A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Efficacy, Pharmacodynamics, and Pharmacokinetics of Lademirsen (SAR339375) for Subcutaneous Injection Administered Every Week in Patients With Alport Syndrome
Phase: PHASE2
Conditions: Alport Syndrome
Sponsor: Genzyme, a Sanofi Company

Lademirsen (SAR339375, formerly RG-012) 
Amended Clinical Trial Protocol 12 
(Genzyme Corporation ACT16248) 
08-Dec-2021
CONFIDENTIAL 
Page 1 of 170 
AMENDED CLINICAL TRIAL PROTOCOL 12 
ACT16248 (formerly RG012-03) 
Protocol Title: 
A Phase 2, Randomized, Double-Blind, 
Placebo-Controlled Study to Evaluate the 
Safety, Efficacy, Pharmacodynamics, and 
Pharmacokinetics of Lademirsen (SAR339375) 
for Subcutaneous Injection Administered Every 
Week in Patients with Alport Syndrome 
Study Name: 
Document Type: 
HERA 
Clinical Study Protocol  
Investigational Medicinal Product: 
Lademirsen (SAR339375, formerly RG-012) 
Phase of Development: 
Phase 2  
Indication: 
Alport syndrome 
Sponsor: 
Genzyme Corporation 
50 Binney Street 
Cambridge, Massachusetts, 02142 
United States 
Protocol Version: 
Amended Protocol 12 
Protocol Date: 
08-Dec-2021
EudraCT Number: 
2019-004394-10 
Any and all information presented in this document shall be treated as confidential and shall 
remain the exclusive property of Genzyme Corporation (or any of its affiliated companies). The 
use of such confidential information must be restricted to the recipient for the agreed purpose and 
must not be disclosed, published, or otherwise communicated to any unauthorized persons, for 
any reason, in any form whatsoever without the prior written consent of Genzyme Corporation (or 
the concerned affiliated company); ‘affiliated company’ means any corporation, partnership, or 
other entity which at the date of communication or afterwards (i) controls directly or indirectly 
Genzyme Corporation, (ii) is directly or indirectly controlled by Genzyme Corporation, with 
‘control’ meaning direct or indirect ownership of more than 50% of the capital stock or the voting 
rights in such corporation, partnership or other entity. 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY 
 
Document 
Country/countries 
impacted by 
amendment 
Date, version 
Amended Clinical Trial Protocol 12 
France 
08 December 2021, version 1 (electronic 12.0) 
Amended Clinical Trial Protocol 11 
All 
10 August 2021, version 1 (electronic 11.0) 
Amended Clinical Trial Protocol 10 
All 
22 January 2021, version 1 (electronic 10.0) 
Amended Clinical Trial Protocol 09 
All 
11 September 2020, version 1 (electronic 9.0) 
Amended Clinical Trial Protocol 08 
China 
18 March 2020, version 1 (electronic 8.0) 
Amended Clinical Trial Protocol 07 
Germany 
20 February 2020, version 1 (electronic 7.0) 
Amended Clinical Trial Protocol 06 
United Kingdom 
15 January 2020, version 1 (electronic 6.0) 
Amended Clinical Trial Protocol 05 
All 
07 November 2019, version 1 (electronic 5.0) 
Amended Clinical Trial Protocol 04 
All 
01 August 2019, version 2 (electronic 4.0) 
Amended Clinical Trial Protocol 03 
All 
23 April 2019, version 1 (electronic 1.0)  
Clinical Study Protocol version 3.0 
All 
16 August 2017, version 3.0 
Clinical Study Protocol version 2.0 
All 
29 June 2017, version 2.0 
Clinical Study Protocol version 1.0 
All 
01 July 2016, version 1.0 
Amended protocol 12 (08 December 2021) 
This amended protocol (amendment 12) is considered to be nonsubstantial based on the criteria 
set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of 
the European Union because it does not significantly impact the safety or physical/mental 
integrity of participants, nor the scientific value of the study. 
OVERALL RATIONALE FOR THE AMENDMENT 
The aim of the amendment is to remove the collection of race for French subjects and, thereby, to 
implement for French subjects the use of the new CKD-EPI equation that no longer needs race 
information (Inker et al, N Engl J Med. 2021 Nov 4;385(19):1737-49). 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Title page 
Revised to indicate that this is Amended protocol 
12. 
To conform with the usual process for 
protocol amendments.  
Protocol Synopsis and 
3.2.1 Inclusion criteria 
Links to the new Section 10.5.3 for France were 
added to I04 and I05. 
This clarification was added for study 
conducted in France. 
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Section # and Name 
Description of Change 
Brief Rationale 
5.1 Screening, 
6.2.14 Laboratory 
assessments, 
6.3.1 Estimated GFR, 
7.2.5 Efficacy analysis, 
and 9.3.9 Data protection 
Links to the new Section 10.5.3 for France were 
added. 
This clarification was added for study 
conducted in France. 
10.5.3 France 
New section was added for study conducted in 
France. 
This was added to clarify that race is not 
collected for French subjects, and thus to 
explain how the eGFR is calculated for these 
subjects.  
10.8.1 Amended Protocol 
11 (10 August 2021) 
New section was created to contain the prior 
amendment’s history, and subsequent sections 
were renumbered accordingly. Minor formatting 
updates were applied. 
To conform with the usual process for 
amendment history. 
11 References 
The Inker, et al. (2021), reference was added as 
reference 33, and the subsequent reference was 
renumbered. 
This is the reference for the race-free eGFR 
equation used for French subjects. 
In addition, minor editorial, stylistic, and/or grammatical changes were made throughout this 
document. 
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NAMES AND ADDRESSES OF:  
MONITORING TEAM’S REPRESENTATIVE 
Name: 
Address: 
Tel: 
Fax: 
E-mail: 
 
 
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PROTOCOL SYNOPSIS  
Study Title: 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, 
Efficacy, Pharmacodynamics, and Pharmacokinetics of Lademirsen (SAR339375) for 
Subcutaneous Injection Administered Every Week in Patients with Alport Syndrome 
Protocol Number: ACT16248 (formerly RG012-03) 
Indication: Treatment of renal dysfunction in subjects with Alport syndrome 
Study Type: Phase 2, randomized, double-blind, placebo-controlled study with an open-label 
extension period 
Sponsor: Genzyme Corporation 
Study Centers: Approximately 20 investigative sites  
Study Objectives 
Primary Objectives 
• To assess the efficacy of lademirsen (SAR339375) in reducing the decline in renal 
function. 
• To assess the safety and tolerability of lademirsen (SAR339375) in subjects with Alport 
syndrome. 
Secondary Objectives: 
• To assess plasma pharmacokinetic (PK) parameters. Cmax will be assessed for the parent 
compound (lademirsen [SAR339375]), its active major metabolite (RG0005), and the 
sum of lademirsen (SAR339375) and RG0005 (SUM) following administration of 
lademirsen (SAR339375). Ctrough will be assessed in terms of SUM only. 
• To assess potential formation of anti-drug antibodies (ADAs) following administration 
of lademirsen (SAR339375). 
• To assess the pharmacodynamic effect of lademirsen (SAR339375) on miR-21 and on 
changes in renal injury and function biomarkers.  
Exploratory Objectives 
• To assess the effect of lademirsen (SAR339375) on urine and blood biomarkers in 
Alport Syndrome subjects. 
• Please see Section 10.5.2.1.1 for China-specific exploratory objectives. 
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Study Endpoints 
Efficacy Endpoints: 
• Annualized change in estimated glomerular filtration rate (eGFR) from baseline during 
the placebo-controlled treatment period 
• Absolute and percent change in eGFR values from baseline at Weeks 24, and 48 
• Number and proportion of subjects who reach end-stage renal disease (ESRD) as 
defined by an eGFR ≤15 mL/min/1.73 m2 or initiation of hemodialysis or renal 
transplantation during the placebo-controlled treatment period 
• Absolute and percent change in eGFR values from baseline at Week 96  
• Proportion of subjects with a reduction from baseline in eGFR of <10%, <20%, <30%, 
or <40% reduction at Week 24, 48 and 96 
Safety Endpoints: 
• Incidence and severity of treatment-emergent adverse events (AEs) and serious adverse 
events (SAEs) 
• Observed values and changes from baseline in clinical laboratory parameters 
(eg, hematology, chemistry, complement, and urinalysis) 
• Observed values and changes from baseline in vital signs 
• Observed changes from baseline in 12-lead electrocardiogram (ECG) 
• Observed changes from baseline in physical examinations 
• Incidence and titer of ADAs 
• Association of ADAs with adverse events 
Pharmacodynamic Endpoints: 
• Changes in circulating miR-21 at Weeks 24, 48, and 96 
• Change in renal injury and function biomarkers from baseline at Weeks 24, 48, and 96: 
- 
In blood only: blood urea nitrogen (BUN);  
- 
In urine only: protein/creatinine ratio, albumin/creatinine ratio, and epidermal 
growth factor (EGF);  
- 
In both blood and urine: creatinine, Cystatin C, transforming growth factor-β 
(TGF-β), and neutrophil gelatinase-associated lipocalin (NGAL). 
Exploratory endpoints: 
• Changes in exploratory biomarkers, which may include but are not necessarily limited 
to: 
- 
In blood only: microRNAs (miRs) other than miR-21; 
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- 
In both blood and urine: β-2 microglobulin, and connective tissue growth factor 
(CTGF); 
- 
In urine only: kidney injury molecule-1 (KIM-1) and calbindin-D28k.  
• Please see Section 10.5.2.1.2 for study conduct in China. 
Pharmacokinetic Endpoints: 
• Plasma concentrations of lademirsen (SAR339375), RG0005, and SUM in Cmax samples 
and SUM only in Ctrough samples. 
Study Design and Methodology 
This will be a randomized, double-blind, placebo-controlled, multi-center, Phase 2 study 
conducted in approximately 45 subjects with Alport Syndrome at multiple investigative centers. 
At the completion of 48 weeks of double-blind, placebo-controlled treatment, all subjects will 
enter the 48-week open-label extension period in which all subjects will receive active 
treatment with lademirsen (SAR339375).  
Screening and Baseline Period 
Subjects may screen for enrollment after participation in the OBS16374 (formerly RG012-01) 
ATHENA Natural History Study (ATHENA) or directly in this study. To qualify for this study, 
subjects must have confirmed Alport Syndrome and meet all eligibility criteria (see below). 
Double-Blind, Placebo-Controlled Treatment Period 
Eligible subjects will be randomized in a 2:1 ratio to receive every week (QW) subcutaneous 
(SC) doses of lademirsen (SAR339375) 110 mg or placebo for 48 weeks with stratification by 
screening eGFR (<60 mL/min/1.73 m2 versus ≥60 mL/min/1.73 m2). Once randomized, the 
subject should be treated within 3 calendar days maximum. 
The Schedule of Events for the double-blind, placebo-controlled treatment period is provided in 
Table 1 and a detailed list of procedures for each study visit is provided see Section 5.2. Study 
drug injections will be administered by trained, qualified personnel on the Investigator site or, 
as deemed acceptable by the Investigator, at home or at an alternate location by a trained, 
qualified healthcare professional. Certain visits outlined in the Schedule of Events (see Table 1) 
may be performed at home or an alternate location by trained, qualified study personnel, to 
which the Investigator has delegated responsibility. See Section 5.7 for more details. 
Open-Label Treatment Extension Period 
Subjects who complete the 48-week double-blind, placebo-controlled treatment period will be 
rolled over into a 48-week open-label treatment extension period in which all subjects will 
receive QW active treatment with lademirsen (SAR339375).  
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The open-label treatment period allows all the subjects to benefit from exposure to lademirsen 
(SAR339375) after the randomized period of the treatment. In addition, this allows us to gain 
long-term safety and efficacy data in Alport subjects. 
Follow-up Period 
Any subject who discontinues early should complete the procedures for an early termination 
(ET) visit, enumerated in the Schedules of Events tables. 
Subjects who complete the open-label treatment extension period or subjects who discontinue 
early and have completed the early termination visit will enter the post-treatment follow-up 
period. During the follow-up period, visits will occur at Follow-up Weeks 2, 4, and 10. Follow-
up weeks are numbered starting from the last scheduled study visit in the active treatment 
period (eg, Follow-up Week 2 will occur 2 weeks after Week 96 or after ET). The Schedule of 
Events for the follow-up period is provided in both Table 1 and Table 2 and a detailed list of 
procedures for each visit in the follow-up period is provided in Section 5.5. 
Safety Management 
Data Monitoring Committee (DMC) 
An independent Data Monitoring Committee (DMC) will oversee the safety and overall 
conduct of this study. The DMC will perform periodic reviews of data during the course of the 
clinical trial, and on an ad hoc basis for review of emergent safety data, as defined in the DMC 
Charter for this clinical trial. 
In addition to safety monitoring, a non-binding interim futility analysis will be performed to 
review efficacy data as well. The study may stop additional accrual or follow-up if the threshold 
for minimum efficacy is not achieved. 
Dose Reduction 
Before administering each dose of study drug, the Investigator or delegate will review a 
subject’s most recent safety data. A subject’s platelet count will be obtained weekly before dose 
administration. Platelet counts may be measured at a central laboratory and can exceptionally 
be measured at a local laboratory. The most recent subject’s platelet counts, but not older than 
10 days, will be reviewed by the Investigator/physician before drug administration.  
Following the resolution of a Grade 2 AE or increase in aminotransferases (return to normal or 
≤ Grade 1) that does not otherwise trigger a stopping rule (see Section 3.4); the Investigator in 
consultation with the Sponsor may reduce an individual subject’s dose to 110 mg every two 
weeks (Q2W). Dose reductions should be discussed with the Sponsor Medical Manager before 
implementation. Once a subject’s dose has been reduced, it will not be increased. 
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Individual Treatment Stopping Criteria 
Any Grade 2 AE (except for renal function parameters related to the underlying disease process 
including eGFR, creatinine, BUN, and urinalysis) not resolved prior to administering the next 
dose and deemed by the Investigator to be at least “possibly related” to study drug would result 
in a pausing of dosing (eg, dose not given) until the AE improves to ≤ Grade 1. Injection site 
reactions (ISRs) will be graded according to Table 6. Any Grade 2 (except erythema/redness) or 
Grade 3 ISRs which had not resolved or reached Grade 1 (“Mild”, eg, limited tenderness, 
and/or induration, except erythema/redness) prior to the next dose, would result in a pausing of 
dosing. The continuation of dosing and dose level would be decided upon review between the 
Investigator and the Sponsor Medical Manager. For further details on dose reduction, see 
Section 4.5. 
Occurrence of any Grade 3 (Severe) or higher AE (except for ISRs and renal function 
parameters related to the underlying disease process including eGFR, creatinine, BUN, and 
urinalysis) will result in the cessation of dosing of the subject, unless it can be shown that the 
event was unrelated to participation in the clinical trial. The DMC will review the 
circumstances of the AE with the Sponsor and unblind the subject, as appropriate, to evaluate 
potential relatedness to study drug and will make a recommendation to the Sponsor regarding 
the further dosing of the subject. After deliberations, DMC will provide guidance to the 
Sponsor who will implement recommendations and communicate to the site. 
With regard to AEs, study drug should be discontinued for subjects who experience any of the 
following: 
• Grade 3 thrombocytopenia (platelet count from <50 000 to 25 000/microL)  
• ALT or AST >5 × ULN, or ALT or AST >3 × ULN in association with total bilirubin 
>2 × ULN 
• An unintended weight loss of ≥20% from baseline 
• ≥50% decline for eGFR from the last measurement or confirmed ESRD (eGFR 
≤15 mL/min/1.73 m2 or dialysis or renal transplantation is needed). 
In case of worsening of eGFR (that do not reach stopping criteria) or urine protein-to-creatinine 
ratio (UPCR), the Investigator or the Sponsor could repeat the test before the next scheduled 
one as often as medically needed. The Sponsor needs to be consulted before a decision to 
discontinue the patient, unless it is a case of emergency.  
Study Suspension and Stopping Criteria 
The occurrence of two similar Grade 3 (or higher) AEs (except for ISRs and renal function 
parameters related to the underlying disease process including eGFR, creatinine, BUN, and 
urinalysis), or any death or two unexpected SAEs considered at least possibly related to 
participation in the clinical trial, or any TEAE that in the opinion of the Sponsor is of potential 
clinical significance for subjects safety will result in the recommendation to suspend all dosing 
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and stop recruitment, then will trigger an ad hoc meeting with the DMC who will be asked to 
consider the appropriateness of study conduct continuation unchanged, early study termination 
or modification. 
Upon suspension of dosing, a full, unblinded review of the AEs will be performed by the DMC 
to evaluate the AEs and potential relationship to exposure to the study drug. Following the full, 
unblinded safety review, one of three outcomes is possible: 
• The study may be terminated 
• The study design may be amended. For example, the dose of study drug may be reduced 
for all subjects (to 110 mg SC every other week (the pre-specified dose reduction for a 
Grade 2 AE), the dose regimen may be changed to reduce the dosing frequency, or 
inclusion/exclusion criteria may be modified (eg, baseline platelet count or other 
relevant laboratory or clinical parameter) 
• Stopping criteria are at the discretion of the DMC, the study may continue as originally 
planned, based on clear evidence that the stopping criteria have not been met and 
measures are in place to ensure subject safety 
Study Duration 
The planned length of participation in the study for each subject is up to approximately 
110 weeks (from screening through completion of follow-up). This includes: 
• Screening period of up to 4 weeks 
• Double-blind, placebo-controlled treatment period of 48 weeks 
• Open-label extension treatment period of 48 weeks 
• Post-treatment follow-up period of 10 weeks  
Investigational Medicinal Product  
Lademirsen (SAR339375) for SC administration is supplied as 110 mg/mL solution in 5 mL 
glass vial. Each vial will contain a withdrawable volume of 2 mL. 
Placebo matching lademirsen (SAR339375) for SC administration is supplied as sodium 
chloride and riboflavin (colorant) solution in 5 mL glass vial. Each vial will contain a 
withdrawable volume of 2 mL. 
Study Population 
Approximately 45 adult subjects with Alport Syndrome who meet all of the inclusion and none 
of the exclusion criteria will be enrolled. 
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Summary of Eligibility Requirements  
Inclusion Criteria  
I 01. Male or female. 
I 02. Confirmed diagnosis of Alport syndrome:  
1. Clinical diagnosis (hematuria, family history, hearing loss, ocular change), AND, 
2. Genetic confirmation of Alport Syndrome in the subject or the family member, OR,  
3. Kidney biopsy showing glomerular basement membrane abnormalities (eg, significant 
thinning, thickening, irregularity or lucencies) consistent with Alport Syndrome. 
I 03. Age 18-55 years old. 
I 04. eGFR >35 mL/min/1.73 m2 and <90 mL/min/1.73 m2 (based on CKD-EPI) at screening 
(for study conducted in France, see Section 10.5.3). 
I 05. Renal Function Criteria (subjects must meet at least one of the following 
CRITERIA A or B or C): 
A) Prior eGFR Slope Criteria is defined as a decline in eGFR of ≥4 mL/min/1.73 m2/year 
(eGFR slope ≤-4 mL/min/1.73 m2/year) based on a linear regression slope analysis of 
≥4 eGFR measurements within 3 years prior to the study and with a minimum of 2-year 
time span (the last, of the screening measurement, and first eGFR measurements should 
be separated by at least 2 years). eGFR should be calculated by using the Chronic 
Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation 
(see Figure 1; for study conducted in France, see Section 10.5.3).  
B) Proteinuria: UPCR >2000 mg/g or urine albumin-to-creatinine ratio (UACR) 
>1000 mg/g 
C) eGFR (based on CKD-EPI): male 18-23 years old with eGFR <90 mL/min/1.73 m2 (for 
study conducted in France, see Section 10.5.3). 
I 06. ACE inhibitor and/or ARB dosing regimen should be stable for at least 30 days prior to 
screening. 
I 07. Sexually active female subjects of childbearing potential and sexually mature male 
subjects must agree to practice true abstinence in line with their preferred and usual 
lifestyle or to use two acceptable effective methods of contraception for the entire 
duration of the study and for at least 10 weeks after last dose. 
Contraceptive use by men or women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. 
 
