4. 
Replacement of Study Patients ...................................................................................46 
5. 
TREATMENTS AND OTHER REQUIREMENTS ..................................................46 
5.1. 
Treatments Administered ............................................................................................46 
5.2. 
Study Drug ..................................................................................................................46 
5.2.1. 
Description ..................................................................................................................46 
5.2.2. 
Dose and Administration ............................................................................................47 
5.2.3. 
Dose Modifications .....................................................................................................47 
5.2.3.1. 
LFT Criteria for Withholding, Monitoring and Stopping Cemdisiran Dosing ...........48 
5.2.4. 
Preparation, Handling, and Storage ............................................................................49 
5.2.5. 
Packaging and Labeling ..............................................................................................50 
5.2.6. 
Accountability .............................................................................................................50 
5.3. 
Concomitant Medications and Procedures .................................................................50 
5.3.1. 
Prohibited Concomitant Medications .........................................................................50 
5.3.2. 
Study-specific Vaccinations .......................................................................................51 
5.3.2.1. 
Meningococcal Vaccinations ......................................................................................51 
5.3.2.2. 
Pneumococcal and Hib Vaccinations .........................................................................51 
5.4. 
Treatment Compliance ................................................................................................52 
5.5. 
Other Requirements ....................................................................................................52 
5.5.1. 
Contraception ..............................................................................................................52 
5.5.2. 
Alcohol Restrictions ...................................................................................................53 
5.5.3. 
Antibiotic Compliance ................................................................................................53 
6. 
STUDY ASSESSMENTS ..........................................................................................53 
6.1. 
Screening Assessments ...............................................................................................53 
6.1.1. 
Rescreening .................................................................................................................54 
6.1.2. 
Retesting .....................................................................................................................54 
6.2. 
Run-in Period ..............................................................................................................54 
6.3. 
Baseline Assessments (Treatment Period) ..................................................................55 
6.4. 
Efficacy Assessments .................................................................................................55 
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6.4.1. 
Urine Protein/Creatinine Ratio ...................................................................................55 
6.4.1.1. 
24-Hour Urine Collection ...........................................................................................55 
6.4.1.2. 
Spot Urine Collection .................................................................................................56 
6.4.2. 
Hematuria ...................................................................................................................56 
6.4.3. 
Changes in Renal Function .........................................................................................56 
6.4.4. 
Markers of Complement Activation, Inflammation and Renal Injury .......................57 
6.5. 
Pharmacodynamic Assessments .................................................................................57 
6.6. 
Pharmacokinetic Assessments ....................................................................................57 
6.7. 
Safety Assessments .....................................................................................................57 
6.7.1. 
Vital Signs ..................................................................................................................57 
6.7.2. 
Weight and Height ......................................................................................................58 
6.7.3. 
Physical Examination .................................................................................................58 
6.7.4. 
Electrocardiogram .......................................................................................................58 
6.7.5. 
Clinical Laboratory Assessments ...............................................................................59 
6.7.5.1. 
Immunogenicity ..........................................................................................................60 
6.7.5.2. 
Pregnancy Testing ......................................................................................................61 
6.7.5.3. 
Additional Liver Function Assessments .....................................................................61 
6.7.6. 
Adverse Events ...........................................................................................................62 
6.7.6.1. 
Definitions ..................................................................................................................62 
6.7.6.2. 
Eliciting and Recording Adverse Events ....................................................................64 
6.7.6.3. 
Reporting Adverse Events of Clinical Interest to Sponsor/Designee .........................65 
6.7.6.4. 
Serious Adverse Events Require Immediate Reporting to Sponsor/Designee ...........65 
6.7.6.5. 
Sponsor Safety Reporting to Regulatory Authorities .................................................66 
6.7.6.6. 
Serious Adverse Event Notification to the Institutional Review 
Board/Independent Ethics Committee ........................................................................66 
6.7.6.7. 
Pregnancy Reporting ..................................................................................................66 
6.7.6.8. 
Overdose Reporting ....................................................................................................66 
6.7.7. 
COVID-19 Data Collection ........................................................................................67 
6.8. 
Biomarkers, DNA Genotyping, and Biospecimen Repository ...................................67 
7. 
STATISTICS ..............................................................................................................67 
7.1. 
Determination of Sample Size ....................................................................................67 
7.2. 
Statistical Methodology ..............................................................................................68 
7.2.1. 
Populations to be Analyzed ........................................................................................68 
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7.2.2. 
Examination of Subgroups .........................................................................................68 
7.2.3. 
Handling of Missing Data ...........................................................................................69 
7.2.4. 
Baseline Evaluations ...................................................................................................69 
7.2.5. 
Efficacy Analyses .......................................................................................................69 
7.2.5.1. 
Primary Endpoint ........................................................................................................69 
7.2.5.2. 
Secondary Efficacy Endpoints ....................................................................................69 
7.2.5.3. 
Exploratory Endpoints ................................................................................................69 
7.2.6. 
Pharmacodynamic Analysis........................................................................................70 
7.2.7. 
Pharmacokinetic Analysis ..........................................................................................70 
7.2.8. 
Safety Analyses ..........................................................................................................70 
7.2.9. 
Immunogenicity Analyses ..........................................................................................71 
7.2.10. 
Biomarker Analyses ....................................................................................................71 
7.2.11. 
Interim Analysis ..........................................................................................................71 
7.2.12. 
Optional Additional Research .....................................................................................71 
8. 
STUDY ADMINISTRATION ...................................................................................71 
8.1. 
Ethical and Regulatory Considerations ......................................................................71 
8.1.1. 
Informed Consent .......................................................................................................71 
8.1.2. 
Ethical Review ............................................................................................................72 
8.1.3. 
Serious Breach of Protocol .........................................................................................72 
8.1.4. 
Study Documentation, Confidentiality, and Records Retention .................................72 
8.1.5. 
End of Study ...............................................................................................................73 
8.1.6. 
Termination of the Clinical Study or Site Closure .....................................................73 
8.2. 
Data Quality Control and Quality Assurance .............................................................73 
8.2.1. 
Data Handling .............................................................................................................73 
8.2.2. 
Study Monitoring ........................................................................................................73 
8.2.3. 
Audits and Inspections ................................................................................................74 
8.3. 
Publication Policy .......................................................................................................74 
9. 
LIST OF REFERENCES ............................................................................................75 
10. 
APPENDICES ............................................................................................................78 
 
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LIST OF TABLES 
Table 1: 
Schedule of Assessments – Run-in and Treatment Periods (Screening 
through Week 36) including Safety Follow-up ..........................................................10 
Table 2: 
Schedule of Assessments – Open-Label Extension Period and Safety 
Follow-up ....................................................................................................................17 
Table 3: 
Pharmacokinetic Time Points .....................................................................................20 
Table 4: 
Monitoring and Dosing Rules for Asymptomatic Patients with Confirmed 
Isolated Elevations of ALT and/or AST >3× ULN, with No Alternative 
Cause Identified ..........................................................................................................49 
Table 5: 
Clinical Laboratory Assessments ...............................................................................59 
Table 6: 
Hepatic Assessments in Patients Who Experience Elevated Transaminases .............62 
 
LIST OF FIGURES 
Figure 1: 
Study Design .................................................................................................................9 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation  
Definition 
ADA 
Antidrug antibodies 
ACE 
Angiotensin-converting enzyme 
AE 
Adverse event 
AECI 
Adverse event of clinical interest 
aHUS 
Atypical hemolytic uremic syndrome 
ALN-CC5 
Cemdisiran 
ALT 
Alanine transaminase 
ARB 
Angiotensin II receptor blocker 
AST 
Aspartate transaminase 
AUC 
Area under the concentration curve 
BMI 
Body mass index 
C3 
Complement component 3 
C3a 
Activated complement 3 
C5 
Complement component 5 
C5a 
Activated complement component 5 
CAP 
Complement alternative pathway 
CCP 
Complement classical pathway 
CFH 
Complement factor H 
CI 
Confidence interval 
CIC 
Circulating immune complexes 
CL/F 
Clearance 
Cmax 
Maximum concentration 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
ELISA 
Enzyme linked immunosorbent assay 
EOS 
End of study 
EOT 
End of treatment 
ESRD 
End-stage renal disease 
GalNAc 
N-acetylgalactosamine 
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Abbreviation  
Definition 
GCP 
Good Clinical Practice 
Gd-IgA1 
Galactose-deficient Immunoglobulin A 1 
GFR 
Glomerular filtration rate 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
Hib 
Haemophilus influenzae type b 
HIV 
Human immunodeficiency virus 
hpf 
High powered field 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonisation 
IEC 
Independent Ethics Committee 
IgA 
Immunoglobulin A 
IgG 
Immunoglobulin G 
IgAN 
IgA Nephropathy 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRS 
Interactive Response System 
ISR 
Injection site reaction 
IV 
Intravenous 
LFT 
Liver function test 
MAC 
Membrane attack complex 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified intent-to-treat 
mRNA 
Messenger RNA 
NHP 
Nonhuman primates 
OLE 
Open-label extension 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic(s) 
PNH 
Paroxysmal nocturnal hemoglobinuria 
RAS 
Renin-angiotensin system 
RBC 
Red blood cell 
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Abbreviation  
Definition 
RNAi 
RNA interference 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous(ly) 
siRNA 
Small interfering RNA 
SUSAR 
Suspected unexpected serious adverse reaction 
t½ 
Terminal half-life 
Tmax 
Time to maximum concentration 
TMF 
Trial Master File 
Tri-GalNAc 
Triantennary N-acetylgalactosamine 
UP 
Urine protein 
UACR 
Urine albumin/creatinine ratio 
ULN 
Upper limit of normal 
UPCR 
Urine protein/creatinine ratio 
V/F 
Volume of distribution 
 
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1. 
INTRODUCTION 
1.1. 
Disease Overview 
Globally, immunoglobulin A nephropathy (IgAN) is the most common primary 
glomerulonephritis that can progress to renal failure.[Lai 2016; Wyatt 1998]  While the exact 
pathogenesis of IgAN is incompletely understood, biochemical, genetic, and clinical data suggest 
IgAN is an autoimmune disease that may originate from overproduction of aberrantly O-
glycosylated IgA1 (Gd-IgA1) and the presence of glycan-specific IgA and immunoglobulin G 
(IgG) autoantibodies that recognize the under-galactosylated IgA1 molecule, resulting in the 
formation of pathogenic immune complexes.  Some of these circulating complexes may deposit 
in glomeruli and induce renal injury.[Knoppova 2016]  The lack of galactose exposes O-linked 
monosaccharide N-acetylgalactosamine (O-GalNAc) moeities in the hinge region of 
IgA1.[Novak 2018] While the binding of autoantibodies to Gd-IgA1 is dependent on the 
presence of multiple O-GalNAc residues, the IgA1 protein backbone and the spatial arrangement 
of O-GalNAc moieties are also thought to play a role in the specificity of autoantibodies to Gd-
IgA1.[Mestecky 2016; Suzuki 2009] 
Both the alternative and lectin complement pathways may be activated, leading to generation of 
the anaphylatoxins activated complement component 3 (C3a) and activated complement 
component 5 (C5a) and the membrane attack complex (MAC) C5b-9, with subsequent 
promotion of inflammatory mediators.[Maillard 2015]  Emerging data indicate that 
mesangial-derived mediators that are released following deposition of IgA1 may lead to 
podocyte and tubulointerstitial injury. 
Given that a biopsy specimen is required to diagnose IgAN, the clinical threshold for performing 
a biopsy will have a major impact on the prevalence of IgAN.  Persistent microscopic hematuria 
alone and/or mild proteinuria alone are not commonly used as a per cause indication for biopsy 
in the United States.  Thus, the prevalence of IgAN is modest in the United States (10 to 20% of 
primary glomerulonephritis), higher in some European countries (20 to 30%), and highest in 
developed countries in Asia (40 to 50%).[Woo 2010]  This considerable geographical variability 
can be explained by several factors including the variation in access to primary care enabling 
early diagnosis and the differences in policies for performing renal biopsies as well as for early 
referrals.  For example, in some countries, urine screening tests are conducted in schools or for 
military service or ahead of employment, explaining the apparent high incidence.[Imai 2007; 
Wyatt 1998]  Ethnic differences can also contribute to the varying prevalence of IgAN.  
Genome-wide association studies have identified candidate genes as well as risk-associated and 
protective alleles, with the highest number of risk alleles present in individuals of East Asian 
origin and the lowest number in those from Africa.[Kiryluk 2014]  These genes are involved in 
antigen presentation, mucosal defense system and notably the alternative complement pathway 
(complement factor H [CFH]/CFHR locus).[Kiryluk 2014]  Finally, patients may present at any 
age with IgAN but there is a peak incidence in the second and third decades of life.  Most cases 
of IgAN occur in sporadic (90 to 95%) rather than in familial patterns (5 to 10%).[Lai 2016] 
Routine screening for IgAN is not feasible given that no specific diagnostic laboratory tests are 
available.  The first indication for making a diagnosis comes after careful microscopic 
examination of a urine sample.  The presence of red blood cell (RBC) casts and dysmorphic 
RBCs indicates glomerular bleeding.  Varying degrees of proteinuria are present in patients with 
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IgAN.  Proteinuria can be quantified with a timed urine collection or a spot urine protein to 
creatinine ratio (UPCR) measurement.  Hence, IgAN can only be diagnosed definitely upon renal 
biopsy and study of kidney tissue using immunofluorescence.  The pathology of IgAN is 
characterized by deposition of pathogenic polymeric IgA1 immune complexes and C3 in the 
glomerular mesangium, proliferation of mesangial cells, increased synthesis of extracellular 
matrix and variable infiltration of macrophages, monocytes and T cells.  A consensus on the 
pathologic classification of IgAN has been developed by the International IgA Nephropathy 
Network in collaboration with the Renal Pathology Society (Oxford classification).[Cattran 
2009; Lai 2016; Roberts 2009] 
The clinical presentation of patients with IgAN is highly variable, ranging from asymptomatic 
microscopic hematuria to a rapidly progressive form of glomerulonephritis which is often 
associated with severe hypertension, but between these extremes, most patients with IgAN 
pursue a chronic indolent course.[Lai 2016]  Some patients present with more severe proteinuria, 
hypertension and renal progression over time, typically reaching end-stage renal disease (ESRD) 
over a span of 20 years.  Thus, the severity of proteinuria upon presentation has significant 
prognostic implications.  More importantly, the change in proteinuria over time is being regarded 
as the current best prognostic indicator: those who had heavy time averaged proteinuria and 
achieved a partial remission of <1 g/24-hours had a similar course to those who had 
<1 g/24-hours throughout and fared far better than those who never achieved partial 
remission.[Reich 2007]  These observations support the notion that every effort should be made 
to reduce proteinuria in IgAN.  In addition to the degree of proteinuria, baseline renal function 
and the degree of histological injury are of prognostic value.  For example, patients with an 
estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 at the time of renal biopsy have 
worse outcomes than those with normal eGFR (90 to 120 mL/min/1.73 m2).  The rate of 
glomerular filtration rate (GFR) decline also correlates with glomerulosclerosis and tubular 
atrophy or interstitial fibrosis on biopsy as outlined by Oxford-MEST-C classification.  
Spontaneous full recovery in IgAN is rare in adults, especially if associated with significant 
proteinuria (>0.5 g/24-hour).[Knoop 2017] 
Patients with minor urine abnormalities, normal blood pressure, and normal GFR usually do well 
and require only monitoring.  For other patients, the therapeutic options are limited and include 
nonspecific treatment to reduce blood pressure and proteinuria by renin-angiotensin system 
(RAS) blockade.  Thus, no disease-specific therapies are currently available, and an unmet need 
persists for novel interventions, particularly in patients who are at risk of progressive disease that 
can result in end-stage renal failure.  The optimal role of immunosuppressive therapy is 
uncertain.  The available studies are not conclusive since most are relatively small and have 
limited follow-up.[Lai 2016]  STOP-IgAN, a German trial, randomly assigned adults with an 
eGFR of >30 mL/min/1.73 m2 and persistent proteinuria of >0.75 g/24-hour despite 6 months of 
supportive care with RAS inhibitors to receive supportive care alone or supportive care plus 
immunosuppression (prednisone alone for those with initial GFR >60 mL/min and prednisone 
combined with cyclophosphamide then azathioprine with initial GFR 30-59 mL/min).  This 
strategy did not significantly improve the renal outcome and was associated with increased 
adverse effects at 36 months.[Rauen 2015]  The TESTING trial demonstrated some GFR effect 
of steroids in Chinese patients, but had to be stopped due to large number of serious adverse 
events (SAEs) in the steroid arm.[Lv 2017]  The 2012 KDIGO guidelines recommend 
corticosteroids, albeit at very low level of evidence.  Thus, steroids may be tried in some cases as 
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Subjects with known C5 deficiencies are generally healthy apart from an increased susceptibility 
to Neisserial infections.  These infections include invasive meningococcal disease, disseminated 
gonococcal infections as well as diseases caused by typically commensal Neisseria 
species.[Crew 2018a; Crew 2018b; McQuillen and Ram 2018; Ram 2010]  In addition, safety 
data on the treatment of healthy volunteers and patients with paroxysmal nocturnal 
hemoglobinuria (PNH) with cemdisiran in Study ALN-CC5-001 indicate that cemdisiran is 
generally well-tolerated; the maximum tolerated dose was 900 mg.  There were no SAEs or 
discontinuations due to adverse events (AEs) during this study, and most AEs were mild or 
moderate in severity.  In Study ALN-CC5-001, the frequency of ADA was low.  Two of 48 
healthy volunteers (1 cemdisiran-treated and 1 placebo-treated) were ADA positive during the 
study.  The cemdisiran-treated volunteer had transient ADA positivity, with a negative result 
later in the study and no impact on PK or PD.  The placebo-treated volunteer was ADA positive 
at baseline (predose) and remained positive through Day 70.  
A detailed description of the chemistry, pharmacology, nonclinical pharmacokinetics (PK) and 
toxicology, as well as preliminary efficacy, and safety of cemdisiran is provided in the current 
edition of the Investigator’s Brochure (IB).
1.3. 
Study Design Rationale 
In contrast to the RBC lysis which characterises the pathophysiology of PNH, which requires 
extremely high level of C5 inhibition for protection, endothelial cells and mesangial cells are the 
cellular targets of dysregulated complement in aHUS and IgAN, respectively.  These cells are 
nucleated cells which possess complement regulatory proteins as well as the ability to shed 
membrane associated MAC to defend against MAC-mediated damage, a key step in thrombotic 
microangiopathy progression in aHUS and renal damage in IgAN.  It is therefore hypothesized 
that a lesser degree of cemdisiran mediated C5 knockdown will be required for disease control in 
patients with IgAN and aHUS than in patients with PNH.[Morgan 1989; Rosse 1973]  This 
hypothesis is supported by the observation that aHUS patients who achieve C5 inhibition 
maintain good disease control despite complement activity levels consistent with higher free C5 
levels.[Cugno 2014]  Therefore, cemdisiran monotherapy may be a viable treatment option in 
patients with IgAN at levels of C5 silencing achieved in Study ALN-CC5-001. 
This therapeutic hypothesis will be tested in a multicenter, multinational, double-blind, 
placebo-controlled study to evaluate the effect of multiple doses of cemdisiran given by SC 
injection in patients with IgAN with persistent proteinuria (≥1 g/24-hours) despite the standard 
of care (angiotensin converting enzyme inhibitors [ACE] or angiotensin II receptor blockers 
[ARB]) and additional medications if necessary for blood pressure control followed by a 
treatment extension to evaluate long-term safety and clinical activity.  The study population has 
been selected based on two major factors: 1) the severity of proteinuria upon presentation has 
significant prognostic implications.[Coppo and D'amico 2005]  IgAN patients with heavy 
proteinuria ≥1 g/24-hours have a significantly worse renal outcome than those who have 
proteinuria <1 g/24-hours.[Reich 2007]  2) For patients with persistent proteinuria, despite the 
nonspecific treatment to reduce blood pressure and proteinuria by RAS blockade, no 
disease-specific therapies are currently available, and an unmet need persists for novel 
interventions.  Since proteinuria can result both from active inflammation as well as irreversible 
scarring of renal tissue and in lieu of a protocol biopsy, we enrich our patients for presence of 
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potentially reversible disease activity by requiring presence of hematuria and relatively preserved 
renal function with eGFR >30 mL/min.  To ensure the selection of patients who are truly at risk 
of progression of kidney disease despite standard of care, the first period of the study consists of 
a run-in period during which patients will not receive study drug (cemdisiran or placebo).  The 
run-in period will be an observational period during which patients’ treatment with standard of
care, blood pressure, kidney function, degree of hematuria, and proteinuria will be documented.  
The standard of care is expected to remain unchanged during this run-in period.  Only patients 
whose  
•
proteinuria level remains ≥1 g/24-hours within 2 weeks before the end of the run-in
period,
•
continue to meet blood pressure and eGFR criteria
will be eligible to enroll in the 36-week treatment period (defined as the time the first dose of 
study drug is administered on Study Day 1 through completion of the Week 36 assessments) 
portion of the study. 
Randomization to cemdisiran or placebo will be performed in a 2:1 ratio so that more patients 
will receive cemdisiran.  This will allow a more precise estimation of the effect of cemdisiran 
with only marginal loss of power.  Inclusion of a placebo arm will allow better assessment of 
safety and interpretation of the efficacy of cemdisiran. 
The primary endpoint for the study is percent change from baseline in 24-hour urine 
protein/creatinine ratio (UPCR) at Week 32.  This is justified for a phase 2 study given the slow 
progression of renal disease and the established role of proteinuria as a marker of disease 
progression. 
1.4. 
Dose Rationale 
In the Phase 1/2 Study (ALN-CC5-001), 32 healthy volunteers were treated with single SC doses 
of cemdisiran ranging from 50 mg to 900 mg, 24 healthy volunteers were treated with multiple 
doses of cemdisiran ranging from 100 mg to 600 mg (dosing weekly, every other week or 
monthly), 6 patients with PNH were treated with cemdisiran at cumulative doses of 3200 mg to 
4200 mg (eculizumab-naïve patients) and 1200 mg to 2400 mg (patients on background 
eculizumab treatment).  Treatment with cemdisiran was generally well tolerated in both healthy 
volunteers and patients with PNH.  There were no SAEs and no discontinuations due to AEs 
during this study, including at the highest doses administered.  Most AEs observed were mild or 
moderate in severity. 
Dose selection for the current study is based on the expected level of C5 and complement 
activity inhibition necessary for efficacy in patients with IgAN and the extent to which different 
doses of cemdisiran can inhibit production of C5.  C5 silencing is a novel approach for the 
treatment of IgAN and little clinical precedent exists for inhibiting the terminal complement 
pathway in this disease.  Since complement regulation is not impaired in IgAN like it is in PNH, 
and the kidney glomerular cells are nucleated cells, it is expected that the level of silencing 
needed for efficacy in IgAN is lower than that needed for PNH (see IB Section 2.4).  For this 
proof-of-concept study, a dose was selected that is expected to produce rapid and robust C5 
suppression and complement activity inhibition across the patient population, allowing an 
unambiguous evaluation of whether C5 silencing results in proteinuria improvement in IgAN.  In 
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Study ALN-CC5-001, a single dose of 600 mg cemdisiran achieved a C5 level of 
12.3±1.47 μg/mL by Day 14 and 2.3±0.76 μg/mL by Day 56, corresponding to 60.9% reduction
in complement alternative pathway (CAP) activity and a 69.3% reduction in complement 
classical pathway (CCP) activity by Day 14 and 90.2% and 91.4% reduction in CAP and CCP 
activities, respectively, by Day 56.  Single and multiple biweekly doses of 600 mg were 
well-tolerated with an acceptable safety profile in healthy volunteers in Study ALN-CC5-001A. 
In this initial study, the cemdisiran dose of 600 mg that was safe and well-tolerated was chosen 
for evaluation.  This dose will yield robust C5 silencing and will have maximal opportunity to 
produce a meaningful clinical effect in patients with IgAN.  Since the relationship between C5 
levels and complement activity is non-linear, with small C5 fluctuations resulting in a larger 
increase in complement activity, a monthly dose regimen was selected to maintain a constant 
level of C5 silencing.  Additionally, a more consistent effect of cemdisiran on C5 protein and 
CCP level is predicted after monthly dosing when compared to quarterly dosing based on a 
modeling approach.   
During the extension treatment period, patients treated with both cemdisiran and placebo will 
have the option to receive a 600 mg dose of cemdisiran every four weeks for an additional 52 
weeks. 
IgAN can result in progressive renal impairment; however, patients with severe renal impairment 
(eGFR<30 mL/min/1.73 m2) who may have sustained irreversible damage to the kidney are not 
eligible for participation in this trial.  As the kidney is not the major elimination pathway for 
cemdisiran and based on available nonclinical and clinical data obtained with cemdisiran (with 
10.6 to 31.6% of the cemdisiran dose recovered in a 24-hour urine collection in the ALN-
CC5-001 study), it is expected that moderate renal impairment (eGFR<60 mL/min/1.73 m2) will 
not affect the PK of cemdisiran to the extent that a dose adjustment would be required.  
Therefore, patients with moderate renal impairment are eligible for study enrollment.  More 
information on urine PK can be found in the IB.   
1.5. 
Benefit-Risk Assessment 
To date, no medications have been approved specifically for the treatment of IgAN.  Therefore, 
there is a large unmet need for novel interventions, particularly in patients who are at risk of 
progressive renal disease such as those with persistent proteinuria despite treatment with RAS 
inhibitors.  Available data from studies on the role of immunosuppressive therapy in IgAN are 
not conclusive as most are relatively small and have limited follow-up.[Lai 2016]  Use of 
immunosuppressive drugs and high-dose steroids are also associated with increased AEs which 
is particularly common in patients with lower GFR.[Sarcina 2016] 
Given the biological target of cemdisiran, the available nonclinical and clinical data, and mode of 
administration, important potential risks for cemdisiran are infections, liver function test (LFT) 
abnormalities and injection site reactions (ISRs).  C5 inhibition is associated with increased 
susceptibility for Neisserial infections (including disseminated gonococcal infections) and the 
potential risk of other infections, particularly those due to encapsulated bacteria including 
Streptococcus pneumoniae and Haemophilus influenzae type b (Hib), as well as Aspergillus in 
immunocompromised and neutropenic patients.  Therefore, prior immunization against N. 
meningitidis using meningococcal group ACWY conjugate vaccine and meningococcal group B 
vaccine are required.  Patients will be instructed to contact study site if any early signs of 
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meningococcal infections are experienced.  In addition, patients with functional or anatomic 
asplenia will be excluded and only patients previously vaccinated or who agree to receive 
vaccination for Hib and Streptococcus pneumoniae according to current national/local 
vaccination guidelines, at Screening, will be enrolled.  Investigators in Study ALN-CC5-005 
should educate patients on the risk of disseminated gonococcal infection and encourage safe sex 
practices.  All national/local screening recommendations for gonorrhea in the general population 
should also be followed.  Finally, given the reported evidence of a higher risk of disseminated 
gonococcal infections with treatment with eculizumab, Investigators are encouraged to evaluate 
any patient who has a Neisseria gonorrhoeae infection for the signs and symptoms of 
disseminated infection.[Crew 2018a; McQuillen and Ram 2018]  No cases of Neisserial 
infection or other infections due to encapsulated bacteria were observed in healthy volunteers or 
in patients with PNH (Study ALN-CC5-001). 
As cemdisiran is targeted for delivery to the liver, patients will be closely monitored for changes 
in LFTs and patients with a medical history or evidence of chronic liver disease or cirrhosis have 
been excluded.  Criteria for dose withholding, and stopping of cemdisiran are provided in 
Section 5.2.3.1.  Patients will also be monitored for the development of ISRs and rotation of 
injection site are recommended during the study.   
Considering anti-glycan autoantibodies recognizing Gd-IgA1 are implicated in the pathogenesis 
of IgA nephropathy, exposure to the GalNAc moiety of cemdisiran may pose a theoretical risk of 
stimulating the production of pathogenic autoantibodies and immune complexes in patients with 
IgA nephropathy.  This could presumably occur when antidrug antibodies (ADAs) to 
cemdisiran’s Tri-GalNAc cross-react with Gd-IgA1.  The risk of developing these cross-reactive 
antibodies is likely low.  This is based on the low incidence of ADA to cemdisiran in study 
ALN-CC5-001 (see Section 1.2) and the distinct difference in structure of the O-GalNAc 
moieties on a Gd-IgA1 glycoprotein and the Tri-GalNAc moiety in cemdisran.  This low risk is 
further mitigated by excluding patients with confirmed pre-existing IgG/IgM/IgA ADAs to total 
drug and real time monitoring for development of de novo IgG/IgM/IgA ADAs after dosing with 
cemdisiran.  Patients with confirmed de novo ADAs will be discontinued from study drug but 
will continue to be monitored until EOS visit and subsequent safety follow-up.  Patients who 
develop positive ADA will be followed until ADA titers return to baseline.  Additional ADA 
samples will also be collected if any clinical evidence of progression of IgAN disease and/or 
relevant safety findings. 
Detailed information about the known and expected benefits and risks of cemdisiran and 
additional information on the clinical and nonclinical data may be found in the current version of 
the IB. 
Cumulatively, clinical data regarding the role of complement pathways in IgAN progression, 
robust nonclinical and clinical data with cemdisiran (see IB for more information), and prior and 
ongoing clinical experience with other RNAi therapeutics in humans suggest cemdisiran will 
have a favorable risk profile in the intended population and supports the initial clinical 
development of cemdisiran in IgAN.  In addition, cemdisiran may address the unmet medical 
need for the first efficacious and disease-specific treatment for patients with IgAN. 
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•
To assess the incidence of antidrug
antibodies (ADA)
•
Change from baseline in the urine
albumin/creatinine ratio (UACR) as
measured in 24-hour urine at Week 32
•
Change from baseline in C5 level over
the course of the study
•
Change from baseline in complement
activity (Complement Alternative
Pathway [CAP] and Complement
Classical Pathway [CCP]) over the
course of the study
•
Evaluation of area under the curve
(AUC), maximum plasma
concentration (Cmax), time to
maximum plasma concentration
(Tmax), terminal half-life (t½),
clearance (CL/F), volume of
distribution (V/F), cumulative amount
excreted unchanged in urine (Ae) and
percent of dose excreted in the urine
(fe) of cemdisiran (25-mer) and 23-
mer
•
Evaluation of AUC, Cmax, Tmax, t½,
CL/F, V/F, Ae and fe of 22-mer
AS(N-1)3’
•
Change from baseline in levels of
renal damage, complement activation
and inflammation markers over the
course of the study
•
Incidence of antidrug antibodies
(ADA)
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the study site (eg, at home) is not possible due to circumstances related to the COVID-19 
pandemic, cemdisiran may be administered by the patient or the caregiver under the oversight of 
the Investigator, and following consultation with the Medical Monitor, as allowed by applicable 
country and local regulations.  In such cases, the patient or the caregiver must receive 
appropriate training on cemdisiran administration prior to dosing.  This measure is intended to 
remain in effect only during periods of time when the COVID-19 pandemic impedes the ability 
of patients to travel to the study site or healthcare professionals to go to a location other than the 
study site (eg, at home) for dosing.  The primary endpoint will be assessed at the end of 
treatment at Week 32. 
At the end of treatment (Week 32), patients in the two treatment arms will enter the optional 
OLE period where they will receive cemdisiran at a dose of 600 mg every 4 weeks in 
combination with standard of care for 52 weeks.  The first study drug administration of the OLE 
will be administered at Week 36.  Patients will return to the study site at Week 40 and every 
8 weeks thereafter during the OLE.  Visits at a location other than the study site (eg, at home), 
where locally feasible, may be arranged for cemdisiran administration in between 8-weekly 
study site visits (Weeks 44, 52, 60, 68 and 76), unless patients are required to visit the study site 
as judged necessary by the Investigator, or if visits at a location other than the study site (eg, at 
home) cannot be arranged.  An end of treatment (EOT) visit will occur at Week 80 (OLE EOT) 
and an end of study (EOS) or early termination (ET) visit will be completed at Week 84 (OLE 
EOS/ET).  For patients who complete the treatment period only who do not consent to continue 
to participate in the study in the OLE period, the EOS/ET visit will be at Week 36. 
Patients will return to the clinical study site for safety follow-up visits approximately 13, 26, 39 
and 52 weeks after the EOS/ET visit (regardless if EOS/ET visit is at Week 36 or Week 84), 
unless enrolled in another study with cemdisiran.  Visits at a location other than the study site 
(eg, at home), where locally feasible, may be arranged during safety follow-up at 13 and 39 
weeks after the EOS/ET visit (regardless if EOS/ET visit is at Week 36 or Week 84). 
Regular reviews of safety and tolerability data will be performed by an independent data 
monitoring committee (DMC) throughout the study with the primary purpose of protecting the 
safety of participating patients and the integrity of the study. 
3.2. 
Duration of Treatment 
Subcutaneous doses of cemdisiran or matching placebo will be administered every 4 weeks over 
a period of 32 weeks during the 36-week treatment period and patients will receive 600 mg SC 
doses of cemdisiran for 52 weeks in the optional OLE.  
3.3. 
Duration of Study 
The maximum estimated total time on study, inclusive of Screening (maximum of 120 days), 
run-in period (14 weeks), treatment period (36 weeks), optional OLE period (52 weeks) and 
safety follow-up (52 weeks), is approximately 43 months or 3 years and 7 months. 
3.3.1. 
Definition of End of Study for an Individual Patient 
A patient is considered to have reached the end of the study if the patient has completed the EOS 
visit (Week 36 for those patients who do not consent to continue to participate in the study in the 
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OLE period and Week 84 for patients who enter the OLE period).  Upon study completion 
(regardless if EOS visit is at Week 36 or Week 84) patients will enter a safety follow-up period 
with visits scheduled at intervals of 13 weeks. 
For patients withdrawing from the study after receiving one dose of cemdisiran at a minimum 
(ET), all efforts should be made to conduct the EOS/ET assessments.  Patients should then be 
encouraged to enter the safety follow-up period. 
3.4. 
Number of Planned Patients 
Approximately 30 patients are planned for randomization in this study. 
3.5. 
Method of Assigning Patients to Treatment Groups 
Using the Interactive Response System (IRS), patients will be randomized 2:1 to the cemdisiran 
or placebo arms.  Randomization will be stratified by baseline urine proteinuria levels (≥1 g/24h
and <2 g/24h versus ≥2 g/24h). 
Each patient will be uniquely identified in the study by a combination of the site number and 
patient identification number.  Upon signing the informed consent form (ICF), the patient will be 
assigned a patient identification number by the IRS.  The Investigator or his/her designee will 
contact the IRS after confirming that the patient fulfills all the inclusion criteria and none of the 
exclusion criteria at Screening and prior to randomization.  
3.6. 
Blinding 
All site personnel including sponsor delegated clinical research associates, data management 
CRO and patients will be blinded to study drug treatment during the efficacy period (up to Week 
36).  Sponsor personnel will not be blinded to study treatment.  Cemdisiran and placebo will be 
packaged identically.  The study drug will be administered under the supervision of the 
Investigator or at a location other than the study site (eg, at home) by a healthcare professional 
(see Section 5.2.2).  If the patient is unable to come to the study site, and a visit by a healthcare 
professional for patients at a location other than the study site (eg, at home) is not possible due to 
circumstances related to the COVID-19 pandemic, cemdisiran may be administered by the 
patient or the caregiver under the oversight of the Investigator, and following consultation with 
the Medical Monitor, as allowed by applicable country and local regulations.  In such cases, the 
patient or the caregiver must receive appropriate training on cemdisiran administration prior to 
dosing.  This measure is intended to remain in effect only during periods of time when the 
COVID-19 pandemic impedes the ability of patients to travel to the study site or healthcare 
professionals to go to a location other than the study site (eg, at home) for dosing.  Since 
cemdisiran may be visually distinguishable from placebo, the syringe will be masked by a site 
pharmacist prior to administration by a healthcare professional or a patient/caregiver.  See the 
Pharmacy Manual for additional details.  Further details on blinding and unblinding 
arrangements will be documented in a Randomization and Blinding Plan document. 
3.6.1. 
Emergency Unblinding 
If the treating physician determines that the clinical management of the patient requires 
knowledge of the study drug assignment, the Investigator may break the blind, as necessary.  If 
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time permits, clinical study site personnel should contact the Medical Monitor before unblinding 
to discuss the need to unblind the patient but must do so within 1 working day after the 
unblinding event.  A record of when the blind was broken, who was unblinded, who broke the 
blind, and why it was broken, will be maintained in the Trial Master File (TMF). 
Further details on blinding and unblinding arrangements will be documented in a Randomization 
and Blinding Plan document. 
3.7. 
Data Monitoring Committee 
An independent DMC will perform regular reviews of safety, tolerability, and immunogenicity 
data throughout the study with the primary purpose of protecting the safety of participating 
patients and the integrity of the study.  The DMC will operate under the rules of a Charter that 
will be reviewed and approved at the organizational meeting of the DMC.  The DMC will 
perform periodic reviews of unblinded data (safety, tolerability, pharmacodynamics (PD), ADA, 
circulating immune complexes (CIC) and efficacy of cemdisiran) during the clinical trial, and on 
an ad hoc basis review emergent safety data.  Details are provided in the DMC Charter. 
4.
SELECTION AND WITHDRAWAL OF PATIENTS
4.1. 
Inclusion Criteria
Patients are eligible to be included in the study if all the following criteria apply: 
Age and Sex 
1. Male or female ≥18 years and ≤65 years of age at the time of informed consent
Patient and Disease Characteristics 
2. Clinical diagnosis of primary IgAN as demonstrated by historical biopsy collected within
60 months of Screening
3. Treated for IgAN with stable, optimal pharmacological therapy.  In general, stable and
optimal treatment will include maximum allowed or tolerated ACE inhibitor or an ARB
for at least 3 months prior to start of run-in period
4. Urine protein ≥1 g/24-hour at Screening from a valid 24-hour urine collection (see
Section 6.4.1.1), and mean urine protein ≥1 g/24-hour from two valid 24-hour urine
collections at the end of the run-in period, prior to randomization
5. Hematuria as defined by ≥10 RBCs per high powered field (RBC/hpf) by microscopy or
a positive urine dipstick (2+ [moderate] and above) measured by a central laboratory at
Screening
6. Females 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, and for 90 days after last dose
administration
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7. Previously vaccinated with meningococcal group ACWY conjugate vaccine and
meningococcal group B vaccine or willingness to receive these vaccinations as well as
prophylactic antibiotic treatment, if required by local standard of care
8. Previously vaccinated or willingness to receive vaccinations for Hib and Streptococcus
pneumoniae according to current national/local vaccination guidelines for vaccination use
Informed Consent 
9. Patient is willing and able to provide written informed consent and to comply with the
study requirements
4.2. 
Exclusion Criteria 
Patients are excluded from the study if any of the following criteria apply: 
Disease-specific Conditions 
1. Concomitant significant renal disease other than IgAN
2. A diagnosis of rapidly progressive glomerulonephritis as measured by eGFR loss >30%
over the duration of the run-in phase
3. Secondary etiologies of IgAN (eg, inflammatory bowel disease, celiac disease)
4. Diagnosis of Henoch-Schonlein Purpura (IgA Vasculitis)
5.
eGFR <30 mL/min/1.73 m2 2 weeks prior to randomization (local results may be used
for assessment of eligibility)
Laboratory Assessments 
6. Has any of the following laboratory parameter assessments:
a.
Alanine transaminase (ALT) >1.5×upper limit of normal (ULN), International
Normalized Ratio (INR) >2 (or >3.5 if on anticoagulants), or total bilirubin
>1.5×ULN (unless bilirubin elevation is due to Gilbert’s syndrome)
7. Confirmed positive IgG/IgM/IgA ADAs to cemdisiran at Screening
8. Clinical laboratory test results considered clinically relevant and unacceptable in the
opinion of the Investigator
9. Positive hepatitis B virus (HBV) surface antigen, HBV core antibody, hepatitis C virus
(HCV) antibody (unless HCV viral load demonstrated negative)
Prior/Concomitant Therapy 
10. Treatment with systemic steroids for more than 7 days or other immunosuppressant
agents in the 6 months prior to randomization
11. Treatment with dual RAS blockade in the 3 months prior to entry into the run-in phase
12. Received an investigational agent within the last 30 days or 5 half-lives, whichever is
longer, prior to the first dose of study drug, or are in follow-up of another clinical study
prior to study enrollment
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Medical Conditions 
13. Known human immunodeficiency virus (HIV) infection, HCV infection or HBV
infection
14. Malignancy (except for non-melanoma skin cancers, cervical in situ carcinoma, breast
ductal carcinoma in situ, or stage 1 prostate cancer) within the last 5 years
15. Active psychiatric disorder, including, but not limited to schizophrenia, bipolar disorder,
or severe depression despite current pharmacological intervention
16. Known medical history or evidence of chronic liver disease or cirrhosis
17. Has other medical conditions or comorbidities which, in the opinion of the Investigator,
would interfere with study compliance or data interpretation
18. History of multiple drug allergies or history of allergic reaction to an oligonucleotide or
GalNAc
19. History of intolerance to SC injection(s) or significant abdominal scarring that could
potentially hinder study drug administration or evaluation of local tolerability
20. Known contraindication to meningococcal vaccines (group ACWY conjugate and group
B vaccines) required for this study.  Refer to the most recent local product information
for each vaccine for the current list of contraindications
21. Unable to take antibiotics for meningococcal prophylaxis, if required by local standard of
care
22. Sustained blood pressure >140/90 mmHg as defined by 2 or more readings during the
run-in period, measured in supine position after 10 minutes of rest
23. Receipt of an organ transplant (including hematologic transplant)
24. History of meningococcal infection within 12 months before Screening
25. Patients with systemic bacterial or fungal infections that require systemic treatment with
antibiotics or antifungals
26. Patients with functional or anatomic asplenia
Alcohol Use 
27. Patients who consume more than 14 units of alcohol a week (unit 1 glass of wine
[125 mL] = 1 measure of spirits [approximately 1 fluid ounce] = ½ pint of beer
[approximately 284 mL])
4.3. 
Removal from Therapy or Assessment 
Patients or their legal guardians are free to discontinue study drug and/or stop participation in the 
study at any time and for any reason, without penalty to their continuing medical care.  The 
Investigator or the Sponsor may stop a patient’s participation in the study at any time if this is 
considered to be in the patient’s best interest.  Any discontinuation of treatment or the stopping 
of the patient’s participation in the study must be fully documented in the electronic case report 
form (eCRF) and should be followed up by the Investigator.   
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Discontinuation of study drug is described in Section 4.3.1, while the stopping of a patient’s
participation in the study is detailed in Section 4.3.2. 
4.3.1. 
Discontinuation of Study Drug or Declining Procedural Assessments 
Reasons for discontinuation of study drug include any of the following: 
•
Significant violation of the protocol
•
Adverse event
•
Non-adherence to treatment regimen
•
Pregnancy
•
Lost to follow-up
•
Other reason (non-AE), including confirmed positive test for ADA to cemdisiran
•
Or, study is terminated by the Sponsor
Patients who are pregnant will be discontinued from study drug dosing immediately (see 
Section 6.7.5.2 for reporting and follow-up of pregnancy).  A positive urine pregnancy test 
should be confirmed by a serum pregnancy test prior to discontinuing study drug. 
Patients who discontinue study drug and/or decline procedural assessments should not be 
automatically removed from study.  In general, patients who discontinue study drug dosing for 
any reason will be encouraged to remain on the study to complete the remaining assessments 
through the Week 36/EOS or Week 84/OLE EOS visit and safety follow-up so that their 
experience is captured in the final analyses.  
If this occurs, the Investigator is to discuss with the patient the appropriate processes for 
discontinuation from study drug and must discuss with the patient the options for continuation of 
the Schedule of Assessments (Table 2), including different options for follow-up and collection 
of data (eg, in person, by phone, by mail, through family or friends, or from options not 
involving patient contact, such as communication with other treating physicians or from review 
of medical records), including endpoints and AEs, and must document this decision in the 
patient’s medical records. 
If a patient discontinues dosing due to an AE, including SAEs, the event should be followed as 
described in Section 6.7.6.  When a patient discontinues study drug dosing, the primary reason 
must be recorded in the eCRF.  Patients who discontinue study drug and remain on study may 
receive treatment consistent with local standard practice for their disease per Investigator 
judgement, as applicable.  
Patients who discontinue from study drug during the 36-week treatment period will be 
encouraged to remain on the study and complete assessments through Week 36; they will also be 
asked to complete safety follow-up visits 13, 26, 39 and 52 weeks thereafter (see Table 1).  
Patients who discontinue study drug during the OLE period will be asked to return for their next 
scheduled visit to complete the OLE EOS/ET assessments; they will also be asked to complete 
safety follow-up visits 13, 26, 39 and 52 weeks thereafter (see Table 2). 
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4.3.2. 
Stopping a Patient’s Study Participation
4.3.2.1. 
Patient or Legal Guardian Stops Participation in the Study 
A patient or their legal guardian may stop participation in the study at any time.  A patient/legal 
guardian considering stopping participation in the study should be informed that they can 
discontinue study drug and/or decline procedural assessments and remain in the study to 
complete their study assessments through the Week 36 visit, including entering the 52-week 
safety follow-up.  If a patient/legal guardian still chooses to discontinue study drug and stop 
participation in all follow-up prior to the completion of the 36-week treatment period, every 
effort should be made to conduct early the assessments scheduled to be performed at the 
Week 36 EOS/ET visit (see Table 1).   
If the patient does not wish to or is unable to continue further study participation, the investigator 
is to discuss with the patient appropriate procedures for stopping participation in the study.  Data 
collected from the patient can continue to be used. 
In addition, in the countries where the collection and processing of the patient data is based on 
the patient consent, if a patient withdraws consent to collect and process his/her data (see 
Section 4.3.2.2), as applicable, patient data up to the withdrawal of consent will be included in 
the analysis of the study.  In addition, where permitted, publicly available data (such as 
appropriate national or regional vital status registry or other relevant databases) can be included 
after withdrawal of consent, where available and allowable by local law. 
4.3.2.2. 
Withdrawal of Consent to Process the Patient’s Personal Data
Where allowed by local law, the patient may decide to withdraw consent to collect, store and use 
biological samples and, as applicable, other personal data, informing the study doctor at any time 
in writing or in any other form that may be locally required.  The Sponsor will continue to keep 
and use the patient’s study information (including any data resulting from the analysis of 
patient’s biological samples until the time of withdrawal) according to applicable law.  The 
process for the storage and, as applicable, further use of remaining samples will be followed per 
local requirements. 
4.3.2.3. 
Investigator or Sponsor Stops Participation of a Patient in the Study 
The Investigator or Sponsor may stop the participation of a patient in the study at any time if this 
is considered to be in the patient’s best interest.  However, study integrity and interpretation are
best maintained if all enrolled patients continue study assessments and follow-up even if study 
drug is discontinued. 
Termination of the clinical study and site closure are described in Section 8.1.6. 
4.3.2.4. 
Recording Reason for Stopping a Patient’s Study Participation 
The primary reason that a patient’s study participation is stopped must be recorded in the 
appropriate section of the eCRF and all efforts will be made to complete and report the 
observations as thoroughly as possible.  If a patient’s study participation is stopped due to an AE, 
including SAEs, the event should be followed as described in Section 6.7.6. 
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4.3.3. 
Lost to Follow-Up 
A patient will be considered lost to follow-up if the patient repeatedly fails to return for 
scheduled visits and is unable to be contacted by the clinical study site.  The following actions 
must be taken if a patient misses a required study visit: 
•
The site must attempt to contact the patient or legal guardian and reschedule the
missed visit as soon as possible and counsel the patient or legal guardian on the
importance of maintaining the assigned visit schedule and ascertain if the patient or
legal guardian wishes to continue in the study, and/or should continue in the study.
•
Before a patient is deemed lost to follow-up, the investigator or designee must make
every effort to regain contact with the patient or legal guardian (where possible, 3
telephone calls and, if necessary, a certified letter to the patient’s last known mailing
address or local equivalent methods).  These contact attempts should be documented
in the patient’s medical record.
•
Should the patient or legal guardian continue to be unreachable, the patient will be
considered to have stopped participation in the study.
•
For patients who are lost to follow-up, the Investigator can search publicly available
records (where permitted and allowed by local law) to ascertain survival status.  This
ensures that the outcome of the study is as comprehensive as possible.
4.3.4. 
Replacement of Study Patients
Patients who discontinue the study drug or stop participation in the study during the 36-week 
treatment period or the OLE will not be replaced. 
5.
TREATMENTS AND OTHER REQUIREMENTS
5.1. 
Treatments Administered
Study drug supplied for this study must not be used for any purpose other than the present study 
and must not be administered to any person not enrolled in the study.  Study drug that has been 
dispensed to a patient and returned unused must not be re-dispensed to a different patient. 
5.2. 
Study Drug 
Detailed information describing the preparation, administration, and storage of cemdisiran and 
placebo is provided in the Pharmacy Manual. 
5.2.1. 
Description 
Cemdisiran will be supplied as a sterile solution for SC injection that contains 200 mg/mL 
cemdisiran sodium (equivalent to 189 mg/mL of cemdisiran), formulated in water for injection 
(WFI) for SC administration.  See the Pharmacy Manual for further details of solution 
concentration and fill volume. 
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The control drug for this study will be a placebo (sodium chloride 0.9% w/v for SC 
administration).  Placebo will be provided by the Sponsor; it will be packaged identically to 
cemdisiran. 
5.2.2. 
Dose and Administration 
Patients will be administered cemdisiran (600 mg) or placebo (at the same volume as the active 
drug) as an SC injection once every 4 weeks in combination with standard of care in the 32-week 
period of the 36-week treatment period.  During the 52-week OLE phase, patients will be 
administered cemdisiran at a dose of 600 mg every 4 weeks in combination with standard of 
care. 
Study drug injections will be administered under the supervision of the Investigator or healthcare 
professional.  Study  drug administration may be conducted by a healthcare professional at a 
location other than the study site (eg, at home) from Week 4 of the treatment period for patients 
that have demonstrated the ability to tolerate the study drug at the study site.  If the patient is 
unable to come to the study site, and a visit by a healthcare professional for patients at a location 
other than the study site (eg, at home) is not possible due to circumstances related to the COVID-
19 pandemic, cemdisiran may be administered by the patient or the caregiver under the oversight 
of the Investigator, and following consultation with the Medical Monitor, as allowed by 
applicable country and local regulations.  In such cases, the patient or the caregiver must receive 
appropriate training on cemdisiran administration prior to dosing.  This measure is intended to 
remain in effect only during periods of time when the COVID-19 pandemic impedes the ability 
of patients to travel to the study site or healthcare professionals to go to a location other than the 
study site (eg, at home) for dosing.  The injection site may 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, if permitted.  Detailed instructions for study drug administration are found in the 
Pharmacy Manual.  In addition, instructions and procedures related to administration of study 
drug by a patient or caregiver will be provided in the Patient/Caregiver Storage and 
Administration Instructions. 
To maintain the blind during the treatment period, the syringes are to be masked prior to study 
drug withdrawal.  A full description of the blinding procedure is included in the Pharmacy 
Manual.  
5.2.3. 
Dose Modifications 
Dose modifications are not permitted. 
The visit window for the treatment period is ±14 days, but the interval between two doses may 
not be shorter than 14 days.  If a dose is not administered within 14 days of the date determined 
by the Schedule of Assessments (see Table 1), then the dose is considered missed and should not 
be given. 
If a study drug-related AE occurs in a patient that the Investigator judges as presenting a 
potential risk to the patient for further dosing, the study drug dose may be held at the discretion 
of the Investigator and the Medical Monitor should be contacted.  In situations where study drug 
is administered at a location other than the study site (eg, at home), or the dose is missed, the 
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study physician (or delegate) will verbally contact the patient to assess any AEs and concomitant 
medications. 
5.2.3.1. 
LFT Criteria for Withholding, Monitoring and Stopping Cemdisiran Dosing   
1. LFT results (Table 5) from the previous visit should be reviewed prior to dosing.  Central
laboratory results are preferable.  If not available, local laboratory results may be used;
however, if a local assessment is drawn, a serum chemistry sample must also be drawn
for analysis at the central laboratory.
2. For any ALT or AST elevation >3×ULN, central laboratory results should be used to
guide subsequent monitoring as detailed in Table 4.
a.
Confirm using central laboratory, as soon as possible, ideally within 2 to 3 days, but
no later than 7 days.
b. Perform assessments per Table 4 and Table 6.
c.
If an alternative cause is found, provide appropriate care.
3. For any ALT or AST elevation >3×ULN without alternative cause that is accompanied
by clinical symptoms consistent with liver injury (eg, nausea, right upper quadrant
abdominal pain, jaundice) or elevated bilirubin to ≥2×ULN or INR ≥1.5, permanently
discontinue dosing.
4. For confirmed ALT or AST elevations >3×ULN without alternative cause and not
accompanied by symptoms or elevated bilirubin ≥2×ULN or INR ≥1.5, see Table 4.
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Table 4: 
Monitoring and Dosing Rules for Asymptomatic Patients with Confirmed 
Isolated Elevations of ALT and/or AST >3× ULN, with No Alternative Cause 
Identified 
Transaminase Level 
Action 
>3× to 5× ULN 
•
May continue dosing
•
Evaluate the initial elevation in LFT per the following assessments:
•
Table 6 (all assessments to be performed once)
•
Hematology, serum chemistry, LFT, and coagulation per Table 5
•
Monitor at least every two weeks: LFT and coagulation per Table 5
•
If elevation persists for ≥2 months, must discuss with the Medical Monitor
before continuing dosing
>5× to 8× ULN 
•
Hold cemdisiran dosing until recovery to ≤1.5×ULN; may resume dosing
after discussion with the Medical Monitor
•
Evaluate the initial elevation in LFT per the following assessments
•
Table 6 (all assessments to be performed once)
•
Hematology, serum chemistry, LFT, and coagulation per Table 5
•
Monitor at least weekly: LFT and coagulation per Table 5 until ALT and/or
AST is declining on 2 consecutive draws, then may decrease monitoring to
biweekly
•
If ALT or AST rises to >5×ULN following resumption of dosing,
permanently discontinue dosing
>8× ULN 
Permanently discontinue dosing after confirmation of the transaminase value 
Abbreviations: ALT=alanine transaminase; AST=aspartate transaminase; LFT=liver function test(s); ULN=upper 
limit of normal. 
Notes:   In addition to these criteria, other assessments or evaluations may be performed per Investigator discretion, 
as appropriate. 
5.2.4. 
Preparation, Handling, and Storage 
Staff at each clinical study site or the healthcare professional performing administration at a 
location other than the study site (eg, at home) will be responsible for preparation of cemdisiran 
doses, according to procedures detailed in the Pharmacy Manual.  In cases where study drug is 
administered at a location other than the study site (eg, at home) by a patient/caregiver, dosing 
may be prepared and administered by the patient/caregiver according to procedures detailed in 
the Patient/Caregiver Storage and Administration Instructions.  No special procedures for the 
safe handling of study drug are required. 
Study drug will be stored upright and refrigerated at approximately 2 to 8°C.  The vial should be 
stored in the carton until ready for use in the storage area of the clinical study site pharmacy, in a 
secure, temperature-controlled, locked environment with restricted access. 
A Sponsor representative or designee will be permitted, upon request, to audit the supplies, 
storage, dispensing procedures, and records. 
Instructions specific to unused study drug and additional storage will be provided in the 
Pharmacy Manual and Patient/Caregiver Storage and Administration Instructions. 
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5.2.5. 
Packaging and Labeling 
All packaging, labeling, and production of study drug will be in compliance with current Good 
Manufacturing Practice specifications, as well as applicable local regulations.  Study drug labels 
and external packaging will include all appropriate information as per local labeling 
requirements.  
Cemdisiran (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 a 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. 
Additional details will be available in the Pharmacy Manual. 
5.2.6. 
Accountability 
The Investigator or designee will maintain accurate records of receipt and the condition of the 
study drug supplied for this study, including dates of receipt.  In addition, accurate records will 
be kept of when and how much study drug is dispensed and administered to each patient in the 
study.  Any reasons for departure from the protocol dispensing regimen must also be recorded. 
At the completion of the study, there will be a final reconciliation of all study drugs.  Used, 
partially used, and unused study drug will be returned to the Sponsor (or designee) or destroyed 
at the clinical study site according to applicable regulations. 
Further instructions about drug accountability will be detailed in the Pharmacy Manual. 
5.3. 
Concomitant Medications and Procedures 
The standard of care treatment should be held stable throughout the run-in and treatment periods. 
Use of concomitant medications and procedures will be recorded on the patient’s eCRF as 
specified in the Schedule of Assessments (see Table 1  and Table 2).  This includes all 
prescription medications, herbal preparations, over the counter medications, vitamins, and 
minerals.  Any changes in medications during the study will also be recorded on the eCRF. 
If patients use nonsteroidal anti-inflammatory drugs intermittently or chronically, they must have 
been able to tolerate them with no previous side effects (eg, gastric distress or bleeding).   
Standard vitamins and topical medications are permitted.  However, topical steroids must not be 
applied anywhere near the injection site(s) unless medically indicated.   
For other permitted concomitant medications administered SC, do not administer in same 
injection site area as the study drug/placebo, for 7 days after the last dose of either study drug or 
placebo.  
Any concomitant medication that is required for the patient’s welfare may be administered by the 
Investigator.  However, it is the responsibility of the Investigator to ensure that details regarding 
the medication are recorded on the eCRF.  Concomitant medication will be coded using an 
internationally recognized and accepted coding dictionary. 
5.3.1. 
Prohibited Concomitant Medications 
The following concomitant medications are prohibited during the study: 
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Systemic steroids (short-term steroid course for <7 days for common conditions not
related to IgAN (i.e. asthma, gout) is permitted)
•
Immunosuppressive agents
•
Fish oil supplements (if started prior to Screening, then may continue during the study
at the same dose)
•
Hydroxychloroquine
5.3.2. 
Study-specific Vaccinations
5.3.2.1. 
Meningococcal Vaccinations 
All patients taking part in this study must be vaccinated against meningitis types A, C, W135, Y 
and B, at least 14 days prior to randomization to cemdisiran or placebo, as per the Schedule of 
Assessments.  Meningococcal group ACWY conjugate vaccine and meningococcal group B 
vaccine will be administered in accordance with the manufacturer’s instructions and according to
the Advisory Committee on Immunization Practices (ACIP) or other locally applicable 
recommendations for patients with complement deficiencies.  On days of vaccination, urinary 
samples should be collected prior to administration of vaccines. 
Patients will be immunized against Neisseria meningitidis according to the following 
specifications: 
•
Patients who have previously completed the recommended series of meningococcal
vaccinations (meningococcal group ACWY conjugate vaccine and meningococcal
group B vaccine) at least 14 days but no more than 3 years from randomization can
start study assessments after confirming eligibility.  Documented vaccine history
must be available to, and verified by, study site staff at the time of Screening.
•
Patients who were previously vaccinated with polysaccharide type vaccines within
3 years of study entry will be revaccinated using conjugate vaccines per the Schedule
of Assessments.
•
Patients who have not been previously vaccinated against Neisseria meningitidis,
those without documentation of vaccination history, or those vaccinated more than
3 years from study randomization will commence the vaccination series with the
recommended meningococcal vaccines (meningococcal group ACWY conjugate
vaccine and meningococcal group B vaccine) per the Schedule of Assessments.
•
If required locally, patients will receive prophylactic antibiotics according to the local
standard of care after randomization to cemdisiran or placebo.
5.3.2.2. 
Pneumococcal and Hib Vaccinations 
Patients will receive vaccinations for Hib and Streptococcus pneumoniae, if not previously 
vaccinated, according to current national/local vaccination guidelines for vaccination use.  Hib 
and pneumococcal vaccinations, if required at Screening per national/local guidelines, should be 
administered at least 14 days prior to randomization.  At Screening, patient vaccination records 
will be checked for compliance with local recommendations for the use of these vaccines.  
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5.4. 
Treatment Compliance 
Compliance with study drug administration will be verified through observation by study staff or 
trained healthcare professionals at a location other than the study site (eg, at home). 
5.5. 
Other Requirements 
5.5.1. 
Contraception 
Females of child-bearing potential must be willing to use a highly effective method of 
contraception from 14 days before first dose, throughout study participation, and for 90 days 
after last dose administration or until study completion.   
Birth control methods which are considered highly effective include: 
•
Placement of an intrauterine device.
•
Placement of an intrauterine hormone-releasing system.
•
Bilateral tubal occlusion.
•
Surgical sterilization of male partner (with the appropriate post-vasectomy
documentation of the absence of sperm in the ejaculate; for female patients on the
study, the vasectomized male partner should be the sole partner for that patient).
•
Established use of oral (except low-dose gestagens), implantable, injectable, or
transdermal hormonal methods of contraception.  Females of child-bearing potential
who use hormonal contraceptives as a method of contraception must also use a barrier
method (condom or occlusive cap [diaphragm or cervical/vault cap] in conjunction
with spermicide [eg, foam, gel, film, cream, or suppository]).
•
True sexual abstinence, when in line with the preferred and usual lifestyle of the
patient.  Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation
methods) and withdrawal are not acceptable methods of contraception.  Abstinent
patients must agree to use one of the above-mentioned contraceptive methods if they
start sexual relationships during the study and for up to 90 days after the last dose of
study drug.
Investigators should advise females of childbearing potential of the most appropriate birth 
control method available within their country taking into account local medical practice. 
Females of child-bearing potential include female patients who have experienced menarche (or 
begin menarche over the course of the study) and who are not postmenopausal or permanently 
sterilized (eg, bilateral tubal occlusion, hysterectomy, or bilateral salpingectomy).  A 
postmenopausal state is defined as the absence of menses for 12 months without an alternative 
medical cause, confirmed by follicle stimulating hormone level within the postmenopausal 
range.  
For male patients, no contraception is required.  However, use by males of contraception 
(condom) may be required in some countries e.g.  France, in order to comply with local 
requirements as described in the corresponding patient consent forms 
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Compliance with contraception requirements will be assessed on a regular basis by the 
Investigator throughout the course of the study (see Section 6.7.5.2). 
5.5.2. 
Alcohol Restrictions 
Patients will limit alcohol consumption throughout the course of the study.  Alcohol is limited to 
no more than 2 units per day (unit:  1 glass of wine [approximately 125 mL] = 1 measure of 
spirits [approximately 1 fluid ounce] = ½ pint of beer [approximately 284 mL]) for the duration 
of the study. 
5.5.3. 
Antibiotic Compliance 
Patients who require prophylactic antibiotics after randomization to cemdisiran or placebo (see 
Section 5.3.2.1) per local standard of care will undergo antibiotic compliance checks.  Antibiotic 
compliance checks will be performed at the time points in the Schedule of Assessments.  
Antibiotic dose adjustments will be permitted in the case of renal impairment.  All dose 
adjustments must comply with the manufacturer’s instructions.
6.
STUDY ASSESSMENTS
The Schedule of Assessments is provided in Table 1 and Table 2.  If a patient is unable to 
complete a site visit due to the COVID-19 pandemic impacting activities at the study site or 
patient ability or willingness to access the site, routine physical examination/body system 
assessment, height, weight, body mass index (BMI), vital signs and collection of blood and urine 
samples for efficacy, safety, PD, PK, and exploratory assessments may be conducted at a 
location other than the study site (eg, at home) by a trained healthcare professional as locally 
feasible (refer to instructions for home nurses in the Laboratory Manual). 
6.1. 
Screening Assessments 
An ICF approved by the appropriate Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) must be signed by the patient (or legal guardian) before the Screening 
procedures are initiated.  All patients (or their legal guardians) will be given a copy of the signed 
and dated ICF.  
The Investigator will notify the Sponsor before screening patients to allow an assessment of the 
ability of the site and any new trial participant to comply with the protocol given limitations 
during the COVID-19 pandemic. 
Patients will be screened to ensure that they meet all the inclusion criteria and none of the 
exclusion criteria.  Rescreening of patients is permitted with consultation of the Medical 
Monitor; see Section 6.1.1.  
Patient demographic data and medical history/disease history will be obtained.  In particular, the 
MEST-C score and degree of IgG, IgA, IgM, C3, C1q, C4d and C5b-9 stains will be obtained 
from pathology reports, if available, and documented.  Any changes to medical history occurring 
between the Screening assessment and Day 1 will be updated prior to study drug administration.  
Additional screening assessments include a full physical examination (with emphasis on 
presence/degree of edema), collection of vital signs, height, weight and BMI, 12-lead 
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electrocardiogram (ECG), clinical laboratory assessments, pregnancy, 24-hours urine proteinuria 
assessment (from a single valid collection; see Section 6.4.1.1), eGFR, urinalysis and ADA and 
CIC assessments.  Vaccination records will also be checked for compliance with national/local 
guidelines for pneumococcal and Hib vaccinations. 
6.1.1. 
Rescreening 
A patient who does not meet all study eligibility criteria due to a transient condition observed at 
Screening (eg, prohibited medications that were subsequently discontinued) will be allowed to 
return for rescreening (once only).  A patient who is unable to complete screening and run-in 
visits due to COVID-19 associated delays may be rescreened with approval of the Sponsor.  A 
patient will be re-consented if rescreening occurs outside of the 120-day screening window.  In 
this case, all screening procedures must be repeated.  
6.1.2. 
Retesting 
If in the Investigator’s judgement, the laboratory abnormalities at Screening or in the run-in 
period are likely to be transient, then laboratory tests may be repeated.  The Investigator’s 
rationale is to be documented.  Laboratory values can be retested once during Screening or the 
run-in period as long as the patient can be evaluated for eligibility and randomized within the 
allowed Screening or run-in period.  Two retests will be permitted for hematuria during 
Screening, if the first test is negative.   
6.2. 
Run-in Period 
During the 14-week run-in period, the following will be performed at time points specified in the 
Schedule of Assessments (Table 1): Hib and pneumococcal vaccinations (if required at 
Screening per national/local guidelines; vaccination should occur at least 14 days prior to 
randomization), vital signs, clinical laboratory assessments, pregnancy test, 24-hour urine 
proteinuria assessment (from 2 single valid collections; see Section 6.4.1.1), urinalysis for 
hematuria, spot urine for proteinuria, and eGFR.  Clinical laboratory tests will be performed 
centrally; however, eGFR may also be assessed locally at the end of the run-in period (Week -2) 
to facilitate assessment of patient eligibility and administer meningococcal vaccination on the 
same day.  Meningococcal vaccines should be administered only if patient eligibility for 
randomization is confirmed and after urine collections are completed.  
If a run-in visit cannot proceed according to schedule, it may be delayed up to 28 days, with 
subsequent visits being rescheduled based on the new date.  Visit windows, as indicated in the 
Schedule of Assessments (Table 1), are applied to the rescheduled date.  Approval from the 
Medical Monitor is required prior to initiation of the treatment period.  If a subject cannot 
proceed to the treatment period as planned, the run-in period can be extended as needed.  If the 
final run-in visit will not be within 56 days of randomization, this visit will be repeated, and the 
new visit will serve as the Week -2 visit to determine eligibility for randomization. 
Sites are encouraged to discuss study information with the patients again at the end of the run-in 
period and to check key inclusion and exclusion criteria when run-in visits are delayed. 
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6.3. 
Baseline Assessments (Treatment Period) 
Prior to dosing on Day 1, patients will be reassessed for eligibility, and blood and urine samples 
for clinical laboratory assessments and exploratory analyses collected, including blood samples 
for complement activity tests (CAP/CCP), C5 analysis, PK, ADA and CIC.  
In addition, prior to administration of study drug, the following assessments will be performed:  
full physical examination, body weight and height, vital signs, ECG, urine pregnancy test, eGFR 
assessment, and urinalysis.  
Collection of blood and urine samples for PK analysis on Day 1 will be performed as outlined in 
Table 3.   
6.4. 
Efficacy Assessments 
6.4.1. 
Urine Protein/Creatinine Ratio 
Primary efficacy will be assessed by determining the percent change from baseline in UPCR 
from a 24-hour urine sample after 32 weeks of treatment. 24-hour urine samples for 
determination of UPCR will be collected throughout the study as outlined in the Schedules of 
Assessments and will be analyzed by a central laboratory. 
6.4.1.1. 
24-Hour Urine Collection 
Patients will be required to provide two separate valid 24-hour urine collections 2 weeks prior to 
randomization (to assess eligibility after the run-in period) and at Week 32 (to assess the primary 
endpoint).  Patients will also be asked to provide a single valid 24-hour urine sample for other 
24-hour urinary assessments outlined in the Schedule of Assessments.  Both UPCR as well as 
UACR will be calculated in an aliquot of each 24-hour urine collection.  Rigorous exercise and 
significant change in diet (in particular salt intake) should be avoided within 48 hours before 
collection of 24-hour urine samples, whenever possible.  The two valid 24-hour urine samples 
may be collected within 2 weeks before assessment is due while the one valid 24-hour urine 
sample may be collected within one week before the assessment takes place.  If any of the 
collections do not meet validity criteria outlined below, then repeat collections must be 
scheduled within the time frames outlined above to assure the minimum number of valid 
collections required for each of the study time points.  The duration of collection and volume of 
urine in the collection will be recorded in the eCRF.  In addition to protein, albumin, sodium and 
creatinine will also be quantified in each of the 24-hour urine samples.  
A 24-hour urine collection will only be considered valid if the following criteria are met, 
otherwise a repeat urine collection will be required: 
•
The collection is between 22-26 hours in duration between the initial discarded void
and the last void or attempt to void.
•
No voids are missed between the start and end time of the collection as indicated by
the patient’s urine collection diary.
Primary efficacy will be evaluated by comparing the percent change from baseline in 24-hour 
UPCR at Week 32 in patients treated with cemdisiran versus those treated with placebo.  
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Blood and urine samples for renal function assessments will be collected prior to administration 
of cemdisiran or placebo on dosing days, if applicable. 
The change from baseline in eGFR will be measured throughout the course of the study.  In 
addition, the slope of eGFR will be computed for the treatment period and the entire study period 
(including the OLE).  
6.4.4. 
Markers of Complement Activation, Inflammation and Renal Injury 
Samples for measurement of markers of complement activation, inflammation and renal injury 
will be collected at the time points outlined in the Schedule of Assessments (Table 1) and 
analyzed by central laboratories.  On dosing days, blood samples will be collected predose. 
6.5. 
Pharmacodynamic Assessments 
Blood samples for PD analysis will be collected at the time points outlined in the Schedule of 
Assessments (Table 1).  Samples will be collected prior to administration of cemdisiran or 
placebo on dosing days. 
Analysis of PD will include the impact of cemdisiran administration on plasma C5 protein levels 
(assessed by a mass spectrometry-based method) and serum complement activity (assessed by 
CAP enzyme linked immunosorbent assay [ELISA] and CCP ELISA).  Samples will be analyzed 
at central laboratories.  Details regarding the collection, processing, shipping, and storage of the 
samples will be provided in the Laboratory Manual. 
6.6. 
Pharmacokinetic Assessments 
Blood samples and urine samples will be collected for assessment of cemdisiran PK parameters 
and possible metabolite analysis at the time points in the Schedule of Assessments.  A detailed 
schedule of time points for the collection of blood samples and urine samples for PK analysis is 
in Table 3. 
The concentration of cemdisiran will be determined using a validated assay.  Details regarding 
sample volumes to be collected, and the processing, shipping, and analysis of the samples will be 
provided in the Laboratory Manual. 
6.7. 
Safety Assessments 
The assessment of safety during the study will consist of the surveillance and recording of the 
frequency of AEs including SAEs, recording of concomitant medication and measurements of 
vital signs, weight and height, physical examination, and ECG findings and laboratory tests, 
including assessment of IgG/IgM/IgA ADA and CIC.  Clinically significant abnormalities 
observed during the physical examination are recorded.   
Safety will be monitored over the course of the study by a DMC as described in Section 3.7. 
6.7.1. 
Vital Signs 
Vital signs will be measured as specified in the Schedule of Assessments (Table 1 and Table 2) 
and include blood pressure, heart rate, body temperature, and respiratory rate.  Vital signs will be 
measured in the seated or supine position, after the patient has rested comfortably for at least 
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10 minutes.  On Day 1, vital signs will be collected predose (no more than 4 hours prior to 
dosing) and 4 hours (±30 minutes) postdose.  On all other dosing days, vital signs will be 
collected predose.  
Blood pressure should be taken using the same arm throughout the study.  Body temperature in 
degrees Celsius will be obtained via oral or tympanic method.  Heart rate will be counted for a 
full minute and recorded in beats per minute, and respiration rate will be counted for a full 
minute and recorded in breaths per minute. 
Additional vital sign assessments, as medically indicated, may be added at the discretion of the 
Investigator, or as per DMC advice. 
Vital signs results will be recorded in the eCRF. 
6.7.2. 
Weight and Height 
Height will be measured in centimeters.  Body weight will be measured in kilograms.  Height 
and body weight measurements will be collected as specified in the Schedule of Assessments 
(Table 1 and Table 2; height at Screening only and dosing weight during the clinical study site 
visits) and will be recorded in the eCRF. 
6.7.3. 
Physical Examination 
Routine physical examinations will be conducted according to the Schedule of Assessments 
(Table 1 and Table 2); if a physical examination is scheduled for a dosing visit, it should be 
conducted prior to dosing.   
At Screening and Day 1 predose, a full physical examination will be performed.  At all other 
time points, including Day 1 at 4 hours (±30 minutes) postdose, a directed physical examination 
will be performed. 
Full physical examinations will include the examination of the following:  general appearance; 
head, eyes, ears, nose and throat; respiratory, cardiovascular, gastrointestinal, musculoskeletal, 
and dermatological systems; thyroid; lymph nodes; and neurological status. 
Directed physical examinations will include examination of the following:  respiratory, 
cardiovascular, dermatological, gastrointestinal, and musculoskeletal systems. 
Clinically significant abnormalities observed during the physical examination are recorded on 
the medical history or AE eCRF. 
6.7.4. 
Electrocardiogram 
Twelve-lead ECGs reporting rhythm, ventricular rate, RR interval, PR interval, QRS duration, 
and QT interval and Fridericia-corrected QT interval will be obtained, as specified in the 
Schedule of Assessments (Table 1 and Table 2).  Patients should be supine for at least 5 minutes 
before each ECG is obtained.  A single 12-lead ECG will be performed at Screening.  At all 
other time points, 12-lead ECGs will be performed in triplicate, with readings approximately 1 
minute apart. 12-lead ECGs will be performed predose (on the same day as dosing); 60 minutes 
(±15 minutes) postdose; and 4 hours (±30 minutes) postdose in relation to the Day 1 and Week 
32 cemdisiran or placebo doses. 
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When ECG and blood sample collection occur at the same time, ECGs should be performed 
before blood samples are drawn. 
The Investigator or qualified designee will review all ECGs to assess whether the results have 
changed since the Baseline visit and to determine the clinical significance of the results.  These 
assessments will be recorded on the eCRF.  Additional ECGs may be collected at the discretion 
of the Investigator, or as per DMC advice.   
6.7.5. 
Clinical Laboratory Assessments 
The following clinical laboratory tests will be evaluated by a central laboratory.  However, to 
assess patient eligibility at the end of the run-in period, eGFR will also be assessed locally.  
Specific instructions for transaminase elevations are provided in Section 5.2.3.1.  For any other 
unexplained clinically relevant abnormal laboratory test occurring after study drug 
administration, the test should be repeated and followed up at the discretion of the Investigator, 
or as per DMC advice, until it has returned to the normal range or stabilized, and/or a diagnosis 
is made to adequately explain the abnormality.  Additional safety laboratories and assessments as 
indicated by the clinical situation may be requested.  Clinical laboratory assessments are listed in 
Table 5 and include: hematology, serum chemistry and urinalysis parameters.  Parameters will be 
assessed as specified in the Schedule of Assessments (Table 1 and Table 2).  
While local laboratory results may be used for urgent clinical and dosing decisions, on the day of 
the clinic visit assessments, all laboratory assessments specified in Table 5 which are measured 
locally should also be sent in parallel to the central laboratory.  In the case of discrepant local 
and central laboratory results on samples drawn on the same day, central laboratory results will 
be relied upon for clinical and dosing decisions.  If central laboratory tests are not feasible due to 
COVID-19 restrictions, local laboratory tests for safety monitoring can be performed with 
approval from the Sponsor. 
Clinical laboratory assessments may be collected at the clinical study site or at a location other 
than the study site (eg, at home) by a trained healthcare professional.  On dosing days blood 
samples will be collected predose. 
For any safety event or laboratory abnormality, additional laboratory assessments, imaging, and 
consultation may be performed for clinical evaluation and/or in consultation with the Medical 
Monitor; results may be collected and should be included in the clinical database. 
Table 5: 
Clinical Laboratory Assessments 
Hematology 
Complete blood count with differential 
Serum Chemistry 
Sodium 
Potassium 
BUN 
Phosphate 
Creatinine and eGFR (using the CKD-EPI formula)  
Albumin 
Uric acid 
Calcium 
Total protein 
Carbon dioxide 
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Glucose 
Chloride 
Liver Function Tests 
AST 
ALP 
ALT 
Bilirubin (total and direct) 
GGT 
Urinalysis 
Visual inspection for appearance and color 
Bilirubin 
pH 
Nitrite 
Specific gravity 
Blood 
Ketones 
Urobilinogen 
Albumin 
Leukocytes 
Glucose 
Microscopy 
Protein 
Coagulation 
Prothrombin time 
International Normalized Ratio 
Partial Thromboplastin Time 
Immunogenicity (see Section 6.7.5.1) 
Antidrug antibodies 
Hepatic Tests (Screening Only) 
Hepatitis C, including:  
HCV RNA PCR – qualitative and quantitative 
assays 
Hepatitis B, including:  
HBs Ag, HBc antibody IgM and IgG 
Pregnancy Testing (Females of Child-bearing Potential Only) (see Section 6.7.5.2) 
β-human chorionic gonadotropin 
Abbreviations:  ALP=alkaline phosphatase; ALT=alanine transaminase; AST=aspartate transaminase; BUN=blood 
urea nitrogen; CKD-EPI=Chronic Kidney Disease Epidemiology Collaboration; eGFR=estimated glomerular 
filtration rate; GGT=gamma glutamyl transferase; HBsAg=hepatitis B virus surface antigen; HBc=hepatitis B virus 
core; HCV=hepatitis C virus; IgG= IgG=immunoglobulin G antibody; IgM=immunoglobulin M antibody; 
PCR=polymerase chain reaction; RNA=ribonucleic acid. 
6.7.5.1. 
Immunogenicity 
Blood samples will be collected to evaluate ADA and CIC.  IgG/IgM/IgA ADA to total drug will 
be assessed at Screening and during the study.  ADA samples will be tested in real time.  Clinical 
study decision will be based on confirmed positive ADA results from the IgG/IgM/IgA assay.  
Confirmed positive ADA samples will be further characterized for cemdisiran domain specificity 
against the Tri-GalNAc component if a reliable method is established.  Blood samples for ADA 
and CIC testing must be collected before study drug administration as specified in the Schedule 
of Assessments (Table 1 and Table 2).  Blood samples to evaluate ADAs will be collected at 
Screening to assess study eligibility and at the Early Termination (ET) visit, if applicable.  ADA 
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and CIC will be routinely monitored during the treatment period and throughout the open-label 
extension period and safety follow-up (ADA only), as indicated in the Schedule of Assessments. 
Finally, ADA and CIC samples will also be collected and analyses will be performed and 
prioritized if any clinical evidence of progression of IgAN disease and/or relevant safety 
findings.  Patients who are confirmed positive for IgG/IgM/IgA ADA at baseline will be 
excluded from study treatment.  In addition, patients who develop de novo ADAs will be 
discontinued from study drug but will be followed until EOS visit and during safety follow-up.  
These patients will also be monitored until ADA levels return to baseline. 
Exploratory analysis of anti-Gd-IgA1 antibody levels will be conducted; serum samples for these 
analyses will be drawn when CIC samples are collected. 
Details regarding the processing, shipping, and analysis of the samples will be provided in the 
Laboratory Manual. 
6.7.5.2. 
Pregnancy Testing 
A pregnancy test will be performed for females of child-bearing potential.  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.  Patients 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.  Patients determined to 
be pregnant while on study will be followed until the pregnancy outcome is known (see Section 
6.7.6.7 for follow-up instructions).  
6.7.5.3. 
Additional Liver Function Assessments 
Additional laboratory assessments will be performed in patients who experience any liver 
function test (LFT) abnormalities.  Following the occurrence of elevated liver transaminases or 
other LFT abnormalities per central laboratory, all assessments in Table 6 will be performed one 
time, as well as hematology, serum chemistry, LFT, and coagulation assessments from Table 5, 
and other assessments or evaluations per Investigator discretion, as appropriate. 
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Table 6: 
Hepatic Assessments in Patients Who Experience Elevated Transaminases 
Extended Hepatic Panel 
Herpes Simplex Virus 1 and 2 antibody IgM, IgG 
HHV-6 
Cytomegalovirus antibodies, IgM, IgG  
HBs Ag, HBc antibody IgM and IgG 
Anti-nuclear antibodies 
Epstein-Barr Virus antibodies, IgM and IgG 
Anti-smooth muscle antibodies 
Anti-mitochondrial antibodies 
HCV antibody 
HAV antibody IgM 
HCV RNA PCR – qualitative and quantitative 
HEV antibody IgM 
Herpes Zoster Virus IgM, IgG 
Imaging 
Abdominal ultrasound with Doppler flow (or CT or MRI) including right upper quadrant 
Focused Medical and Travel History 
Use of any potentially hepatotoxic concomitant 
medications, including over the counter medications 
and herbal remedies 
Alcohol consumption  
Other potentially hepatotoxic agents including any 
work-related exposures 
Recent travels to areas where hepatitis A or E 
is endemic 
Abbreviations:  CT=computed tomography; HAV=hepatitis A virus; HBc=hepatitis B core; HBsAg=hepatitis B 
virus surface antigen; HCV=hepatitis C virus; HEV=hepatitis E virus; HHV-6=human herpesvirus 6; 
IgG=immunoglobulin G antibody; IgM=immunoglobulin M antibody; MRI=magnetic resonance imagery; 
PCR=polymerase chain reaction; RNA=ribonucleic acid. 
Note: 
•
All assessments will be measured in central laboratory.  The full panel of assessments should only be
performed once; individual assessments may be repeated, as needed.
6.7.6. 
Adverse Events 
6.7.6.1. 
Definitions 
Adverse Event 
According to the International Council on Harmonisation (ICH) E2A guideline Definitions and 
Standards for Expedited Reporting, and 21 CFR 312.32, investigational new drug (IND) Safety 
Reporting, an AE is any untoward medical occurrence in a patient or clinical investigational 
subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
•
Results in death
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•
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
•
Is an important medical event that may not be immediately life-threatening or result
in death or hospitalization but may jeopardize the patient and may require
intervention to prevent one of the other outcomes listed in the definition above (eg,
events include allergic bronchospasm requiring intensive treatment in an emergency
room or at a location other than the study site (eg, at home), blood dyscrasias,
convulsions, or the development of drug dependency or abuse).
Adverse Events of Clinical Interest 
Based on the biological target and the available nonclinical and clinical data, AEs of Clinical 
Interest (AECI) for this study are: 
•
Severe infections as judged by the investigator
•
ALT or AST >3×ULN
•
Severe or serious injection site reactions (ISRs); ISRs that are associated with a recall
phenomenon (reaction at the site of a prior injection with subsequent injections), or
those that lead to temporary dose interruption or permanent discontinuation of
cemdisiran.
An ISR is defined as a local reaction at or near the site of injection.  “At or near” the
injection site includes reactions at the injection site, adjacent to the injection site, or a
reaction which may shift slightly away from the injection site due to gravity (eg, as
may occur with swelling or hematoma).  A systemic reaction which includes the
injection site (eg, generalized urticaria, other distinct entities or conditions like
lymphadenopathy that may be near the injection site) is not considered an ISR.
For information on recording and reporting of AECIs, see Section 6.7.6.2 and Section 6.7.6.3 , 
respectively. 
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Adverse Event Severity 
AEs are to be graded according to the categories detailed below: 
Mild: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Moderate: 
Moderate; minimal, local or noninvasive intervention indicated; limiting age 
appropriate instrumental activities of daily living (eg, preparing meals, 
shopping for groceries or clothes, using the telephone, managing money). 
Severe: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care activities of daily living (ie, bathing, dressing and undressing, feeding 
self, using the toilet, taking medications, and not bedridden); OR life-
threatening consequences; urgent intervention indicated; OR death related to 
an 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.  AEs characterized as intermittent require 
documentation of the start and stop of each incidence.  When changes in the severity of an AE 
occur more frequently than once a day, the maximum severity for the experience that day should 
be noted.  If the severity category changes over a number of days, then those changes should be 
recorded separately (with distinct onset dates). 
AE severity and seriousness are assessed independently.  ‘Severity’ characterizes the intensity of
an AE.  ‘Serious’ is a regulatory definition and serves as a guide to the Sponsor for defining 
regulatory reporting obligations (see definition for SAE). 
Relationship of the Adverse Event to Study Drug 
The relationship of each AE to study drug should be evaluated by the Investigator by a “yes” or 
“no” response to the question: “Is there a reasonable possibility that the event may have been 
caused by the study drug?” 
6.7.6.2. 
Eliciting and Recording Adverse Events 
Eliciting Adverse Events 
The patient and legal guardian, if applicable, should be asked about medically relevant changes 
in the patient’s health since the last visit.  The patient and legal guardian, if applicable, should 
also be asked if the patient has been hospitalized, had any accidents, used any new medications, 
or changed concomitant medication routines (both prescription and over-the-counter).  In 
addition to patient observations, AEs will be documented from any clinically relevant laboratory 
findings, physical examination findings, ECG changes, or other findings that are relevant to 
patient safety. 
Recording Adverse Events 
The Investigator is responsible for recording all SAEs and only AEs related to study procedures 
that are observed or reported by the patient during the run-in period (before the administration of 
the first dose of study drug) regardless of their relationship to study drug through the end of 
study.  All AEs, including non-serious AEs, occurring after signing of the ICF and before study 
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drug administration will be captured as medical history (see Section 6.1).  All AEs will be 
collected starting after administration of the first dose through the end of the safety follow-up 
period.  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 site and in the eCRF for the 
patient, whether or not they are considered to be drug-related.  Each AE must be described in 
detail:  onset time and date, description of event, severity, relationship to study drug, action 
taken, and outcome (including time and date of resolution, if applicable). 
For SAEs, record the event(s) on both the eCRF and the SAE form. 
For AEs that are considered AEs of clinical interest (Section 6.7.6.1), the supplemental AEs of 
Clinical Interest eCRF should be completed.  Additional clinical and laboratory information may 
be collected.  Refer to CRF completion guidelines for details on reporting events in the 
supplemental AEs of Clinical Interest eCRF.   
For all ISRs, the Investigator, or delegate, should submit a supplemental ISR eCRF, recording 
additional information (eg, descriptions, onset and resolution date, severity, treatment given, 
event outcome). 
6.7.6.3. 
Reporting Adverse Events of Clinical Interest to Sponsor/Designee 
For AEs that are considered AECIs (Section 6.7.6.1), the Sponsor or its designee should be 
notified within 24 hours using a supplemental AEs of Clinical Interest eCRF. 
6.7.6.4. 
Serious Adverse Events Require Immediate Reporting to Sponsor/Designee 
An assessment of the seriousness of each AE will be made by the Investigator.  Any AE and 
laboratory abnormality that meets the SAE criteria in Section 6.7.6.1 must be reported to the 
Sponsor or designee within 24 hours from the time that clinical study site staff first learns of the 
event.  All SAEs must be reported regardless of the relationship to study drug. 
The initial report should include at least the following information: 
•
Patient’s study number
•
Description and date of onset of the event
•
Criterion for serious
•
Preliminary assignment of relationship to study drug, and
•
Investigator/site information
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To report the SAE, complete the 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 Investigator Site File. 
Appropriate remedial measures should be taken by the Investigator using his/her best medical 
judgment to treat the SAE.  These measures and the patient’s response to these measures should 
be recorded.  All SAEs, regardless of relationship to study drug, will be followed by the 
Investigator until satisfactory resolution or the Investigator deems the SAE to be chronic or 
stable.  Clinical, laboratory, and diagnostic measures should be employed by the Investigator as 
needed to adequately determine the etiology of the event. 
6.7.6.5. 
Sponsor Safety Reporting to Regulatory Authorities 
The Sponsor or its representative will report certain study events in an expedited manner to the 
Food and Drug Administration, the European Medicines Agency’s EudraVigilance electronic 
system according to Directive 2001/20/EC, and to all country Regulatory Authorities where the 
study is being conducted, according to local applicable regulations. 
6.7.6.6. 
Serious Adverse Event Notification to the Institutional Review 
Board/Independent Ethics Committee 
Suspected unexpected serious adverse reactions (SUSARs) will be reported to the IRB/IEC per 
their institutional policy by the Investigator or Sponsor (or Sponsor designee) according to 
country requirements.  Copies of each report and documentation of IRB/IEC notification and 
acknowledgement of receipt will be kept in the Investigator’s study file. 
6.7.6.7. 
Pregnancy Reporting 
If a female patient becomes pregnant during the study through 90 days following the last dose of 
study drug, the Investigator must report the pregnancy to the Sponsor or designee within 
24 hours of being notified of the pregnancy.  Details of the pregnancy will be recorded on the 
pregnancy reporting form.  The patient should receive any necessary counseling regarding the 
risks of continuing the pregnancy 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 6.7.6.4. 
6.7.6.8. 
Overdose Reporting 
An overdose is defined as any dose administered to or taken by a patient (accidentally or 
intentionally) that exceeds the highest daily dose, or is at a higher frequency, than included in the 
protocol.  The investigator will decide whether a dose is to be considered an overdose, in 
consultation with the Sponsor.  In the event of an overdose, the actual dose administered must be 
recorded in the eCRF. 
All reports of overdose (with or without an AE) must be reported within 24 hours to the Sponsor 
or designee. 
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6.7.7. 
COVID-19 Data Collection 
Information on the COVID-19 infection status of the patient, if known, and other information on 
the impact of the COVID-19 pandemic and the patient's participation in the study will be 
collected. 
6.8. 
Biomarkers, DNA Genotyping, and Biospecimen Repository 
Alnylam’s RNAi therapeutics platform permits the highly specific targeting of investigational 
therapies based on genetic sequence.  It is possible that variations in the target genetic sequence 
will result in variations in drug effect. 
More generally, genetic variations may account for the well-described heterogeneous 
manifestations of disease in patients with IgAN, as well as their responses to treatment. 
To permit exploratory investigations and the application of novel approaches to bioanalyses that 
may further elucidate the outcomes of this study, or potentially advance understanding of the 
safety, mechanism of action, and/or efficacy of cemdisiran, a set of biological specimens will be 
collected at the intervals indicated in the Schedule of Assessments (Table 1 and Table 2). 
The biospecimen repository will also include residual material from routine samples (safety 
laboratory samples, PK samples, etc.) that are obtained during the study. 
These specimens will be securely stored in a central biorepository for up to 10 years following 
the completion of this clinical study (ie, last patient last visit), or as per local regulations.  After 
10 years have elapsed, samples will be destroyed. 
Where allowed per local regulations, ethics committee (IRB/IEC) approval, and patient consent, 
the samples will be collected as part of this study.  Examples of potential exploratory 
investigations would include DNA, RNA or biochemical metabolite assessments as they relate to 
disease progression, efficacy or safety.  
Details regarding the collection, processing, storage, and shipping of the samples will be 
provided in the Laboratory Manual. 
Exploratory analysis of these biospecimens will be performed by Alnylam Pharmaceuticals or its 
designees. 
When biobanking is permitted by local regulation, study participants will be advised during the 
informed consent process of these biobanking details and the potential for exploratory 
investigation of their samples. 
7.
STATISTICS
A Statistical Analysis Plan (SAP) will be finalized before database lock.  The plan will detail the 
implementation of the statistical analyses in accordance with the principle features stated in the 
protocol. 
7.1. 
Determination of Sample Size 
The sample size of the study was determined based on the precision of the estimate of the 
treatment effect for the primary endpoint – the percent change from baseline in UPCR from a 
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24-hour urine sample at Week 32.  It should be noted that geometric mean ratio of UPCR at 
Week 32 to baseline is statistically equivalent to mean of the change from baseline in logarithm 
of UPCR.  Therefore, the effect size of the study is defined as the difference of change from 
baseline between cemdisiran and placebo in the logarithm of UPCR.  
Based on the [Fellstrom 2017] study, we assume that in the placebo arm the geometric mean 
ratio of UPCR at Week 32 to baseline is 0.88 (log standard deviation [SD] 0.597), corresponding 
to a 12% reduction, while the geometric mean ratio is 0.5, or a 50% reduction for the cemdisiran 
arm.  Using these assumptions, sample size of 9 and 18 in the placebo and cemdisiran arms will 
provide a width of 0.80 (± 0.4) for the 90% confidence interval (CI) for treatment effect size 
estimate (cemdisiran – placebo) in log scale. 
7.2. 
Statistical Methodology 
The statistical and analytical plans presented below are brief summaries of planned analyses.  
More complete plans will be detailed in the statistical analysis plan (SAP).  Changes to the 
methods described in the final SAP will be described and justified as needed in the clinical study 
report.  For information on study endpoints, see Section 2. 
Descriptive statistics including the number of patients, mean, median, standard deviation (SD), 
interquartile range (Q1, Q3), minimum, and maximum values will be presented for continuous 
variables.  Frequencies and percentages will be presented for categorical and ordinal variables. 
Additional data summaries to help understand any impact of COVID-19 on PK/PD, efficacy and 
safety assessments will be outlined in the SAP. 
7.2.1. 
Populations to be Analyzed 
The following populations will be analyzed: 
•
Modified Intent-to-treat (mITT): All patients who receive any amount of study drug
and have at least one post baseline assessment in proteinuria.  Patients will be
grouped by assigned treatments (ie, as randomized).
•
Safety Analysis Set: All patients who received any amount of study drug.  Patients
who received any amount of cemdisiran will be included in the cemdisiran arm.
Patients in the Safety Analysis Set will be grouped by treatment received.
•
PK Analysis Set: All patients who receive any amount of study drug and have at least
one postdose blood or urine sample for PK concentration.
•
PD Analysis Set: All patients who receive any amount of study drug and who have at
least one postdose blood sample for the determination of plasma C5 level.
The primary population used to evaluate efficacy will be the mITT Population.  Safety will be 
analyzed using the Safety Analysis Set.  The PK and PD Analysis Sets will be used to conduct 
PK and PD analyses, respectively.  
7.2.2. 
Examination of Subgroups 
Subgroup analyses may be conducted for selected endpoints.  Detailed methodology will be 
provided in the SAP. 
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7.2.3. 
Handling of Missing Data 
Handling of missing data will be described in the SAP. 
7.2.4. 
Baseline Evaluations 
Demographics and other baseline characteristics, including disease-specific information, will be 
summarized descriptively by treatment arm and overall for the mITT and Safety Analysis Set. 
Baseline value for 24-hour UPCR will be calculated as the average of two valid 24-hour urine 
assessments before randomization (at the Week -2 visit). 
7.2.5. 
Efficacy Analyses 
7.2.5.1. 
Primary Endpoint 
The primary endpoint of the study is the percentage change from baseline in 24-hour UPCR at 
Week 32.  The 24-hour UPCR will be log transformed for analyses.  The primary analysis will 
be performed using a restricted maximum likelihood (REML) based Mixed-Effect Model 
Repeated Measures (MMRM) approach.  The outcome variable is change from baseline in 24-
hour UPCR in log-scale at the Week 16 and Week 32 visits.  Analysis will include fixed effects 
of treatment (cemdisiran vs. placebo), scheduled visits (Week 16 and Week 32), interaction term 
of treatment and scheduled visits, baseline 24-hour UPCR in log-scale (continuous), and patient 
as a random effect.  The least square mean difference and its 90% confidence interval will be 
estimated .  In addition, placebo-adjusted geometric mean percent change at the Week 32 visit 
and its 90% CI will be presented. 
A sensitivity analysis for the impact of missing data and the normality assumptions on the log-
transformed UPCR data will be performed.  Details will be provided in the SAP. 
7.2.5.2. 
Secondary Efficacy Endpoints
The secondary efficacy endpoints include percent change from baseline in 24-hour proteinuria 
(g/24 hours) at Week 32, percent of patients with partial clinical remission (UP <1.0 g/24-hours), 
percent of patients with >50% reduction in 24-hour proteinuria, change from baseline in UPCR 
as measured in a spot urine at Week 32 and change from baseline in hematuria at Week 32. 
The percentage of patients with partial clinical remission or with >50% reduction in 24-hour 
proteinuria for each treatment arm and the difference between treatment arms will be presented 
together with an approximate 90% confidence interval based on Wilson score method.  
Change from baseline in UP in 24-hour urine assessments and UPCR by spot urine at Week 32 
will be analyzed similarly to the analysis of the primary variable as appropriate.  The descriptive 
statistics for change from baseline in hematuria (urine dipstick) at Week 32 will be provided.  
7.2.5.3. 
Exploratory Endpoints
Change from baseline in exploratory efficacy variables will be summarized.  Percent of patients 
in full clinical remission and incidence of ADA will be tabulated by treatments.  
The slope of eGFR for the double-blind period will be estimated for each treatment and the slope 
of eGFR for the entire study period including the OLE will be analyzed.  Other inferential 
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statistics for exploratory efficacy variables may be presented as needed.  Details will be 
described in the SAP.  
7.2.6. 
Pharmacodynamic Analysis 
Assessment of the PD effect of the treatment will be performed descriptively, including plotting 
graphically levels of serum C5 protein and CAP/CCP over time and relative to baseline levels.  
Inferential statistics may be generated as deemed necessary. 
7.2.7. 
Pharmacokinetic Analysis 
Pharmacokinetic analyses will be conducted using noncompartmental methods.  Pharmacokinetic 
parameters include, but will not be limited to:  AUC, Cmax, Tmax, t½, CL/F, V/F, cumulative 
amount excreted unchanged in urine (Ae), and percent of dose excreted (fe) in the urine of 
cemdisiran (25-mer) and 23-mer.  
Other parameters may be calculated, if deemed necessary.  Summary statistics and figures will 
be presented.  Inferential statistics may be generated when deemed necessary. 
7.2.8. 
Safety Analyses 
The primary parameter is the frequency of treatment-emergent AEs (hereafter referred to simply 
as AEs).  Safety parameters also include vital signs, ECGs, clinical laboratory assessments, and 
physical exams.  The extent of exposure will be summarized by treatment arm and overall. 
AEs will be classified according to the Medical Dictionary for Regulatory Activities (MedDRA) 
System Organ Class and Preferred Term.  Prior and concomitant medications will be classified 
according to the World Health Organization (WHO) drug dictionary.  All SAEs occurring before 
the first dose of study drug and AEs related to study procedures will be listed.  The number and 
percentage of patients experiencing AEs after the first dose of the study drug or events that 
worsened in severity after dosing will be summarized.  AEs will be presented by maximum 
severity and relationship to study medication.  SAEs and AEs leading to discontinuation of 
treatment will also be tabulated. 
By-subject listings will be provided for deaths, SAEs, and AEs leading to study discontinuation. 
Frequency of AEs of clinical interest will also be summarized and by-subject listings will be 
provided. 
Descriptive statistics will be provided for clinical laboratory data, 12-lead ECG interval data and 
vital signs data, presented as both actual values and changes from baseline over time.  
Laboratory shift tables from baseline to worst values will be presented.  Baseline will be defined 
as the last observation on or prior to Study Day 1.  
Abnormal physical examination findings and 12-lead ECG data will be presented in a by-patient 
data listing.  Details of any abnormalities will be included in patient listings. 
Other safety summaries will be presented as appropriate.  Further details will be specified in the 
SAP. 
All safety analyses will be conducted using the Safety Analysis Set. 
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Additional data summaries to help understand any impact of COVID-19 on safety assessments 
will be outlined in the SAP. 
7.2.9. 
Immunogenicity Analyses 
Antidrug antibody, CIC and anti-Gd-IgA1 antibody results will be summarized descriptively.  
7.2.10. 
Biomarker Analyses 
Urine and serum complement activation products, inflammation and renal injury markers will be 
summarized descriptively.  
7.2.11. 
Interim Analysis 
No formal interim analysis is planned. 
7.2.12. 
Optional Additional Research 
Optional additional research may be conducted in the future on the biological samples and/or 
data collected during the study in accordance with the strict terms of the ICF (see Section 4.3.2). 
8.
STUDY ADMINISTRATION
8.1. 
Ethical and Regulatory Considerations
This study will be conducted in accordance with the protocol, all applicable regulatory 
requirements, and the current guidelines of Good Clinical Practice (GCP).  Compliance with 
GCP provides public assurance that the rights, safety, and well-being of study patients are 
protected consistent with the principles that have their origin in the Declaration of Helsinki. 
8.1.1. 
Informed Consent 
The Investigator will ensure that the patient/legal guardian is given full and adequate oral and 
written information about the nature, purpose, possible risk and benefit of the study.  
Patients/legal guardians must also be notified that they are free to discontinue from the study at 
any time.  The patient/legal guardian should be given the opportunity to ask questions and 
allowed time to consider the information provided.   
The patient’s/legal guardian’s signed and dated informed consent must be obtained before 
conducting any study tests or procedures that are not part of routine care.   
The Investigator must maintain the original, signed ICF.  A copy of the signed ICF must be 
given to the patient/legal guardian. 
The Investigator will inform the patient/legal guardian if new information becomes available that 
may be relevant to the patient’s/legal guardian’s willingness to continue participation in the 
study.  Communication of this information should be documented. 
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8.1.2. 
Ethical Review 
The study protocol, including the ICF, must be approved or given a favorable opinion in writing 
by an IRB or IEC, as appropriate.  The Investigator must submit written approval before he or 
she can enroll any patient into the study. 
The Investigator is responsible for informing the IRB or IEC of any amendment to the protocol 
in accordance with local requirements.  In addition, the IRB or IEC must approve all patient 
materials for the study (except those that support the need to remove an apparent immediate 
hazard to the patient).  The protocol must be reapproved by the IRB or IEC upon receipt of 
amendments and annually, as local regulations require. 
Initial IRB approval of the protocol, and all materials approved by the IRB for this study 
including the patient consent form and recruitment materials must be maintained by the 
Investigator and made available for inspection. 
The Investigator will submit reports of SAEs as outlined in Section 6.7.6.  In addition, the 
Investigator agrees to submit progress reports to the IRB or IEC per their local reporting 
requirements, or at least annually and at the conclusion of the study.  The reports will be made 
available to the Sponsor or designee. 
Any communications from regulatory agencies, IRBs, or IECs in regard to inspections, other 
studies that impact this protocol or the qualifications of study personnel should be promptly 
reported to the Sponsor or its designee. 
The Investigator is also responsible for providing the IRB with reports of any reportable serious 
adverse drug reactions from any other study conducted with the study drug.  The Sponsor or 
designee will provide this information to the Investigator. 
Major changes in this research activity, except those to remove an apparent immediate hazard to 
the patient, must be reviewed and approved by the Sponsor and the IRB or IEC that approved the 
study.  Amendments to the protocol must be submitted in writing to the Investigator’s IRB or
IEC and the Regulatory Authority for approval before patients are randomized under the 
amended protocol, and patients must be re-consented to the most current version of the ICF. 
8.1.3. 
Serious Breach of Protocol 
Investigators must notify the Medical Monitor within 24 hours of becoming aware of a serious 
breach of the protocol.  A serious breach is a breach that is likely to affect to a significant degree 
the safety and rights of a study participant or the reliability and robustness of the data generated 
in the clinical trial. 
8.1.4. 
Study Documentation, Confidentiality, and Records Retention 
All documentation relating to the study should be retained for 2 years after the last approval in an 
ICH territory or as locally required, whichever is longer.  If it becomes necessary for the 
Sponsor, the Sponsor’s designee, applicable IRB/IEC, or applicable regulatory authorities to 
review or audit any documentation relating to the study, the Investigator must permit direct 
access to all source documents/data.  Records will not be destroyed without informing the 
Sponsor in writing and giving the Sponsor the opportunity to store the records for a longer period 
of time at the Sponsor’s expense.  
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The Investigator must ensure that the patients’ confidentiality will be maintained.  On the eCRFs 
or other documents submitted to the Sponsor or designees, patients should not be identified by 
their names, but by the assigned patient number or code.  If patient names are included on copies 
of documents submitted to the Sponsor or designees, the names will be obliterated, and the 
assigned patient number added to the document.  Documents not for submission to the Sponsor 
(eg, signed ICFs) should be maintained by the Investigator in strict confidence. 
The Investigator must treat all information related to the study and the compiled data as 
confidential, whose use is for the purpose of conducting the study.  The Sponsor must approve 
any transfer of information not directly involved in the study. 
To comply with local and/or regional regulations, this clinical study may be registered, and study 
results may be posted on public registries, such as ClinicalTrials.gov. 
8.1.5. 
End of Study 
The end of study is defined as the last patient last visit. 
8.1.6. 
Termination of the Clinical Study or Site Closure 
The Sponsor reserves the right to terminate the study for clinical or administrative reasons at any 
time.  If the site does not recruit at a reasonable rate, or if there is insufficient adherence to the 
protocol requirements, the study may be closed 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, IRB/IEC and 
Regulatory Authorities will be promptly informed of the termination and the reason for the 
decision.  The Investigator should promptly inform the patients and assure appropriate therapy 
and follow-up. 
8.2. 
Data Quality Control and Quality Assurance 
8.2.1. 
Data Handling 
Study data must be recorded on CRFs (paper and/or electronic) provided by the Sponsor or 
designee on behalf of the Sponsor.  Case report forms must be completed only by persons 
designated by the Investigator.  If eCRFs are used, study data must be entered by trained site 
personnel with access to a valid and secure eCRF system.  All data entered into the eCRF must 
also be available in the source documents.  Corrections on paper CRFs must be made so as to not 
obliterate the original data and must be initialed and dated by the person who made the 
correction. 
8.2.2. 
Study Monitoring 
The Monitor, as a representative of the Sponsor, has an obligation to closely follow the study 
conduct at the site.  The Monitor will visit the Investigator and clinical study site periodically 
and will maintain frequent telephone and written contact.  The Monitor will maintain current 
personal knowledge of the study through observation, review of study records and source 
documentation, and discussion of the conduct of the study with the Investigator and staff. 
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The Monitor will review source documents, systems and CRFs to ensure overall quality and 
completeness of the data and to confirm study procedures are complied with the requirements in 
the study protocol accurately.  The Sponsor, or its designee, will be allowed to conduct site visits 
to the investigation facilities for the purpose of monitoring any aspect of the study.  The 
Investigator agrees to allow the Monitor to inspect the drug storage area, study drug stocks, drug 
accountability records, patient charts and study source documents, site standard operating 
procedures and training records, and other records relative to study conduct. 
8.2.3. 
Audits and Inspections 
Periodically, the Sponsor or its authorized representatives audit clinical investigative sites as an 
independent review of core trial processes and documents to determine whether these activities 
were conducted, and data were recorded, analyzed, and accurately reported according to the 
protocol, GCP guidelines of the ICH, and any applicable regulatory requirements.  A regulatory 
authority, an IRB/IEC may visit the site to perform audits or inspections, including source data 
verification.  The Investigator should contact the Sponsor and designee, immediately if contacted 
by a regulatory agency or an IRB/IEC about an inspection. 
8.3. 
Publication Policy 
It is intended that after completion of the study, the data are to be submitted for publication in a 
scientific journal and/or for reporting at a scientific meeting.  A separate publication by 
Institution or Investigator may not be submitted for publication until after this primary 
manuscript is published or following the period of 18 months after completion of the study at all 
sites.  A copy of any proposed publication (eg, manuscript, abstracts, oral/slide presentations, 
book chapters) based on this study, must be provided and confirmed received at the Sponsor at 
least 30 days before its submission.  The Clinical Trial Agreement among the institution, 
Investigator, and Alnylam will detail the procedures for Alnylam’s review of publications.
Authorship of any publications resulting from this study will be determined on the basis of the 
Uniform Requirement for Manuscripts Submitted to Biomedical Journals (International 
Committee of Medical Journal Editors). 
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9.
LIST OF REFERENCES
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of circulating glycoproteins. Advances in Enzymology and Related Areas of Molecular Biology, 
Volume 41. 2006:99-128. 
Cattran DC, Coppo R, Cook HT, Feehally J, Roberts IS, Troyanov S, et al. The Oxford 
classification of IgA nephropathy: rationale, clinicopathological correlations, and classification. 
Kidney international. 2009;76(5):534-45. 
Coppo R,D'amico G. Factors predicting progression of IgA nephropathies. Journal of 
nephrology. 2005;18(5):503-12. 
Crew PE, Abara WE, McCulley L, Waldron PE, Kirkcaldy RD, Weston EJ, et al. Disseminated 
gonococcal infections in patients receiving eculizumab: a case series. Clinical Infectious 
Diseases. 2018a. 
Crew PE, McNamara L, Waldron PE, McCulley L, Jones SC,Bersoff-Matcha SJ. Unusual 
Neisseria species as a cause of infection in patients taking eculizumab. Journal of Infection. 
2018b. 
Cugno M, Gualtierotti R, Possenti I, Testa S, Tel F, Griffini S, et al. Complement functional tests 
for monitoring eculizumab treatment in patients with atypical hemolytic uremic syndrome. 
Journal of Thrombosis and Haemostasis. 2014;12(9):1440-8. 
Elbashir SM, Lendeckel W,Tuschl T. RNA interference is mediated by 21-and 22-nucleotide 
RNAs. Genes & development. 2001;15(2):188-200. 
Fellstrom BC, Barratt J, Cook H, Coppo R, Feehally J, de Fijter JW, et al. Targeted-release 
budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, 
randomised, placebo-controlled phase 2b trial. Lancet. 2017 May 27;389(10084):2117-27. 
Imai E, Yamagata K, Iseki K, Iso H, Horio M, Mkino H, et al. Kidney disease screening program 
in Japan: history, outcome, and perspectives. Clinical journal of the American Society of 
Nephrology. 2007;2(6):1360-6. 
Kiryluk K, Li Y, Scolari F, Sanna-Cherchi S, Choi M, Verbitsky M, et al. Discovery of new risk 
loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens. 
Nature genetics. 2014;46(11):1187. 
Knoop T, Vikse BE, Mwakimonga A, Leh S,Bjørneklett R. Long-term outcome in 145 patients 
with assumed benign immunoglobulin A nephropathy. Nephrology Dialysis Transplantation. 
2017;32(11):1841-50. 
Knoppova B, Reily C, Maillard N, Rizk DV, Moldoveanu Z, Mestecky J, et al. The origin and 
activities of IgA1-containing immune complexes in IgA nephropathy. Frontiers in immunology. 
2016;7:117. 
Lafayette RA, Canetta PA, Rovin BH, Appel GB, Novak J, Nath KA, et al. A randomized, 
controlled trial of rituximab in IgA nephropathy with proteinuria and renal dysfunction. Journal 
of the American Society of Nephrology. 2016:ASN. 2016060640. 
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Lai KN, Tang SC, Schena FP, Novak J, Tomino Y, Fogo AB, et al. IgA nephropathy. Nature 
Reviews Disease Primers. 2016;2:16001. 
Lv J, Zhang H, Wong MG, Jardine MJ, Hladunewich M, Jha V, et al. Effect of Oral 
Methylprednisolone on Clinical Outcomes in Patients With IgA Nephropathy. Jama. 
2017;318(5):432. 
Maillard N, Wyatt RJ, Julian BA, Kiryluk K, Gharavi A, Fremeaux-Bacchi V, et al. Current 
understanding of the role of complement in IgA nephropathy. Journal of the American Society of 
Nephrology. 2015;26(7):1503-12. 
McQuillen DP,Ram S. No good deed goes unpunished: eculizumab and invasive neisserial 
infections. Clinical Infectious Diseases. 2018. 
Medjeral-Thomas NR, Troldborg A, Constantinou N, Lomax-Browne HJ, Hansen AG, 
Willicombe M, et al. Progressive IgA Nephropathy Is Associated With Low Circulating 
Mannan-Binding Lectin–Associated Serine Protease-3 (MASP-3) and Increased Glomerular 
Factor H–Related Protein-5 (FHR5) Deposition. Kidney international reports. 2018;3(2):426-38. 
Mestecky J, Novak J, Moldoveanu Z,Raska M. IgA nephropathy enigma. Clinical Immunology. 
2016;172:72-7. 
Morgan BP. Complement membrane attack on nucleated cells: resistance, recovery and non-
lethal effects. Biochemical Journal. 1989;264(1):1. 
Novak J, Barratt J, Julian BA,Renfrow MB, editors. Aberrant Glycosylation of the IgA1 
Molecule in IgA Nephropathy. Seminars in nephrology; 2018: Elsevier. 
Ram S, Lewis LA,Rice PA. Infections of people with complement deficiencies and patients who 
have undergone splenectomy. Clinical microbiology reviews. 2010;23(4):740-80. 
Rauen T, Eitner F, Fitzner C, Sommerer C, Zeier M, Otte B, et al. Intensive supportive care plus 
immunosuppression in IgA nephropathy. New England Journal of Medicine. 2015;373(23):2225-
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Reich HN, Troyanov S, Scholey JW,Cattran DC. Remission of proteinuria improves prognosis in 
IgA nephropathy. Journal of the American Society of Nephrology. 2007;18(12):3177-83. 
Roberts IS, Cook HT, Troyanov S, Alpers CE, Amore A, Barratt J, et al. The Oxford 
classification of IgA nephropathy: pathology definitions, correlations, and reproducibility. 
Kidney international. 2009;76(5):546-56. 
Ross SC,Densen P. Complement deficiency states and infection: epidemiology, pathogenesis and 
consequences of neisserial and other infections in an immune deficiency. Medicine. 
1984;63(5):243-73. 
Rosse WF. Variations in the red cells in paroxysmal nocturnal haemoglobinuria. British journal 
of haematology. 1973;24(3):327-42. 
Sarcina C, Tinelli C, Ferrario F, Pani A, De Silvestri A, Scaini P, et al. Changes in proteinuria 
and side effects of corticosteroids alone or in combination with azathioprine at different stages of 
IgA nephropathy. Clinical journal of the American Society of Nephrology. 2016;11(6):973-81. 
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Soutschek J, Akinc A, Bramlage B, Charisse K, Constien R, Donoghue M, et al. Therapeutic 
silencing of an endogenous gene by systemic administration of modified siRNAs. Nature. 
2004;432(7014):173-8. 
Suzuki H, Fan R, Zhang Z, Brown R, Hall S, Julian BA, et al. Aberrantly glycosylated IgA1 in 
IgA nephropathy patients is recognized by IgG antibodies with restricted heterogeneity. The 
Journal of clinical investigation. 2009;119(6):1668-77. 
Woo K-T, Chan C-M, Chin YM, Choong H-L, Tan H-K, Foo M, et al. Global evolutionary trend 
of the prevalence of primary glomerulonephritis over the past three decades. Nephron Clinical 
practice. 2010;116(4):c337-c46. 
Wyatt RJ, Julian BA, Baehler RW, Stafford CC, McMorrow RG, Ferguson T, et al. 
Epidemiology of IgA nephropathy in central and eastern Kentucky for the period 1975 through 
1994. Central Kentucky Region of the Southeastern United States IgA Nephropathy 
DATABANK Project. Journal of the American Society of Nephrology. 1998;9(5):853-8. 
Zimmermann TS, Lee AC, Akinc A, Bramlage B, Bumcrot D, Fedoruk MN, et al. RNAi-
mediated gene silencing in non-human primates. Nature. 2006;441(7089):111-4. 
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10.
APPENDICES
None. 
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ALN-CC5-005 PROTOCOL AMENDMENT 3 
SUMMARY OF CHANGES DATED 27 APRIL 2020 
Protocol Title 
A Phase 2, Randomized, Double-blind, Placebo-controlled Study of Cemdisiran in Adult Patients 
with IgA Nephropathy 
1. 
RATIONALE FOR PROTOCOL AMENDMENT 
The purpose of this protocol amendment is to incorporate Urgent Safety Measures (USMs) that 
were communicated to investigators in a Dear Investigator Letter (DIL) dated 06 April 2020.  
The USMs were implemented immediately by investigator sites on receipt of the DIL to 
minimize the serious risk caused by the COVID-19 pandemic to research participants in this 
trial.  The changes focus on assuring the safety of trial participants while maintaining compliance 
with good clinical practice (GCP) and minimizing risks to trial integrity, and are in line with 
guidance published by the European Medicines Agency [EMA 2020] and the US Food and Drug 
Administration [FDA 2020]. The USMs are summarized in Section 1.1 and Table 1. 
In order to reduce burden to investigator sites at this time of increased demands due to the 
COVID-19 pandemic, this protocol amendment also incorporates additional study changes that 
are not considered USMs.  These changes are summarized in Section 1.2 and Table 2, and will 
only be implemented following receipt of appropriate Health Authority and Ethics Committee 
(EC) or Institutional Review Board (IRB) approval. 
1.1. 
Urgent Safety Measures due to the Impact of the COVID-19 
Pandemic 
Urgent Safety Measures were implemented by the Sponsor, as mentioned above, to ensure the 
safety of study participants and the integrity of study data in response to the impact of the 
COVID-19 pandemic.  The changes are outlined below, and a detailed summary of the USMs is 
provided in Section 2 in Table 1. 
• Screening Period (expansion of screening window and notification of Sponsor 
prior to screening of new trial participants) 
The Screening window has been widened from 90 to 120 days ranging from Day-219 
to Day-99 for completion of assessments. 
In addition, the Investigator will notify the Sponsor before screening patients to allow 
an assessment of the ability of the site and any new trial participant to comply with 
the protocol given COVID-19 limitations.   
• Run-in Period (completion of visits at a later time with the approval of the 
Medical Monitor) 
If a run-in visit cannot proceed according to schedule, it may be delayed up to 28 
days, with subsequent visits being rescheduled based on the new date. Approval from 
the Medical Monitor is required prior to initiation of the treatment period. If a subject 
cannot proceed to the treatment period, as planned, the run-in period can be extended 
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as needed. If the final run-in visit will not be within 56 days of randomization, this 
visit will be repeated, and the new visit will serve as the Week -2 visit to determine 
eligibility for randomization. 
Sites are encouraged to discuss study information with the patients again and to check 
key inclusion and exclusion criteria at the end of the run-in period if run-in visits are 
delayed.  
Since the run-in period is designed to be observational and aims at ensuring a stable 
clinical state prior to the treatment period, allowing a delay in run-in visits is not 
expected to impact the study. 
• Study Visit Window (Treatment Period) 
The visit window for the treatment period is expanded to ±14 days (previously ±3 
days), but the interval between two doses may not be shorter than 14 days. If a dose is 
not administered within 14 days of the date determined by the schedule of 
assessments, then the dose is considered missed and should not be given. 
The change is being made to increase flexibility given transportation and scheduling 
challenges associated with COVID-19.  A previous study of cemdisiran (ALN-CC5-
001) established the safety of dosing at 14-day intervals, and hence this is set as the 
minimum interval between doses. 
• Cemdisiran Dosing Outside the Study Site 
Following appropriate training on cemdisiran administration, dosing at a location 
other than the study site (eg, at home) may be arranged in place of in-site visits from 
Week 4 in the 36-week double-blinded Treatment Period, if feasible and approved by 
the Medical Monitor. 
Dosing at a location other than the study site (eg, at home) may be administered by a 
healthcare professional with the oversight of the Investigator.  Administration by the 
patient or a caregiver is allowed following training with approval of the Investigator 
and Medical Monitor.  This measure is intended to remain in effect only during 
periods of time when the COVID-19 pandemic impedes the ability of patients to 
travel to the study site or healthcare professionals to go to a location other than the 
study site (eg, patients' homes) for dosing. 
• All Study Assessments 
• Following appropriate training, study assessments may be conducted at site visits or 
at a location other than the study site (eg, at home) by a healthcare professional, as 
locally feasible.  
• PK Assessments 
Blood samples for PK assessment will be collected at 1, 2, 4 and 6 hours postdose 
and, where locally feasible, at 8 and 24 hours postdose. 
This change is implemented to reduce study burden since it may not be practical to 
collect PK blood samples on all originally scheduled time points. 
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• Assessment of Adverse Events through Verbal Contact 
The Investigator or designee may remotely contact patients verbally to assess adverse 
events (AEs) and concomitant medications in situations where study drug is 
administered at a location other than the study site (eg, at home), or the dose is 
missed.  
• Collection of Information Related to COVID-19 
Information related to the impact of the COVID-19 pandemic on patient participation 
in the study will be collected for each patient.  Additional information regarding 
collection of this information, including completion of a new case report form 
specific to COVID-19, will be provided separately. 
This change is implemented to enable analysis of the impact of the COVID-19 global 
pandemic on clinical trial data. 
• Updates to Study Administration 
Text was updated to provide clarification on Investigator responsibilities regarding 
communication of new study information to patients and IRB/Independent Ethics 
Committees (IECs). 
1.2. 
Changes Not Related to Urgent Safety Measures 
The following changes are being made to the protocol.  As noted above in Section 1 , these 
changes will not be implemented prior to approval from the concerned Health Authority and EC 
or IRB.   
• Removal of creatinine-based criteria to assess 24-hour urinary creatinine sample 
validity.  The protocol included creatinine-based criteria that were intended to assess 
the completeness of the 24-hour urine collection.  However, based on a review of the 
references used in the protocol, [Fellstrom 2017; Rauen 2015]  it is considered that 
these criteria are not appropriate for this use in the study as intended.  Therefore, 
these criteria have been removed from the protocol, to avoid the rejection of valid 
samples.  
• Exchange of primary and secondary endpoints for the evaluation of proteinuria, to use 
the UPCR rather than the total protein (g/24-hrs) as the primary endpoint.  To 
mitigate against the risk of under/over collection of urine, which cannot be reliably 
controlled by the creatinine-based criteria (see above change), the assessment of 
proteinuria by total protein content will be changed from the primary, to the 
secondary endpoint.  The UPCR normalizes the assessment of urinary protein and 
protects against variability from collection factors.  To reflect this, the UPCR is being 
changed to the primary endpoint. The use of the UPCR from a timed sample as a 
primary endpoint is in line with published studies (NEFIGAN and STOP-IgAN) 
[Fellstrom 2017; Rauen 2015] and relevant EU guidance [EMA 2016]. 
• Including the use of urine dipstick for hematuria analyses for improved reliability.  
The inclusion criteria for hematuria previously required the presence of ≥10 red blood 
cells (RBCs) per high power field (HPF), based on microscopic analysis of urine at a 
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central laboratory.  Delays inherent in transport of urine samples from local sites to 
the central laboratory can result in degradation of RBCs and falsely low measurement 
of RBCs.  Measurement of hematuria by urine dipstick at the central laboratory is 
resilient to these effects of delays as it can detect both intact and degraded RBCs and 
has been performed in a standardized manner from the initiation of the study.  Thus, 
the presence of ≥10 RBCs/HPF on microscopy or a positive urine dipstick (2+ 
[moderate] and above) measured by a central laboratory will be used to define 
hematuria for assessing inclusion criteria during Screening. 
• Removal of pharmacokinetics (PK) periodic review by a Data Monitoring Committee 
(DMC).  The DMC remains in place to perform periodic reviews of unblinded data 
(safety, tolerability, pharmacodynamics [PD], ADA, circulating immune complexes 
[CIC] and efficacy of cemdisiran) during the clinical trial, and on an ad hoc basis 
review emergent safety data.  Due to the short plasma exposure of cemdisiran, PK 
measurements are not considered informative for the assessment of safety or efficacy. 
Additional changes are being implemented as outlined below.  
• Reducing the prior exclusion for systemic steroid exposure or other 
immunosuppressant agents from 12 months to 6 months 
• Clarifying the prohibition of dual RAS blockade in the eligibility criteria 
• Clarification to specific eligibility criteria and safety assessment timeframes 
A detailed summary of changes is provided in Table 2 of Section 2 .  The following changes are 
not detailed: administrative changes, changes associated with administrative letters (between 
protocol amendments 2 and 3), and corrections to typographical errors, punctuation, grammar, 
abbreviations, and formatting. 
References 
FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic: 
Guidance for Industry, Investigators, and Institutional Review Boards. 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/fda-guidance-
conduct-clinical-trials-medical-products-during-covid-19-pandemic 
Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) Pandemic, 
Version 2 (27/03/2020). https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
10/guidanceclinicaltrials_covid19_en.pdf 
Guideline on the clinical investigation of medicinal products to prevent development/slow 
progression of chronic renal insufficiency (EMA/CHMP/500825/2016). 
https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-clinical-investigation-
medicinal-products-prevent-development/slow-progression-chronic-renal-insufficiency_en.pdf 
Fellstrom BC, Barratt J, Cook H, Coppo R, Feehally J, de Fijter J W, et al. Targeted-release 
budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, 
randomised, placebo-controlled phase 2b trial. Lancet. 2017;389:2117–27 
Rauen T, Eitner F, Fitzner C, Sommerer C, Zeier M, Otte B, et al. Intensive Supportive Care plus 
Immunosuppression in IgA Nephropathy. New England Journal of Medicine. 2015;373:2225-36 
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2. 
PROTOCOL AMENDMENT 3 DETAILED SUMMARY OF CHANGES 
The primary section(s) of the protocol affected by the changes in Protocol Amendment 3 are indicated.  The corresponding text has 
been revised throughout the protocol.  Deleted text is indicated by strikeout; added text is indicated by bold font.  
Table 1: 
Urgent Safety Measure COVID-19-related Changes to be Adopted Immediately 
Purpose:  To widen the Screening Period window from 90 to 120 days. 
The primary change occurs in Table 1 (Schedule of Assessments – Run-in and Treatment Periods (Screening through Week 36) 
including Safety Follow up) 
Revised text:  The Screening Period window is now for a duration of 120 days ranging from Day-219 to Day-99. 
Sections also reflecting this change: 
• Synopsis 
• Figure 1, Study Design 
• Section 3.1, Summary of Study Design 
• Section 3.3, Duration of Study 
• Section 6.1.1, Rescreening 
Purpose:  To widen the total time of study duration mainly due to the widening of the Screening Period window. 
The primary change occurs in Section 3.3, Duration of Study 
Revised text:  The maximum estimated total time on study, inclusive of Screening (maximum of 90 120 days), run in period (14 
weeks), treatment period (36 weeks), optional OLE period (52 weeks) and safety follow-up (52 weeks), is approximately 36 43 
months or 3 years and 7 months. 
Section also reflecting this change: 
• Synopsis 
Purpose:  To allow ongoing, safe administration of study drug by ensuring Sponsor notification before patient screening. 
The primary change occurs in Section 3.1, Summary of Study Design 
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Revised text:  The Investigator will notify the Sponsor before screening patients to allow an assessment of the ability of the site 
and new trial participants to comply with the protocol given limitations during the COVID-19 pandemic. 
Sections also reflecting this change: 
• Synopsis 
• Section 6.1, Screening Assessments 
Purpose:  To allow rescreening of patients who are unable to complete screening and run-in visits. 
The primary change occurs in Section 6.1.1, Rescreening 
Revised text:  A patient who does not meet all study eligibility criteria due to a transient condition observed at Screening (eg, 
prohibited medications that were subsequently discontinued) will be allowed to return for rescreening (once only).  A patient who is 
unable to complete screening and run-in visits due to COVID-19 associated delays may be rescreened with approval of the 
Sponsor.  A patient will be re-consented if rescreening occurs outside of the 90 120-day screening window.  In this case, all screening 
procedures must be repeated.   
Purpose:  To allow the completion of visits at a later time during the run-in period following approval by the Medical Monitor 
The primary change occurs in Section 6.2, Run-in Period 
Revised text:  Patients will then return to the study center every 4 weeks after the start of study drug treatment period. If a run-in visit 
cannot proceed according to schedule, it may be delayed up to 28 days, with subsequent visits being rescheduled based on the 
new date.  Visit windows, as indicated in the Schedule of Assessments (Table 1), are applied to the rescheduled date.  Approval 
from the Medical Monitor is required prior to initiation of the treatment period.  If a subject cannot proceed to the treatment 
period as planned, the run-in period can be extended as needed.  If the final run-in visit will not be within 56 days of 
randomization, this visit will be repeated, and the new visit will serve as the Week -2 visit to determine eligibility for 
randomization. 
Sites are encouraged to discuss study information with the patients again at the end of the run-in period and to check key inclusion 
and exclusion criteria when run-in visits are delayed. 
Sections also reflecting this change: 
• Synopsis  
• Schedule of Assessments (Table 1 footnotes) 
• Section 3.1, Summary of Study Design 
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Purpose:  To expand the visit window and to allow the study Investigator (or delegate) to verbally contact patients within the study 
visit window to assess for any adverse events 
The primary change occurs in Section 5.2.3, Dose Modifications 
Revised text:  Dose modifications are not permitted. 
The visit window for the treatment period is ±14 days, but the interval between two doses may not be shorter than 14 days.  If 
a dose is not administered within 14 days of the date determined by the Schedule of Assessments (see Table 1), then the dose is 
considered missed and should not be given. 
If a study drug-related AE occurs in a patient that the Investigator judges as presenting a potential risk to the patient for further dosing, 
the study drug dose may be held at the discretion of the Investigator and the Medical Monitor should be contacted.  In situations 
where study drug is administered at a location other than the study site (eg, at home), or the dose is missed, the study 
physician (or delegate) will verbally contact the patient to assess any AEs and concomitant medications.  
Section also reflecting this change: 
• Table 1, Schedule of Assessments and footnotes 
Purpose:  To allow offsite and self-administration from Week 4 of the Treatment Period with the oversight of the Investigator and 
approval of the Medical Monitor. 
The primary change occurs in Section 5.2.2, Dose and Administration 
Revised text:  Study drug administration may be conducted by a healthcare professional at a location other than the study site 
(eg, at home) from Week 4 of the treatment period for patients that have demonstrated the ability to tolerate the study drug at 
the study site.  If the patient is unable to come to the study site, and a visit by a healthcare professional for patients at a 
location other than the study site (eg, at home) is not possible due to circumstances related to the COVID-19 pandemic, 
cemdisiran may be administered by the patient or the caregiver under the oversight of the Investigator, and following 
consultation with the Medical Monitor, as allowed by applicable country and local regulations.  In such cases, the patient or 
the caregiver must receive appropriate training on cemdisiran administration prior to dosing.  This measure is intended to 
remain in effect only during periods of time when the COVID-19 pandemic impedes the ability of patients to travel to the 
study site or healthcare professionals to go to a location other than the study site (eg, at home) for dosing. At home dosing may 
be administered by a healthcare professional.  The injection site may 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, if permitted.  Detailed instructions for study drug administration are found in the Pharmacy 
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Manual.   In addition, instructions and procedures related to administration of study drug by a patient or caregiver will be 
provided in the Patient/Caregiver Storage and Administration Instructions. 
Sections also reflecting this change: 
• Synopsis 
• Schedule of Assessments (Table 1 footnotes) 
• Section 3.1, Summary of Study Design 
• Section 3.6, Blinding 
• Section 5.4, Treatment Compliance 
Purpose:  To allow offsite administration during the open-label extension (OLE) period and safety follow-up.  
The primary change occurs in Section 3.1, Summary of Study Design 
Revised text:  Home visits Visits at a location other than the study site (eg, at home), where locally feasible, may be arranged for 
cemdisiran administration in between 8-weekly study site visits (Weeks 44, 52, 60, 68 and 76), unless patients are required to visit the 
study site as judged necessary by the Investigator, or if home visits at a location other than the study site (eg, at home) cannot be 
arranged.  An end of treatment (EOT) visit will occur at Week 80 (OLE EOT) and an end of study (EOS) or early termination (ET) 
visit will be completed at Week 84 (OLE EOS/ET).  For patients who complete the treatment period only who do not consent to 
continue to participate in the study in the OLE period, the EOS/ET visit will be at Week 36. 
Patients will return to the clinical study site for safety follow-up visits approximately 13, 26, 39 and 52 weeks after the EOS/ET visit 
(regardless if EOS/ET visit is at Week 36 or Week 84), unless enrolled in another study with cemdisiran.  Home visits Visits at a 
location other than the study site (eg, at home), where locally feasible, may be arranged during safety follow-up at 13 and 39 weeks 
after the EOS/ET visit (regardless if EOS/ET visit is at Week 36 or Week 84). 
Section also reflecting this change: 
• Synopsis 
Purpose:  To allow offsite cemdisiran preparation, handling and storage by a health care professional or patient/caregiver 
The primary change occurs in Section 5.2.4, Preparation, Handling, and Storage 
Revised text:  Staff at each clinical study site or the home healthcare professional performing administration at a location other 
than the study site (eg, at home) will be responsible for preparation of cemdisiran doses, according to procedures detailed in the 
Pharmacy Manual.  In cases where study drug is administered at a location other than the study site (eg, at home) by a 
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patient/caregiver, dosing may be prepared and administered by the patient/caregiver according to procedures detailed in the 
Patient/Caregiver Storage and Administration Instructions.  No special procedures for the safe handling of study drug are 
required. 
Study drug will be stored upright and refrigerated at approximately 2 to 8°C.  The vial should be stored in the carton until ready for 
use in the storage area of the clinical study site pharmacy, in a secure, temperature-controlled, locked environment with restricted 
access.  Deviations from the recommended storage conditions should be reported to the Sponsor and use of the study drug halted until 
authorization for its continued use has been provided by the Sponsor or designee, as described in the Pharmacy Manual. 
A Sponsor representative or designee will be permitted, upon request, to audit the supplies, storage, dispensing procedures, and 
records. 
Instructions specific to unused study drug and additional storage will be provided in the Pharmacy Manual and Patient/Caregiver 
Storage and Administration Instructions.   
Purpose:  To allow study visit assessments to be performed offsite by a healthcare professional 
The primary change occurs in Section 6, Study Assessments 
Revised text:  The Schedule of Assessments is provided in Table 1 and Table 2.  If a patient is unable to complete a site visit due to 
the COVID-19 pandemic impacting activities at the study site or patient ability or willingness to access the site, routine 
physical examination/body system assessment, height, weight, body mass index (BMI), vital signs and collection of blood and 
urine samples for efficacy, safety, PD, PK, and exploratory assessments may be conducted at a location other than the study 
site (eg, at home) by a trained healthcare professional as locally feasible (refer to instructions for home nurses in the 
Laboratory Manual).   
Section also reflecting this change: 
• Schedule of Assessments (Table 1 footnotes) 
Purpose:  To collect PK samples, where locally feasible, at 8 and 24 hours postdose. 
The primary change occurs in Table 3, Pharmacokinetic Time Points 
Revised text:  Blood samples for PK assessment will be collected at 1, 2, 4 and 6 hours postdose and, where locally feasible, at 8 and 
24 hours postdose. 
Purpose:  To enable local laboratory tests to be performed if central laboratory tests are not feasible. 
The primary change occurs in Section 6.7.5, Clinical Laboratory Assessments 
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Revised text:  In the case of discrepant local and central laboratory results on samples drawn on the same day, central laboratory 
results will be relied upon for clinical and dosing decisions. If central laboratory tests are not feasible due to COVID-19 
restrictions, local laboratory tests for safety monitoring can be performed with approval from the Sponsor.  
Clinical laboratory assessments may be collected at the clinical study site or at home a location other than the study site (eg, at 
home) by a trained healthcare professional.  On dosing days blood samples will be collected predose. 
Purpose:  To reiterate that a serious adverse event can occur at a location other than the study site (eg, at home). 
The primary change occurs in Section 6.7.6.1, Definitions 
Revised text:  An SAE is any untoward medical occurrence that at any dose: 
• • 
Results in death 
• • 
Is life-threatening (an event which places the patient at immediate risk of death from the event as it occurred.  It does 
not include an event that had it occurred in a more severe form might have caused death) 
• • 
Requires in-patient hospitalization or prolongation of existing hospitalization 
• • 
Results in persistent or significant disability or incapacity 
• • 
Is a congenital anomaly or birth defect 
• • 
Is an important medical event that may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the patient and may require intervention to prevent one of the other outcomes listed in the definition above (eg, 
events include allergic bronchospasm requiring intensive treatment in an emergency room or at home a location other 
than the study site (eg, at home), blood dyscrasias, convulsions, or the development of drug dependency or abuse). 
Purpose:  To outline additional data summaries on PK/PD, efficacy and safety assessments in the Statistical Analysis Plan (SAP). 
The primary change occurs in Section 7.2, Statistical Methodology 
Revised text:  Additional data summaries to help understand any impact of COVID-19 on PK/PD, efficacy and safety 
assessments will be outlined in the SAP.  
Section also reflecting this change: 
• Section 7.2.8, Safety Analyses 
Purpose:  To communicate and document new information that becomes available that may be relevant to the patient’s/legal 
guardian’s willingness to continue participation in the study. 
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The primary change occurs in Section 8.1.1, Informed Consent 
Revised text:  The Investigator will inform the patient/legal guardian if new information becomes available that may be 
relevant to the patient’s/legal guardian’s willingness to continue participation in the study.  Communication of this 
information should be documented.  
Purpose:  IRB or IEC approval of all patient materials for the study except those that support the need to remove an apparent 
immediate hazard to the patient. 
The primary change occurs in Section 8.1.2, Ethical Review 
Revised text:  The Investigator is responsible for informing the IRB or IEC of any amendment to the protocol in accordance with local 
requirements.  In addition, the IRB or IEC must approve all patient materials for the study (except those that support the need to 
remove an apparent immediate hazard to the patient).  The protocol must be reapproved by the IRB or IEC upon receipt of 
amendments and annually, as local regulations require.  
Purpose:  To clarify lost to follow-up if a patient misses a required study visit. 
The primary change occurs in Section 4.3.3, Lost to Follow-Up 
Revised text:  A patient will be considered lost to follow-up if the patient repeatedly fails to return for scheduled visits and is unable to 
be contacted by the clinical study site.  The following actions must be taken if a patient misses fails to return to the clinical for a 
required study visit: 
• The site must attempt to contact the patient or legal guardian and reschedule the missed visit as soon as possible and 
counsel the patient or legal guardian on the importance of maintaining the assigned visit schedule and ascertain if the 
patient or legal guardian wishes to continue in the study, and/or should continue in the study.  
• Before a patient is deemed lost to follow up, the investigator or designee must make every effort to regain contact with the 
patient or legal guardian (where possible, 3 telephone calls and, if necessary, a certified letter to the patient’s last known 
mailing address or local equivalent methods).  These contact attempts should be documented in the patient’s medical 
record. 
• Should the patient or legal guardian continue to be unreachable, the patient will be considered to have stopped participation 
in the study. 
• For patients who are lost to follow-up, the Investigator can search publicly available records (where permitted and allowed 
by local law) to ascertain survival status.  This ensures that the outcome of the study is as comprehensive as possible. 
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Purpose:  Collect information related to the impact of the COVID-19 pandemic on patient participation in the study, to enable 
analysis of the impact of the COVID-19 global pandemic on clinical trial data 
The primary change occurs in Section 6.7.7, COVID-19 Data Collection 
Added text:  Information on the COVID-19 infection status of the patient, if known, and other information on the impact of the 
COVID-19 pandemic and the patient's participation in the study will be collected. 
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Table 2: 
Changes Not Related to Urgent Safety Measures to be Implemented After EMA and FDA Approval 
Purpose:  Switched total protein to secondary endpoint and protein:creatinine ratio to primary endpoint. 
The primary change occurs in Section 2, Objectives and Endpoints 
Revised text:  Objectives 
Secondary: 
• To evaluate the effect of cemdisiran on remission additional measures of proteinuria in adult patients with IgAN 
• To evaluate the effect of cemdisiran on hematuria in adult patients with IgAN 
• To evaluate the safety and tolerability of cemdisiran 
Exploratory: 
• To evaluate the effect of cemdisiran on renal function parameters  
• To evaluate the effect of cemdisiran on full clinical remission and measures of albuminuria in adult patients with 
IgAN 
• To evaluate the pharmacodynamic (PD) effect of cemdisiran in adult patients with IgAN ie, C5 level and CAP/CCP 
• To characterize the pharmacokinetics (PK) of cemdisiran and relevant metabolites in plasma and urine in adult patients 
with IgAN 
• To evaluate the effect of cemdisiran on serum and urine markers of complement activation, renal damage and inflammation 
• To assess the incidence of antidrug antibodies (ADA) 
Endpoints 
Primary: 
• Percent change from baseline in urine protein/creatinine ratio (UPCR) as measured in 24-hour proteinuria (g/24 hours) 
urine at Week 32 
Secondary: 
• Percent change from baseline in 24-hour proteinuria (g/24-hours) at Week 32 
• Percent of patients with partial clinical remission (urine protein [UP] <1.0 g/24-hours) at Week 32 
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• Percent of patients with >50% reduction in 24-hour proteinuria at Week 32   
• Change from baseline in urine protein/creatinine ratio (UPCR; in g/g) as measured in 24 hour urine at Week 32 
• Change from baseline in UPCR as measured in a spot urine at Week 32   
• Change from baseline in hematuria at Week 32 (red blood cells per high powered field [RBC/hpf])  
• Frequency of adverse events (AEs) 
Exploratory: 
• The slope of eGFR computed for the first 32 36 weeks using all assessments during the period 
Sections also reflecting this change: 
• Synopsis 
• Section 1.3, Study Design Rationale 
• Section 6.4.1, Urine Protein/Creatinine Ratio 
• Section 6.4.1.1, 24-Hour Urine Collection 
• Section 7.1, Determination of Sample Size 
• Section 7.2.4, Baseline Evaluations 
• Section 7.2.5, Efficacy Analyses 
• Table 5, Clinical Laboratory Assessments 
Purpose:  Included the use of urine dipstick testing for the hematuria secondary analyses.   
The primary change occurs in Section 7.2.5.2, Secondary Efficacy Endpoints 
Revised text:  The secondary efficacy endpoints include percent change from baseline in 24-hour proteinuria (g/24 hours) at 
Week 32, percent of patients with partial clinical remission (UP <1.0 g/24-hours), percent of patients with >50% reduction in 24-hour 
proteinuria, change from baseline in UPCR as measured in 24 hour urine at Week 32, change from baseline in urine protein/creatinine 
ratio (UPCR) as measured in a spot urine at Week 32 and change from baseline in hematuria at Week 32. 
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The percentage of patients with partial clinical remission or with >50% reduction in 24-hour proteinuria for each treatment arm and 
the difference between treatment arms will be presented together with an approximate 90% confidence interval based on Wilson score 
method.  
Change from baseline in UP in 24-hour urine protein / creatinine ration (assessments and UPCR) by spot urine at Week 32 will be 
analyzed similarly to the analysis of the primary variable as appropriate.  UPCR The descriptive statistics for change from baseline 
in hematuria (urine dipstick) at Week 32 will be log transformed first before analysis provided.  
Purpose:  Removed creatinine-based criteria to assess 24-hour urinary creatinine sample validity, and updated an inclusion criterion 
pertaining to and clarifying the validity of 24-hour urine collections. 
The primary change occurs in Section 6.4.1.1, 24-Hour Urine Collection 
Revised text:  Completeness of the 24 hour urine collection can be estimated from rate of creatinine excretion. Normal values of 
creatinine excretion vary with age and body weight. An aliquot of the 24 hour urine collection will be used to determine urinary 
creatinine content to determine if the 24 hour urine collections need to be repeated. Hence, a A 24-hour urine collection will only be 
considered valid if all the following criteria are met, otherwise a repeat urine collection will be required: 
• The collection is between 22-26 hours in duration between the initial discarded void and the last void or attempt to void. 
• No voids are missed between the start and end time of the collection as indicated by the patient’s urine collection diary. 
• The 24 hour creatinine content is within 25% of expected range as estimated by the following formula:  [(140 age) x 
weight]/5000, where weight is in kilograms. This result is multiplied by 0.85 in women.[Ix 2011] 
• In case of need of two valid samples, the maximum variation in total 24 hour urine creatinine between the two urine 
collections must be <25%. 
Sections also reflecting this change: 
• Synopsis 
• Section 4.1, Inclusion Criteria – Criterion 4 
Purpose:  Removed the need for a periodic review of PK by a DMC. 
The primary change occurs in Section 3.7, Data Monitoring Committee 
Revised text:  The DMC will perform periodic reviews of unblinded data (safety, tolerability, PK, pharmacodynamics (PD), ADA, 
circulating immune complexes (CIC) and efficacy of cemdisiran) during the clinical trial, and on an ad hoc basis review emergent 
safety data.  Details are provided in the DMC Charter. 
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Purpose:  Increased the window for patients to receive pneumococcal and Haemophilus influenzae type b (Hib) vaccination, if not 
previously vaccinated, based on local guidance for some countries which can be vaccination during Screening. 
The primary change occurs in Table 1 (Schedule of Assessments – Run-in and Treatment Periods (Screening through Week 36) 
including Safety Follow up) 
Revised text:  The period window for patients to receive pneumococcal and Hib vaccination, if not previously vaccinated, based on 
local guidance for some countries which can be vaccination during Screening is now from the Screening visit to Week 8 in the 
treatment period, and should be administered at least 14 days prior to randomization. 
Sections also reflecting this change: 
• Section 5.3.2.2, Pneumococcal and Hib Vaccinations 
• Section 6.2, Run-in Period 
Purpose:  Clarified when patients need to receive meningococcal vaccination. 
The primary change occurs in Table 1 (Schedule of Assessments – Run-in and Treatment Periods (Screening through Week 36) 
including Safety Follow up) 
Revised text:  All patients taking part in this study must be vaccinated against meningitis types A, C, W135, Y and B, upon 
determination of eligibility at the end of run in period, 2 weeks least 14 days prior to randomization to cemdisiran or placebo, as per 
the Schedule of Assessments. 
Sections also reflecting this change: 
• Section 5.3.2.1, Meningococcal Vaccinations 
• Section 6.2, Run-in Period 
Purpose:  Reduced prior exclusion for systemic steroid exposure or other immunosuppressant agents from 12 months to 6 months 
based on feedback from investigators, and literature. 
The primary change occurs in Section 4.2, Exclusion Criteria 
Revised text: 
• Criterion 10:  Treatment with systemic steroids for more than 7 days or other immunosuppressant agents in the 12 6 
months prior to randomization 
Section also reflecting this change: 
• Synopsis 
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Purpose:  Added an exclusion criterion to clarify that dual RAS blockade is prohibited. 
The primary change occurs in Section 4.2, Exclusion Criteria 
Revised text: 
• Criterion 11:  Treatment with dual RAS blockade in the 3 months prior to entry into the run-in phase. 
Section also reflecting this change: 
• Synopsis 
Purpose:  Clarified an exclusion criterion on hepatitis B virus (HBV) and hepatitis C virus (HCV), and moved known human 
immunodeficiency virus (HIV), HBV and HCV infections under medical conditions. 
The primary change occurs in Section 4.2, Exclusion Criteria 
Revised text:  Laboratory Assessments 
• Criterion 9:  Known human immunodeficiency virus (HIV) infection Positive hepatitis B virus (HBV) surface antigen, 
HBV core antibody, hepatitis C virus (HCV) infection or hepatitis B virus (HBV) infection antibody (unless HCV viral 
load demonstrated negative) 
Medical Conditions 
• Criterion 13:  Known human immunodeficiency virus (HIV) infection, HCV infection or HBV infection 
Purpose:  Clarified predose and postdose timeframes for the collection of vital signs on Day 1. 
The primary change occurs in Section 6.7.1, Vital Signs 
Revised text:  Vital signs will be measured in the seated or supine position, after the patient has rested comfortably for at least 10 
minutes.  On Day 1, vital signs will be collected at predose (no more than 4 hours prior to dosing) and 4 hours (±30 15 minutes) 
postdose.  On all other dosing days, vital signs will be collected predose. 
Purpose:  Clarified predose and postdose timeframes for the performance of 12-lead electrocardiograms on Day 1 and Week 32. 
The primary change occurs in Section 6.7.4, Electrocardiogram 
Revised text:  12 lead ECGs will be performed; predose (on the same day as dosing); 60 minutes (±15 minutes) postdose; and 4 
hours (±30 minutes) postdose in relation to the Day 1 and Week 32 cemdisiran or placebo doses. 
Purpose:  Clarified that antidrug antibodies will be monitored during the safety follow-up period. 
The primary change occurs in Section 6.7.5.1, Immunogenicity 
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Revised text:  ADA and CIC will be routinely monitored during the treatment period and throughout the open label extension period 
phase and safety follow-up (ADA only), as indicated in the Schedule of Assessments. 
Purpose:  Clarified that a Randomization and Blinding Plan document will detail arrangements on blinding and unblinding. 
The primary change occurs in Section 3.6, Blinding 
Revised text:  Further details on blinding and unblinding arrangements will be documented in a separate plan/manual Randomization 
and Blinding Plan document. 
Section also reflecting this change: 
• Section 3.6.1, Emergency Unblinding 
Purpose:  Administrative changes, changes associated with administrative letters (between protocol amendments 2 and 3), and 
corrections to typographical errors, punctuation, grammar, abbreviations, and formatting.  
These changes are not listed individually. 
 