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A) Male subjects 
Male subjects are eligible to participate if they agree to the following during the 
intervention period and for at least 10 weeks after the last dose of study intervention:  
• Refrain from donating sperm 
Plus either:  
• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent 
OR 
• Must agree to use contraception/barrier as detailed below 
- 
Agree to use a male condom and should also be advised of the benefit for a 
female partner to use a highly effective method of contraception as a condom 
may break or leak when having sexual intercourse with a woman of 
childbearing potential who is not currently pregnant 
B) Female subjects 
• A female subject is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies: 
- 
Is not a woman of childbearing potential (WOCBP) 
OR 
- 
Is a WOCBP and using a contraceptive method that is highly effective (with a 
failure rate of <1% per year), preferably with low user dependency, as described 
in Section 10.4 during the intervention period and for at least 10 weeks after the 
last dose of study intervention and agrees not to donate eggs (ova, oocytes) for 
the purpose of reproduction during the study and for a period of six weeks. The 
Investigator should evaluate the effectiveness of the contraceptive method in 
relationship to the first dose of study intervention. 
• A WOCBP must have a negative highly sensitive pregnancy test (urine as required 
by local regulations) within 24 hours before the first dose of study intervention. 
- 
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a 
serum pregnancy test is required. In such cases, the subject must be excluded 
from participation if the serum pregnancy result is positive.  
• Additional requirements for pregnancy testing during and after study intervention 
are located in Section 10.4. 
- 
The Investigator is responsible for review of medical history, menstrual history, 
and recent sexual activity to decrease the risk for inclusion of a woman with an 
early undetected pregnancy. 
I 08. Negative drug screen for opiates, cocaine, heroin, phencyclidine, amphetamines 
(including ecstasy), barbiturates, benzodiazepines, and cannabinoids. At the 
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Investigator’s discretion, subjects prescribed benzodiazepines, cannabinoids, or opiates 
with positive results on a drug screen may be allowed. 
I 09. Negative screening results for hepatitis B surface antigen (HBsAg), hepatitis C virus 
(HCV) antibody, and human immunodeficiency virus (HIV) antibody. 
• Hepatitis A virus (HAV) screening is not necessary, screenings required above are for 
identification of chronic diseases. 
I 10. Screening hematology, clinical chemistries, coagulation, and urinalysis are not clinically 
significant, as assessed by the Investigator, and meet the following criteria: 
A) Platelets, total white blood cell (WBC) count, and absolute neutrophil count within 
normal limits 
B) Hemoglobin (Hb) ≥11 g/dL 
C) Total and direct bilirubin <1.5 x upper limit of normal (ULN), unless elevated bilirubin 
is associated with a known benign condition (eg, Gilbert’s syndrome) 
D) Alanine aminotransferase (ALT) <1.5 x ULN 
E) Aspartate aminotransferase (AST) <1.5 x ULN 
F) Alkaline phosphatase (ALP) <1.5 x ULN 
G) Gamma-glutamyl transferase (GGT) <1.5 x ULN 
Note: At the discretion of the Investigator, screening laboratory testing may be repeated 
once to confirm out-of-range (exclusionary) results. 
I 11. Agree to report any new prescription medication, dose adjustment to existing 
medication, over-the-counter medication, or herbal supplement to the Investigator. 
I 12. Able to understand all study procedures in the informed consent form (ICF) and willing 
to comply with all aspects of the protocol. 
Exclusion Criteria 
E 01. Causes of chronic kidney disease aside from Alport syndrome (including but not limited 
to other heritable disorders leading to chronic kidney disease, diabetic nephropathy, 
hypertensive nephropathy, lupus nephritis, IgA nephropathy). 
E 02. ESRD as evidenced by ongoing dialysis therapy or history of renal transplantation. 
E 03. Any clinically significant illness within 30 days before screening or surgical or medical 
condition (other than Alport syndrome) that could interfere with the subject’s study 
compliance; confound the study results; impact subject safety; or significantly alter the 
distribution, metabolism, or excretion of drugs, including but not limited to the 
following: 
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• Significant or unstable cardiac disease (unstable angina, myocardial infarction within 
the last 6 months, symptomatic coronary artery disease, congestive heart failure [New 
York Heart Association ≥Grade 3], prolonged QT syndrome [torsade de pointes], 
significant arrhythmia, and/or any other clinically significant ECG abnormalities) 
• Uncontrolled seizure disorder (eg, seizure in the last 12 months) 
• Chronic infection (eg, tuberculosis) 
• Metabolic disease (eg, diabetes mellitus) 
• Evidence of urinary obstruction or difficulty in voiding at screening 
• History of hypocomplementemia (low complement levels or activity) 
• Maintenance medication known to cause QT prolongation 
E 04. Weight >110 kg. 
E 05. Any history of active malignancy within the last 1 year (history of localized basal cell or 
squamous cell carcinoma and cervical carcinoma in situ that has been 
excised/appropriately treated or a fully excised malignant lesion with a low probability 
of recurrence will not be considered exclusionary). 
E 06. History or presence of alcoholism or drug abuse within 2 years before screening or other 
concurrent social conditions that would potentially interfere with the subject’s study 
compliance, at the discretion of the Investigator. 
E 07. Mental impairment or history of or current significant psychiatric disease that may 
impair ability to provide informed consent or impact compliance with study procedures. 
E 08. Participation in a recent investigational study and receipt of an investigational drug or 
investigational use of a licensed drug within 30 days or 5 half-lives, whichever is longer, 
prior to screening. 
E 09. Prior treatment with Bardoxolone within 90 days prior to screening. 
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E 10. History or presence of hypersensitivity or idiosyncratic, allergic, or other clinically 
significant reaction to the study drug (including placebo), inactive ingredients, or related 
compounds (eg, other oligonucleotide products). 
E 11. Any other condition or circumstance that may make the subject unlikely to complete the 
study or comply with study procedures and requirements, or may pose a risk to the 
subject’s safety and well-being. 
E 12. Subjects dependent on the Sponsor or Investigator or employees of the clinical study site 
or any other individuals directly involved in the conduct of the study, or immediate 
family members of such individuals. 
E 13. Subjects that are accommodated in an institution because of regulatory or legal order. 
E 14. Prisoners or subjects who are legally institutionalized. 
Treatment Assignment 
For the double-blind, placebo-controlled treatment period, approximately 45 eligible subjects will 
be centrally randomized in a 2:1 ratio to lademirsen (SAR339375) 110 mg or placebo SC QW 
for 48 weeks, with stratification by screening eGFR (<60 mL/min/1.73 m2 versus 
≥60 mL/min/1.73 m2). 
For the open-label extension, all subjects will receive lademirsen (SAR339375) 110 mg SC QW 
for up to 48 weeks. Subjects who require dose reduction to 110 mg Q2W during the blinded 
phase of the study will receive lademirsen (SAR339375) as per the same dose that they received 
in the blinded phase of the study. 
Pharmacokinetic Assessment 
Plasma PK samples will be collected 4 hours post-dose on Day 1, Week 24, and Week 48 of the 
Treatment Period, for determination of maximum plasma concentrations (approximate Cmax) of 
lademirsen (SAR339375), RG0005, and SUM. In addition, pre-dose plasma PK samples will be 
collected (up to 4 hours before dose administration) on Day 1 and Weeks 4, 12, 24, 36, 48, 60, 
72, 84, and 96 for determination of minimum plasma concentrations (Ctrough) of SUM (see 
Table 1). No PK samples will be withdrawn on Weeks 4, 12, 24, 36, 48, 60, 72, 84, and 96 if 
injection is not administered. In case visit is performed (without injection administered), only 
pre-dose PK sample will be withdrawn. Time and date of PK sampling, as well as the date of 
the last prior administration of study drug should be recorded in the electronic case report form 
(eCRF). 
A manual for blood sampling, collection, processing, and shipment will be provided. 
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Disposition of Samples after Study Completion 
Collected blood and urine samples, excluding PK and ADA samples, may be stored and used in 
the future for the discovery, analysis, verification, and/or validation of other biomarkers or tests 
for renal disease. PK samples will be disposed of once the clinical study report (CSR) has been 
finalized. Based on the ADA data from the study, ADA samples may be disposed of upon 
finalization of the CSR or retained for further assay development and/or characterization of 
ADA. 
For study conduct in China, see Section 10.5.2.3. 
Statistical Considerations 
Sample Size Determination 
An approximate 45 total subjects will be randomized in 2:1 ratio to lademirsen (SAR339375) 
versus placebo. The sample size will provide approximately 75% power to detect a reduced rate 
of decline of 5 mL/min/1.73 m2/year (~50% reduction) in eGFR annualized rate under 
lademirsen (SAR339375) treatment, in comparison to placebo.  
Power calculations were based on simulations. The following model parameters were obtained 
from preliminary analysis of the ATHENA Natural History Study (OBS16374) data: 
• Average linear decline in eGFR of 10 mL/min/1.73 m2/year in placebo arm 
• Standard deviation (SD) for the residual error of eGFR of 
 mL/min/1.73 m2 and SD 
for random effect of slope to be 
 mL/min/1.73 m2/year 
• Mean and SD for intercept to be 
 mL/min/1.73 m2 and 
 mL/min/1.73 m2 
correspondingly 
In addition, and power calculations were based on a success criterion defined in Section 7.2.5 
and 10% dropout rate was assumed. 
Analysis populations 
The primary efficacy analysis population will be the Intent-to-Treat (ITT) Population, 
defined as all randomized subjects analyzed according to the treatment group allocated by 
randomization.  
The Safety Population will include all subjects who receive at least one dose or partial of a 
dose of the Investigational Medicinal Product (IMP), analyzed according to the treatment 
actually received.  
The PK Population will consist of all subjects who receive at least one dose of the IMP and 
have at least one post-dose PK sample to determine plasma concentrations of lademirsen 
(SAR339375). 
VV-CLIN-0473423 12.0

Lademirsen (SAR339375, formerly RG-012)  
 
Amended Clinical Trial Protocol 12  
(Genzyme Corporation ACT16248) 
 
08-Dec-2021 
 
CONFIDENTIAL 
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Primary efficacy analysis 
Annualized rate of change in eGFR during the placebo-controlled treatment period will be 
compared between lademirsen (SAR339375) and placebo using a linear mixed effect model. 
ATHENA Natural History Study (OBS16374) data will be used as prior information 
supplementing the placebo arm, using a Bayesian approach.  
Safety analysis 
The safety variables, including adverse events (AEs), laboratory parameters, vital signs, ECG 
and physical examinations will be summarized using descriptive statistics. 
Pharmacokinetic analysis  
Measured plasma concentrations (observed PK parameters Cmax and Ctrough) for lademirsen 
(SAR339375), RG0005, and SUM (as applicable) will be summarized using descriptive 
statistics (eg, mean, standard deviation [SD], median, min-max, and coefficient of variation 
[%CV]). 
 