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CLINICAL STUDY PROTOCOL 
ALN-CC5-005 
 
Protocol Title: 
A Phase 2, Randomized, Double-blind, 
Placebo-controlled Study of Cemdisiran in Adult 
Patients with IgA Nephropathy 
Short Title: 
A Phase 2 Study of Cemdisiran in Adult Patients 
with IgA Nephropathy 
Study Drug: 
Cemdisiran (ALN-CC5)  
EudraCT Number: 
2018-002716-27 
IND Number: 
140087 
Protocol Date: 
 
Original protocol 10 September 2018 
Amendment 1 [26 November 2018] 
Amendment 2 [20 September 2019] 
Sponsor: 
Alnylam Pharmaceuticals, Inc. 
300 Third Street 
Cambridge, MA  02142 USA 
Telephone:  
 
Sponsor Contact:   
 
 
Development 
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. 
 
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INVESTIGATOR’S AGREEMENT 
 
I have read the ALN-CC5-005 protocol and agree to conduct the study in accordance with the 
protocol and all applicable regulations.  I agree to maintain the confidentiality of all information 
received or developed in connection with this protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 
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• 
To characterize the pharmacokinetics 
(PK) of cemdisiran and relevant 
metabolites in plasma and urine in adult 
patients with IgAN 
• 
To evaluate the effect of cemdisiran on 
serum and urine markers of complement 
activation, renal damage and 
inflammation 
• 
To assess the incidence of antidrug 
antibodies (ADA) 
• 
The slope of eGFR computed for the first 
32 weeks using all assessments during the 
period  
• 
The slope of eGFR computed for the 
entire study period including the open 
label extension using all assessments 
during the study. 
• 
Change from baseline in creatinine 
clearance at Week 32 
• 
Percent of patients in full clinical 
remission (Urine Protein [UP] 
<0.3 g/24-hours) at Week 32  
• 
Change from baseline in 24-hour 
albuminuria at Week 32 
• 
Change from baseline in the urine 
albumin/creatinine ratio (UACR) as 
measured in 24-hour urine at Week 32 
• 
Change from baseline in C5 level over the 
course of the study 
• 
Change from baseline in complement 
activity (Complement Alternative 
Pathway [CAP] and Complement 
Classical Pathway [CCP]) over the course 
of the study 
• 
Evaluation of area under the curve 
(AUC), maximum plasma concentration 
(Cmax), time to maximum plasma 
concentration (Tmax), terminal half-life 
(t½), clearance (CL/F), volume of 
distribution (V/F), cumulative amount 
excreted unchanged in urine (Ae) and 
percent of dose excreted in the urine (fe) 
of cemdisiran (25-mer) and 23-mer 
• 
Evaluation of AUC, Cmax, Tmax, t½, CL/F, 
V/F, Ae and fe of 22-mer AS(N-1)3’ 
• 
Change from baseline in levels of renal 
damage, complement activation and 
inflammation markers over the course of 
the study 
• 
Incidence of antidrug antibodies (ADA) 
Study Design 
This is a multicenter, double-blind, placebo-controlled study comprised of three periods (Figure 1).  The 
first period of the study is an observational 14-week run-in period during which patients’ blood pressure, 
kidney function, degree of hematuria, and proteinuria will be measured.  The standard of care is expected 
to remain unchanged during this run-in period.  Patients will not receive study drug (cemdisiran or 
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placebo) during this time.  The second study period is a 36-week treatment period which will evaluate the 
efficacy and safety of subcutaneous (SC) cemdisiran compared to SC placebo in combination with 
standard of care in patients with IgAN and persistent proteinuria.  The third period of the study is a 
52-week optional open-label extension (OLE) period to further evaluate the long-term safety and clinical 
activity of cemdisiran.  During the OLE, all patients (including those initially on placebo) will be treated 
with cemdisiran in combination with standard of care. 
The study will include Screening of up to 90 days to determine eligibility of patients and to complete 
disease-related assessments.  Patients will provide written informed consent and visit the study center 
approximately 2 weeks before starting the run-in period to complete the protocol screening assessments.  
Following successful screening, the 14-week run-in period will commence, during which patients’ blood 
pressure, kidney function, degree of hematuria and proteinuria as well as treatment with standard of care 
will be documented by the Investigator.  The standard of care is expected to remain unchanged during this 
run-in period.  Patients whose proteinuria level remains ≥1 g/24-hours within 2 weeks of the end of the 
run-in period, and who meet blood pressure and estimated glomerular filtration rate (eGFR) criteria will 
be eligible to enroll in the 36-week treatment period.  Upon confirmation of eligibility followed by 
vaccination against meningococcal infections, patients will be randomized at a 2:1 ratio to receive 600 mg 
of cemdisiran or placebo every 4 weeks in combination with standard of care.  Approximately 30 patients 
are planned to be randomized in total, 20 in the cemdisiran arm and 10 in the placebo arm.  Patients 
excluded before randomization will be replaced at Screening.  
During the run-in period, patients will visit the study center 14, 8, and 2 weeks prior to randomization 
(Weeks 0, 6 and 12 of the run-in period).  Patients will then return to the study center every 4 weeks after 
the start of study drug treatment period. The primary endpoint will be assessed at the end of treatment at 
Week 32. 
At the end of treatment (Week 32), patients in the two treatment arms will enter the optional OLE period 
where they will receive cemdisiran at a dose of 600 mg every 4 weeks in combination with standard of 
care for 52 weeks.  The first study drug administration of the OLE will be administered at Week 36.  
Patients will return to the study center at Week 40 and every 8 weeks thereafter during the OLE.  Home 
visits, where locally feasible, may be arranged for cemdisiran administration in between 8-weekly study 
center visits (Weeks 44, 52, 60, 68 and 76), unless patients are required to visit the study center as judged 
necessary by the Investigator, or if home visits cannot be arranged.  An end of treatment (EOT) visit will 
occur at Week 80 (OLE EOT) and an end of study (EOS) or early termination (ET) visit will be 
completed at Week 84 (OLE EOS/ET). For patients who complete the treatment period only and who do 
not consent to continue to participate in the study in the OLE period, the EOS/ET visit will be at Week 
36. 
Patients will return to the clinical study center for safety follow-up visits approximately 13, 26, 39 and 52 
weeks after the EOS/ET visit (regardless if EOS/ET visit is at Week 36 or Week 84), unless enrolled in 
another study with cemdisiran. Home visits, where locally feasible, may be arranged during safety 
follow-up at 13 and 39 weeks after the EOS/ET visit (regardless if EOS/ET visit is at Week 36 or Week 
84). 
Regular reviews of safety and tolerability data will be performed by a Data Monitoring Committee 
(DMC) throughout the study with the primary purpose of protecting the safety of participating patients 
and the integrity of the study. 
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Number of Planned Patients 
Approximately 30 patients are planned for randomization in this study. 
Diagnosis and Main Eligibility Criteria 
This study will include adults (≥18 years and ≤ 65 years of age) with a clinical diagnosis of primary 
immunoglobulin A (IgA) Nephropathy based on historical biopsy collected within 60 months of 
Screening, treated for IgA Nephropathy with stable, optimal pharmacological therapy including 
maximum allowed or tolerated angiotensin converting enzyme (ACE) inhibitor or angiotensin II receptor 
blocker (ARB) for at least 3 months prior to the start of the run-in period. Eligible patients must have 
urine protein levels of ≥1 g/24-hour at Screening and mean urine protein ≥1 g/24-hour from two valid 24-
hour urine collections at the end of the run-in period, prior to randomization. In addition, eligible patients 
must have hematuria defined by ≥10 red blood cells per high powered field (RBC/hpf) at Screening. 
Eligible patients are required to have been previously vaccinated with meningococcal group ACWY 
conjugate vaccine and meningococcal group B vaccine or be willing to receive these vaccinations as well 
as prophylactic antibiotic treatment, if required by local standard of care. In addition, patients not 
previously vaccinated against Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) must 
be willing to receive these vaccinations according to local guidelines. 
Patients will be excluded from the study if eGFR <30 mL/min/1.73 m2 2 weeks prior to randomization; 
treated with systemic steroids for more than 7 days or other immunosuppressant agents in the 12 months 
prior to randomization; have a diagnosis of rapidly progressive glomerulonephritis as measured by eGFR 
loss >30% over the duration of the run-in phase; sustained blood pressure >140/90 mmHg as defined by 2 
or more readings during the run-in period measured in supine position after 10 minutes of rest; have 
received organ transplant (including hematologic transplant) or have secondary etiologies of IgAN (eg, 
inflammatory bowel disease, celiac disease).  
Study Drug, Dose, and Mode of Administration 
Cemdisiran is a synthetic small interfering RNA (siRNA) targeting complement component 5 
(C5) mRNA that is covalently linked to a triantennary N-acetylgalactosamine (GalNAc) ligand.  
Cemdisiran will be supplied as a sterile solution for SC injection that contains 200 mg/mL 
cemdisiran sodium (equivalent to 189 mg/mL of cemdisiran), formulated in water for injection 
(WFI) for SC administration.  Doses of 600 mg of cemdisiran will be administered every 
4 weeks during the 32-week treatment phase and the optional OLE period.  
Placebo (normal saline 0.9% for SC administration) will be packaged and administered identically to 
cemdisiran. 
Reference Treatment, Dose, and Mode of Administration 
Angiotensin converting enzyme inhibitors (ACE) or angiotensin II receptor blockers (ARB) per physician 
and manufacturer‘s instructions. 
Duration of Treatment and Study 
Subcutaneous doses of cemdisiran or matching placebo will be administered every 4 weeks over a period 
of 32 weeks during the treatment period and patients will receive SC doses of cemdisiran for a further 52 
weeks in the optional OLE. The estimated total time on study, inclusive of Screening (90 days), run-in 
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period (14 weeks), treatment period (36 weeks), extension period (52 weeks) and safety follow-up 
(52 weeks), for patients is approximately 36 months or 3.0 years. 
Statistical Methods 
Approximately 30 patients are planned to be randomized 2:1 (cemdisiran:placebo) in this study based on 
the assumption that, in the placebo arm, the estimated geometric mean ratio of proteinuria at Week 32 to 
baseline is 0.88 (log standard deviation [SD] 0.597), corresponding to a 12% reduction. A sample size of 
27 with 2:1 randomization (cemdisiran:placebo) will provide a width of 0.80 for the 90% confidence 
interval (CI) for treatment effect size estimate (cemdisiran – placebo) in log scale.  This corresponds to a 
90% CI of (15%, 62%) for the treatment difference in the percentage scale if the true Week 32 reduction 
is 50% for the cemdisiran arm. To account for potential dropouts, approximately 30 patients are planned 
to be randomized stratified by baseline urine protein levels (≥1 g/24h and <2 g/24h versus ≥2 g/24h). 
The analysis populations include: 
• 
The modified Intent-to-treat (mITT) population will include all patients who receive any 
amount of study drug and have at least one post baseline 24-hour proteinuria assessment. 
Patients will be grouped by assigned treatments (ie, as randomized).  
• 
The Safety Analysis Set will include all patients who received any amount of study drug. 
Patients who received any amount of cemdisiran will be included in the cemdisiran arm. 
Patients in the Safety Analysis Set will be grouped by treatment received.  
• 
PK Analysis Set: All patients who receive any amount of study drug and have at least one 
postdose blood or urine sample for PK concentration.  
• 
PD Analysis Set: All patients who receive any amount of study drug and who have at least 
one postdose blood sample for the determination of plasma C5 level. 
The primary endpoint of the study is the percentage reduction from baseline in 24-hour proteinuria at 
Week 32. The primary analysis will be performed on the change from baseline in log transformed urine 
protein using a linear model with log transformed baseline urine protein as covariate and treatment and 
randomization stratification factor as fixed effect. The least square mean difference and its 90% 
confidence interval (CI) will be estimated and then back transformed to original scale. In the end, the 
estimated ratio of percentage reduction in urine protein for cemdisiran to placebo and its 90% CI will be 
presented.  
A sensitivity analysis using all urine protein assessments including a single 24-hour assessment will be 
conducted using mixed-effects model repeated measures (MMRM) method. 
The efficacy endpoints will be analyzed in the mITT population. PK and PD parameters will be analyzed 
in the PK and PD analysis sets, respectively. 
Safety data will be summarized with descriptive statistics. Treatment-emergent adverse events will be 
summarized by SOC and PT (all events, related events, and serious events), in addition to being 
summarized by severity (all events). In addition, summaries will be provided for any AEs leading to 
discontinuation of study drug or death. Serious adverse events and procedure related adverse events in the 
run-in period will be listed. 
 
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Figure 1: 
Study Design  
 
Abbreviations:  Q4W=once every 4 weeks; EOS=end of study; EOT=end of treatment 
 
 
Screening (up to 90 days)
Run-in Period 
(14 Weeks)
EOS
(Week 84)
Treatment Period 
(36 Weeks)
EOT
(Week 80)
Safety Follow-up
(52 Weeks)
Placebo (n=10)
+ Standard of care
ALN-CC5 600mg 
Q4W (n=20)
+ Standard of care
Standard of care
Randomization (2:1)
Open-label Extension Period 
(52 Weeks)
Primary endpoint assessment
ALN-CC5 
600mg Q4W 
+ Standard of care
EOS
(Week 36)
EOT
(Week 32)
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Table 3: 
Pharmacokinetic Time Points 
Phase 
Study Day 
Protocol Time Relative to 
Dosing 
(hh:mm)a 
PK Blood Pooled Urineb 
Treatment phase 
Day 1 
Predose (within 60 mins) 
X 
 
00:00 (dose) 
 
X 
01:00 (±5 mins) 
X 
02:00 (±15 mins) 
X 
04:00 (±15 mins) 
X 
06:00 (±15 mins) 
X 
08:00 (±30 mins) 
X 
X 
12:00 (±30 mins) 
 
24:00 (±120 mins) 
X 
X 
Abbreviations:   hh=hours; mm=minutes; mins=minutes; PK=pharmacokinetics. 
a The actual time of blood sample collection must be recorded. 
b The pooled urine 6-12 hours and 12-24 hours can be collected as outpatient. 
 
 
 
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TABLE OF CONTENTS 
SPONSOR PROTOCOL APPROVAL ...........................................................................................2 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
PROTOCOL SYNOPSIS ................................................................................................................4 
TABLE OF CONTENTS ...............................................................................................................19 
LIST OF TABLES .........................................................................................................................22 
LIST OF FIGURES .......................................................................................................................23 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................24 
1. 
INTRODUCTION ......................................................................................................27 
1.1. 
Disease Overview .......................................................................................................27 
1.2. 
Cemdisiran ..................................................................................................................29 
1.3. 
Study Design Rationale ..............................................................................................30 
1.4. 
Dose Rationale ............................................................................................................31 
1.5. 
Benefit-Risk Assessment ............................................................................................32 
2. 
OBJECTIVES AND ENDPOINTS ............................................................................34 
3. 
INVESTIGATIONAL PLAN .....................................................................................36 
3.1. 
Summary of Study Design ..........................................................................................36 
3.2. 
Duration of Treatment ................................................................................................37 
3.3. 
Duration of Study .......................................................................................................37 
3.3.1. 
Definition of End of Study for an Individual Patient .................................................37 
3.4. 
Number of Planned Patients .......................................................................................37 
3.5. 
Method of Assigning Patients to Treatment Groups ..................................................37 
3.6. 
Blinding ......................................................................................................................38 
3.6.1. 
Emergency Unblinding ...............................................................................................38 
3.7. 
Data Monitoring Committee .......................................................................................38 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................39 
4.1. 
Inclusion Criteria ........................................................................................................39 
4.2. 
Exclusion Criteria .......................................................................................................39 
4.3. 
Removal from Therapy or Assessment.......................................................................41 
4.3.1. 
Discontinuation of Study Drug or Declining Procedural Assessments ......................41 
4.3.2. 
Stopping a Patient’s Study Participation ....................................................................42 
4.3.2.1. 
Patient or Legal Guardian Stops Participation in the Study .......................................42 
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4.3.2.2. 
Withdrawal of Consent to Process the Patient’s Personal Data .................................43 
4.3.2.3. 
Investigator or Sponsor Stops Participation of a Patient in the Study ........................43 
4.3.2.4. 
Recording Reason for Stopping a Patient’s Study Participation ................................43 
4.3.3. 
Lost to Follow-Up.......................................................................................................43 
4.3.4. 
Replacement of Study Patients ...................................................................................44 
5. 
TREATMENTS AND OTHER REQUIREMENTS ..................................................45 
5.1. 
Treatments Administered ............................................................................................45 
5.2. 
Study Drug ..................................................................................................................45 
5.2.1. 
Description ..................................................................................................................45 
5.2.2. 
Dose and Administration ............................................................................................45 
5.2.3. 
Dose Modifications .....................................................................................................45 
5.2.3.1. 
LFT Criteria for Withholding, Monitoring and Stopping Cemdisiran Dosing ...........46 
5.2.4. 
Preparation, Handling, and Storage ............................................................................47 
5.2.5. 
Packaging and Labeling ..............................................................................................48 
5.2.6. 
Accountability .............................................................................................................48 
5.3. 
Concomitant Medications and Procedures .................................................................48 
5.3.1. 
Prohibited Concomitant Medications .........................................................................48 
5.3.2. 
Study-specific Vaccinations .......................................................................................49 
5.3.2.1. 
Meningococcal Vaccinations ......................................................................................49 
5.3.2.2. 
Pneumococcal and Hib Vaccinations .........................................................................49 
5.4. 
Treatment Compliance ................................................................................................50 
5.5. 
Other Requirements ....................................................................................................50 
5.5.1. 
Contraception ..............................................................................................................50 
5.5.2. 
Alcohol Restrictions ...................................................................................................51 
5.5.3. 
Antibiotic Compliance ................................................................................................51 
6. 
STUDY ASSESSMENTS ..........................................................................................52 
6.1. 
Screening Assessments ...............................................................................................52 
6.1.1. 
Rescreening .................................................................................................................52 
6.1.2. 
Retesting .....................................................................................................................52 
6.2. 
Run-in Period ..............................................................................................................52 
6.3. 
Baseline Assessments (Treatment Period) ..................................................................53 
6.4. 
Efficacy Assessments .................................................................................................53 
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6.4.1. 
Proteinuria ...................................................................................................................53 
6.4.1.1. 
24-Hour Urine Collection ...........................................................................................53 
6.4.1.2. 
Spot Urine Collection .................................................................................................54 
6.4.2. 
Hematuria ...................................................................................................................54 
6.4.3. 
Changes in Renal Function .........................................................................................55 
6.4.4. 
Markers of Complement Activation, Inflammation and Renal Injury .......................55 
6.5. 
Pharmacodynamic Assessments .................................................................................55 
6.6. 
Pharmacokinetic Assessments ....................................................................................55 
6.7. 
Safety Assessments .....................................................................................................56 
6.7.1. 
Vital Signs ..................................................................................................................56 
6.7.2. 
Weight and Height ......................................................................................................56 
6.7.3. 
Physical Examination .................................................................................................56 
6.7.4. 
Electrocardiogram .......................................................................................................57 
6.7.5. 
Clinical Laboratory Assessments ...............................................................................57 
6.7.5.1. 
Immunogenicity ..........................................................................................................59 
6.7.5.2. 
Pregnancy Testing ......................................................................................................59 
6.7.5.3. 
Additional Liver Function Assessments .....................................................................59 
6.7.6. 
Adverse Events ...........................................................................................................60 
6.7.6.1. 
Definitions ..................................................................................................................60 
6.7.6.2. 
Eliciting and Recording Adverse Events ....................................................................62 
6.7.6.3. 
Reporting Adverse Events of Clinical Interest to Sponsor/Designee .........................63 
6.7.6.4. 
Serious Adverse Events Require Immediate Reporting to Sponsor/Designee ...........63 
6.7.6.5. 
Sponsor Safety Reporting to Regulatory Authorities .................................................64 
6.7.6.6. 
Serious Adverse Event Notification to the Institutional Review 
Board/Independent Ethics Committee ........................................................................64 
6.7.6.7. 
Pregnancy Reporting ..................................................................................................64 
6.7.6.8. 
Overdose Reporting ....................................................................................................64 
6.8. 
Biomarkers, DNA Genotyping, and Biospecimen Repository ...................................65 
7. 
STATISTICS ..............................................................................................................66 
7.1. 
Determination of Sample Size ....................................................................................66 
7.2. 
Statistical Methodology ..............................................................................................66 
7.2.1. 
Populations to be Analyzed ........................................................................................66 
7.2.2. 
Examination of Subgroups .........................................................................................67 
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7.2.3. 
Handling of Missing Data ...........................................................................................67 
7.2.4. 
Baseline Evaluations ...................................................................................................67 
7.2.5. 
Efficacy Analyses .......................................................................................................67 
7.2.5.1. 
Primary Endpoint ........................................................................................................67 
7.2.5.2. 
Secondary Efficacy Endpoints ....................................................................................67 
7.2.5.3. 
Exploratory Endpoints ................................................................................................67 
7.2.6. 
Pharmacodynamic Analysis........................................................................................68 
7.2.7. 
Pharmacokinetic Analysis ..........................................................................................68 
7.2.8. 
Safety Analyses ..........................................................................................................68 
7.2.9. 
Immunogenicity Analyses ..........................................................................................69 
7.2.10. 
Biomarker Analyses ....................................................................................................69 
7.2.11. 
Interim Analysis ..........................................................................................................69 
7.2.12. 
Optional Additional Research .....................................................................................69 
8. 
STUDY ADMINISTRATION ...................................................................................70 
8.1. 
Ethical and Regulatory Considerations ......................................................................70 
8.1.1. 
Informed Consent .......................................................................................................70 
8.1.2. 
Ethical Review ............................................................................................................70 
8.1.3. 
Serious Breach of Protocol .........................................................................................71 
8.1.4. 
Study Documentation, Confidentiality, and Records Retention .................................71 
8.1.5. 
End of Study ...............................................................................................................71 
8.1.6. 
Termination of the Clinical Study or Site Closure .....................................................71 
8.2. 
Data Quality Control and Quality Assurance .............................................................72 
8.2.1. 
Data Handling .............................................................................................................72 
8.2.2. 
Study Monitoring ........................................................................................................72 
8.2.3. 
Audits and Inspections ................................................................................................72 
8.3. 
Publication Policy .......................................................................................................72 
9. 
LIST OF REFERENCES ............................................................................................74 
10. 
APPENDICES ............................................................................................................77 
 
LIST OF TABLES 
Table 1: 
Schedule of Assessments – Run-in and Treatment Periods (Screening 
through Week 36) including Safety Follow up...........................................................10 
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Table 2: 
Schedule of Assessments – Open-Label Extension Period and Safety Follow 
up ................................................................................................................................15 
Table 3: 
Pharmacokinetic Time Points .....................................................................................18 
Table 4: 
Monitoring and Dosing Rules for Asymptomatic Patients with Confirmed 
Isolated Elevations of ALT and/or AST >3× ULN, with No Alternative 
Cause Identified ..........................................................................................................47 
Table 5: 
Clinical Laboratory Assessments ...............................................................................58 
Table 6: 
Hepatic Assessments in Patients Who Experience Elevated Transaminases .............60 
 
LIST OF FIGURES 
Figure 1: 
Study Design .................................................................................................................9 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation  
Definition 
ADA 
Antidrug antibodies 
ACE 
Angiotensin-converting enzyme 
AE 
Adverse event 
AECI 
Adverse event of clinical interest 
aHUS 
Atypical hemolytic uremic syndrome 
ALN-CC5 
Cemdisiran 
ALT 
Alanine transaminase 
ARB 
Angiotensin II receptor blocker 
AST 
Aspartate transaminase 
AUC 
Area under the concentration curve 
BMI 
Body mass index 
C3 
Complement component 3 
C3a 
Activated complement 3 
C5 
Complement component 5 
C5a 
Activated complement component 5 
CAP 
Complement alternative pathway 
CCP 
Complement classical pathway 
CFH 
Complement factor H 
CI 
Confidence interval 
CIC 
Circulating immune complexes 
CL/F 
Clearance 
Cmax 
Maximum concentration 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
ELISA 
Enzyme linked immunosorbent assay 
EOS 
End of study 
EOT 
End of treatment 
ESRD 
End-stage renal disease 
GalNAc 
N-acetylgalactosamine 
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Abbreviation  
Definition 
GCP 
Good Clinical Practice 
Gd-IgA1 
Galactose-deficient Immunoglobulin A 1 
GFR 
Glomerular filtration rate 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
Hib 
Haemophilus influenzae type b 
HIV 
Human immunodeficiency virus 
hpf 
High powered field 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonisation 
IEC 
Independent Ethics Committee 
IgA 
Immunoglobulin A 
IgG 
Immunoglobulin G 
IgAN 
IgA Nephropathy 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRS 
Interactive Response System 
ISR 
Injection site reaction 
IV 
Intravenous 
LFT 
Liver function test 
MAC 
Membrane attack complex 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified intent-to-treat 
mRNA 
Messenger RNA 
NHP 
Nonhuman primates 
OLE 
Open-label extension 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic(s) 
PNH 
Paroxysmal nocturnal hemoglobinuria 
RAS 
Renin-angiotensin system 
RBC 
Red blood cell 
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Abbreviation  
Definition 
RNAi 
RNA interference 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous(ly) 
siRNA 
Small interfering RNA 
SUSAR 
Suspected unexpected serious adverse reaction 
t½ 
Terminal half-life 
Tmax 
Time to maximum concentration 
TMF 
Trial Master File 
Tri-GalNAc 
Triantennary N-acetylgalactosamine 
UP 
Urine protein 
UACR 
Urine albumin:creatinine ratio 
ULN 
Upper limit of normal 
UPCR 
Urine protein:creatinine ratio 
V/F 
Volume of distribution 
 
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1. 
INTRODUCTION 
1.1. 
Disease Overview 
Globally, immunoglobulin A nephropathy (IgAN) is the most common primary 
glomerulonephritis that can progress to renal failure.[Lai 2016; Wyatt 1998]  While the exact 
pathogenesis of IgAN is incompletely understood, biochemical, genetic, and clinical data suggest 
IgAN is an autoimmune disease that may originate from overproduction of aberrantly O-
glycosylated IgA1 (Gd-IgA1) and the presence of glycan-specific IgA and immunoglobulin G 
(IgG) autoantibodies that recognize the under-galactosylated IgA1 molecule, resulting in the 
formation of pathogenic immune complexes. Some of these circulating complexes may deposit 
in glomeruli and induce renal injury.[Knoppova 2016]  The lack of galactose exposes O-linked 
monosaccharide N-acetylgalactosamine (O-GalNAc) moeities in the hinge region of 
IgA1.[Novak 2018] While the binding of autoantibodies to Gd-IgA1 is dependent on the 
presence of multiple O-GalNAc residues, the IgA1 protein backbone and the spatial arrangement 
of O-GalNAc moieties are also thought to play a role in the specificity of autoantibodies to Gd-
IgA1.[Mestecky 2016; Suzuki 2009] 
Both the alternative and lectin complement pathways may be activated, leading to generation of 
the anaphylatoxins activated complement component 3 (C3a) and activated complement 
component 5 (C5a) and the membrane attack complex (MAC) C5b-9, with subsequent 
promotion of inflammatory mediators.[Maillard 2015]  Emerging data indicate that 
mesangial-derived mediators that are released following deposition of IgA1 may lead to 
podocyte and tubulointerstitial injury. 
Given that a biopsy specimen is required to diagnose IgAN, the clinical threshold for performing 
a biopsy will have a major impact on the prevalence of IgAN. Persistent microscopic hematuria 
alone and/or mild proteinuria alone are not commonly used as a per cause indication for biopsy 
in the United States.  Thus, the prevalence of IgAN is modest in the United States (10 to 20% of 
primary glomerulonephritis), higher in some European countries (20 to 30%), and highest in 
developed countries in Asia (40 to 50%).[Woo 2010]  This considerable geographical variability 
can be explained by several factors including the variation in access to primary care enabling 
early diagnosis and the differences in policies for performing renal biopsies as well as for early 
referrals.  For example, in some countries, urine screening tests are conducted in schools or for 
military service or ahead of employment, explaining the apparent high incidence.[Imai 2007; 
Wyatt 1998]  Ethnic differences can also contribute to the varying prevalence of IgAN.  
Genome-wide association studies have identified candidate genes as well as risk-associated and 
protective alleles, with the highest number of risk alleles present in individuals of East Asian 
origin and the lowest number in those from Africa.[Kiryluk 2014]  These genes are involved in 
antigen presentation, mucosal defense system and notably the alternative complement pathway 
(complement factor H [CFH]/CFHR locus).[Kiryluk 2014]  Finally, patients may present at any 
age with IgAN but there is a peak incidence in the second and third decades of life.  Most cases 
of IgAN occur in sporadic (90 to 95%) rather than in familial patterns (5 to 10%).[Lai 2016] 
Routine screening for IgAN is not feasible given that no specific diagnostic laboratory tests are 
available.  The first indication for making a diagnosis comes after careful microscopic 
examination of a urine sample.  The presence of red blood cell (RBC) casts and dysmorphic 
RBCs indicates glomerular bleeding.  Varying degrees of proteinuria are present in patients with 
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IgAN. Proteinuria can be quantified with a timed urine collection or a spot urine protein to 
creatinine ratio (UPCR) measurement.  Hence, IgAN can only be diagnosed definitely upon renal 
biopsy and study of kidney tissue using immunofluorescence.  The pathology of IgAN is 
characterized by deposition of pathogenic polymeric IgA1 immune complexes and C3 in the 
glomerular mesangium, proliferation of mesangial cells, increased synthesis of extracellular 
matrix and variable infiltration of macrophages, monocytes and T cells.  A consensus on the 
pathologic classification of IgAN has been developed by the International IgA Nephropathy 
Network in collaboration with the Renal Pathology Society (Oxford classification).[Cattran 
2009; Lai 2016; Roberts 2009] 
The clinical presentation of patients with IgAN is highly variable, ranging from asymptomatic 
microscopic hematuria to a rapidly progressive form of glomerulonephritis which is often 
associated with severe hypertension, but between these extremes, most patients with IgAN 
pursue a chronic indolent course.[Lai 2016]  Some patients present with more severe proteinuria, 
hypertension and renal progression over time, typically reaching end-stage renal disease (ESRD) 
over a span of 20 years.  Thus, the severity of proteinuria upon presentation has significant 
prognostic implications.  More importantly, the change in proteinuria over time is being regarded 
as the current best prognostic indicator: those who had heavy time averaged proteinuria and 
achieved a partial remission of <1 g/24-hours had a similar course to those who had 
<1 g/24-hours throughout and fared far better than those who never achieved partial 
remission.[Reich 2007]  These observations support the notion that every effort should be made 
to reduce proteinuria in IgAN.  In addition to the degree of proteinuria, baseline renal function 
and the degree of histological injury are of prognostic value.  For example, patients with an 
estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 at the time of renal biopsy have 
worse outcomes than those with normal eGFR (90 to 120 mL/min/1.73 m2).  The rate of 
glomerular filtration rate (GFR) decline also correlates with glomerulosclerosis and tubular 
atrophy or interstitial fibrosis on biopsy as outlined by Oxford-MEST-C classification.  
Spontaneous full recovery in IgAN is rare in adults, especially if associated with significant 
proteinuria (>0.5 g/24-hour).[Knoop 2017] 
Patients with minor urine abnormalities, normal blood pressure, and normal GFR usually do well 
and require only monitoring.  For other patients, the therapeutic options are limited and include 
nonspecific treatment to reduce blood pressure and proteinuria by renin-angiotensin system 
(RAS) blockade.  Thus, no disease-specific therapies are currently available, and an unmet need 
persists for novel interventions, particularly in patients who are at risk of progressive disease that 
can result in end-stage renal failure.  The optimal role of immunosuppressive therapy is 
uncertain.  The available studies are not conclusive since most are relatively small and have 
limited follow-up.[Lai 2016]  STOP-IgAN, a German trial, randomly assigned adults with an 
eGFR of >30 mL/min/1.73 m2 and persistent proteinuria of >0.75 g/24-hour despite 6 months of 
supportive care with RAS inhibitors to receive supportive care alone or supportive care plus 
immunosuppression (prednisone alone for those with initial GFR >60 mL/min and prednisone 
combined with cyclophosphamide then azathioprine with initial GFR 30-59 mL/min).  This 
strategy did not significantly improve the renal outcome and was associated with increased 
adverse effects at 36 months.[Rauen 2015]  The TESTING trial demonstrated some GFR effect 
of steroids in Chinese patients, but had to be stopped due to large number of serious adverse 
events (SAEs) in the steroid arm.[Lv 2017]  The 2012 KDIGO guidelines recommend 
corticosteroids, albeit at very low level of evidence. Thus, steroids may be tried in some cases as 
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rescue therapy if proteinuria markedly increases or GFR rapidly falls. Further studies to address 
the role of steroids in IgAN are currently under way.  Finally, Rituximab seems to be ineffective 
in the treatment of patients with progressive IgAN.[Lafayette 2016] 
1.2. 
Cemdisiran 
Alnylam Pharmaceuticals, Inc. is developing cemdisiran (ALN-CC5), a synthetic RNA 
interference (RNAi) therapeutic designed to suppress liver production of C5 protein, for the 
treatment of atypical hemolytic uremic syndrome (aHUS) and IgAN.  Cemdisiran comprises a 
small interfering RNA (siRNA) targeting C5 messenger RNA (mRNA) that is covalently linked 
to a triantennary N-acetylgalactosamine (GalNAc) ligand.   
RNAi is a naturally occurring cellular mechanism for regulating gene expression that is mediated 
by siRNAs.  Synthetic siRNAs are short (19-25 base pairs), double-stranded oligonucleotides in 
a staggered duplex with an overhang at one or both 3-prime ends.  Such siRNAs can be designed 
to target the mRNA transcript of a given gene.  When formulated for tissue delivery and 
introduced into cells, the guide (or antisense) strand of the siRNA loads into an enzyme complex 
called the RNA-induced silencing complex.  This enzyme complex subsequently binds to its 
complementary mRNA sequence, mediating cleavage of the mRNA and the suppression of the 
target protein encoded by the mRNA.[Elbashir 2001]  Since unmodified siRNAs are rapidly 
eliminated and do not achieve significant tissue distribution upon systemic administration 
[Soutschek 2004], various formulations are currently used to target their distribution to tissues, 
and to facilitate uptake of siRNAs into the relevant cell type.  One approach that has been used 
successfully in vivo in animal models (including in rodents and nonhuman primates [NHP]) and 
humans employs intravenous (IV) delivery of siRNA in lipid nanoparticle 
formulations.[Soutschek 2004; Zimmermann 2006]  Another approach for liver-specific gene 
silencing is subcutaneously administered siRNA conjugated to a GalNAc carbohydrate 
ligand.[Ashwell 2006]  Conjugation of a triantennary GalNAc ligand to an siRNA enables 
hepatocyte binding and subsequent cellular uptake via the asialoglycoprotein receptor, resulting 
in engagement of the RNAi pathway and downregulation of hepatic proteins. 
Cemdisiran (containing siRNA drug substance, ALN-62643, targeting C5 mRNA) is a synthetic 
investigational RNAi therapeutic designed to suppress liver production of C5 protein, when 
administered via subcutaneous (SC) injection.  C5 is encoded by a single gene and is expressed 
and secreted predominantly by hepatocytes.  Through the mechanism of RNAi, the cemdisiran 
siRNA enables the downregulation of C5 mRNA in the liver, thereby reducing levels of 
circulating C5 protein and resulting in inhibition of terminal complement pathway activity and 
prevention of MAC formation and C5a release.  This in turn would be expected to reduce 
mesangial cell proliferation and tissue injury in patients with IgAN resulting in renal function 
improvement.[Maillard 2015] Both lectin and alternative pathways of complement have been 
implicated in IgAN pathology.  Cemdisiran-mediated silencing of C5 will inhibit MAC 
formation and C5a release regardless of the activating pathway and may be a superior approach 
in IgAN where the contribution of different pathways may be heterogenous between 
patients.[Medjeral-Thomas 2018] 
The safety of reducing C5 is supported by clinical precedence of C5 inhibition with eculizumab 
treatment and the absence of any phenotypic abnormalities, other than an increased susceptibility 
to Neisserial infections, in subjects with known genetic C5 deficiencies.[Ross 1984]  Subjects 
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with known C5 deficiencies are generally healthy apart from an increased susceptibility to 
Neisserial infections. These infections include invasive meningococcal disease, disseminated 
gonococcal infections as well as diseases caused by typically commensal Neisseria 
species.[Crew 2018; Crew 2018; McQuillen 2018; Ram 2010]  In addition, safety data on the 
treatment of healthy volunteers and patients with paroxysmal nocturnal hemoglobinuria (PNH) 
with cemdisiran in Study ALN-CC5-001 indicate that cemdisiran is generally well-tolerated; the 
maximum tolerated dose was 900 mg.  There were no serious adverse events (SAEs) or 
discontinuations due to adverse events (AEs) during this study, and most AEs were mild or 
moderate in severity. In Study ALN-CC5-001, the frequency of ADA was low.  Two of 48 
healthy volunteers (1 cemdisiran-treated and 1 placebo-treated) were ADA positive during the 
study. The cemdisiran-treated volunteer had transient ADA positivity, with a negative result later 
in the study and no impact on PK or PD. The placebo-treated volunteer was ADA positive at 
baseline (predose) and remained positive through Day 70.  
A detailed description of the chemistry, pharmacology, nonclinical pharmacokinetics (PK) and 
toxicology, as well as preliminary efficacy, and safety of cemdisiran is provided in the current 
edition of the Investigator’s Brochure (IB). 
1.3. 
Study Design Rationale 
In contrast to the RBC lysis which characterises the pathophysiology of PNH, which requires 
extremely high level of C5 inhibition for protection, endothelial cells and mesangial cells are the 
cellular targets of dysregulated complement in aHUS and IgAN, respectively.  These cells are 
nucleated cells which possess complement regulatory proteins as well as the ability to shed 
membrane associated MAC to defend against MAC-mediated damage, a key step in thrombotic 
microangiopathy progression in aHUS and renal damage in IgAN.  It is therefore hypothesized 
that a lesser degree of cemdisiran mediated C5 knockdown will be required for disease control in 
patients with IgAN and aHUS than in patients with PNH.[Morgan 1989; Rosse 1973]  This 
hypothesis is supported by the observation that aHUS patients who achieve C5 inhibition 
maintain good disease control despite complement activity levels consistent with higher free C5 
levels.[Cugno 2014]  Therefore, cemdisiran monotherapy may be a viable treatment option in 
patients with IgAN at levels of C5 silencing achieved in Study ALN-CC5-001. 
This therapeutic hypothesis will be tested in a multicenter, multinational, double-blind, 
placebo-controlled study to evaluate the effect of multiple doses of cemdisiran given by SC 
injection in patients with IgAN with persistent proteinuria (≥1 g/24-hours) despite the standard 
of care (angiotensin converting enzyme inhibitors [ACE] or angiotensin II receptor blockers 
[ARB]) and additional medications if necessary for blood pressure control followed by a 
treatment extension to evaluate long-term safety and clinical activity.  The study population has 
been selected based on two major factors: 1) the severity of proteinuria upon presentation has 
significant prognostic implications.[Coppo 2005]  IgAN patients with heavy proteinuria ≥1 g/24-
hours have a significantly worse renal outcome than those who have proteinuria 
<1 g/24-hours.[Reich 2007]  2) For patients with persistent proteinuria, despite the nonspecific 
treatment to reduce blood pressure and proteinuria by RAS blockade, no disease-specific 
therapies are currently available, and an unmet need persists for novel interventions. Since 
proteinuria can result both from active inflammation as well as irreversible scarring of renal 
tissue and in lieu of a protocol biopsy, we enrich our patients for presence of potentially 
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reversible disease activity by requiring presence of hematuria and relatively preserved renal 
function with eGFR >30 mL/min. To ensure the selection of patients who are truly at risk of 
progression of kidney disease despite standard of care, the first period of the study consists of a 
run-in period during which patients will not receive study drug (cemdisiran or placebo).  The 
run-in period will be an observational period during which patients’ treatment with standard of 
care, blood pressure, kidney function, degree of hematuria, and proteinuria will be documented.  
The standard of care is expected to remain unchanged during this run-in period. Only patients 
whose  
• proteinuria level remains ≥1 g/24-hours within 2 weeks before the end of the run-in 
period,  
• continue to meet blood pressure and eGFR criteria  
will be eligible to enroll in the 36-week treatment period portion of the study. 
Randomization to cemdisiran or placebo will be performed in a 2:1 ratio so that more patients 
will receive cemdisiran. This will allow a more precise estimation of the effect of cemdisiran 
with only marginal loss of power. Inclusion of a placebo arm will allow better assessment of 
safety and interpretation of the efficacy of cemdisiran. 
The primary endpoint for the study is percent change from baseline in 24-hour proteinuria 
(g/24-hours) at Week 32.  This is justified for a phase 2 study given the slow progression of renal 
disease and the established role of proteinuria as a marker of disease progression. 
1.4. 
Dose Rationale 
In the Phase 1/2 Study (ALN-CC5-001), 32 healthy volunteers were treated with single SC doses 
of cemdisiran ranging from 50 mg to 900 mg, 24 healthy volunteers were treated with multiple 
doses of cemdisiran ranging from 100 mg to 600 mg (dosing weekly, every other week or 
monthly), 6 patients with PNH were treated with cemdisiran at cumulative doses of 3200 mg to 
4200 mg (eculizumab-naïve patients) and 1200 mg to 2400 mg (patients on background 
eculizumab treatment).  Treatment with cemdisiran was generally well tolerated in both healthy 
volunteers and patients with PNH.  There were no SAEs and no discontinuations due to AEs 
during this study, including at the highest doses administered.  Most AEs observed were mild or 
moderate in severity. 
Dose selection for the current study is based on the expected level of C5 and complement 
activity inhibition necessary for efficacy in patients with IgAN and the extent to which different 
doses of cemdisiran can inhibit production of C5.  C5 silencing is a novel approach for the 
treatment of IgAN and little clinical precedent exists for inhibiting the terminal complement 
pathway in this disease.  Since complement regulation is not impaired in IgAN like it is in PNH, 
and the kidney glomerular cells are nucleated cells, it is expected that the level of silencing 
needed for efficacy in IgAN is lower than that needed for PNH (see IB Section 2.4).  For this 
proof-of-concept study, a dose was selected that is expected to produce rapid and robust C5 
suppression and complement activity inhibition across the patient population, allowing an 
unambiguous evaluation of whether C5 silencing results in proteinuria improvement in IgAN.  In 
Study ALN-CC5-001, a single dose of 600 mg cemdisiran achieved a C5 level of 
12.3±1.47 μg/mL by Day 14 and 2.3±0.76 μg/mL by Day 56, corresponding to 60.9% reduction 
in complement alternative pathway (CAP) activity and a 69.3% reduction in complement 
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classical pathway (CCP) activity by Day 14 and 90.2% and 91.4% reduction in CAP and CCP 
activities, respectively, by Day 56. Single and multiple biweekly doses of 600 mg were 
well-tolerated with an acceptable safety profile in healthy volunteers in Study ALN-CC5-001A. 
In this initial study, the cemdisiran dose of 600 mg that was safe and well-tolerated was chosen 
for evaluation. This dose will yield robust C5 silencing and will have maximal opportunity to 
produce a meaningful clinical effect in patients with IgAN.  Since the relationship between C5 
levels and complement activity is non-linear, with small C5 fluctuations resulting in a larger 
increase in complement activity, a monthly dose regimen was selected to maintain a constant 
level of C5 silencing.  Additionally, a more consistent effect of cemdisiran on C5 protein and 
CCP level is predicted after monthly dosing when compared to quarterly dosing based on a 
modeling approach.   
During the extension treatment phase, patients treated with both cemdisiran and placebo will 
have the option to receive a 600 mg dose of cemdisiran every four weeks for an additional 52 
weeks. 
IgAN can result in progressive renal impairment; however, patients with severe renal impairment 
(eGFR<30 mL/min/1.73 m2) who may have sustained irreversible damage to the kidney are not 
eligible for participation in this trial.  As the kidney is not the major elimination pathway for 
cemdisiran and based on available nonclinical and clinical data obtained with cemdisiran (with 
10.6 to 31.6% of the cemdisiran dose recovered in a 24-hour urine collection in the ALN-
CC5-001 study), it is expected that moderate renal impairment (eGFR<60 mL/min/1.73 m2) will 
not affect the PK of cemdisiran to the extent that a dose adjustment would be required.  
Therefore, patients with moderate renal impairment are eligible for study enrollment. More 
information on urine PK can be found in the IB.   
1.5. 
Benefit-Risk Assessment 
To date, no medications have been approved specifically for the treatment of IgAN.  Therefore, 
there is a large unmet need for novel interventions, particularly in patients who are at risk of 
progressive renal disease such as those with persistent proteinuria despite treatment with RAS 
inhibitors.  Available data from studies on the role of immunosuppressive therapy in IgAN are 
not conclusive as most are relatively small and have limited follow-up.[Lai 2016]  Use of 
immunosuppressive drugs and high-dose steroids are also associated with increased AEs which 
is particularly common in patients with lower GFR.[Sarcina 2016] 
Given the biological target of cemdisiran, the available nonclinical and clinical data, and mode of 
administration, important potential risks for cemdisiran are infections, liver function test (LFT) 
abnormalities and injection site reactions (ISRs).  C5 inhibition is associated with increased 
susceptibility for Neisserial infections (including disseminated gonococcal infections) and the 
potential risk of other infections, particularly those due to encapsulated bacteria including 
Streptococcus pneumoniae and Haemophilus influenzae type b (Hib), as well as Aspergillus in 
immunocompromised and neutropenic patients. Therefore, prior immunization against N. 
meningitidis using meningococcal group ACWY conjugate vaccine and meningococcal group B 
vaccine are required. Patients will be instructed to contact study site if any early signs of 
meningococcal infections are experienced. In addition, patients with functional or anatomic 
asplenia will be excluded and only patients previously vaccinated or who agree to receive 
vaccination for Hib and Streptococcus pneumoniae according to current national/local 
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vaccination guidelines, at Screening, will be enrolled.  Investigators in Study ALN-CC5-005 
should educate patients on the risk of disseminated gonococcal infection and encourage safe sex 
practices.  All national/local screening recommendations for gonorrhea in the general population 
should also be followed.  Finally, given the reported evidence of a higher risk of disseminated 
gonococcal infections with treatment with eculizumab, Investigators are encouraged to evaluate 
any patient who has a Neisseria gonorrhoeae infection for the signs and symptoms of 
disseminated infection.[Crew 2018; McQuillen 2018]  No cases of Neisserial infection or other 
infections due to encapsulated bacteria were observed in healthy volunteers or in patients with 
PNH (Study ALN-CC5-001). 
As cemdisiran is targeted for delivery to the liver, patients will be closely monitored for changes 
in LFTs and patients with a medical history or evidence of chronic liver disease or cirrhosis have 
been excluded.  Criteria for dose withholding, and stopping of cemdisiran are provided in 
Section 5.2.3.1. Patients will also be monitored for the development of ISRs and rotation of 
injection site are recommended during the study.   
Considering anti-glycan autoantibodies recognizing Gd-IgA1 are implicated in the pathogenesis 
of IgA nephropathy, exposure to the GalNAc moiety of cemdisiran may pose a theoretical risk of 
stimulating the production of pathogenic autoantibodies and immune complexes in patients with 
IgA nephropathy. This could presumably occur when antidrug antibodies (ADAs) to 
cemdisiran’s triantennary GalNAc (Tri-GalNAc) cross-react with Gd-IgA1. The risk of 
developing these cross-reactive antibodies is likely low. This is based on the low incidence of 
ADA to cemdisiran in study ALN-CC5-001 (see Section 1.2) and the distinct difference in 
structure of the O-GalNAc moieties on a Gd-IgA1 glycoprotein and the Tri-GalNAc moiety in 
cemdisran. This low risk is further mitigated by excluding patients with confirmed pre-existing 
IgG/IgM/IgA ADAs to total drug and real time monitoring for development of de novo 
IgG/IgM/IgA ADAs after dosing with cemdisiran. Patients with confirmed de novo ADAs will 
be discontinued from study drug but will continue to be monitored until EOS visit and 
subsequent safety follow up. Patients who develop positive ADA will be followed until ADA 
titers return to baseline. Additional ADA samples will also be collected if any clinical evidence 
of progression of IgAN disease and/or relevant safety findings.  
Detailed information about the known and expected benefits and risks of cemdisiran and 
additional information on the clinical and nonclinical data may be found in the current version of 
the IB. 
Cumulatively, clinical data regarding the role of complement pathways in IgAN progression, 
robust nonclinical and clinical data with cemdisiran (see IB for more information), and prior and 
ongoing clinical experience with other RNAi therapeutics in humans suggest cemdisiran will 
have a favorable risk profile in the intended population and supports the initial clinical 
development of cemdisiran in IgAN.  In addition, cemdisiran may address the unmet medical 
need for the first efficacious and disease-specific treatment for patients with IgAN. 
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• Change from baseline in 24-hour 
albuminuria at Week 32 
• Change from baseline in the urine 
albumin/creatinine ratio (UACR) as 
measured in 24-hour urine at Week 32 
• Change from baseline in C5 level over 
the course of the study 
• Change from baseline in complement 
activity (Complement Alternative 
Pathway [CAP] and Complement 
Classical Pathway [CCP]) over the 
course of the study 
• Evaluation of area under the curve 
(AUC), maximum plasma 
concentration (Cmax), time to 
maximum plasma concentration 
(Tmax), terminal half-life (t½), 
clearance (CL/F), volume of 
distribution (V/F), cumulative amount 
excreted unchanged in urine (Ae) and 
percent of dose excreted in the urine 
(fe) of cemdisiran (25-mer) and 23-
mer 
• Evaluation of AUC, Cmax, Tmax, t½, 
CL/F, V/F, Ae and fe of 22-mer 
AS(N-1)3’ 
• Change from baseline in levels of 
renal damage, complement activation 
and inflammation markers over the 
course of the study 
• 
Incidence of antidrug antibodies 
(ADA) 
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3. 
INVESTIGATIONAL PLAN 
3.1. 
Summary of Study Design 
This is a multicenter, double-blind, placebo-controlled study comprised of three periods 
(Figure 1).  The first period of the study is an observational 14-week run-in period during which 
patients’ blood pressure, kidney function, degree of hematuria, and proteinuria will be measured.  
Patients will not receive study drug (cemdisiran or placebo) during this time.  The standard of 
care is expected to remain unchanged during this run-in period.  The second study period is a 
36-week treatment period which will evaluate the efficacy and safety of SC cemdisiran 
compared to SC placebo in combination with standard of care in patients with IgAN and 
persistent proteinuria.  The third period of the study is a 52-week optional open-label extension 
(OLE) period to further evaluate the long-term safety and clinical activity of cemdisiran.  During 
the OLE, all patients (including those initially on placebo) will be treated with cemdisiran in 
combination with standard of care. 
The study will include Screening of up to 90 days to determine eligibility of patients and to 
complete disease-related assessments.  Patients will provide written informed consent and visit 
the study center approximately 2 weeks before starting the run-in period to complete the protocol 
screening assessments.  Following successful screening, the 14-week run-in period will 
commence, during which patients’ blood pressure, kidney function, degree of hematuria and 
proteinuria as well as treatment with standard of care will be documented by the Investigator.  
The standard of care is expected to remain unchanged during this run-in period.  Patients whose 
proteinuria level remains ≥1 g/24-hours within 2 weeks of the end of the run-in period, and who 
meet blood pressure and eGFR criteria will be eligible to enroll in the 36-week treatment period.  
Upon confirmation of eligibility followed by vaccination against meningococcal infections, 
patients will be randomized at a 2:1 ratio to receive 600 mg of cemdisiran or placebo every 4 
weeks in combination with standard of care.  Approximately 30 patients are planned to be 
randomized in total, 20 in the cemdisiran arm and 10 in the placebo arm.  Patients excluded 
before randomization will be replaced at Screening.  
During the run-in period, patients will visit the study center 14, 8, and 2 weeks prior to 
randomization (Weeks 0, 6 and 12 of the run-in period).  Patients will then return to the study 
center every 4 weeks after the start of study drug treatment period. The primary endpoint will be 
assessed at the end of treatment at Week 32. 
At the end of treatment (Week 32), patients in the two treatment arms will enter the optional 
OLE period where they will receive cemdisiran at a dose of 600 mg every 4 weeks in 
combination with standard of care for 52 weeks.  The first study drug administration of the OLE 
will be administered at Week 36.  Patients will return to the study center at Week 40 and every 
8 weeks thereafter during the OLE.  Home visits, where locally feasible, may be arranged for 
cemdisiran administration in between 8-weekly study center visits (Weeks 44, 52, 60, 68 and 
76), unless patients are required to visit the study center as judged necessary by the Investigator, 
or if home visits cannot be arranged.  An end of treatment (EOT) visit will occur at Week 80 
(OLE EOT) and an end of study (EOS) or early termination (ET) visit will be completed at Week 
84 (OLE EOS/ET).  For patients who complete the treatment period only who do not consent to 
continue to participate in the study in the OLE period, the EOS/ET visit will be at Week 36. 
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Patients will return to the clinical study center for safety follow-up visits approximately 13, 26, 
39 and 52 weeks after the EOS/ET visit (regardless if EOS/ET visit is at Week 36 or Week 84), 
unless enrolled in another study with cemdisiran. Home visits, where locally feasible, may be 
arranged during safety follow-up at 13 and 39 weeks after the EOS/ET visit (regardless if 
EOS/ET visit is at Week 36 or Week 84). 
Regular reviews of safety and tolerability data will be performed by an independent data 
monitoring committee (DMC) throughout the study with the primary purpose of protecting the 
safety of participating patients and the integrity of the study. 
3.2. 
Duration of Treatment  
Subcutaneous doses of cemdisiran or matching placebo will be administered every 4 weeks over 
a period of 32 weeks during the treatment period and patients will receive 600 mg SC doses of 
cemdisiran for 52 weeks in the optional OLE.  
3.3. 
Duration of Study 
The maximum estimated total time on study, inclusive of Screening (maximum of 90 days), 
run-in period (14 weeks), treatment period (36 weeks), optional OLE period (52 weeks) and 
safety follow-up (52 weeks), is approximately 36 months or 3.0 years. 
3.3.1. 
Definition of End of Study for an Individual Patient 
A patient is considered to have reached the end of the study if the patient has completed the EOS 
visit (Week 36 for those patients who do not consent to continue to participate in the study in the 
OLE period and Week 84 for patients who enter the OLE period). Upon study completion 
(regardless if EOS visit is at Week 36 or Week 84) patients will enter a safety follow-up period 
with visits scheduled at intervals of 13 weeks. 
For patients withdrawing from the study after receiving one dose of cemdisiran at a minimum 
(ET), all efforts should be made to conduct the EOS/ET assessments. Patients should then be 
encouraged to enter the safety follow up period. 
3.4. 
Number of Planned Patients 
Approximately 30 patients are planned for randomization in this study. 
3.5. 
Method of Assigning Patients to Treatment Groups 
Using the Interactive Response System (IRS), patients will be randomized 2:1 to the cemdisiran 
or placebo arms.  Randomization will be stratified by baseline urine proteinuria levels (≥1 g/24h 
and <2 g/24h versus ≥2 g/24h). 
Each patient will be uniquely identified in the study by a combination of the site number and 
patient identification number.  Upon signing the informed consent form (ICF), the patient will be 
assigned a patient identification number by the IRS.  The Investigator or his/her designee will 
contact the IRS after confirming that the patient fulfills all the inclusion criteria and none of the 
exclusion criteria at Screening and prior to randomization.  
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3.6. 
Blinding 
All site personnel including sponsor delegated clinical research associates, data management 
CRO and patients will be blinded to study drug treatment during the efficacy period (up to Week 
36). Sponsor personnel will not be blinded to study treatment. Cemdisiran and placebo will be 
packaged identically.  The study drug will be administered under the supervision of the 
Investigator or at the patient’s home by a healthcare professional (see Section 5.2.2).  Since 
cemdisiran may be visually distinguishable from placebo, the syringe will be masked by a site 
pharmacist prior to administration by a healthcare professional.  See the Pharmacy Manual for 
additional details. Further details on blinding and unblinding arrangements will be documented 
in a separate plan /manual. 
3.6.1. 
Emergency Unblinding 
If the treating physician determines that the clinical management of the patient requires 
knowledge of the study drug assignment, the Investigator may break the blind, as necessary.  If 
time permits, clinical study center personnel should contact the Medical Monitor before 
unblinding to discuss the need to unblind the patient but must do so within 1 working day after 
the unblinding event.  A record of when the blind was broken, who was unblinded, who broke 
the blind, and why it was broken, will be maintained in the Trial Master File (TMF). 
Further details on blinding and unblinding arrangements will be documented in a separate plan / 
manual. 
3.7. 
Data Monitoring Committee 
An independent DMC will perform regular reviews of safety, tolerability, and immunogenicity 
data throughout the study with the primary purpose of protecting the safety of participating 
patients and the integrity of the study.  The DMC will operate under the rules of a Charter that 
will be reviewed and approved at the organizational meeting of the DMC.  The DMC will 
perform periodic reviews of unblinded data (safety, tolerability, PK, pharmacodynamics (PD), 
ADA, circulating immune complexes (CIC) and efficacy of cemdisiran) during the clinical trial, 
and on an ad hoc basis review emergent safety data.  Details are provided in the DMC Charter. 
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4. 
SELECTION AND WITHDRAWAL OF PATIENTS 
4.1. 
Inclusion Criteria 
Patients are eligible to be included in the study if all the following criteria apply: 
Age and Sex 
1. Male or female ≥18 years and ≤65 years of age at the time of informed consent 
Patient and Disease Characteristics 
2. Clinical diagnosis of primary IgAN as demonstrated by historical biopsy collected within 
60 months of Screening 
3. Treated for IgAN with stable, optimal pharmacological therapy.  In general, stable and 
optimal treatment will include maximum allowed or tolerated ACE inhibitor or an ARB 
for at least 3 months prior to start of run-in period 
4. Urine protein ≥1 g/24-hour at Screening and mean urine protein ≥1 g/24-hour from two 
valid 24-hour urine collections at the end of the run-in period, prior to randomization  
5. Hematuria as defined by ≥10 RBCs per high powered field (RBC/hpf) at Screening 
6. Females 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, and for 90 days after last dose 
administration  
7. Previously vaccinated with meningococcal group ACWY conjugate vaccine and 
meningococcal group B vaccine or willingness to receive these vaccinations as well as 
prophylactic antibiotic treatment, if required by local standard of care 
8. Previously vaccinated or willingness to receive vaccinations for Hib and Streptococcus 
pneumoniae according to current national/local vaccination guidelines for vaccination use 
Informed Consent 
9. Patient is willing and able to provide written informed consent and to comply with the 
study requirements 
4.2. 
Exclusion Criteria 
Patients are excluded from the study if any of the following criteria apply: 
Disease-specific Conditions 
1. Concomitant significant renal disease other than IgAN 
2. A diagnosis of rapidly progressive glomerulonephritis as measured by eGFR loss >30% 
over the duration of the run-in phase 
3. Secondary etiologies of IgAN (eg, inflammatory bowel disease, celiac disease) 
4. Diagnosis of Henoch-Schonlein Purpura (IgA Vasculitis) 
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5.  eGFR <30 mL/min/1.73 m2 2 weeks prior to randomization (local results will be used for 
assessment of eligibility) 
Laboratory Assessments 
6. Has any of the following laboratory parameter assessments:  
a. Alanine transaminase (ALT) >1.5×upper limit of normal (ULN), International 
Normalized Ratio (INR) >2 (or >3.5 if on anticoagulants), or total bilirubin 
>1.5×ULN (unless bilirubin elevation is due to Gilbert’s syndrome)  
7. Confirmed positive IgG/IgM/IgA ADAs to cemdisiran at Screening 
8. Clinical laboratory test results considered clinically relevant and unacceptable in the 
opinion of the Investigator 
9. Known human immunodeficiency virus (HIV) infection, hepatitis C virus (HCV) 
infection or hepatitis B virus (HBV) infection 
Prior/Concomitant Therapy 
10. Treatment with systemic steroids for more than 7 days or other immunosuppressant 
agents in the 12 months prior to randomization 
11. Received an investigational agent within the last 30 days or 5 half-lives, whichever is 
longer, prior to the first dose of study drug, or are in follow-up of another clinical study 
prior to study enrollment 
Medical Conditions 
12. Malignancy (except for non-melanoma skin cancers, cervical in situ carcinoma, breast 
ductal carcinoma in situ, or stage 1 prostate cancer) within the last 5 years 
13. Active psychiatric disorder, including, but not limited to schizophrenia, bipolar disorder, 
or severe depression despite current pharmacological intervention 
14. Known medical history or evidence of chronic liver disease or cirrhosis 
15. Has other medical conditions or comorbidities which, in the opinion of the Investigator, 
would interfere with study compliance or data interpretation 
16. History of multiple drug allergies or history of allergic reaction to an oligonucleotide or 
GalNAc 
17. History of intolerance to SC injection(s) or significant abdominal scarring that could 
potentially hinder study drug administration or evaluation of local tolerability 
18. Known contraindication to meningococcal vaccines (group ACWY conjugate and group 
B vaccines) required for this study.  Refer to the most recent local product information 
for each vaccine for the current list of contraindications 
19. Unable to take antibiotics for meningococcal prophylaxis, if required by local standard of 
care 
20. Sustained blood pressure >140/90 mmHg as defined by 2 or more readings during the 
run-in period, measured in supine position after 10 minutes of rest 
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21. Receipt of an organ transplant (including hematologic transplant) 
22. History of meningococcal infection within 12 months before Screening 
23.  Patients with systemic bacterial or fungal infections that require systemic treatment with 
antibiotics or antifungals  
24. Patients with functional or anatomic asplenia 
Alcohol Use 
25. Patients who consume more than 14 units of alcohol a week (unit 1 glass of wine 
[125 mL] = 1 measure of spirits [approximately 1 fluid ounce] = ½ pint of beer 
[approximately 284 mL])  
4.3. 
Removal from Therapy or Assessment 
Patients or their legal guardians are free to discontinue study drug and/or stop participation in the 
study at any time and for any reason, without penalty to their continuing medical care.  The 
Investigator or the Sponsor may stop a patient’s participation in the study at any time if this is 
considered to be in the patient’s best interest.  Any discontinuation of treatment or the stopping 
of the patient’s participation in the study must be fully documented in the electronic case report 
form (eCRF) and should be followed up by the Investigator.   
Discontinuation of study drug is described in Section 4.3.1, while the stopping of a patient’s 
participation in the study is detailed in Section 4.3.2. 
4.3.1. 
Discontinuation of Study Drug or Declining Procedural Assessments 
Reasons for discontinuation of study drug include any of the following: 
• Significant violation of the protocol 
• Adverse event  
• Non-adherence to treatment regimen 
• Pregnancy 
• Lost to follow-up 
• Other reason (non-adverse event), including confirmed positive test for ADA to 
cemdisiran 
• Or, study is terminated by the Sponsor 
Patients who are pregnant will be discontinued from study drug dosing immediately (see 
Section 6.7.5.2 for reporting and follow-up of pregnancy).  A positive urine pregnancy test 
should be confirmed by a serum pregnancy test prior to discontinuing study drug. 
Patients who discontinue study drug and/or decline procedural assessments should not be 
automatically removed from study.  In general, patients who discontinue study drug dosing for 
any reason will be encouraged to remain on the study to complete the remaining assessments 
through the Week 36/EOS or Week 84/OLE EOS visit and safety follow-up so that their 
experience is captured in the final analyses.  
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If this occurs, the Investigator is to discuss with the patient the appropriate processes for 
discontinuation from study drug and must discuss with the patient the options for continuation of 
the Schedule of Assessments (Table 2), including different options for follow-up and collection 
of data (eg, in person, by phone, by mail, through family or friends, or from options not 
involving patient contact, such as communication with other treating physicians or from review 
of medical records), including endpoints and adverse events, and must document this decision in 
the patient’s medical records.  
If a patient discontinues dosing due to an AE, including SAEs, the event should be followed as 
described in Section 6.7.6.  When a patient discontinues study drug dosing, the primary reason 
must be recorded in the eCRF.  Patients who discontinue study drug and remain on study may 
receive treatment consistent with local standard practice for their disease per Investigator 
judgement, as applicable.  
Patients who discontinue from study drug during the 36-week treatment period (defined as the 
time the first dose of study drug is administered on Study Day 1 through completion of the 
Week 36 assessments) will be encouraged to remain on the study and complete assessments 
through Week 36; they will also be asked to complete safety follow-up visits 13, 26, 39 and 52 
weeks thereafter (see Table 1).  
Patients who discontinue study drug during the OLE period will be asked to return for their next 
scheduled visit to complete the OLE EOS/ET assessments; they will also be asked to complete 
safety follow-up visits 13, 26, 39 and 52 weeks thereafter (see Table 2). 
4.3.2. 
Stopping a Patient’s Study Participation 
4.3.2.1. 
Patient or Legal Guardian Stops Participation in the Study 
A patient or their legal guardian may stop participation in the study at any time.  A patient/legal 
guardian considering stopping participation in the study should be informed that they can 
discontinue study drug and/or decline procedural assessments and remain in the study to 
complete their study assessments through the Week 36 visit, including entering the 52-week 
safety follow-up.  If a patient/legal guardian still chooses to discontinue study drug and stop 
participation in all follow-up prior to the completion of the 36-week treatment period, every 
effort should be made to conduct early the assessments scheduled to be performed at the 
Week 36 EOS/ET visit (see Table 1).   
If the patient does not wish to or is unable to continue further study participation, the investigator 
is to discuss with the patient appropriate procedures for stopping participation in the study. Data 
collected from the patient can continue to be used. 
In addition, in the countries where the collection and processing of the patient data is based on 
the patient consent, if a patient withdraws consent to collect and process his/her data (see 
Section 4.3.2.2), as applicable, patient data up to the withdrawal of consent will be included in 
the analysis of the study.  In addition, where permitted, publicly available data (such as 
appropriate national or regional vital status registry or other relevant databases) can be included 
after withdrawal of consent, where available and allowable by local law. 
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4.3.2.2. 
Withdrawal of Consent to Process the Patient’s Personal Data  
Where allowed by local law, the patient may decide to withdraw consent to collect, store and use 
biological samples and, as applicable, other personal data, informing the study doctor at any time 
in writing or in any other form that may be locally required.  The Sponsor will continue to keep 
and use the patient’s study information (including any data resulting from the analysis of 
patient’s biological samples until the time of withdrawal) according to applicable law. The 
process for the storage and, as applicable, further use of remaining samples will be followed per 
local requirements. 
4.3.2.3. 
Investigator or Sponsor Stops Participation of a Patient in the Study 
The Investigator or Sponsor may stop the participation of a patient in the study at any time if this 
is considered to be in the patient’s best interest.  However, study integrity and interpretation are 
best maintained if all enrolled patients continue study assessments and follow-up even if study 
drug is discontinued. 
Termination of the clinical study and site closure are described in Section 8.1.6. 
4.3.2.4. 
Recording Reason for Stopping a Patient’s Study Participation 
The primary reason that a patient’s study participation is stopped must be recorded in the 
appropriate section of the eCRF and all efforts will be made to complete and report the 
observations as thoroughly as possible.  If a patient’s study participation is stopped due to an 
adverse event (AE), including serious adverse events (SAEs), the event should be followed as 
described in Section 6.7.6. 
4.3.3. 
Lost to Follow-Up 
A patient will be considered lost to follow-up if the patient repeatedly fails to return for 
scheduled visits and is unable to be contacted by the clinical study center.  The following actions 
must be taken if a patient fails to return to the clinic for a required study visit: 
• The site must attempt to contact the patient or legal guardian and reschedule the 
missed visit as soon as possible and counsel the patient or legal guardian on the 
importance of maintaining the assigned visit schedule and ascertain if the patient or 
legal guardian wishes to continue in the study, and/or should continue in the study.  
• Before a patient is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the patient or legal guardian (where possible, 3 
telephone calls and, if necessary, a certified letter to the patient’s last known mailing 
address or local equivalent methods).  These contact attempts should be documented 
in the patient’s medical record. 
• Should the patient or legal guardian continue to be unreachable, the patient will be 
considered to have stopped participation in the study. 
• For patients who are lost to follow-up, the Investigator can search publicly available 
records (where permitted and allowed by local law) to ascertain survival status.  This 
ensures that the outcome of the study is as comprehensive as possible. 
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4.3.4. 
Replacement of Study Patients  
Patients who discontinue the study drug or stop participation in the study during the 36-week 
treatment period or the OLE will not be replaced. 
 
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5. 
TREATMENTS AND OTHER REQUIREMENTS 
5.1. 
Treatments Administered 
Study drug supplied for this study must not be used for any purpose other than the present study 
and must not be administered to any person not enrolled in the study.  Study drug that has been 
dispensed to a patient and returned unused must not be re-dispensed to a different patient. 
5.2. 
Study Drug 
Detailed information describing the preparation, administration, and storage of cemdisiran and 
placebo is provided in the Pharmacy Manual. 
5.2.1. 
Description  
Cemdisiran will be supplied as a sterile solution for SC injection that contains 200 mg/mL 
cemdisiran sodium (equivalent to 189 mg/mL of cemdisiran), formulated in water for injection 
(WFI) for SC administration.  See the Pharmacy Manual for further details of solution 
concentration and fill volume. 
The control drug for this study will be a placebo (sodium chloride 0.9% w/v for SC 
administration).  Placebo will be provided by the Sponsor; it will be packaged identically to 
cemdisiran. 
5.2.2. 
Dose and Administration 
Patients will be administered cemdisiran (600 mg) or placebo (at the same volume as the active 
drug) as an SC injection once every 4 weeks in combination with standard of care in the 32-week 
treatment phase.  During the 52-week OLE phase, patients will be administered cemdisiran at a 
dose of 600 mg every 4 weeks in combination with standard of care. 
Study drug injections will be administered under the supervision of the Investigator or healthcare 
professional.  At-home dosing may be administered by a healthcare professional.  The injection 
site may 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, if permitted.  Detailed instructions for study 
drug administration are found in the Pharmacy Manual. 
To maintain the blind during the treatment period, the syringes are to be masked prior to study 
drug withdrawal.  A full description of the blinding procedure is included in the Pharmacy 
Manual.  
5.2.3. 
Dose Modifications 
Dose modifications are not permitted. 
If a study drug-related AE occurs in a patient that the Investigator judges as presenting a 
potential risk to the patient for further dosing, the study drug dose may be held at the discretion 
of the Investigator and the Medical Monitor should be contacted. 
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5.2.3.1. 
LFT Criteria for Withholding, Monitoring and Stopping Cemdisiran Dosing   
1. LFT results (Table 5) from the previous visit should be reviewed prior to dosing.  Central 
laboratory results are preferable.  If not available, local laboratory results may be used; 
however, if a local assessment is drawn, a serum chemistry sample must also be drawn 
for analysis at the central laboratory.  
2. For any ALT or AST elevation >3×ULN, central laboratory results should be used to 
guide subsequent monitoring as detailed in Table 4.  
3. For any ALT or AST elevation >3×ULN:  
a. Confirm using central laboratory, as soon as possible, ideally within 2 to 3 days, but 
no later than 7 days. 
b. Perform assessments per Table 4 and Table 6. 
c. If an alternative cause is found, provide appropriate care. 
4. For any ALT or AST elevation >3×ULN without alternative cause that is accompanied 
by clinical symptoms consistent with liver injury (eg, nausea, right upper quadrant 
abdominal pain, jaundice) or elevated bilirubin to ≥2×ULN or INR ≥1.5, permanently 
discontinue dosing. 
5. For confirmed ALT or AST elevations >3×ULN without alternative cause and not 
accompanied by symptoms or elevated bilirubin ≥2×ULN or INR ≥1.5, see Table 4  
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Table 4: Monitoring and Dosing Rules for Asymptomatic Patients with Confirmed 
Isolated Elevations of ALT and/or AST >3× ULN, with No Alternative Cause Identified 
Transaminase Level 
Action 
>3× to 5× ULN 
• 
May continue dosing   
• 
Evaluate the initial elevation in LFT per the following assessments: 
• 
Table 6 (all assessments to be performed once) 
• 
Hematology, serum chemistry, LFT, and coagulation per Table 5 
• 
Monitor at least every two weeks: LFT and coagulation per Table 5 
• 
If elevation persists for ≥2 months, must discuss with the Medical Monitor 
before continuing dosing 
>5× to 8× ULN 
• 
Hold cemdisiran dosing until recovery to ≤1.5×ULN; may resume dosing 
after discussion with the Medical Monitor 
• 
Evaluate the initial elevation in LFT per the following assessments 
• 
Table 6 (all assessments to be performed once) 
• 
Hematology, serum chemistry, LFT, and coagulation per Table 5 
• 
Monitor at least weekly: LFT and coagulation per Table 5 until ALT and/or 
AST is declining on 2 consecutive draws, then may decrease monitoring to 
biweekly 
• 
If ALT or AST rises to >5×ULN following resumption of dosing, 
permanently discontinue dosing 
>8× ULN 
Permanently discontinue dosing after confirmation of the transaminase value 
Abbreviations: ALT=alanine transaminase; AST=aspartate transaminase; INR=international normalized ratio; 
LFT=liver function test(s); ULN=upper limit of normal. 
Notes:   In addition to these criteria, other assessments or evaluations may be performed per Investigator discretion, 
as appropriate. 
5.2.4. 
Preparation, Handling, and Storage 
Staff at each clinical study center or the home healthcare professional will be responsible for 
preparation of cemdisiran doses, according to procedures detailed in the Pharmacy Manual.  No 
special procedures for the safe handling of study drug are required. 
Study drug will be stored upright and refrigerated at approximately 2 to 8°C.  The vial should be 
stored in the carton until ready for use in the storage area of the clinical study site pharmacy, in a 
secure, temperature-controlled, locked environment with restricted access.  Deviations from the 
recommended storage conditions should be reported to the Sponsor and use of the study drug 
halted until authorization for its continued use has been provided by the Sponsor or designee, as 
described in the Pharmacy Manual. 
A Sponsor representative or designee will be permitted, upon request, to audit the supplies, 
storage, dispensing procedures, and records. 
Instructions specific to unused study drug and additional storage will be provided in the 
Pharmacy Manual. 
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5.2.5. 
Packaging and Labeling 
All packaging, labeling, and production of study drug will be in compliance with current Good 
Manufacturing Practice specifications, as well as applicable local regulations. Study drug labels 
and external packaging will include all appropriate information as per local labeling 
requirements.  
Cemdisiran (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 a 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. 
Additional details will be available in the Pharmacy Manual. 
5.2.6. 
Accountability 
The Investigator or designee will maintain accurate records of receipt and the condition of the 
study drug supplied for this study, including dates of receipt.  In addition, accurate records will 
be kept of when and how much study drug is dispensed and administered to each patient in the 
study.  Any reasons for departure from the protocol dispensing regimen must also be recorded. 
At the completion of the study, there will be a final reconciliation of all study drugs.  Used, 
partially used, and unused study drug will be returned to the Sponsor (or designee) or destroyed 
at the clinical study center according to applicable regulations. 
Further instructions about drug accountability will be detailed in the Pharmacy Manual. 
5.3. 
Concomitant Medications and Procedures 
The standard of care treatment should be held stable throughout the run-in and treatment periods. 
Use of concomitant medications and procedures will be recorded on the patient’s eCRF as 
specified in the Schedule of Assessments (see Table 1 and Table 2).  This includes all 
prescription medications, herbal preparations, over the counter medications, vitamins, and 
minerals.  Any changes in medications during the study will also be recorded on the eCRF. 
If patients use nonsteroidal anti-inflammatory drugs intermittently or chronically, they must have 
been able to tolerate them with no previous side effects (eg, gastric distress or bleeding).   
Standard vitamins and topical medications are permitted.  However, topical steroids must not be 
applied anywhere near the injection site(s) unless medically indicated.   
For other permitted concomitant medications administered SC, do not administer in same 
injection site area as the study drug/placebo, for 7 days after the last dose of either study drug or 
placebo.  
Any concomitant medication that is required for the patient’s welfare may be administered by the 
Investigator.  However, it is the responsibility of the Investigator to ensure that details regarding 
the medication are recorded on the eCRF.  Concomitant medication will be coded using an 
internationally recognized and accepted coding dictionary. 
5.3.1. 
Prohibited Concomitant Medications 
The following concomitant medications are prohibited during the study:  
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• Systemic steroids (short-term steroid course for <7 days for common conditions not 
related to IgAN (i.e. asthma, gout) is permitted) 
• Immunosuppressive agents 
• Fish oil supplements (if started prior to Screening, then may continue during the study 
at the same dose) 
• Hydroxychloroquine 
5.3.2. 
Study-specific Vaccinations 
5.3.2.1. 
Meningococcal Vaccinations 
All patients taking part in this study must be vaccinated against meningitis types A, C, W135, Y 
and B, upon determination of eligibility at the end of run-in period, 2 weeks prior to 
randomization to cemdisiran or placebo, as per the Schedule of Assessments.  Meningococcal 
group ACWY conjugate vaccine and meningococcal group B vaccine will be administered in 
accordance with the manufacturer’s instructions and according to the Advisory Committee on 
Immunization Practices (ACIP) or other locally applicable recommendations for patients with 
complement deficiencies. On days of vaccination, urinary samples should be collected prior to 
administration of vaccines. 
Patients will be immunized against Neisseria meningitidis according to the following 
specifications: 
• Patients who have previously completed the recommended series of meningococcal 
vaccinations (meningococcal group ACWY conjugate vaccine and meningococcal 
group B vaccine) at least 14 days but no more than 3 years from randomization can 
start study assessments after confirming eligibility.  Documented vaccine history 
must be available to, and verified by, study site staff at the time of Screening. 
• Patients who were previously vaccinated with polysaccharide type vaccines within 
3 years of study entry will be revaccinated using conjugate vaccines if found eligible 
at the end of the run-in period.   
• Patients who have not been previously vaccinated against Neisseria meningitidis, 
those without documentation of vaccination history, or those vaccinated more than 
3 years from study randomization will commence the vaccination series with the 
recommended meningococcal vaccines (meningococcal group ACWY conjugate 
vaccine and meningococcal group B vaccine) per the Schedule of Assessments if 
determined to be eligible for the study at the end of the run-in period.   
• If required locally, patients will receive prophylactic antibiotics according to the local 
standard of care after randomization to cemdisiran or placebo. 
5.3.2.2. 
Pneumococcal and Hib Vaccinations 
Patients will receive vaccinations for Hib and Streptococcus pneumoniae, if not previously 
vaccinated, according to current national/local vaccination guidelines for vaccination use. Hib 
and pneumococcal vaccinations (if required at Screening per national/local guidelines; 
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vaccination should occur prior to Week-2. At Screening, patient vaccination records will be 
checked for compliance with local recommendations for the use of these vaccines.  
5.4. 
Treatment Compliance 
Compliance with study drug administration will be verified through observation by study staff or 
trained home healthcare professionals. 
5.5. 
Other Requirements 
5.5.1. 
Contraception 
Females of child-bearing potential must be willing to use a highly effective method of 
contraception from 14 days before first dose, throughout study participation, and for 90 days 
after last dose administration or until study completion.   
Birth control methods which are considered highly effective include: 
• Placement of an intrauterine device. 
• Placement of an intrauterine hormone-releasing system.  
• Bilateral tubal occlusion. 
• Surgical sterilization of male partner (with the appropriate post-vasectomy 
documentation of the absence of sperm in the ejaculate; for female patients on the 
study, the vasectomized male partner should be the sole partner for that patient). 
• Established use of oral (except low-dose gestagens), implantable, injectable, or 
transdermal hormonal methods of contraception. Females of child-bearing potential 
who use hormonal contraceptives as a method of contraception must also use a barrier 
method (condom or occlusive cap [diaphragm or cervical/vault cap] in conjunction 
with spermicide [eg, foam, gel, film, cream, or suppository]).   
• True sexual abstinence, when in line with the preferred and usual lifestyle of the 
patient.  Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception.  Abstinent 
patients must agree to use one of the above-mentioned contraceptive methods if they 
start sexual relationships during the study and for up to 90 days after the last dose of 
study drug. 
Investigators should advise females of childbearing potential of the most appropriate birth 
control method available within their country taking into account local medical practice. 
Females of child-bearing potential include female patients who have experienced menarche (or 
begin menarche over the course of the study) and who are not postmenopausal or permanently 
sterilized (eg, bilateral tubal occlusion, hysterectomy, or bilateral salpingectomy).  A 
postmenopausal state is defined as the absence of menses for 12 months without an alternative 
medical cause, confirmed by follicle stimulating hormone level within the postmenopausal 
range.  
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For male patients, no contraception is required. However, use by males of contraception 
(condom) may be required in some countries e.g. France, in order to comply with local 
requirements as described in the corresponding patient consent forms 
Compliance with contraception requirements will be assessed on a regular basis by the 
Investigator throughout the course of the study (see Section 6.7.5.2). 
5.5.2. 
Alcohol Restrictions 
Patients will limit alcohol consumption throughout the course of the study.  Alcohol is limited to 
no more than 2 units per day (unit:  1 glass of wine [approximately 125 mL] = 1 measure of 
spirits [approximately 1 fluid ounce] = ½ pint of beer [approximately 284 mL]) for the duration 
of the study. 
5.5.3. 
Antibiotic Compliance 
Patients who require prophylactic antibiotics after randomization to cemdisiran or placebo (see 
Section 5.3.2.1) per local standard of care will undergo antibiotic compliance checks.  Antibiotic 
compliance checks will be performed at the time points in the Schedule of Assessments.  
Antibiotic dose adjustments will be permitted in the case of renal impairment.  All dose 
adjustments must comply with the manufacturer’s instructions. 
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6. 
STUDY ASSESSMENTS 
The Schedule of Assessments is provided in Table 1 and Table 2. 
6.1. 
Screening Assessments 
An ICF approved by the appropriate Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) must be signed by the patient (or legal guardian) before the Screening 
procedures are initiated.  All patients (or their legal guardians) will be given a copy of the signed 
and dated ICF.  
Patients will be screened to ensure that they meet all the inclusion criteria and none of the 
exclusion criteria.  Rescreening of patients is permitted with consultation of the Medical 
Monitor; see Section 6.1.1.  
Patient demographic data and medical history/disease history will be obtained. In particular, the 
MEST-C score and degree of IgG, IgA, IgM, C3, C1q, C4d and C5b-9 stains will be obtained 
from pathology reports, if available, and documented. Any changes to medical history occurring 
between the Screening assessment and Day 1 will be updated prior to study drug administration. 
Additional screening assessments include a full physical examination (with emphasis on 
presence/degree of edema), collection of vital signs, height, weight and body mass index (BMI), 
12-lead electrocardiogram (ECG), clinical laboratory assessments, pregnancy, 24-hours urine 
proteinuria assessment (from a single valid collection; see Section 6.4.1.1), eGFR, urinalysis and 
ADA and CIC assessments. Vaccination records will also be checked for compliance with 
national/local guidelines for pneumococcal and Hib vaccinations. 
6.1.1. 
Rescreening 
A patient who does not meet all study eligibility criteria due to a transient condition observed at 
Screening (eg, prohibited medications that were subsequently discontinued) will be allowed to 
return for rescreening (once only).  A patient will be re-consented if rescreening occurs outside 
of the 90-day screening window.  In this case, all screening procedures must be repeated.  
6.1.2. 
Retesting 
If in the Investigator’s judgement, the laboratory abnormalities at Screening or in the run-in 
period are likely to be transient, then laboratory tests may be repeated.  The Investigator’s 
rationale is to be documented.  Laboratory values can be retested once during Screening or the 
run-in period as long as the patient can be evaluated for eligibility and randomized within the 
allowed Screening or run-in period.  Two retests will be permitted for hematuria during 
Screening, if the first test is negative.   
6.2. 
Run-in Period 
During the 14-week run-in period, the following will be performed at time points specified in the 
Schedule of Assessments (Table 1): Hib and pneumococcal vaccinations (if required at 
Screening per national/local guidelines; vaccination should occur prior to Week-2), vital signs, 
clinical laboratory assessments, pregnancy test, 24-hour urine proteinuria assessment (from 2 
single valid collections; see Section 6.4.1.1), urinalysis for hematuria, spot urine for proteinuria, 
and eGFR.  Clinical laboratory tests will be performed centrally; however, eGFR will also be 
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assessed locally at the end of the run-in period (Week-2) to facilitate assessment of patient 
eligibility and administer meningococcal vaccination on the same day.  Meningococcal vaccines 
should be administered only if patient eligibility for randomization is confirmed and after urine 
collections are completed.  
Sites are encouraged to discuss study information with the patients again at the end of the run-in 
period. 
6.3. 
Baseline Assessments (Treatment Period) 
Prior to dosing on Day 1, patients will be reassessed for eligibility and blood and urine samples 
for clinical laboratory assessments and exploratory analyses collected, including blood samples 
for complement activity tests (CAP/CCP), C5 analysis, PK, ADA and CIC.  
In addition, prior to administration of study drug, the following assessments will be performed:  
full physical examination, body weight and height, vital signs, ECG, urine pregnancy test, eGFR 
assessment, and urinalysis.  
Collection of blood and urine samples for PK analysis on Day 1 will be performed as outlined in 
Table 3.   
6.4. 
Efficacy Assessments 
6.4.1. 
Proteinuria 
Primary efficacy will be assessed by determining the percent change from baseline in 24 hour 
proteinuria (g/24-hour) after 32 weeks of treatment. 24 hour urine samples for determination of 
proteinuria will be collected throughout the study as outlined in the Schedules of Assessments 
and will be analyzed by a central laboratory. 
6.4.1.1. 
24-Hour Urine Collection 
Patients will be required to provide two separate valid 24-hour urine collections 2 weeks prior to 
randomization (to assess eligibility after the run-in period) and at Week 32 (to assess the primary 
endpoint). Patients will also be asked to provide a single valid 24-hour urine sample for other 
24-hour urinary assessments outlined in the Schedule of Assessments. Rigorous exercise and 
significant change in diet (in particular salt intake) should be avoided within 48 hours before 
collection of 24-hour urine samples, whenever possible. The two valid 24-hour urine samples 
may be collected within 2 weeks before assessment is due while the one valid 24-hour urine 
sample may be collected within one week before the assessment takes place. If any of the 
collections do not meet validity criteria outlined below, then repeat collections must be 
scheduled within the time frames outlined above to assure the minimum number of valid 
collections required for each of the study time points. The duration of collection and volume of 
urine in the collection will be recorded in the eCRF. In addition to protein, albumin, sodium and 
creatinine will also be quantified in each of the 24-hour urine samples. Both protein/creatinine 
(UPCR) as well as albumin/creatinine ratios (UACR) will also be calculated in an aliquot of the 
24-hour urine collection.   
Completeness of the 24-hour urine collection can be estimated from rate of creatinine excretion. 
Normal values of creatinine excretion vary with age and body weight. An aliquot of the 24-hour 
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urine collection will be used to determine urinary creatinine content to determine if the 24-hour 
urine collections need to be repeated. Hence, a 24-hour urine collection will only be considered 
valid if all the following criteria are met, otherwise a repeat urine collection will be required: 
• The collection is between 22-26 hours in duration between the initial discarded void 
and the last void or attempt to void. 
• No voids are missed between the start and end time of the collection as indicated by 
the patient’s urine collection diary. 
• The 24-hour creatinine content is within 25% of expected range as estimated by the 
following formula:  [(140-age) x weight]/5000, where weight is in kilograms. This 
result is multiplied by 0.85 in women.[Ix 2011] 
• In case of need of two valid samples, the maximum variation in total 24-hour urine 
creatinine between the two urine collections must be <25%. 
Primary efficacy will be evaluated by comparing the percent change from baseline in 24-hour 
proteinuria (g/24-hours) at Week 32 in patients treated with cemdisiran versus those treated with 
placebo.  
Secondary and exploratory efficacy assessments include comparisons of the proportion of 
patients with partial or complete clinical remission, respectively, as measured by the amount of 
urine protein (UP) in a 24-hour urine sample.  Partial clinical remission is defined as having UP 
<1 g/24-hours and complete clinical remission is defined as UP <0.3 g/24-hours.  Each will be 
assessed at Week 32. 
Additionally, using 24-hour samples, the change from baseline in the UP/creatinine ratio (UPCR) 
will be evaluated as a secondary endpoint and the change from baseline in urine 
albumin/creatinine ratio (UACR) at Week 32 as an exploratory endpoint. 
6.4.1.2. 
Spot Urine Collection 
Urinary protein, albumin and creatinine levels from spot urine collections prior to dosing will 
also be measured to assess the effect of cemdisiran on urinary protein/creatinine (UPCR) and 
albumin/creatinine (UACR) as outlined in the Schedule of Assessments. 
The change from baseline in UPCR at Week 32 will be evaluated in spot urine samples.  Spot 
urine samples will be collected at the time points outlined in the Schedule of Assessments 
(Table 1).   
6.4.2. 
Hematuria 
Hematuria from spot urine collections will also be evaluated to assess the effect of cemdisiran on 
disease course in patients with IgAN. The degree of hematuria will be assessed by examination 
of the spun urine sediment by microscopy (RBC/hpf). Single void collections for random urine 
sample for hematuria evaluation should be collected. If the investigator determines that the 
hematuria is transient due to menses in women or exercise, the sample may need to be repeated. 
Random spot urine samples for hematuria measurement will be collected throughout the study as 
outlined in the Schedule of Assessments and will be analyzed by a central laboratory.  On dosing 
days, samples should be collected prior to study drug administration, if applicable. 
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6.4.3. 
Changes in Renal Function 
Changes in renal function will be monitored using measurements of serum creatinine and eGFR 
(mL/min/1.73m2) as outlined in the Schedule of Assessments. The calculation will be based on 
the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula for all patients. 
For assessment of eligibility at the last visit of run-in period, 2 weeks prior to randomization, 
local lab can be utilized. This will allow evaluation for eligibility on the same day. A sample will 
also be sent to central lab. 
Renal function will also be estimated as creatinine clearance based on the 24-hour urine 
collection. The creatinine clearance is a widely used test to estimate the GFR using the following 
formula: 
GFR  =  [UCr  x  V] / SCr 
SCr is the serum creatinine concentration and the value assessed closest to collection of 24-hour 
urine collection will be utilized for purpose of above calculation. UCr is the urine creatinine 
concentration and V is the urine flow rate or volume. 
Blood and urine samples for renal function assessments will be collected prior to administration 
of cemdisiran or placebo on dosing days, if applicable. 
The change from baseline in eGFR will be measured throughout the course of the study. In 
addition, the slope of eGFR will be computed for the first 32 weeks and the entire study period 
(including the OLE).  
6.4.4. 
Markers of Complement Activation, Inflammation and Renal Injury 
Samples for measurement of markers of complement activation, inflammation and renal injury 
will be collected at the time points outlined in the Schedule of Assessments (Table 1) and 
analyzed by central laboratories. On dosing days, blood samples will be collected predose. 
6.5. 
Pharmacodynamic Assessments 
Blood samples for PD analysis will be collected at the time points outlined in the Schedule of 
Assessments (Table 1).  Samples will be collected prior to administration of cemdisiran or 
placebo on dosing days. 
Analysis of PD will include the impact of cemdisiran administration on plasma C5 protein levels 
(assessed by a mass spectrometry-based method) and serum complement activity (assessed by 
CAP enzyme linked immunosorbent assay [ELISA] and CCP ELISA).  Samples will be analyzed 
at central laboratories.  Details regarding the collection, processing, shipping, and storage of the 
samples will be provided in the Laboratory Manual. 
6.6. 
Pharmacokinetic Assessments 
Blood samples and urine samples will be collected for assessment of cemdisiran PK parameters 
and possible metabolite analysis at the time points in the Schedule of Assessments.  A detailed 
schedule of time points for the collection of blood samples and urine samples for PK analysis is 
in Table 3. 
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The concentration of cemdisiran will be determined using a validated assay.  Details regarding 
sample volumes to be collected, and the processing, shipping, and analysis of the samples will be 
provided in the Laboratory Manual. 
6.7. 
Safety Assessments 
The assessment of safety during the study will consist of the surveillance and recording of the 
frequency of AEs including SAEs, recording of concomitant medication and measurements of 
vital signs, weight and height, physical examination, and ECG findings and laboratory tests, 
including assessment of IgG/IgM/IgA ADA and CIC. Clinically significant abnormalities 
observed during the physical examination are recorded.   
Safety will be monitored over the course of the study by a DMC as described in Section 3.7. 
6.7.1. 
Vital Signs 
Vital signs will be measured as specified in the Schedule of Assessments (Table 1 and Table 2) 
and include blood pressure, heart rate, body temperature, and respiratory rate.  Vital signs will be 
measured in the seated or supine position, after the patient has rested comfortably for 10 minutes.  
On Day 1, vital signs will be collected at predose and 4 hours (±15 minutes) postdose.  On all 
other dosing days, vital signs will be collected predose.  
Blood pressure should be taken using the same arm throughout the study.  Body temperature in 
degrees Celsius will be obtained via oral or tympanic method.  Heart rate will be counted for a 
full minute and recorded in beats per minute, and respiration rate will be counted for a full 
minute and recorded in breaths per minute. 
Additional vital sign assessments, as medically indicated, may be added at the discretion of the 
Investigator, or as per DMC advice. 
Vital signs results will be recorded in the eCRF. 
6.7.2. 
Weight and Height 
Height will be measured in centimeters.  Body weight will be measured in kilograms.  Height 
and body weight measurements will be collected as specified in the Schedule of Assessments 
(Table 1 and Table 2; height at Screening only and dosing weight during the clinical study center 
visits) and will be recorded in the eCRF. 
6.7.3. 
Physical Examination 
Routine physical examinations will be conducted according to the Schedule of Assessments 
(Table 1 and Table 2); if a physical examination is scheduled for a dosing visit, it should be 
conducted prior to dosing.   
At Screening and Day 1 predose, a full physical examination will be performed.  At all other 
time points, including Day 1 at 4 hours (±30 minutes) postdose, a directed physical examination 
will be performed. 
Full physical examinations will include the examination of the following:  general appearance; 
head, eyes, ears, nose and throat; respiratory, cardiovascular, gastrointestinal, musculoskeletal, 
and dermatological systems; thyroid; lymph nodes; and neurological status. 
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Directed physical examinations will include examination of the following:  respiratory, 
cardiovascular, dermatological, gastrointestinal, and musculoskeletal systems. 
Clinically significant abnormalities observed during the physical examination are recorded on 
the medical history or AE eCRF. 
6.7.4. 
Electrocardiogram 
Twelve-lead ECGs reporting rhythm, ventricular rate, RR interval, PR interval, QRS duration, 
and QT interval and Fridericia-corrected QT interval will be obtained, as specified in the 
Schedule of Assessments (Table 1 and Table 2). Patients should be supine for at least 5 minutes 
before each ECG is obtained.  A single 12-lead ECG will be performed at Screening.  At all 
other time points, 12-lead ECGs will be performed in triplicate, with readings approximately 1 
minute apart. 12-lead ECGs will be performed at predose; 60 minutes postdose; and 4 hours 
postdose in relation to the Day 1 and Week 32 cemdisiran or placebo doses. 
When ECG and blood sample collection occur at the same time, ECGs should be performed 
before blood samples are drawn. 
The Investigator or qualified designee will review all ECGs to assess whether the results have 
changed since the Baseline visit and to determine the clinical significance of the results.  These 
assessments will be recorded on the eCRF.  Additional ECGs may be collected at the discretion 
of the Investigator, or as per DMC advice.   
6.7.5. 
Clinical Laboratory Assessments 
The following clinical laboratory tests will be evaluated by a central laboratory. However, to 
assess patient eligibility at the end of the run-in period, eGFR will also be assessed locally. 
Specific instructions for transaminase elevations are provided in Section 5.2.3.1.  For any other 
unexplained clinically relevant abnormal laboratory test occurring after study drug 
administration, the test should be repeated and followed up at the discretion of the Investigator, 
or as per DMC advice, until it has returned to the normal range or stabilized, and/or a diagnosis 
is made to adequately explain the abnormality.  Additional safety laboratories and assessments as 
indicated by the clinical situation may be requested.  Clinical laboratory assessments are listed in 
Table 5 and include: hematology, serum chemistry and urinalysis parameters. Parameters will be 
assessed as specified in the Schedule of Assessments (Table 1 and Table 2).  
While local laboratory results may be used for urgent clinical and dosing decisions, on the day of 
the clinic visit assessments, all laboratory assessments specified in Table 5 which are performed 
at the clinic should also be sent in parallel to the central laboratory.  In the case of discrepant 
local and central laboratory results on samples drawn on the same day, central laboratory results 
will be relied upon for clinical and dosing decisions. 
Clinical laboratory assessments may be collected at the clinical study center or at home by a 
trained healthcare professional. On dosing days blood samples will be collected predose. 
For any safety event or laboratory abnormality, additional laboratory assessments, imaging, and 
consultation may be performed for clinical evaluation and/or in consultation with the Medical 
Monitor; results may be collected and should be included in the clinical database. 
 
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Table 5: 
Clinical Laboratory Assessments 
Hematology 
Complete blood count with differential 
 
Serum Chemistry 
Sodium 
Potassium 
BUN 
Phosphate 
Creatinine and eGFR (using the CKD-EPI formula)  
Albumin 
Uric acid 
Calcium 
Total protein 
Carbon dioxide 
Glucose 
Chloride 
Liver Function Tests 
 
AST 
ALP 
ALT 
Bilirubin (total and direct) 
GGT  
 
Urinalysis 
Visual inspection for appearance and color 
Bilirubin 
pH 
Nitrite 
Specific gravity 
RBCs 
Ketones 
Urobilinogen 
Albumin 
Leukocytes 
Glucose 
Microscopy 
Protein 
 
Coagulation  
Prothrombin time 
International Normalized Ratio 
Partial Thromboplastin Time 
 
Immunogenicity (see Section 6.7.5.1) 
Antidrug antibodies 
Hepatic Tests (Screening Only)  
Hepatitis C, including:  
HCV RNA PCR – qualitative and quantitative 
assays 
Hepatitis B, including:  
HBs Ag, HBc antibody IgM and IgG 
Pregnancy Testing (Females of Child-bearing Potential Only) (see Section 6.7.5.2) 
β-human chorionic gonadotropin 
Abbreviations:  ALP=alkaline phosphatase; ALT=alanine transaminase; AST=aspartate transaminase; BUN=blood 
urea nitrogen; CKD-EPI=Chronic Kidney Disease Epidemiology Collaboration; eGFR=estimated glomerular 
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filtration rate; GGT=gamma glutamyl transferase; HAV=hepatitis A virus; HBsAg=hepatitis B virus surface 
antigen; HBc=hepatitis B virus core; HCV=hepatitis C virus; IgG= IgG=immunoglobulin G antibody; 
IgM=immunoglobulin M antibody; PCR=polymerase chain reaction; RBC=red blood cell; RNA=ribonucleic acid. 
6.7.5.1. 
Immunogenicity 
Blood samples will be collected to evaluate ADA and CIC.  IgG/IgM/IgA ADA to total drug will 
be assessed at Screening and during the study. ADA samples will be tested in real time. Clinical 
study decision will be based on confirmed positive ADA results from the IgG/IgM/IgA assay. 
Confirmed positive ADA samples will be further characterized for cemdisiran domain specificity 
against the Tri-GalNAc component if a reliable method is established.  Blood samples for ADA 
and CIC testing must be collected before study drug administration as specified in the Schedule 
of Assessments (Table 1 and Table 2).  Blood samples to evaluate ADAs will be collected at 
Screening to assess study eligibility and at the Early Termination (ET) visit, if applicable. ADA 
and CIC will be routinely monitored during the treatment period and throughout the open-label 
extension phase and safety follow up, as indicated in the Schedule of Assessments. Finally, ADA 
and CIC samples will also be collected and analyses will be performed and prioritized if any 
clinical evidence of progression of IgAN disease and/or relevant safety findings. Patients who 
are confirmed positive for IgG/IgM/IgA ADA at baseline will be excluded from study treatment. 
In addition, patients who develop de novo ADAs will be discontinued from study drug but will 
be followed until EOS visit and during safety follow up. These patients will also be monitored 
until ADA levels return to baseline. 
Exploratory analysis of anti-Gd-IgA1 antibody levels will be conducted; serum samples for these 
analyses will be drawn when CIC samples are collected. 
Details regarding the processing, shipping, and analysis of the samples will be provided in the 
Laboratory Manual. 
6.7.5.2. 
Pregnancy Testing 
A pregnancy test will be performed for females of child-bearing potential.  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.  Patients 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.  Patients determined to 
be pregnant while on study will be followed until the pregnancy outcome is known (see Section 
6.7.6.7 for follow-up instructions).  
6.7.5.3. 
Additional Liver Function Assessments 
Additional laboratory assessments will be performed in patients who experience any liver 
function test (LFT) abnormalities.  Following the occurrence of elevated liver transaminases or 
other LFT abnormalities per central laboratory, all assessments in Table 6 will be performed one 
time, as well as hematology, serum chemistry, LFT, and coagulation assessments from Table 5, 
and other assessments or evaluations per Investigator discretion, as appropriate. 
 
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Table 6: 
Hepatic Assessments in Patients Who Experience Elevated Transaminases 
Extended Hepatic Panel 
Herpes Simplex Virus 1 and 2 antibody IgM, IgG 
HHV-6 
Cytomegalovirus antibodies, IgM, IgG  
HBs Ag, HBc antibody IgM and IgG 
Anti-nuclear antibodies 
Epstein-Barr Virus antibodies, IgM and IgG 
Anti-smooth muscle antibodies 
Anti-mitochondrial antibodies 
HCV antibody 
HAV antibody IgM 
HCV RNA PCR – qualitative and quantitative 
HEV antibody IgM 
Herpes Zoster Virus IgM, IgG 
 
Imaging 
Abdominal ultrasound with Doppler flow (or CT or MRI) including right upper quadrant 
Focused Medical and Travel History 
Use of any potentially hepatotoxic concomitant 
medications, including over the counter medications 
and herbal remedies 
Alcohol consumption  
Other potentially hepatotoxic agents including any 
work-related exposures 
Recent travels to areas where hepatitis A or E 
is endemic 
Abbreviations:  CT=computed tomography; HAV=hepatitis A virus; HBc=hepatitis B core; HBsAg=hepatitis B 
virus surface antigen; HCV=hepatitis C virus; HEV=hepatitis E virus; HHV-6=human herpesvirus 6; 
IgG=immunoglobulin G antibody; IgM=immunoglobulin M antibody; MRI=magnetic resonance imagery; 
PCR=polymerase chain reaction; RNA=ribonucleic acid. 
Note: 
• 
All assessments will be measured in central laboratory. The full panel of assessments should only be 
performed once; individual assessments may be repeated, as needed. 
 
6.7.6. 
Adverse Events 
6.7.6.1. 
Definitions 
Adverse Event  
According to the International Council on Harmonisation (ICH) E2A guideline Definitions and 
Standards for Expedited Reporting, and 21 CFR 312.32, investigational new drug (IND) Safety 
Reporting, an AE is any untoward medical occurrence in a patient or clinical investigational 
subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death 
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• 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 
• Is an important medical event that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient and may require 
intervention to prevent one of the other outcomes listed in the definition above (eg, 
events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias, convulsions, or the development of drug 
dependency or abuse). 
Adverse Events of Clinical Interest 
Based on the biological target and the available nonclinical and clinical data, AEs of Clinical 
Interest (AECI) for this study are: 
• Severe infections as judged by the investigator  
• ALT or AST >3×ULN 
• Severe or serious injection site reactions (ISRs); ISRs that are associated with a recall 
phenomenon (reaction at the site of a prior injection with subsequent injections), or 
those that lead to temporary dose interruption or permanent discontinuation of 
cemdisiran. 
An ISR is defined as a local reaction at or near the site of injection.  “At or near” the 
injection site includes reactions at the injection site, adjacent to the injection site, or a 
reaction which may shift slightly away from the injection site due to gravity (eg, as 
may occur with swelling or hematoma).  A systemic reaction which includes the 
injection site (eg, generalized urticaria, other distinct entities or conditions like 
lymphadenopathy that may be near the injection site) is not considered an ISR.  
For information on recording and reporting of AECIs, see Section 6.7.6.2 and Section 6.7.6.3 , 
respectively. 
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Adverse Event Severity 
Adverse events are to be graded according to the categories detailed below: 
Mild: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Moderate: 
Moderate; minimal, local or noninvasive intervention indicated; limiting age 
appropriate instrumental activities of daily living (eg, preparing meals, 
shopping for groceries or clothes, using the telephone, managing money). 
Severe: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care activities of daily living (ie, bathing, dressing and undressing, feeding 
self, using the toilet, taking medications, and not bedridden); OR life-
threatening consequences; urgent intervention indicated; OR death related to 
an 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 SAE). 
Relationship of the Adverse Event to Study Drug 
The relationship of each AE to study drug should be evaluated by the Investigator by a “yes” or 
“no” response to the question: “Is there a reasonable possibility that the event may have been 
caused by the study drug?” 
6.7.6.2. 
Eliciting and Recording Adverse Events 
Eliciting Adverse Events 
The patient and legal guardian, if applicable, should be asked about medically relevant changes 
in the patient’s health since the last visit.  The patient and legal guardian, if applicable, should 
also be asked if the patient has been hospitalized, had any accidents, used any new medications, 
or changed concomitant medication routines (both prescription and over-the-counter).  In 
addition to patient observations, AEs will be documented from any clinically relevant laboratory 
findings, physical examination findings, ECG changes, or other findings that are relevant to 
patient safety. 
Recording Adverse Events 
The Investigator is responsible for recording all SAEs and only AEs related to study procedures 
that are observed or reported by the patient during the run-in period (before the administration of 
the first dose of study drug) regardless of their relationship to study drug through the end of 
study.  All AEs, including non-serious AEs, occurring after signing of the ICF and before study 
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drug administration will be captured as medical history (see Section 6.1).  All AEs will be 
collected starting after administration of the first dose through the end of the safety follow-up 
period. 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 study drug, action 
taken, and outcome (including time and date of resolution, if applicable). 
For SAEs, record the event(s) on both the eCRF and the SAE form.  
For AEs that are considered AEs of clinical interest (Section 6.7.6.1), the supplemental AEs of 
Clinical Interest eCRF should be completed.  Additional clinical and laboratory information may 
be collected.  Refer to CRF completion guidelines for details on reporting events in the 
supplemental AEs of Clinical Interest eCRF.   
For all ISRs, the Investigator, or delegate, should submit a supplemental ISR eCRF, recording 
additional information (eg, descriptions, onset and resolution date, severity, treatment given, 
event outcome). 
6.7.6.3. 
Reporting Adverse Events of Clinical Interest to Sponsor/Designee 
For AEs that are considered AECIs (Section 6.7.6.1), the Sponsor or its designee should be 
notified within 24 hours using a supplemental AEs of Clinical Interest eCRF. 
6.7.6.4. 
Serious Adverse Events Require Immediate Reporting to Sponsor/Designee 
An assessment of the seriousness of each AE will be made by the Investigator.  Any AE and 
laboratory abnormality that meets the SAE criteria in Section 6.7.6.1 must be reported to the 
Sponsor or designee within 24 hours from the time that clinical study center staff first learns of 
the event.  All SAEs must be reported regardless of the relationship to study drug. 
The initial report should include at least the following information: 
• Patient’s study number 
• Description and date of onset of the event 
• Criterion for serious 
• Preliminary assignment of relationship to study drug, and 
• Investigator/site information 
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To report the SAE, complete the 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 Investigator Site File. 
Appropriate remedial measures should be taken by the Investigator using his/her best medical 
judgment to treat the SAE.  These measures and the patient’s response to these measures should 
be recorded.  All SAEs, regardless of relationship to study drug, will be followed by the 
Investigator until satisfactory resolution or the Investigator deems the SAE to be chronic or 
stable.  Clinical, laboratory, and diagnostic measures should be employed by the Investigator as 
needed to adequately determine the etiology of the event. 
6.7.6.5. 
Sponsor Safety Reporting to Regulatory Authorities 
The Sponsor or its representative will report certain study events in an expedited manner to the 
Food and Drug Administration, the European Medicines Agency’s EudraVigilance electronic 
system according to Directive 2001/20/EC, and to all country Regulatory Authorities where the 
study is being conducted, according to local applicable regulations. 
6.7.6.6. 
Serious Adverse Event Notification to the Institutional Review 
Board/Independent Ethics Committee 
Suspected unexpected serious adverse reactions (SUSARs) will be reported to the IRB/IEC per 
their institutional policy by the Investigator or Sponsor (or Sponsor designee) according to 
country requirements.  Copies of each report and documentation of IRB/IEC notification and 
acknowledgement of receipt will be kept in the Investigator’s study file. 
6.7.6.7. 
Pregnancy Reporting 
If a female patient becomes pregnant during the study through 90 days following the last dose of 
study drug, the Investigator must report the pregnancy to the Sponsor or designee within 
24 hours of being notified of the pregnancy. Details of the pregnancy will be recorded on the 
pregnancy reporting form.  The patient should receive any necessary counseling regarding the 
risks of continuing the pregnancy 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 6.7.6.4. 
6.7.6.8. 
Overdose Reporting 
An overdose is defined as any dose administered to or taken by a patient (accidentally or 
intentionally) that exceeds the highest daily dose, or is at a higher frequency, than included in the 
protocol.  The investigator will decide whether a dose is to be considered an overdose, in 
consultation with the Sponsor.  In the event of an overdose, the actual dose administered must be 
recorded in the eCRF. 
All reports of overdose (with or without an AE) must be reported within 24 hours to the Sponsor 
or designee. 
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6.8. 
Biomarkers, DNA Genotyping, and Biospecimen Repository 
Alnylam’s RNAi therapeutics platform permits the highly specific targeting of investigational 
therapies based on genetic sequence.  It is possible that variations in the target genetic sequence 
will result in variations in drug effect. 
More generally, genetic variations may account for the well-described heterogeneous 
manifestations of disease in patients with IgAN, as well as their responses to treatment. 
To permit exploratory investigations and the application of novel approaches to bioanalyses that 
may further elucidate the outcomes of this study, or potentially advance understanding of the 
safety, mechanism of action, and/or efficacy of cemdisiran, a set of biological specimens will be 
collected at the intervals indicated in the Schedule of Assessments (Table 1 and Table 2). 
The biospecimen repository will also include residual material from routine samples (safety 
laboratory samples, PK samples, etc.) that are obtained during the study. 
These specimens will be securely stored in a central biorepository for up to 10 years following 
the completion of this clinical study (ie, last patient last visit), or as per local regulations.  After 
10 years have elapsed, samples will be destroyed. 
Where allowed per local regulations, ethics committee (IRB/IEC) approval, and patient consent, 
the samples will be collected as part of this study.  Examples of potential exploratory 
investigations would include DNA, RNA or biochemical metabolite assessments as they relate to 
disease progression, efficacy or safety.  
Details regarding the collection, processing, storage, and shipping of the samples will be 
provided in the Laboratory Manual. 
Exploratory analysis of these biospecimens will be performed by Alnylam Pharmaceuticals or its 
designees. 
When biobanking is permitted by local regulation, study participants will be advised during the 
informed consent process of these biobanking details and the potential for exploratory 
investigation of their samples. 
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7. 
STATISTICS 
A Statistical Analysis Plan (SAP) will be finalized before database lock.  The plan will detail the 
implementation of the statistical analyses in accordance with the principle features stated in the 
protocol. 
7.1. 
Determination of Sample Size 
Approximately 30 patients are planned to be randomized 2:1 (cemdisiran:placebo) in this study.  
This is based on the assumption that, in the placebo arm, the estimated geometric mean ratio of 
proteinuria at Week 32 to baseline is 0.88 (log standard deviation [SD] 0.597), corresponding to 
a 12% reduction.  A sample size of 27 with 2:1 randomization (cemdisiran:placebo) will provide 
a width of 0.80 for the 90% confidence interval (CI) for treatment effect size estimate 
(cemdisiran – placebo) in log scale.  This corresponds to a 90% CI of (15%, 62%) for the 
treatment difference in the percentage scale if the true Week 32 reduction is 50% for the 
cemdisiran arm.  To account for potential dropouts, approximately 30 patients are planned to be 
randomized stratified by baseline urine protein levels (≥1 g/24h and <2 g/24h versus ≥2 g/24h). 
7.2. 
Statistical Methodology 
The statistical and analytical plans presented below are brief summaries of planned analyses.  
More complete plans will be detailed in the statistical analysis plan (SAP).  Changes to the 
methods described in the final SAP will be described and justified as needed in the clinical study 
report.  For information on study endpoints, see Section 2. 
7.2.1. 
Populations to be Analyzed 
The following populations will be analyzed: 
• Modified Intent-to-treat (mITT): All patients who receive any amount of study drug 
and have at least one post baseline assessment in proteinuria. Patients will be grouped 
by assigned treatments (ie, as randomized). 
• Safety Analysis Set: All patients who received any amount of study drug. Patients 
who received any amount of cemdisiran will be included in the cemdisiran arm. 
Patients in the Safety Analysis Set will be grouped by treatment received. 
• PK Analysis Set: All patients who receive any amount of study drug and have at least 
one postdose blood or urine sample for PK concentration. 
• PD Analysis Set: All patients who receive any amount of study drug and who have at 
least one postdose blood sample for the determination of plasma C5 level. 
The primary population used to evaluate efficacy will be the mITT Population.  Sensitivity 
analyses for efficacy will be performed using the Per Protocol Analysis Set.  Safety will be 
analyzed using the Safety Analysis Set.  The PK and PD Analysis Sets will be used to conduct 
PK and PD analyses, respectively.  
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E x a mi n ati o n of S u b gr o u ps  
S u b gr o u p a n al ys es ma y be c o n d ucte d f or selecte d e n d p oi nts.  Detaile d met h o d ol o g y will be 
pr o vi de d i n t he S A P.  
7. 2. 3.  
H a n dli n g of Missi n g D at a  
Ha n dli n g of missi n g data will be descri be d i n t he S A P.  
7. 2. 4.  
B aseli ne E v al u ati o ns  
De m o gra p hics a n d ot her baseli ne c haracteristics, i ncl u di n g diseas e -s pecific i nf or mati o n, will be 
s u m marize d descripti vel y b y treat me nt ar m a n d o verall f or t he mI T T a n d Safet y A nal ysis Set.  
Baseli ne v al ue f or pr otei n uria will be calc ul ate d as t he a vera ge of t w o v ali d 2 4 -h o ur uri ne 
pr otei n le vels bef ore ra n d o mizati o n.  
7. 2. 5.  
Effic ac y A n al yses  
7. 2. 5. 1.  
Pri m ar y E n d p oi nt  
T he pri mar y e n d p o i nt of t he st u d y is t he perce nta ge re d ucti o n fr o m baseli ne i n 2 4-h o ur 
pr otei n uria at W ee k  3 2. T he 2 4 -h o ur uri n e pr otei n will be l o g tra nsf or me d f or a nal yses. T he 
pri mar y a nal ysis will be perf or me d o n t h e c ha n ge fr o m baseli ne i n l o g tra nsf or me d uri ne pr otei n 
usi n g a li near m o del wit h l o g tra nsf or me d bas eli ne uri ne pr otei n as c o v ariat e a n d treat me nt a n d 
ra n d o mizati o n stratificati o n fact or as fi x e d effect. T he least s q uare mea n differe nce a n d its 9 0 % 
c o nfi de nce i nter val will be esti mate d a n d t he n bac k tra nsf or m e d t o ori gi n al scale.   
A se nsiti vit y a nal ysis usi n g all uri ne pr otei n assess me nts i ncl u di n g a si n gle 2 4 -h o ur assess me nt 
will be c o n d ucte d usi n g mi x e d -effects m o del re p eate d meas ures ( M M R M) met h o d.  
7. 2. 5. 2.  
Sec o n d ar y Effic ac y E n d p oi nts   
T he sec o n d ar y efficac y e n d p oi nts i ncl u de perce nt of patie nts wit h partial cli nical re missi o n ( U P 
< 1. 0  g/ 2 4 -h o urs), perce nt of patie nts wit h > 5 0 % re d ucti o n i n 2 4 -h o ur pr otei n uria, c ha n ge fr o m 
baseli ne i n U P C R as meas ure d i n 2 4 -h o ur uri n e at Wee k 3 2, c ha n ge fr o m b aseli ne i n uri ne 
pr ot ei n/creati ni ne rati o ( U P C R) as meas ure d i n a s p ot uri ne at Wee k 3 2 a n d c ha n ge fr o m 
baseli ne i n he mat uria at W ee k 3 2.  
T he perce nta ge of patie nts wit h partial cli nical re missi o n or wit h > 5 0 % re d u cti o n i n 2 4 -h o ur 
pr otei n uria f or eac h treat me nt ar m a n d t he dif fere nce bet w ee n treat me nt ar ms will be prese nte d 
t o get her wit h a n a p pr o xi mate 9 0 % c o nfi d e nce i nt er val bas e d o n Wils o n sc ore met h o d.  
C ha n ge fr o m bas eli ne i n uri ne pr otei n / creati ni ne rati o ( U P C R) will be a nal yz e d si milarl y t o t he 
a nal ysis of t he pri mar y v aria ble as a p pr o pri ate. U P C R will be l o g tra nsf or me d first bef ore 
a nal ysis.  
7. 2. 5. 3.  
E x pl or at or y E n d p oi nts   
C ha n ge fr o m bas eli ne i n e x pl orat or y efficac y varia bles will be s u m marize d. Perce nt of p atie nts 
i n f ull cli nical re missi o n a n d i nci de nce of A D A will be ta b ulate d b y tr eat m e nts. I nfere ntial 
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statistics f or e x pl orat or y effic ac y varia bles ma y b e prese nt e d as nee de d. Details will be descri be d 
i n t he S A P. 
T he sl o pe of e G F R f or t h e first 3 2 wee ks will be esti mate d f or eac h s u bject wit h t he li near 
re gressi o n met h o d usi n g all assess me nt data d uri n g t he peri o d.  
Descri pti ve statistics i ncl u di n g t he n u m ber of pati e nts, mea n, me dia n, sta n dar d de viati o n ( S D), 
i nter q uartile ra n ge ( Q 1, Q 3), mi ni m u m, a n d ma xi m u m val ues will be prese nte d f or c o nti n u o us 
varia bles. Fre q u e ncies a n d perce nt a ges will be prese nte d f or cate g ori cal a n d or di nal varia bles.  
7. 2. 6.  
P h ar m a c o d y n a mi c A n al ysis  
Assess me nt of t he P D effect of t he tr eat me nt will be perf or me d des cri pti vel y, i ncl u di n g pl otti n g 
gra p hicall y le vels of s er u m C 5 pr otei n a n d C A P/ C C P o ver ti me a n d relati ve t o baseli ne le vels. 
I nfere ntial statistics ma y be ge nerate d as d ee me d necessar y. 
7. 2. 7.  
P h ar m a c o ki netic A n al ysis  
P har mac o ki netic a n al yses will be c o n d ucte d usi n g n o nc o m part me ntal met h o ds. P har mac o ki netic 
para meters i ncl u de, b ut will n ot be li mite d t o:  A U C, C ma x , Tma x , t½, C L/ F, V/ F, c u m ulati ve 
a m o u nt e x crete d u nc ha n ge d i n uri n e ( Ae), a n d p erce nt of d ose e x crete d (fe) i n t he uri ne of 
ce m disira n ( 2 5 -m er) a n d 2 3 -mer.  
Ot her para meters m a y be calc ulate d, if d ee me d necessar y. S u m mar y statistics a n d fi g ures will be 
prese nte d. I nfere ntial statistics ma y be ge nerate d w he n dee m e d necessar y.  
7. 2. 8.  
S afet y A n al yses  
T he pri mar y para meter is t he fre q u e nc y of treat me nt -e mer ge nt A Es ( hereaft er referre d t o si m pl y 
as A Es). Safet y p ara m eters als o i ncl u de vital si g ns, E C Gs, cli nical la b orat or y ass ess me nts, a n d 
p h ysical e x a ms.  T he e xte nt of e x p os ure will be s u m marize d b y d ose le vel a n d o verall.  
A d verse e ve nts will be cl assifie d acc or di n g t o t he Me dical Dicti o nar y f or R e g ul at or y Acti vities 
( Me d D R A) S yste m Or ga n Class a n d Preferre d T er m. Pri or a n d c o nc o mita nt me dicati o ns will be 
classifie d acc or di n g t o t h e W orl d Healt h Or ga nizati o n ( W H O) dr u g di cti o nar y. All S A Es 
occ urri n g b ef ore t he first d ose of st u d y dr u g a n d A Es relate d t o st u d y pr oce d ures will be liste d. 
T he n u m ber a n d p erc e nta ge of patie nts e x perie nci n g A Es after t h e first d os e of t he st u d y dr u g or 
e ve nts t hat w orse n e d i n se verit y aft er d osi n g will be s u m marize d. A Es will be prese nt e d b y 
ma xi m u m se verit y a n d relati o ns hi p t o st u d y me dicati o n. S A Es a n d A Es lea di n g t o 
disc o nti n uati o n of treat me nt will als o be ta b ulate d.  
B y -s u bject listi n gs will be pr o vi de d f or deat hs, S A Es, a n d A Es lea di n g t o st u d y disc o nti n uati o n.  
Fre q u e nc y of a d verse e v e nts of cli nical i nterest will als o be s u m marize d a n d b y -s u bject listi n gs 
will be pr o vi de d.  
Descri pti ve statistics will be pr o vi de d f or cli nical l a b orat or y d ata, 1 2 -lea d E C G i nter val data a n d 
vital si g ns data, prese nte d as b ot h act ual val ues a n d c ha n ges fr o m baseli ne o ver ti me. La b orat or y 
s hift ta bles fr o m baseli ne t o w orst val ues will be prese nte d. Bas eli ne will be defi ne d as t he last 
o bser vati o n o n or pri or t o St u d y Da y 1.  
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Abnormal physical examination findings and 12-lead ECG data will be presented in a by-patient 
data listing. Details of any abnormalities will be included in patient listings. 
Other safety summaries will be presented as appropriate. Further details will be specified in the 
SAP. 
All safety analyses will be conducted using the Safety Analysis Set. 
7.2.9. 
Immunogenicity Analyses 
Antidrug antibody, CIC and anti-Gd-IgA1 antibody results will be summarized descriptively.   
7.2.10. 
Biomarker Analyses 
Urine and serum complement activation products, inflammation and renal injury markers will be 
summarized descriptively.  
7.2.11. 
Interim Analysis 
No formal interim analysis is planned. 
7.2.12. 
Optional Additional Research 
Optional additional research may be conducted in the future on the biological samples and/or 
data collected during the study in accordance with the strict terms of the ICF (see Section 4.3.2). 
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8. 
STUDY ADMINISTRATION 
8.1. 
Ethical and Regulatory Considerations 
This study will be conducted in accordance with the protocol, all applicable regulatory 
requirements, and the current guidelines of Good Clinical Practice (GCP).  Compliance with 
GCP provides public assurance that the rights, safety, and well-being of study patients are 
protected consistent with the principles that have their origin in the Declaration of Helsinki. 
8.1.1. 
Informed Consent 
The Investigator will ensure that the patient/legal guardian is given full and adequate oral and 
written information about the nature, purpose, possible risk and benefit of the study.  
Patients/legal guardians must also be notified that they are free to discontinue from the study at 
any time.  The patient/legal guardian should be given the opportunity to ask questions and 
allowed time to consider the information provided.   
The patient’s/legal guardian’s signed and dated informed consent must be obtained before 
conducting any study tests or procedures that are not part of routine care.   
The Investigator must maintain the original, signed ICF.  A copy of the signed ICF must be 
given to the patient/legal guardian. 
8.1.2. 
Ethical Review 
The study protocol, including the ICF, must be approved or given a favorable opinion in writing 
by an IRB or IEC, as appropriate.  The Investigator must submit written approval before he or 
she can enroll any patient into the study. 
The Investigator is responsible for informing the IRB or IEC of any amendment to the protocol 
in accordance with local requirements.  In addition, the IRB or IEC must approve all patient 
materials for the study.  The protocol must be reapproved by the IRB or IEC upon receipt of 
amendments and annually, as local regulations require. 
Initial IRB approval of the protocol, and all materials approved by the IRB for this study 
including the patient consent form and recruitment materials must be maintained by the 
Investigator and made available for inspection. 
The Investigator will submit reports of SAEs as outlined in Section 6.7.6.  In addition, the 
Investigator agrees to submit progress reports to the IRB or IEC per their local reporting 
requirements, or at least annually and at the conclusion of the study.  The reports will be made 
available to the Sponsor or designee. 
Any communications from regulatory agencies, IRBs, or IECs in regard to inspections, other 
studies that impact this protocol or the qualifications of study personnel should be promptly 
reported to the Sponsor or its designee. 
The Investigator is also responsible for providing the IRB with reports of any reportable serious 
adverse drug reactions from any other study conducted with the study drug.  The Sponsor or 
designee will provide this information to the Investigator. 
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Major changes in this research activity, except those to remove an apparent immediate hazard to 
the patient, must be reviewed and approved by the Sponsor and the IRB or IEC that approved the 
study.  Amendments to the protocol must be submitted in writing to the Investigator’s IRB or 
IEC and the Regulatory Authority for approval before patients are randomized under the 
amended protocol, and patients must be re-consented to the most current version of the ICF. 
8.1.3. 
Serious Breach of Protocol 
Investigators must notify the Medical Monitor within 24 hours of becoming aware of a serious 
breach of the protocol.  A serious breach is a breach that is likely to affect to a significant degree 
the safety and rights of a study participant or the reliability and robustness of the data generated 
in the clinical trial. 
8.1.4. 
Study Documentation, Confidentiality, and Records Retention 
All documentation relating to the study should be retained for 2 years after the last approval in an 
ICH territory or as locally required, whichever is longer.  If it becomes necessary for the 
Sponsor, the Sponsor’s designee, applicable IRB/IEC, or applicable regulatory authorities to 
review or audit any documentation relating to the study, the Investigator must permit direct 
access to all source documents/data.  Records will not be destroyed without informing the 
Sponsor in writing and giving the Sponsor the opportunity to store the records for a longer period 
of time at the Sponsor’s expense.   
The Investigator must ensure that the patients’ confidentiality will be maintained.  On the eCRFs 
or other documents submitted to the Sponsor or designees, patients should not be identified by 
their names, but by the assigned patient number or code.  If patient names are included on copies 
of documents submitted to the Sponsor or designees, the names will be obliterated, and the 
assigned patient number added to the document.  Documents not for submission to the Sponsor 
(eg, signed ICFs) should be maintained by the Investigator in strict confidence. 
The Investigator must treat all information related to the study and the compiled data as 
confidential, whose use is for the purpose of conducting the study. The Sponsor must approve 
any transfer of information not directly involved in the study. 
To comply with local and/or regional regulations, this clinical study may be registered, and study 
results may be posted on public registries, such as ClinicalTrials.gov. 
8.1.5. 
End of Study 
The end of study is defined as the last patient last visit. 
8.1.6. 
Termination of the Clinical Study or Site Closure 
The Sponsor reserves the right to terminate the study for clinical or administrative reasons at any 
time.  If the site does not recruit at a reasonable rate, or if there is insufficient adherence to the 
protocol requirements, the study may be closed 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, IRB/IEC and 
Regulatory Authorities will be promptly informed of the termination and the reason for the 
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decision.  The Investigator should promptly inform the patients and assure appropriate therapy 
and follow-up. 
8.2. 
Data Quality Control and Quality Assurance 
8.2.1. 
Data Handling 
Study data must be recorded on CRFs (paper and/or electronic) provided by the Sponsor or 
designee on behalf of the Sponsor.  Case report forms must be completed only by persons 
designated by the Investigator.  If eCRFs are used, study data must be entered by trained site 
personnel with access to a valid and secure eCRF system.  All data entered into the eCRF must 
also be available in the source documents.  Corrections on paper CRFs must be made so as to not 
obliterate the original data and must be initialed and dated by the person who made the 
correction. 
8.2.2. 
Study Monitoring 
The Monitor, as a representative of the Sponsor, has an obligation to closely follow the study 
conduct at the site.  The Monitor will visit the Investigator and clinical study center periodically 
and will maintain frequent telephone and written contact.  The Monitor will maintain current 
personal knowledge of the study through observation, review of study records and source 
documentation, and discussion of the conduct of the study with the Investigator and staff. 
The Monitor will review source documents, systems and CRFs to ensure overall quality and 
completeness of the data and to confirm study procedures are complied with the requirements in 
the study protocol accurately. The Sponsor, or its designee, will be allowed to conduct site visits 
to the investigation facilities for the purpose of monitoring any aspect of the study.  The 
Investigator agrees to allow the Monitor to inspect the drug storage area, study drug stocks, drug 
accountability records, patient charts and study source documents, site standard operating 
procedures and training records, and other records relative to study conduct. 
8.2.3. 
Audits and Inspections 
Periodically, the Sponsor or its authorized representatives audit clinical investigative sites as an 
independent review of core trial processes and documents to determine whether these activities 
were conducted, and data were recorded, analyzed, and accurately reported according to the 
protocol, GCP guidelines of the ICH, and any applicable regulatory requirements.  A regulatory 
authority, an IRB/IEC may visit the site to perform audits or inspections, including source data 
verification.  The Investigator should contact the Sponsor and designee, immediately if contacted 
by a regulatory agency or an IRB/IEC about an inspection. 
8.3. 
Publication Policy 
It is intended that after completion of the study, the data are to be submitted for publication in a 
scientific journal and/or for reporting at a scientific meeting.  A separate publication by 
Institution or Investigator may not be submitted for publication until after this primary 
manuscript is published or following the period of 18 months after completion of the study at all 
centers.  A copy of any proposed publication (eg, manuscript, abstracts, oral/slide presentations, 
book chapters) based on this study, must be provided and confirmed received at the Sponsor at 
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least 30 days before its submission.  The Clinical Trial Agreement among the institution, 
Investigator, and Alnylam will detail the procedures for Alnylam’s review of publications. 
Authorship of any publications resulting from this study will be determined on the basis of the 
Uniform Requirement for Manuscripts Submitted to Biomedical Journals (International 
Committee of Medical Journal Editors). 
 
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9. 
LIST OF REFERENCES 
Ashwell G,Morell AG. The role of surface carbohydrates in the hepatic recognition and transport 
of circulating glycoproteins. Advances in Enzymology and Related Areas of Molecular Biology, 
Volume 41. 2006:99-128. 
Cattran DC, Coppo R, Cook HT, Feehally J, Roberts IS, Troyanov S, et al. The Oxford 
classification of IgA nephropathy: rationale, clinicopathological correlations, and classification. 
Kidney international. 2009;76(5):534-45. 
Coppo R,D'amico G. Factors predicting progression of IgA nephropathies. Journal of 
nephrology. 2005;18(5):503-12. 
Crew PE, Abara WE, McCulley L, Waldron PE, Kirkcaldy RD, Weston EJ, et al. Disseminated 
gonococcal infections in patients receiving eculizumab: a case series. Clinical Infectious 
Diseases. 2018. 
Crew PE, McNamara L, Waldron PE, McCulley L, Jones SC,Bersoff-Matcha SJ. Unusual 
Neisseria species as a cause of infection in patients taking eculizumab. Journal of Infection. 
2018. 
Cugno M, Gualtierotti R, Possenti I, Testa S, Tel F, Griffini S, et al. Complement functional tests 
for monitoring eculizumab treatment in patients with atypical hemolytic uremic syndrome. 
Journal of Thrombosis and Haemostasis. 2014;12(9):1440-8. 
Elbashir SM, Lendeckel W,Tuschl T. RNA interference is mediated by 21-and 22-nucleotide 
RNAs. Genes & development. 2001;15(2):188-200. 
Imai E, Yamagata K, Iseki K, Iso H, Horio M, Mkino H, et al. Kidney disease screening program 
in Japan: history, outcome, and perspectives. Clinical journal of the American Society of 
Nephrology. 2007;2(6):1360-6. 
Ix JH, Wassel CL, Stevens LA, Beck GJ, Froissart M, Navis G, et al. Equations to estimate 
creatinine excretion rate: the CKD epidemiology collaboration. Clinical journal of the American 
Society of Nephrology. 2011;6(1):184-91. 
Kiryluk K, Li Y, Scolari F, Sanna-Cherchi S, Choi M, Verbitsky M, et al. Discovery of new risk 
loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens. 
Nature genetics. 2014;46(11):1187. 
Knoop T, Vikse BE, Mwakimonga A, Leh S,Bjørneklett R. Long-term outcome in 145 patients 
with assumed benign immunoglobulin A nephropathy. Nephrology Dialysis Transplantation. 
2017;32(11):1841-50. 
Knoppova B, Reily C, Maillard N, Rizk DV, Moldoveanu Z, Mestecky J, et al. The origin and 
activities of IgA1-containing immune complexes in IgA nephropathy. Frontiers in immunology. 
2016;7:117. 
Lafayette RA, Canetta PA, Rovin BH, Appel GB, Novak J, Nath KA, et al. A randomized, 
controlled trial of rituximab in IgA nephropathy with proteinuria and renal dysfunction. Journal 
of the American Society of Nephrology. 2016:ASN. 2016060640. 
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Lai KN, Tang SC, Schena FP, Novak J, Tomino Y, Fogo AB, et al. IgA nephropathy. Nature 
Reviews Disease Primers. 2016;2:16001. 
Lv J, Zhang H, Wong MG, Jardine MJ, Hladunewich M, Jha V, et al. Effect of Oral 
Methylprednisolone on Clinical Outcomes in Patients With IgA Nephropathy. Jama. 
2017;318(5):432. 
Maillard N, Wyatt RJ, Julian BA, Kiryluk K, Gharavi A, Fremeaux-Bacchi V, et al. Current 
understanding of the role of complement in IgA nephropathy. Journal of the American Society of 
Nephrology. 2015;26(7):1503-12. 
McQuillen DP,Ram S. No good deed goes unpunished: eculizumab and invasive neisserial 
infections. Clinical Infectious Diseases. 2018. 
Medjeral-Thomas NR, Troldborg A, Constantinou N, Lomax-Browne HJ, Hansen AG, 
Willicombe M, et al. Progressive IgA Nephropathy Is Associated With Low Circulating 
Mannan-Binding Lectin–Associated Serine Protease-3 (MASP-3) and Increased Glomerular 
Factor H–Related Protein-5 (FHR5) Deposition. Kidney international reports. 2018;3(2):426-38. 
Mestecky J, Novak J, Moldoveanu Z,Raska M. IgA nephropathy enigma. Clinical Immunology. 
2016;172:72-7. 
Morgan BP. Complement membrane attack on nucleated cells: resistance, recovery and non-
lethal effects. Biochemical Journal. 1989;264(1):1. 
Novak J, Barratt J, Julian BA,Renfrow MB, editors. Aberrant Glycosylation of the IgA1 
Molecule in IgA Nephropathy. Seminars in nephrology; 2018: Elsevier. 
Ram S, Lewis LA,Rice PA. Infections of people with complement deficiencies and patients who 
have undergone splenectomy. Clinical microbiology reviews. 2010;23(4):740-80. 
Rauen T, Eitner F, Fitzner C, Sommerer C, Zeier M, Otte B, et al. Intensive supportive care plus 
immunosuppression in IgA nephropathy. New England Journal of Medicine. 2015;373(23):2225-
36. 
Reich HN, Troyanov S, Scholey JW,Cattran DC. Remission of proteinuria improves prognosis in 
IgA nephropathy. Journal of the American Society of Nephrology. 2007;18(12):3177-83. 
Roberts IS, Cook HT, Troyanov S, Alpers CE, Amore A, Barratt J, et al. The Oxford 
classification of IgA nephropathy: pathology definitions, correlations, and reproducibility. 
Kidney international. 2009;76(5):546-56. 
Ross SC,Densen P. Complement deficiency states and infection: epidemiology, pathogenesis and 
consequences of neisserial and other infections in an immune deficiency. Medicine. 
1984;63(5):243-73. 
Rosse WF. Variations in the red cells in paroxysmal nocturnal haemoglobinuria. British journal 
of haematology. 1973;24(3):327-42. 
Sarcina C, Tinelli C, Ferrario F, Pani A, De Silvestri A, Scaini P, et al. Changes in proteinuria 
and side effects of corticosteroids alone or in combination with azathioprine at different stages of 
IgA nephropathy. Clinical journal of the American Society of Nephrology. 2016;11(6):973-81. 
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Soutschek J, Akinc A, Bramlage B, Charisse K, Constien R, Donoghue M, et al. Therapeutic 
silencing of an endogenous gene by systemic administration of modified siRNAs. Nature. 
2004;432(7014):173-8. 
Suzuki H, Fan R, Zhang Z, Brown R, Hall S, Julian BA, et al. Aberrantly glycosylated IgA1 in 
IgA nephropathy patients is recognized by IgG antibodies with restricted heterogeneity. The 
Journal of clinical investigation. 2009;119(6):1668-77. 
Woo K-T, Chan C-M, Chin YM, Choong H-L, Tan H-K, Foo M, et al. Global evolutionary trend 
of the prevalence of primary glomerulonephritis over the past three decades. Nephron Clinical 
practice. 2010;116(4):c337-c46. 
Wyatt RJ, Julian BA, Baehler RW, Stafford CC, McMorrow RG, Ferguson T, et al. 
Epidemiology of IgA nephropathy in central and eastern Kentucky for the period 1975 through 
1994. Central Kentucky Region of the Southeastern United States IgA Nephropathy 
DATABANK Project. Journal of the American Society of Nephrology. 1998;9(5):853-8. 
Zimmermann TS, Lee AC, Akinc A, Bramlage B, Bumcrot D, Fedoruk MN, et al. RNAi-
mediated gene silencing in non-human primates. Nature. 2006;441(7089):111-4. 
 
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10. 
APPENDICES 
None. 
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ALN-CC5-005 PROTOCOL AMENDMENT 2 
SUMMARY OF CHANGES DATED 20 SEPTEMBER 2019 
Protocol Title 
A Phase 2, Randomized, Double-blind, Placebo controlled Study of Cemdisiran in Adult Patients 
with IgA Nephropathy 
Rationale for Protocol Amendment 
The primary purpose for this protocol amendment is to incorporate changes previously made to a 
regional protocol amendment (Amendment 1.1: Canada) into the global protocol.  These changes 
ensure all relevant safety assessments (eg, safety laboratory, pregnancy tests) in the open-label 
extension (OLE) period mirror safety assessments made at initial treatment with study drug after 
randomization, because patients initially randomized to placebo will be treated with cemdisiran 
for the first time in the OLE period.  The timing of this global protocol amendment ensures these 
changes are adopted prior to any patients crossing over to the OLE period.  Additional changes 
include updates to specific eligibility criteria and certain safety assessment timeframes.   
An overview of the changes made to the protocol include: 
• Addition of timepoints for clinical laboratory and pregnancy tests such that patients are 
monitored every 4 weeks, from Week 36 until Week 64, in the OLE period 
• Clarifying the blood sample collection for circulating immune complex (CIC) analysis 
and anti-Gd IgA1 antibody assessment at specified timepoints from Screening through 
Week 36 
• Addition of a ±3 day window to Day 1 to make it easier to observe the mandatory 14-day 
minimum interval between completion of the meningococcal vaccinations series at 
Week-2 and randomization, and to allow study sites some flexibility around the 
scheduling of the Day 1 visit 
• Removal of the optional blood sample B-cell function analysis during the Screening visit 
• Removal of part of the inclusion criterion to screen for hematuria at the end of the run-in 
period, prior to randomization 
• Removal of the dose-specific part of the exclusion criterion to screen for treatment with 
systemic steroids in the 12 months prior to randomization 
• Clarifying the collection of vital signs on Day 1 at 4 hours (±15 minutes) postdose along 
with the addition of tympanic temperature measurement 
• Clarifying routine physical examination on Day 1 at 4 hours (±30 minutes) postdose 
• Correction to table number references for the monitoring of liver function test (LFT) and 
coagulation 
• Removal of human immunodeficiency virus (HIV) testing from patients who experience 
elevated transaminases 
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• Clarifying that all adverse events, both serious and non-serious, are to be collected from 
the time of signing the ICF through the end of the study.  Non-serious events not related 
to study procedures will be included in medical history 
A detailed summary of changes is provided in Table 1.  Corrections to typographical errors, 
punctuation, grammar, abbreviations, and formatting (including administrative changes between 
the protocol amendments 1 and 2) are not detailed.   
 