 
 
 
  
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Lademirsen (SAR339375, formerly RG-012)  
 
 
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(Genzyme Corporation ACT16248) 
 
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CONFIDENTIAL 
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Table 1 - Schedule of events for screening and double-blind, placebo-controlled treatment period and follow-up period  
 
Scra 
 
Double-Blind, Placebo-Controlled Treatment Periodb 
 USVjj ETc Follow-upd 
STUDY WEEK -4 to 
0 
0 
1 
2 
3 
4 
6 
8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48e 
 
 
2 
4 
10  
STUDY DAY 
 
1f 8 15 22 29 43 57 71 85 99 113 127 141 155 169 183197 211 225 239 253 267 281 295309 323 337 
 
 
15 29 71  
Site Visitsg 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X 
X X X 
X 
X X X X X X 
X 
X 
X 
X X X 
X 
Alt. location 
optionh 
 
 
X 
X 
X 
 
X 
X 
X 
 
X X 
X 
X 
X 
 
X X X 
X 
X 
 
X X X X 
X 
 
Xkk 
 
X X 
 
Informed consenti 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical historyj 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Family historyk 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COL4A3/4/5 
genotypingff 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medications/ 
therapyl 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Concomitant 
medicationsm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signsn and 
body weight 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
 
 
X 
Physical 
examinationo 
Xg 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
 
 
X 
12-lead ECGee 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
 
 
 
Hearing 
Assessment 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
Drug and alcohol 
screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VV-CLIN-0473423 12.0

Lademirsen (SAR339375, formerly RG-012)  
 
 
Amended Clinical Trial Protocol 12  
(Genzyme Corporation ACT16248) 
 
08-Dec-2021 
 
 
CONFIDENTIAL 
Page 19 of 170 
 
 
Scra 
 
Double-Blind, Placebo-Controlled Treatment Periodb 
 USVjj ETc Follow-upd 
STUDY WEEK -4 to 
0 
0 
1 
2 
3 
4 
6 
8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48e 
 
 
2 
4 
10  
STUDY DAY 
 
1f 8 15 22 29 43 57 71 85 99 113 127 141 155 169 183197 211 225 239 253 267 281 295309 323 337 
 
 
15 29 71  
Site Visitsg 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X 
X X X 
X 
X X X X X X 
X 
X 
X 
X X X 
X 
Alt. location 
optionh 
 
 
X 
X 
X 
 
X 
X 
X 
 
X X 
X 
X 
X 
 
X X X 
X 
X 
 
X X X X 
X 
 
Xkk 
 
X X 
 
HBsAg, HCV, and 
HIV-1/2 screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject collects 
24-hour urine 
sample prior to 
visitp 
Xe, g  X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
 
 
 
Spot urine protein-
to-creatinine ratio 
(UPCR) 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
Urinalysisq 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
 
 
X 
CBCr 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation panels 
X 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
 
X 
Serum 
chemistryt, w 
Xg 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
 
X 
Lipid panelu, 
hs-CRP 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
 
 
X 
Blood 
pregnancyv, w 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Urine pregnancyv 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
PK pre-dosex 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
PK post-dosex 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
ADAy 
 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
 
 
X 
Complementz 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
X 
VV-CLIN-0473423 12.0

Lademirsen (SAR339375, formerly RG-012)  
 
 
Amended Clinical Trial Protocol 12  
(Genzyme Corporation ACT16248) 
 
08-Dec-2021 
 
 
CONFIDENTIAL 
Page 20 of 170 
 
 
Scra 
 
Double-Blind, Placebo-Controlled Treatment Periodb 
 USVjj ETc Follow-upd 
STUDY WEEK -4 to 
0 
0 
1 
2 
3 
4 
6 
8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48e 
 
 
2 
4 
10  
STUDY DAY 
 
1f 8 15 22 29 43 57 71 85 99 113 127 141 155 169 183197 211 225 239 253 267 281 295309 323 337 
 
 
15 29 71  
Site Visitsg 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X 
X X X 
X 
X X X X X X 
X 
X 
X 
X X X 
X 
Alt. location 
optionh 
 
 
X 
X 
X 
 
X 
X 
X 
 
X X 
X 
X 
X 
 
X X X 
X 
X 
 
X X X X 
X 
 
Xkk 
 
X X 
 
Markers of 
inflammationii 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
 
 
X 
microRNA-21  
(miR 21) 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
X 
Renal 
biomarkersaa 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
 
 
 
Plasma/serum for 
storage (for study 
conduct in China, 
see 
Section 10.5.2.3) 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
Exploratory 
biomarkersbb 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
Assignment to 
treatment groupgg 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRT contact 
X 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
x 
 
 
 
 
 
Assessment of 
ISRscc, dd 
 
To be completed weekly 
 
 
 
 
Study drug 
administration 
 
To be completed weekly 
 
 
 
 
1 day post injection 
follow-updd 
 
To be completed weekly 
 
 
 
 
Record adverse 
events 
To be assessed and reported throughout the study 
VV-CLIN-0473423 12.0

Lademirsen (SAR339375, formerly RG-012)  
 
 
Amended Clinical Trial Protocol 12  
(Genzyme Corporation ACT16248) 
 
08-Dec-2021 
 
 
CONFIDENTIAL 
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Scra 
 
Double-Blind, Placebo-Controlled Treatment Periodb 
 USVjj ETc Follow-upd 
STUDY WEEK -4 to 
0 
0 
1 
2 
3 
4 
6 
8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48e 
 
 
2 
4 
10  
STUDY DAY 
 
1f 8 15 22 29 43 57 71 85 99 113 127 141 155 169 183197 211 225 239 253 267 281 295309 323 337 
 
 
15 29 71  
Site Visitsg 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X 
X X X 
X 
X X X X X X 
X 
X 
X 
X X X 
X 
Alt. location 
optionh 
 
 
X 
X 
X 
 
X 
X 
X 
 
X X 
X 
X 
X 
 
X X X 
X 
X 
 
X X X X 
X 
 
Xkk 
 
X X 
 
Product 
Complainthh 
To be assessed and reported throughout the study 
 
Abbreviations: ADA, anti-drug antibodies; CBC, complete blood count; COL4A3/4/5, type IV collagen alpha chain genes 3, 4, and 5; ECG, electrocardiogram; ET, early termination; HBsAg, hepatitis B surface antigen; 
HCV, hepatitis C virus; HIV, human immunodeficiency virus; hs-CRP, high-sensitivity C-reactive protein; ISR, injection site reaction; PK, pharmacokinetics; Scr, Screening; USV, unscheduled visit; IRT, Interactive 
Response Technology; UPCR, urine protein-to-creatinine ratio 
a Screening data may be collected at more than 1 visit. 
b After Day 1, the visits will be done every 7 days. During the active treatment period, the visit window is ±2 days for each visit. Subjects who complete the double-blind, placebo-controlled treatment period will be 
rolled over directly into the open-label treatment extension (see Table 2). Subjects who complete the double-blind, placebo-controlled treatment period but who will not continue with the open-label treatment 
extension will enter the follow-up period, which is the same for all subjects.  
c Except for complete blood count (CBC), serum and urine chemistry, and coagulation panel, laboratory tests scheduled for the early termination (ET) visit do not need to be completed if the tests were completed as 
part of a study visit within 4 weeks of the last visit. ET will be done 7 days ±2 days after the last study visit. 
d Follow-up days and weeks are numbered starting from the last scheduled visit in the active treatment period. Thus, for subjects who discontinue early, Follow-up Week 2 is 2 weeks after the ET visit. The visit 
window is ±3 days for all follow-up visits. 
e For subjects who complete the double-blind, placebo-controlled treatment period and will enter the open-label treatment extension, the Week 48 visit will serve as the baseline visit of the open-label extension. 
f 
Day 1 is the baseline visit. 
g See Section 5 for visit windows, and Section 5.2 for odds visit details. 
h Option for Investigator to delegate visit assessments to be performed at an alternate location, including the subject’s home, conducted by trained, qualified study personnel. During the last 6 months of the double-
blind period, the subject will be trained on self-administration of the study drug and will be observed in self-administration technique. 
i 
Informed consent will be obtained prior to performing any study-related procedures. 
j 
Prior and ongoing illnesses, surgeries, use of tobacco/alcohol/recreational drugs, and allergic reactions/hypersensitivity.  
k Family history relevant to Alport syndrome and renal disease. 
l 
Prior medication/therapy is any medication or therapy given within 30 days before study entry (eg, before signing the informed consent form [ICF]), as well as ongoing medication or therapy. 
m Any medication taken after signing the ICF will be collected at each visit. 
n Systolic and diastolic blood pressure measurements, pulse rate, body temperature, and respiratory rate. Vital signs collection will be performed prior to drug administration throughout the study; specifically on 
Day 1 and W48, vital signs will be done at 0.5 to 1 hour pre- and 4 hours post-dose. 
o Complete examination at screening, baseline, Week 24, Week 48, ET, and Follow-up Week 10. Limited (symptom-directed) examination at Weeks 12 and 36. Height should be measured at screening.  
p 24-hour urine chemistry panel (albumin, creatinine, sodium, total protein). 
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q Urinalysis: assessment of colour and appearance, and dipstick test for specific gravity, erythrocytes, pH, protein, glucose, ketones, leukocyte esterase, nitrate, bilirubin, and urobilinogen will be done locally. 
Microscopic examination of urine sediment, microalbuminuria, urine creatinine, and urine protein will be a laboratory test.  
r 
Full hematology panel performed weekly during treatment period and at each visit timepoint during the follow up period: hemoglobin, hematocrit, red blood cell (RBC) count, white blood cell (WBC) count with 
differential, and platelet count.  
s Coagulation panel: prothrombin time, activated partial thromboplastin time (aPTT), international normalized ratio (INR), and fibrinogen.  
t 
Total protein, glucose, Cystatin C, creatinine for calculation of estimated glomerular filtration rate (eGFR), uric acid, lactate dehydrogenase, sodium, potassium, chloride, bicarbonate, calcium, iron, phosphate, 
blood urea nitrogen (BUN), and hepatic function panel (albumin, total bilirubin, direct bilirubin, alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], and gamma-glutamyl 
transferase [GGT]). In the event of elevated aminotransferases (ALT or AST) >3 xULN, see Section 10.3.2 for guidance on additional monitoring. If subject experienced low protein <1 g the investigation will be 
done by the Investigator as per local practice. In case of worsening of eGFR, the Investigator could repeat the eGFR before the next scheduled test. 
u Total cholesterol, triglycerides, high-density lipoprotein (HDL), and low-density lipoprotein (LDL). 
v For women of child bearing potential, a blood pregnancy and a monthly urine pregnancy test will be performed; in case the urine test is positive, injections will be stopped and a blood test will be performed to 
confirm the pregnancy. 
w Serum chemistry will be done centrally except for exceptional circumstances, and urine pregnancy can be done locally. 
x PK sampling time points on Day 1, Week 24 and Week 48 will be pre-dose (up to 4 hours before dose administration) and 4 hours post-dose. PK samples on other visits (Week 4, Week 12 and Week 36) will be 
pre-dose only (up to 4 hours before dose administration). No PK samples will be withdrawn on W4, W12, W24, W36, and W48, if injection is not administered and visit not performed. In case visit is performed 
(without injection administered), only pre-dose PK sample will be withdrawn. Time and date of PK sampling, as well as the date of the last prior administration of study drug should be recorded in the electronic 
case report form (eCRF). 
y All ADA samples should be collected pre-dose (up to 4 hours before dose administration). 
z Complement C3, C3a, C4, and Bb will be measured on Day 1 in samples obtained 0.5 hour pre-dose and 0.5, and 4 hours post-dose. On other visits, complement C3, C3A, c4, AND Bb will be measured pre-dose 
only. 
aa Blood Urea Nitrogen, Albumin/creatinine ratio, urine Cystatin C: Urine Neutrophil Gelatinase Associated Lipocalin (NGAL), blood and urine transforming growth factor-β (TGF-β), and EGF see Section 6.4 and 
Section 10.5.2.2 (for study conduct in China). In addition Urine protein/creatinine ratio will be performed every 4 weeks, either using spot urine or 24h-h urine collection (at D1, W12, W24, W36, W48, and ET). In 
case of worsening of UPCR, the Investigator could repeat the UPCR before the next scheduled test.  
bb May include but are not necessarily limited to the following: additional blood microRNAs, Kidney Injury Molecule-1, β-2 Microglobulin, and urine connective tissue growth factor (CTGF); and urine calbindin-D28k. 
For study conduct in China, see Section 10.5.2.2. 
cc Study drug administration and ISR assessment and reporting will be performed after each injection. 
dd Subjects will be monitored for at least 2 hours after the first injection at baseline to ensure subject safety. In subsequent injections, the healthcare professional will monitor the subject’s injection site for 15 minutes. 
The study staff will contact the subjects 1 day post injection to check on any occurrence of ISR and associated symptoms.  
ee 12-lead ECG will be performed before IMP administration during the study treatment period.  
ff Genotyping is not needed for randomization except for patient for whom historical data for genetic confirmation of Alport syndrome and a kidney biopsy showing glomerular basement membrane abnormalities 
consistent with Alport Syndrome are not available at screening visit. 
gg Day 1 should be within 3 calendar days maximum after assignment to treatment group. 
hh Please refer to Section 6.2.9. 
ii Markers of inflammation: quantitative immunoglobulin (γ-globulin, IgG, IgM). 
jj At unscheduled visits, only blood samples that are needed for abnormal laboratory value follow up will be collected. ECGs will only be performed in case an abnormality potentially has an impact on the continuity 
of the study drug administration, as deemed by the Investigator. 
kk The USVs may be done at alternative location visit (as described in footnote h), except when abnormal safety parameters are linked to physical examination. 
VV-CLIN-0473423 12.0