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Table 1: 
Protocol Amendment 2 Detailed Summary of Changes 
The primary sections of the protocol affected by the changes in Protocol Amendment 2 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:  Updated the Schedule of Assessments (Table 2) to include safety laboratory tests every 4 weeks, from Week 36 until Week 64 in the OLE 
period 
The primary change occurs in Table 2 (Schedule of Assessments – OLE period and safety follow-up) 
Added text: 
“X” has been added against clinical laboratory assessments and pregnancy tests planned to be conducted during the OLE 
period every 4 weeks from Week 36 until Week 64.  Previously, clinical laboratory assessments and pregnancy tests were 
included every 8 weeks after the first 4-week assessment starting at Week 36. 
Purpose:  Updated the Schedule of Assessments (Table 1) to clarify the blood sample collection for CIC analysis and serum sample collection for 
exploratory anti-Gd IgA1 antibody assessment at specified timepoints from Screening through Week 36 
The primary change occurs in Table 1 - Schedule of Assessments – Run-in and Treatment Periods (Screening through Week 36) including Safety 
Follow up 
Added text: 
Blood Samples for CIC Analysis and Exploratory anti-Gd IgA1 Antibody Assessment.   
Sections also containing this change: 
• 
Section 6.7.5.1 (Immunogenicity) 
o Exploratory analysis of anti-Gd-IgA1 antibody levels and IgA containing immune complexes may will be conducted; blood 
serum samples for these analyses will be drawn when CIC samples are collected to enable these assays. 
• 
Section 7.2.9 (Immunogenicity Analyses) 
o Antidrug antibody, CIC and CIC anti-Gd-IgA1 antibody results will be summarized descriptively. 
Purpose:  Updated the Schedule of Assessments (Table 1) to include a ±3 day window to Day 1 
The primary change occurs in Table 1 (Schedule of Assessments – Run-in and Treatment Periods (Screening through Week 36) including Safety 
Follow up) 
Added text: 
“±3” has been added to Day 1 to make it easier to observe the mandatory 14-day minimum interval between completion 
of the meningococcal vaccinations series at Week-2 and randomization, and to allow study sites some flexibility around 
the scheduling of the Day 1 visit 
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Purpose:  Updated the Schedule of Assessments (Table 1) to remove the optional blood sample B-cell function analysis during the Screening visit 
The primary change occurs in Table 1 - Schedule of Assessments – Run-in and Treatment Periods (Screening through Week 36) including Safety 
Follow up 
Deleted text: 
Optional Blood Sample for B cell function Analysis 
“X” was removed from the Screening visit. 
Section also containing this change: 
• 
Section 6.7.5.1 (Immunogenicity) 
o For US patients only, an optional blood sample may be collected at screening to evaluate any potential for B cell stimulation by 
cemdisiran, at the Sponsor’s discretion. 
Purpose:  Updated inclusion criterion to remove screening for hematuria at the end of the run-in period 
The primary changes occur in Section 4, Selection and Withdrawal of Patients 
• 
Section 4.1 (Inclusion Criteria) 
o Criterion 5:  Hematuria as defined by ≥10 RBCs per high powered field (RBC/hpf) at sScreening and either ≥10 RBC/hpf or a 
positive urinary dipstick (1+ and above) at the end of the run in period, prior to randomization (local result accepted for 
assessment of eligibility at the end of the run in period) 
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Sections also containing these changes 
• 
Synopsis (Study Design) 
o Patients whose proteinuria level remains >≥1 g/24-hours within 2 weeks of the end of the run-in period, who continue to have 
hematuria, and who meet blood pressure and estimated glomerular filtration rate (eGFR) criteria will be eligible to enroll in the 
36-week treatment period. 
• 
Synopsis (Diagnosis and Main Eligibility Criteria) 
o Eligible patients must have urine protein levels of ≥1g/24-hour at sScreening and mean urine protein ≥ 1g/24 hour from two valid 
24-hour urine collections at the end of the run-in period, prior to randomization. In addition, eligible patients must have hematuria 
defined by ≥ 10 red blood cells per high powered field (RBC/hpf) at sScreening and either ≥10 RBC/hpf or a positive urinary 
dipstick (1+ and above) at the end of the run in period. 
• 
Section 1.3 (Study Design Rationale) 
The standard of care is expected to remain unchanged during this run-in period. Only patients whose  
o proteinuria level remains above ≥1 g/24-hours within 2 weeks before the end of the run-in period,  
o continue to have hematuria, and meet blood pressure and eGFR criteria  
• 
Section 3.1 (Summary of Study Design) 
o Patients whose proteinuria level remains >≥1 g/24-hours within 2 weeks of the end of the run-in period, who continue to have 
hematuria, and who meet blood pressure and eGFR criteria will be eligible to enroll in the 36-week treatment period. 
• 
Section 6.2 (Run-in Period) 
o Clinical laboratory tests will be performed centrally; however, hematuria and eGFR will also be assessed locally at the end of the 
run-in period (Week-2) to facilitate assessment of patient eligibility and administer meningococcal vaccination on the same day. 
• 
Section 6.4.2 (Hematuria) 
o To allow evaluation of eligibility on the same day at the end of the run in period, 2 weeks prior to randomization, the single void 
can be split in two containers, one evaluated by local lab and another by central lab. The local hematuria evaluation by microscopy 
or urinary dipstick will be utilized to determine eligibility for the study at the end of the run in period. 
• 
Section 6.7.5 (Clinical Laboratory Assessments) 
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o The following clinical laboratory tests will be evaluated by a central laboratory. However, to assess patient eligibility at the end of 
the run-in period, hematuria and eGFR will also be assessed locally. 
Purpose:  Updated exclusion criterion pertaining to the treatment with systemic steroids to remove the ambiguity around the permitted duration of 
doses <20 mg/day of prednisone-equivalent for more than 7 days in the 12 months prior to randomization 
The primary changes occur in Section 4, Selection and Withdrawal of Patients 
• 
Section 4.2 (Exclusion Criteria) 
o Criterion 10:  Treatment with systemic steroids at dosages exceeding 20 mg prednisone equivalent for more than 7 days or other 
immunosuppressant agents in the 12 months prior to randomization 
Section also containing this change 
• 
Synopsis (Diagnosis and Main Eligibility Criteria) 
o Patients will be excluded from the study if eGFR <30 mL/min/1.73 m2 2 weeks prior to randomization; treated with systemic 
steroids at dosages exceeding 20 mg prednisone equivalent for more than 7 days or other immunosuppressant agents in the 12 
months prior to randomization 
Purpose:  Updated retesting wording to clarify that laboratory tests may be repeated if laboratory abnormalities at Screening or the run-in period 
are likely to be transient.  In addition, 2 retests will be permitted for hematuria during Screening, if the first test is negative 
The primary changes occur in Section 6.1, Screening Assessments 
• 
Section 6.1.2 (Retesting) 
o If in the Investigator’s judgement, the screening laboratory abnormalities at Screening or in the run-in period are likely to be 
transient, then laboratory tests may be repeated.  The Investigator’s rationale is to be documented.  Laboratory values can be 
retested once during Screening or the run-in period as long as the patient can be evaluated for eligibility and randomized within 
the allowed Screening or run-in period.  Two retests will be permitted for hematuria during Screening, if the first test is 
negative. 
Purpose:  Updated physical examination wording to add more clarity to the routine physical examination assessment row in the Schedule of 
Assessments tables 
The primary changes occur in Section 6.7, Safety Assessments 
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• 
Section 6.7.3 (Physical Examination) 
o Routine Full physical examinations will be conducted according to the Schedule of Assessments (Table 1 and Table 2); if a 
physical examination is scheduled for a dosing visit, it should be conducted prior to dosing.   
At Screening and Day 1 predose, a full physical examination will be performed.  At all other time points, including Day 1 
at 4 hours (±30 minutes) postdose, a directed physical examination will be performed.  On Day 1, routine physical 
examination will be performed at predose and 4 hours (±30 minutes) postdose.  On all other dosing days, the routine physical 
examination will be performed predose. 
Purpose:  Updated safety assessments to clarify the collection of vital signs and the conduct of routine physical examination on Day 1 at 4 hours 
postdose and to include tympanic temperature measurement 
The primary change occurs in Section 6.7, Safety Assessments 
• 
Section 6.7.1 (Vital Signs) 
Added text: 
Vital signs will be measured as specified in the Schedule of Assessments (Table 1 and Table 2) and include blood 
pressure, heart rate, oral body temperature, and respiratory rate.  Vital signs will be measured in the seated or supine 
position, after the patient has rested comfortably for 10 minutes.  On Day 1, vital signs will be collected at predose and 4 
hours (±15 minutes) postdose. 
Blood pressure should be taken using the same arm throughout the study.  Body temperature in degrees Celsius will be 
obtained via oral or tympanic method.   
• 
Section 6.7.3 (Physical Examination) 
Added text: 
At Screening and Day 1 predose, a full physical examination will be performed.  At all other time points, including 
Day 1 at 4 hours (±30 minutes) postdose, a directed physical examination will be performed. On Day 1, routine 
physical examination will be performed at predose and 4 hours postdose. 
Purpose:  Corrected table number references for the monitoring of LFT and coagulation 
The primary changes occur in Table 4 - Monitoring and Dosing Rules for Asymptomatic Patients with Confirmed Isolated Elevations of ALT 
and/or AST >3× ULN, with No Alternative Cause Identified 
Transaminase level 
>3× to 5× ULN: 
Monitor at least every two weeks: LFT and coagulation per Table 5 Table 6 
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Transaminase level 
>5× to 8× ULN: 
Monitor at least weekly: LFT and coagulation per Table 5 Table 6 until ALT and/or AST is declining on 2 consecutive 
draws, then may decrease monitoring to biweekly 
Purpose:  Updated the hepatic assessments in patients who experience elevated transaminases (Table 6) to remove HIV testing 
The primary change occurs in Table 6 - Hepatic Assessments in Patients Who Experience Elevated Transaminases 
Deleted text: 
HIV 1 and 2a 
“HIV=human immunodeficiency virus” and footnote a “HIV testing will not be performed where prohibited by local 
regualtions” were removed from the footnotes of Table 6. 
Purpose:  Updated primary endpoint efficacy analyses wording to remove the presentation of the estimated ratio of percentage reduction in urine 
protein for cemdisiran to placebo and its 90% confidence interval 
The primary changes occur in Section 7.2.5, Efficacy Analyses 
• 
Section 7.2.5.1 (Primary Endpoint) 
o The primary endpoint of the study is the percentage reduction from baseline in 24-hour proteinuria at Week 32. The 24-hour urine 
protein will be log transformed for analyses. The primary analysis will be performed on the change from baseline in log 
transformed urine protein using a linear model with log transformed baseline urine protein as covariate and treatment and 
randomization stratification factor as fixed effect. The least square mean difference and its 90% confidence interval will be 
estimated and then back transformed to original scale. In the end the estimated ratio of percentage reduction in urine protein for 
cemdisiran to placebo and its 90% confidence interval will be presented.   
Purpose:  Updated adverse events wording to clarify that all adverse events, including serious and non-serious, will be collected from the time of 
signing the ICF through the end of the study 
The primary changes occur in Section 6.7.6, Adverse Events 
• 
Section 6.7.6.2 (Eliciting and Recording Adverse Events) 
o Events All AEs, including non-serious AEs, occurring after signing of the ICF and before study drug administration will be 
captured as medical history (see Section 6.1).  All AEs will be collected starting after administration of the first dose through the 
end of the safety follow-up period. Non serious AEs will be followed until the end of study. 
 
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INVESTIGATOR’S AGREEMENT 
 
I have read the ALN-CC5-005 protocol and agree to conduct the study in accordance with the 
protocol and all applicable regulations.  I agree to maintain the confidentiality of all information 
received or developed in connection with this protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 
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 
To characterize the pharmacokinetics 
(PK) of cemdisiran and relevant 
metabolites in plasma and urine in adult 
patients with IgAN 
 
To evaluate the effect of cemdisiran on 
serum and urine markers of complement 
activation, renal damage and 
inflammation 
 
To assess the incidence of antidrug 
antibodies (ADA) 
 
The slope of eGFR computed for the 
entire study period including the open 
label extension using all assessments 
during the study. 
 
Change from baseline in creatinine 
clearance at Week 32 
 
Percent of patients in full clinical 
remission (Urine Protein [UP] 
<0.3 g/24-hours) at Week 32  
 
Change from baseline in 24-hour 
albuminuria at Week 32 
 
Change from baseline in the urine 
albumin/creatinine ratio (UACR) as 
measured in 24-hour urine at Week 32 
 
Change from baseline in C5 level over the 
course of the study 
 
Change from baseline in complement 
activity (Complement Alternative 
Pathway [CAP] and Complement 
Classical Pathway [CCP]) over the course 
of the study 
 
Evaluation of area under the curve 
(AUC), maximum plasma concentration 
(Cmax), time to maximum plasma 
concentration (Tmax), terminal half-life 
(t1/2), clearance (CL/F), volume of 
distribution (V/F), cumulative amount 
excreted unchanged in urine (Ae) and 
percent of dose excreted in the urine (fe) 
of cemdisiran (25-mer) and 23-mer 
 
Evaluation of AUC, Cmax, Tmax, t1/2, 
CL/F, V/F, Ae and fe of 22-mer 
AS(N-1)3’ 
 
Change from baseline in levels of renal 
damage, complement activation and 
inflammation markers over the course of 
the study 
 
Incidence of antidrug antibodies (ADA) 
Study Design 
This is a multicenter, double-blind, placebo-controlled study comprised of three periods (Figure 1).  The 
first period of the study is an observational 14-week run-in period during which patients’ blood pressure, 
kidney function, degree of hematuria, and proteinuria will be measured.  The standard of care is expected 
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to remain unchanged during this run-in period.  Patients will not receive study drug (cemdisiran or 
placebo) during this time.  The second study period is a 36-week treatment period which will evaluate the 
efficacy and safety of subcutaneous (SC) cemdisiran compared to SC placebo in combination with 
standard of care in patients with IgAN and persistent proteinuria.  The third period of the study is a 
52-week optional open-label extension (OLE) period to further evaluate the long-term safety and clinical 
activity of cemdisiran.  During the OLE, all patients (including those initially on placebo) will be treated 
with cemdisiran in combination with standard of care. 
The study will include Screening of up to 90 days to determine eligibility of patients and to complete 
disease-related assessments.  Patients will provide written informed consent and visit the study center 
approximately 2 weeks before starting the run-in period to complete the protocol screening assessments.  
Following successful screening, the 14-week run-in period will commence, during which patients’ blood 
pressure, kidney function, degree of hematuria and proteinuria as well as treatment with standard of care 
will be documented by the Investigator.  The standard of care is expected to remain unchanged during this 
run-in period.  Patients whose proteinuria level remains >1 g/24-hours within 2 weeks of the end of the 
run-in period, who continue to have hematuria, and who meet blood pressure and estimated glomerular 
filtration rate (eGFR) criteria will be eligible to enroll in the 36-week treatment period.  Upon 
confirmation of eligibility followed by vaccination against meningococcal infections, patients will be 
randomized at a 2:1 ratio to receive 600 mg of cemdisiran or placebo every 4 weeks in combination with 
standard of care.  Approximately 30 patients are planned to be randomized in total, 20 in the cemdisiran 
arm and 10 in the placebo arm.  Patients excluded before randomization will be replaced at Screening.  
During the run-in period, patients will visit the study center 14, 8, and 2 weeks prior to randomization 
(Weeks 0, 6 and 12 of the run-in period).  Patients will then return to the study center every 4 weeks after 
the start of study drug treatment period. The primary endpoint will be assessed at the end of treatment at 
Week 32. 
At the end of treatment (Week 32), patients in the two treatment arms will enter the optional OLE period 
where they will receive cemdisiran at a dose of 600 mg every 4 weeks in combination with standard of 
care for 52 weeks.  The first study drug administration of the OLE will be administered at Week 36.  
Patients will return to the study center at Week 40 and every 8 weeks thereafter during the OLE.  Home 
visits, where locally feasible, may be arranged for cemdisiran administration in between 8-weekly study 
center visits (Weeks 44, 52, 60, 68 and 76), unless patients are required to visit the study center as judged 
necessary by the Investigator, or if home visits cannot be arranged.  An end of treatment (EOT) visit will 
occur at Week 80 (OLE EOT) and an end of study (EOS) or early termination (ET) visit will be 
completed at Week 84 (OLE EOS/ET). For patients who complete the treatment period only and who do 
not consent to continue to participate in the study in the OLE period, the EOS/ET visit will be at Week 
36. 
Patients will return to the clinical study center for safety follow-up visits approximately 13, 26, 39 and 52 
weeks after the EOS/ET visit (regardless if EOS/ET visit is at Week 36 or Week 84), unless enrolled in 
another study with cemdisiran. Home visits, where locally feasible, may be arranged during safety 
follow-up at 13 and 39 weeks after the EOS/ET visit (regardless if EOS/ET visit is at Week 36 or Week 
84). 
Regular reviews of safety and tolerability data will be performed by a Data Monitoring Committee 
(DMC) throughout the study with the primary purpose of protecting the safety of participating patients 
and the integrity of the study. 
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Number of Planned Patients 
Approximately 30 patients are planned for randomization in this study. 
Diagnosis and Main Eligibility Criteria 
This study will include adults (≥18 years and ≤ 65 years of age) with a clinical diagnosis of primary 
immunoglobulin A (IgA) Nephropathy based on historical biopsy collected within 60 months of 
Screening, treated for IgA Nephropathy with stable, optimal pharmacological therapy including 
maximum allowed or tolerated angiotensin converting enzyme (ACE) inhibitor or angiotensin II receptor 
blocker (ARB) for at least 3 months prior to the start of the run-in period. Eligible patients must have 
urine protein levels of ≥1g/24-hour at screening and mean urine protein ≥ 1g/24-hour from two valid 24-
hour urine collections at the end of the run-in period, prior to randomization. In addition, eligible patients 
must have hematuria defined by ≥ 10 red blood cells per high powered field (RBC/hpf) at screening and 
either ≥10 RBC/hpf or a positive urinary dipstick (1+ and above) at the end of the run-in period. Eligible 
patients are required to have been previously vaccinated with meningococcal group ACWY conjugate 
vaccine and meningococcal group B vaccine or be willing to receive these vaccinations as well as 
prophylactic antibiotic treatment, if required by local standard of care. In addition, patients not previously 
vaccinated against Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) must be willing 
to receive these vaccinations according to local guidelines. 
Patients will be excluded from the study if eGFR <30 mL/min/1.73 m2 2 weeks prior to randomization; 
treated with systemic steroids at dosages exceeding 20 mg prednisone-equivalent for more than 7 days or 
other immunosuppressant agents in the 12 months prior to randomization; have a diagnosis of rapidly 
progressive glomerulonephritis as measured by eGFR loss >30% over the duration of the run-in phase; 
sustained blood pressure >140/90 mmHg as defined by 2 or more readings during the run-in period 
measured in supine position after 10 minutes of rest; have received organ transplant (including 
hematologic transplant) or have secondary etiologies of IgAN (eg, inflammatory bowel disease, celiac 
disease).  
Study Drug, Dose, and Mode of Administration 
Cemdisiran is a synthetic small interfering RNA (siRNA) targeting complement component 5 (C5) 
mRNA that is covalently linked to a triantennary N-acetylgalactosamine (GalNAc) ligand.  Cemdisiran 
will be supplied as a sterile solution for SC injection that contains 200 mg/mL cemdisiran sodium 
(equivalent to 189 mg/mL of cemdisiran), formulated in water for injection (WFI) for SC administration.  
Doses of 600 mg of cemdisiran will be administered every 4 weeks during the 32-week treatment phase 
and the optional OLE period.  
Placebo (normal saline 0.9% for SC administration) will be packaged and administered identically to 
cemdisiran. 
Reference Treatment, Dose, and Mode of Administration 
Angiotensin converting enzyme inhibitors (ACE) or angiotensin II receptor blockers (ARB) per physician 
and manufacturer‘s instructions. 
Duration of Treatment and Study 
Subcutaneous doses of cemdisiran or matching placebo will be administered every 4 weeks over a period 
of 32 weeks during the treatment period and patients will receive SC doses of cemdisiran for a further 52 
weeks in the the optional OLE. The estimated total time on study, inclusive of Screening (90 days), run-in 
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period (14 weeks), treatment period (36 weeks), extension period (52 weeks) and safety follow-up 
(52 weeks), for patients is approximately 36 months or 3.0 years. 
Statistical Methods 
Approximately 30 patients are planned to be randomized 2:1 (cemdisiran:placebo) in this study based on 
the assumption that, in the placebo arm, the estimated geometric mean ratio of proteinuria at Week 32 to 
baseline is 0.88 (log standard deviation [SD] 0.597), corresponding to a 12% reduction. A sample size of 
27 with 2:1 randomization (cemdisiran:placebo) will provide a width of 0.80 for the 90% confidence 
interval (CI) for treatment effect size estimate (cemdisiran – placebo) in log scale.  This corresponds to a 
90% CI of (15%, 62%) for the treatment difference in the percentage scale if the true Week 32 reduction 
is 50% for the cemdisiran arm. To account for potential dropouts, approximately 30 patients are planned 
to be randomized stratified by baseline urine protein levels (≥ 1g/24h and <2g/24h versus >=2g/24h). 
The analysis populations include: 
 
The modified Intent-to-treat (mITT) population will include all patients who receive any 
amount of study drug and have at least one post baseline 24-hour proteinuria assessment. 
Patients will be grouped by assigned treatments (ie, as randomized).  
 
The Safety Analysis Set will include all patients who received any amount of study drug. 
Patients who received any amount of cemdisiran will be included in the cemdisiran arm. 
Patients in the Safety Analysis Set will be grouped by treatment received.  
 
PK Analysis Set: All patients who receive any amount of study drug and have at least one 
postdose blood or urine sample for PK concentration.  
 
PD Analysis Set: All patients who receive any amount of study drug and who have at least 
one postdose blood sample for the determination of plasma C5 level. 
The primary endpoint of the study is the percentage reduction from baseline in 24-hour proteinuria at 
Week 32. The primary analysis will be performed on the change from baseline in log transformed urine 
protein using a linear model with log transformed baseline urine protein as covariate and treatment and 
randomization stratification factor as fixed effect. The least square mean difference and its 90% 
confidence interval (CI) will be estimated and then back transformed to original scale. In the end, the 
estimated ratio of percentage reduction in urine protein for cemdisiran to placebo and its 90% CI will be 
presented.  
A sensitivity analysis using all urine protein assessments including a single 24-hour assessment will be 
conducted using mixed-effects model repeated measures (MMRM) method. 
The efficacy endpoints will be analyzed in the mITT population. PK and PD parameters will be analyzed 
in the PK and PD analysis sets, respectively. 
Safety data will be summarized with descriptive statistics. Treatment-emergent adverse events will be 
summarized by SOC and PT (all events, related events, and serious events), in addition to being 
summarized by severity (all events). In addition, summaries will be provided for any AEs leading to 
discontinuation of study drug or death. Serious adverse events and procedure related adverse events in the 
run-in period will be listed. 
 
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Figure 1: 
Study Design  
 
Abbreviations:  Q4W=once every 4 weeks; EOS=end of study; EOT=end of treatment 
 
 
Screening (up to 90 days)
Run-in Period 
(14 Weeks)
EOS
(Week 84)
Treatment Period 
(36 Weeks)
EOT
(Week 80)
Safety Follow-up
(52 Weeks)
Placebo (n=10)
+ Standard of care
ALN-CC5 600mg 
Q4W (n=20)
+ Standard of care
Standard of care
Randomization (2:1)
Open-label Extension Period 
(52 Weeks)
Primary endpoint assessment
ALN-CC5 
600mg Q4W 
+ Standard of care
EOS
(Week 36)
EOT
(Week 32)
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Table 3: 
Pharmacokinetic Time Points 
 
Phase 
Study Day 
Protocol Time Relative to Dosing 
(hh:mm)a 
PK Blood 
Pooled Urineb 
Treatment phase 
Day 1  
Predose (within 60 mins) 
X 
 
00:00 (dose) 
 
X 
01:00 (±5 mins) 
X 
02:00 (±15 mins) 
X 
04:00 (±15 mins) 
X 
06:00 (±15 mins) 
X 
08:00 (±30 mins) 
X 
X 
12:00 (±30 mins) 
 
24:00 (±120 mins) 
X 
X 
Abbreviations:   hh=hours; mm=minutes; mins=minutes; PK=pharmacokinetics. 
a The actual time of blood sample collection must be recorded. 
b The pooled urine 6-12 hours and 12-24 hours can be collected as outpatient. 
 
 
 
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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ................................................................................................................4 
TABLE OF CONTENTS ...............................................................................................................18 
LIST OF TABLES .........................................................................................................................21 
LIST OF FIGURES .......................................................................................................................22 
1. 
INTRODUCTION ......................................................................................................25 
1.1. 
Disease Overview .......................................................................................................25 
1.2. 
Cemdisiran ..................................................................................................................27 
1.3. 
Study Design Rationale ..............................................................................................28 
1.4. 
Dose Rationale ............................................................................................................29 
1.5. 
Benefit-Risk Assessment ............................................................................................30 
2. 
OBJECTIVES AND ENDPOINTS ............................................................................32 
3. 
INVESTIGATIONAL PLAN .....................................................................................34 
3.1. 
Summary of Study Design ..........................................................................................34 
3.2. 
Duration of Treatment ................................................................................................35 
3.3. 
Duration of Study .......................................................................................................35 
3.3.1. 
Definition of End of Study for an Individual Patient .................................................35 
3.4. 
Number of Planned Patients .......................................................................................35 
3.5. 
Method of Assigning Patients to Treatment Groups ..................................................35 
3.6. 
Blinding ......................................................................................................................36 
3.6.1. 
Emergency Unblinding ...............................................................................................36 
3.7. 
Data Monitoring Committee .......................................................................................36 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................37 
4.1. 
Inclusion Criteria ........................................................................................................37 
4.2. 
Exclusion Criteria .......................................................................................................37 
4.3. 
Removal from Therapy or Assessment.......................................................................39 
4.3.1. 
Discontinuation of Study Drug or Declining Procedural Assessments ......................39 
4.3.2. 
Stopping a Patient’s Study Participation ....................................................................40 
4.3.2.1. 
Patient or Legal Guardian Stops Participation in the Study .......................................40 
4.3.2.2. 
Withdrawal of Consent to Process the Patient’s Personal Data .................................41 
4.3.2.3. 
Investigator or Sponsor Stops Participation of a Patient in the Study ........................41 
4.3.2.4. 
Recording Reason for Stopping a Patient’s Study Participation ................................41 
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4.3.3. 
Lost to Follow-Up.......................................................................................................41 
4.3.4. 
Replacement of Study Patients ...................................................................................42 
5. 
TREATMENTS AND OTHER REQUIREMENTS ..................................................43 
5.1. 
Treatments Administered ............................................................................................43 
5.2. 
Study Drug ..................................................................................................................43 
5.2.1. 
Description ..................................................................................................................43 
5.2.2. 
Dose and Administration ............................................................................................43 
5.2.3. 
Dose Modifications .....................................................................................................43 
5.2.3.1. 
LFT Criteria for Withholding, Monitoring and Stopping Cemdisiran Dosing ...........44 
5.2.4. 
Preparation, Handling, and Storage ............................................................................45 
5.2.5. 
Packaging and Labeling ..............................................................................................46 
5.2.6. 
Accountability .............................................................................................................46 
5.3. 
Concomitant Medications and Procedures .................................................................46 
5.3.1. 
Prohibited Concomitant Medications .........................................................................46 
5.3.2. 
Study-specific Vaccinations .......................................................................................47 
5.3.2.1. 
Meningococcal Vaccinations ......................................................................................47 
5.3.2.2. 
Pneumococcal and Hib Vaccinations .........................................................................47 
5.4. 
Treatment Compliance ................................................................................................48 
5.5. 
Other Requirements ....................................................................................................48 
5.5.1. 
Contraception ..............................................................................................................48 
5.5.2. 
Alcohol Restrictions ...................................................................................................49 
5.5.3. 
Antibiotic Compliance ................................................................................................49 
6. 
STUDY ASSESSMENTS ..........................................................................................50 
6.1. 
Screening Assessments ...............................................................................................50 
6.1.1. 
Rescreening .................................................................................................................50 
6.1.2. 
Retesting .....................................................................................................................50 
6.2. 
Run-in Period ..............................................................................................................50 
6.3. 
Baseline Assessments (Treatment Period) ..................................................................51 
6.4. 
Efficacy Assessments .................................................................................................51 
6.4.1. 
Proteinuria ...................................................................................................................51 
6.4.1.1. 
24-Hour Urine Collection ...........................................................................................51 
6.4.1.2. 
Spot Urine Collection .................................................................................................52 
6.4.2. 
Hematuria ...................................................................................................................52 
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6.4.3. 
Changes in Renal Function .........................................................................................53 
6.4.4. 
Markers of Complement Activation, Inflammation and Renal Injury .......................53 
6.5. 
Pharmacodynamic Assessments .................................................................................53 
6.6. 
Pharmacokinetic Assessments ....................................................................................53 
6.7. 
Safety Assessments .....................................................................................................54 
6.7.1. 
Vital Signs ..................................................................................................................54 
6.7.2. 
Weight and Height ......................................................................................................54 
6.7.3. 
Physical Examination .................................................................................................54 
6.7.4. 
Electrocardiogram .......................................................................................................55 
6.7.5. 
Clinical Laboratory Assessments ...............................................................................55 
6.7.5.1. 
Immunogenicity ..........................................................................................................57 
6.7.5.2. 
Pregnancy Testing ......................................................................................................57 
6.7.5.3. 
Additional Liver Function Assessments .....................................................................57 
6.7.6. 
Adverse Events ...........................................................................................................58 
6.7.6.1. 
Definitions ..................................................................................................................58 
6.7.6.2. 
Eliciting and Recording Adverse Events ....................................................................60 
6.7.6.3. 
Reporting Adverse Events of Clinical Interest to Sponsor/Designee .........................61 
6.7.6.4. 
Serious Adverse Events Require Immediate Reporting to Sponsor/Designee ...........61 
6.7.6.5. 
Sponsor Safety Reporting to Regulatory Authorities .................................................62 
6.7.6.6. 
Serious Adverse Event Notification to the Institutional Review 
Board/Independent Ethics Committee ........................................................................62 
6.7.6.7. 
Pregnancy Reporting ..................................................................................................62 
6.7.6.8. 
Overdose Reporting ....................................................................................................62 
6.8. 
Biomarkers, DNA Genotyping, and Biospecimen Repository ...................................63 
7. 
STATISTICS ..............................................................................................................64 
7.1. 
Determination of Sample Size ....................................................................................64 
7.2. 
Statistical Methodology ..............................................................................................64 
7.2.1. 
Populations to be Analyzed ........................................................................................64 
7.2.2. 
Examination of Subgroups .........................................................................................65 
7.2.3. 
Handling of Missing Data ...........................................................................................65 
7.2.4. 
Baseline Evaluations ...................................................................................................65 
7.2.5. 
Efficacy Analyses .......................................................................................................65 
7.2.5.1. 
Primary Endpoint ........................................................................................................65 
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7.2.5.2. 
Secondary Efficacy Endpoints ....................................................................................65 
7.2.5.3. 
Exploratory Endpoints ................................................................................................66 
7.2.6. 
Pharmacodynamic Analysis........................................................................................66 
7.2.7. 
Pharmacokinetic Analysis ..........................................................................................66 
7.2.8. 
Safety Analyses ..........................................................................................................66 
7.2.9. 
Immunogenicity Analyses ..........................................................................................67 
7.2.10. 
Biomarker Analyses ....................................................................................................67 
7.2.11. 
Interim Analysis ..........................................................................................................67 
7.2.12. 
Optional Additional Research .....................................................................................67 
8. 
STUDY ADMINISTRATION ...................................................................................68 
8.1. 
Ethical and Regulatory Considerations ......................................................................68 
8.1.1. 
Informed Consent .......................................................................................................68 
8.1.2. 
Ethical Review ............................................................................................................68 
8.1.3. 
Serious Breach of Protocol .........................................................................................69 
8.1.4. 
Study Documentation, Confidentiality, and Records Retention .................................69 
8.1.5. 
End of Study ...............................................................................................................69 
8.1.6. 
Termination of the Clinical Study or Site Closure .....................................................69 
8.2. 
Data Quality Control and Quality Assurance .............................................................70 
8.2.1. 
Data Handling .............................................................................................................70 
8.2.2. 
Study Monitoring ........................................................................................................70 
8.2.3. 
Audits and Inspections ................................................................................................70 
8.3. 
Publication Policy .......................................................................................................70 
9. 
LIST OF REFERENCES ............................................................................................72 
10. 
APPENDICES ............................................................................................................75 
 
LIST OF TABLES 
Table 1: 
Schedule of Assessments  Run-in and Treatment Periods (Screening 
through Week 36) including Safety Follow up...........................................................10 
Table 2: 
Schedule of Assessments  Open-Label Extension Period and Safety Follow 
up ................................................................................................................................14 
Table 3: 
Pharmacokinetic Time Points .....................................................................................17 
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Table 4: 
Monitoring and Dosing Rules for Asymptomatic Patients with Confirmed 
Isolated Elevations of ALT and/or AST >3× ULN, with No Alternative 
Cause Identified ..........................................................................................................45 
Table 5: 
Clinical Laboratory Assessments ...............................................................................56 
Table 6: 
Hepatic Assessments in Patients Who Experience Elevated Transaminases .............58 
 
LIST OF FIGURES 
Figure 1: 
Study Design .................................................................................................................9 
List of Abbreviations and Definitions of Terms 
Abbreviation  
Definition 
ADA 
Antidrug antibodies 
ACE 
Angiotensin-converting enzyme 
AE 
Adverse event 
AECI 
Adverse event of clinical interest 
aHUS 
Atypical hemolytic uremic syndrome 
ALN-CC5 
Cemdisiran 
ALT 
Alanine transaminase 
ARB 
Angiotensin II receptor blocker 
AST 
Aspartate transaminase 
AUC 
Area under the concentration curve 
BMI 
Body mass index 
C3 
Complement component 3 
C3a 
Activated complement 3 
C5 
Complement component 5 
C5a 
Activated complement component 5 
CAP 
Complement alternative pathway 
CCP 
Complement classical pathway 
CFH 
Complement factor H 
CI 
Confidence interval 
CIC 
Circulating immune complexes 
CL/F 
Clearance 
Cmax 
Maximum concentration 
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Abbreviation  
Definition 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
ELISA 
Enzyme linked immunosorbent assay 
EOS 
End of study 
EOT 
End of treatment 
ESRD 
End-stage renal disease 
GalNAc 
N-acetylgalactosamine 
GCP 
Good Clinical Practice 
Gd-IgA1 
Galactose-deficient Immunoglobulin A 1 
GFR 
Glomerular filtration rate 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
Hib 
Haemophilus influenzae type b 
HIV 
Human immunodeficiency virus 
hpf 
High powered field 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonisation 
IEC 
Independent Ethics Committee 
IgA 
Immunoglobulin A 
IgG 
Immunoglobulin G 
IgAN 
IgA Nephropathy 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRS 
Interactive Response System 
ISR 
Injection site reaction 
IV 
Intravenous 
LFT 
Liver function test 
MAC 
Membrane attack complex 
MedDRA 
Medical Dictionary for Regulatory Activities 
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Abbreviation  
Definition 
mITT 
Modified intent-to-treat 
mRNA 
Messenger RNA 
NHP 
Nonhuman primates 
OLE 
Open-label extension 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic(s) 
PNH 
Paroxysmal nocturnal hemoglobinuria 
RAS 
Renin-angiotensin system 
RBC 
Red blood cell 
RNAi 
RNA interference 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous(ly) 
siRNA 
Small interfering RNA 
SUSAR 
Suspected unexpected serious adverse reaction 
t½ 
Terminal half-life 
Tmax 
Time to maximum concentration 
TMF 
Trial Master File 
Tri-GalNAc 
Triantennary N-acetylgalactosamine 
UP 
Urine protein 
UACR 
Urine albumin:creatinine ratio 
ULN 
Upper limit of normal 
UPCR 
Urine protein:creatinine ratio 
V/F 
Volume of distribution 
 
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1. 
INTRODUCTION 
1.1. 
Disease Overview 
Globally, immunoglobulin A nephropathy (IgAN) is the most common primary 
glomerulonephritis that can progress to renal failure.[Lai 2016; Wyatt 1998]  While the exact 
pathogenesis of IgAN is incompletely understood, biochemical, genetic, and clinical data suggest 
IgAN is an autoimmune disease that may originate from overproduction of aberrantly O-
glycosylated IgA1 (Gd-IgA1) and the presence of glycan-specific IgA and immunoglobulin G 
(IgG) autoantibodies that recognize the under-galactosylated IgA1 molecule, resulting in the 
formation of pathogenic immune complexes. Some of these circulating complexes may deposit 
in glomeruli and induce renal injury.[Knoppova 2016]  The lack of galactose exposes O-linked 
monosaccharide N-acetylgalactosamine (O-GalNAc) moeities in the hinge region of 
IgA1.[Novak 2018] While the binding of autoantibodies to Gd-IgA1 is dependent on the 
presence of multiple O-GalNAc residues, the IgA1 protein backbone and the spatial arrangement 
of O-GalNAc moieties are also thought to play a role in the specificity of autoantibodies to Gd-
IgA1.[Mestecky 2016; Suzuki 2009] 
Both the alternative and lectin complement pathways may be activated, leading to generation of 
the anaphylatoxins activated complement component 3 (C3a) and activated complement 
component 5 (C5a) and the membrane attack complex (MAC) C5b-9, with subsequent 
promotion of inflammatory mediators.[Maillard 2015]  Emerging data indicate that 
mesangial-derived mediators that are released following deposition of IgA1 may lead to 
podocyte and tubulointerstitial injury. 
Given that a biopsy specimen is required to diagnose IgAN, the clinical threshold for performing 
a biopsy will have a major impact on the prevalence of IgAN. Persistent microscopic hematuria 
alone and/or mild proteinuria alone are not commonly used as a per cause indication for biopsy 
in the United States.  Thus, the prevalence of IgAN is modest in the United States (10 to 20% of 
primary glomerulonephritis), higher in some European countries (20 to 30%), and highest in 
developed countries in Asia (40 to 50%).[Woo 2010]  This considerable geographical variability 
can be explained by several factors including the variation in access to primary care enabling 
early diagnosis and the differences in policies for performing renal biopsies as well as for early 
referrals.  For example, in some countries, urine screening tests are conducted in schools or for 
military service or ahead of employment, explaining the apparent high incidence.[Imai 2007; 
Wyatt 1998]  Ethnic differences can also contribute to the varying prevalence of IgAN.  
Genome-wide association studies have identified candidate genes as well as risk-associated and 
protective alleles, with the highest number of risk alleles present in individuals of East Asian 
origin and the lowest number in those from Africa.[Kiryluk 2014]  These genes are involved in 
antigen presentation, mucosal defense system and notably the alternative complement pathway 
(complement factor H [CFH]/CFHR locus).[Kiryluk 2014]  Finally, patients may present at any 
age with IgAN but there is a peak incidence in the second and third decades of life.  Most cases 
of IgAN occur in sporadic (90 to 95%) rather than in familial patterns (5 to 10%).[Lai 2016] 
Routine screening for IgAN is not feasible given that no specific diagnostic laboratory tests are 
available.  The first indication for making a diagnosis comes after careful microscopic 
examination of a urine sample.  The presence of red blood cell (RBC) casts and dysmorphic 
RBCs indicates glomerular bleeding.  Varying degrees of proteinuria are present in patients with 
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IgAN. Proteinuria can be quantified with a timed urine collection or a spot urine protein to 
creatinine ratio (UPCR) measurement.  Hence, IgAN can only be diagnosed definitely upon renal 
biopsy and study of kidney tissue using immunofluorescence.  The pathology of IgAN is 
characterized by deposition of pathogenic polymeric IgA1 immune complexes and C3 in the 
glomerular mesangium, proliferation of mesangial cells, increased synthesis of extracellular 
matrix and variable infiltration of macrophages, monocytes and T cells.  A consensus on the 
pathologic classification of IgAN has been developed by the International IgA Nephropathy 
Network in collaboration with the Renal Pathology Society (Oxford classification).[Cattran 
2009; Lai 2016; Roberts 2009] 
The clinical presentation of patients with IgAN is highly variable, ranging from asymptomatic 
microscopic hematuria to a rapidly progressive form of glomerulonephritis which is often 
associated with severe hypertension, but between these extremes, most patients with IgAN 
pursue a chronic indolent course.[Lai 2016]  Some patients present with more severe proteinuria, 
hypertension and renal progression over time, typically reaching end-stage renal disease (ESRD) 
over a span of 20 years.  Thus, the severity of proteinuria upon presentation has significant 
prognostic implications.  More importantly, the change in proteinuria over time is being regarded 
as the current best prognostic indicator: those who had heavy time averaged proteinuria and 
achieved a partial remission of <1 g/24-hours had a similar course to those who had 
<1 g/24-hours throughout and fared far better than those who never achieved partial 
remission.[Reich 2007]  These observations support the notion that every effort should be made 
to reduce proteinuria in IgAN.  In addition to the degree of proteinuria, baseline renal function 
and the degree of histological injury are of prognostic value.  For example, patients with an 
estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 at the time of renal biopsy have 
worse outcomes than those with normal eGFR (90 to 120 mL/min/1.73 m2).  The rate of 
glomerular filtration rate (GFR) decline also correlates with glomerulosclerosis and tubular 
atrophy or interstitial fibrosis on biopsy as outlined by Oxford-MEST-C classification.  
Spontaneous full recovery in IgAN is rare in adults, especially if associated with significant 
proteinuria (>0.5 g/24-hour).[Knoop 2017] 
Patients with minor urine abnormalities, normal blood pressure, and normal GFR usually do well 
and require only monitoring.  For other patients, the therapeutic options are limited and include 
nonspecific treatment to reduce blood pressure and proteinuria by renin-angiotensin system 
(RAS) blockade.  Thus, no disease-specific therapies are currently available, and an unmet need 
persists for novel interventions, particularly in patients who are at risk of progressive disease that 
can result in end-stage renal failure.  The optimal role of immunosuppressive therapy is 
uncertain.  The available studies are not conclusive since most are relatively small and have 
limited follow-up.[Lai 2016]  STOP-IgAN, a German trial, randomly assigned adults with an 
eGFR of >30 mL/min/1.73 m2 and persistent proteinuria of >0.75 g/24-hour despite 6 months of 
supportive care with RAS inhibitors to receive supportive care alone or supportive care plus 
immunosuppression (prednisone alone for those with initial GFR >60 mL/min and prednisone 
combined with cyclophosphamide then azathioprine with initial GFR 30-59 mL/min).  This 
strategy did not significantly improve the renal outcome and was associated with increased 
adverse effects at 36 months.[Rauen 2015]  The TESTING trial demonstrated some GFR effect 
of steroids in Chinese patients, but had to be stopped due to large number of serious adverse 
events (SAEs) in the steroid arm.[Lv 2017]  The 2012 KDIGO guidelines recommend 
corticosteroids, albeit at very low level of evidence. Thus, steroids may be tried in some cases as 
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rescue therapy if proteinuria markedly increases or GFR rapidly falls. Further studies to address 
the role of steroids in IgAN are currently under way.  Finally, Rituximab seems to be ineffective 
in the treatment of patients with progressive IgAN.[Lafayette 2016] 
1.2. 
Cemdisiran 
Alnylam Pharmaceuticals, Inc. is developing cemdisiran (ALN-CC5), a synthetic RNA 
interference (RNAi) therapeutic designed to suppress liver production of C5 protein, for the 
treatment of atypical hemolytic uremic syndrome (aHUS) and IgAN.  Cemdisiran comprises a 
small interfering RNA (siRNA) targeting C5 messenger RNA (mRNA) that is covalently linked 
to a triantennary N-acetylgalactosamine (GalNAc) ligand.   
RNAi is a naturally occurring cellular mechanism for regulating gene expression that is mediated 
by siRNAs.  Synthetic siRNAs are short (19-25 base pairs), double-stranded oligonucleotides in 
a staggered duplex with an overhang at one or both 3-prime ends.  Such siRNAs can be designed 
to target the mRNA transcript of a given gene.  When formulated for tissue delivery and 
introduced into cells, the guide (or antisense) strand of the siRNA loads into an enzyme complex 
called the RNA-induced silencing complex.  This enzyme complex subsequently binds to its 
complementary mRNA sequence, mediating cleavage of the mRNA and the suppression of the 
target protein encoded by the mRNA.[Elbashir 2001]  Since unmodified siRNAs are rapidly 
eliminated and do not achieve significant tissue distribution upon systemic administration 
[Soutschek 2004], various formulations are currently used to target their distribution to tissues, 
and to facilitate uptake of siRNAs into the relevant cell type.  One approach that has been used 
successfully in vivo in animal models (including in rodents and nonhuman primates [NHP]) and 
humans employs intravenous (IV) delivery of siRNA in lipid nanoparticle 
formulations.[Soutschek 2004; Zimmermann 2006]  Another approach for liver-specific gene 
silencing is subcutaneously administered siRNA conjugated to a GalNAc carbohydrate 
ligand.[Ashwell 2006]  Conjugation of a triantennary GalNAc ligand to an siRNA enables 
hepatocyte binding and subsequent cellular uptake via the asialoglycoprotein receptor, resulting 
in engagement of the RNAi pathway and downregulation of hepatic proteins. 
Cemdisiran (containing siRNA drug substance, ALN-62643, targeting C5 mRNA) is a synthetic 
investigational RNAi therapeutic designed to suppress liver production of C5 protein, when 
administered via subcutaneous (SC) injection.  C5 is encoded by a single gene and is expressed 
and secreted predominantly by hepatocytes.  Through the mechanism of RNAi, the cemdisiran 
siRNA enables the downregulation of C5 mRNA in the liver, thereby reducing levels of 
circulating C5 protein and resulting in inhibition of terminal complement pathway activity and 
prevention of MAC formation and C5a release.  This in turn would be expected to reduce 
mesangial cell proliferation and tissue injury in patients with IgAN resulting in renal function 
improvement.[Maillard 2015] Both lectin and alternative pathways of complement have been 
implicated in IgAN pathology.  Cemdisiran-mediated silencing of C5 will inhibit MAC 
formation and C5a release regardless of the activating pathway and may be a superior approach 
in IgAN where the contribution of different pathways may be heterogenous between 
patients.[Medjeral-Thomas 2018] 
The safety of reducing C5 is supported by clinical precedence of C5 inhibition with eculizumab 
treatment and the absence of any phenotypic abnormalities, other than an increased susceptibility 
to Neisserial infections, in subjects with known genetic C5 deficiencies.[Ross 1984]  Subjects 
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with known C5 deficiencies are generally healthy apart from an increased susceptibility to 
Neisserial infections. These infections include invasive meningococcal disease, disseminated 
gonococcal infections as well as diseases caused by typically commensal Neisseria 
species.[Crew 2018; Crew 2018; McQuillen 2018; Ram 2010]  In addition, safety data on the 
treatment of healthy volunteers and patients with paroxysmal nocturnal hemoglobinuria (PNH) 
with cemdisiran in Study ALN-CC5-001 indicate that cemdisiran is generally well-tolerated; the 
maximum tolerated dose was 900 mg.  There were no serious adverse events (SAEs) or 
discontinuations due to adverse events (AEs) during this study, and most AEs were mild or 
moderate in severity. In Study ALN-CC5-001, the frequency of ADA was low.  Two of 48 
healthy volunteers (1 cemdisiran-treated and 1 placebo-treated) were ADA positive during the 
study. The cemdisiran-treated volunteer had transient ADA positivity, with a negative result later 
in the study and no impact on PK or PD. The placebo-treated volunteer was ADA positive at 
baseline (predose) and remained positive through Day 70.  
A detailed description of the chemistry, pharmacology, nonclinical pharmacokinetics (PK) and 
toxicology, as well as preliminary efficacy, and safety of cemdisiran is provided in the current 
edition of the Investigator’s Brochure (IB). 
1.3. 
Study Design Rationale 
In contrast to the RBC lysis which characterises the pathophysiology of PNH, which requires 
extremely high level of C5 inhibition for protection, endothelial cells and mesangial cells are the 
cellular targets of dysregulated complement in aHUS and IgAN, respectively.  These cells are 
nucleated cells which possess complement regulatory proteins as well as the ability to shed 
membrane associated MAC to defend against MAC-mediated damage, a key step in thrombotic 
microangiopathy progression in aHUS and renal damage in IgAN.  It is therefore hypothesized 
that a lesser degree of cemdisiran mediated C5 knockdown will be required for disease control in 
patients with IgAN and aHUS than in patients with PNH.[Morgan 1989; Rosse 1973]  This 
hypothesis is supported by the observation that aHUS patients who achieve C5 inhibition 
maintain good disease control despite complement activity levels consistent with higher free C5 
levels.[Cugno 2014]  Therefore, cemdisiran monotherapy may be a viable treatment option in 
patients with IgAN at levels of C5 silencing achieved in Study ALN-CC5-001. 
This therapeutic hypothesis will be tested in a multicenter, multinational, double-blind, 
placebo-controlled study to evaluate the effect of multiple doses of cemdisiran given by SC 
injection in patients with IgAN with persistent proteinuria (>1 g/24-hours) despite the standard 
of care (angiotensin converting enzyme inhibitors [ACE] or angiotensin II receptor blockers 
[ARB]) and additional medications if necessary for blood pressure control followed by a 
treatment extension to evaluate long-term safety and clinical activity.  The study population has 
been selected based on two major factors: 1) the severity of proteinuria upon presentation has 
significant prognostic implications.[Coppo 2005]  IgAN patients with heavy proteinuria >1 g/24-
hours have a significantly worse renal outcome than those who have proteinuria 
<1 g/24-hours.[Reich 2007]  2) For patients with persistent proteinuria, despite the nonspecific 
treatment to reduce blood pressure and proteinuria by RAS blockade, no disease-specific 
therapies are currently available, and an unmet need persists for novel interventions. Since 
proteinuria can result both from active inflammation as well as irreversible scarring of renal 
tissue and in lieu of a protocol biopsy, we enrich our patients for presence of potentially 
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reversible disease activity by requiring presence of hematuria and relatively preserved renal 
function with eGFR >30 mL/min. To ensure the selection of patients who are truly at risk of 
progression of kidney disease despite standard of care, the first period of the study consists of a 
run-in period during which patients will not receive study drug (cemdisiran or placebo).  The 
run-in period will be an observational period during which patients’ treatment with standard of 
care, blood pressure, kidney function, degree of hematuria, and proteinuria will be documented.  
The standard of care is expected to remain unchanged during this run-in period. Only patients 
whose  
 proteinuria level remains above 1 g/24-hours within 2 weeks before the end of the 
run-in period,  
 continue to have hematuria, and meet blood pressure and eGFR criteria  
will be eligible to enroll in the 36-week treatment period portion of the study. 
Randomization to cemdisiran or placebo will be performed in a 2:1 ratio so that more patients 
will receive cemdisiran. This will allow a more precise estimation of the effect of cemdisiran 
with only marginal loss of power. Inclusion of a placebo arm will allow better assessment of 
safety and interpretation of the efficacy of cemdisiran. 
The primary endpoint for the study is percent change from baseline in 24-hour proteinuria 
(g/24-hours) at Week 32.  This is justified for a phase 2 study given the slow progression of renal 
disease and the established role of proteinuria as a marker of disease progression. 
1.4. 
Dose Rationale 
In the Phase 1/2 Study (ALN-CC5-001), 32 healthy volunteers were treated with single SC doses 
of cemdisiran ranging from 50 mg to 900 mg, 24 healthy volunteers were treated with multiple 
doses of cemdisiran ranging from 100 mg to 600 mg (dosing weekly, every other week or 
monthly), 6 patients with PNH were treated with cemdisiran at cumulative doses of 3200 mg to 
4200 mg (eculizumab-naïve patients) and 1200 mg to 2400 mg (patients on background 
eculizumab treatment).  Treatment with cemdisiran was generally well tolerated in both healthy 
volunteers and patients with PNH.  There were no SAEs and no discontinuations due to AEs 
during this study, including at the highest doses administered.  Most AEs observed were mild or 
moderate in severity. 
Dose selection for the current study is based on the expected level of C5 and complement 
activity inhibition necessary for efficacy in patients with IgAN and the extent to which different 
doses of cemdisiran can inhibit production of C5.  C5 silencing is a novel approach for the 
treatment of IgAN and little clinical precedent exists for inhibiting the terminal complement 
pathway in this disease.  Since complement regulation is not impaired in IgAN like it is in PNH, 
and the kidney glomerular cells are nucleated cells, it is expected that the level of silencing 
needed for efficacy in IgAN is lower than that needed for PNH (see IB Section 2.4).  For this 
proof-of-concept study, a dose was selected that is expected to produce rapid and robust C5 
suppression and complement activity inhibition across the patient population, allowing an 
unambiguous evaluation of whether C5 silencing results in proteinuria improvement in IgAN.  In 
Study ALN-CC5-001, a single dose of 600 mg cemdisiran achieved a C5 level of 
12.3±1.47 μg/mL by Day 14 and 2.3±0.76 μg/mL by Day 56, corresponding to 60.9% reduction 
in complement alternative pathway (CAP) activity and a 69.3% reduction in complement 
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classical pathway (CCP) activity by Day 14 and 90.2% and 91.4% reduction in CAP and CCP 
activities, respectively, by Day 56. Single and multiple biweekly doses of 600 mg were 
well-tolerated with an acceptable safety profile in healthy volunteers in Study ALN-CC5-001A. 
In this initial study, the cemdisiran dose of 600 mg that was safe and well-tolerated was chosen 
for evaluation. This dose will yield robust C5 silencing and will have maximal opportunity to 
produce a meaningful clinical effect in patients with IgAN.  Since the relationship between C5 
levels and complement activity is non-linear, with small C5 fluctuations resulting in a larger 
increase in complement activity, a monthly dose regimen was selected to maintain a constant 
level of C5 silencing.  Additionally, a more consistent effect of cemdisiran on C5 protein and 
CCP level is predicted after monthly dosing when compared to quarterly dosing based on a 
modeling approach.   
During the extension treatment phase, patients treated with both cemdisiran and placebo will 
have the option to receive a 600 mg dose of cemdisiran every four weeks for an additional 52 
weeks. 
IgAN can result in progressive renal impairment; however, patients with severe renal impairment 
(eGFR<30 mL/min/1.73 m2) who may have sustained irreversible damage to the kidney are not 
eligible for participation in this trial.  As the kidney is not the major elimination pathway for 
cemdisiran and based on available nonclinical and clinical data obtained with cemdisiran (with 
10.6 to 31.6% of the cemdisiran dose recovered in a 24-hour urine collection in the ALN-
CC5-001 study), it is expected that moderate renal impairment (eGFR<60 mL/min/1.73 m2) will 
not affect the PK of cemdisiran to the extent that a dose adjustment would be required.  
Therefore, patients with moderate renal impairment are eligible for study enrollment. More 
information on urine PK can be found in the IB.   
1.5. 
Benefit-Risk Assessment 
To date, no medications have been approved specifically for the treatment of IgAN.  Therefore, 
there is a large unmet need for novel interventions, particularly in patients who are at risk of 
progressive renal disease such as those with persistent proteinuria despite treatment with RAS 
inhibitors.  Available data from studies on the role of immunosuppressive therapy in IgAN are 
not conclusive as most are relatively small and have limited follow-up.[Lai 2016]  Use of 
immunosuppressive drugs and high-dose steroids are also associated with increased AEs which 
is particularly common in patients with lower GFR.[Sarcina 2016] 
Given the biological target of cemdisiran, the available nonclinical and clinical data, and mode of 
administration, important potential risks for cemdisiran are infections, liver function test (LFT) 
abnormalities and injection site reactions (ISRs).  C5 inhibition is associated with increased 
susceptibility for Neisserial infections (including disseminated gonococcal infections) and the 
potential risk of other infections, particularly those due to encapsulated bacteria including 
Streptococcus pneumoniae and Haemophilus influenzae type b (Hib), as well as Aspergillus in 
immunocompromised and neutropenic patients. Therefore, prior immunization against N. 
meningitidis using meningococcal group ACWY conjugate vaccine and meningococcal group B 
vaccine are required. Patients will be instructed to contact study site if any early signs of 
meningococcal infections are experienced. In addition, patients with functional or anatomic 
asplenia will be excluded and only patients previously vaccinated or who agree to receive 
vaccination for Hib and Streptococcus pneumoniae according to current national/local 
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vaccination guidelines, at screening, will be enrolled.  Investigators in Study ALN-CC5-005 
should educate patients on the risk of disseminated gonococcal infection and encourage safe sex 
practices.  All national/local screening recommendations for gonorrhea in the general population 
should also be followed.  Finally, given the reported evidence of a higher risk of disseminated 
gonococcal infections with treatment with eculizumab, Investigators are encouraged to evaluate 
any patient who has a Neisseria gonorrhoeae infection for the signs and symptoms of 
disseminated infection.[Crew 2018; McQuillen 2018]  No cases of Neisserial infection or other 
infections due to encapsulated bacteria were observed in healthy volunteers or in patients with 
PNH (Study ALN-CC5-001). 
As cemdisiran is targeted for delivery to the liver, patients will be closely monitored for changes 
in LFTs and patients with a medical history or evidence of chronic liver disease or cirrhosis have 
been excluded.  Criteria for dose withholding, and stopping of cemdisiran are provided in 
Section 5.2.3.1. Patients will also be monitored for the development of ISRs and rotation of 
injection site are recommended during the study.   
Considering anti-glycan autoantibodies recognizing Gd-IgA1 are implicated in the pathogenesis 
of IgA nephropathy, exposure to the GalNAc moiety of cemdisiran may pose a theoretical risk of 
stimulating the production of pathogenic autoantibodies and immune complexes in patients with 
IgA nephropathy. This could presumably occur when antidrug antibodies (ADAs) to 
cemdisiran’s triantennary GalNAc (Tri-GalNAc) cross-react with Gd-IgA1. The risk of 
developing these cross-reactive antibodies is likely low. This is based on the low incidence of 
ADA to cemdisiran in study ALN-CC5-001 (see Section 1.2) and the distinct difference in 
structure of the O-GalNAc moieties on a Gd-IgA1 glycoprotein and the Tri-GalNAc moiety in 
cemdisran. This low risk is further mitigated by excluding patients with confirmed pre-existing 
IgG/IgM/IgA ADAs to total drug and real time monitoring for development of de novo 
IgG/IgM/IgA ADAs after dosing with cemdisiran. Patients with confirmed de novo ADAs will 
be discontinued from study drug but will continue to be monitored until EOS visit and 
subsequent safety follow up. Patients who develop positive ADA will be followed until ADA 
titers return to baseline. Additional ADA samples will also be collected if any clinical evidence 
of progression of IgAN disease and/or relevant safety findings.  
Detailed information about the known and expected benefits and risks of cemdisiran and 
additional information on the clinical and nonclinical data may be found in the current version of 
the IB. 
Cumulatively, clinical data regarding the role of complement pathways in IgAN progression, 
robust nonclinical and clinical data with cemdisiran (see IB for more information), and prior and 
ongoing clinical experience with other RNAi therapeutics in humans suggest cemdisiran will 
have a favorable risk profile in the intended population and supports the initial clinical 
development of cemdisiran in IgAN.  In addition, cemdisiran may address the unmet medical 
need for the first efficacious and disease-specific treatment for patients with IgAN. 
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 Change from baseline in 24-hour 
albuminuria at Week 32 
 Change from baseline in the urine 
albumin/creatinine ratio (UACR) as 
measured in 24-hour urine at Week 32 
 Change from baseline in C5 level over 
the course of the study 
 Change from baseline in complement 
activity (Complement Alternative 
Pathway [CAP] and Complement 
Classical Pathway [CCP]) over the 
course of the study 
 Evaluation of area under the curve 
(AUC), maximum plasma 
concentration (Cmax), time to 
maximum plasma concentration 
(Tmax), terminal half-life (t1/2), 
clearance (CL/F), volume of 
distribution (V/F), cumulative amount 
excreted unchanged in urine (Ae) and 
percent of dose excreted in the urine 
(fe) of cemdisiran (25-mer) and 23-
mer 
 Evaluation of AUC, Cmax, Tmax, 
t1/2, CL/F, V/F, Ae and fe of 22-mer 
AS(N-1)3’ 
 Change from baseline in levels of 
renal damage, complement activation 
and inflammation markers over the 
course of the study 
 Incidence of antidrug antibodies 
(ADA) 
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3. 
INVESTIGATIONAL PLAN 
3.1. 
Summary of Study Design 
This is a multicenter, double-blind, placebo-controlled study comprised of three periods 
(Figure 1).  The first period of the study is an observational 14-week run-in period during which 
patients’ blood pressure, kidney function, degree of hematuria, and proteinuria will be measured.  
Patients will not receive study drug (cemdisiran or placebo) during this time.  The standard of 
care is expected to remain unchanged during this run-in period.  The second study period is a 
36-week treatment period which will evaluate the efficacy and safety of SC cemdisiran 
compared to SC placebo in combination with standard of care in patients with IgAN and 
persistent proteinuria.  The third period of the study is a 52-week optional open-label extension 
(OLE) period to further evaluate the long-term safety and clinical activity of cemdisiran.  During 
the OLE, all patients (including those initially on placebo) will be treated with cemdisiran in 
combination with standard of care. 
The study will include Screening of up to 90 days to determine eligibility of patients and to 
complete disease-related assessments.  Patients will provide written informed consent and visit 
the study center approximately 2 weeks before starting the run-in period to complete the protocol 
screening assessments.  Following successful screening, the 14-week run-in period will 
commence, during which patients’ blood pressure, kidney function, degree of hematuria and 
proteinuria as well as treatment with standard of care will be documented by the Investigator.  
The standard of care is expected to remain unchanged during this run-in period.  Patients whose 
proteinuria level remains >1 g/24-hours within 2 weeks of the end of the run-in period, who 
continue to have hematuria, and who meet blood pressure and eGFR criteria will be eligible to 
enroll in the 36-week treatment period.  Upon confirmation of eligibility followed by vaccination 
against meningococcal infections, patients will be randomized at a 2:1 ratio to receive 600 mg of 
cemdisiran or placebo every 4 weeks in combination with standard of care.  Approximately 30 
patients are planned to be randomized in total, 20 in the cemdisiran arm and 10 in the placebo 
arm.  Patients excluded before randomization will be replaced at Screening.  
During the run-in period, patients will visit the study center 14, 8, and 2 weeks prior to 
randomization (Weeks 0, 6 and 12 of the run-in period).  Patients will then return to the study 
center every 4 weeks after the start of study drug treatment period. The primary endpoint will be 
assessed at the end of treatment at Week 32. 
At the end of treatment (Week 32), patients in the two treatment arms will enter the optional 
OLE period where they will receive cemdisiran at a dose of 600 mg every 4 weeks in 
combination with standard of care for 52 weeks.  The first study drug administration of the OLE 
will be administered at Week 36.  Patients will return to the study center at Week 40 and every 
8 weeks thereafter during the OLE.  Home visits, where locally feasible, may be arranged for 
cemdisiran administration in between 8-weekly study center visits (Weeks 44, 52, 60, 68 and 
76), unless patients are required to visit the study center as judged necessary by the Investigator, 
or if home visits cannot be arranged.  An end of treatment (EOT) visit will occur at Week 80 
(OLE EOT) and an end of study (EOS) or early termination (ET) visit will be completed at Week 
84 (OLE EOS/ET).  For patients who complete the treatment period only who do not consent to 
continue to participate in the study in the OLE period, the EOS/ET visit will be at Week 36. 
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Patients will return to the clinical study center for safety follow-up visits approximately 13, 26, 
39 and 52 weeks after the EOS/ET visit (regardless if EOS/ET visit is at Week 36 or Week 84), 
unless enrolled in another study with cemdisiran. Home visits, where locally feasible, may be 
arranged during safety follow-up at 13 and 39 weeks after the EOS/ET visit (regardless if 
EOS/ET visit is at Week 36 or Week 84). 
Regular reviews of safety and tolerability data will be performed by an independent data 
monitoring committee (DMC) throughout the study with the primary purpose of protecting the 
safety of participating patients and the integrity of the study. 
3.2. 
Duration of Treatment  
Subcutaneous doses of cemdisiran or matching placebo will be administered every 4 weeks over 
a period of 32 weeks during the treatment period and patients will receive 600 mg SC doses of 
cemdisiran for 52 weeks in the optional OLE.  
3.3. 
Duration of Study 
The maximum estimated total time on study, inclusive of Screening (maximum of 90 days), 
run-in period (14 weeks), treatment period (36 weeks), optional OLE period (52 weeks) and 
safety follow-up (52 weeks), is approximately 36 months or 3.0 years. 
3.3.1. 
Definition of End of Study for an Individual Patient 
A patient is considered to have reached the end of the study if the patient has completed the EOS 
visit (Week 36 for those patients who do not consent to continue to participate in the study in the 
OLE period and Week 84 for patients who enter the OLE period). Upon study completion 
(regardless if EOS visit is at Week 36 or Week 84) patients will enter a safety follow-up period 
with visits scheduled at intervals of 13 weeks. 
For patients withdrawing from the study after receiving one dose of cemdisiran at a minimum 
(ET), all efforts should be made to conduct the EOS/ET assessments. Patients should then be 
encouraged to enter the safety follow up period. 
3.4. 
Number of Planned Patients 
Approximately 30 patients are planned for randomization in this study. 
3.5. 
Method of Assigning Patients to Treatment Groups 
Using the Interactive Response System (IRS), patients will be randomized 2:1 to the cemdisiran 
or placebo arms.  Randomization will be stratified by baseline urine proteinuria levels (≥ 1g/24h 
and <2g/24h versus >=2g/24h). 
Each patient will be uniquely identified in the study by a combination of the site number and 
patient identification number.  Upon signing the informed consent form (ICF), the patient will be 
assigned a patient identification number by the IRS.  The Investigator or his/her designee will 
contact the IRS after confirming that the patient fulfills all the inclusion criteria and none of the 
exclusion criteria at screening and prior to randomization.  
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3.6. 
Blinding 
All site personnel including sponsor delegated clinical research associates, data management 
CRO and patients will be blinded to study drug treatment during the efficacy period (up to Week 
36). Sponsor personnel will not be blinded to study treatment. Cemdisiran and placebo will be 
packaged identically.  The study drug will be administered under the supervision of the 
Investigator or at the patient’s home by a healthcare professional (see Section 5.2.2).  Since 
cemdisiran may be visually distinguishable from placebo, the syringe will be masked by a site 
pharmacist prior to administration by a healthcare professional.  See the Pharmacy Manual for 
additional details. Further details on blinding and unblinding arrangements will be documented 
in a separate plan /manual. 
3.6.1. 
Emergency Unblinding 
If the treating physician determines that the clinical management of the patient requires 
knowledge of the study drug assignment, the Investigator may break the blind, as necessary.  If 
time permits, clinical study center personnel should contact the Medical Monitor before 
unblinding to discuss the need to unblind the patient but must do so within 1 working day after 
the unblinding event.  A record of when the blind was broken, who was unblinded, who broke 
the blind, and why it was broken, will be maintained in the Trial Master File (TMF). 
Further details on blinding and unblinding arrangements will be documented in a separate plan / 
manual. 
3.7. 
Data Monitoring Committee 
An independent DMC will perform regular reviews of safety, tolerability, and immunogenicity 
data throughout the study with the primary purpose of protecting the safety of participating 
patients and the integrity of the study.  The DMC will operate under the rules of a Charter that 
will be reviewed and approved at the organizational meeting of the DMC.  The DMC will 
perform periodic reviews of unblinded data (safety, tolerability, PK, pharmacodynamics (PD), 
ADA, circulating immune complexes (CIC) and efficacy of cemdisiran) during the clinical trial, 
and on an ad hoc basis review emergent safety data.  Details are provided in the DMC Charter. 
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4. 
SELECTION AND WITHDRAWAL OF PATIENTS 
4.1. 
Inclusion Criteria 
Patients are eligible to be included in the study if all the following criteria apply: 
Age and Sex 
1. Male or female ≥18 years and ≤65 years of age at the time of informed consent 
Patient and Disease Characteristics 
2. Clinical diagnosis of primary IgAN as demonstrated by historical biopsy collected within 
60 months of screening 
3. Treated for IgAN with stable, optimal pharmacological therapy.  In general, stable and 
optimal treatment will include maximum allowed or tolerated ACE inhibitor or an ARB 
for at least 3 months prior to start of run-in period 
4. Urine protein ≥1g/24-hour at screening and mean urine protein ≥1g/24-hour from two 
valid 24-hour urine collections at the end of the run-in period, prior to randomization  
5. Hematuria as defined by ≥10 RBCs per high powered field (RBC/hpf) at screening and 
either ≥10 RBC/hpf or a positive urinary dipstick (1+ and above) at the end of the run-in 
period, prior to randomization (local result accepted for assessment of eligibility at the 
end of the run-in period)  
6. Females 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, and for 90 days after last dose 
administration  
7. Previously vaccinated with meningococcal group ACWY conjugate vaccine and 
meningococcal group B vaccine or willingness to receive these vaccinations as well as 
prophylactic antibiotic treatment, if required by local standard of care 
8. Previously vaccinated or willingness to receive vaccinations for Hib and Streptococcus 
pneumoniae according to current national/local vaccination guidelines for vaccination use 
Informed Consent 
9. Patient is willing and able to provide written informed consent and to comply with the 
study requirements 
4.2. 
Exclusion Criteria 
Patients are excluded from the study if any of the following criteria apply: 
Disease-specific Conditions 
1. Concomitant significant renal disease other than IgAN 
2. A diagnosis of rapidly progressive glomerulonephritis as measured by eGFR loss >30% 
over the duration of the run-in phase 
3. Secondary etiologies of IgAN (eg, inflammatory bowel disease, celiac disease) 
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4. Diagnosis of Henoch-Schonlein Purpura (IgA Vasculitis) 
5.  eGFR <30 mL/min/1.73 m2 2 weeks prior to randomization (local results will be used for 
assessment of eligibility) 
Laboratory Assessments 
6. Has any of the following laboratory parameter assessments:  
a. Alanine transaminase (ALT) >1.5×upper limit of normal (ULN), International 
Normalized Ratio (INR) >2 (or >3.5 if on anticoagulants), or total bilirubin 
>1.5×ULN (unless bilirubin elevation is due to Gilbert’s syndrome)  
7. Confirmed positive IgG/IgM/IgA ADAs to cemdisiran at Screening 
8. Clinical laboratory test results considered clinically relevant and unacceptable in the 
opinion of the Investigator 
9. Known human immunodeficiency virus (HIV) infection, hepatitis C virus (HCV) 
infection or hepatitis B virus (HBV) infection 
Prior/Concomitant Therapy 
10. Treatment with systemic steroids at dosages exceeding 20 mg prednisone-equivalent for 
more than 7 days or other immunosuppressant agents in the 12 months prior to 
randomization 
11. Received an investigational agent within the last 30 days or 5 half-lives, whichever is 
longer, prior to the first dose of study drug, or are in follow-up of another clinical study 
prior to study enrollment 
Medical Conditions 
12. Malignancy (except for non-melanoma skin cancers, cervical in situ carcinoma, breast 
ductal carcinoma in situ, or stage 1 prostate cancer) within the last 5 years 
13. Active psychiatric disorder, including, but not limited to schizophrenia, bipolar disorder, 
or severe depression despite current pharmacological intervention 
14. Known medical history or evidence of chronic liver disease or cirrhosis 
15. Has other medical conditions or comorbidities which, in the opinion of the Investigator, 
would interfere with study compliance or data interpretation 
16. History of multiple drug allergies or history of allergic reaction to an oligonucleotide or 
GalNAc 
17. History of intolerance to SC injection(s) or significant abdominal scarring that could 
potentially hinder study drug administration or evaluation of local tolerability 
18. Known contraindication to meningococcal vaccines (group ACWY conjugate and group 
B vaccines) required for this study.  Refer to the most recent local product information 
for each vaccine for the current list of contraindications 
19. Unable to take antibiotics for meninigococcal prophylaxis, if required by local standard 
of care 
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20. Sustained blood pressure >140/90 mmHg as defined by 2 or more readings during the 
run-in period, measured in supine position after 10 minutes of rest 
21. Receipt of an organ transplant (including hematologic transplant) 
22. History of meningococcal infection within 12 months before Screening 
23.  Patients with systemic bacterial or fungal infections that require systemic treatment with 
antibiotics or antifungals  
24. Patients with functional or anatomic asplenia 
Alcohol Use 
25. Patients who consume more than 14 units of alcohol a week (unit 1 glass of wine 
[125 mL] = 1 measure of spirits [approximately 1 fluid ounce] = ½ pint of beer 
[approximately 284 mL])  
4.3. 
Removal from Therapy or Assessment 
Patients or their legal guardians are free to discontinue study drug and/or stop participation in the 
study at any time and for any reason, without penalty to their continuing medical care.  The 
Investigator or the Sponsor may stop a patient’s participation in the study at any time if this is 
considered to be in the patient’s best interest.  Any discontinuation of treatment or the stopping 
of the patient’s participation in the study must be fully documented in the electronic case report 
form (eCRF) and should be followed up by the Investigator.   
Discontinuation of study drug is described in Section 4.3.1, while the stopping of a patient’s 
participation in the study is detailed in Section 4.3.2. 
4.3.1. 
Discontinuation of Study Drug or Declining Procedural Assessments 
Reasons for discontinuation of study drug include any of the following: 
 Significant violation of the protocol 
 Adverse event  
 Non-adherence to treatment regimen 
 Pregnancy 
 Lost to follow-up 
 Other reason (non-adverse event), including confirmed positive test for ADA to 
cemdisiran 
 Or, study is terminated by the Sponsor 
Patients who are pregnant will be discontinued from study drug dosing immediately (see 
Section 6.7.5.2 for reporting and follow-up of pregnancy).  A positive urine pregnancy test 
should be confirmed by a serum pregnancy test prior to discontinuing study drug. 
Patients who discontinue study drug and/or decline procedural assessments should not be 
automatically removed from study.  In general, patients who discontinue study drug dosing for 
any reason will be encouraged to remain on the study to complete the remaining assessments 
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through the Week 36/EOS or Week 84/OLE EOS visit and safety follow-up so that their 
experience is captured in the final analyses.  
If this occurs, the Investigator is to discuss with the patient the appropriate processes for 
discontinuation from study drug and must discuss with the patient the options for continuation of 
the Schedule of Assessments (Table 2), including different options for follow-up and collection 
of data (eg, in person, by phone, by mail, through family or friends, or from options not 
involving patient contact, such as communication with other treating physicians or from review 
of medical records), including endpoints and adverse events, and must document this decision in 
the patient’s medical records.  
If a patient discontinues dosing due to an AE, including SAEs, the event should be followed as 
described in Section 6.7.6.  When a patient discontinues study drug dosing, the primary reason 
must be recorded in the eCRF.  Patients who discontinue study drug and remain on study may 
receive treatment consistent with local standard practice for their disease per Investigator 
judgement, as applicable.  
Patients who discontinue from study drug during the 36-week treatment period (defined as the 
time the first dose of study drug is administered on Study Day 1 through completion of the 
Week 36 assessments) will be encouraged to remain on the study and complete assessments 
through Week 36; they will also be asked to complete safety follow-up visits 13, 26, 39 and 52 
weeks thereafter (see Table 1).  
Patients who discontinue study drug during the OLE period will be asked to return for their next 
scheduled visit to complete the OLE EOS/ET assessments; they will also be asked to complete 
safety follow-up visits 13, 26, 39 and 52 weeks thereafter (see Table 2). 
4.3.2. 
Stopping a Patient’s Study Participation 
4.3.2.1. 
Patient or Legal Guardian Stops Participation in the Study 
A patient or their legal guardian may stop participation in the study at any time.  A patient/legal 
guardian considering stopping participation in the study should be informed that they can 
discontinue study drug and/or decline procedural assessments and remain in the study to 
complete their study assessments through the Week 36 visit, including entering the 52-week 
safety follow-up.  If a patient/legal guardian still chooses to discontinue study drug and stop 
participation in all follow-up prior to the completion of the 36-week treatment period, every 
effort should be made to conduct early the assessments scheduled to be performed at the 
Week 36 EOS/ET visit (see Table 1).   
If the patient does not wish to or is unable to continue further study participation, the investigator 
is to discuss with the patient appropriate procedures for stopping participation in the study. Data 
collected from the patient can continue to be used. 
In addition, in the countries where the collection and processing of the patient data is based on 
the patient consent, if a patient withdraws consent to collect and process his/her data (see 
Section 4.3.2.2), as applicable, patient data up to the withdrawal of consent will be included in 
the analysis of the study.  In addition, where permitted, publicly available data (such as 
appropriate national or regional vital status registry or other relevant databases) can be included 
after withdrawal of consent, where available and allowable by local law. 
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4.3.2.2. 
Withdrawal of Consent to Process the Patient’s Personal Data  
Where allowed by local law, the patient may decide to withdraw consent to collect, store and use 
biological samples and, as applicable, other personal data, informing the study doctor at any time 
in writing or in any other form that may be locally required.  The Sponsor will continue to keep 
and use the patient’s study information (including any data resulting from the analysis of 
patient’s biological samples until the time of withdrawal) according to applicable law. The 
process for the storage and, as applicable, further use of remaining samples will be followed per 
local requirements. 
4.3.2.3. 
Investigator or Sponsor Stops Participation of a Patient in the Study 
The Investigator or Sponsor may stop the participation of a patient in the study at any time if this 
is considered to be in the patient’s best interest.  However, study integrity and interpretation are 
best maintained if all enrolled patients continue study assessments and follow-up even if study 
drug is discontinued. 
Termination of the clinical study and site closure are described in Section 8.1.6. 
4.3.2.4. 
Recording Reason for Stopping a Patient’s Study Participation 
The primary reason that a patient’s study participation is stopped must be recorded in the 
appropriate section of the eCRF and all efforts will be made to complete and report the 
observations as thoroughly as possible.  If a patient’s study participation is stopped due to an 
adverse event (AE), including serious adverse events (SAEs), the event should be followed as 
described in Section 6.7.6. 
4.3.3. 
Lost to Follow-Up 
A patient will be considered lost to follow-up if the patient repeatedly fails to return for 
scheduled visits and is unable to be contacted by the clinical study center.  The following actions 
must be taken if a patient fails to return to the clinic for a required study visit: 
 The site must attempt to contact the patient or legal guardian and reschedule the 
missed visit as soon as possible and counsel the patient or legal guardian on the 
importance of maintaining the assigned visit schedule and ascertain if the patient or 
legal guardian wishes to continue in the study, and/or should continue in the study.  
 Before a patient is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the patient or legal guardian (where possible, 3 
telephone calls and, if necessary, a certified letter to the patient’s last known mailing 
address or local equivalent methods).  These contact attempts should be documented 
in the patient’s medical record. 
 Should the patient or legal guardian continue to be unreachable, the patient will be 
considered to have stopped participation in the study. 
 For patients who are lost to follow-up, the Investigator can search publicly available 
records (where permitted and allowed by local law) to ascertain survival status.  This 
ensures that the outcome of the study is as comprehensive as possible. 
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4.3.4. 
Replacement of Study Patients  
Patients who discontinue the study drug or stop participation in the study during the 36-week 
treatment period or the OLE will not be replaced. 
 
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5. 
TREATMENTS AND OTHER REQUIREMENTS 
5.1. 
Treatments Administered 
Study drug supplied for this study must not be used for any purpose other than the present study 
and must not be administered to any person not enrolled in the study.  Study drug that has been 
dispensed to a patient and returned unused must not be re-dispensed to a different patient. 
5.2. 
Study Drug 
Detailed information describing the preparation, administration, and storage of cemdisiran and 
placebo is provided in the Pharmacy Manual. 
5.2.1. 
Description  
Cemdisiran will be supplied as a sterile solution for SC injection that contains 200 mg/mL 
cemdisiran sodium (equivalent to 189 mg/mL of cemdisiran), formulated in water for injection 
(WFI) for SC administration.  See the Pharmacy Manual for further details of solution 
concentration and fill volume. 
The control drug for this study will be a placebo (sodium chloride 0.9% w/v for SC 
administration).  Placebo will be provided by the Sponsor; it will be packaged identically to 
cemdisiran. 
5.2.2. 
Dose and Administration 
Patients will be administered cemdisiran (600 mg) or placebo (at the same volume as the active 
drug) as an SC injection once every 4 weeks in combination with standard of care in the 32-week 
treatment phase.  During the 52-week OLE phase, patients will be administered cemdisiran at a 
dose of 600 mg every 4 weeks in combination with standard of care. 
Study drug injections will be administered under the supervision of the Investigator or healthcare 
professional.  At-home dosing may be administered by a healthcare professional.  The injection 
site may 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, if permitted.  Detailed instructions for study 
drug administration are found in the Pharmacy Manual. 
To maintain the blind during the treatment period, the syringes are to be masked prior to study 
drug withdrawal.  A full description of the blinding procedure is included in the Pharmacy 
Manual.  
5.2.3. 
Dose Modifications 
Dose modifications are not permitted. 
If a study drug-related AE occurs in a patient that the Investigator judges as presenting a 
potential risk to the patient for further dosing, the study drug dose may be held at the discretion 
of the Investigator and the Medical Monitor should be contacted. 
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5.2.3.1. 
LFT Criteria for Withholding, Monitoring and Stopping Cemdisiran Dosing   
1. LFT results (Table 5) from the previous visit should be reviewed prior to dosing.  Central 
laboratory results are preferable.  If not available, local laboratory results may be used; 
however, if a local assessment is drawn, a serum chemistry sample must also be drawn 
for analysis at the central laboratory.  
2. For any ALT or AST elevation >3×ULN, central laboratory results should be used to 
guide subsequent monitoring as detailed in Table 4.  
3. For any ALT or AST elevation >3×ULN:  
a. Confirm using central laboratory, as soon as possible, ideally within 2 to 3 days, but 
no later than 7 days. 
b. Perform assessments per Table 4 and Table 6. 
c. If an alternative cause is found, provide appropriate care. 
4. For any ALT or AST elevation >3×ULN without alternative cause that is accompanied 
by clinical symptoms consistent with liver injury (eg, nausea, right upper quadrant 
abdominal pain, jaundice) or elevated bilirubin to ≥2×ULN or INR ≥1.5, permanently 
discontinue dosing. 
5. For confirmed ALT or AST elevations >3×ULN without alternative cause and not 
accompanied by symptoms or elevated bilirubin ≥2×ULN or INR ≥1.5, see Table 4  
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Table 4: Monitoring and Dosing Rules for Asymptomatic Patients with Confirmed 
Isolated Elevations of ALT and/or AST >3× ULN, with No Alternative Cause Identified 
Transaminase Level 
Action 
>3× to 5× ULN 
• 
May continue dosing   
• 
Evaluate the initial elevation in LFT per the following assessments: 
• 
Table 6 (all assessments to be performed once) 
• 
Hematology, serum chemistry, LFT, and coagulation per Table 5 
• 
Monitor at least every two weeks: LFT and coagulation per Table 6 
• 
If elevation persists for ≥2 months, must discuss with the Medical Monitor 
before continuing dosing 
>5× to 8× ULN 
• 
Hold cemdisiran dosing until recovery to ≤1.5×ULN; may resume dosing 
after discussion with the Medical Monitor 
• 
Evaluate the initial elevation in LFT per the following assessments 
• 
Table 6 (all assessments to be performed once) 
• 
Hematology, serum chemistry, LFT, and coagulation per Table 5 
• 
Monitor at least weekly: LFT and coagulation per Table 6 until ALT and/or 
AST is declining on 2 consecutive draws, then may decrease monitoring to 
biweekly 
• 
If ALT or AST rises to >5×ULN following resumption of dosing, 
permanently discontinue dosing 
>8× ULN 
Permanently discontinue dosing after confirmation of the transaminase value 
Abbreviations: ALT=alanine transaminase; AST=aspartate transaminase; INR=international normalized ratio; 
LFT=liver function test(s); ULN=upper limit of normal. 
Notes:   In addition to these criteria, other assessments or evaluations may be performed per Investigator discretion, 
as appropriate. 
5.2.4. 
Preparation, Handling, and Storage 
Staff at each clinical study center or the home healthcare professional will be responsible for 
preparation of cemdisiran doses, according to procedures detailed in the Pharmacy Manual.  No 
special procedures for the safe handling of study drug are required. 
Study drug will be stored upright and refrigerated at approximately 2 to 8°C.  The vial should be 
stored in the carton until ready for use in the storage area of the clinical study site pharmacy, in a 
secure, temperature-controlled, locked environment with restricted access.  Deviations from the 
recommended storage conditions should be reported to the Sponsor and use of the study drug 
halted until authorization for its continued use has been provided by the Sponsor or designee, as 
described in the Pharmacy Manual. 
A Sponsor representative or designee will be permitted, upon request, to audit the supplies, 
storage, dispensing procedures, and records. 
Instructions specific to unused study drug and additional storage will be provided in the 
Pharmacy Manual. 
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5.2.5. 
Packaging and Labeling 
All packaging, labeling, and production of study drug will be in compliance with current Good 
Manufacturing Practice specifications, as well as applicable local regulations. Study drug labels 
and external packaging will include all appropriate information as per local labeling 
requirements.  
Cemdisiran (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 a 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. 
Additional details will be available in the Pharmacy Manual. 
5.2.6. 
Accountability 
The Investigator or designee will maintain accurate records of receipt and the condition of the 
study drug supplied for this study, including dates of receipt.  In addition, accurate records will 
be kept of when and how much study drug is dispensed and administered to each patient in the 
study.  Any reasons for departure from the protocol dispensing regimen must also be recorded. 
At the completion of the study, there will be a final reconciliation of all study drugs.  Used, 
partially used, and unused study drug will be returned to the Sponsor (or designee) or destroyed 
at the clinical study center according to applicable regulations. 
Further instructions about drug accountability will be detailed in the Pharmacy Manual. 
5.3. 
Concomitant Medications and Procedures 
The standard of care treatment should be held stable throughout the run-in and treatment periods. 
Use of concomitant medications and procedures will be recorded on the patient’s eCRF as 
specified in the Schedule of Assessments (see Table 1 and Table 2).  This includes all 
prescription medications, herbal preparations, over the counter medications, vitamins, and 
minerals.  Any changes in medications during the study will also be recorded on the eCRF. 
If patients use nonsteroidal anti-inflammatory drugs intermittently or chronically, they must have 
been able to tolerate them with no previous side effects (eg, gastric distress or bleeding).   
Standard vitamins and topical medications are permitted.  However, topical steroids must not be 
applied anywhere near the injection site(s) unless medically indicated.   
For other permitted concomitant medications administered SC, do not administer in same 
injection site area as the study drug/placebo, for 7 days after the last dose of either study drug or 
placebo.  
Any concomitant medication that is required for the patient’s welfare may be administered by the 
Investigator.  However, it is the responsibility of the Investigator to ensure that details regarding 
the medication are recorded on the eCRF.  Concomitant medication will be coded using an 
internationally recognized and accepted coding dictionary. 
5.3.1. 
Prohibited Concomitant Medications 
The following concomitant medications are prohibited during the study:  
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 Systemic steroids (short-term steroid course for <7 days for common conditions not 
related to IgAN (i.e. asthma, gout) is permitted) 
 Immunosuppressive agents 
 Fish oil supplements (if started prior to screening, then may continue during the study 
at the same dose) 
 Hydroxychloroquine 
5.3.2. 
Study-specific Vaccinations 
5.3.2.1. 
Meningococcal Vaccinations 
All patients taking part in this study must be vaccinated against meningitis types A, C, W135, Y 
and B, upon determination of eligibility at the end of run-in period, 2 weeks prior to 
randomization to cemdisiran or placebo, as per the Schedule of Assessments.  Meningococcal 
group ACWY conjugate vaccine and meningococcal group B vaccine will be administered in 
accordance with the manufacturer’s instructions and according to the Advisory Committee on 
Immunization Practices (ACIP) or other locally applicable recommendations for patients with 
complement deficiencies. On days of vaccination, urinary samples should be collected prior to 
administration of vaccines. 
Patients will be immunized against Neisseria meningitidis according to the following 
specifications: 
 Patients who have previously completed the recommended series of meningococcal 
vaccinations (meningococcal group ACWY conjugate vaccine and meningococcal 
group B vaccine) at least 14 days but no more than 3 years from randomization can 
start study assessments after confirming eligibility.  Documented vaccine history 
must be available to, and verified by, study site staff at the time of Screening. 
 Patients who were previously vaccinated with polysaccharide type vaccines within 
3 years of study entry will be revaccinated using conjugate vaccines if found eligible 
at the end of the run-in period.   
 Patients who have not been previously vaccinated against Neisseria meningitidis, 
those without documentation of vaccination history, or those vaccinated more than 
3 years from study randomization will commence the vaccination series with the 
recommended meningococcal vaccines (meningococcal group ACWY conjugate 
vaccine and meningococcal group B vaccine) per the Schedule of Assessments if 
determined to be eligible for the study at the end of the run-in period.   
 If required locally, patients will receive prophylactic antibiotics according to the local 
standard of care after randomization to cemdisiran or placebo. 
5.3.2.2. 
Pneumococcal and Hib Vaccinations 
Patients will receive vaccinations for Hib and Streptococcus pneumoniae, if not previously 
vaccinated, according to current national/local vaccination guidelines for vaccination use. Hib 
and pneumococcal vaccinations (if required at screening per national/local guidelines; 
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vaccination should occur prior to Week-2. At screening, patient vaccination records will be 
checked for compliance with local recommendations for the use of these vaccines.  
5.4. 
Treatment Compliance 
Compliance with study drug administration will be verified through observation by study staff or 
trained home healthcare professionals. 
5.5. 
Other Requirements 
5.5.1. 
Contraception 
Females of child-bearing potential must be willing to use a highly effective method of 
contraception from 14 days before first dose, throughout study participation, and for 90 days 
after last dose administration or until study completion.   
Birth control methods which are considered highly effective include: 
 Placement of an intrauterine device. 
 Placement of an intrauterine hormone-releasing system.  
 Bilateral tubal occlusion. 
 Surgical sterilization of male partner (with the appropriate post-vasectomy 
documentation of the absence of sperm in the ejaculate; for female patients on the 
study, the vasectomized male partner should be the sole partner for that patient). 
 Established use of oral (except low-dose gestagens), implantable, injectable, or 
transdermal hormonal methods of contraception. Females of child-bearing potential 
who use hormonal contraceptives as a method of contraception must also use a barrier 
method (condom or occlusive cap [diaphragm or cervical/vault cap] in conjunction 
with spermicide [eg, foam, gel, film, cream, or suppository]).   
 True sexual abstinence, when in line with the preferred and usual lifestyle of the 
patient.  Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception.  Abstinent 
patients must agree to use one of the above-mentioned contraceptive methods if they 
start sexual relationships during the study and for up to 90 days after the last dose of 
study drug. 
Investigators should advise females of childbearing potential of the most appropriate birth 
control method available within their country taking into account local medical practice. 
Females of child-bearing potential include female patients who have experienced menarche (or 
begin menarche over the course of the study) and who are not postmenopausal or permanently 
sterilized (eg, bilateral tubal occlusion, hysterectomy, or bilateral salpingectomy).  A 
postmenopausal state is defined as the absence of menses for 12 months without an alternative 
medical cause, confirmed by follicle stimulating hormone level within the postmenopausal 
range.  
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For male patients, no contraception is required. However, use by males of contraception 
(condom) may be required in some countries e.g. France, in order to comply with local 
requirements as described in the corresponding patient consent forms 
Compliance with contraception requirements will be assessed on a regular basis by the 
Investigator throughout the course of the study (see Section 6.7.5.2). 
5.5.2. 
Alcohol Restrictions 
Patients will limit alcohol consumption throughout the course of the study.  Alcohol is limited to 
no more than 2 units per day (unit:  1 glass of wine [approximately 125 mL] = 1 measure of 
spirits [approximately 1 fluid ounce] = ½ pint of beer [approximately 284 mL]) for the duration 
of the study. 
5.5.3. 
Antibiotic Compliance 
Patients who require prophylactic antibiotics after randomization to cemdisiran or placebo (see 
Section 5.3.2.1) per local standard of care will undergo antibiotic compliance checks.  Antibiotic 
compliance checks will be performed at the time points in the Schedule of Assessments.  
Antibiotic dose adjustments will be permitted in the case of renal impairment.  All dose 
adjustments must comply with the manufacturer’s instructions. 
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6. 
STUDY ASSESSMENTS 
The Schedule of Assessments is provided in Table 1 and Table 2. 
6.1. 
Screening Assessments 
An ICF approved by the appropriate Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) must be signed by the patient (or legal guardian) before the Screening 
procedures are initiated.  All patients (or their legal guardians) will be given a copy of the signed 
and dated ICF.  
Patients will be screened to ensure that they meet all the inclusion criteria and none of the 
exclusion criteria.  Rescreening of patients is permitted with consultation of the Medical 
Monitor; see Section 6.1.1.  
Patient demographic data and medical history/disease history will be obtained. In particular, the 
MEST-C score and degree of IgG, IgA, IgM, C3, C1q, C4d and C5b-9 stains will be obtained 
from pathology reports, if available, and documented. Any changes to medical history occurring 
between the Screening assessment and Day 1 will be updated prior to study drug administration. 
Additional screening assessments include a full physical examination (with emphasis on 
presence/degree of edema), collection of vital signs, height, weight and body mass index (BMI), 
12-lead electrocardiogram (ECG), clinical laboratory assessments, pregnancy, 24-hours urine 
proteinuria assessment (from a single valid collection; see Section 6.4.1.1), eGFR, urinalysis and 
ADA and CIC assessments. Vaccination records will also be checked for compliance with 
national/local guidelines for pneumococcal and Hib vaccinations. 
6.1.1. 
Rescreening 
A patient who does not meet all study eligibility criteria due to a transient condition observed at 
Screening (eg, prohibited medications that were subsequently discontinued) will be allowed to 
return for rescreening (once only).  A patient will be re-consented if rescreening occurs outside 
of the 90-day screening window.  In this case, all screening procedures must be repeated.  
6.1.2. 
Retesting 
If in the Investigator’s judgement, the screening laboratory abnormalities are likely to be 
transient, then laboratory tests may be repeated.  The Investigator’s rationale is to be 
documented.  Laboratory values can be retested once during Screening as long as the patient can 
be evaluated for eligibility and randomized within the allowed Screening period. 
6.2. 
Run-in Period 
During the 14-week run-in period, the following will be performed at time points specified in the 
Schedule of Assessments (Table 1): Hib and pneumococcal vaccinations (if required at screening 
per national/local guidelines; vaccination should occur prior to Week-2), vital signs, clinical 
laboratory assessments, pregnancy test, 24-hour urine proteinuria assessment (from 2 single valid 
collections; see Section 6.4.1.1), urinalysis for hematuria, spot urine for proteinuria, and eGFR.  
Clinical laboratory tests will be performed centrally; however, hematuria and eGFR will also be 
assessed locally at the end of the run-in period (Week-2) to facilitate assessment of patient 
eligibility and administer meninogococcal vaccination on the same day.  Meningococcal 
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vaccines should be administered only if patient eligibility for randomization is confirmed and 
after urine collections are completed.  
Sites are encouraged to discuss study information with the patients again at the end of the run-in 
period. 
6.3. 
Baseline Assessments (Treatment Period) 
Prior to dosing on Day 1, patients will be reassessed for eligibility and blood and urine samples 
for clinical laboratory assessments and exploratory analyses collected, including blood samples 
for complement activity tests (CAP/CCP), C5 analysis, PK, ADA and CIC.  
In addition, prior to administration of study drug, the following assessments will be performed:  
full physical examination, body weight and height, vital signs, ECG, urine pregnancy test, eGFR 
assessment, and urinalysis.  
Collection of blood and urine samples for PK analysis on Day 1 will be performed as outlined in 
Table 3.   
6.4. 
Efficacy Assessments 
6.4.1. 
Proteinuria 
Primary efficacy will be assessed by determining the percent change from baseline in 24 hour 
proteinuria (g/24-hour) after 32 weeks of treatment. 24 hour urine samples for determination of 
proteinuria will be collected throughout the study as outlined in the Schedules of Assessments 
and will be analyzed by a central laboratory. 
6.4.1.1. 
24-Hour Urine Collection 
Patients will be required to provide two separate valid 24-hour urine collections 2 weeks prior to 
randomization (to assess eligibility after the run-in period) and at Week 32 (to assess the primary 
endpoint). Patients will also be asked to provide a single valid 24-hour urine sample for other 
24-hour urinary assessments outlined in the Schedule of Assessments. Rigorous exercise and 
significant change in diet (in particular salt intake) should be avoided within 48 hours before 
collection of 24-hour urine samples, whenever possible. The two valid 24-hour urine samples 
may be collected within 2 weeks before assessment is due while the one valid 24-hour urine 
sample may be collected within one week before the assessment takes place. If any of the 
collections do not meet validity criteria outlined below, then repeat collections must be 
scheduled within the time frames outlined above to assure the minimum number of valid 
collections required for each of the study time points. The duration of collection and volume of 
urine in the collection will be recorded in the eCRF. In addition to protein, albumin, sodium and 
creatinine will also be quantified in each of the 24-hour urine samples. Both protein/creatinine 
(UPCR) as well as albumin/creatinine ratios (UACR) will also be calculated in an aliquot of the 
24-hour urine collection.   
Completeness of the 24-hour urine collection can be estimated from rate of creatinine excretion. 
Normal values of creatinine excretion vary with age and body weight. An aliquot of the 24-hour 
urine collection will be used to determine urinary creatinine content to determine if the 24-hour 
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urine collections need to be repeated. Hence, a 24-hour urine collection will only be considered 
valid if all the following criteria are met, otherwise a repeat urine collection will be required: 
 The collection is between 22-26 hours in duration between the initial discarded void 
and the last void or attempt to void. 
 No voids are missed between the start and end time of the collection as indicated by 
the patient’s urine collection diary. 
 The 24-hour creatinine content is within 25% of expected range as estimated by the 
following formula:  [(140-age) x weight]/5000, where weight is in kilograms. This 
result is multiplied by 0.85 in women.[Ix 2011] 
 In case of need of two valid samples, the maximum variation in total 24-hour urine 
creatinine between the two urine collections must be <25%. 
Primary efficacy will be evaluated by comparing the percent change from baseline in 24-hour 
proteinuria (g/24-hours) at Week 32 in patients treated with cemdisiran versus those treated with 
placebo.  
Secondary and exploratory efficacy assessments include comparisons of the proportion of 
patients with partial or complete clinical remission, respectively, as measured by the amount of 
urine protein (UP) in a 24-hour urine sample.  Partial clinical remission is defined as having UP 
<1 g/24-hours and complete clinical remission is defined as UP <0.3 g/24-hours.  Each will be 
assessed at Week 32. 
Additionally, using 24-hour samples, the change from baseline in the UP/creatinine ratio (UPCR) 
will be evaluated as a secondary endpoint and the change from baseline in urine 
albumin/creatinine ratio (UACR) at Week 32 as an exploratory endpoint. 
6.4.1.2. 
Spot Urine Collection 
Urinary protein, albumin and creatinine levels from spot urine collections prior to dosing will 
also be measured to assess the effect of cemdisiran on urinary protein/creatinine (UPCR) and 
albumin/creatinine (UACR) as outlined in the Schedule of Assessments. 
The change from baseline in UPCR at Week 32 will be evaluated in spot urine samples.  Spot 
urine samples will be collected at the time points outlined in the Schedule of Assessments 
(Table 1).   
6.4.2. 
Hematuria 
Hematuria from spot urine collections will also be evaluated to assess the effect of cemdisiran on 
disease course in patients with IgAN. The degree of hematuria will be assessed by examination 
of the spun urine sediment by microscopy (RBC/hpf). Single void collections for random urine 
sample for hematuria evaluation should be collected. If the investigator determines that the 
hematuria is transient due to menses in women or exercise, the sample may need to be repeated. 
Random spot urine samples for hematuria measurement will be collected throughout the study as 
outlined in the Schedule of Assessments and will be analyzed by a central laboratory.  On dosing 
days, samples should be collected prior to study drug administration, if applicable. 
To allow evaluation of eligibility on the same day at the end of the run in period, 2 weeks prior 
to randomization, the single void can be split in two containers, one evaluated by local lab and 
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another by central lab. The local hematuria evaluation by microscopy or urinary dipstick will be 
utilized to determine eligibility for the study at the end of the run-in period. 
6.4.3. 
Changes in Renal Function 
Changes in renal function will be monitored using measurements of serum creatinine and eGFR 
(mL/min/1.73m2) as outlined in the Schedule of Assessments. The calculation will be based on 
the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula for all patients. 
For assessment of eligibility at the last visit of run-in period, 2 weeks prior to randomization, 
local lab can be utilized. This will allow evaluation for eligibility on the same day. A sample will 
also be sent to central lab. 
Renal function will also be estimated as creatinine clearance based on the 24-hour urine 
collection. The creatinine clearance is a widely used test to estimate the GFR using the following 
formula: 
GFR  =  [UCr  x  V] / SCr 
SCr is the serum creatinine concentration and the value assessed closest to collection of 24-hour 
urine collection will be utilized for purpose of above calculation. UCr is the urine creatinine 
concentration and V is the urine flow rate or volume. 
Blood and urine samples for renal function assessments will be collected prior to administration 
of cemdisiran or placebo on dosing days, if applicable. 
The change from baseline in eGFR will be measured throughout the course of the study. In 
addition, the slope of eGFR will be computed for the first 32 weeks and the entire study period 
(including the OLE).  
6.4.4. 
Markers of Complement Activation, Inflammation and Renal Injury 
Samples for measurement of markers of complement activation, inflammation and renal injury 
will be collected at the time points outlined in the Schedule of Assessments (Table 1) and 
analyzed by central laboratories. On dosing days, blood samples will be collected predose. 
6.5. 
Pharmacodynamic Assessments 
Blood samples for PD analysis will be collected at the time points outlined in the Schedule of 
Assessments (Table 1).  Samples will be collected prior to administration of cemdisiran or 
placebo on dosing days. 
Analysis of PD will include the impact of cemdisiran administration on plasma C5 protein levels 
(assessed by a mass spectrometry-based method) and serum complement activity (assessed by 
CAP enzyme linked immunosorbent assay [ELISA] and CCP ELISA).  Samples will be analyzed 
at central laboratories.  Details regarding the collection, processing, shipping, and storage of the 
samples will be provided in the Laboratory Manual. 
6.6. 
Pharmacokinetic Assessments 
Blood samples and urine samples will be collected for assessment of cemdisiran PK parameters 
and possible metabolite analysis at the time points in the Schedule of Assessments.  A detailed 
schedule of time points for the collection of blood samples and urine samples for PK analysis is 
in Table 3. 
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The concentration of cemdisiran will be determined using a validated assay.  Details regarding 
sample volumes to be collected, and the processing, shipping, and analysis of the samples will be 
provided in the Laboratory Manual. 
6.7. 
Safety Assessments 
The assessment of safety during the study will consist of the surveillance and recording of the 
frequency of AEs including SAEs, recording of concomitant medication and measurements of 
vital signs, weight and height, physical examination, and ECG findings and laboratory tests, 
including assessment of IgG/IgM/IgA ADA and CIC. Clinically significant abnormalities 
observed during the physical examination are recorded.   
Safety will be monitored over the course of the study by a DMC as described in Section 3.7. 
6.7.1. 
Vital Signs 
Vital signs will be measured as specified in the Schedule of Assessments (Table 1 and Table 2) 
and include blood pressure, heart rate, oral body temperature, and respiratory rate.  Vital signs 
will be measured in the seated or supine position, after the patient has rested comfortably for 
10 minutes.  On Day 1, vital signs will be collected at predose and 4 hours postdose.  On all 
other dosing days, vital signs will be collected predose.  
Blood pressure should be taken using the same arm throughout the study.  Body temperature in 
degrees Celsius will be obtained via oral method.  Heart rate will be counted for a full minute 
and recorded in beats per minute, and respiration rate will be counted for a full minute and 
recorded in breaths per minute. 
Additional vital sign assessments, as medically indicated, may be added at the discretion of the 
Investigator, or as per DMC advice. 
Vital signs results will be recorded in the eCRF. 
6.7.2. 
Weight and Height 
Height will be measured in centimeters.  Body weight will be measured in kilograms.  Height 
and body weight measurements will be collected as specified in the Schedule of Assessments 
(Table 1 and Table 2; height at Screening only and dosing weight during the clinical study center 
visits) and will be recorded in the eCRF. 
6.7.3. 
Physical Examination 
Full physical examinations will be conducted according to the Schedule of Assessments (Table 1 
and Table 2); if a physical examination is scheduled for a dosing visit, it should be conducted 
prior to dosing.  On Day 1, routine physical examination will be performed at predose and 4 
hours postdose.  On all other dosing days, the routine physical examination will be performed 
predose. 
Full physical examinations will include the examination of the following:  general appearance; 
head, eyes, ears, nose and throat; respiratory, cardiovascular, gastrointestinal, musculoskeletal, 
and dermatological systems; thyroid; lymph nodes; and neurological status. 
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Directed physical examinations will include examination of the following:  respiratory, 
cardiovascular, dermatological, gastrointestinal, and musculoskeletal systems. 
Clinically significant abnormalities observed during the physical examination are recorded on 
the medical history or AE eCRF. 
6.7.4. 
Electrocardiogram 
Twelve-lead ECGs reporting rhythm, ventricular rate, RR interval, PR interval, QRS duration, 
and QT interval and Fridericia-corrected QT interval will be obtained, as specified in the 
Schedule of Assessments (Table 1 and Table 2). Patients should be supine for at least 5 minutes 
before each ECG is obtained. A single 12-lead ECG will be performed at Screening.  At all other 
time points, 12-lead ECGs will be performed in triplicate, with readings approximately 1 minute 
apart. 12-lead ECGs will be performed at predose; 60 minutes postdose; and 4 hours postdose in 
relation to the Day 1 and Week 32 cemdisiran or placebo doses. 
When ECG and blood sample collection occur at the same time, ECGs should be performed 
before blood samples are drawn. 
The Investigator or qualified designee will review all ECGs to assess whether the results have 
changed since the Baseline visit and to determine the clinical significance of the results.  These 
assessments will be recorded on the eCRF.  Additional ECGs may be collected at the discretion 
of the Investigator, or as per DMC advice.   
6.7.5. 
Clinical Laboratory Assessments 
The following clinical laboratory tests will be evaluated by a central laboratory. However, to 
assess patient eligibility at the end of the run-in period, hematuria and eGFR will also be 
assessed locally. Specific instructions for transaminase elevations are provided in 
Section 5.2.3.1.  For any other unexplained clinically relevant abnormal laboratory test occurring 
after study drug administration, the test should be repeated and followed up at the discretion of 
the Investigator, or as per DMC advice, until it has returned to the normal range or stabilized, 
and/or a diagnosis is made to adequately explain the abnormality.  Additional safety laboratories 
and assessments as indicated by the clinical situation may be requested.  Clinical laboratory 
assessments are listed in Table 5 and include: hematology, serum chemistry and urinalysis 
parameters. Parameters will be assessed as specified in the Schedule of Assessments (Table 1 
and Table 2).  
While local laboratory results may be used for urgent clinical and dosing decisions, on the day of 
the clinic visit assessments, all laboratory assessments specified in Table 5 which are performed 
at the clinic should also be sent in parallel to the central laboratory.  In the case of discrepant 
local and central laboratory results on samples drawn on the same day, central laboratory results 
will be relied upon for clinical and dosing decisions. 
Clinical laboratory assessments may be collected at the clinical study center or at home by a 
trained healthcare professional. On dosing days blood samples will be collected predose. 
For any safety event or laboratory abnormality, additional laboratory assessments, imaging, and 
consultation may be performed for clinical evaluation and/or in consultation with the Medical 
Monitor; results may be collected and should be included in the clinical database. 
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Table 5: 
Clinical Laboratory Assessments 
Hematology 
Complete blood count with differential 
 
Serum Chemistry 
Sodium 
Potassium 
BUN 
Phosphate 
Creatinine and eGFR (using the CKD-EPI formula)  
Albumin 
Uric acid 
Calcium 
Total protein 
Carbon dioxide 
Glucose 
Chloride 
Liver Function Tests 
 
AST 
ALP 
ALT 
Bilirubin (total and direct) 
GGT  
 
Urinalysis 
Visual inspection for appearance and color 
Bilirubin 
pH (dipstick) 
Nitrite 
Specific gravity 
RBCs 
Ketones 
Urobilinogen 
Albumin 
Leukocytes 
Glucose 
Microscopy 
Protein 
 
Coagulation  
Prothrombin time 
International Normalized Ratio 
Partial Thromboplastin Time 
 
Immunogenicity (see Section 6.7.5.1) 
Antidrug antibodies 
Hepatic Tests (Screening Only)  
Hepatitis C, including:  
HCV RNA PCR – qualitative and quantitative 
assays 
Hepatitis B, including:  
HBs Ag, HBc antibody IgM and IgG 
Pregnancy Testing (Females of Child-bearing Potential Only) (see Section 6.7.5.2) 
β-human chorionic gonadotropin 
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Abbreviations:  ALP=alkaline phosphatase; ALT=alanine transaminase; AST=aspartate transaminase; BUN=blood 
urea nitrogen; CKD-EPI=Chronic Kidney Disease Epidemiology Collaboration; eGFR=estimated glomerular 
filtration rate; GGT=gamma glutamyl transferase; HAV=hepatitis A virus; HBsAg=hepatitis B virus surface 
antigen; HBc=hepatitis B virus core; HCV=hepatitis C virus; IgG= IgG=immunoglobulin G antibody; 
IgM=immunoglobulin M antibody; PCR=polymerase chain reaction; RBC=red blood cell; RNA=ribonucleic acid. 
6.7.5.1. 
Immunogenicity 
Blood samples will be collected to evaluate ADA and CIC.  IgG/IgM/IgA ADA to total drug will 
be assessed at screening and during the study. ADA samples will be tested in real time. Clinical 
study decision will be based on confirmed positive ADA results from the IgG/IgM/IgA assay. 
Confirmed positive ADA samples will be further characterized for cemdisiran domain specificity 
against the Tri-GalNAc component if a reliable method is established.  Blood samples for ADA 
and CIC testing must be collected before study drug administration as specified in the Schedule 
of Assessments (Table 1 and Table 2).  Blood samples to evaluate ADAs will be collected at 
Screening to assess study eligibility and at the Early Termination (ET) visit, if applicable. ADA 
and CIC will be routinely monitored during the treatment period and throughout the open-label 
extension phase and safety follow up, as indicated in the Schedule of Assessments. Finally, ADA 
and CIC samples will also be collected and analyses will be performed and prioritized if any 
clinical evidence of progression of IgAN disease and/or relevant safety findings. Patients who 
are confirmed positive for IgG/IgM/IgA ADA at baseline will be excluded from study treatment. 
In addition, patients who develop de novo ADAs will be discontinued from study drug but will 
be followed until EOS visit and during safety follow up. These patients will also be monitored 
until ADA levels return to baseline. 
Exploratory analysis of Gd-IgA1 levels and IgA-containing immune complexes may be 
conducted; blood samples for these analyses will be drawn when CIC samples are collected to 
enable these assays. 
For US patients only, an optional blood sample may be collected at screening to evaluate any 
potential for B-cell stimulation by cemdisiran, at the Sponsor’s discretion. 
Details regarding the processing, shipping, and analysis of the samples will be provided in the 
Laboratory Manual. 
6.7.5.2. 
Pregnancy Testing 
A pregnancy test will be performed for females of child-bearing potential.  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.  Patients 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.  Patients determined to 
be pregnant while on study will be followed until the pregnancy outcome is known (see Section 
6.7.6.7 for follow-up instructions).  
6.7.5.3. 
Additional Liver Function Assessments 
Additional laboratory assessments will be performed in patients who experience any liver 
function test (LFT) abnormalities.  Following the occurrence of elevated liver transaminases or 
other LFT abnormalities per central laboratory, all assessments in Table 6 will be performed one 
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time, as well as hematology, serum chemistry, LFT, and coagulation assessments from Table 5, 
and other assessments or evaluations per Investigator discretion, as appropriate. 
 
Table 6: 
Hepatic Assessments in Patients Who Experience Elevated Transaminases 
Extended Hepatic Panel 
Herpes Simplex Virus 1 and 2 antibody IgM, IgG 
Herpes Zoster Virus IgM, IgG 
HIV 1 and 2a 
HHV-6  
Cytomegalovirus antibodies, IgM, IgG 
HBs Ag, HBc antibody IgM and IgG 
Anti-nuclear antibodies 
Epstein-Barr Virus antibodies, IgM and IgG 
Anti-smooth muscle antibodies 
Anti-mitochondrial antibodies 
HCV antibody 
HAV antibody IgM 
HCV RNA PCR – qualitative and quantitative 
HEV antibody IgM 
Imaging 
Abdominal ultrasound with Doppler flow (or CT or MRI) including right upper quadrant 
Focused Medical and Travel History 
Use of any potentially hepatotoxic concomitant 
medications, including over the counter medications 
and herbal remedies 
Alcohol consumption  
Other potentially hepatotoxic agents including any 
work-related exposures 
Recent travels to areas where hepatitis A or E 
is endemic 
Abbreviations:  CT=computed tomography; HAV=hepatitis A virus; HBc=hepatitis B core; HBsAg=hepatitis B 
virus surface antigen; HCV=hepatitis C virus; HEV=hepatitis E virus; HHV-6=human herpesvirus 6; HIV=human 
immunodeficiency virus; IgG=immunoglobulin G antibody; IgM=immunoglobulin M antibody; MRI=magnetic 
resonance imagery; PCR=polymerase chain reaction; RNA=ribonucleic acid. 
Note: 
 
All assessments will be measured in central laboratory. The full panel of assessments should only be 
performed once; individual assessments may be repeated, as needed. 
 
a HIV testing will not be performed where prohibited by local regulations. 
6.7.6. 
Adverse Events 
6.7.6.1. 
Definitions 
Adverse Event  
According to the International Council on Harmonisation (ICH) E2A guideline Definitions and 
Standards for Expedited Reporting, and 21 CFR 312.32, investigational new drug (IND) Safety 
Reporting, an AE is any untoward medical occurrence in a patient or clinical investigational 
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subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
 Results in death 
 Is life-threatening (an event which places the patient at immediate risk of death from 
the event as it occurred.  It does not include an event that had it occurred in a more 
severe form might have caused death) 
 Requires in-patient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability or incapacity 
 Is a congenital anomaly or birth defect 
 Is an important medical event that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient and may require 
intervention to prevent one of the other outcomes listed in the definition above (eg, 
events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias, convulsions, or the development of drug 
dependency or abuse). 
Adverse Events of Clinical Interest 
Based on the biological target and the available nonclinical and clinical data, AEs of Clinical 
Interest (AECI) for this study are: 
 Severe infections as judged by the investigator  
 ALT or AST >3×ULN 
 Severe or serious injection site reactions (ISRs); ISRs that are associated with a recall 
phenomenon (reaction at the site of a prior injection with subsequent injections), or 
those that lead to temporary dose interruption or permanent discontinuation of 
cemdisiran. 
An ISR is defined as a local reaction at or near the site of injection.  “At or near” the 
injection site includes reactions at the injection site, adjacent to the injection site, or a 
reaction which may shift slightly away from the injection site due to gravity (eg, as 
may occur with swelling or hematoma).  A systemic reaction which includes the 
injection site (eg, generalized urticaria, other distinct entities or conditions like 
lymphadenopathy that may be near the injection site) is not considered an ISR.  
For information on recording and reporting of AECIs, see Section 6.7.6.2 and Section 6.7.6.3 , 
respectively. 
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Adverse Event Severity 
Adverse events are to be graded according to the categories detailed below: 
Mild: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Moderate: 
Moderate; minimal, local or noninvasive intervention indicated; limiting age 
appropriate instrumental activities of daily living (eg, preparing meals, 
shopping for groceries or clothes, using the telephone, managing money). 
Severe: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care activities of daily living (ie, bathing, dressing and undressing, feeding 
self, using the toilet, taking medications, and not bedridden); OR life-
threatening consequences; urgent intervention indicated; OR death related to 
an 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 SAE). 
Relationship of the Adverse Event to Study Drug 
The relationship of each AE to study drug should be evaluated by the Investigator by a “yes” or 
“no” response to the question: “Is there a reasonable possibility that the event may have been 
caused by the study drug?” 
6.7.6.2. 
Eliciting and Recording Adverse Events 
Eliciting Adverse Events 
The patient and legal guardian, if applicable, should be asked about medically relevant changes 
in the patient’s health since the last visit.  The patient and legal guardian, if applicable, should 
also be asked if the patient has been hospitalized, had any accidents, used any new medications, 
or changed concomitant medication routines (both prescription and over-the-counter).  In 
addition to patient observations, AEs will be documented from any clinically relevant laboratory 
findings, physical examination findings, ECG changes, or other findings that are relevant to 
patient safety. 
Recording Adverse Events 
The Investigator is responsible for recording all SAEs and only AEs related to study procedures 
that are observed or reported by the patient during the run-in period (before the administration of 
the first dose of study drug) regardless of their relationship to study drug through the end of 
study.  Events occurring after signing of the ICF and before study drug administration will be 
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captured as medical history (see Section 6.1).  All AEs will be collected starting after 
administration of the first dose through the end of the safety follow-up period. 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 study drug, action 
taken, and outcome (including time and date of resolution, if applicable). 
For SAEs, record the event(s) on both the eCRF and the SAE form.  
For AEs that are considered AEs of clinical interest (Section 6.7.6.1), the supplemental AEs of 
Clinical Interest eCRF should be completed.  Additional clinical and laboratory information may 
be collected.  Refer to CRF completion guidelines for details on reporting events in the 
supplemental AEs of Clinical Interest eCRF.   
For all ISRs, the Investigator, or delegate, should submit a supplemental ISR eCRF, recording 
additional information (eg, descriptions, onset and resolution date, severity, treatment given, 
event outcome). 
6.7.6.3. 
Reporting Adverse Events of Clinical Interest to Sponsor/Designee 
For AEs that are considered AECIs (Section 6.7.6.1), the Sponsor or its designee should be 
notified within 24 hours using a supplemental AEs of Clinical Interest eCRF. 
6.7.6.4. 
Serious Adverse Events Require Immediate Reporting to Sponsor/Designee 
An assessment of the seriousness of each AE will be made by the Investigator.  Any AE and 
laboratory abnormality that meets the SAE criteria in Section 6.7.6.1 must be reported to the 
Sponsor or designee within 24 hours from the time that clinical study center staff first learns of 
the event.  All SAEs must be reported regardless of the relationship to study drug. 
The initial report should include at least the following information: 
 Patient’s study number 
 Description and date of onset of the event 
 Criterion for serious 
 Preliminary assignment of relationship to study drug, and 
 Investigator/site information 
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To report the SAE, complete the 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 Investigator Site File. 
Appropriate remedial measures should be taken by the Investigator using his/her best medical 
judgment to treat the SAE.  These measures and the patient’s response to these measures should 
be recorded.  All SAEs, regardless of relationship to study drug, will be followed by the 
Investigator until satisfactory resolution or the Investigator deems the SAE to be chronic or 
stable.  Clinical, laboratory, and diagnostic measures should be employed by the Investigator as 
needed to adequately determine the etiology of the event. 
6.7.6.5. 
Sponsor Safety Reporting to Regulatory Authorities 
The Sponsor or its representative will report certain study events in an expedited manner to the 
Food and Drug Administration, the European Medicines Agency’s EudraVigilance electronic 
system according to Directive 2001/20/EC, and to all country Regulatory Authorities where the 
study is being conducted, according to local applicable regulations. 
6.7.6.6. 
Serious Adverse Event Notification to the Institutional Review 
Board/Independent Ethics Committee 
Suspected unexpected serious adverse reactions (SUSARs) will be reported to the IRB/IEC per 
their institutional policy by the Investigator or Sponsor (or Sponsor designee) according to 
country requirements.  Copies of each report and documentation of IRB/IEC notification and 
acknowledgement of receipt will be kept in the Investigator’s study file. 
6.7.6.7. 
Pregnancy Reporting 
If a female patient becomes pregnant during the study through 90 days following the last dose of 
study drug, the Investigator must report the pregnancy to the Sponsor or designee within 
24 hours of being notified of the pregnancy. Details of the pregnancy will be recorded on the 
pregnancy reporting form.  The patient should receive any necessary counseling regarding the 
risks of continuing the pregnancy 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 6.7.6.4. 
6.7.6.8. 
Overdose Reporting 
An overdose is defined as any dose administered to or taken by a patient (accidentally or 
intentionally) that exceeds the highest daily dose, or is at a higher frequency, than included in the 
protocol.  The investigator will decide whether a dose is to be considered an overdose, in 
consultation with the Sponsor.  In the event of an overdose, the actual dose administered must be 
recorded in the eCRF. 
All reports of overdose (with or without an AE) must be reported within 24 hours to the Sponsor 
or designee. 
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6.8. 
Biomarkers, DNA Genotyping, and Biospecimen Repository 
Alnylam’s RNAi therapeutics platform permits the highly specific targeting of investigational 
therapies based on genetic sequence.  It is possible that variations in the target genetic sequence 
will result in variations in drug effect. 
More generally, genetic variations may account for the well-described heterogeneous 
manifestations of disease in patients with IgAN, as well as their responses to treatment. 
To permit exploratory investigations and the application of novel approaches to bioanalyses that 
may further elucidate the outcomes of this study, or potentially advance understanding of the 
safety, mechanism of action, and/or efficacy of cemdisiran, a set of biological specimens will be 
collected at the intervals indicated in the Schedule of Assessments (Table 1 and Table 2). 
The biospecimen repository will also include residual material from routine samples (safety 
laboratory samples, PK samples, etc.) that are obtained during the study. 
These specimens will be securely stored in a central biorepository for up to 10 years following 
the completion of this clinical study (ie, last patient last visit), or as per local regulations.  After 
10 years have elapsed, samples will be destroyed. 
Where allowed per local regulations, ethics committee (IRB/IEC) approval, and patient consent, 
the samples will be collected as part of this study.  Examples of potential exploratory 
investigations would include DNA, RNA or biochemical metabolite assessments as they relate to 
disease progression, efficacy or safety.  
Details regarding the collection, processing, storage, and shipping of the samples will be 
provided in the Laboratory Manual. 
Exploratory analysis of these biospecimens will be performed by Alnylam Pharmaceuticals or its 
designees. 
When biobanking is permitted by local regulation, study participants will be advised during the 
informed consent process of these biobanking details and the potential for exploratory 
investigation of their samples. 
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7. 
STATISTICS 
A Statistical Analysis Plan (SAP) will be finalized before database lock.  The plan will detail the 
implementation of the statistical analyses in accordance with the principle features stated in the 
protocol. 
7.1. 
Determination of Sample Size 
Approximately 30 patients are planned to be randomized 2:1 (cemdisiran:placebo) in this study.  
This is based on the assumption that, in the placebo arm, the estimated geometric mean ratio of 
proteinuria at Week 32 to baseline is 0.88 (log standard deviation [SD] 0.597), corresponding to 
a 12% reduction.  A sample size of 27 with 2:1 randomization (cemdisiran:placebo) will provide 
a width of 0.80 for the 90% confidence interval (CI) for treatment effect size estimate 
(cemdisiran  placebo) in log scale.  This corresponds to a 90% CI of (15%, 62%) for the 
treatment difference in the percentage scale if the true Week 32 reduction is 50% for the 
cemdisiran arm.  To account for potential dropouts, approximately 30 patients are planned to be 
randomized stratified by baseline urine protein levels (≥ 1g/24h and <2g/24h versus >=2g/24h). 
7.2. 
Statistical Methodology 
The statistical and analytical plans presented below are brief summaries of planned analyses.  
More complete plans will be detailed in the statistical analysis plan (SAP).  Changes to the 
methods described in the final SAP will be described and justified as needed in the clinical study 
report.  For information on study endpoints, see Section 2. 
7.2.1. 
Populations to be Analyzed 
The following populations will be analyzed: 
 Modified Intent-to-treat (mITT): All patients who receive any amount of study drug 
and have at least one post baseline assessment in proteinuria. Patients will be grouped 
by assigned treatments (ie, as randomized). 
 Safety Analysis Set: All patients who received any amount of study drug. Patients 
who received any amount of cemdisiran will be included in the cemdisiran arm. 
Patients in the Safety Analysis Set will be grouped by treatment received. 
 PK Analysis Set: All patients who receive any amount of study drug and have at least 
one postdose blood or urine sample for PK concentration. 
 PD Analysis Set: All patients who receive any amount of study drug and who have at 
least one postdose blood sample for the determination of plasma C5 level. 
The primary population used to evaluate efficacy will be the mITT Population.  Sensitivity 
analyses for efficacy will be performed using the Per Protocol Analysis Set.  Safety will be 
analyzed using the Safety Analysis Set.  The PK and PD Analysis Sets will be used to conduct 
PK and PD analyses, respectively.  
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7.2.2. 
Examination of Subgroups 
Subgroup analyses may be conducted for selected endpoints.  Detailed methodology will be 
provided in the SAP. 
7.2.3. 
Handling of Missing Data 
Handling of missing data will be described in the SAP. 
7.2.4. 
Baseline Evaluations 
Demographics and other baseline characteristics, including disease-specific information, will be 
summarized descriptively by treatment arm and overall for the mITT and Safety Analysis Set. 
Baseline value for proteinuria will be calculated as the average of two valid 24-hour urine 
protein levels before randomization. 
7.2.5. 
Efficacy Analyses 
7.2.5.1. 
Primary Endpoint 
The primary endpoint of the study is the percentage reduction from baseline in 24-hour 
proteinuria at Week 32. The 24-hour urine protein will be log transformed for analyses. The 
primary analysis will be performed on the change from baseline in log transformed urine protein 
using a linear model with log transformed baseline urine protein as covariate and treatment and 
randomization stratification factor as fixed effect. The least square mean difference and its 90% 
confidence interval will be estimated and then back transformed to original scale. In the end the 
estimated ratio of percentage reduction in urine protein for cemdisiran to placebo and its 90% 
confidence interval will be presented.  
A sensitivity analysis using all urine protein assessments including a single 24-hour assessment 
will be conducted using mixed-effects model repeated measures (MMRM) method. 
7.2.5.2. 
Secondary Efficacy Endpoints  
The secondary efficacy endpoints include percent of patients with partial clinical remission (UP 
<1.0 g/24-hours), percent of patients with >50% reduction in 24-hour proteinuria, change from 
baseline in UPCR as measured in 24-hour urine at Week 32, change from baseline in urine 
protein/creatinine ratio (UPCR) as measured in a spot urine at Week 32 and change from 
baseline in hematuria at Week 32. 
The percentage of patients with partial clinical remission or with >50% reduction in 24-hour 
proteinuria for each treatment arm and the difference between treatment arms will be presented 
together with an approximate 90% confidence interval based on Wilson score method.  
Change from baseline in urine protein / creatinine ratio (UPCR) will be analyzed similarly to the 
analysis of the primary variable as appropriate. UPCR will be log transformed first before 
analysis.  
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7.2.5.3. 
Exploratory Endpoints  
Change from baseline in exploratory efficacy variables will be summarized. Percent of patients 
in full clinical remission and incidence of ADA will be tabulated by treatments. Inferential 
statistics for exploratory efficacy variables may be presented as needed. Details will be described 
in the SAP. 
The slope of eGFR for the first 32 weeks will be estimated for each subject with the linear 
regression method using all assessment data during the period.  
Descriptive statistics including the number of patients, mean, median, standard deviation (SD), 
interquartile range (Q1, Q3), minimum, and maximum values will be presented for continuous 
variables. Frequencies and percentages will be presented for categorical and ordinal variables.  
7.2.6. 
Pharmacodynamic Analysis 
Assessment of the PD effect of the treatment will be performed descriptively, including plotting 
graphically levels of serum C5 protein and CAP/CCP over time and relative to baseline levels. 
Inferential statistics maybe generated as deemed necessary. 
7.2.7. 
Pharmacokinetic Analysis 
Pharmacokinetic analyses will be conducted using noncompartmental methods. Pharmacokinetic 
parameters include, but will not be limited to:  AUC, Cmax, Tmax, T½, CL/F, V/F, cumulative 
amount excreted unchanged in urine (Ae), and percent of dose excreted (fe) in the urine of 
cemdisiran (25-mer) and 23-mer.  
Other parameters may be calculated, if deemed necessary. Summary statistics and figures will be 
presented. Inferential statistics may be generated when deemed necessary. 
7.2.8. 
Safety Analyses 
The primary parameter is the frequency of treatment-emergent AEs (hereafter referred to simply 
as AEs). Safety parameters also include vital signs, ECGs, clinical laboratory assessments, and 
physical exams.  The extent of exposure will be summarized by dose level and overall. 
Adverse events will be classified according to the Medical Dictionary for Regulatory Activities 
(MedDRA) System Organ Class and Preferred Term. Prior and concomitant medications will be 
classified according to the World Health Organization (WHO) drug dictionary. All SAEs 
occurring before the first dose of study drug and AEs related to study procedures will be listed. 
The number and percentage of patients experiencing AEs after the first dose of the study drug or 
events that worsened in severity after dosing will be summarized. AEs will be presented by 
maximum severity and relationship to study medication. SAEs and AEs leading to 
discontinuation of treatment will also be tabulated. 
By-subject listings will be provided for deaths, SAEs, and AEs leading to study discontinuation. 
Frequency of adverse events of clinical interest will also be summarized and by-subject listings 
will be provided. 
Descriptive statistics will be provided for clinical laboratory data, 12-lead ECG interval data and 
vital signs data, presented as both actual values and changes from baseline over time. Laboratory 
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shift tables from baseline to worst values will be presented. Baseline will be defined as the last 
observation on or prior to Study Day 1.  
Abnormal physical examination findings and 12-lead ECG data will be presented in a by-patient 
data listing. Details of any abnormalities will be included in patient listings. 
Other safety summaries will be presented as appropriate. Further details will be specified in the 
SAP. 
All safety analyses will be conducted using the Safety Analysis Set. 
7.2.9. 
Immunogenicity Analyses 
Antidrug antibody and CIC results will be summarized descriptively.   
7.2.10. 
Biomarker Analyses 
Urine and serum complement activation products, inflammation and renal injury markers will be 
summarized descriptively.  
7.2.11. 
Interim Analysis 
No formal interim analysis is planned. 
7.2.12. 
Optional Additional Research 
Optional additional research may be conducted in the future on the biological samples and/or 
data collected during the study in accordance with the strict terms of the ICF (see Section 4.3.2). 
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8. 
STUDY ADMINISTRATION 
8.1. 
Ethical and Regulatory Considerations 
This study will be conducted in accordance with the protocol, all applicable regulatory 
requirements, and the current guidelines of Good Clinical Practice (GCP).  Compliance with 
GCP provides public assurance that the rights, safety, and well-being of study patients are 
protected consistent with the principles that have their origin in the Declaration of Helsinki. 
8.1.1. 
Informed Consent 
The Investigator will ensure that the patient/legal guardian is given full and adequate oral and 
written information about the nature, purpose, possible risk and benefit of the study.  
Patients/legal guardians must also be notified that they are free to discontinue from the study at 
any time.  The patient/legal guardian should be given the opportunity to ask questions and 
allowed time to consider the information provided.   
The patient’s/legal guardian’s signed and dated informed consent must be obtained before 
conducting any study tests or procedures that are not part of routine care.   
The Investigator must maintain the original, signed ICF.  A copy of the signed ICF must be 
given to the patient/legal guardian. 
8.1.2. 
Ethical Review 
The study protocol, including the ICF, must be approved or given a favorable opinion in writing 
by an IRB or IEC, as appropriate.  The Investigator must submit written approval before he or 
she can enroll any patient into the study. 
The Investigator is responsible for informing the IRB or IEC of any amendment to the protocol 
in accordance with local requirements.  In addition, the IRB or IEC must approve all patient 
materials for the study.  The protocol must be reapproved by the IRB or IEC upon receipt of 
amendments and annually, as local regulations require. 
Initial IRB approval of the protocol, and all materials approved by the IRB for this study 
including the patient consent form and recruitment materials must be maintained by the 
Investigator and made available for inspection. 
The Investigator will submit reports of SAEs as outlined in Section 6.7.6.  In addition, the 
Investigator agrees to submit progress reports to the IRB or IEC per their local reporting 
requirements, or at least annually and at the conclusion of the study.  The reports will be made 
available to the Sponsor or designee. 
Any communications from regulatory agencies, IRBs, or IECs in regard to inspections, other 
studies that impact this protocol or the qualifications of study personnel should be promptly 
reported to the Sponsor or its designee. 
The Investigator is also responsible for providing the IRB with reports of any reportable serious 
adverse drug reactions from any other study conducted with the study drug.  The Sponsor or 
designee will provide this information to the Investigator. 
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Major changes in this research activity, except those to remove an apparent immediate hazard to 
the patient, must be reviewed and approved by the Sponsor and the IRB or IEC that approved the 
study.  Amendments to the protocol must be submitted in writing to the Investigator’s IRB or 
IEC and the Regulatory Authority for approval before patients are randomized under the 
amended protocol, and patients must be re-consented to the most current version of the ICF. 
8.1.3. 
Serious Breach of Protocol 
Investigators must notify the Medical Monitor within 24 hours of becoming aware of a serious 
breach of the protocol.  A serious breach is a breach that is likely to affect to a significant degree 
the safety and rights of a study participant or the reliability and robustness of the data generated 
in the clinical trial. 
8.1.4. 
Study Documentation, Confidentiality, and Records Retention 
All documentation relating to the study should be retained for 2 years after the last approval in an 
ICH territory or as locally required, whichever is longer.  If it becomes necessary for the 
Sponsor, the Sponsor’s designee, applicable IRB/IEC, or applicable regulatory authorities to 
review or audit any documentation relating to the study, the Investigator must permit direct 
access to all source documents/data.  Records will not be destroyed without informing the 
Sponsor in writing and giving the Sponsor the opportunity to store the records for a longer period 
of time at the Sponsor’s expense.   
The Investigator must ensure that the patients’ confidentiality will be maintained.  On the eCRFs 
or other documents submitted to the Sponsor or designees, patients should not be identified by 
their names, but by the assigned patient number or code.  If patient names are included on copies 
of documents submitted to the Sponsor or designees, the names will be obliterated, and the 
assigned patient number added to the document.  Documents not for submission to the Sponsor 
(eg, signed ICFs) should be maintained by the Investigator in strict confidence. 
The Investigator must treat all information related to the study and the compiled data as 
confidential, whose use is for the purpose of conducting the study. The Sponsor must approve 
any transfer of information not directly involved in the study. 
To comply with local and/or regional regulations, this clinical study may be registered, and study 
results may be posted on public registries, such as ClinicalTrials.gov. 
8.1.5. 
End of Study 
The end of study is defined as the last patient last visit. 
8.1.6. 
Termination of the Clinical Study or Site Closure 
The Sponsor reserves the right to terminate the study for clinical or administrative reasons at any 
time.  If the site does not recruit at a reasonable rate, or if there is insufficient adherence to the 
protocol requirements, the study may be closed 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, IRB/IEC and 
Regulatory Authorities will be promptly informed of the termination and the reason for the 
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decision.  The Investigator should promptly inform the patients and assure appropriate therapy 
and follow-up. 
8.2. 
Data Quality Control and Quality Assurance 
8.2.1. 
Data Handling 
Study data must be recorded on CRFs (paper and/or electronic) provided by the Sponsor or 
designee on behalf of the Sponsor.  Case report forms must be completed only by persons 
designated by the Investigator.  If eCRFs are used, study data must be entered by trained site 
personnel with access to a valid and secure eCRF system.  All data entered into the eCRF must 
also be available in the source documents.  Corrections on paper CRFs must be made so as to not 
obliterate the original data and must be initialed and dated by the person who made the 
correction. 
8.2.2. 
Study Monitoring 
The Monitor, as a representative of the Sponsor, has an obligation to closely follow the study 
conduct at the site.  The Monitor will visit the Investigator and clinical study center periodically 
and will maintain frequent telephone and written contact.  The Monitor will maintain current 
personal knowledge of the study through observation, review of study records and source 
documentation, and discussion of the conduct of the study with the Investigator and staff. 
The Monitor will review source documents, systems and CRFs to ensure overall quality and 
completeness of the data and to confirm study procedures are complied with the requirements in 
the study protocol accurately. The Sponsor, or its designee, will be allowed to conduct site visits 
to the investigation facilities for the purpose of monitoring any aspect of the study.  The 
Investigator agrees to allow the Monitor to inspect the drug storage area, study drug stocks, drug 
accountability records, patient charts and study source documents, site standard operating 
procedures and training records, and other records relative to study conduct. 
8.2.3. 
Audits and Inspections 
Periodically, the Sponsor or its authorized representatives audit clinical investigative sites as an 
independent review of core trial processes and documents to determine whether these activities 
were conducted, and data were recorded, analyzed, and accurately reported according to the 
protocol, GCP guidelines of the ICH, and any applicable regulatory requirements.  A regulatory 
authority, an IRB/IEC may visit the site to perform audits or inspections, including source data 
verification.  The Investigator should contact the Sponsor and designee, immediately if contacted 
by a regulatory agency or an IRB/IEC about an inspection. 
8.3. 
Publication Policy 
It is intended that after completion of the study, the data are to be submitted for publication in a 
scientific journal and/or for reporting at a scientific meeting.  A separate publication by 
Institution or Investigator may not be submitted for publication until after this primary 
manuscript is published or following the period of 18 months after completion of the study at all 
centers.  A copy of any proposed publication (eg, manuscript, abstracts, oral/slide presentations, 
book chapters) based on this study, must be provided and confirmed received at the Sponsor at 
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least 30 days before its submission.  The Clinical Trial Agreement among the institution, 
Investigator, and Alnylam will detail the procedures for Alnylam’s review of publications. 
Authorship of any publications resulting from this study will be determined on the basis of the 
Uniform Requirement for Manuscripts Submitted to Biomedical Journals (International 
Committee of Medical Journal Editors). 
 
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9. 
LIST OF REFERENCES 
Ashwell G,Morell AG. The role of surface carbohydrates in the hepatic recognition and transport 
of circulating glycoproteins. Advances in Enzymology and Related Areas of Molecular Biology, 
Volume 41. 2006:99-128. 
Cattran DC, Coppo R, Cook HT, Feehally J, Roberts IS, Troyanov S, et al. The Oxford 
classification of IgA nephropathy: rationale, clinicopathological correlations, and classification. 
Kidney international. 2009;76(5):534-45. 
Coppo R,D'amico G. Factors predicting progression of IgA nephropathies. Journal of 
nephrology. 2005;18(5):503-12. 
Crew PE, Abara WE, McCulley L, Waldron PE, Kirkcaldy RD, Weston EJ, et al. Disseminated 
gonococcal infections in patients receiving eculizumab: a case series. Clinical Infectious 
Diseases. 2018. 
Crew PE, McNamara L, Waldron PE, McCulley L, Jones SC,Bersoff-Matcha SJ. Unusual 
Neisseria species as a cause of infection in patients taking eculizumab. Journal of Infection. 
2018. 
Cugno M, Gualtierotti R, Possenti I, Testa S, Tel F, Griffini S, et al. Complement functional tests 
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Elbashir SM, Lendeckel W,Tuschl T. RNA interference is mediated by 21-and 22-nucleotide 
RNAs. Genes & development. 2001;15(2):188-200. 
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Lv J, Zhang H, Wong MG, Jardine MJ, Hladunewich M, Jha V, et al. Effect of Oral 
Methylprednisolone on Clinical Outcomes in Patients With IgA Nephropathy. Jama. 
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Maillard N, Wyatt RJ, Julian BA, Kiryluk K, Gharavi A, Fremeaux-Bacchi V, et al. Current 
understanding of the role of complement in IgA nephropathy. Journal of the American Society of 
Nephrology. 2015;26(7):1503-12. 
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infections. Clinical Infectious Diseases. 2018. 
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and side effects of corticosteroids alone or in combination with azathioprine at different stages of 
IgA nephropathy. Clinical journal of the American Society of Nephrology. 2016;11(6):973-81. 
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Suzuki H, Fan R, Zhang Z, Brown R, Hall S, Julian BA, et al. Aberrantly glycosylated IgA1 in 
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10. 
APPENDICES 
None. 
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ALN-CC5-005 PROTOCOL AMENDMENT 1  
SUMMARY OF CHANGES DATED 26 NOVEMBER 2018 
Protocol Title 
A Phase 2, Randomized, Double-blind, Placebo-controlled Study of Cemdisiran in Adult Patients 
with IgA Nephropathy 
Rationale for Protocol Amendment 
The main purpose of this protocol amendment is to incorporate changes requested by a Health 
Authority. The primary changes pertain to safety monitoring and risk mitigation measures within 
the protocol to address two risks possibly associated with cemdisiran treatment of the target 
patient population: 1) the theoretical risk of increased production of pathogenic autoantibodies 
and immune complexes in patients with IgA nephropathy associated with exposure to the 
N-Acetylgalactosamine (GalNAc) moiety of cemdisiran, and 2) an increase in susceptibility to 
encapsulated bacterial infections other than Neisserial infections. 
An overview of the changes made to this protocol in response to Health Authority feedback 
includes: 
 Exclusion of patients with confirmed pre-existing IgG/IgM/IgA anti-drug antibodies 
(ADA) to cemdisiran at screening 
 Discontinuation of dosing in patients who develop de novo confirmed IgG/IgM/IgA 
ADA 
 Collection of an additional blood sample for ADA testing 4 weeks after the last dose of 
treatment (Week 36) for any subject who does not continue in the open-label extension 
period. 
 Inclusion of the theoretical risk of other types of infections, particularly those due to 
encapsulated bacteria, and measures to mitigate this risk including vaccination, according 
to national/local guidelines. 
Additional changes have also been made based on the results of feasibility assessments and to 
improve clarity. 
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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Table 1: 
Protocol Amendment 1 Detailed Summary of Changes 
The primary sections of the protocol affected by the changes in Protocol Amendment 1 are indicated.  The corresponding text has been 
revised throughout the protocol.  Deleted text is indicated by strikeout; added text is indicated by bold font. 
Purpose:  Updated to include the theoretical risk of increased production of pathogenic autoantibodies and immune complexes in patients with 
IgA nephropathy associated with exposure to the GalNAc moiety of cemdisiran 
The primary change occurs in Section 1.1, Disease Overview 
Formerly read: 
While the exact pathogenesis of IgAN is incompletely understood, biochemical, genetic, and clinical data suggest IgAN is 
an autoimmune disease that may originate from overproduction of aberrantly glycosylated IgA1 and the development of 
glycan-specific IgA and immunoglobulin G (IgG) autoantibodies that recognize the under-galactosylated IgA1 molecule. 
Now reads: 
While the exact pathogenesis of IgAN is incompletely understood, biochemical, genetic, and clinical data suggest IgAN is 
an autoimmune disease that may originate from overproduction of aberrantly O-glycosylated IgA1 (Gd-IgA1) and the 
development presence of glycan-specific IgA and immunoglobulin G (IgG) autoantibodies that recognize the 
under-galactosylated IgA1 molecule, resulting in the formation of pathogenic immune complexes. Some of these 
circulating complexes may deposit in glomeruli and induce renal injury.[Knoppova 2016] The lack of galactose 
exposes O-linked monosaccharide N-acetylgalactosamine (O-GalNAc) moeities in the hinge region of IgA1.[Novak 
2018] While the binding of autoantibodies to Gd-IgA1 is dependent on the presence of multiple O-GalNAc 
residues, the IgA1 protein backbone and the spatial arrangement of O-GalNAc moieties are also thought to play a 
role in the specificity of autoantibodies to Gd-IgA1.[Mestecky 2016; Suzuki 2009] 
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Sections also changed include: 
 
Section 1.5 (Benefit-Risk Assessment) 
o Considering anti-glycan autoantibodies recognizing Gd-IgA1 are implicated in the pathogenesis of IgA nephropathy, 
exposure to the GalNAc moiety of cemdisiran may pose a theoretical risk of stimulating the production of pathogenic 
autoantibodies and immune complexes in patients with IgA nephropathy. This could presumably occur when antidrug 
antibodies (ADAs) to cemdisiran’s triantennary GalNAc (Tri-GalNAc) cross-react with Gd IgA1. The risk of developing 
these cross-reactive antibodies is likely low. This is based on the low incidence of ADA to cemdisiran in study ALN-CC5-
001 (see Section 1.2) and the distinct difference in structure of the O GalNAc moieties on a Gd IgA1 glycoprotein and the 
Tri-GalNAc moiety in cemdisran. This low risk is further mitigated by excluding patients with confirmed pre-existing 
IgG/IgM/IgA ADAs to total drug and real time monitoring for development of de novo IgG/IgM/IgA ADAs after dosing 
with cemdisiran. Patients with confirmed de novo ADAs will be discontinued from study drug but will continue to be 
monitored until EOS visit and subsequent safety follow up. Patients who develop positive ADA will be followed until ADA 
titers return to baseline. Additional ADA samples will also be collected if any clinical evidence of progression of IgAN 
disease and/or relevant safety findings. 
 
Section 1.2 (Cemdisiran): Updated to include the results of ADA analyses in Study ALN-CC5-001 
o In Study ALN-CC5-001, the frequency of ADA was low.  Two of 48 healthy volunteers (1 cemdisiran-treated and 1 
placebo-treated) were ADA positive during the study. The cemdisiran-treated volunteer had transient ADA positivity, with 
a negative result later in the study and no impact on PK or PD. The placebo-treated volunteer was ADA positive at 
baseline (predose) and remained positive through Day 70. 
 
Section 3.7 (Data Monitoring Committee): Updated to include mitigation measures for the risk of autoantibody development 
o An independent DMC will perform regular reviews of safety, tolerability, and immunogenicity data throughout the study with 
the primary purpose of protecting the safety of participating patients and the integrity of the study.  The DMC will operate under 
the rules of a Charter that will be reviewed and approved at the organizational meeting of the DMC.  The DMC will perform 
periodic reviews of unblinded data (safety, tolerability, PK, pharmacodynamics (PD), ADA, CIC and efficacy of cemdisiran) 
during the clinical trial, and on an ad hoc basis review emergent safety data.  Details are provided in the DMC Charter. 
 
Schedule of Assessments:  
o Added more time points for blood sample collection for the analysis of ADAs (Table 1 and Table 2) 
 
“X” was added to “Blood Sample for Antidrug Antibodies” at the Screening visit, Week 36 and Safety Follow up visits at 
Weeks 49, 62, 75, 88 (Table 1); and Weeks 97, 110, 123, 136 (Table 2) 
o Added time points for blood sample collection for the analysis of CIC (Table 1) 
 
A new row was added for the collection of blood samples for circulating immune complexes at all timepoints where ADA 
samples are collected. During the Treatment Period (Table 1), “X” was added at the Screening visit, Day 1 and at Weeks 
4, 8, 12, 24 and 32. 
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o Added a time point for an optional blood sample collection for B-cell function analysis (Table 1) 
 
A new row was added for an optional collection of blood samples for B-cell function analysis. During the Treatment 
Period (Table 1), “X” was added at the Screening visit. 
 
Section 4.2 (Exclusion Criteria): Updated to include a risk mitigation measure for ADA (excluding patients with confirmed positive 
IgG/IgM/IgA ADA at screening) 
o New Criterion 7: Confirmed positive IgG/IgM/IgA ADAs to cemdisiran at Screening  
 
Sections 6.1, 6.3 and 6.7: Updated to include the assessment of ADA and/or CIC. 
o Section 6.1 (Screening Assessments) 
 
Additional screening assessments include a full physical examination (with emphasis on presence/degree of edema), 
collection of vital signs, height, weight and body mass index (BMI), 12-lead electrocardiogram (ECG), clinical laboratory 
assessments, pregnancy, 24-hours urine proteinuria assessment (from a single valid collection; see Section 6.4.1.1), eGFR, 
and urinalysis and ADA and CIC assessments. 
o Section 6.3 (Baseline Assessments – Treatment Period) 
 
Prior to dosing on Day 1, patients will be reassessed for eligibility and blood and urine samples for clinical laboratory 
assessments and exploratory analyses collected, including blood samples for complement activity tests (CAP/CCP), C5 
analysis, PK, ADA and ADA.CIC. 
o Section 6.7 (Safety Assessments) 
 
The assessment of safety during the study will consist of the surveillance and recording of the frequency of AEs including 
SAEs, recording of concomitant medication and measurements of vital signs, weight and height, physical examination, 
and ECG findings and laboratory tests, including assessment of IgG/IgM/IgA ADA and CIC. 
 