Lademirsen (SAR339375, formerly RG-012)  
 
 
Amended Clinical Trial Protocol 12  
(Genzyme Corporation ACT16248) 
 
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CONFIDENTIAL 
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Table 2 - Schedule of events for open-label treatment extension period and follow-up period  
 
Open-Label Treatment Extension Perioda 
USVaaETb Follow-upc 
STUDY WEEK 48 49 50 52 54 56 58 60 62 64 66 68 70 72 74 76 78 80 82 84 86 88 90 92 94 
96 
 
 
2 
4 
10  
STUDY DAY 337 344 351 365 379 393 407 421 435 449 463 477 491 505 519 533 547 561 575 589 603 617 631 645 659 673 
 
 
15 29 71  
Site Visitsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Alt. location 
optione 
 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
Xbb 
 
X 
X 
 
Concomitant 
medications 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
 
X 
Vital signsf and 
body weight 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
 
  
X 
Physical 
examinationg 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
 
 
X 
12-lead ECGv  
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
 
 
 
Hearing 
Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
Spot urine protein-
to-creatinine ratio 
(UPCR) 
X 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
Subject collects 
24-hour urine 
sample prior to 
visith 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
 
 
 
Urinalysisi 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
 
 
X 
CBCw 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation panelj 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
 
X 
Serum chemistryk, n  X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
 
X 
Lipid panell, 
hs-CRP 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
 
 
X 
Blood pregnancym 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VV-CLIN-0473423 12.0

Lademirsen (SAR339375, formerly RG-012)  
 
 
Amended Clinical Trial Protocol 12  
(Genzyme Corporation ACT16248) 
 
08-Dec-2021 
 
 
CONFIDENTIAL 
Page 24 of 170 
 
 
Open-Label Treatment Extension Perioda 
USVaaETb Follow-upc 
STUDY WEEK 48 49 50 52 54 56 58 60 62 64 66 68 70 72 74 76 78 80 82 84 86 88 90 92 94 
96 
 
 
2 
4 
10  
STUDY DAY 337 344 351 365 379 393 407 421 435 449 463 477 491 505 519 533 547 561 575 589 603 617 631 645 659 673 
 
 
15 29 71  
Site Visitsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Alt. location 
optione 
 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
Xbb 
 
X 
X 
 
Urine pregnancym 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
ADAo, p 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
 
 
X 
PK pre-dosex 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
PK post-dose 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complementq 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
X 
Markers of 
inflammationz 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
 
 
X 
microRNA-21 
(miR 21) 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
X 
Renal 
function/injury 
biomarkersr 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
 
 
 
Exploratory 
biomarkerss 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
Record adverse 
events 
To be assessed and reported throughout the study 
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Open-Label Treatment Extension Perioda 
USVaaETb Follow-upc 
STUDY WEEK 48 49 50 52 54 56 58 60 62 64 66 68 70 72 74 76 78 80 82 84 86 88 90 92 94 
96 
 
 
2 
4 
10  
STUDY DAY 337 344 351 365 379 393 407 421 435 449 463 477 491 505 519 533 547 561 575 589 603 617 631 645 659 673 
 
 
15 29 71  
Site Visitsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Alt. location 
optione 
 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
Xbb 
 
X 
X 
 
Product 
Complainty 
To be assessed and reported throughout the study 
 
IRT contact 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Assessment of 
ISRst 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
1 day post 
injection 
follow-upcc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Study drug 
administrationu 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Abbreviations: ADA, anti-drug antibodies; CBC, complete blood count; ECG, electrocardiogram; ET, early termination; hs-CRP, high-sensitivity C-reactive protein; ISR, injection site reaction; PK, pharmacokinetics, 
USV, unscheduled visit; IRT, Interactive Response Technology; UPCR, urine protein-to-creatinine ratio 
a The visits will be done every 7 days. During the active treatment period, the visit window is ±2 days for each visit.  
b With the exception of complete blood count (CBC), serum and urine chemistry, and coagulation panel, laboratory tests scheduled for the early termination (ET) visit do not need to be completed if the tests were 
completed as part of a study visit within 4 weeks. ET will be done 7 days ±2 days after the last study visit. 
c Follow-up days and weeks are numbered starting from the last scheduled visit in the active treatment period. Thus, for subjects who complete the open-label treatment extension, Follow-up Week 2 is 2 weeks 
after the ET visit or Week 96. The visit window is ±3 days for all follow-up visits. 
d These study visits are required to be on site visits.  
e Option for Investigator to delegate visit assessments to be performed at an alternate location, including the subject’s home, conducted by trained, qualified study personnel. Upon completion of training during the 
last 6 months of double-blind period, the Investigator may decide if self-administration at home is possible, please see Section 4.4. 
f 
Systolic and diastolic blood pressure measurements, pulse rate, body temperature, and respiratory rate. Vital signs should be measured before blood is drawn and respiratory rate will be determined by 
observation for at least 30 seconds. At Week 48, vital signs will be done at 0.5 to 1 hour pre and 4 hour post-dose. 
g Complete physical examination at Weeks 48, 72, and 96; ET; and Follow-up Week 10. Limited (symptom-directed) physical examination at Weeks 60 and 84. 
h 24-hour urine chemistry panel (albumin, creatinine, sodium, total protein). 
i 
Urinalysis: assessment of colour and appearance, and dipstick test for specific gravity, erythrocytes, pH, protein, glucose, ketones, leukocyte esterase, nitrate, bilirubin, and urobilinogen will be done locally. 
Microscopic examination of urine sediment, microalbuminuria, urine creatinine, and urine protein will be a laboratory test.  
j 
Coagulation panel: prothrombin time, activated partial thromboplastin time (aPTT), international normalized ratio (INR), and fibrinogen. 
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k Total protein, glucose (in fasting condition as per site habit), Cystatin C, creatinine for calculation of estimated glomerular filtration rate (eGFR), uric acid, lactate dehydrogenase, sodium, potassium, chloride, 
bicarbonate, calcium, iron, phosphate, blood urea nitrogen (BUN), and hepatic function panel (albumin, total bilirubin, direct bilirubin, alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline 
phosphatase [ALP], and gamma-glutamyl transferase [GGT]). In the event of elevated aminotransferases (ALT or AST) >3 xULN, see Section 10.3.2 for guidance on additional monitoring.  
l 
Total cholesterol, triglycerides, high-density lipoprotein (HDL), and low-density lipoprotein (LDL). 
m For women of child bearing potential, a blood pregnancy and a monthly urine pregnancy test will be performed; in case the urine test is positive, injections will be stopped and a blood test will be performed to 
confirm the pregnancy. 
n Serum chemistry will be done centrally except for exceptional circumstances, and urine pregnancy can be done locally. 
o After the Week 96 sample, additional ADA samples will only need to be collected at Follow-up and ET, if the Week 96 sample was confirmed positive for ADA.  
p ADA samples will be collected pre-dose (up to 4 hours before dose administration), see Section 5.5, follow up visit Week 10. 
q Complement C3, C3a, C4, and Bb will be measured pre-dose. 
r 
Blood urea nitrogen (BUN); albumin/creatinine ratio, urine Cystatin C, and neutrophil gelatinase-associated lipocalin (NGAL), blood and urine transforming growth factor-β (TGF-β) and EGF. For study conduct in 
China, see Section 10.5.2.2. In addition Urine protein/creatinine ratio will be performed every 4 weeks, either using spot urine or 24h-h urine collection (at W48, W60, W72, W84, W96, and ET). In case of 
worsening of UPCR, the Investigator could repeat the UPCR before the next scheduled test.  
s May include but are not necessarily limited to the following: additional blood microRNAs, kidney injury molecule-1 (KIM-1), β-2 microglobulin, and urine connective tissue growth factor (CTGF); and 
urine calbindin-D28k. For study conduct in China, see Section 10.5.2.2. 
t 
Study drug administration and ISR assessment and reporting will be performed after each injection. 
u Subjects will be monitored for at least 2 hours after injection at Week 48 to ensure subject safety. In the subsequent injections: 
• 
In case of home injection the healthcare professional will continue to monitor the subject’s injection site for 15 minutes. The study staff will contact the subjects 1 day post injection to check on any occurrence 
of ISR and associated symptoms, 
• 
When lademirsen (SAR339375) is self-administered, study drug administration should be done after blood sampling. The Investigator or delegate will call the subject on the planned day of injection and will 
collect and review safety assessments (AEs, concomitant medication). The study staff will contact the subjects 1 day post injection to check on any occurrence of ISR and associated symptoms.  
v 12-lead electrocardiogram (ECG) will be performed before IMP administration during the study treatment period.  
w Full hematology panel performed weekly during treatment period and at each visit timepoint during follow up period: hemoglobin, hematocrit, red blood cell (RBC) count, white blood cell (WBC) count with 
differential, and platelet count.  
x Pre-dose plasma PK samples will be collected (up to 4 hours before dose administration). No PK samples will be withdrawn on W60, W72, W84 and W96 if injection is not administered and visit not performed. In 
case visit is performed (without injection administered), only pre-dose PK sample will be withdrawn.  
y Please refer to Section 6.2.9. 
z Markers of inflammation: quantitative immunoglobulin (γ-globulin, IgG, IgM). 
aa At unscheduled visits, only blood samples that are needed for abnormal laboratory value follow up will be collected. ECGs will only be performed in case an abnormality potentially has an impact on the continuity 
of the study drug administration, as deemed by the Investigator. 
bb The USVs may be done at alternative location visit (as described in footnote h), except when abnormal safety parameters are linked to physical examination. 
cc The study staff will contact the subjects 1 day post injection to check on any occurrence of ISR and associated symptoms, and will schedule the next injection with the subject. 
 