Sections 6.7.5.1 and 7.2.9: Updated to clarify immunogenicity testing and analyses 
o Section 6.7.5.1 (Immunogenicity) 
 
Blood samples will be collected to evaluate ADA.  Blood samples for antidrug antibody and CIC.  IgG/IgM/IgA ADA to 
total drug will be assessed at screening and during the study. ADA samples will be tested in real time.  Clinical 
study decision will be based on confirmed positive ADA results from the IgG/IgM/IgA assay. Confirmed positive 
ADA samples will be further characterized for cemdisiran domain specificity against the Tri-GalNAc component if 
a reliable method is established.  Blood samples for ADA and CIC testing must be collected before study drug 
administration as specified in the Schedule of Assessments (Table 1 and Table 2).  A blood sampleBlood samples to 
evaluate antidrug antibodiesADAs will be collected at Screening to assess study eligibility and at the Early Termination 
(ET) visit, if applicable. ADA and CIC will be routinely monitored during the treatment period and throughout the 
open-label extension phase and safety follow up, as indicated in the Schedule of Assessments. Finally, ADA and 
CIC samples will also be collected and analyses will be performed and prioritized if any clinical evidence of 
progression of IgAN disease and/or relevant safety findings. Patients who are confirmed positive for IgG/IgM/IgA 
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ADA at baseline will be excluded from study treatment. In addition, patients who develop de novo ADAs will be 
discontinued from study drug but will be followed until EOS visit and during safety follow up. These patients will 
also be monitored until ADA levels return to baseline. 
Exploratory analysis of Gd-IgA1 levels and IgA-containing immune complexes may be conducted; blood samples 
for these analyses will be drawn when CIC samples are collected to enable these assays. 
For US patients only, an optional blood sample may be collected at screening to evaluate any potential for B-cell 
stimulation by cemdisiran, at the Sponsor’s discretion. 
o Section 7.2.9 (Immunogenicity Analyses) 
 
Antidrug antibody and CIC results will be summarized descriptively. 
 
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Purpose: Updated the benefit risk section in recognition of an increase in susceptibility to infections by encapsulated bacteria other than N. 
meninigitidis  
The primary change occurs in Section 1.5, Benefit-Risk Assessment 
Added text:  
Given the biological target of cemdisiran, the available nonclinical and clinical data, and mode of administration, important potential risks for 
cemdisiran are infections, liver function test (LFT) abnormalities and injection site reactions (ISRs).  Since C5 inhibition is associated with 
increased susceptibility for Neisserial infections (including disseminated gonococcal infections) and the potential risk of other infections, 
particularly those due to encapsulated bacteria including Streptococcus pneumoniae and Haemophilus influenzae type b (Hib), as well as 
Aspergillus in immunocompromised and neutropenic patients. Therefore, prior immunization against N. meningitidis using meningococcal 
group ACWY conjugate vaccine and meningococcal group B vaccine are required. Patients will be instructed to contact study site if any early 
signs of meningococcal infections are experienced. In addition, patients with functional or anatomic asplenia will be excluded and only 
patients previously vaccinated or who agree to receive vaccination for Hib and Streptococcus pneumoniae according to current 
national/local vaccination guidelines, at screening, will be enrolled.  Investigators in Study ALN-CC5-005 should educate patients on the 
risk of disseminated gonococcal infection and encourage safe sex practices.  All national/local screening recommendations for gonorrhea 
in the general population should also be followed.  Finally, given the reported evidence of a higher risk of disseminated gonococcal 
infections with treatment with eculizumab, Investigators are encouraged to evaluate any patient who has a Neisseria gonorrhoeae infection 
for the signs and symptoms of disseminated infection.[Crew 2018; McQuillen 2018] No cases of Neisserial infection or other infections due 
to encapsulated bacteria were observed in healthy volunteers or in patients with PNH (Study ALN CC5-001). 
 
Other sections changed include: 
 
Section 1.2 (Cemdisiran) 
o Added text: The safety of reducing C5 is supported by clinical precedence of C5 inhibition with eculizumab treatment and the 
absence of any phenotypic abnormalities, other than an increased susceptibility to Neisserial infections, in subjects with 
known genetic C5 deficiencies.[Ross 1984] Subjects with known C5 deficiencies are generally healthy apart from an increased 
susceptibility to Neisserial infections. These infections include invasive meningococcal disease, disseminated gonococcal 
infections as well as diseases caused by typically commensal Neisseria species.[Crew 2018; Crew 2018; McQuillen 2018; 
Ram 2010] 
 
Schedule of Assessments (Table 1) 
o Purpose: Updated to include a vaccination record check for pneumococcal and Hib vaccines 
 
Added text: A new row was added “Review Routine Vaccination Status” at the Screening visit (D-112±7). 
o Purpose: Updated to include pneumococcal and Hib vaccination, if required per local guidance, for patients who have not been 
previously vaccinated 
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 
Added text: A new row was added “Pneumococcal and Haemophilus influenzae type b (Hib) vaccination, if not 
previously vaccinated and required per local guidance.”  “X” was added in the Schedule of Assessments (Table 1) for 
the procedure to occur between D-112 and Day-56 
 
Section 4 (Selection and Withdrawal of Patients) 
o Section 4.1 (Inclusion Criteria) 
 
New Criterion 8: Previously vaccinated or willingness to receive vaccinations for Hib and Streptococcus pneumoniae 
according to current national/local vaccination guidelines for vaccination use 
 
Other section including change is the Synopsis (Diagnosis and Main Eligibility Criteria) 
o Section 4.2 (Exclusion Criteria) 
 
Criterion 19: Unable to take antibiotics for meninigococcal prophylaxis, if required by local standard of care 
 
Criterion 23: Patients with systemic bacterial or fungal infections, as demonstrated by a positive culture result, that require 
systemic treatment with antibiotics or antifungals 
 
New Criterion 24: Patients with functional or anatomic asplenia 
 
Section 5.3.2.2 
o Purpose: Included a new section on pneumoccal and Hib vaccinations (Section 5.3.2.2) 
 
Added text: Section 5.3.2.2 Pneumococcal and Hib Vaccinations 
 
Patients will receive vaccinations for Hib and Streptococcus pneumoniae, if not previously vaccinated, 
according to current national/local vaccination guidelines for vaccination use. Hib and pneumococcal 
vaccinations (if required at screening per national/local guidelines; vaccination should occur prior to 
Week-2. At screening, patient vaccination records will be checked for compliance with local 
recommendations for the use of these vaccines. 
 
Section 6.1 (Screening Assessments) 
o Added text: Vaccination records will also be checked for compliance with national/local guidelines for pneumococcal and 
Hib vaccinations. 
 
Section 6.2 (Run-in Period) 
o Added text:  
 
During the 14-week run-in period, the following will be performed at time points specified in the Schedule of 
Assessments (Table 1): Hib and pneumococcal vaccination (if required at screening per national/local guidelines; 
vaccination should occur prior to Week-2), vital signs, clinical laboratory assessments, pregnancy test, 24-hour urine 
proteinuria assessment (from 2 single valid collections; see Section 6.4.1.1), urinalysis for hematuria, spot urine for 
proteinuria, and eGFR. 
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 
Clinical laboratory tests will be performed centrally; however, hematuria and eGFR will also be assessed locally at the 
end of the run-in period (Week-2) to facilitate assessment of patient eligibility and administer meninogococcal 
vaccination on the same day. During this period, patients will begin the recommended meningitis vaccination regimen if 
eligible for the study. Vaccines Meningococcal vaccines should be administered only if patient eligibility for 
randomization is confirmed and after urine collections are completed. 
Purpose: Updated the number of clinical study centers 
The primary change occurs in the Synopsis 
Added text: The study will be conducted at approximately 30-40 clinical study centers worldwide 
Purpose: Updated to improve clarity 
The primary change occurs in the Synopsis (Diagnosis and Main Eligibility Criteria) 
Added text: Eligible patients must have urine protein levels of ≥1g/24-hour at screening and mean urine protein ≥ 1g/24 hour from two valid 
24-hour urine collections at the end of the run-in period, prior to randomization. 
Purpose: Updated the Schedule of Assessments (Table 1) to include safety follow up visits for patients who do not enter the OLE phase, for 
clarification 
The primary change occurs in Table 1 (Schedule of Assessments – Run-in and Treatment Periods [Screening through Week 36]) 
Added columns for visit Weeks 49, 62, 75 and 88. “X” has been added against all assessments planned to be conducted during safety follow-up 
consistent with Table 2. Previously, safety follow up assessments were only provided in Table 2.  
Purpose: Added a row for “Optional Home Visit” in the Schedule of Assessments (Table 1) 
The primary change occurs in Table 1 (Schedule of Assessments – Run-in and Treatment Periods [Screening through Week 36]) 
Added text: A new row was added for “Optional Home Visit” during safety follow-up for patients who do not enter the OLE phase. “X” was 
added at Weeks 49 and 75. 
Purpose: Corrected the note on “Optional Home Visit” in the Schedule of Assessments (Table 2) to reflect that cemdisiran is not administered 
during safety follow-up 
The primary change occurs in Table 2 (Schedule of Assessments – Open-Label Extension Period) – Optional home visit 
Added text: Will be arranged for cemdisiran administration in between 8-weekly study site visits at Weeks 44, 52, 60, 68 and 76, 97 and 123 during the 
extension phase, and where feasible, during safety follow up at Weeks 97 and 123, unless patients are required to visit the study center as judged necessary by 
the Investigator. 
Purpose: Corrected one footnote in Table 3 (Pharmacokinetic Time Points) to align with the timing of pooled urine in the table 
The primary change occurs in Table 3 footnote b 
Added text: The pooled urine 86-12 hours and 12-24 hours can be collected as outpatient. 
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Purpose: Corrected the start visit for the OLE period of the study to align with the schedule of assessments 
The primary change occurs in Section 3.1 (Study Design)  
Added text:  The first study drug administration of the OLE will be administered at Week 3236.  Patients will return to the study center at Weeks 
3640 and every 8 weeks thereafter during the OLE. 
Other section including the change is the Synopsis (Study Design) 
Purpose: For patients who do not consent to participate in the OLE period, added Week 36 as the EOS visit instead of a joint EOT and EOS visit 
at Week 32 
The primary change occurs in Section 3.1 (Study Design) 
Added text: Patients will return to the clinical study center for safety follow-up visits approximately 13, 26, 39 and 52 weeks after the EOS/ET 
visit (regardless if EOS/ET visit is at Week 36 or Week 84), unless enrolled in another study with cemdisiran. Home visits, where locally feasible, 
may be arranged during safety follow-up at visit 13 and 39 weeks after the EOS visit (regardless if EOS/ET visit is at Week 36 or Week 
84)Weeks 97 (13 weeks after the EOS visit) and 123 (39 weeks after the EOS visit). 
Other sections changed include: 
 
Synopsis (Study Design; see also Figure 1) 
 
Schedule of Assessments (Table 1) 
 
Section 3.3 (Duration of Study) including corresponding section in the Synopsis 
o The maximum estimated total time on study, inclusive of Screening (maximum of 90 days), run-in period (14 weeks), treatment 
period (3236 weeks), optional OLE period (52 weeks) and safety follow-up (52 weeks), is up to approximately 36 months or 
3.0 years. 
o A patient is considered to have reached the end of the study if the patient has completed the EOS (Week 84) visit or the (Week 32 
36 for those patients who do not consent to continue to participate in the study in the OLE period and Week 84 for patients who 
enter the OLE period). Upon study completion (regardless if EOS visit is at Week 32 36 or Week 84) patients will enter a safety 
follow-up period with visits scheduled at intervals of 13 weeks. 
 
Section 3.6 (Blinding) 
 
Section 4.3.1 
 
Section 4.3.2.1 
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Purpose: Clarified the end of treatment (EOT), end of study (EOS) and early termination (ET) visit for patients who only consent to participate in 
the treatment period of the study (EOT/EOS/ET) versus those who consent to continue in the OLE period (OLE EOT/EOS/ET) 
The primary change occurs in Section 3.1 (Study Design) 
Added text: An end of treatment (EOT) visit will occur at Week 80 (OLE EOT) and an end of study (EOS) or early termination (ET) visit will 
be completed at Week 84 (OLE EOS/ET).  For patients who complete the treatment period only who do not consent to continue to participate in 
the study in the OLE period, the EOS/ET visit will be at Week 32 36. 
Patients will return to the clinical study center for safety follow-up visits approximately 13, 26, 39 and 52 weeks after the EOS/ET visit (regardless 
if EOS/ET visit is at Week 32 36 or Week 84), unless enrolled in another study with cemdisiran. Home visits, where locally feasible, may be 
arranged during safety follow-up at visit Weeks 97 (13 weeks after the EOS visit) 13 and 123 39 weeks after the EOS/ET visit (regardless if 
EOS/ET visit is at Week 36 or Week 84). 
Other sections changed include: 
 
Synopsis (Study Design) 
 
Schedule of Assessments (Table 1 and Table 2) 
 
Section 3.3.1 
 
Section 4.3.1 
Purpose: Updated to include blinding of data management CRO 
The primary change occurs in Section 3.6 (Blinding) 
Added text: All site personnel including sponsor delegated clinical research associates, data management CRO and patients will be blinded to 
study drug treatment during the efficacy period (up to Week 36). 
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Purpose: Updated to remove direct renin-inhibitors from the list of allowed standard of care and include another method of assessment for 
hematuria. 
The primary changes occur in Section 4 (Selection and Withdrawal of Patients) 
Added text: 
Inclusion Criteria (Section 4.1) 
 
Criterion 3: Treated for IgAN with stable, optimal pharmacological therapy.  In general, stable and optimal treatment will include 
maximum allowed or tolerated ACE inhibitor or an ARB or a direct renin inhibitor for at least 3 months prior to start of run-in period 
o This change also occurs in the Synopsis (Diagnosis and Main Eligibility Criteria) 
 
Criterion 5: Hematuria as defined by ≥10 RBCs per high powered field (RBC/hpf) at screening and either ≥10 RBC/hpf or a positive 
urinary dipstick (1+ and above) at the end of the run-in period, prior to randomization (local result accepted for assessment of eligibility 
at the end of the run-in period) 
o This change also occurs in the Synopsis (Diagnosis and Main Eligibility Criteria) and in Section 1.3 (Study Design Rationale)  
Other section including the update in the method of assessment of hematuria is Section 6.4.2 
Added text: The local hematuria evaluation by microscopy or urinary dipstick will be utilized to determine eligibility for the study at the end of 
the end of the run-in period. 
Purpose: Corrected information on study discontinuation 
The primary change occurs in Section 4.3.1 (Discontinuation of Study Drug or Declining Procedural Assessments) 
Added text:  
Reasons for discontinuation of study drug include any of the following: 
 
Other reason (non-adverse event), including confirmed positive test for ADA to cemdisiran 
Deleted text: The Investigator will confer with the Sponsor or Medical Monitor before discontinuing dosing in the patient.   
Purpose: Updated for clarification 
The primary change occurs in Section 5.3.1 (Prohibited Concomitant Medications)  
Added text:  
 
Fish oil supplements (if started prior to screening, then may continue during the study at the same dose) 
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Clinical Study Protocol ALN-CC5-005 
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Amendment 1 Summary of Changes, 26 November 2018 
 
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Purpose: Updated to clarify the timing of meningococcal vaccination and its administration based on local recommendations 
The primary change occurs in Section 5.3.2.1 
Added text:  
Section 5.3.2.1 (Meningococcal Vaccinations) 
All patients taking part in this study must be vaccinated against meningitis types A, C, W135, Y and B, upon determination of eligibility at the end 
of run-in period, 2 weeks prior to administering cemdisiran, as per the Schedule of Assessments.  Meningococcal group ACWY conjugate 
vaccine and meningococcal group B vaccine will be administered in accordance with the manufacturer’s instructions and according to the 
Advisory Committee on Immunization Practices (ACIP) or other locally applicable recommendations for patients with complement 
deficiencies. On days of vaccination, urinary samples should be collected prior to administration of vaccines. 
 
Patients who were previously vaccinated with polysaccharide type vaccines within 3 years of study entry will be revaccinated using 
conjugate vaccines if found eligible at the end of the run-in period.  Patients who complete the vaccination series after starting cemdisiran 
will receive prophylactic antibiotics according to local standard of care for at least 2 weeks after completing the recommended series of 
meningococcal vaccinations (meningococcal group ACWY conjugate vaccine and meningococcal group B vaccine) or longer, if required 
by local standard of care. 
 
Patients who either completed the recommended series of meningococcal vaccines less than 14 days from initiation of treatment with 
cemdisiran or those who have an incomplete meningococcal vaccination series will receive prophylactic antibiotic treatment according to 
local standard of care for at least 2 weeks after completing the recommended series of meningococcal vaccinations (meningococcal group 
ACWY conjugate vaccine and meningococcal group B vaccine) or longer, if required by local standard of care. 
 
Patients who have not been previously vaccinated against Neisseria meningitidis, those without documentation of vaccination history, or 
those vaccinated more than 3 years from study randomization will commence the vaccination series with the recommended meningococcal 
vaccines (meningococcal group ACWY conjugate vaccine and meningococcal group B vaccine) per the Schedule of Assessments if 
determined to be eligible for the study at the end of the run-in period.  Patients who complete the vaccine series after receiving cemdisiran 
will receive prophylactic antibiotics according to the local standard of care for at least 2 weeks after completing the recommended series 
of meningococcal vaccinations or longer, if required by local standard of care. 
 
If required locally, patients will receive prophylactic antibiotics according to the local standard of care after randomization to 
cemdisiran or placebo. 
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Clinical Study Protocol ALN-CC5-005 
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Purpose: Updated to reflect the use of highly effective methods of contraception in line with European Guidance (Clinical Trial Facilitation 
Group, 'Recommendations related to contraception and pregnancy testing in clinical trials'; September 2014). 
The primary change occurs in Section 5.5.1 
Added text: Females of child-bearing potential must be willing to use acceptable methods a highly effective method of contraception from 14 
days before first dose, throughout study participation, and for 90 days after last dose administration or until study completion.   
Birth control methods which are considered acceptable highly effective include: 
 
Established use of oral (except low-dose gestagens), implantable, injectable, or transdermal hormonal methods of contraception. Females 
of child-bearing potential who use hormonal contraceptives as a method of contraception must also use a barrier method (condom or 
occlusive cap [diaphragm or cervical/vault cap] in conjunction with spermicide [eg, foam, gel, film, cream, or suppository]). 
 
If hormonal methods of contraception are medically contraindicated due to their underlying disease, a double barrier method (combination 
of male condom with cap, diaphragm, or sponge, in conjunction with spermicide) is also considered an acceptable method of 
contraception. 
Investigators should advise females of childbearing potential of the most appropriate birth control method available within their country 
taking into account local medical practice. 
For male patients, no contraception is required. However, use by males of contraception (condom) may be required in some countries e.g. 
France, in order to comply with local requirements as described in the corresponding patient consent forms. 
Purpose: Corrected to reflect start of antibiotic prophylaxis after the start of cemdisiran treatment, if required per local guidance 
The primary change occurs in Section 5.5.3 
Added text: Patients who require prophylactic antibiotics following study specific vaccinationsafter randomization to cemdisiran or placebo 
(see Section 5.3.2.1) per local standard of care will undergo antibiotic compliance checks. 
Purpose:Added text (previously included in Table 1) encouraging sites to re-discuss study information at the end of the run-in period 
The primary change occurs in Sections 6.2 (Run-in Period) 
Added text: Sites are encouraged to discuss study information with the patients again at the end of the run-in period. 
Purpose: Clarified change from baseline in urine albumin/creatinine ratio (UACR) at Week 32 as an exploratory endpoint in line with Section 2 
The primary change occurs in Sections 6.4.1.1 
Added text: Additionally secondary endpoints that will be evaluated using 24-hour samples include the change from baseline in the UP/creatinine 
ratio (UPCR) will be evaluated as a secondary endpoint and the change from baseline in the urine UP/albumin albumin/creatinine ratio 
(UACR) at Week 32 as an exploratory endpoint. 
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Clinical Study Protocol ALN-CC5-005 
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Amendment 1 Summary of Changes, 26 November 2018 
 
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Purpose: Updated to clarify study treatment 
The primary change occurs in Section 6.4.3 
Added text: Blood and urine samples for renal function assessments will be collected prior to administration of cemdisiran or placebo on dosing 
days, if applicable. 
Other sections changed include: Section 6.5 and Section 6.7.4 
Purpose: Moved text from the notes section in the Schedule of Assessments to the relevant section in the body of the protocol 
The primary change occurs in Section 6.2 (Run-in Period) and Section 6.7.5 (Clinical Laboratory Assessments) 
Added text:  
Section6.2: Sites are encouraged to discuss study information with the patients again at the end of the run-in period. 
Section 6.7.5: Clinical laboratory assessments may be collected at the clinical study center or at home by a trained healthcare professional. On 
dosing days blood samples will be collected predose.  
Purpose: Updated to clarify the sample size and stratification by baseline proteinuria 
The primary change occurs in Section 7.1 
Added text: ThirtyApproximately 30 patients are planned to be randomized 2:1 (cemdisiran:placebo) in this study. 
To account for potential dropouts, approximately 30 patients are planned to be randomized stratified by baseline urine protein levels (≥ 1g/24h 
and <2g/24h versus >=2g/24h). 
Other sections including the change are: 
 
Synopsis 
 
Section 3.1 
 
Section 3.4 
Purpose:  Correct typographical errors, punctuation, grammar, abbreviations, and formatting. 
These changes are not listed individually. 
 
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CLINICAL STUDY PROTOCOL 
ALN-CC5-005 
 
Protocol Title: 
A Phase 2, Randomized, Double-blind, 
Placebo-controlled Study of Cemdisiran in Adult 
Patients with IgA Nephropathy 
Short Title: 
A Phase 2 Study of Cemdisiran in Adult Patients 
with IgA Nephropathy 
Study Drug: 
Cemdisiran (ALN-CC5)  
EudraCT Number: 
2018-002716-27 
IND Number: 
140087 
Protocol Date: 
 
Original protocol 10 September 2018 
Sponsor: 
Alnylam Pharmaceuticals, Inc. 
300 Third Street 
Cambridge, MA  02142 USA 
Telephone:  
 
Sponsor Contact:   
 
 
 
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. 
 
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Clinical Study Protocol ALN-CC5-005 
 
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INVESTIGATOR’S AGREEMENT 
 
I have read the ALN-CC5-005 protocol and agree to conduct the study in accordance with the 
protocol and all applicable regulations.  I agree to maintain the confidentiality of all information 
received or developed in connection with this protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 
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Clinical Study Protocol ALN-CC5-005 
 
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Original 10 September 2018 
 
 
 
Alnylam Pharmaceuticals 
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 
To characterize the pharmacokinetics 
(PK) of cemdisiran and relevant 
metabolites in plasma and urine in adult 
patients with IgAN 
 
To evaluate the effect of cemdisiran on 
serum and urine markers of complement 
activation, renal damage and 
inflammation 
 
To assess the incidence of antidrug 
antibodies (ADA) 
 
The slope of eGFR computed for the 
entire study period including the open 
label extension using all assessments 
during the study. 
 
Change from baseline in creatinine 
clearance at Week 32 
 
Percent of patients in full clinical 
remission (Urine Protein [UP] 
<0.3 g/24-hours) at Week 32  
 
Change from baseline in 24-hour 
albuminuria at Week 32 
 
Change from baseline in the urine 
albumin/creatinine ratio (UACR) as 
measured in 24-hour urine at Week 32 
 
Change from baseline in C5 level over the 
course of the study 
 
Change from baseline in complement 
activity (Complement Alternative 
Pathway [CAP] and Complement 
Classical Pathway [CCP]) over the course 
of the study 
 
Evaluation of area under the curve 
(AUC), maximum plasma concentration 
(Cmax), time to maximum plasma 
concentration (Tmax), terminal half-life 
(t1/2), clearance (CL/F), volume of 
distribution (V/F), cumulative amount 
excreted unchanged in urine (Ae) and 
percent of dose excreted in the urine (fe) 
of cemdisiran (25-mer) and 23-mer 
 
Evaluation of AUC, Cmax, Tmax, t1/2, 
CL/F, V/F, Ae and fe of 22-mer 
AS(N-1)3’ 
 
Change from baseline in levels of renal 
damage, complement activation and 
inflammation markers over the course of 
the study 
 
Incidence of antidrug antibodies (ADA) 
Study Design 
This is a multicenter, double-blind, placebo-controlled study comprised of three periods (Figure 1).  The 
first period of the study is an observational 14-week run-in period during which patients’ blood pressure, 
kidney function, degree of hematuria, and proteinuria will be measured.  The standard of care is expected 
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Clinical Study Protocol ALN-CC5-005 
 
ALN-CC5 (cemdisiran) 
Original 10 September 2018 
 
 
 
Alnylam Pharmaceuticals 
Confidential 
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to remain unchanged during this run-in period.  Patients will not receive study drug (cemdisiran or 
placebo) during this time.  The second study period is a 32-week treatment period which will evaluate the 
efficacy and safety of subcutaneous (SC) cemdisiran compared to SC placebo in combination with 
standard of care in patients with IgAN and persistent proteinuria.  The third period of the study is a 
52-week optional open-label extension (OLE) period to further evaluate the long-term safety and clinical 
activity of cemdisiran.  During the OLE, all patients (including those initially on placebo) will be treated 
with cemdisiran in combination with standard of care. 
The study will include Screening of up to 90 days to determine eligibility of patients and to complete 
disease-related assessments.  Patients will provide written informed consent and visit the study center 
approximately 2 weeks before starting the run-in period to complete the protocol screening assessments.  
Following successful screening, the 14-week run-in period will commence, during which patients’ blood 
pressure, kidney function, degree of hematuria and proteinuria as well as treatment with standard of care 
will be documented by the Investigator.  The standard of care is expected to remain unchanged during this 
run-in period.  Patients whose proteinuria level remains >1 g/24-hours within 2 weeks of the end of the 
run-in period, who continue to have hematuria, and who meet blood pressure and estimated glomerular 
filtration rate (eGFR) criteria will be eligible to enroll in the 32-week treatment period.  Upon 
confirmation of eligibility followed by vaccination against meningococcal infections, patients will be 
randomized at a 2:1 ratio to receive 600 mg of cemdisiran or placebo every 4 weeks in combination with 
standard of care.  Thirty patients are planned to be randomized in total, 20 in the cemdisiran arm and 10 in 
the placebo arm.  Patients excluded before randomization will be replaced at Screening.  
During the run-in period, patients will visit the study center 14, 8, and 2 weeks prior to randomization 
(Weeks 0, 6 and 12 of the run-in period).  Patients will then return to the study center every 4 weeks after 
the start of study drug treatment period. The primary endpoint will be assessed at the end of the treatment 
period at Week 32. 
At the end of the treatment period (Week 32), patients in the two treatment arms will enter the optional 
OLE period where they will receive cemdisiran at a dose of 600 mg every 4 weeks in combination with 
standard of care for 52 weeks.  The first study drug administration of the OLE will be administered at 
Week 32.  Patients will return to the study center at Weeks 36, 40, and every 8 weeks thereafter during 
the OLE.  Home visits, where locally feasible, may be arranged for cemdisiran administration in between 
8-weekly study center visits (Weeks 44, 52, 60, 68 and 76), unless patients are required to visit the study 
center as judged necessary by the Investigator, or if home visits cannot be arranged.  An end of treatment 
(EOT) visit will occur at Week 80 and an end of study (EOS) visit will be completed at Week 84. For 
patients who complete the treatment period only and who do not consent to continue to participate in the 
study in the OLE period, the EOS will be at Week 32. 
Patients will return to the clinical study center for safety follow-up visits approximately 13, 26, 39 and 52 
weeks after the EOS visit (regardless if EOS visit is at Week 32 or Week 84), unless enrolled in another 
study with cemdisiran. Home visits, where locally feasible, may be arranged during safety follow-up at 
visit Weeks 97 (13 weeks after the EOS visit) and 123 (39 weeks after the EOS visit). 
Regular reviews of safety and tolerability data will be performed by a Data Monitoring Committee 
(DMC) throughout the study with the primary purpose of protecting the safety of participating patients 
and the integrity of the study. 
Number of Planned Patients 
Thirty patients are planned for randomization in this study. 
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Clinical Study Protocol ALN-CC5-005 
 
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Diagnosis and Main Eligibility Criteria 
This study will include adults (≥18 years and ≤ 65 years of age) with a clinical diagnosis of primary 
immunoglobulin A (IgA) Nephropathy based on historical biopsy collected within 60 months of 
Screening, treated for IgA Nephropathy with stable, optimal pharmacological therapy including 
maximum allowed or tolerated angiotensin converting enzyme (ACE) inhibitor or angiotensin II receptor 
blocker (ARB) or a direct renin-inhibitor for at least 3 months prior to the start of the run-in period. 
Eligible patients must have mean urine protein ≥ 1g/24-hour from two valid 24-hour urine collections at 
the end of the run-in period, prior to randomization. In addition, eligible patients must have hematuria 
≥ 10 red blood cells per high powered field (RBC/hpf) at screening and at the end of the run-in period, 2 
weeks prior to randomization. Eligible patients are required to have been previously vaccinated with 
meningococcal group ACWY conjugate vaccine and meningococcal group B vaccine or be willing to 
receive these vaccinations as well as prophylactic antibiotic treatment if required. 
Patients will be excluded from the study if eGFR <30 mL/min/1.73 m2 2 weeks prior to randomization; 
treated with systemic steroids at dosages exceeding 20 mg prednisone-equivalent for more than 7 days or 
other immunosuppressant agents in the 12 months prior to randomization; have a diagnosis of rapidly 
progressive glomerulonephritis as measured by eGFR loss >30% over the duration of the run-in phase; 
sustained blood pressure >140/90 mmHg as defined by 2 or more readings during the run-in period 
measured in supine position after 10 minutes of rest; have received organ transplant (including 
hematologic transplant) or have secondary etiologies of IgAN (eg, inflammatory bowel disease, celiac 
disease).  
Study Drug, Dose, and Mode of Administration 
Cemdisiran is a synthetic small interfering RNA (siRNA) targeting complement component 5 (C5) 
mRNA that is covalently linked to a triantennary N-acetylgalactosamine (GalNAc) ligand.  Cemdisiran 
will be supplied as a sterile solution for SC injection that contains 200 mg/mL cemdisiran sodium 
(equivalent to 189 mg/mL of cemdisiran), formulated in water for injection (WFI) for SC administration.  
Doses of 600 mg of cemdisiran will be administered every 4 weeks during the 32-week treatment phase 
and the optional OLE period.  
Placebo (normal saline 0.9% for SC administration) will be packaged and administered identically to 
cemdisiran. 
Reference Treatment, Dose, and Mode of Administration 
Angiotensin converting enzyme inhibitors (ACE) or angiotensin II receptor blockers (ARB) or direct 
renin inhibitors per physician and manufacturer‘s instructions. 
Duration of Treatment and Study 
Subcutaneous doses of cemdisiran or matching placebo will be administered every 4 weeks over a period 
of 32 weeks during the treatment period and patients will receive SC doses of cemdisiran for a further 52 
weeks in the the optional OLE. The estimated total time on study, inclusive of Screening (90 days), run-in 
period (14 weeks), treatment period (32 weeks), extension period (52 weeks) and safety follow-up 
(52 weeks), for patients is up to approximately 36 months or 3.0 years. 
Statistical Methods 
Thirty patients are planned to be randomized 2:1 (cemdisiran:placebo) in this study based on the 
assumption that, in the placebo arm, the estimated geometric mean ratio of proteinuria at Week 32 to 
baseline is 0.88 (log standard deviation [SD] 0.597), corresponding to a 12% reduction. A sample size of 
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Clinical Study Protocol ALN-CC5-005 
 
ALN-CC5 (cemdisiran) 
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Confidential 
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27 with 2:1 randomization (cemdisiran:placebo) will provide a width of 0.80 for the 90% confidence 
interval (CI) for treatment effect size estimate (cemdisiran – placebo) in log scale.  This corresponds to a 
90% CI of (15%, 62%) for the treatment difference in the percentage scale if the true Week 32 reduction 
is 50% for the cemdisiran arm. To account for potential dropouts, 30 patients are planned to be 
randomized. 
The modified Intent-to-treat (mITT) population will include all patients who receive any amount of study 
drug and have at least one post baseline 24-hour proteinuria assessment. Patients will be grouped by 
assigned treatments (ie, as randomized). The Safety Analysis Set will include all patients who received 
any amount of study drug. Patients who received any amount of cemdisiran will be included in the 
cemdisiran arm. Patients in the Safety Analysis Set will be grouped by treatment received. PK Analysis 
Set: All patients who receive any amount of study drug and have at least one postdose blood or urine 
sample for PK concentration. PD Analysis Set: All patients who receive any amount of study drug and 
who have at least one postdose blood sample for the determination of plasma C5 level. 
The primary endpoint of the study is the percentage reduction from baseline in 24-hour proteinuria at 
Week 32. The primary analysis will be performed on the change from baseline in log transformed urine 
protein using a linear model with log transformed baseline urine protein as covariate and treatment and 
randomization stratification factor as fixed effect. The least square mean difference and its 90% 
confidence interval (CI) will be estimated and then back transformed to original scale. In the end, the 
estimated ratio of percentage reduction in urine protein for cemdisiran to placebo and 90% CI will be 
presented.  
A sensitivity analysis using all urine protein assessments including a single 24-hour assessment will be 
conducted using mixed-effects model repeated measures (MMRM) method. 
The efficacy endpoints will be analyzed in the mITT population. PK and PD parameters will be analyzed 
in the PK and PD analysis sets, respectively. 
Safety data will be summarized with descriptive statistics. Treatment-emergent adverse events will be 
summarized by SOC and PT (all events, related events, and serious events), in addition to being 
summarized by severity (all events). In addition, summaries will be provided for any AEs leading to 
discontinuation of study drug or death. Serious adverse events and procedure related adverse events in the 
run-in period will be listed. 
 
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Clinical Study Protocol ALN-CC5-005 
 
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Figure 1: 
Study Design  
 
Abbreviations:  Q4W=once every 4 weeks; EOS=end of study; EOT=end of treatment 
 
Screening (up to 90 days)
Run-in Period 
(14 Weeks)
EOS
(Week 84)
Treatment Period 
(32 Weeks)
EOT
(Week 80)
Safety Follow-up 
(52 Weeks)
Placebo (n=10)
+ Standard of care
ALN-CC5 600mg Q4W (n=20)
+ Standard of care
Standard of care
Randomization (2:1)
Open-label Extension Period 
(52 Weeks)
Primary endpoint assessment
ALN-CC5 
600mg Q4W 
+ Standard of care
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Clinical Study Protocol ALN-CC5-005 
 
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Table 1: Schedule of Assessments – Run-in and Treatment Periods (Screening through Week 32 Assessments) 
Study Visit (Day/Week) 
 
Screening 
Run-in 
Period 
(14 
weeks) 
Treatment Period 
(32 weeks) 
 
Screening 
visit 
Week -14 
Week -8 
Week -2 
Day 1 
Week 4 
Week 8 
Week 12 
Week 16 
Week 20 
Week 24 
Week 28 
Week 32 
Notes 
D-189 
to D-99 
D-112 ±7 
D-98 ±7 
D-56 ±7 
D-14 ±3 
D1 
D28 ±3 
D56 ±3 
D84 ±3 
D112 ±3 
D140 ±3 
D168 ±3 
D196 ±3 
D224 ±3 
Discuss Study Information and Collect 
Informed Consent 
Sites are encouraged to discuss the study 
information with the patients again at the 
end of the run-in period. 
X 
 
 
(X) 
 
 
 
 
 
 
 
 
(X) 
Medical History 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
Routine Physical Exam 
See Section 6.7.3.  
 
X 
 
 
 
X 
 
X 
 
 
 
 
 
X 
Height, Weight and BMI 
See Section 6.7.2.  
 
X 
 
 
 
X 
 
X 
 
 
 
 
 
X 
Vital Signs 
See Section 6.7.1.  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG 
See Section 6.7.4. 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
Clinical Laboratory Assessment 
On dosing days blood samples will be 
collected predose; see Section 6.7.5.  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test 
See Section 6.7.5.2.  
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Start of Meningitis Vaccination 
Sites to use locally approved vaccines 
and follow the manufacturer’s 
instructions applicable to patients with 
persistent complement component 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
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Clinical Study Protocol ALN-CC5-005 
 
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Study Visit (Day/Week) 
 
Screening 
Run-in 
Period 
(14 
weeks) 
Treatment Period 
(32 weeks) 
 
Screening 
visit 
Week -14 
Week -8 
Week -2 
Day 1 
Week 4 
Week 8 
Week 12 
Week 16 
Week 20 
Week 24 
Week 28 
Week 32 
Notes 
D-189 
to D-99 
D-112 ±7 
D-98 ±7 
D-56 ±7 
D-14 ±3 
D1 
D28 ±3 
D56 ±3 
D84 ±3 
D112 ±3 
D140 ±3 
D168 ±3 
D196 ±3 
D224 ±3 
deficiency; see Section 5.3.2  and 
Section 6.2.  
Confirmation of Vaccine Injection 
Schedule Compliance 
As applicable and dependent on which 
vaccine will be used. 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Randomization 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Study Drug Administration 
See Section 5.2.2.  
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
24-hours Urine Proteinuria Assessment 
(from 2 valid collections) 
Collected within two weeks before the 
assessment is due to take place; see 
Section 6.4.1.1.  
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
24-hours Urine Proteinuria Assessment 
(from a single valid collection) 
Collected within one week before the 
assessment is due to take place; see 
Section 6.4.1.1.  
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
CAP/CCP Blood Sample 
Samples will be collected predose; see 
Section 6.5. 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C5 Levels Blood Sample 
Samples will be collected predose; see 
Section 6.5.  
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
eGFR Calculation 
See Section 6.4.3.  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Sample for Urinalysis 
See Section 6.4.1.1.  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Spot Urine for Albumin, Protein and 
Creatinine 
See Section 6.4.1.2.  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Study Visit (Day/Week) 
 
Screening 
Run-in 
Period 
(14 
weeks) 
Treatment Period 
(32 weeks) 
 
Screening 
visit 
Week -14 
Week -8 
Week -2 
Day 1 
Week 4 
Week 8 
Week 12 
Week 16 
Week 20 
Week 24 
Week 28 
Week 32 
Notes 
D-189 
to D-99 
D-112 ±7 
D-98 ±7 
D-56 ±7 
D-14 ±3 
D1 
D28 ±3 
D56 ±3 
D84 ±3 
D112 ±3 
D140 ±3 
D168 ±3 
D196 ±3 
D224 ±3 
Antidrug Antibodies 
Antidrug antibodies samples will be 
collected predose; see Section 6.7.5.1. 
 
 
 
 
 
X 
X 
 
X 
 
 
X 
 
X 
Exploratory Blood Sample 
See Section 6.4.4.  
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Blood Sample for Exploratory Genetic 
Analysis 
See Section 6.8. 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Exploratory Urine Sample  
See Section 6.4.4.  
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Plasma and Urine PK 
Blood samples for PK will be collected 
at timepoints noted in Table 3.  
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Adverse Events 
See Section 6.7.6.2.  All SAEs and only 
AEs related to study procedures will be 
collected during the run-in period.  
 
 
 
 
 
X 
Concomitant Medications 
See Section 5.3.  
X 
X 
X 
Antibiotics Compliance (if applicable) 
See Section 5.5.3.  
 
 
 
 
X 
IgAN standard of Care Compliance 
 
 
X 
 
 
 
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Table 3: 
Pharmacokinetic Time Points 
 
Phase 
Study Day 
Protocol Time Relative to Dosing 
(hh:mm)a 
PK Blood 
Pooled Urine
b 
Treatment phase 
Day 1  
Predose (within 60 mins) 
X 
 
00:00 (dose) 
 
X 
01:00 (±5 mins) 
X 
02:00 (±15 mins) 
X 
04:00 (±15 mins) 
X 
06:00 (±15 mins) 
X 
08:00 (±30 mins) 
X 
X 
12:00 (±30 mins) 
 
24:00 (±120 mins) 
X 
X 
Abbreviations:   hh=hours; mm=minutes; mins=minutes; PK=pharmacokinetics. 
a The actual time of blood sample collection must be recorded. 
b The pooled urine 8-12 hours and 12-24 hours can be collected as outpatient. 
 
 
 
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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ................................................................................................................4 
TABLE OF CONTENTS ...............................................................................................................17 
LIST OF TABLES .........................................................................................................................20 
LIST OF FIGURES .......................................................................................................................21 
1. 
INTRODUCTION ......................................................................................................24 
1.1. 
Disease Overview .......................................................................................................24 
1.2. 
Cemdisiran ..................................................................................................................25 
1.3. 
Study Design Rationale ..............................................................................................27 
1.4. 
Dose Rationale ............................................................................................................28 
1.5. 
Benefit-Risk Assessment ............................................................................................29 
2. 
OBJECTIVES AND ENDPOINTS ............................................................................30 
3. 
INVESTIGATIONAL PLAN .....................................................................................32 
3.1. 
Summary of Study Design ..........................................................................................32 
3.2. 
Duration of Treatment ................................................................................................33 
3.3. 
Duration of Study .......................................................................................................33 
3.3.1. 
Definition of End of Study for an Individual Patient .................................................33 
3.4. 
Number of Planned Patients .......................................................................................33 
3.5. 
Method of Assigning Patients to Treatment Groups ..................................................33 
3.6. 
Blinding ......................................................................................................................34 
3.6.1. 
Emergency Unblinding ...............................................................................................34 
3.7. 
Data Monitoring Committee .......................................................................................34 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................35 
4.1. 
Inclusion Criteria ........................................................................................................35 
4.2. 
Exclusion Criteria .......................................................................................................35 
4.3. 
Removal from Therapy or Assessment.......................................................................37 
4.3.1. 
Discontinuation of Study Drug or Declining Procedural Assessments ......................37 
4.3.2. 
Stopping a Patient’s Study Participation ....................................................................38 
4.3.2.1. 
Patient or Legal Guardian Stops Participation in the Study .......................................38 
4.3.2.2. 
Withdrawal of Consent to Process the Patient’s Personal Data .................................39 
4.3.2.3. 
Investigator or Sponsor Stops Participation of a Patient in the Study ........................39 
4.3.2.4. 
Recording Reason for Stopping a Patient’s Study Participation ................................39 
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4.3.3. 
Lost to Follow-Up.......................................................................................................39 
4.3.4. 
Replacement of Study Patients ...................................................................................40 
5. 
TREATMENTS AND OTHER REQUIREMENTS ..................................................41 
5.1. 
Treatments Administered ............................................................................................41 
5.2. 
Study Drug ..................................................................................................................41 
5.2.1. 
Description ..................................................................................................................41 
5.2.2. 
Dose and Administration ............................................................................................41 
5.2.3. 
Dose Modifications .....................................................................................................41 
5.2.3.1. 
LFT Criteria for Withholding, Monitoring and Stopping Cemdisiran Dosing ...........42 
5.2.4. 
Preparation, Handling, and Storage ............................................................................43 
5.2.5. 
Packaging and Labeling ..............................................................................................44 
5.2.6. 
Accountability .............................................................................................................44 
5.3. 
Concomitant Medications and Procedures .................................................................44 
5.3.1. 
Prohibited Concomitant Medications .........................................................................44 
5.3.2. 
Study-specific Vaccinations .......................................................................................45 
5.4. 
Treatment Compliance ................................................................................................46 
5.5. 
Other Requirements ....................................................................................................46 
5.5.1. 
Contraception ..............................................................................................................46 
5.5.2. 
Alcohol Restrictions ...................................................................................................47 
5.5.3. 
Antibiotic Compliance ................................................................................................47 
6. 
STUDY ASSESSMENTS ..........................................................................................48 
6.1. 
Screening Assessments ...............................................................................................48 
6.1.1. 
Rescreening .................................................................................................................48 
6.1.2. 
Retesting .....................................................................................................................48 
6.2. 
Run-in Period ..............................................................................................................48 
6.3. 
Baseline Assessments (Treatment Period) ..................................................................49 
6.4. 
Efficacy Assessments .................................................................................................49 
6.4.1. 
Proteinuria ...................................................................................................................49 
6.4.1.1. 
24-Hour Urine Collection ...........................................................................................49 
6.4.1.2. 
Spot Urine Collection .................................................................................................50 
6.4.2. 
Hematuria ...................................................................................................................50 
6.4.3. 
Changes in Renal Function .........................................................................................51 
6.4.4. 
Markers of Complement Activation, Inflammation and Renal Injury .......................51 
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6.5. 
Pharmacodynamic Assessments .................................................................................51 
6.6. 
Pharmacokinetic Assessments ....................................................................................51 
6.7. 
Safety Assessments .....................................................................................................52 
6.7.1. 
Vital Signs ..................................................................................................................52 
6.7.2. 
Weight and Height ......................................................................................................52 
6.7.3. 
Physical Examination .................................................................................................52 
6.7.4. 
Electrocardiogram .......................................................................................................53 
6.7.5. 
Clinical Laboratory Assessments ...............................................................................53 
6.7.5.1. 
Immunogenicity ..........................................................................................................55 
6.7.5.2. 
Pregnancy Testing ......................................................................................................55 
6.7.5.3. 
Additional Liver Function Assessments .....................................................................55 
6.7.6. 
Adverse Events ...........................................................................................................56 
6.7.6.1. 
Definitions ..................................................................................................................56 
6.7.6.2. 
Eliciting and Recording Adverse Events ....................................................................58 
6.7.6.3. 
Reporting Adverse Events of Clinical Interest to Sponsor/Designee .........................59 
6.7.6.4. 
Serious Adverse Events Require Immediate Reporting to Sponsor/Designee ...........59 
6.7.6.5. 
Sponsor Safety Reporting to Regulatory Authorities .................................................60 
6.7.6.6. 
Serious Adverse Event Notification to the Institutional Review 
Board/Independent Ethics Committee ........................................................................60 
6.7.6.7. 
Pregnancy Reporting ..................................................................................................60 
6.7.6.8. 
Overdose Reporting ....................................................................................................60 
6.8. 
Biomarkers, DNA Genotyping, and Biospecimen Repository ...................................61 
7. 
STATISTICS ..............................................................................................................62 
7.1. 
Determination of Sample Size ....................................................................................62 
7.2. 
Statistical Methodology ..............................................................................................62 
7.2.1. 
Populations to be Analyzed ........................................................................................62 
7.2.2. 
Examination of Subgroups .........................................................................................62 
7.2.3. 
Handling of Missing Data ...........................................................................................63 
7.2.4. 
Baseline Evaluations ...................................................................................................63 
7.2.5. 
Efficacy Analyses .......................................................................................................63 
7.2.5.1. 
Primary Endpoint ........................................................................................................63 
7.2.5.2. 
Secondary Efficacy Endpoints ....................................................................................63 
7.2.5.3. 
Exploratory Endpoints ................................................................................................63 
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7.2.6. 
Pharmacodynamic Analysis........................................................................................64 
7.2.7. 
Pharmacokinetic Analysis ..........................................................................................64 
7.2.8. 
Safety Analyses ..........................................................................................................64 
7.2.9. 
Immunogenicity Analyses ..........................................................................................65 
7.2.10. 
Biomarker Analyses ....................................................................................................65 
7.2.11. 
Interim Analysis ..........................................................................................................65 
7.2.12. 
Optional Additional Research .....................................................................................65 
8. 
STUDY ADMINISTRATION ...................................................................................66 
8.1. 
Ethical and Regulatory Considerations ......................................................................66 
8.1.1. 
Informed Consent .......................................................................................................66 
8.1.2. 
Ethical Review ............................................................................................................66 
8.1.3. 
Serious Breach of Protocol .........................................................................................67 
8.1.4. 
Study Documentation, Confidentiality, and Records Retention .................................67 
8.1.5. 
End of Study ...............................................................................................................67 
8.1.6. 
Termination of the Clinical Study or Site Closure .....................................................67 
8.2. 
Data Quality Control and Quality Assurance .............................................................68 
8.2.1. 
Data Handling .............................................................................................................68 
8.2.2. 
Study Monitoring ........................................................................................................68 
8.2.3. 
Audits and Inspections ................................................................................................68 
8.3. 
Publication Policy .......................................................................................................68 
9. 
LIST OF REFERENCES ............................................................................................70 
10. 
APPENDICES ............................................................................................................72 
 
LIST OF TABLES 
Table 1: 
Schedule of Assessments  Run-in and Treatment Periods (Screening 
through Week 32 Assessments) ..................................................................................10 
Table 2: 
Schedule of Assessments  Open-Label Extension Period and Safety Follow 
up ................................................................................................................................13 
Table 3: 
Pharmacokinetic Time Points .....................................................................................16 
Table 4: 
Monitoring and Dosing Rules for Asymptomatic Patients with Confirmed 
Isolated Elevations of ALT and/or AST >3× ULN, with No Alternative 
Cause Identified ..........................................................................................................43 
Table 5: 
Clinical Laboratory Assessments ...............................................................................53 
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Table 6: 
Hepatic Assessments in Patients Who Experience Elevated Transaminases .............56 
 
LIST OF FIGURES 
Figure 1: 
Study Design .................................................................................................................9 
List of Abbreviations and Definitions of Terms 
Abbreviation  
Definition 
ADA 
Antidrug antibodies 
ACE 
Angiotensin-converting enzyme 
AE 
Adverse event 
AECI 
Adverse event of clinical interest 
aHUS 
Atypical hemolytic uremic syndrome 
ALN-CC5 
Cemdisiran 
ALT 
Alanine transaminase 
ARB 
Angiotensin II receptor blocker 
AST 
Aspartate transaminase 
AUC 
Area under the concentration curve 
BMI 
Body mass index 
C3 
Complement component 3 
C3a 
Activated complement 3 
C5 
Complement component 5 
C5a 
Activated complement component 5 
CAP 
Complement alternative pathway 
CCP 
Complement classical pathway 
CFH 
Complement factor H 
CI 
Confidence interval 
CL/F 
Clearance 
Cmax 
Maximum concentration 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
ELISA 
Enzyme linked immunosorbent assay 
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Abbreviation  
Definition 
EOS 
End of study 
EOT 
End of treatment 
ESRD 
End-stage renal disease 
GalNAc 
N-acetylgalactosamine 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
hpf 
High powered field 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonisation 
IEC 
Independent Ethics Committee 
IgA 
Immunoglobulin A 
IgG 
Immunoglobulin G 
IgAN 
IgA Nephropathy 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRS 
Interactive Response System 
ISR 
Injection site reaction 
IV 
Intravenous 
LFT 
Liver function test 
MAC 
Membrane attack complex 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified intent-to-treat 
mRNA 
Messenger RNA 
NHP 
Nonhuman primates 
OLE 
Open-label extension 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic(s) 
PNH 
Paroxysmal nocturnal hemoglobinuria 
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Abbreviation  
Definition 
RAS 
Renin-angiotensin system 
RBC 
Red blood cell 
RNAi 
RNA interference 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous(ly) 
siRNA 
Small interfering RNA 
SUSAR 
Suspected unexpected serious adverse reaction 
t½ 
Terminal half-life 
Tmax 
Time to maximum concentration 
TMF 
Trial Master File 
UP 
Urine protein 
UACR 
Urine albumin:creatinine ratio 
ULN 
Upper limit of normal 
UPCR 
Urine protein:creatinine ratio 
V/F 
Volume of distribution 
 
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1. 
INTRODUCTION 
1.1. 
Disease Overview 
Globally, immunoglobulin A nephropathy (IgAN) is the most common primary 
glomerulonephritis that can progress to renal failure.[1, 2]  While the exact pathogenesis of IgAN 
is incompletely understood, biochemical, genetic, and clinical data suggest IgAN is an 
autoimmune disease that may originate from overproduction of aberrantly glycosylated IgA1 and 
the development of glycan-specific IgA and immunoglobulin G (IgG) autoantibodies that 
recognize the under-galactosylated IgA1 molecule.  Both the alternative and lectin complement 
pathways may be activated, leading to generation of the anaphylatoxins activated complement 
component 3 (C3a) and activated complement component 5 (C5a) and the membrane attack 
complex (MAC) C5b-9, with subsequent promotion of inflammatory mediators.[3]  Emerging 
data indicate that mesangial-derived mediators that are released following deposition of IgA1 
may lead to podocyte and tubulointerstitial injury. 
Given that a biopsy specimen is required to diagnose IgAN, the clinical threshold for performing 
a biopsy will have a major impact on the prevalence of IgAN. Persistent microscopic hematuria 
alone and/or mild proteinuria alone are not commonly used as a per cause indication for biopsy 
in the United States.  Thus, the prevalence of IgAN is modest in the United States (10 to 20% of 
primary glomerulonephritis), higher in some European countries (20 to 30%), and highest in 
developed countries in Asia (40 to 50%).[4]  This considerable geographical variability can be 
explained by several factors including the variation in access to primary care enabling early 
diagnosis and the differences in policies for performing renal biopsies as well as for early 
referrals.  For example, in some countries, urine screening tests are conducted in schools or for 
military service or ahead of employment, explaining the apparent high incidence.[2, 5]  Ethnic 
differences can also contribute to the varying prevalence of IgAN.  Genome-wide association 
studies have identified candidate genes as well as risk-associated and protective alleles, with the 
highest number of risk alleles present in individuals of East Asian origin and the lowest number 
in those from Africa.[6]  These genes are involved in antigen presentation, mucosal defense 
system and notably the alternative complement pathway (complement factor H [CFH]/CFHR 
locus).[6]  Finally, patients may present at any age with IgAN but there is a peak incidence in the 
second and third decades of life.  Most cases of IgAN occur in sporadic (90 to 95%) rather than 
in familial patterns (5 to 10%).[1] 
Routine screening for IgAN is not feasible given that no specific diagnostic laboratory tests are 
available.  The first indication for making a diagnosis comes after careful microscopic 
examination of a urine sample.  The presence of red blood cell (RBC) casts and dysmorphic 
RBCs indicates glomerular bleeding.  Varying degrees of proteinuria are present in patients with 
IgAN. Proteinuria can be quantified with a timed urine collection or a spot urine protein to 
creatinine ratio (UPCR) measurement.  Hence, IgAN can only be diagnosed definitely upon renal 
biopsy and study of kidney tissue using immunofluorescence.  The pathology of IgAN is 
characterized by deposition of pathogenic polymeric IgA1 immune complexes and C3 in the 
glomerular mesangium, proliferation of mesangial cells, increased synthesis of extracellular 
matrix and variable infiltration of macrophages, monocytes and T cells.  A consensus on the 
pathologic classification of IgAN has been developed by the International IgA Nephropathy 
Network in collaboration with the Renal Pathology Society (Oxford classification).[1, 7, 8] 
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The clinical presentation of patients with IgAN is highly variable, ranging from asymptomatic 
microscopic hematuria to a rapidly progressive form of glomerulonephritis which is often 
associated with severe hypertension, but between these extremes, most patients with IgAN 
pursue a chronic indolent course.[1]  Some patients present with more severe proteinuria, 
hypertension and renal progression over time, typically reaching end-stage renal disease (ESRD) 
over a span of 20 years.  Thus, the severity of proteinuria upon presentation has significant 
prognostic implications.  More importantly, the change in proteinuria over time is being regarded 
as the current best prognostic indicator: those who had heavy time averaged proteinuria and 
achieved a partial remission of <1 g/24-hours had a similar course to those who had 
<1 g/24-hours throughout and fared far better than those who never achieved partial 
remission.[9]  These observations support the notion that every effort should be made to reduce 
proteinuria in IgAN.  In addition to the degree of proteinuria, baseline renal function and the 
degree of histological injury are of prognostic value.  For example, patients with an estimated 
glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 at the time of renal biopsy have worse 
outcomes than those with normal eGFR (90 to 120 mL/min/1.73 m2).  The rate of glomerular 
filtration rate (GFR) decline also correlates with glomerulosclerosis and tubular atrophy or 
interstitial fibrosis on biopsy as outlined by Oxford-MEST-C classification.  Spontaneous full 
recovery in IgAN is rare in adults, especially if associated with significant proteinuria 
(>0.5 g/24-hour).[10] 
Patients with minor urine abnormalities, normal blood pressure, and normal GFR usually do well 
and require only monitoring.  For other patients, the therapeutic options are limited and include 
nonspecific treatment to reduce blood pressure and proteinuria by renin-angiotensin system 
(RAS) blockade.  Thus, no disease-specific therapies are currently available, and an unmet need 
persists for novel interventions, particularly in patients who are at risk of progressive disease that 
can result in end-stage renal failure.  The optimal role of immunosuppressive therapy is 
uncertain.  The available studies are not conclusive since most are relatively small and have 
limited follow-up.[1]  STOP-IgAN, a German trial, randomly assigned adults with an eGFR of 
>30 mL/min/1.73 m2 and persistent proteinuria of >0.75 g/24-hour despite 6 months of 
supportive care with RAS inhibitors to receive supportive care alone or supportive care plus 
immunosuppression (prednisone alone for those with initial GFR >60 mL/min and prednisone 
combined with cyclophosphamide then azathioprine with initial GFR 30-59 mL/min).  This 
strategy did not significantly improve the renal outcome and was associated with increased 
adverse effects at 36 months.[11]  The TESTING trial demonstrated some GFR effect of steroids 
in Chinese patients, but had to be stopped due to large number of serious adverse events (SAEs) 
in the steroid arm.[12]  The 2012 KDIGO guidelines recommend corticosteroids, albeit at very 
low level of evidence. Thus, steroids may be tried in some cases as rescue therapy if proteinuria 
markedly increases or GFR rapidly falls. Further studies to address the role of steroids in IgAN 
are currently under way.  Finally, Rituximab seems to be ineffective in the treatment of patients 
with progressive IgAN.[13] 
1.2. 
Cemdisiran 
Alnylam Pharmaceuticals, Inc. is developing cemdisiran (ALN-CC5), a synthetic RNA 
interference (RNAi) therapeutic designed to suppress liver production of C5 protein, for the 
treatment of atypical hemolytic uremic syndrome (aHUS) and IgAN.  Cemdisiran comprises a 
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small interfering RNA (siRNA) targeting C5 messenger RNA (mRNA) that is covalently linked 
to a triantennary N-acetylgalactosamine (GalNAc) ligand.   
RNAi is a naturally occurring cellular mechanism for regulating gene expression that is mediated 
by siRNAs.  Synthetic siRNAs are short (19-25 base pairs), double-stranded oligonucleotides in 
a staggered duplex with an overhang at one or both 3-prime ends.  Such siRNAs can be designed 
to target the mRNA transcript of a given gene.  When formulated for tissue delivery and 
introduced into cells, the guide (or antisense) strand of the siRNA loads into an enzyme complex 
called the RNA-induced silencing complex.  This enzyme complex subsequently binds to its 
complementary mRNA sequence, mediating cleavage of the mRNA and the suppression of the 
target protein encoded by the mRNA.[14]  Since unmodified siRNAs are rapidly eliminated and 
do not achieve significant tissue distribution upon systemic administration [15], various 
formulations are currently used to target their distribution to tissues, and to facilitate uptake of 
siRNAs into the relevant cell type.  One approach that has been used successfully in vivo in 
animal models (including in rodents and nonhuman primates [NHP]) and humans employs 
intravenous (IV) delivery of siRNA in lipid nanoparticle formulations.[15, 16]  Another 
approach for liver-specific gene silencing is subcutaneously administered siRNA conjugated to a 
GalNAc carbohydrate ligand.[17]  Conjugation of a triantennary GalNAc ligand to an siRNA 
enables hepatocyte binding and subsequent cellular uptake via the asialoglycoprotein receptor, 
resulting in engagement of the RNAi pathway and downregulation of hepatic proteins. 
Cemdisiran (containing siRNA drug substance, ALN-62643, targeting C5 mRNA) is a synthetic 
investigational RNAi therapeutic designed to suppress liver production of C5 protein, when 
administered via subcutaneous (SC) injection.  C5 is encoded by a single gene and is expressed 
and secreted predominantly by hepatocytes.  Through the mechanism of RNAi, the cemdisiran 
siRNA enables the downregulation of C5 mRNA in the liver, thereby reducing levels of 
circulating C5 protein and resulting in inhibition of terminal complement pathway activity and 
prevention of MAC formation and C5a release.  This in turn would be expected to reduce 
mesangial cell proliferation and tissue injury in patients with IgAN resulting in renal function 
improvement.[3] Both lectin and alternative pathways of complement have been implicated in 
IgAN pathology.  Cemdisiran-mediated silencing of C5 will inhibit MAC formation and C5a 
release regardless of the activating pathway and may be a superior approach in IgAN where the 
contribution of different pathways may be heterogenous between patients.[18] 
The safety of reducing C5 is supported by clinical precedence of C5 inhibition with eculizumab 
treatment and the absence of any phenotypic abnormalities in subjects with known genetic C5 
deficiencies.[19]  Subjects with known C5 deficiencies are generally healthy apart from an 
increased susceptibility to Neisserial infections. In addition, safety data on the treatment of 
healthy volunteers and patients with paroxysmal nocturnal hemoglobinuria (PNH) with 
cemdisiran in Study ALN-CC5-001 indicate that cemdisiran is generally well-tolerated; the 
maximum tolerated dose was 900 mg.  There were no serious adverse events (SAEs) or 
discontinuations due to adverse events (AEs) during this study, and most AEs were mild or 
moderate in severity. 
A detailed description of the chemistry, pharmacology, nonclinical pharmacokinetics (PK) and 
toxicology, as well as preliminary efficacy, and safety of cemdisiran is provided in the current 
edition of the Investigator’s Brochure (IB). 
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1.3. 
Study Design Rationale 
In contrast to the RBC lysis which characterises the pathophysiology of PNH, which requires 
extremely high level of C5 inhibition for protection, endothelial cells and mesangial cells are the 
cellular targets of dysregulated complement in aHUS and IgAN, respectively.  These cells are 
nucleated cells which possess complement regulatory proteins as well as the ability to shed 
membrane associated MAC to defend against MAC-mediated damage, a key step in thrombotic 
microangiopathy progression in aHUS and renal damage in IgAN.  It is therefore hypothesized 
that a lesser degree of cemdisiran mediated C5 knockdown will be required for disease control in 
patients with IgAN and aHUS than in patients with PNH.[20, 21]  This hypothesis is supported 
by the observation that aHUS patients who achieve C5 inhibition maintain good disease control 
despite complement activity levels consistent with higher free C5 levels.[22]  Therefore, 
cemdisiran monotherapy may be a viable treatment option in patients with IgAN at levels of C5 
silencing achieved in Study ALN-CC5-001. 
This therapeutic hypothesis will be tested in a multicenter, multinational, double-blind, 
placebo-controlled study to evaluate the effect of multiple doses of cemdisiran given by SC 
injection in patients with IgAN with persistent proteinuria (>1 g/24-hours) despite the standard 
of care (angiotensin converting enzyme inhibitors [ACE], angiotensin II receptor blockers [ARB] 
or direct renin inhibitors) and additional medications if necessary for blood pressure control 
followed by a treatment extension to evaluate long-term safety and clinical activity.  The study 
population has been selected based on two major factors: 1) the severity of proteinuria upon 
presentation has significant prognostic implications.[23]  IgAN patients with heavy proteinuria 
>1 g/24-hours have a significantly worse renal outcome than those who have proteinuria 
<1 g/24-hours.[9]  2) For patients with persistent proteinuria, despite the nonspecific treatment to 
reduce blood pressure and proteinuria by RAS blockade, no disease-specific therapies are 
currently available, and an unmet need persists for novel interventions. Since proteinuria can 
result both from active inflammation as well as irreversible scarring of renal tissue and in lieu of 
a protocol biopsy, we enrich our patients for presence of potentially reversible disease activity by 
requiring presence of hematuria and relatively preserved renal function with eGFR >30 mL/min. 
To ensure the selection of patients who are truly at risk of progression of kidney disease despite 
standard of care, the first period of the study consists of a run-in period during which patients 
will not receive study drug (cemdisiran or placebo).  The run-in period will be an observational 
period during which patients’ treatment with standard of care, blood pressure, kidney function, 
degree of hematuria, and proteinuria will be documented.  The standard of care is expected to 
remain unchanged during this run-in period. Only patients whose  
 proteinuria level remains above 1 g/24-hours within 2 weeks before the end of the 
run-in period,  
 continue to have hematuria, and meet blood pressure and eGFR criteria  
will be eligible to enroll in the 32-week treatment period portion of the study. 
Randomization to cemdisiran or placebo will be performed in a 2:1 ratio so that more patients 
will receive cemdisiran. This will allow a more precise estimation of the effect of cemdisiran 
with only marginal loss of power. Inclusion of a placebo arm will allow better assessment of 
safety and interpretation of the efficacy of cemdisiran. 
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The primary endpoint for the study is percent change from baseline in 24-hour proteinuria 
(g/24-hours) at Week 32.  This is justified for a phase 2 study given the slow progression of renal 
disease and the established role of proteinuria as a marker of disease progression. 
1.4. 
Dose Rationale 
In the Phase 1/2 Study (ALN-CC5-001), 32 healthy volunteers were treated with single SC doses 
of cemdisiran ranging from 50 mg to 900 mg, 24 healthy volunteers were treated with multiple 
doses of cemdisiran ranging from 100 mg to 600 mg (dosing weekly, every other week or 
monthly), 6 patients with PNH were treated with cemdisiran at cumulative doses of 3200 mg to 
4200 mg (eculizumab-naïve patients) and 1200 mg to 2400 mg (patients on background 
eculizumab treatment).  Treatment with cemdisiran was generally well tolerated in both healthy 
volunteers and patients with PNH.  There were no SAEs and no discontinuations due to AEs 
during this study, including at the highest doses administered.  Most AEs observed were mild or 
moderate in severity. 
Dose selection for the current study is based on the expected level of C5 and complement 
activity inhibition necessary for efficacy in patients with IgAN and the extent to which different 
doses of cemdisiran can inhibit production of C5.  C5 silencing is a novel approach for the 
treatment of IgAN and little clinical precedent exists for inhibiting the terminal complement 
pathway in this disease.  Since complement regulation is not impaired in IgAN like it is in PNH, 
and the kidney glomerular cells are nucleated cells, it is expected that the level of silencing 
needed for efficacy in IgAN is lower than that needed for PNH (see IB Section 2.4).  For this 
proof-of-concept study, a dose was selected that is expected to produce rapid and robust C5 
suppression and complement activity inhibition across the patient population, allowing an 
unambiguous evaluation of  whether C5 silencing results in proteinuria improvement in IgAN.  
In Study ALN-CC5-001, a single dose of 600 mg cemdisiran achieved a C5 level of 
12.3±1.47 μg/mL by Day 14 and 2.3±0.76 μg/mL by Day 56, corresponding to 60.9% reduction 
in complement alternative pathway (CAP) activity and a 69.3% reduction in complement 
classical pathway (CCP) activity by Day 14 and 90.2% and 91.4% reduction in CAP and CCP 
activities, respectively, by Day 56. Single and multiple biweekly doses of 600 mg were 
well-tolerated with an acceptable safety profile in healthy volunteers in Study ALN-CC5-001A. 
In this initial study, the cemdisiran dose of 600 mg that was safe and well-tolerated was chosen 
for evaluation. This dose will yield robust C5 silencing and will have maximal opportunity to 
produce a meaningful clinical effect in patients with IgAN.  Since the relationship between C5 
levels and complement activity is non-linear, with small C5 fluctuations resulting in a larger 
increase in complement activity, a monthly dose regimen was selected to maintain a constant 
level of C5 silencing.  Additionally, a more consistent effect of cemdisiran on C5 protein and 
CCP level is predicted after monthly dosing when compared to quarterly dosing based on a 
modeling approach.   
During the extension treatment phase, patients treated with both cemdisiran and placebo will 
have the option to receive a 600 mg dose of cemdisiran every four weeks for an additional 52 
weeks. 
IgAN can result in progressive renal impairment; however, patients with severe renal impairment 
(eGFR<30 mL/min/1.73 m2) who may have sustained irreversible damage to the kidney are not 
eligible for participation in this trial.  As the kidney is not the major elimination pathway for 
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cemdisiran and based on available nonclinical and clinical data obtained with cemdisiran (with 
10.6 to 31.6% of the cemdisiran dose recovered in a 24-hour urine collection in the ALN-
CC5-001 study), it is expected that moderate renal impairment (eGFR<60 mL/min/1.73 m2) will 
not affect the PK of cemdisiran to the extent that a dose adjustment would be required.  
Therefore, patients with moderate renal impairment are eligible for study enrollment. More 
information on urine PK can be found in the IB.   
1.5. 
Benefit-Risk Assessment 
To date, no medications have been approved specifically for the treatment of IgAN.  Therefore, 
there is a large unmet need for novel interventions, particularly in patients who are at risk of 
progressive renal disease such as those with persistent proteinuria despite treatment with RAS 
inhibitors.  Available data from studies on the role of immunosuppressive therapy in IgAN are 
not conclusive as most are relatively small and have limited follow-up.[1]  Use of 
immunosuppressive drugs and high-dose steroids are also associated with increased AEs which 
is particularly common in patients with lower GFR.[24] 
Given the biological target of cemdisiran, the available nonclinical and clinial data, and mode of 
administration, important potential risks for cemdisiran are infections, liver function test (LFT) 
abnormalities and injection site reactions (ISRs).  Since C5 inhibition is associated with 
increased susceptibility for Neisserial infections, prior immunization against N. meningitidis 
using meningococcal group ACWY conjugate vaccine and meningococcal group B vaccine are 
required. Patients will be instructed to contact study site if any early signs of meningococcal 
infections are experienced. As cemdisiran is targeted for delivery to the liver, patients will be 
closely monitored for changes in LFTs and patients with a medical history or evidence of chronic 
liver disease or cirrhosis have been excluded.  Criteria for dose withholding, and stopping of 
cemdisiran are provided in Section 5.2.3.1. Patients will also be monitored for the development 
of ISRs and rotation of injection site are recommended during the study.   
Detailed information about the known and expected benefits and risks of cemdisiran and 
additional information on the clinical and nonclinical data may be found in the current version of 
the IB. 
An independent data monitoring committee (DMC) will be monitoring the program for safety. 
Cumulatively, clinical data regarding the role of complement pathways in IgAN progression, 
robust nonclinical and clinical data with cemdisiran (see IB for more information), and prior and 
ongoing clinical experience with other RNAi therapeutics in humans suggest cemdisiran will 
have a favorable risk profile in the intended population and supports the initial clinical 
development of cemdisiran in IgAN.  In addition, cemdisiran may address the unmet medical 
need for the first efficacious and disease-specific treatment for patients with IgAN. 
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 Change from baseline in 24-hour 
albuminuria at Week 32 
 Change from baseline in the urine 
albumin/creatinine ratio (UACR) as 
measured in 24-hour urine at Week 32 
 Change from baseline in C5 level over 
the course of the study 
 Change from baseline in complement 
activity (Complement Alternative 
Pathway [CAP] and Complement 
Classical Pathway [CCP]) over the 
course of the study 
 Evaluation of area under the curve 
(AUC), maximum plasma 
concentration (Cmax), time to 
maximum plasma concentration 
(Tmax), terminal half-life (t1/2), 
clearance (CL/F), volume of 
distribution (V/F), cumulative amount 
excreted unchanged in urine (Ae) and 
percent of dose excreted in the urine 
(fe) of cemdisiran (25-mer) and 23-
mer 
 Evaluation of AUC, Cmax, Tmax, 
t1/2, CL/F, V/F, Ae and fe of 22-mer 
AS(N-1)3’ 
 Change from baseline in levels of 
renal damage, complement activation 
and inflammation markers over the 
course of the study 
 Incidence of antidrug antibodies 
(ADA) 
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3. 
INVESTIGATIONAL PLAN 
3.1. 
Summary of Study Design 
This is a multicenter, double-blind, placebo-controlled study comprised of three periods 
(Figure 1).  The first period of the study is an observational 14-week run-in period during which 
patients’ blood pressure, kidney function, degree of hematuria, and proteinuria will be measured.  
Patients will not receive study drug (cemdisiran or placebo) during this time.  The standard of 
care is expected to remain unchanged during this run-in period.  The second study period is a 
32-week treatment period which will evaluate the efficacy and safety of SC cemdisiran 
compared to SC placebo in combination with standard of care in patients with IgAN and 
persistent proteinuria.  The third period of the study is a 52-week optional open-label extension 
(OLE) period to further evaluate the long-term safety and clinical activity of cemdisiran.  During 
the OLE, all patients (including those initially on placebo) will be treated with cemdisiran in 
combination with standard of care. 
The study will include Screening of up to 90 days to determine eligibility of patients and to 
complete disease-related assessments.  Patients will provide written informed consent and visit 
the study center approximately 2 weeks before starting the run-in period to complete the protocol 
screening assessments.  Following successful screening, the 14-week run-in period will 
commence, during which patients’ blood pressure, kidney function, degree of hematuria and 
proteinuria as well as treatment with standard of care will be documented by the Investigator.  
The standard of care is expected to remain unchanged during this run-in period.  Patients whose 
proteinuria level remains >1 g/24-hours within 2 weeks of the end of the run-in period, who 
continue to have hematuria, and who meet blood pressure and eGFR criteria will be eligible to 
enroll in the 32-week treatment period.  Upon confirmation of eligibility followed by vaccination 
against meningococcal infections, patients will be randomized at a 2:1 ratio to receive 600 mg of 
cemdisiran or placebo every 4 weeks in combination with standard of care.  Thirty patients are 
planned to be randomized in total, 20 in the cemdisiran arm and 10 in the placebo arm.  Patients 
excluded before randomization will be replaced at Screening.  
During the run-in period, patients will visit the study center 14, 8, and 2 weeks prior to 
randomization (Weeks 0, 6 and 12 of the run-in period).  Patients will then return to the study 
center every 4 weeks after the start of study drug treatment period. The primary endpoint will be 
assessed at the end of the treatment period at Week 32. 
At the end of the treatment period (Week 32), patients in the two treatment arms will enter the 
optional OLE period where they will receive cemdisiran at a dose of 600 mg every 4 weeks in 
combination with standard of care for 52 weeks.  The first study drug administration of the OLE 
will be administered at Week 32.  Patients will return to the study center at Weeks 36, 40, and 
every 8 weeks thereafter during the OLE.  Home visits, where locally feasible, may be arranged 
for cemdisiran administration in between 8-weekly study center visits (Weeks 44, 52, 60, 68 and 
76), unless patients are required to visit the study center as judged necessary by the Investigator, 
or if home visits cannot be arranged.  An end of treatment (EOT) visit will occur at Week 80 and 
an end of study (EOS) visit will be completed at Week 84.  For patients who complete the 
treatment period only who do not consent to continue to participate in the study in the OLE 
period, the EOS will be at Week 32. 
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Patients will return to the clinical study center for safety follow-up visits approximately 13, 26, 
39 and 52 weeks after the EOS visit (regardless if EOS visit is at Week 32 or Week 84), unless 
enrolled in another study with cemdisiran. Home visits, where locally feasible, may be arranged 
during safety follow-up at visit Weeks 97 (13 weeks after the EOS visit) and 123 (39 weeks after 
the EOS visit). 
Regular reviews of safety and tolerability data will be performed by a DMC throughout the study 
with the primary purpose of protecting the safety of participating patients and the integrity of the 
study. 
3.2. 
Duration of Treatment  
Subcutaneous doses of cemdisiran or matching placebo will be administered every 4 weeks over 
a period of 32 weeks during the treatment period and patients will receive 600 mg SC doses of 
cemdisiran for 52 weeks in the optional OLE.  
3.3. 
Duration of Study 
The maximum estimated total time on study, inclusive of Screening (maximum of 90 days), 
run-in period (14 weeks), treatment period (32 weeks), optional OLE period (52 weeks) and 
safety follow-up (52 weeks), is up to approximately 36 months or 3.0 years. 
3.3.1. 
Definition of End of Study for an Individual Patient 
A patient is considered to have reached the end of the study if the patient has completed the EOS 
(Week 84) visit or the Week 32 assessments for those patients who do not consent to continue to 
participate in the study in the OLE period. Upon study completion (regardless if EOS visit is at 
Week 32 or Week 84) patients will enter a safety follow-up period with visits scheduled at 
intervals of 13 weeks. 
For patients withdrawing from the study after receiving one dose of cemdisiran at a minimum, all 
efforts should be made to conduct the EOS assessments. Patients should then be encouraged to 
enter the safety follow up period. 
3.4. 
Number of Planned Patients 
Thirty patients are planned for randomization in this study. 
3.5. 
Method of Assigning Patients to Treatment Groups 
Using the Interactive Response System (IRS), patients will be randomized 2:1 to the cemdisiran 
or placebo arms.  Randomization will be stratified by baseline urine proteinuria levels (≥ 1g/24h 
and <2g/24h versus >=2g/24h). 
Each patient will be uniquely identified in the study by a combination of the site number and 
patient identification number.  Upon signing the informed consent form (ICF), the patient will be 
assigned a patient identification number by the IRS.  The Investigator or his/her designee will 
contact the IRS after confirming that the patient fulfills all the inclusion criteria and none of the 
exclusion criteria at screening and prior to randomization.  
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3.6. 
Blinding 
All site personnel including sponsor delegated clinical research associates and patients will be 
blinded to study drug treatment during the efficacy period (up to Week 32). Sponsor personnel 
will not be blinded to study treatment. Cemdisiran and placebo will be packaged identically.  The 
study drug will be administered under the supervision of the Investigator or at the patient’s home 
by a healthcare professional (see Section 5.2.2).  Since cemdisiran may be visually 
distinguishable from placebo, the syringe will be masked by a site pharmacist prior to 
administration by a healthcare professional.  See the Pharmacy Manual for additional details. 
Further details on blinding and unblinding arrangements will be documented in a separate plan 
/manual. 
3.6.1. 
Emergency Unblinding 
If the treating physician determines that the clinical management of the patient requires 
knowledge of the study drug assignment, the Investigator may break the blind, as necessary.  If 
time permits, clinical study center personnel should contact the Medical Monitor before 
unblinding to discuss the need to unblind the patient but must do so within 1 working day after 
the unblinding event.  A record of when the blind was broken, who was unblinded, who broke 
the blind, and why it was broken, will be maintained in the Trial Master File (TMF). 
Further details on blinding and unblinding arrangements will be documented in a separate plan / 
manual. 
3.7. 
Data Monitoring Committee 
An independent DMC will perform regular reviews of safety and tolerability data throughout the 
study with the primary purpose of protecting the safety of participating patients and the integrity 
of the study.  The DMC will operate under the rules of a charter that will be reviewed and 
approved at the organizational meeting of the DMC.  The DMC will perform periodic reviews of 
data during the clinical trial, and on an ad hoc basis review of emergent safety data.  Details are 
provided in the DMC Charter. 
 