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TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 12 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
PROTOCOL SYNOPSIS ................................................................................................................................. 5 
TABLE OF CONTENTS ................................................................................................................................ 27 
LIST OF TABLES ......................................................................................................................................... 33 
LIST OF FIGURES ........................................................................................................................................ 33 
1 
INTRODUCTION ............................................................................................................................ 34 
1.1 
BACKGROUND ............................................................................................................................. 34 
1.1.1 
Alport syndrome ............................................................................................................................. 34 
1.1.2 
Lademirsen (SAR339375) ............................................................................................................. 35 
1.1.3 
Nonclinical experience ................................................................................................................... 35 
1.1.4 
Clinical experience to date ............................................................................................................. 37 
1.1.4.1 
Study RG012-02 ............................................................................................................................ 37 
1.1.4.2 
Study RG012-05 ............................................................................................................................ 38 
1.1.4.3 
Study PDY16327 ............................................................................................................................ 38 
1.2 
RATIONALE ................................................................................................................................... 39 
1.2.1 
Justification of target ...................................................................................................................... 39 
1.2.2 
Justification of study design ........................................................................................................... 39 
1.2.3 
Justification of route and dose regimen ......................................................................................... 40 
1.3 
RISKS AND BENEFITS ................................................................................................................. 41 
1.3.1 
Potential and identified risks .......................................................................................................... 41 
1.3.2 
Potential benefits ............................................................................................................................ 42 
2 
STUDY OBJECTIVES ................................................................................................................... 43 
2.1 
PRIMARY OBJECTIVES ............................................................................................................... 43 
2.2 
SECONDARY OBJECTIVES ......................................................................................................... 43 
2.3 
EXPLORATORY OBJECTIVES ..................................................................................................... 43 
3 
INVESTIGATIONAL PLAN ........................................................................................................... 44 
3.1 
OVERALL STUDY DESIGN .......................................................................................................... 44 
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3.2 
STUDY POPULATION ................................................................................................................... 46 
3.2.1 
Inclusion criteria ............................................................................................................................. 46 
3.2.2 
Exclusion criteria ............................................................................................................................ 49 
3.3 
SCREEN FAILURES...................................................................................................................... 50 
3.3.1 
Withdrawal, removal, and replacement of subjects ....................................................................... 51 
3.3.1.1 
Individual treatment stopping criteria ............................................................................................. 52 
3.3.1.2 
Follow-up for drug discontinuation/subject withdrawal from the study .......................................... 53 
3.4 
DISCONTINUATION OF THE STUDY .......................................................................................... 53 
4 
TREATMENT PROCEDURES ...................................................................................................... 55 
4.1 
INVESTIGATIONAL PRODUCTS .................................................................................................. 55 
4.1.1 
Identity of investigational products ................................................................................................. 55 
4.1.2 
Packaging and labeling, handling and accountability .................................................................... 55 
4.2 
TREATMENT ASSIGNMENT ........................................................................................................ 56 
4.3 
TREATMENT ADMINISTRATION ................................................................................................. 56 
4.4 
HOME INJECTION ........................................................................................................................ 56 
4.5 
DOSE REDUCTION....................................................................................................................... 58 
4.6 
RANDOMIZATION CODE BREAKING DURING THE STUDY ..................................................... 59 
4.7 
TREATMENT COMPLIANCE ........................................................................................................ 60 
4.8 
PRIOR AND CONCOMITANT MEDICATIONS ............................................................................. 60 
4.9 
DIETARY GUIDANCE.................................................................................................................... 60 
5 
STUDY PROCEDURES ................................................................................................................ 61 
5.1 
SCREENING .................................................................................................................................. 61 
5.2 
DOUBLE-BLIND, PLACEBO-CONTROLLED TREATMENT PERIOD ......................................... 62 
5.3 
OPEN-LABEL EXTENSION TREATMENT PERIOD ..................................................................... 65 
5.4 
EARLY TERMINATION ................................................................................................................. 68 
5.5 
FOLLOW-UP PERIOD ................................................................................................................... 68 
5.6 
UNSCHEDULED VISITS ............................................................................................................... 69 
5.7 
ALTERNATE LOCATION VISIT .................................................................................................... 71 
5.8 
END OF STUDY DEFINITION ....................................................................................................... 71 
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6 
BACKGROUND, SAFETY, EFFICACY, PHARMACODYNAMIC, AND 
PHARMACOKINETIC ASSESSMENTS ....................................................................................... 72 
6.1 
MEDICAL HISTORY AND FAMILY HISTORY .............................................................................. 72 
6.2 
SAFETY ASSESSMENTS ............................................................................................................. 72 
6.2.1 
Adverse events .............................................................................................................................. 72 
6.2.2 
Adverse event of special interest ................................................................................................... 73 
6.2.3 
Adverse events grading ................................................................................................................. 74 
6.2.4 
Adverse event outcome ................................................................................................................. 75 
6.2.5 
Serious adverse events ................................................................................................................. 76 
6.2.6 
Follow-up of AEs and SAEs ........................................................................................................... 77 
6.2.7 
Procedures in case of pregnancy .................................................................................................. 77 
6.2.8 
Regulatory reporting requirements for SAEs ................................................................................. 78 
6.2.9 
Guidelines for reporting product complaints (lademirsen [SAR339375]) ....................................... 78 
6.2.10 
Physical examination/body system assessments .......................................................................... 78 
6.2.11 
Vital signs and body weight ........................................................................................................... 79 
6.2.12 
Electrocardiogram assessment ...................................................................................................... 79 
6.2.13 
Hearing assessment ...................................................................................................................... 79 
6.2.14 
Laboratory assessments ................................................................................................................ 79 
6.2.15 
Monitoring of platelet count ............................................................................................................ 81 
6.2.16 
Injection site reactions ................................................................................................................... 81 
6.2.17 
Safety oversight ............................................................................................................................. 82 
6.3 
EFFICACY ASSESSMENTS ......................................................................................................... 83 
6.3.1 
Estimated GFR ............................................................................................................................... 83 
6.4 
PHARMACODYNAMIC ASSESSMENTS AND BIOMARKERS .................................................... 83 
6.5 
PHARMACOKINETIC ASSESSMENTS ........................................................................................ 83 
6.6 
DISPOSITION OF SAMPLES AFTER STUDY COMPLETION ..................................................... 84 
7 
STATISTICAL ANALYSIS ............................................................................................................ 85 
7.1 
ENDPOINTS .................................................................................................................................. 85 
7.1.1 
Efficacy endpoints .......................................................................................................................... 85 
7.1.2 
Safety endpoints ............................................................................................................................ 85 
7.1.3 
Pharmacodynamic endpoints ......................................................................................................... 85 
7.1.4 
Exploratory endpoints .................................................................................................................... 85 
7.1.5 
Pharmacokinetic endpoint .............................................................................................................. 86 
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7.2 
STATISTICAL METHODS AND ANALYSES ................................................................................ 86 
7.2.1 
Determination of sample size ......................................................................................................... 86 
7.2.2 
Analysis populations ...................................................................................................................... 86 
7.2.3 
Demographic and baseline characteristics .................................................................................... 87 
7.2.4 
Safety analysis ............................................................................................................................... 87 
7.2.5 
Efficacy analysis ............................................................................................................................. 88 
7.2.6 
Other analyses ............................................................................................................................... 89 
7.2.7 
Interim analysis .............................................................................................................................. 89 
8 
DATA MANAGEMENT .................................................................................................................. 90 
8.1 
DATA HANDLING .......................................................................................................................... 90 
8.2 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ................................................................ 90 
8.3 
PROTECTION OF PERSONAL DATA .......................................................................................... 90 
8.4 
CODING DICTIONARIES .............................................................................................................. 91 
8.5 
DATABASE MANAGEMENT AND QUALITY CONTROL ............................................................. 91 
9 
STUDY MANAGEMENT/PROCEDURES AND INSTRUCTIONS ................................................ 92 
9.1 
SAFETY-RELATED PROCEDURES ............................................................................................. 92 
9.1.1 
Rapid notification on serious adverse events ................................................................................ 92 
9.1.2 
Dosing deviations ........................................................................................................................... 92 
9.2 
REGULATORY ISSUES, ETHICS, AND GOOD CLINICAL PRACTICE ...................................... 93 
9.2.1 
Regulatory guidelines..................................................................................................................... 93 
9.2.2 
Ethical review ................................................................................................................................. 93 
9.2.3 
Informed consent ........................................................................................................................... 93 
9.2.4 
Regulatory and ethical considerations ........................................................................................... 94 
9.2.5 
Sponsor obligation ......................................................................................................................... 94 
9.2.6 
Principal Investigator ...................................................................................................................... 95 
9.2.7 
Guidelines for reporting product complaints (lademirsen [SAR339375]) ....................................... 96 
9.3 
ADMINISTRATIVE PROCEDURES .............................................................................................. 96 
9.3.1 
Protocol amendment and protocol deviations ................................................................................ 96 
9.3.2 
Monitoring procedures ................................................................................................................... 96 
9.3.3 
Study documentation, confidentiality, and records retention ......................................................... 97 
9.3.4 
Data quality control and quality assurance .................................................................................... 97 
9.3.4.1 
Data handling ................................................................................................................................. 97 
9.3.5 
Audits and inspections ................................................................................................................... 98 
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9.3.6 
Financing and insurance ................................................................................................................ 98 
9.3.7 
Publication policy ........................................................................................................................... 98 
9.3.8 
Dissemination of clinical study data ............................................................................................... 98 
9.3.9 
Data protection ............................................................................................................................... 99 
9.3.10 
Data quality assurance .................................................................................................................. 99 
9.3.11 
Source documents ....................................................................................................................... 100 
9.3.12 
Study and site closure .................................................................................................................. 100 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ...................... 102 
10.1 
APPENDIX 1: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING .............................................. 102 
10.2 
APPENDIX 2: CLINICAL LABORATORY .................................................................................... 106 
10.3 
APPENDIX 3: SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP ASSESSMENTS ........... 108 
10.3.1 
Neutropenia .................................................................................................................................. 108 
10.3.2 
Abnormal liver function ................................................................................................................ 109 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION ............................................................................................................................ 110 
10.5 
APPENDIX 5: COUNTRY-SPECIFIC REQUIREMENTS ............................................................ 112 
10.5.1 
Germany ...................................................................................................................................... 112 
10.5.1.1 Additional details regarding potential risks associated with study participation........................... 112 
10.5.2 
China ............................................................................................................................................ 114 
10.5.2.1 Study objectives and endpoints ................................................................................................... 114 
10.5.2.2 Pharmacodynamic assessments and biomarkers ....................................................................... 114 
10.5.2.3 Sample storage and disposition of samples after study completion ............................................ 115 
10.5.3 
France .......................................................................................................................................... 115 
10.6 
APPENDIX 6: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY ................................. 115 
10.6.1 
Informed consent ......................................................................................................................... 116 
10.6.2 
Study procedures ......................................................................................................................... 116 
10.6.3 
Temporary discontinuation ........................................................................................................... 117 
10.6.4 
Statistical analysis ........................................................................................................................ 117 
10.7 
APPENDIX 7: ABBREVIATIONS ................................................................................................. 118 
10.8 
APPENDIX 8: PROTOCOL AMENDMENT HISTORY ................................................................ 120 
10.8.1 
Amended protocol 11 (10 August 2021) ...................................................................................... 120 
10.8.2 
Amended protocol 10 (22 January 2021) .................................................................................... 125 
10.8.3 
Amended protocol 09 (11 September 2020) ................................................................................ 129 
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10.8.4 
Amended protocol 08 (18 March 2020) ....................................................................................... 135 
10.8.5 
Amended protocol 07 (20 February 2020) ................................................................................... 137 
10.8.6 
Amended protocol 06 (15 January 2020) .................................................................................... 138 
10.8.7 
Amended protocol 05 (07 November 2019) ................................................................................. 139 
10.8.8 
Amended protocol 04 (01 August 2019) ...................................................................................... 139 
10.8.9 
Amended protocol 03 (23 April 2019) .......................................................................................... 146 
10.8.10 Clinical study protocol Version 3.0 (16 August 2017) .................................................................. 160 
10.8.11 Clinical study protocol Version 2.0 (29 June 2017) ..................................................................... 162 
11 
REFERENCES ............................................................................................................................. 168 
 
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LIST OF TABLES  
Table 1 - Schedule of events for screening and double-blind, placebo-controlled treatment period and 
follow-up period ............................................................................................................................................. 18 
Table 2 - Schedule of events for open-label treatment extension period and follow-up period .................... 23 
Table 3 - Grading system for the definition of AESIs .................................................................................... 74 
Table 4 - Classification of adverse events by severity .................................................................................. 75 
Table 5 - Adverse event outcome ................................................................................................................. 75 
Table 6 - Injection site grading (local reaction) ............................................................................................. 82 
Table 7 - Protocol required safety laboratory assessments ........................................................................ 107 
Table 8 - Summary of key changes to Protocol RG012-03, Version 3.0 .................................................... 160 
Table 9 - Summary of key changes to Protocol RG012-03, Version 2.0 .................................................... 162 
 
LIST OF FIGURES  
Figure 1 - Renal function criteria ................................................................................................................... 47 
 
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1 
INTRODUCTION  
1.1 
BACKGROUND  
1.1.1 Alport syndrome  
Alport syndrome is an inherited form of kidney disease characterized by progressive 
glomerulonephritis, leading to glomerulosclerosis, tubulo-interstitial disease, and organ failure 
(1, 2, 3). Alport syndrome is caused by mutations in genes coding for the capillary basement 
membrane protein collagen IV. The prevalence of mutations in the collagen IV family of genes is 
estimated to be 1 in 5000 individuals (4). Multiple mutations have been identified in each of 
3 distinct collagen IV alpha genes (COL4A3, COL4A4, and COL4A5) that encode different 
collagen IV alpha chains (the α3(IV), α4(IV), and α5(IV) chains, respectively). Each chain is a 
key component of the collagen IV α3/α4/α5 network critical for maintaining the structure and 
integrity of the glomerular basement membrane. Mutations in these genes result in enhanced 
glomerular permeability that is also strongly linked to the development of interstitial fibrosis. The 
majority of subjects diagnosed with Alport syndrome have mutations in COL4A5, a gene located 
on the X-chromosome, and Alport syndrome has also been known as X-linked Alport syndrome 
(XLAS) or X-linked nephritis. COL4A3 and COL4A4 are located on chromosome 2, and 
mutations in either of those genes can lead to autosomal recessive Alport syndrome (ARAS) or, 
rarely, autosomal dominant Alport syndrome (ADAS) (5, 6). The clinical data describing XLAS 
and ARAS in the literature are summarized in the lademirsen (SAR339375) Investigator’s 
Brochure. 
Although the type of mutation may affect the rate of disease progression, all subjects with Alport 
syndrome eventually develop end-stage renal disease ESRD requiring dialysis or renal 
transplantation, and subjects with Alport syndrome are thought to account for approximately 
2.5% of all renal transplants in the US. Although renal transplantation has been shown to increase 
the survival of subjects with Alport syndrome (7), it is associated with significant morbidity, even 
if successful in preventing death. In the US, there are no approved agents to delay time to ESRD 
for subjects with Alport syndrome. Numerous agents have been investigated for their ability to 
reduce proteinuria and improve other symptoms associated with Alport syndrome. These agents 
include cyclosporine (8, 9), angiotensin-converting enzyme (ACE) inhibitors (10), angiotensin II 
Type I receptor blockers (ARBs) (11, 12), and mineralocorticoid receptor antagonists (13, 14). 
Only ACE inhibitors have been shown to extend the time to dialysis in treated subjects over that 
of family relatives with Alport syndrome who were not receiving ACE inhibitors (10). Thus, an 
urgent need remains for the development of new therapeutics that can reduce the degree of 
fibrosis and renal inflammation, improve renal function, and delay dialysis for subjects with 
Alport syndrome. 
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1.1.2 Lademirsen (SAR339375)  
Lademirsen (INN, USAN), also referred to as SAR339375, RG-012 or RG456070, is an 
octadecasodium salt of a 19-base, single-stranded, chemically modified oligonucleotide. 
Lademirsen (SAR339375) is formulated as an aqueous solution in 0.3% sodium chloride and will 
be administered by the subcutaneous (SC) route.  
The mechanism of action through which lademirsen (SAR339375) is expected to treat renal 
dysfunction in subjects with Alport syndrome is pharmacological inhibition of microRNA-21 
(miR-21). miR-21 is a ubiquitously expressed and highly conserved microRNA in vertebrates. 
Mice deficient in miR-21 develop normally and have no overt abnormality. However, in response 
to stress, miR-21 is upregulated, and this upregulation contributes to fibrosis and disease 
progression, as demonstrated using both genetic deletion and pharmacologic inhibition of miR-21 
in multiple rodent disease models. For example, in response to kidney injury in wild-type mice, 
miR-21 is activated and represses multiple target mRNAs, including peroxisome 
proliferator-activated receptor alpha (PPARα), which exaggerates tissue damage by causing 
fibrosis (15). In contrast, mice deficient in miR-21 or wild-type mice treated with miR-21 anti-
miRs do not show repression of PPARα and suffer less interstitial fibrosis and loss of renal 
function in response to kidney injury (15). The current hypothesis is that lademirsen 
(SAR339375) modulates multiple mRNAs involved in maintaining mitochondrial function, such 
as PPARα, Fads6, and Mpv17l. 
miR-21 is upregulated in a wide variety of human disease states, including fibrosis of multiple 
organs (15, 16, 17, 18, 19). Notably, miR-21 is upregulated in human kidneys in various chronic 
kidney disease states, especially those characterized by accumulation of renal fibrosis. The results 
in rodent models suggest that inhibition of miR-21 is a viable therapeutic approach for treating 
conditions involving renal fibrosis, including Alport syndrome. 
1.1.3 Nonclinical experience  
The efficacy of lademirsen (SAR339375) has been evaluated in a number of different in vivo 
models using a variety of endpoints, including improvement in survival, renal function, pathology, 
and modulation of relevant biomarkers that reflect phenotypic improvement. Lademirsen 
(SAR339375) produced improvement in multiple endpoints in mouse models with renal damage 
and fibrosis:  
• In the unilateral ureteral obstruction (UUO) model, lademirsen (SAR339375) increased 
miR-21 target mRNAs such as PPARα and decreased renal fibrosis measured via COL1A1 
and COL3A1 gene expression.  
• In the IR/Nx model, lademirsen (SAR339375) reduced albumin-to-creatinine ratio (ACR) 
and prolonged survival after removal of the healthy kidney.  
In the COL4A3 mutant model, which produces a phenotype that parallels human Alport 
syndrome, lademirsen (SAR339375) improved the disruption in glomerular basement membrane 
that leads to loss of tubular epithelial cell viability, reduced development of both interstitial and 
glomerular fibrosis/sclerosis, reduced loss of podocytes, decreased infiltration of inflammatory 
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cells, improved renal function, and increased survival by up to 44%. Lademirsen (SAR339375) 
was efficacious in increasing survival at dose levels of 12.5 to 50 mg/kg once weekly and 
25 mg/kg every 2 weeks (Q2W). Moreover, lademirsen (SAR339375) in combination with the 
ACE inhibitor ramipril, a common treatment in Alport syndrome subjects, produced better 
efficacy than either treatment alone. The toxicity of lademirsen (SAR339375) has been evaluated 
in mice and monkeys, and the pharmacokinetic (PK) and toxicokinetic (TK) properties of 
lademirsen (SAR339375), including its absorption, distribution, metabolism, and elimination 
characteristics, have been investigated in mice, rabbits, and cynomolgus monkeys. To enable the 
planned Phase 2 clinical study, Genzyme Corporation has completed Good Laboratory Practice 
(GLP)–compliant chronic toxicity studies of 26 weeks in mice and 39 weeks in monkeys, as well 
as definitive embryofetal development studies (in mice and rabbits), a fertility and early-
embryonic-development-to-implantation study (in mice), and the full battery of genotoxicity tests. 
The chronic toxicity study in mice tested SC doses of 0, 50, 100, and 300 mg/kg/week for 
26 weeks. Lademirsen (SAR339375) administered to male and female mice at 100 and 
300 mg/kg/week resulted in mortality. Fourteen of 118 animals at 300 mg/kg/week were found 
dead or euthanized between Weeks 22 and 27. At 100 mg/kg/week, 6 of 118 animals died or were 
sacrificed early; the majority of deaths occurred after ≥23 weeks of dosing. Although the deaths of 
several of these animals may be attributed to other causes, a relationship between the remaining 
deaths and lademirsen (SAR339375) cannot be excluded. Dose levels of ≥100 mg/kg/week were 
also associated with body weight decreases, decreases in red blood cell (RBC) mass and serum 
chemistry parameters including albumin, total protein, total cholesterol, and triglycerides. Other 
findings included increases in alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
and alkaline phosphatase (ALP). Microscopic findings were observed in the kidney, liver, spleen, 
thymus, adrenals, mesenteric lymph nodes, and testes, often with correlating gross observations 
and/or organ weight changes. At 50 mg/kg/week, no mortality occurred, and lademirsen 
(SAR339375)-related effects were limited to minimal changes in body weight (males only), 
decreases in platelet counts, and minimal changes in target organs. Although recovery was not 
assessed at 50 mg/kg/week, full or partial reversibility of the majority of these findings was 
evident at 100 mg/kg/week. 
The chronic toxicity study in monkeys tested SC doses of 0, 3, 10, 30, and 100 mg/kg/week for 
39 weeks. Lademirsen (SAR339375) administered at 30 mg/kg/week and 100 mg/kg/week was 
associated with mortality (death or early euthanasia) in 2 of 16 animals and 6 of 16 animals, 
respectively. These unscheduled deaths were typically preceded by body weight loss and/or serum 
albumin concentrations below 2.0 g/dL. Test article-related findings at 30 and/or 100 mg/kg/week 
included hunched posture, thin appearance, ataxia, shaking, eyelid closure, and in appetence in 
100 mg/kg animals and a few 30 mg/kg females. Additionally, lademirsen (SAR339375)-related 
decreases in body weight and/or decreased body condition score were apparent in 30 and/or 
100 mg/kg males and females, and required veterinary intervention. These dose levels were also 
associated with decreases in indices of RBCs (mean corpuscular volume [MCV], mean 
corpuscular hemoglobin [MCH], and mean corpuscular hemoglobin concentration [MCHC]). In 
addition, lower platelet counts were observed during the dosing and/or recovery period in several 
animals at 30 or 100 mg/kg/week, including 1 animal with a platelet count as low as 15 x 109/L. 
At these dose levels, mean activated partial thromboplastin time (aPTT) also showed 
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dose-dependent and sometimes statistically significant increases at 4 hours post-dosing on some 
dosing days, with reversal by 48 hours. Changes in the serum chemistry data included consistently 
and often statistically significantly lower mean albumin and albumin/globulin ratios throughout 
the dosing phase and into the recovery period, primarily in animals dosed at 30 or 100 mg/kg/week 
and to a lesser extent in animals dosed at 10 mg/kg/week. Other noteworthy findings include 
elevated urea nitrogen, creatinine, inorganic phosphorus, and potassium and lower sodium and 
chloride values in a few animals dosed at 100 mg/kg/week. Microscopic findings were observed 
in the liver, kidney, spleen, thymus, adrenal gland, brain (choroid plexus), bone marrow, and 
lymph nodes, often with correlating gross observations and/or organ weight changes. Although 
the majority of these findings were partially to fully reversed upon cessation of dosing, renal 
findings persisted and included fibroplasia. 
The no-observed-adverse-effect levels (NOAELs) in the chronic mouse and monkey studies were 
50 mg/kg/week and 3 mg/kg/week, respectively. These and other previously conducted 
Investigational New Drug (IND)-enabling toxicology studies have shown that lademirsen 
(SAR339375) produces toxicities generally consistent with those reported for this class of 
oligonucleotides (20, 21, 22, 23, 24, 25, 26).  
The development of anti-drug antibodies (ADA) was seen with chronic dosing of lademirsen 
(SAR339375) in monkeys and appears generally consistent with class effects of oligonucleotides 
(27). ADA will be monitored in this clinical study. 
Overall, the findings of the nonclinical program indicate that the species and dose regimens 
evaluated are appropriate to support the planned dosing of up to 110 mg lademirsen (SAR339375) 
QW for up to 96 weeks in humans. For additional information on the nonclinical program, 
including calculation of safety margins, refer to the Investigator’s Brochure. 
1.1.4 Clinical experience to date  
For additional information on lademirsen (SAR339375) clinical experience, refer to the 
Investigator’s Brochure. 
1.1.4.1 Study RG012-02  
Safety, tolerability, and PK were evaluated in a Phase 1 study in which single ascending SC doses 
of lademirsen (0.5, 1.0, 2.0, 4.0, and 8.0 mg/kg) were administered to healthy adult subjects 
(males and females between 18 and 55 years of age). Pharmacokinetics of the parent compound 
(lademirsen [SAR339375]), its active metabolite (RG0005), and the sum of lademirsen 
(SAR339375) and RG0005 (SUM) were evaluated. 
Lademirsen (SAR339375) was well tolerated, with an adverse event (AE) profile consistent with 
that anticipated for a second-generation oligonucleotide. All 40 subjects who enrolled successfully 
completed the study. There were no serious AEs or deaths, and all AEs were considered mild or 
moderate in severity.  
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The most commonly reported AEs in the overall study population were injection site events, with 
183 events reported by 29 subjects (73%). Injection site AEs included erythema (63%), pain 
(63%), induration (28%), swelling (20%), hemorrhage (10%), and pruritus (10%). All injection 
site events resolved spontaneously or with minor intervention (eg, application of ice packs). 
Other AEs that were reported in ≥5% of subjects and more frequently reported in lademirsen 
(SAR339375)-treated subjects than placebo-treated subjects were abdominal pain (3 subjects 
[8%]), abdominal pain lower (2 [5%]), and back pain (2 [5%]). 
There were no clinically important trends observed related to clinical laboratory, vital sign, 
electrocardiogram (ECG), or physical examination assessments. 
PK results showed dose-dependent increases in plasma Cmax (maximum concentration) and AUC 
(area under the concentration-time curve) consistent with the findings from nonclinical studies.  
1.1.4.2 Study RG012-05  
A Phase 1 study evaluated the safety, tolerability, and PK of multiple SC doses of lademirsen 
(SAR339375) in healthy adult subjects (males and females between 18 and 55 years of age). In 
the double-blind, multiple ascending dose study, 8 subjects in each of 3 sequential dose cohorts 
were randomized in a 3:1 ratio to receive 5 once-weekly fixed doses of either lademirsen 
(SAR339375) or matching placebo, with lademirsen (SAR339375) dose escalation from 55 mg 
(Cohort 1) to 110 mg (Cohort 2) to 220 mg (Cohort 3) dependent on review of the safety and PK 
data in each cohort by a Safety Evaluation Committee (SEC). The SEC had approved escalation to 
the weekly 110 mg fixed dose (corresponding to approximately 1.5 mg/kg in a 73 kg subject) and 
to the weekly 220 mg fixed dose (corresponding to approximately 3.0 mg/kg in a 73 kg subject). 
A single AE of asymptomatic thrombocytopenia with a platelet count nadir of 92 000/microL that 
resolved spontaneously over 10 weeks was observed in the 220 mg cohort. The remaining 
5 subjects in the 220 mg cohort also experienced a mild reduction in platelet count; however, 
these did not drop below the lower limit of normal (LLN) and resolved following discontinuation 
of study drug. 
1.1.4.3 Study PDY16327  
PDY16327 was a Phase 1, open-label study to evaluate the safety, pharmacodynamics, and 
pharmacokinetics of subcutaneous lademirsen (SAR339375) for injection in subjects with Alport 
syndrome. The primary objective was to assess the safety and tolerability of lademirsen 
(SAR339375) in patients with Alport syndrome, and to assess the effect of lademirsen 
(SAR339375) on endogenous renal miR-21. 
A total of 4 patients entered Part A of the study, in which 2 patients were allocated to each cohort: 
• Part A Cohort 1, in which patients received 4 doses of lademirsen ([SAR339375] 
1.5 mg/kg Q2W) and were assessed over 8 weeks. 
• Part A Cohort 2, in which patients received a single 1.5 mg/kg dose of lademirsen 
(SAR339375) and were assessed over 4 weeks. 
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All 4 patients finished Part A and proceeded to Part B, in which all received lademirsen 
(SAR339375) 1.5 mg/kg Q2W for up to 48 weeks. All patients completed the study as planned. 
Of the 4 subjects included in PDY16327, 3 were female; all of patients were white, with a mean 
age of 45.3 years and a mean weight of 71.2 kg.  
Lademirsen (SAR339375) was generally well tolerated with the exception of ISRs, which 
occurred in all 4 patients who participated. All AEs were of mild/moderate severity. There were 
no deaths, SAEs, or subject discontinuations due to AEs reported. All TEAEs in Part A resolved. 
In Part B, erythema at the injection site and injection site discoloration were considered not 
resolved for one patient; all other TEAEs related or possibly related to lademirsen (SAR339375) 