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4. 
SELECTION AND WITHDRAWAL OF PATIENTS 
4.1. 
Inclusion Criteria 
Patients are eligible to be included in the study if all the following criteria apply: 
Age and Sex 
1. Male or female ≥18 years and ≤65 years of age at the time of informed consent 
Patient and Disease Characteristics 
2. Clinical diagnosis of primary IgAN as demonstrated by historical biopsy collected within 
60 months of screening 
3. Treated for IgAN with stable, optimal pharmacological therapy.  In general, stable and 
optimal treatment will include maximum allowed or tolerated ACE inhibitor or an ARB 
or a direct renin-inhibitor for at least 3 months prior to start of run-in period 
4. Urine protein ≥1g/24-hour at screening and mean urine protein ≥1g/24-hour from two 
valid 24-hour urine collections at the end of the run-in period, prior to randomization  
5. Hematuria ≥10 RBCs per high powered field (RBC/hpf) at screening and at the end of the 
run-in period, prior to randomization (local result accepted for assessment of eligibility at 
the end of the run-in period)  
6. Females 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, and for 90 days after last dose 
administration  
7. Previously vaccinated with meningococcal group ACWY conjugate vaccine and 
meningococcal group B vaccine or willingness to receive these vaccinations as well as 
prophylactic antibiotic treatment if required 
Informed Consent 
8. Patient is willing and able to provide written informed consent and to comply with the 
study requirements 
4.2. 
Exclusion Criteria 
Patients are excluded from the study if any of the following criteria apply: 
Disease-specific Conditions 
1. Concomitant significant renal disease other than IgAN 
2. A diagnosis of rapidly progressive glomerulonephritis as measured by eGFR loss >30% 
over the duration of the run-in phase 
3. Secondary etiologies of IgAN (eg, inflammatory bowel disease, celiac disease) 
4. Diagnosis of Henoch-Schonlein Purpura (IgA Vasculitis) 
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5.  eGFR <30 mL/min/1.73 m2 2 weeks prior to randomization (local results will be used for 
assessment of eligibility) 
Laboratory Assessments 
6. Has any of the following laboratory parameter assessments:  
a. Alanine transaminase (ALT) >1.5×upper limit of normal (ULN), International 
Normalized Ratio (INR) >2 (or >3.5 if on anticoagulants), or total bilirubin 
>1.5×ULN (unless bilirubin elevation is due to Gilbert’s syndrome)  
7. Clinical laboratory test results considered clinically relevant and unacceptable in the 
opinion of the Investigator 
8. Known human immunodeficiency virus (HIV) infection, hepatitis C virus (HCV) 
infection or hepatitis B virus (HBV) infection 
Prior/Concomitant Therapy 
9. Treatment with systemic steroids at dosages exceeding 20 mg prednisone-equivalent for 
more than 7 days or other immunosuppressant agents in the 12 months prior to 
randomization 
10. Received an investigational agent within the last 30 days or 5 half-lives, whichever is 
longer, prior to the first dose of study drug, or are in follow-up of another clinical study 
prior to study enrollment 
Medical Conditions 
11. Malignancy (except for non-melanoma skin cancers, cervical in situ carcinoma, breast 
ductal carcinoma in situ, or stage 1 prostate cancer) within the last 5 years 
12. Active psychiatric disorder, including, but not limited to schizophrenia, bipolar disorder, 
or severe depression despite current pharmacological intervention 
13. Known medical history or evidence of chronic liver disease or cirrhosis 
14. Has other medical conditions or comorbidities which, in the opinion of the Investigator, 
would interfere with study compliance or data interpretation 
15. History of multiple drug allergies or history of allergic reaction to an oligonucleotide or 
GalNAc 
16. History of intolerance to SC injection(s) or significant abdominal scarring that could 
potentially hinder study drug administration or evaluation of local tolerability 
17. Known contraindication to meningococcal vaccines (group ACWY conjugate and group 
B vaccines) required for this study.  Refer to the most recent local product information 
for each vaccine for the current list of contraindications 
18. Unable to take antibiotics for meninigococcal prophylaxis 
19. Sustained blood pressure >140/90 mmHg as defined by 2 or more readings during the 
run-in period, measured in supine position after 10 minutes of rest 
20. Receipt of an organ transplant (including hematologic transplant) 
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21. History of meningococcal infection within 12 months before Screening 
22. Patients with systemic bacterial or fungal infections, as demonstrated by a positive 
culture result, that require systemic treatment with antibiotics or antifungals 
a. Patients receiving empiric or prophylactic antibiotics are not excluded 
Alcohol Use 
23. Patients who consume more than 14 units of alcohol a week (unit 1 glass of wine 
[125 mL] = 1 measure of spirits [approximately 1 fluid ounce] = ½ pint of beer 
[approximately 284 mL])  
4.3. 
Removal from Therapy or Assessment 
Patients or their legal guardians are free to discontinue study drug and/or stop participation in the 
study at any time and for any reason, without penalty to their continuing medical care.  The 
Investigator or the Sponsor may stop a patient’s participation in the study at any time if this is 
considered to be in the patient’s best interest.  Any discontinuation of treatment or the stopping 
of the patient’s participation in the study must be fully documented in the electronic case report 
form (eCRF) and should be followed up by the Investigator.   
Discontinuation of study drug is described in Section 4.3.1, while the stopping of a patient’s 
participation in the study is detailed in Section 4.3.2. 
4.3.1. 
Discontinuation of Study Drug or Declining Procedural Assessments 
Reasons for discontinuation of study drug include any of the following: 
 Significant violation of the protocol 
 Adverse event  
 Non-adherence to treatment regimen 
 Pregnancy 
 Lost to follow-up 
 Other reason (non-adverse event) 
 Or, study is terminated by the Sponsor 
The Investigator will confer with the Sponsor or Medical Monitor before discontinuing dosing in 
the patient.  Patients who are pregnant will be discontinued from study drug dosing immediately 
(see Section 6.7.5.2 for reporting and follow-up of pregnancy).  A positive urine pregnancy test 
should be confirmed by a serum pregnancy test prior to discontinuing study drug. 
Patients who discontinue study drug and/or decline procedural assessments should not be 
automatically removed from study.  In general, patients who discontinue study drug dosing for 
any reason will be encouraged to remain on the study to complete the remaining assessments 
through the Week 80/EOT visit and safety follow-up so that their experience is captured in the 
final analyses.  
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If this occurs, the Investigator is to discuss with the patient the appropriate processes for 
discontinuation from study drug and must discuss with the patient the options for continuation of 
the Schedule of Assessments (Table 2), including different options for follow-up and collection 
of data (eg, in person, by phone, by mail, through family or friends, or from options not 
involving patient contact, such as communication with other treating physicians or from review 
of medical records), including endpoints and adverse events, and must document this decision in 
the patient’s medical records.  
If a patient discontinues dosing due to an AE, including SAEs, the event should be followed as 
described in Section 6.7.6.  When a patient discontinues study drug dosing, the primary reason 
must be recorded in the eCRF.  Patients who discontinue study drug and remain on study may 
receive treatment consistent with local standard practice for their disease per Investigator 
judgement, as applicable.  
Patients who discontinue from study drug during the 32-week treatment period (defined as the 
time the first dose of study drug is administered on Study Day 1 through completion of the 
Week 32 assessments) will be encouraged to remain on the study and complete assessments 
through Week 32; they will also be asked to complete safety follow-up visits 13, 26, 39 and 52 
weeks after their last dose of study drug (see Table 2).  
Patients who discontinue study drug during the OLE period will be asked to return for their next 
scheduled visit to complete EOS/EOT assessments; they will also be asked to complete safety 
follow-up visits 13, 26, 39 and 52 weeks after their last dose of study drug (see Table 2). 
4.3.2. 
Stopping a Patient’s Study Participation 
4.3.2.1. 
Patient or Legal Guardian Stops Participation in the Study 
A patient or their legal guardian may stop participation in the study at any time.  A patient/legal 
guardian considering stopping participation in the study should be informed that they can 
discontinue study drug and/or decline procedural assessments and remain in the study to 
complete their study assessments through the Week 32 visit, including entering the 52-week 
safety follow-up.  If a patient/legal guardian still chooses to discontinue study drug and stop 
participation in all follow-up prior to the completion of the 32-week treatment period, every 
effort should be made to conduct early the assessments scheduled to be performed at the 
Week 32 visit (see Table 1).   
If the patient does not wish to or is unable to continue further study participation, the investigator 
is to discuss with the patient appropriate procedures for stopping participation in the study. Data 
collected from the patient can continue to be used. 
In addition, in the countries where the collection and processing of the patient data is based on 
the patient consent, if a patient withdraws consent to collect and process his/her data (see 
Section 4.3.2.2), as applicable, patient data up to the withdrawal of consent will be included in 
the analysis of the study.  In addition, where permitted, publicly available data (such as 
appropriate national or regional vital status registry or other relevant databases) can be included 
after withdrawal of consent, where available and allowable by local law. 
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4.3.2.2. 
Withdrawal of Consent to Process the Patient’s Personal Data  
Where allowed by local law, the patient may decide to withdraw consent to collect, store and use 
biological samples and, as applicable, other personal data, informing the study doctor at any time 
in writing or in any other form that may be locally required.  The Sponsor will continue to keep 
and use the patient’s study information (including any data resulting from the analysis of 
patient’s biological samples until the time of withdrawal) according to applicable law. The 
process for the storage and, as applicable, further use of remaining samples will be followed per 
local requirements. 
4.3.2.3. 
Investigator or Sponsor Stops Participation of a Patient in the Study 
The Investigator or Sponsor may stop the participation of a patient in the study at any time if this 
is considered to be in the patient’s best interest.  However, study integrity and interpretation are 
best maintained if all enrolled patients continue study assessments and follow-up even if study 
drug is discontinued. 
Termination of the clinical study and site closure are described in Section 8.1.6. 
4.3.2.4. 
Recording Reason for Stopping a Patient’s Study Participation 
The primary reason that a patient’s study participation is stopped must be recorded in the 
appropriate section of the eCRF and all efforts will be made to complete and report the 
observations as thoroughly as possible.  If a patient’s study participation is stopped due to an 
adverse event (AE), including serious adverse events (SAEs), the event should be followed as 
described in Section 6.7.6. 
4.3.3. 
Lost to Follow-Up 
A patient will be considered lost to follow-up if the patient repeatedly fails to return for 
scheduled visits and is unable to be contacted by the clinical study center.  The following actions 
must be taken if a patient fails to return to the clinic for a required study visit: 
 The site must attempt to contact the patient or legal guardian and reschedule the 
missed visit as soon as possible and counsel the patient or legal guardian on the 
importance of maintaining the assigned visit schedule and ascertain if the patient or 
legal guardian wishes to continue in the study, and/or should continue in the study.  
 Before a patient is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the patient or legal guardian (where possible, 3 
telephone calls and, if necessary, a certified letter to the patient’s last known mailing 
address or local equivalent methods).  These contact attempts should be documented 
in the patient’s medical record. 
 Should the patient or legal guardian continue to be unreachable, the patient will be 
considered to have stopped participation in the study. 
 For patients who are lost to follow-up, the Investigator can search publicly available 
records (where permitted and allowed by local law) to ascertain survival status.  This 
ensures that the outcome of the study is as comprehensive as possible. 
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4.3.4. 
Replacement of Study Patients  
Patients who discontinue the study drug or stop participation in the study during the 32-week 
treatment period or the OLE will not be replaced. 
 
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5. 
TREATMENTS AND OTHER REQUIREMENTS 
5.1. 
Treatments Administered 
Study drug supplied for this study must not be used for any purpose other than the present study 
and must not be administered to any person not enrolled in the study.  Study drug that has been 
dispensed to a patient and returned unused must not be re-dispensed to a different patient. 
5.2. 
Study Drug 
Detailed information describing the preparation, administration, and storage of cemdisiran and 
placebo is provided in the Pharmacy Manual. 
5.2.1. 
Description  
Cemdisiran will be supplied as a sterile solution for SC injection that contains 200 mg/mL 
cemdisiran sodium (equivalent to 189 mg/mL of cemdisiran), formulated in water for injection 
(WFI) for SC administration.  See the Pharmacy Manual for further details of solution 
concentration and fill volume. 
The control drug for this study will be a placebo (sodium chloride 0.9% w/v for SC 
administration).  Placebo will be provided by the Sponsor; it will be packaged identically to 
cemdisiran. 
5.2.2. 
Dose and Administration 
Patients will be administered cemdisiran (600 mg) or placebo (at the same volume as the active 
drug) as an SC injection once every 4 weeks in combination with standard of care in the 32-week 
treatment phase.  During the 52-week OLE phase, patients will be administered cemdisiran at a 
dose of 600 mg every 4 weeks in combination with standard of care. 
Study drug injections will be administered under the supervision of the Investigator or healthcare 
professional.  At-home dosing may be administered by a healthcare professional.  The injection 
site may 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, if permitted.  Detailed instructions for study 
drug administration are found in the Pharmacy Manual. 
To maintain the blind during the treatment period, the syringes are to be masked prior to study 
drug withdrawal.  A full description of the blinding procedure is included in the Pharmacy 
Manual.  
5.2.3. 
Dose Modifications 
Dose modifications are not permitted. 
If a study drug-related AE occurs in a patient that the Investigator judges as presenting a 
potential risk to the patient for further dosing, the study drug dose may be held at the discretion 
of the Investigator and the Medical Monitor should be contacted. 
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5.2.3.1. 
LFT Criteria for Withholding, Monitoring and Stopping Cemdisiran Dosing   
1. LFT results (Table 5) from the previous visit should be reviewed prior to dosing.  Central 
laboratory results are preferable.  If not available, local laboratory results may be used; 
however, if a local assessment is drawn, a serum chemistry sample must also be drawn 
for analysis at the central laboratory.  
2. For any ALT or AST elevation >3×ULN, central laboratory results should be used to 
guide subsequent monitoring as detailed in Table 4.  
3. For any ALT or AST elevation >3×ULN:  
a. Confirm using central laboratory, as soon as possible, ideally within 2 to 3 days, but 
no later than 7 days. 
b. Perform assessments per Table 4 and Table 6. 
c. If an alternative cause is found, provide appropriate care. 
4. For any ALT or AST elevation >3×ULN without alternative cause that is accompanied 
by clinical symptoms consistent with liver injury (eg, nausea, right upper quadrant 
abdominal pain, jaundice) or elevated bilirubin to ≥2×ULN or INR ≥1.5, permanently 
discontinue dosing. 
5. For confirmed ALT or AST elevations >3×ULN without alternative cause and not 
accompanied by symptoms or elevated bilirubin ≥2×ULN or INR ≥1.5, see Table 4  
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Table 4: Monitoring and Dosing Rules for Asymptomatic Patients with Confirmed 
Isolated Elevations of ALT and/or AST >3× ULN, with No Alternative Cause Identified 
Transaminase Level 
Action 
>3× to 5× ULN 
• 
May continue dosing   
• 
Evaluate the initial elevation in LFT per the following assessments: 
• 
Table 6 (all assessments to be performed once) 
• 
Hematology, serum chemistry, LFT, and coagulation per Table 5 
• 
Monitor at least every two weeks: LFT and coagulation per Table 6 
• 
If elevation persists for ≥2 months, must discuss with the Medical Monitor 
before continuing dosing 
>5× to 8× ULN 
• 
Hold cemdisiran dosing until recovery to ≤1.5×ULN; may resume dosing 
after discussion with the Medical Monitor 
• 
Evaluate the initial elevation in LFT per the following assessments 
• 
Table 6 (all assessments to be performed once) 
• 
Hematology, serum chemistry, LFT, and coagulation per Table 5 
• 
Monitor at least weekly: LFT and coagulation per Table 6 until ALT and/or 
AST is declining on 2 consecutive draws, then may decrease monitoring to 
biweekly 
• 
If ALT or AST rises to >5×ULN following resumption of dosing, 
permanently discontinue dosing 
>8× ULN 
Permanently discontinue dosing after confirmation of the transaminase value 
Abbreviations: ALT=alanine transaminase; AST=aspartate transaminase; INR=international normalized ratio; 
LFT=liver function test(s); ULN=upper limit of normal. 
Notes:   In addition to these criteria, other assessments or evaluations may be performed per Investigator discretion, 
as appropriate. 
5.2.4. 
Preparation, Handling, and Storage 
Staff at each clinical study center or the home healthcare professional will be responsible for 
preparation of cemdisiran doses, according to procedures detailed in the Pharmacy Manual.  No 
special procedures for the safe handling of study drug are required. 
Study drug will be stored upright and refrigerated at approximately 2 to 8°C.  The vial should be 
stored in the carton until ready for use in the storage area of the clinical study site pharmacy, in a 
secure, temperature-controlled, locked environment with restricted access.  Deviations from the 
recommended storage conditions should be reported to the Sponsor and use of the study drug 
halted until authorization for its continued use has been provided by the Sponsor or designee, as 
described in the Pharmacy Manual. 
A Sponsor representative or designee will be permitted, upon request, to audit the supplies, 
storage, dispensing procedures, and records. 
Instructions specific to unused study drug and additional storage will be provided in the 
Pharmacy Manual. 
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5.2.5. 
Packaging and Labeling 
All packaging, labeling, and production of study drug will be in compliance with current Good 
Manufacturing Practice specifications, as well as applicable local regulations. Study drug labels 
and external packaging will include all appropriate information as per local labeling 
requirements.  
Cemdisiran (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 a 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. 
Additional details will be available in the Pharmacy Manual. 
5.2.6. 
Accountability 
The Investigator or designee will maintain accurate records of receipt and the condition of the 
study drug supplied for this study, including dates of receipt.  In addition, accurate records will 
be kept of when and how much study drug is dispensed and administered to each patient in the 
study.  Any reasons for departure from the protocol dispensing regimen must also be recorded. 
At the completion of the study, there will be a final reconciliation of all study drugs.  Used, 
partially used, and unused study drug will be returned to the Sponsor (or designee) or destroyed 
at the clinical study center according to applicable regulations. 
Further instructions about drug accountability will be detailed in the Pharmacy Manual. 
5.3. 
Concomitant Medications and Procedures 
The standard of care treatment should be held stable throughout the run-in and treatment periods. 
Use of concomitant medications and procedures will be recorded on the patient’s eCRF as 
specified in the Schedule of Assessments (see Table 1 and Table 2).  This includes all 
prescription medications, herbal preparations, over the counter medications, vitamins, and 
minerals.  Any changes in medications during the study will also be recorded on the eCRF. 
If patients use nonsteroidal anti-inflammatory drugs intermittently or chronically, they must have 
been able to tolerate them with no previous side effects (eg, gastric distress or bleeding).   
Standard vitamins and topical medications are permitted.  However, topical steroids must not be 
applied anywhere near the injection site(s) unless medically indicated.   
For other permitted concomitant medications administered SC, do not administer in same 
injection site area as the study drug/placebo, for 7 days after the last dose of either study drug or 
placebo.  
Any concomitant medication that is required for the patient’s welfare may be administered by the 
Investigator.  However, it is the responsibility of the Investigator to ensure that details regarding 
the medication are recorded on the eCRF.  Concomitant medication will be coded using an 
internationally recognized and accepted coding dictionary. 
5.3.1. 
Prohibited Concomitant Medications 
The following concomitant medications are prohibited during the study:  
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 Systemic steroids (short-term steroid course for <7 days for common conditions not 
related to IgAN (i.e. asthma, gout) is permitted) 
 Immunosuppressive agents 
 Fish oil supplements 
 Hydroxychloroquine 
5.3.2. 
Study-specific Vaccinations 
All patients taking part in this study must be vaccinated against meningitis types A, C, W135, Y 
and B, upon determination of eligibility at the end of run-in period as per the schedule of 
assessments.  Meningococcal group ACWY conjugate vaccine and meningococcal group B 
vaccine will be administered in accordance with the manufacturer’s instructions. On days of 
vaccination, urinary samples should be collected prior to administration of vaccines. 
Patients will be immunized against Neisseria meningitidis according to the following 
specifications: 
 Patients who have previously completed the recommended series of meningococcal 
vaccinations (meningococcal group ACWY conjugate vaccine and meningococcal 
group B vaccine) at least 14 days but no more than 3 years from randomization can 
start study assessments after confirming eligibility.  Documented vaccine history 
must be available to, and verified by, study site staff at the time of Screening. 
 Patients who were previously vaccinated with polysaccharide type vaccines within 
3 years of study entry will be revaccinated using conjugate vaccines if found eligible 
at the end of the run-in period.  Patients who complete the vaccination series after 
starting cemdisiran will receive prophylactic antibiotics according to local standard of 
care for at least 2 weeks after completing the recommended series of meningococcal 
vaccinations (meningococcal group ACWY conjugate vaccine and meningococcal 
group B vaccine) or longer, if required by local standard of care. 
 Patients who either completed the recommended series of meningococcal vaccines 
less than 14 days from initiation of treatment with cemdisiran or those who have an 
incomplete meningococcal vaccination series will receive prophylactic antibiotic 
treatment according to local standard of care for at least 2 weeks after completing the 
recommended series of meningococcal vaccinations (meningococcal group ACWY 
conjugate vaccine and meningococcal group B vaccine) or longer, if required by local 
standard of care. 
 Patients who have not been previously vaccinated against Neisseria meningitidis, 
those without documentation of vaccination history, or those vaccinated more than 
3 years from study randomization will commence the vaccination series with the 
recommended meningococcal vaccines (meningococcal group ACWY conjugate 
vaccine and meningococcal group B vaccine) per the schedule of assessments if 
determined to be eligible for the study at the end of the run-in period.   Patients who 
complete the vaccine series after receiving cemdisiran will receive prophylactic 
antibiotics according to the local standard of care for at least 2 weeks after completing 
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the recommended series of meningococcal vaccinations or longer, if required by local 
standard of care. 
5.4. 
Treatment Compliance 
Compliance with study drug administration will be verified through observation by study staff or 
trained home healthcare professionals. 
5.5. 
Other Requirements 
5.5.1. 
Contraception 
Females of child-bearing potential must be willing to use acceptable methods of contraception 
from 14 days before first dose, throughout study participation, and for 90 days after last dose 
administration.   
Birth control methods which are considered acceptable include: 
 Placement of an intrauterine device. 
 Placement of an intrauterine hormone-releasing system.  
 Bilateral tubal occlusion. 
 Surgical sterilization of male partner (with the appropriate post-vasectomy 
documentation of the absence of sperm in the ejaculate; for female patients on the 
study, the vasectomized male partner should be the sole partner for that patient). 
 Established use of oral, implantable, injectable, or transdermal hormonal methods of 
contraception. Females of child-bearing potential who use hormonal contraceptives as 
a method of contraception must also use a barrier method (condom or occlusive cap 
[diaphragm or cervical/vault cap] in conjunction with spermicide [eg, foam, gel, film, 
cream, or suppository]).   
 If hormonal methods of contraception are medically contraindicated due to their 
underlying disease, a double-barrier method (combination of male condom with cap, 
diaphragm, or sponge, in conjunction with spermicide) is also considered an 
acceptable method of contraception. 
 True sexual abstinence, when in line with the preferred and usual lifestyle of the 
patient.  Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception.  Abstinent 
patients must agree to use one of the above-mentioned contraceptive methods if they 
start sexual relationships during the study and for up to 90 days after the last dose of 
study drug. 
Females of child-bearing potential include female patients who have experienced menarche (or 
begin menarche over the course of the study) and who are not postmenopausal or permanently 
sterilized (eg, bilateral tubal occlusion, hysterectomy, or bilateral salpingectomy).  A 
postmenopausal state is defined as the absence of menses for 12 months without an alternative 
medical cause, confirmed by follicle stimulating hormone level within the postmenopausal 
range.  
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Compliance with contraception requirements will be assessed on a regular basis by the 
Investigator throughout the course of the study. 
5.5.2. 
Alcohol Restrictions 
Patients will limit alcohol consumption throughout the course of the study.  Alcohol is limited to 
no more than 2 units per day (unit:  1 glass of wine [approximately 125 mL] = 1 measure of 
spirits [approximately 1 fluid ounce] = ½ pint of beer [approximately 284 mL]) for the duration 
of the study. 
5.5.3. 
Antibiotic Compliance 
Patients who require prophylactic antibiotics following study specific vaccinations (see 
Section 5.3.1) per local standard of care will undergo antibiotic compliance checks.  Antibiotic 
compliance checks will be performed at the time points in the Schedule of Assessments.  
Antibiotic dose adjustments will be permitted in the case of renal impairment.  All dose 
adjustments must comply with the manufacturer’s instructions. 
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6. 
STUDY ASSESSMENTS 
The Schedule of Assessments is provided in Table 1 and Table 2. 
6.1. 
Screening Assessments 
An ICF approved by the appropriate Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) must be signed by the patient (or legal guardian) before the Screening 
procedures are initiated.  All patients (or their legal guardians) will be given a copy of the signed 
and dated ICF.  
Patients will be screened to ensure that they meet all the inclusion criteria and none of the 
exclusion criteria.  Rescreening of patients is permitted with consultation of the Medical 
Monitor; see Section 6.1.1.  
Patient demographic data and medical history/disease history will be obtained. In particular, the 
MEST-C score and degree of IgG, IgA, IgM, C3, C1q, C4d and C5b-9 stains will be obtained 
from pathology reports, if available, and documented. Any changes to medical history occurring 
between the Screening assessment and Day 1 will be updated prior to study drug administration. 
Additional screening assessments include a full physical examination (with emphasis on 
presence/degree of edema), collection of vital signs, height, weight and body mass index (BMI), 
12-lead electrocardiogram (ECG), clinical laboratory assessments, pregnancy, 24-hours urine 
proteinuria assessment (from a single valid collection; see Section 6.4.1.1), eGFR, and urinalysis.   
6.1.1. 
Rescreening 
A patient who does not meet all study eligibility criteria due to a transient condition observed at 
Screening (eg, prohibited medications that were subsequently discontinued) will be allowed to 
return for rescreening (once only).  A patient will be re-consented, if rescreening occurs outside 
of the 90-day screening window.  In this case, all screening procedures must be repeated.  
6.1.2. 
Retesting 
If in the Investigator’s judgement, the screening laboratory abnormalities are likely to be 
transient, then laboratory tests may be repeated.  The investigator’s rationale is to be 
documented.  Laboratory values can be retested once during Screening as long as the patient can 
be evaluated for eligibility and randomized within the allowed Screening period. 
6.2. 
Run-in Period 
During the 14-week run-in period, the following will be performed at time points specified in the 
Schedule of Assessments (Table 1): vital signs, clinical laboratory assessments, pregnancy test, 
24-hour urine proteinuria assessment (from 2 single valid collections; see Section 6.4.1.1), 
urinalysis for hematuria, spot urine for proteinuria, and eGFR.  Clinical laboratory tests will be 
performed centrally; however, hematuria and eGFR will also be assessed locally at the end of the 
run-in period to facilitate assessment of patient eligibility and administer vaccination on the same 
day. During this period, patients will begin the recommended meningitis vaccination regimen if 
eligible for the study. Vaccines should be administered only if patient eligibility for 
randomization is confirmed and after urine collections are completed.  
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6.3. 
Baseline Assessments (Treatment Period) 
Prior to dosing on Day 1, patients will be reassessed for eligibility and blood and urine samples 
for clinical laboratory assessments and exploratory analyses collected, including blood samples 
for complement activity tests (CAP/CCP), C5 analysis, PK and ADA. 
In addition, prior to administration of study drug, the following assessments will be performed:  
full physical examination, body weight and height, vital signs, ECG, urine pregnancy test, eGFR 
assessment, and urinalysis.  
Collection of blood and urine samples for PK analysis on Day 1 will be performed as outlined in 
Table 3.   
6.4. 
Efficacy Assessments 
6.4.1. 
Proteinuria 
Primary efficacy will be assessed by determining the percent change from baseline in 24 hour 
proteinuria (g/24-hour) after 32 weeks of treatment. 24 hour urine samples for determination of 
proteinuria will be collected throughout the study as outlined in the Schedules of Assessments 
and will be analyzed by a central laboratory. 
6.4.1.1. 
24-Hour Urine Collection 
Patients will be required to provide two separate valid 24-hour urine collections 2 weeks prior to 
randomization (to assess eligibility after the run-in period), at Week 32 (to assess the primary 
endpoint) and at Week 84/EOS visit. Patients will also be asked to provide a single valid 24-hour 
urine sample for other 24-hour urinary assessments outlined in the Schedule of Assessments. 
Rigorous exercise and significant change in diet (in particular salt intake) should be avoided 
within 48 hours of collection of 24-hour urine samples whenever possible.The two valid 24-hour 
urine samples may be collected within 2 weeks before assessment is due while the one valid 
24-hour urine sample may be collected within one week before the assessment takes place. If any 
of the collections do not meet validity criteria outlined below, then repeat collections must be 
scheduled within the time frames outlined above to assure the minimum number of valid 
collections required for each of the study time points. The duration of collection and volume of 
urine in the collection will be recorded in the eCRF. In addition to protein, albumin, sodium and 
creatinine will also be quantified in each of the 24-hour urine samples. Both protein/creatinine 
(UPCR) as well as albumin/creatinine ratios (UACR) will also be calculated in an aliquot of the 
24-hour urine collection.   
Completeness of the 24-hour urine collection can be estimated from rate of creatinine excretion. 
Normal values of creatinine excretion vary with age and body weight. An aliquot of the 24-hour 
urine collection will be used to determine urinary creatinine content to determine if the 24-hour 
urine collections need to be repeated. Hence, a 24-hour urine collection will only be considered 
valid if all the following criteria are met, otherwise a repeat urine collection will be required: 
 The collection is between 22-26 hours in duration between the initial discarded void 
and the last void or attempt to void. 
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 No voids are missed between the start and end time of the collection as indicated by 
the patient’s urine collection diary. 
 The 24-hour creatinine content is within 25% of expected range as estimated by the 
following formula:  [(140-age) x weight]/5000, where weight is in kilograms. This 
result is multiplied by 0.85 in women.[25] 
 In case of need of two valid samples, the maximum variation in total 24-hour urine 
creatinine between the two urine collections must be <25%. 
Primary efficacy will be evaluated by comparing the percent change from baseline in 24-hour 
proteinuria (g/24-hours) at Week 32 in patients treated with cemdisiran versus those treated with 
placebo.  
Secondary and exploratory efficacy assessments include comparisons of the proportion of 
patients with partial or complete clinical remission, respectively, as measured by the amount of 
urine protein (UP) in a 24-hour urine sample.  Partial clinical remission is defined as having UP 
<1 g/24-hours and complete clinical remission is defined as UP <0.3 g/24-hours.  Each will be 
assessed at Week 32. 
Additional secondary endpoints that will be evaluated using 24-hour samples include the change 
from baseline in the UP/creatinine ratio (UPCR) and the change from baseline in the UP/albumin 
ratio (UACR) at Week 32. 
6.4.1.2. 
Spot Urine Collection 
Urinary protein, albumin and creatinine levels from spot urine collections prior to dosing will 
also be measured to assess the effect of cemdisiran on urinary protein/creatinine (UPCR) and 
albumin/creatinine (UACR) as outlined in the Schedule of Assessments. 
The change from baseline in UPCR at Week 32 will be evaluated in spot urine samples.  Spot 
urine samples will be collected at the time points outlined in the Schedule of Assessments 
(Table 1).   
6.4.2. 
Hematuria 
Hematuria from spot urine collections will also be evaluated to assess the effect of cemdisiran on 
disease course in patients with IgAN. The degree of hematuria will be assessed by examination 
of the spun urine sediment by microscopy (RBC/hpf). Single void collections for random urine 
sample for hematuria evaluation should be collected as a first morning void when possible. If the 
investigator determines that the hematuria is transient due to menses in women or exercise, the 
sample may need to be repeated. 
Random spot urine samples for hematuria measurement will be collected throughout the study as 
outlined in the Schedule of Assessments and will be analyzed by a central laboratory.  On dosing 
days, samples should be collected prior to cemdisiran administration, if applicable. 
To allow evaluation of eligibility on the same day at the end of the run in period, 2 weeks prior 
to randomization, the single void can be split in two containers, one evaluated by local lab and 
another by central lab. The local hematuria evaluation will be utilized to determine eligibility for 
study. 
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6.4.3. 
Changes in Renal Function 
Changes in renal function will be monitored using measurements of serum creatinine and eGFR 
(mL/min/1.73m2) as outlined in the Schedule of Assessments. The calculation will be based on 
the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula for all patients. 
For assessment of eligibility at the last visit of run-in period, 2 weeks prior to randomization, 
local lab can be utilized. This will allow evaluation for eligibility on the same day. A sample will 
also be sent to central lab. 
Renal function will also be estimated as creatinine clearance based on the 24-hour urine 
collection. The creatinine clearance is a widely used test to estimate the GFR using the following 
formula: 
GFR  =  [UCr  x  V] / SCr 
SCr is the serum creatinine concentration and the value assessed closest to collection of 24-hour 
urine collection will be utilized for purpose of above calculation. UCr is the urine creatinine 
concentration and V is the urine flow rate or volume. 
Blood and urine samples for renal function assessments will be collected prior to administration 
of cemdisiran on dosing days, if applicable. 
The change from baseline in eGFR will be measured throughout the course of the study. In 
addition, the slope of eGFR will be computed for the first 32 weeks and the entire study period 
(including the OLE).  
6.4.4. 
Markers of Complement Activation, Inflammation and Renal Injury 
Samples for measurement of markers of complement activation, inflammation and renal injury 
will be collected at the time points outlined in the Schedule of Assessments (Table 1) and 
analyzed by central laboratories. On dosing days, blood samples will be collected predose. 
6.5. 
Pharmacodynamic Assessments 
Blood samples for PD analysis will be collected at the time points outlined in the Schedule of 
Assessments (Table 1).  Samples will be collected prior to administration of cemdisiran on 
dosing days. 
Analysis of PD will include the impact of cemdisiran administration on plasma C5 protein levels 
(assessed by a mass spectrometry-based method) and serum complement activity (assessed by 
CAP enzyme linked immunosorbent assay [ELISA] and CCP ELISA).  Samples will be analyzed 
at central laboratories.  Details regarding the collection, processing, shipping, and storage of the 
samples will be provided in the Laboratory Manual. 
6.6. 
Pharmacokinetic Assessments 
Blood samples and urine samples will be collected for assessment of cemdisiran PK parameters 
and possible metabolite analysis at the time points in the Schedule of Assessments.  A detailed 
schedule of time points for the collection of blood samples and urine samples for PK analysis is 
in Table 3. 
The concentration of cemdisiran will be determined using a validated assay.  Details regarding 
sample volumes to be collected, and the processing, shipping, and analysis of the samples will be 
provided in the Laboratory Manual. 
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6.7. 
Safety Assessments 
The assessment of safety during the study will consist of the surveillance and recording of the 
frequency of AEs including SAEs, recording of concomitant medication and measurements of 
vital signs, weight and height, physical examination, and ECG findings and laboratory tests. 
Clinically significant abnormalities observed during the physical examination are recorded.   
Safety will be monitored over the course of the study by a DMC as described in Section 3.7. 
6.7.1. 
Vital Signs 
Vital signs will be measured as specified in the Schedule of Assessments (Table 1 and Table 2) 
and include blood pressure, heart rate, oral body temperature, and respiratory rate.  Vital signs 
will be measured in the seated or supine position, after the patient has rested comfortably for 
10 minutes.  On Day 1, vital signs will be collected at predose and 4 hours postdose.  On all 
other dosing days, vital signs will be collected predose.  
Blood pressure should be taken using the same arm throughout the study.  Body temperature in 
degrees Celsius will be obtained via oral method.  Heart rate will be counted for a full minute 
and recorded in beats per minute, and respiration rate will be counted for a full minute and 
recorded in breaths per minute. 
Additional vital sign assessments, as medically indicated, may be added at the discretion of the 
Investigator, or as per DMC advice. 
Vital signs results will be recorded in the eCRF. 
6.7.2. 
Weight and Height 
Height will be measured in centimeters.  Body weight will be measured in kilograms.  Height 
and body weight measurements will be collected as specified in the Schedule of Assessments 
(Table 1 and Table 2; height at Screening only and dosing weight during the clinical study center 
visits) and will be recorded in the eCRF. 
6.7.3. 
Physical Examination 
Full and directed physical examinations will be conducted according to the Schedule of 
Assessments (Table 1 and Table 2); if a physical examination is scheduled for a dosing visit, it 
should be conducted prior to dosing.  On Day 1, routine physical examination will be performed 
at predose and 4 hours postdose.  On all other dosing days, the routine physical examination will 
be performed predose. 
Full physical examinations will include the examination of the following:  general appearance; 
head, eyes, ears, nose and throat; respiratory, cardiovascular, gastrointestinal, musculoskeletal, 
and dermatological systems; thyroid; lymph nodes; and neurological status. 
Directed physical examinations will include examination of the following:  respiratory, 
cardiovascular, dermatological, gastrointestinal, and musculoskeletal systems. 
Clinically significant abnormalities observed during the physical examination are recorded on 
the medical history or AE eCRF. 
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6.7.4. 
Electrocardiogram 
Twelve-lead ECGs reporting rhythm, ventricular rate, RR interval, PR interval, QRS duration, 
and QT interval and Fridericia corrected QT interval will be obtained, as specified in the 
Schedule of Assessments (Table 1 and Table 2). Patients should be supine for at least 5 minutes 
before each ECG is obtained. A single 12-lead ECG will be performed at Screening.  At all other 
time points, 12-lead ECGs will be performed in triplicate, with readings approximately 1 minute 
apart. 12-lead ECGs will be performed at predose; 60 minutes postdose; and 4 hours postdose in 
relation to the Day 1 and Week 32 cemdisiran doses. 
When ECG and blood sample collection occur at the same time, ECGs should be performed 
before blood samples are drawn. 
The Investigator or qualified designee will review all ECGs to assess whether the results have 
changed since the Baseline visit and to determine the clinical significance of the results.  These 
assessments will be recorded on the eCRF.  Additional ECGs may be collected at the discretion 
of the Investigator, or as per DMC advice.   
6.7.5. 
Clinical Laboratory Assessments 
The following clinical laboratory tests will be evaluated by a central laboratory. However, to 
assess patient eligibility at the end of the run-in period, hematuria and eGFR will also be 
assessed locally. Specific instructions for transaminase elevations are provided in 
Section 5.2.3.1.  For any other unexplained clinically relevant abnormal laboratory test occurring 
after study drug administration, the test should be repeated and followed up at the discretion of 
the Investigator, or as per DMC advice, until it has returned to the normal range or stabilized, 
and/or a diagnosis is made to adequately explain the abnormality.  Additional safety laboratories 
and assessments as indicated by the clinical situation may be requested.  Clinical laboratory 
assessments are listed in Table 5 and include: hematology, serum chemistry and urinalysis 
parameters. Parameters will be assessed as specified in the Schedule of Assessments (Table 1 
and Table 2).  
While local laboratory results may be used for urgent clinical and dosing decisions, on the day of 
the clinic visit assessments, all laboratory assessments specified in Table 5 which are performed 
at the clinic should also be sent in parallel to the central laboratory.  In the case of discrepant 
local and central laboratory results on samples drawn on the same day, central laboratory results 
will be relied upon for clinical and dosing decisions. 
Clinical laboratory assessments may be collected at the clinical study center or at home by a 
trained healthcare professional. 
For any safety event or laboratory abnormality, additional laboratory assessments, imaging, and 
consultation may be performed for clinical evaluation and/or in consultation with the Medical 
Monitor; results may be collected and should be included in the clinical database. 
 
Table 5: 
Clinical Laboratory Assessments 
Hematology 
Complete blood count with differential 
 
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Serum Chemistry 
Sodium 
Potassium 
BUN 
Phosphate 
Creatinine and eGFR (using the CKD-EPI formula)  
Albumin 
Uric acid 
Calcium 
Total protein 
Carbon dioxide 
Glucose 
Chloride 
Liver Function Tests 
 
AST 
ALP 
ALT 
Bilirubin (total and direct) 
GGT  
 
Urinalysis 
Visual inspection for appearance and color 
Bilirubin 
pH (dipstick) 
Nitrite 
Specific gravity 
RBCs 
Ketones 
Urobilinogen 
Albumin 
Leukocytes 
Glucose 
Microscopy 
Protein 
 
Coagulation  
Prothrombin time 
International Normalized Ratio 
Partial Thromboplastin Time 
 
Immunogenicity (see Section 6.7.5.1) 
Antidrug antibodies 
Hepatic Tests (Screening Only)  
Hepatitis C, including:  
HCV RNA PCR – qualitative and quantitative 
assays 
Hepatitis B, including:  
HBs Ag, HBc antibody IgM and IgG 
Pregnancy Testing (Females of Child-bearing Potential Only) (see Section 6.7.5.2) 
β-human chorionic gonadotropin 
Abbreviations:  ALP=alkaline phosphatase; ALT=alanine transaminase; AST=aspartate transaminase; BUN=blood 
urea nitrogen; CKD-EPI=Chronic Kidney Disease Epidemiology Collaboration; eGFR=estimated glomerular 
filtration rate; GGT=gamma glutamyl transferase; HAV=hepatitis A virus; HBsAg=hepatitis B virus surface 
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antigen; HBc=hepatitis B virus core; HCV=hepatitis C virus; IgG= IgG=immunoglobulin G antibody; 
IgM=immunoglobulin M antibody; PCR=polymerase chain reaction; RBC=red blood cell; RNA=ribonucleic acid. 
6.7.5.1. 
Immunogenicity 
Blood samples will be collected to evaluate ADA.  Blood samples for antidrug antibody testing 
must be collected before study drug administration as specified in the Schedule of Assessments 
(Table 1 and Table 2).  A blood sample to evaluate antidrug antibodies will be collected at the 
Early Termination visit, if applicable. 
Details regarding the processing, shipping, and analysis of the samples will be provided in the 
Laboratory Manual. 
6.7.5.2. 
Pregnancy Testing 
A pregnancy test will be performed for females of child-bearing potential.  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.  Patients 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.  Patients determined to 
be pregnant while on study will be followed until the pregnancy outcome is known (see Section 
6.7.6.7 for follow-up instructions).  
6.7.5.3. 
Additional Liver Function Assessments 
Additional laboratory assessments will be performed in patients who experience any liver 
function test (LFT) abnormalities.  Following the occurrence of elevated liver transaminases or 
other LFT abnormalities per central laboratory, all assessments in Table 6 will be performed one 
time, as well as hematology, serum chemistry, LFT, and coagulation assessments from Table 5, 
and other assessments or evaluations per Investigator discretion, as appropriate. 
 
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Table 6: 
Hepatic Assessments in Patients Who Experience Elevated Transaminases 
Extended Hepatic Panel 
Herpes Simplex Virus 1 and 2 antibody IgM, IgG 
Herpes Zoster Virus IgM, IgG 
HIV 1 and 2a 
HHV-6  
Cytomegalovirus antibodies, IgM, IgG 
HBs Ag, HBc antibody IgM and IgG 
Anti-nuclear antibodies 
Epstein-Barr Virus antibodies, IgM and IgG 
Anti-smooth muscle antibodies 
Anti-mitochondrial antibodies 
HCV antibody 
HAV antibody IgM 
HCV RNA PCR – qualitative and quantitative 
HEV antibody IgM 
Imaging 
Abdominal ultrasound with Doppler flow (or CT or MRI) including right upper quadrant 
Focused Medical and Travel History 
Use of any potentially hepatotoxic concomitant 
medications, including over the counter medications 
and herbal remedies 
Alcohol consumption  
Other potentially hepatotoxic agents including any 
work-related exposures 
Recent travels to areas where hepatitis A or E 
is endemic 
Abbreviations:  CT=computed tomography; HAV=hepatitis A virus; HBc=hepatitis B core; HBsAg=hepatitis B 
virus surface antigen; HCV=hepatitis C virus; HEV=hepatitis E virus; HHV-6=human herpesvirus 6; HIV=human 
immunodeficiency virus; IgG=immunoglobulin G antibody; IgM=immunoglobulin M antibody; MRI=magnetic 
resonance imagery; PCR=polymerase chain reaction; RNA=ribonucleic acid. 
Note: 
 
All assessments will be measured in central laboratory. The full panel of assessments should only be 
performed once; individual assessments may be repeated, as needed. 
 
a HIV testing will not be performed where prohibited by local regulations. 
6.7.6. 
Adverse Events 
6.7.6.1. 
Definitions 
Adverse Event  
According to the International Council on Harmonisation (ICH) E2A guideline Definitions and 
Standards for Expedited Reporting, and 21 CFR 312.32, investigational new drug (IND) Safety 
Reporting, an AE is any untoward medical occurrence in a patient or clinical investigational 
subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
 Results in death 
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 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 
 Is an important medical event that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient and may require 
intervention to prevent one of the other outcomes listed in the definition above (eg, 
events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias, convulsions, or the development of drug 
dependency or abuse). 
Adverse Events of Clinical Interest 
Based on the biological target and the available nonclinical and clinical data, AEs of Clinical 
Interest (AECI) for this study are: 
 Severe infections as judged by the investigator  
 ALT or AST >3×ULN 
 Severe or serious injection site reactions (ISRs); ISRs that are associated with a recall 
phenomenon (reaction at the site of a prior injection with subsequent injections), or 
those that lead to temporary dose interruption or permanent discontinuation of 
cemdisiran. 
An ISR is defined as a local reaction at or near the site of injection.  “At or near” the 
injection site includes reactions at the injection site, adjacent to the injection site, or a 
reaction which may shift slightly away from the injection site due to gravity (eg, as 
may occur with swelling or hematoma).  A systemic reaction which includes the 
injection site (eg, generalized urticaria, other distinct entities or conditions like 
lymphadenopathy that may be near the injection site) is not considered an ISR.  
For information on recording and reporting of AECIs, see Section 6.7.6.2 and Section 6.7.6.3 , 
respectively. 
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Adverse Event Severity 
Adverse events are to be graded according to the categories detailed below: 
Mild: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Moderate: 
Moderate; minimal, local or noninvasive intervention indicated; limiting age 
appropriate instrumental activities of daily living (eg, preparing meals, 
shopping for groceries or clothes, using the telephone, managing money). 
Severe: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care activities of daily living (ie, bathing, dressing and undressing, feeding 
self, using the toilet, taking medications, and not bedridden); OR life-
threatening consequences; urgent intervention indicated; OR death related to 
an 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 SAE). 
Relationship of the Adverse Event to Study Drug 
The relationship of each AE to study drug should be evaluated by the Investigator by a “yes” or 
“no” response to the question: “Is there a reasonable possibility that the event may have been 
caused by the study drug?” 
6.7.6.2. 
Eliciting and Recording Adverse Events 
Eliciting Adverse Events 
The patient and legal guardian, if applicable, should be asked about medically relevant changes 
in the patient’s health since the last visit.  The patient and legal guardian, if applicable, should 
also be asked if the patient has been hospitalized, had any accidents, used any new medications, 
or changed concomitant medication routines (both prescription and over-the-counter).  In 
addition to patient observations, AEs will be documented from any clinically relevant laboratory 
findings, physical examination findings, ECG changes, or other findings that are relevant to 
patient safety. 
Recording Adverse Events 
The Investigator is responsible for recording all SAEs and only AEs related to study procedures 
that are observed or reported by the patient during the run-in period (before the administration of 
the first dose of study drug) regardless of their relationship to study drug through the end of 
study.  Events occurring after signing of the ICF and before study drug administration will be 
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captured as medical history (see Section 6.1).  All AEs will be collected starting after 
administration of the first dose through the end of the safety follow-up period. 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 study drug, action 
taken, and outcome (including time and date of resolution, if applicable). 
For SAEs, record the event(s) on both the eCRF and the SAE form.  
For AEs that are considered AEs of clinical interest (Section 6.7.6.1), the Sponsor or its designee 
should complete the supplemental AEs of Clinical Interest eCRF.  Additional clinical and 
laboratory information may be collected.  Refer to CRF completion guidelines for details on 
reporting events in the supplemental AEs of Clinical Interest eCRF.   
For all ISRs, the Investigator, or delegate, should submit a supplemental ISR eCRF, recording 
additional information (eg, descriptions, onset and resolution date, severity, treatment given, 
event outcome). 
6.7.6.3. 
Reporting Adverse Events of Clinical Interest to Sponsor/Designee 
For AEs that are considered AECIs (Section 6.7.6.1), the Sponsor or its designee should be 
notified within 24 hours using a supplemental AEs of Clinical Interest eCRF. 
6.7.6.4. 
Serious Adverse Events Require Immediate Reporting to Sponsor/Designee 
An assessment of the seriousness of each AE will be made by the Investigator.  Any AE and 
laboratory abnormality that meets the SAE criteria in Section 6.7.6.1 must be reported to the 
Sponsor or designee within 24 hours from the time that clinical study center staff first learns of 
the event.  All SAEs must be reported regardless of the relationship to study drug. 
The initial report should include at least the following information: 
 Patient’s study number 
 Description and date of onset of the event 
 Criterion for serious 
 Preliminary assignment of relationship to study drug, and 
 Investigator/site information 
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To report the SAE, complete the 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 Investigator Site File. 
Appropriate remedial measures should be taken by the Investigator using his/her best medical 
judgment to treat the SAE.  These measures and the patient’s response to these measures should 
be recorded.  All SAEs, regardless of relationship to study drug, will be followed by the 
Investigator until satisfactory resolution or the Investigator deems the SAE to be chronic or 
stable.  Clinical, laboratory, and diagnostic measures should be employed by the Investigator as 
needed to adequately determine the etiology of the event. 
6.7.6.5. 
Sponsor Safety Reporting to Regulatory Authorities 
The Sponsor or its representative will report certain study events in an expedited manner to the 
Food and Drug Administration, the European Medicines Agency’s EudraVigilance electronic 
system according to Directive 2001/20/EC, and to all country Regulatory Authorities where the 
study is being conducted, according to local applicable regulations. 
6.7.6.6. 
Serious Adverse Event Notification to the Institutional Review 
Board/Independent Ethics Committee 
Suspected unexpected serious adverse reactions (SUSARs) will be reported to the IRB/IEC per 
their institutional policy by the Investigator or Sponsor (or Sponsor designee) according to 
country requirements.  Copies of each report and documentation of IRB/IEC notification and 
acknowledgement of receipt will be kept in the Investigator’s study file. 
6.7.6.7. 
Pregnancy Reporting 
If a female patient becomes pregnant during the study through 90 days following the last dose of 
study drug, the Investigator must report the pregnancy to the Sponsor or designee within 
24 hours of being notified of the pregnancy. Details of the pregnancy will be recorded on the 
pregnancy reporting form.  The patient should receive any necessary counseling regarding the 
risks of continuing the pregnancy 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 6.7.6.4. 
6.7.6.8. 
Overdose Reporting 
An overdose is defined as any dose administered to or taken by a patient (accidentally or 
intentionally) that exceeds the highest daily dose, or is at a higher frequency, than included in the 
protocol.  The investigator will decide whether a dose is to be considered an overdose, in 
consultation with the Sponsor.  In the event of an overdose, the actual dose administered must be 
recorded in the eCRF. 
All reports of overdose (with or without an AE) must be reported within 24 hours to the Sponsor 
or designee. 
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6.8. 
Biomarkers, DNA Genotyping, and Biospecimen Repository 
Alnylam’s RNAi therapeutics platform permits the highly specific targeting of investigational 
therapies based on genetic sequence.  It is possible that variations in the target genetic sequence 
will result in variations in drug effect. 
More generally, genetic variations may account for the well-described heterogeneous 
manifestations of disease in patients with IgAN, as well as their responses to treatment. 
To permit exploratory investigations and the application of novel approaches to bioanalyses that 
may further elucidate the outcomes of this study, or potentially advance understanding of the 
safety, mechanism of action, and/or efficacy of cemdisiran, a set of biological specimens will be 
collected at the intervals indicated in the Schedule of Assessments (Table 1 and Table 2). 
The biospecimen repository will also include residual material from routine samples (safety 
laboratory samples, PK samples, etc.) that are obtained during the study. 
These specimens will be securely stored in a central biorepository for up to 10 years following 
the completion of this clinical study (ie, last patient last visit), or as per local regulations.  After 
10 years have elapsed, samples will be destroyed. 
Where allowed per local regulations, ethics committee (IRB/IEC) approval, and patient consent, 
the samples will be collected as part of this study.  Examples of potential exploratory 
investigations would include DNA, RNA or biochemical metabolite assessments as they relate to 
disease progression, efficacy or safety.  
Details regarding the collection, processing, storage, and shipping of the samples will be 
provided in the Laboratory Manual. 
Exploratory analysis of these biospecimens will be performed by Alnylam Pharmaceuticals or its 
designees. 
When biobanking is permitted by local regulation, study participants will be advised during the 
informed consent process of these biobanking details and the potential for exploratory 
investigation of their samples. 
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7. 
STATISTICS 
A Statistical Analysis Plan (SAP) will be finalized before database lock.  The plan will detail the 
implementation of the statistical analyses in accordance with the principle features stated in the 
protocol. 
7.1. 
Determination of Sample Size 
Thirty patients are planned to be randomized 2:1 (cemdisiran:placebo) in this study.  This is 
based on the assumption that, in the placebo arm, the estimated geometric mean ratio of 
proteinuria at Week 32 to baseline is 0.88 (log standard deviation [SD] 0.597), corresponding to 
a 12% reduction.  A sample size of 27 with 2:1 randomization (cemdisiran:placebo) will provide 
a width of 0.80 for the 90% confidence interval (CI) for treatment effect size estimate 
(cemdisiran  placebo) in log scale.  This corresponds to a 90% CI of (15%, 62%) for the 
treatment difference in the percentage scale if the true Week 32 reduction is 50% for the 
cemdisiran arm.  To account for potential dropouts, 30 patients are planned to be randomized. 
7.2. 
Statistical Methodology 
The statistical and analytical plans presented below are brief summaries of planned analyses.  
More complete plans will be detailed in the statistical analysis plan (SAP).  Changes to the 
methods described in the final SAP will be described and justified as needed in the clinical study 
report.  For information on study endpoints, see Section 2. 
7.2.1. 
Populations to be Analyzed 
The following populations will be analyzed: 
 Modified Intent-to-treat (mITT): All patients who receive any amount of study drug 
and have at least one post baseline assessment in proteinuria. Patients will be grouped 
by assigned treatments (ie, as randomized). 
 Safety Analysis Set: All patients who received any amount of study drug. Patients 
who received any amount of cemdisiran will be included in the cemdisiran arm and 
will be grouped by treatment received. 
 PK Analysis Set: All patients who receive any amount of study drug and have at least 
one postdose blood or urine sample for PK concentration. 
 PD Analysis Set: All patients who receive any amount of study drug and who have at 
least one postdose blood sample for the determination of plasma C5 level. 
The primary population used to evaluate efficacy will be the mITT Population.  Sensitivity 
analyses for efficacy will be performed using the Per Protocol Analysis Set.  Safety will be 
analyzed using the Safety Analysis Set.  The PK and PD Analysis Sets will be used to conduct 
PK and PD analyses, respectively.  
7.2.2. 
Examination of Subgroups 
Subgroup analyses may be conducted for selected endpoints.  Detailed methodology will be 
provided in the SAP. 
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7.2.3. 
Handling of Missing Data 
Handling of missing data will be described in the SAP. 
7.2.4. 
Baseline Evaluations 
Demographics and other baseline characteristics, including disease-specific information, will be 
summarized descriptively by treatment arm and overall for the mITT and Safety Analysis Set. 
Baseline value for proteinuria will be calculated as average of two valid 24-hour urine protein 
levels before randomization. 
7.2.5. 
Efficacy Analyses 
7.2.5.1. 
Primary Endpoint 
The primary endpoint of the study is the percentage reduction from baseline in 24-hour 
proteinuria at Week 32. The 24-hour urine protein will be log transformed for analyses. The 
primary analysis will be performed on the change from baseline in log transformed urine protein 
using a linear model with log transformed baseline urine protein as covariate and treatment and 
randomization stratification factor as fixed effect. The least square mean difference and its 90% 
confidence interval will be estimated and then back transformed to original scale. In the end the 
estimated ratio of percentage reduction in urine protein for cemdisiran to placebo and 90% 
confidence interval will be presented.  
A sensitivity analysis using all urine protein assessments including a single 24-hour assessment 
will be conducted using mixed-effects model repeated measures (MMRM) method. 
7.2.5.2. 
Secondary Efficacy Endpoints  
The secondary efficacy endpoints include percent of patients with partial clinical remission (UP 
<1.0 g/24-hours), percent of patients with >50% reduction in 24-hour proteinuria, change from 
baseline in UPCR as measured in 24-hour urine at Week 32, change from baseline in urine 
protein/creatinine ratio (UPCR) as measured in a spot urine at Week 32 and change from 
baseline in hematuria at Week 32. 
The percentage of patients with partial clinical remission or with >50% reduction in 24-hour 
proteinuria for each treatment arm and the difference between treatment arms will be presented 
together with an approximate 90% confidence interval based on Wilson score method.  
Change from baseline in urine protein / creatinine ratio (UPCR) will be analyzed similarly to the 
analysis of the primary variable as appropriate. UPCR will be log transformed first before 
analysis.  
7.2.5.3. 
Exploratory Endpoints  
Change from baseline in exploratory efficacy variables will be summarized. Percent of patients 
in full clinical remission and incidence of ADA will be tabulated by treatments. Inferential 
statistics for exploratory efficacy variables may be presented as needed. Details will be described 
in the SAP. 
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The slope of eGFR for the first 32 weeks will be estimated for each subject with the linear 
regression method using all assessment data during the period.  
Descriptive statistics including the number of patients, mean, median, standard deviation (SD), 
interquartile range (Q1, Q3), minimum, and maximum values will be presented for continuous 
variables. Frequencies and percentages will be presented for categorical and ordinal variables.  
7.2.6. 
Pharmacodynamic Analysis 
Assessment of the PD effect of the treatment will be performed descriptively, including plotting 
graphically levels of serum C5 protein and CAP/CCP over time and relative to baseline levels. 
Inferential statistics maybe generated as deemed necessary. 
7.2.7. 
Pharmacokinetic Analysis 
Pharmacokinetic analyses will be conducted using noncompartmental methods. Pharmacokinetic 
parameters include, but will not be limited to:  AUC, Cmax, Tmax, T½, CL/F, V/F, cumulative 
amount excreted unchanged in urine (Ae), and percent of dose excreted (fe) in the urine of 
cemdisiran (25-mer) and 23-mer.  
Other parameters may be calculated, if deemed necessary. Summary statistics and figures will be 
presented. Inferential statistics may be generated when deemed necessary. 
7.2.8. 
Safety Analyses 
The primary parameter is the frequency of treatment-emergent AEs (hereafter referred to simply 
as AEs). Safety parameters also include vital signs, ECGs, clinical laboratory assessments, and 
physical exams.  The extent of exposure will be summarized by dose level and overall. 
Adverse events will be classified according to the Medical Dictionary for Regulatory Activities 
(MedDRA) System Organ Class and Preferred Term. Prior and concomitant medications will be 
classified according to the World Health Organization (WHO) drug dictionary. All SAEs 
occurring before the first dose of study drug and AEs related to study procedures will be listed. 
The number and percentage of patients experiencing AEs after the first dose of the study drug or 
events that worsened in severity after dosing will be summarized. AEs will be presented by 
maximum severity and relationship to study medication. SAEs and AEs leading to 
discontinuation of treatment will also be tabulated. 
By-subject listings will be provided for deaths, SAEs, and AEs leading to study discontinuation. 
Frequency of adverse events of clinical interest will also be summarized and by-subject listings 
will be provided. 
Descriptive statistics will be provided for clinical laboratory data, 12-lead ECG interval data and 
vital signs data, presented as both actual values and changes from baseline over time. Laboratory 
shift tables from baseline to worst values will be presented. Baseline will be defined as the last 
observation on or prior to Study Day 1.  
Abnormal physical examination findings and 12-lead ECG data will be presented in a by-patient 
data listing. Details of any abnormalities will be included in patient listings. 
Other safety summaries will be presented as appropriate. Further details will be specified in the 
SAP. 
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All safety analyses will be conducted using the Safety Analysis Set. 
7.2.9. 
Immunogenicity Analyses 
Antidrug antibody results will be summarized descriptively.   
7.2.10. 
Biomarker Analyses 
Urine and serum complement activation products, inflammation and renal injury markers will be 
summarized descriptively.  
7.2.11. 
Interim Analysis 
No formal interim analysis is planned. 
7.2.12. 
Optional Additional Research 
Optional additional research may be conducted in the future on the biological samples and/or 
data collected during the study in accordance with the strict terms of the ICF (see Section 4.3.2). 
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8. 
STUDY ADMINISTRATION 
8.1. 
Ethical and Regulatory Considerations 
This study will be conducted in accordance with the protocol, all applicable regulatory 
requirements, and the current guidelines of Good Clinical Practice (GCP).  Compliance with 
GCP provides public assurance that the rights, safety, and well-being of study patients are 
protected consistent with the principles that have their origin in the Declaration of Helsinki. 
8.1.1. 
Informed Consent 
The Investigator will ensure that the patient/legal guardian is given full and adequate oral and 
written information about the nature, purpose, possible risk and benefit of the study.  
Patients/legal guardians must also be notified that they are free to discontinue from the study at 
any time.  The patient/legal guardian should be given the opportunity to ask questions and 
allowed time to consider the information provided.   
The patient’s/legal guardian’s signed and dated informed consent must be obtained before 
conducting any study tests or procedures that are not part of routine care.   
The Investigator must maintain the original, signed ICF.  A copy of the signed ICF must be 
given to the patient/legal guardian. 
8.1.2. 
Ethical Review 
The study protocol, including the ICF, must be approved or given a favorable opinion in writing 
by an IRB or IEC, as appropriate.  The Investigator must submit written approval before he or 
she can enroll any patient into the study. 
The Investigator is responsible for informing the IRB or IEC of any amendment to the protocol 
in accordance with local requirements.  In addition, the IRB or IEC must approve all patient 
materials for the study.  The protocol must be reapproved by the IRB or IEC upon receipt of 
amendments and annually, as local regulations require. 
Initial IRB approval of the protocol, and all materials approved by the IRB for this study 
including the patient consent form and recruitment materials must be maintained by the 
Investigator and made available for inspection. 
The Investigator will submit reports of SAEs as outlined in Section 6.7.6.  In addition, the 
Investigator agrees to submit progress reports to the IRB or IEC per their local reporting 
requirements, or at least annually and at the conclusion of the study.  The reports will be made 
available to the Sponsor or designee. 
Any communications from regulatory agencies, IRBs, or IECs in regard to inspections, other 
studies that impact this protocol or the qualifications of study personnel should be promptly 
reported to the Sponsor or its designee. 
The Investigator is also responsible for providing the IRB with reports of any reportable serious 
adverse drug reactions from any other study conducted with the study drug.  The Sponsor or 
designee will provide this information to the Investigator. 
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Major changes in this research activity, except those to remove an apparent immediate hazard to 
the patient, must be reviewed and approved by the Sponsor and the IRB or IEC that approved the 
study.  Amendments to the protocol must be submitted in writing to the Investigator’s IRB or 
IEC and the Regulatory Authority for approval before patients are randomized under the 
amended protocol, and patients must be re-consented to the most current version of the ICF. 
8.1.3. 
Serious Breach of Protocol 
Investigators must notify the Medical Monitor within 24 hours of becoming aware of a serious 
breach of the protocol.  A serious breach is a breach that is likely to affect to a significant degree 
the safety and rights of a study participant or the reliability and robustness of the data generated 
in the clinical trial. 
8.1.4. 
Study Documentation, Confidentiality, and Records Retention 
All documentation relating to the study should be retained for 2 years after the last approval in an 
ICH territory or as locally required, whichever is longer.  If it becomes necessary for the 
Sponsor, the Sponsor’s designee, applicable IRB/IEC, or applicable regulatory authorities to 
review or audit any documentation relating to the study, the Investigator must permit direct 
access to all source documents/data.  Records will not be destroyed without informing the 
Sponsor in writing and giving the Sponsor the opportunity to store the records for a longer period 
of time at the Sponsor’s expense.   
The Investigator must ensure that the patients’ confidentiality will be maintained.  On the eCRFs 
or other documents submitted to the Sponsor or designees, patients should not be identified by 
their names, but by the assigned patient number or code.  If patient names are included on copies 
of documents submitted to the Sponsor or designees, the names will be obliterated, and the 
assigned patient number added to the document.  Documents not for submission to the Sponsor 
(eg, signed ICFs) should be maintained by the Investigator in strict confidence. 
The Investigator must treat all information related to the study and the compiled data as 
confidential, whose use is for the purpose of conducting the study. The Sponsor must approve 
any transfer of information not directly involved in the study. 
To comply with local and/or regional regulations, this clinical study may be registered, and study 
results may be posted on public registries, such as ClinicalTrials.gov. 
8.1.5. 
End of Study 
The end of study is defined as the last patient last visit. 
8.1.6. 
Termination of the Clinical Study or Site Closure 
The Sponsor reserves the right to terminate the study for clinical or administrative reasons at any 
time.  If the site does not recruit at a reasonable rate, or if there is insufficient adherence to the 
protocol requirements, the study may be closed 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, IRB/IEC and 
Regulatory Authorities will be promptly informed of the termination and the reason for the 
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decision.  The Investigator should promptly inform the patients and assure appropriate therapy 
and follow-up. 
8.2. 
Data Quality Control and Quality Assurance 
8.2.1. 
Data Handling 
Study data must be recorded on CRFs (paper and/or electronic) provided by the Sponsor or 
designee on behalf of the Sponsor.  Case report forms must be completed only by persons 
designated by the Investigator.  If eCRFs are used, study data must be entered by trained site 
personnel with access to a valid and secure eCRF system.  All data entered into the eCRF must 
also be available in the source documents.  Corrections on paper CRFs must be made so as to not 
obliterate the original data and must be initialed and dated by the person who made the 
correction. 
8.2.2. 
Study Monitoring 
The Monitor, as a representative of the Sponsor, has an obligation to closely follow the study 
conduct at the site.  The Monitor will visit the Investigator and clinical study center periodically 
and will maintain frequent telephone and written contact.  The Monitor will maintain current 
personal knowledge of the study through observation, review of study records and source 
documentation, and discussion of the conduct of the study with the Investigator and staff. 
The Monitor will review source documents, systems and CRFs to ensure overall quality and 
completeness of the data and to confirm study procedures are complied with the requirements in 
the study protocol accurately. The Sponsor, or its designee, will be allowed to conduct site visits 
to the investigation facilities for the purpose of monitoring any aspect of the study.  The 
Investigator agrees to allow the Monitor to inspect the drug storage area, study drug stocks, drug 
accountability records, patient charts and study source documents, site standard operating 
procedures and training records, and other records relative to study conduct. 
8.2.3. 
Audits and Inspections 
Periodically, the Sponsor or its authorized representatives audit clinical investigative sites as an 
independent review of core trial processes and documents to determine whether these activities 
were conducted, and data were recorded, analyzed, and accurately reported according to the 
protocol, GCP guidelines of the ICH, and any applicable regulatory requirements.  A regulatory 
authority, an IRB/IEC may visit the site to perform audits or inspections, including source data 
verification.  The Investigator should contact the Sponsor and designee, immediately if contacted 
by a regulatory agency or an IRB/IEC about an inspection. 
8.3. 
Publication Policy 
It is intended that after completion of the study, the data are to be submitted for publication in a 
scientific journal and/or for reporting at a scientific meeting.  A separate publication by 
Institution or Investigator may not be submitted for publication until after this primary 
manuscript is published or following the period of 18 months after completion of the study at all 
centers.  A copy of any proposed publication (eg, manuscript, abstracts, oral/slide presentations, 
book chapters) based on this study, must be provided and confirmed received at the Sponsor at 
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least 30 days before its submission.  The Clinical Trial Agreement among the institution, 
Investigator, and Alnylam will detail the procedures for Alnylam’s review of publications. 
Authorship of any publications resulting from this study will be determined on the basis of the 
Uniform Requirement for Manuscripts Submitted to Biomedical Journals (International 
Committee of Medical Journal Editors). 
 
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9. 
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10. 
APPENDICES 
None. 
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