had resolved. AESIs of elevated liver enzymes were reported by 3 patients, but these events were 
not considered to be clinically significant and resolved by the end of the study. Two of the 
4 patients developed positive ADA titers; neither patient experienced any AEs suggestive of 
systemic hypersensitivity reactions. Platelet counts were within the normal range for all patients 
during the study.  
Available pharmacodynamics data for miR-21 and other biomarkers were limited and variable, 
and the number of patients was low, precluding any definitive conclusions. 
1.2 
RATIONALE  
1.2.1 Justification of target  
Dysregulation of miR-21 has been demonstrated to contribute to disease progression in multiple 
animal disease models of renal damage and fibrosis, including models of Alport syndrome. 
Optimal lademirsen (SAR339375) concentrations and dose administration schedules have been 
explored extensively in nonclinical rodent models of Alport syndrome. The nonclinical studies 
have demonstrated that lademirsen (SAR339375) effectively neutralizes miR-21 and decreases 
renal fibrosis. Thus, miR-21 is considered an excellent therapeutic target, and inhibition of 
miR-21 using lademirsen (SAR339375) may be effective for treating the renal fibrosis associated 
with Alport syndrome. 
1.2.2 Justification of study design  
In the double-blind, placebo-controlled treatment period of this study, subjects will be randomized 
in a 2:1 ratio to receive either lademirsen (SAR339375) 110 mg or placebo QW for 48 weeks. The 
purpose of the double-blind, placebo-controlled treatment period is to test the hypothesis that 
lademirsen (SAR339375) reduces the decline in renal function in subjects with Alport syndrome. 
A double-blind, placebo-controlled study design is the most rigorous way to test this hypothesis. 
Upon completion of the double-blind, placebo-controlled treatment period, subjects will be rolled 
into the open-label treatment period of this study, in which subjects will receive up to 48 weeks of 
lademirsen (SAR339375) QW treatment. The rationale for the length of both the double-blind, 
placebo-controlled period and the open-label extension is that, because Alport syndrome is a 
chronic, progressive disease, it is anticipated that long-term treatment with lademirsen 
(SAR339375) will be necessary for subjects to derive efficacy benefits. 
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1.2.3 Justification of route and dose regimen  
Lademirsen (SAR339375) is administered by SC injection because oligonucleotide therapeutics 
are not orally bioavailable. 
The dose regimen in the initial protocol (RG012-03) was 1.5 mg/kg, Q2W. The dose regimen 
proposed in this protocol amendment (ACT16248) is a fixed 110 mg once weekly (Q1W) dose. 
The reason for this change in dose regimen is based on the observed SUM 
(SAR339375 + RG0005) kidney concentrations in patients (Study PDY16327) with a 1.5 mg 
Q2W dose regimen being lower than the target SUM kidney concentrations at which efficacy had 
been seen in the Col4a3 mutant mouse model for Alport Syndrome. The human kidney 
concentration data were not available at the time of RG012-03 protocol preparation and, thus, 
predicted concentrations based on monkey data were used for dose regimen selection at that time. 
A dose regimen of 110 mg lademirsen (SAR339375) Q1W is supported by the following: 
• Safety and tolerability data from the single ascending dose study (RG012-02) in healthy 
volunteers (single doses of 0.5 to 8 mg/kg, equivalent to 35 to 560 mg/70 kg), and from 
the multiple ascending dose study (RG012-05) in healthy volunteers (5 x Q1W doses of 
55 110 and 220 mg, equivalent to approximately 0.8, 1.6, and 3.1 mg/kg). 
• Safety margins (animal/human exposure ratios) of 3.9 to 5.2-fold between plasma AUC at 
the NOAEL doses in the nonclinical chronic toxicity studies (50 mg/kg/week in mice and 
3 mg/kg/week in monkeys) and the plasma AUC observed in healthy volunteers after 
5 doses of 110 mg Q1W (Study RG012-05). 
• Observed kidney concentrations in patients (Study PDY16327) relative to the target 
kidney concentrations observed in Col4a3 mouse model at effective doses, and observed 
kidney concentrations in monkeys, the species used to extrapolate human kidney 
concentrations based on the assumption that mg/kg dose scaling applies between monkeys 
and humans (28). 
Summaries of the nonclinical and clinical data which support the 110 mg Q1W dose regimen are 
presented below:  
Nonclinical kidney SUM concentration data: 
• In pharmacology studies in Col4a3 mutant mice, good pharmacological activity (reduction 
in the increase in BUN and extended survival in Col4a3 mouse models of Alport 
syndrome) was observed at the 25 to 50 mg/kg dose levels; these doses correspond to 
estimated kidney SUM concentrations of approximately 87 to 141 μg/g. 
• Improved multiple endpoints in Col4a3 mice such as renal function (measured by BUN) as 
well as kidney fibrosis (measured by Col1a1 gene expression) were generally associated 
with 15-50 μg/g concentrations of SUM in kidney, whereas increased survival was 
generally associated with estimated kidney concentrations of 50-140 μg/g of SUM.  
• Mean SUM kidney concentration in cynomolgus monkeys on Day 7 after the last (4th) 
1.5 mg/kg Q2W dose was 70.2 µg/g (range 55.0 to 103 µg/g).  
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Kidney SUM concentrations in Alport patients 
• Observed SUM concentrations in human kidney biopsies at 1.5 mg/kg (corresponding to 
approximately 110 mg fixed dose) administered Q2W were: 
- 
Subject 36-001, Day 9 after last (4th) dose = 47.8 µg/g (mean of 2 observations) 
- 
Subject 36-003, Day 8 after last (4th) dose = 17.8 µg/g (mean of 2 observations) 
Although the patient kidney concentration data are limited (n=2 patients with multiple dose data), 
the SUM concentrations observed in patients are lower than, or at the low end of, the target 
concentrations (~50-140 µg/g) predicted to demonstrate robust efficacy in terms of decrease in 
BUN and potential increase in survival rate. Since the kidney concentrations in the PDY16327 
study were measured at approximately one week after the last Q2W dose (instead of 2 weeks to 
correspond to Ctrough), trough concentrations following Q2W dosing are likely to be even lower 
than the Day 8 or 9 concentrations observed in the 2 subjects above. Thus, a dosing frequency of 
Q1W, instead of Q2W is proposed in order to increase kidney SUM concentrations and maximize 
the potential to see efficacy in this (ACT16248) study. A potential increase in kidney SUM 
concentrations of ~2-fold can be expected with Q1W dosing relative to Q2W regimen. 
Pre-clinical Toxicology:  
The NOAELs for chronic weekly SC administration of lademirsen (SAR339375) in mouse and 
monkey were 50 mg/kg and 3 mg/kg, respectively. The calculated exposure ratios for SAR339375 
(SUM), based on comparison of actual mean plasma exposures in mouse (50 mg/kg QW), 
monkey (3 mg/kg QW), and human (110 mg/kg QW) are approximately 5X and 4X for mouse 
and monkey respectively.  
In addition to the change in dosing frequency, a flat-fixed dose of 110 mg, instead of a mg/kg 
dose of 1.5 mg, is selected for this study based on reports of no readily apparent impact of total 
body weight changes on plasma clearance of oligonucleotides (8, 29) and given that this class of 
compounds is typically administered as a flat-fixed dose in humans (28). 
1.3 
RISKS AND BENEFITS  
1.3.1 Potential and identified risks  
Based on a comprehensive review of available data for the lademirsen clinical development 
program, thrombocytopenia and ISRs are considered as important identified risks; and 
nephrotoxicity based on non-clinical histologic findings in the glomerulus, hepatotoxicity, 
clinically meaningful immunogenicity, and embryo-fetal toxicity are considered as important 
potential risks. 
For additional information on lademirsen (SAR339375) risks and benefits, refer to the 
Investigator’s Brochure. 
For study conduct in Germany, please see Section 10.5.1.1 for further details. 
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1.3.2 Potential benefits  
Benefits of treatment with lademirsen (SAR339375) in subjects with Alport syndrome have not 
been studied. However, the efficacy of lademirsen (SAR339375), either as monotherapy or in 
combination with ramipril, the current standard of care for subjects with Alport syndrome, has 
been demonstrated in genetic mouse models of Alport syndrome, as outlined above and detailed 
in the Investigator’s Brochure. Given the monitorable risks, the margin of safety, and 
demonstrated efficacy in preclinical models, it is reasonable to examine the safety and efficacy of 
lademirsen (SAR339375) in subjects with Alport syndrome. It is unknown at this time whether 
subjects with Alport syndrome will derive clinical benefit from treatment with lademirsen 
(SAR339375). 
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2 
STUDY OBJECTIVES  
2.1 
PRIMARY OBJECTIVES  
• To assess the efficacy of lademirsen (SAR339375) in reducing the decline in renal 
function. 
• To assess the safety and tolerability of lademirsen (SAR339375) in subjects with Alport 
syndrome. 
2.2 
SECONDARY OBJECTIVES  
• To assess plasma pharmacokinetic (PK) parameters. Cmax will be assessed for the parent 
compound (lademirsen [SAR339375]), its active major metabolite (RG0005), and the sum 
of lademirsen (SAR339375) and RG0005 (SUM) following administration of lademirsen 
(SAR339375). Ctrough will be assessed in terms of SUM only. 
• To assess potential formation of anti-drug antibodies (ADAs) following administration of 
lademirsen (SAR339375). 
• To assess the pharmacodynamic effect of lademirsen (SAR339375) on miR-21 and on 
changes in renal injury and function biomarkers. 
2.3 
EXPLORATORY OBJECTIVES  
• To assess the effect of lademirsen (SAR339375) on urine and blood biomarkers in Alport 
Syndrome subjects. 
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3 
INVESTIGATIONAL PLAN  
3.1 
OVERALL STUDY DESIGN  
This will be a randomized, double-blind, placebo-controlled, multi-center, Phase 2 study 
conducted in approximately 45 subjects with Alport syndrome at multiple investigative sites. At 
the completion of 48 weeks of double-blind, placebo-controlled treatment, all subjects will enter 
the 48-week open-label extension period in which all subjects will receive active treatment with 
lademirsen (SAR339375). 
Screening and Baseline Period 
Subjects may screen for enrollment after participation in the OBS16374 ATHENA Natural 
History Study or directly in this study. To qualify for this study, subjects must have confirmed 
Alport syndrome and meet all eligibility criteria described in Section 3.2. 
For subjects from the ATHENA study, genotype, demographics, prior/concomitant medications, 
medical history, and family history data from that study may be used to satisfy entry criteria in the 
current study.  
Double-Blind, Placebo-Controlled Treatment Period 
Eligible subjects will be randomized in a 2:1 ratio to receive QW SC doses of lademirsen 
(SAR339375) 110 mg or placebo for 48 weeks with stratification by screening eGFR 
(<60 mL/min/1.73 m2 versus ≥60 mL/min/1.73 m2). Once randomized, the subject should be 
treated within 3 calendar days maximum. 
The Schedule of Events for the double-blind, placebo-controlled treatment period is provided in 
Table 1, and a detailed list of procedures for each study visit is provided see Section 5.2. Certain 
visits outlined in the Schedule of Events (see Table 1) may be performed at home or at an 
alternate location by trained, qualified study personnel, to which the Investigator has delegated 
responsibility. See Section 5.7 for more details. 
Study drug injections will be administered by trained, qualified personnel on the Investigator site 
or, as deemed acceptable by the Investigator, at home or at an alternate location by a trained, 
qualified healthcare professional.  
Angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) 
should be maintained at a stable dose and regimen for the duration of the trial. All other 
concomitant medications should also be maintained at a stable dose and regimen during this 
period. Concomitant medications may be adjusted to maintain standard of care. Any changes to 
concomitant medications must be documented in the eCRF. 
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Open-Label Treatment Extension Period 
Subjects who complete the 48-week double-blind, placebo-controlled treatment period will be 
rolled over into a 48-week open-label treatment extension period in which all subjects will receive 
QW active treatment with lademirsen (SAR339375).  
The open-label treatment period allows all the subjects to benefit from exposure to lademirsen 
(SAR339375) after the randomized period of the treatment. In addition, this allows us to gain 
long-term safety and efficacy data in Alport subjects. 
The Schedule of Events for the open-label extension period is provided in Table 2, and a detailed 
list of study procedures is provided in Section 5.3. The Week 48 visit of the double-blind, 
placebo-controlled treatment period will serve as the baseline visit of the open-label extension for 
those placebo subjects who treated in the open-label extension. Procedures for study visits in the 
48-week open-label extension will be nearly identical to those for the 48-week double-blind, 
placebo-controlled treatment period. 
Study drug injections will be administered by trained, qualified personnel on the Investigator site 
or, as deemed acceptable by the Investigator, at home or an alternate location by a trained, 
qualified healthcare professional or on self-administration. 
Dose Reduction 
Before administering each dose of study drug, the Investigator or delegate will review a subject’s 
most recent safety data. A subject’s platelet count will be obtained weekly before dose 
administration. Platelet counts may be measured from a central laboratory and can exceptionally 
be measured at a local laboratory. The most recent subject’s platelet counts, but not older than 
10 days will be reviewed by the Investigator/physician before drug administration.  
Following the resolution of a Grade 2 AE or increase in aminotransferases (return to normal or 
≤ Grade 1 for AE) that does not otherwise trigger a stopping rule (see Section 3.4), the 
Investigator in consultation with the Sponsor Medical Manager may reduce an individual 
subject’s dose down to 110 mg Q2W. Dose reductions should be discussed with the Sponsor 
Medical Manager before implementation. Once a subject’s dose has been reduced, it will not be 
increased. 
Follow-up Period 
Any subject who discontinues early should complete the procedures for an early termination (ET) 
visit, enumerated in the Schedules of Events tables. 
Subjects who complete the open-label treatment extension period will enter the post-treatment 
follow-up period. During the follow-up period, visits will occur at Follow-up Weeks 2, 4, and 10. 
Follow-up weeks are numbered starting from the last scheduled study visit in the active treatment 
period (eg, Follow-up Week 2 will occur 2 weeks after Week 96 or after ET). The Schedule of 
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Events for the follow-up period is provided in both Table 1 and Table 2, and a detailed list of 
procedures for each visit in the follow-up period is provided in Section 5.5. 
3.2 
STUDY POPULATION  
Approximately 45 adult subjects will be enrolled. Subjects must meet all of the inclusion and none 
of the exclusion criteria to be eligible for study entry. 
3.2.1 Inclusion criteria  
I 01. Male or female.  
I 02. Confirmed diagnosis of Alport syndrome. 
1. Clinical diagnosis (hematuria, family history, hearing loss, ocular change), AND 
2. Genetic confirmation of Alport Syndrome in the subject or the family member, OR 
3. Kidney biopsy showing glomerular basement membrane abnormalities (eg, significant 
thinning, thickening, irregularity or lucencies) consistent with Alport Syndrome. 
I 03. Age 18-55 years old. 
I 04. eGFR >35 mL/min/1.73 m2 and <90 mL/min/1.73 m2 (based on CKD-EPI) at screening 
(for study conducted in France, see Section 10.5.3). 
I 05. Renal Function Criteria (subjects must meet at least one of the following CRITERIA 
A or B or C): 
A) Prior eGFR Slope Criteria is defined as a decline in eGFR of ≥4 mL/min/1.73 m2/year 
(eGFR slope ≤-4 mL/min/1.73 m2/year) based on a linear regression slope analysis of 
≥4 eGFR measurements within 3 years prior to the study and with a minimum of 2-year 
time span (the last, of the screening measurement, and first eGFR measurements should be 
separated by at least 2 years). eGFR should be calculated by using the Chronic Kidney 
Disease Epidemiology Collaboration (CKD-EPI) creatinine equation (see Figure 1; for 
study conducted in France, see Section 10.5.3).  
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Figure 1 - Renal function criteria  
 
B) Proteinuria: UPCR >2000 mg/g or UACR >1000 mg/g 
C) eGFR (based on CKD-EPI): male 18-23 years old with eGFR <90 mL/min/1.73 m2 (for 
study conducted in France, see Section 10.5.3). 
I 06. ACE inhibitor and/or ARB, the dosing regimen should be stable for at least 30 days prior 
to screening. 
I 07. Sexually active female subjects of childbearing potential and sexually mature male 
subjects must agree to practice true abstinence in line with their preferred and usual 
lifestyle or to use 2 acceptable effective methods of contraception for the entire duration of 
the study and for at least 10 weeks after last dose. 
Contraceptive use by men or women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. 
A) Male subjects 
Male subjects are eligible to participate if they agree to the following during the 
intervention period and for at least 10 weeks after the last dose of study intervention:  
• Refrain from donating sperm 
Plus either:  
• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent  
OR 
• Must agree to use contraception/barrier as detailed below 
- 
Agree to use a male condom and should also be advised of the benefit for a female 
partner to use a highly effective method of contraception as a condom may break 
or leak when having sexual intercourse with a woman of childbearing potential 
who is not currently pregnant. 
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B) Female subjects 
• A female subject is eligible to participate if she is not pregnant or breastfeeding, and at 
least one of the following conditions applies: 
- 
Is not a woman of childbearing potential (WOCBP)  
OR 
- 
Is a WOCBP and using a contraceptive method that is highly effective (with a 
failure rate of <1% per year), preferably with low user dependency, as described in 
Section 10.4 during the intervention period and for at least 10 weeks after the last 
dose of study intervention and agrees not to donate eggs (ova, oocytes) for the 
purpose of reproduction during the study and for a period of six weeks. The 
Investigator should evaluate the effectiveness of the contraceptive method in 
relationship to the first dose of study intervention. 
• A WOCBP must have a negative highly sensitive pregnancy test (urine as required by 
local regulations) within 24 hours before the first dose of study intervention. 
- 
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the subject must be excluded from 
participation if the serum pregnancy result is positive.  
• Additional requirements for pregnancy testing during and after study intervention are 
located in Section 10.4. 
- 
The Investigator is responsible for review of medical history, menstrual history, 
and recent sexual activity to decrease the risk for inclusion of a woman with an 
early undetected pregnancy. 
I 08. Negative drug screen for opiates, cocaine, heroin, phencyclidine, amphetamines (including 
ecstasy), barbiturates, benzodiazepines, and cannabinoids. At the Investigator’s discretion, 
subjects prescribed benzodiazepines, cannabinoids, or opiates with positive results on a 
drug screen may be allowed. 
I 09. Negative screening results for hepatitis B surface antigen (HBsAg), hepatitis C virus 
(HCV) antibody, and human immunodeficiency virus (HIV) antibody. 
• Hepatitis A virus (HAV) screening is not necessary, screenings required above is for 
identification of chronic diseases. 
I 10. Screening hematology, clinical chemistries, coagulation, and urinalysis are not clinically 
significant, as assessed by the Investigator, and meet the following criteria: 
A) Platelets, total white blood cell (WBC) count, and absolute neutrophil count within normal 
limits 
B) Hemoglobin (Hb) ≥11 g/Dl 
C) Total and direct bilirubin <1.5 x upper limit of normal (ULN), unless elevated bilirubin is 
associated with a known benign condition (eg, Gilbert’s syndrome) 
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D) Alanine aminotransferase (ALT) <1.5 x ULN 
E) Aspartate aminotransferase (AST) <1.5 x ULN 
F) Alkaline phosphatase (ALP) <1.5 x ULN 
G) Gamma-glutamyl transferase (GGT) <1.5 x ULN 
Note: At the discretion of the Investigator, screening laboratory testing may be repeated once to 
confirm out-of-range (exclusionary) results. 
I 11. Agree to report any new prescription medication, dose adjustment to existing medication, 
over-the-counter medication, or herbal supplement to the Investigator. 
I 12. Able to understand all study procedures in the informed consent form (ICF) and willing to 
comply with all aspects of the protocol. 
3.2.2 Exclusion criteria  
Subjects meeting any of the following criteria will be ineligible to participate in this study: 
E 01. Causes of chronic kidney disease aside from Alport syndrome (including but not limited to 
other heritable disorders leading to chronic kidney disease, diabetic nephropathy, 
hypertensive nephropathy, lupus nephritis, IgA nephropathy). 
E 02. ESRD as evidenced by ongoing dialysis therapy or history of renal transplantation. 
E 03. Any clinically significant illness within 30 days before screening or surgical or medical 
condition (other than Alport syndrome) that could interfere with the subject’s study 
compliance; confound the study results; impact subject safety; or significantly alter the 
distribution, metabolism, or excretion of drugs, including but not limited to the following: 
• Significant or unstable cardiac disease (unstable angina, myocardial infarction within the 
last 6 months, symptomatic coronary artery disease, congestive heart failure [New York 
Heart Association ≥ Grade 3], prolonged QT syndrome [torsade de pointes], significant 
arrhythmia, and/or any other clinically significant ECG abnormalities) 
• Uncontrolled seizure disorder (eg, seizure in the last 12 months) 
• Chronic infection (eg, tuberculosis) 
• Metabolic disease (eg, diabetes mellitus) 
• Evidence of urinary obstruction or difficulty in voiding at screening 
• History of hypocomplementemia (low complement levels or activity) 
• Maintenance medication known to cause QT prolongation 
E 04. Weight >110 kg. 
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E 05. Any history of active malignancy within the last 1 year (history of localized basal cell or 
squamous cell carcinoma and cervical carcinoma in situ that has been 
excised/appropriately treated or a fully excised malignant lesion with a low probability of 
recurrence will not be considered exclusionary). 
E 06. History or presence of alcoholism or drug abuse within 2 years before screening or other 
concurrent social conditions that would potentially interfere with the subject’s study 
compliance, at the discretion of the Investigator. 
E 07. Mental impairment or history of or current significant psychiatric disease that may impair 
ability to provide informed consent or impact compliance with study procedures. 
E 08. Participation in a recent investigational study and receipt of an investigational drug or 
investigational use of a licensed drug within 30 days or 5 half-lives, whichever is longer, 
prior to screening. 
E 09. Prior treatment with Bardoxolone within 90 days prior to screening. 
E 10. History or presence of hypersensitivity or idiosyncratic, allergic, or other clinically 
significant reaction to the study drug (including placebo), inactive ingredients, or related 
compounds (eg, other oligonucleotide products). 
E 11. Any other condition or circumstance that may make the subject unlikely to complete the 
study or comply with study procedures and requirements, or may pose a risk to the 
subject’s safety and well-being. 
E 12. Subjects dependent on the Sponsor or Investigator or employees of the clinical study site 
or any other individuals directly involved in the conduct of the study, or immediate family 
members of such individuals. 
E 13. Subjects that are accommodated in an institution because of regulatory or legal order. 
E 14. Prisoners or subjects who are legally institutionalized. 
3.3 
SCREEN FAILURES  
Screen failures are defined as subjects who consent to participate in the clinical study but are not 
subsequently entered in the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure subjects to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, 
and any SAE. 
For individuals who do not meet the criteria for participation in this study (screen failure) and for 
whom resolution of the screen failure reason may not be expected within a reasonable time frame, 
the screen failure will be performed. The subject may be rescreened; if their clinical condition 
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changes, subject numbers will not be reused and a new subject number will be assigned. All the 
screening procedures will be repeated and entered in the screening visit pages.  
In case the subject is a temporary screen failure, there is no need to have subject re-consent 
(eg, new ICF signed) if the subject finally participates in the trial. However, if the reason for 
temporary screen failure is a reason that might have altered the initial given agreement of the 
subject to participate, the Investigator should ensure the willingness of the subject to continue or 
redo some screening procedures and his/her participation to the trial. This oral agreement should 
be documented in the subject’s chart. All the tests out of protocol window should be repeated and 
entered to the additional pages. 
3.3.1 Withdrawal, removal, and replacement of subjects  
All subjects will be informed that they have the right to discontinue study drug or to withdraw 
from the study at any time, for any reason, without prejudice, and without having to justify their 
reasons or decisions. Additionally, the Investigator may discontinue a subject’s study drug at any 
time if he/she considers that to be in the subject’s best interest or if the Investigator determines 
that continuing study drug would result in a significant safety risk for the subject.  
A discontinuation of study drug occurs when an enrolled subject ceases study drug, regardless of 
the circumstances, prior to completion of the study. However, every effort should be made to 
observe subjects who have been dosed until the scheduled end of the follow-up period, even if 
they prematurely discontinue study drug.  
Withdrawal of consent for intervention should be distinguished from withdrawal of consent for 
follow-up visits and from withdrawal of consent for non-subject contact follow-up, eg, medical 
record checks. The site should document any case of withdrawal of consent. 
If subjects no longer wish to take the IMP, they will be encouraged to remain in the study. The 
Investigators should discuss with them key visits to attend. The value of all their study data 
collected during their continued involvement will be emphasized as important to the public health 
value of the study. Subjects who withdraw from the study intervention should be explicitly asked 
about the contribution of possible AEs to their decision, and any AE information elicited must be 
documented. All study withdrawals should be recorded by the Investigator in the appropriate 
screens of the eCRF and in the subject’s medical records. In the medical record, at least the date 
of the withdrawal and the reason should be documented. 
In case of premature discontinuation of study drug, the Investigator should schedule an early 
termination visit to record AE data and to collect samples for laboratory evaluations. This visit 
should be documented in the appropriate eCRF. The Investigator will record the reason for the 
study drug discontinuation, provide or arrange for appropriate follow-up for such subjects, and 
document the course of the subject’s condition. In addition, the Investigator will report the 
subject’s study drug discontinuation or study withdrawal to the Sponsor immediately.  
Valid reasons for a subject to discontinue the study drug or to withdraw from this clinical study 
include but are not limited to:  
• Withdrawal of informed consent 
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• Subject’s decision to discontinue study drug 
• Reaching the treatment stopping rules. Please see Section 3.3.1.1 below 
• Occurrence of AEs for which permanent discontinuation is considered necessary by the 
Investigator 
• Investigator’s decision (eg, if in the Investigator’s opinion it is not in the best medical 
interest of the subject to continue participation in the study) 
• Any protocol deviation that may result in a significant risk to the subject’s safety or 
protocol deviations that will interfere with the efficacy endpoints of this study 
• Lost to follow-up (the subject stopped coming for visits, and study personnel are unable to 
contact the subject) 
3.3.1.1 Individual treatment stopping criteria  
Any Grade 2 AE (except for renal function parameters related to the underlying disease process 
including eGFR, creatinine, BUN, and urinalysis) not resolved prior to the administering the next 
dose and deemed by the Investigator to be at least “possibly related” to study drug would result in 
a pausing of dosing (eg, dose not given) until the AE improves to ≤ Grade 1. Injection site 
reactions will be graded according to Table 6. Any Grade 2 (except erythema/redness) or Grade 3 
ISRs which had not resolved or reached Grade 1 (“Mild”, eg, limited tenderness, and/or 
induration, except erythema/redness) prior to the next dose, would result in a pausing of dosing. 
The continuation of dosing and dose level would be decided upon review between the Investigator 
and the Genzyme Corporation Study Medical Manager. For further details in dose reduction, see 
Section 4.5. 
Occurrence of any Grade 3 (Severe) or higher AE (except for ISRs and renal function parameters 
related to the underlying disease process including eGFR, creatinine, BUN, and urinalysis) will 
result in the cessation of dosing of the subject, unless it can be shown that the event was unrelated 
to participation in the clinical trial. The DMC will review the circumstances of the AE with the 
Sponsor and unblind the subject, as appropriate, to evaluate potential relatedness to study drug 
and will make a recommendation regarding the further dosing of the subject to the Sponsor. After 
deliberations, DMC will provide guidance to the Sponsor who will implement recommendations 
and communicate to the site. 
With regard to AEs, study drug should be discontinued for subjects who experience any of the 
following: 
• Grade 3 thrombocytopenia (platelet count from <50 000 to 25 000/microL) will trigger 
cessation of dosing for the subject. 
• ALT or AST >5 × ULN, or ALT or AST >3 × ULN in association with total bilirubin 
>2 × ULN. 
• An unintended weight loss of ≥20% from baseline. 
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• ≥50% decline for eGFR from the last measurement or confirmed ESRD (eGFR 
≤15 mL/min/1.73 m2 or dialysis or renal transplantation is needed). 
In case of worsening of eGFR (that do not reach stopping criteria) or UPCR, the Investigator or 
the Sponsor could repeat the test before the next scheduled one as often as medically needed. The 
Sponsor needs to be consulted before a decision to discontinue the patient, unless it is a case of 
emergency.  
3.3.1.2 Follow-up for drug discontinuation/subject withdrawal from the study  
If a subject discontinues or is discontinued from study drug, the Investigator should take the 
following actions: 
• Record discontinuation reason within the eCRF 
• Complete the early termination visit (see Section 5.3) 
If a subject is discontinued from study drug due to an AE, the Investigator will arrange follow-up 
with the subject as appropriate until the event has been resolved or stabilized. Every effort will be 
made to follow up with subjects who discontinue study drug because of serious AEs (SAEs) 
considered related to the study drug unless they withdraw informed consent. 
If a subject fails to attend scheduled assessments, the Investigator must document the reasons and 
the circumstances as completely and accurately as possible.  
For subjects who are lost to follow-up (eg, subjects whose status is unclear because they fail to 
appear for the study visits without stating an intention to withdraw), the Investigator should 
document in the source documents any steps taken to contact the subject (eg, dates of telephone 
calls, emails, registered letters). 
Subjects who withdraw informed consent will not have further information or data collected from 
them, with the exception of follow-up information about AEs ongoing at the time of withdrawal. 
3.4 
DISCONTINUATION OF THE STUDY  
The Sponsor may terminate the study at any time for any reason. In the event the study is 
terminated, the Institutional Review Board (IRB)/Ethics Committee (EC) and Competent 
Authority will be notified of the decision. 
Study Suspension and Stopping Criteria 
The occurrence of two similar Grade 3 (or higher) AEs (except for ISRs and renal function 
parameters related to the underlying disease process including eGFR, creatinine, BUN, and 
urinalysis), or any death or two unexpected SAEs considered at least possibly related to 
participation in the clinical trial, or any TEAE that in the opinion of the Sponsor is of potential 
clinical significance for subjects safety will result in the recommendation to suspend all dosing 
and stop recruitment, then will trigger an ad hoc meeting with the DMC who will be asked to 
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consider the appropriateness of study conduct continuation unchanged, early study termination or 
modification. 
Upon suspension of dosing, a full, unblinded review of the AEs will be performed by the DMC to 
evaluate the AEs and potential relationship to exposure to the study drug. Following the full, 
unblinded safety review, one of three outcomes is possible: 
1. The study may be terminated. 
2. The study design may be amended. For example, the dose of study drug may be reduced 
for all subjects (to 110 mg SC every other week (the pre-specified dose reduction for a 
Grade 2 AE), the dose regimen may be changed to reduce the dosing frequency, or 
inclusion/exclusion criteria may be modified (eg, baseline platelet count or other relevant 
laboratory or clinical parameter). 
3. Stopping criteria are at the discretion of the DMC, the study may continue as originally 
planned, based on clear evidence that the stopping criteria have not been met and measures 
are in place to ensure subject safety. 
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4 
TREATMENT PROCEDURES  
4.1 
INVESTIGATIONAL PRODUCTS  
The investigational products may be supplied at the site or from the Investigator/site to the 
participant via a Sponsor-approved courier company where allowed by local regulations and 
agreed upon by the participant. 
4.1.1 Identity of investigational products  
Lademirsen (SAR339375) for SC administration is supplied as 110 mg/mL solution in 5 mL glass 
vial. Each vial will contain a withdrawable volume of 2 mL.  
Placebo matching lademirsen (SAR339375) for SC administration is supplied as sodium chloride 
and riboflavin (colorant) solution in 5 mL glass vial. Each vial will contain a withdrawable 
volume of 2 mL.  
4.1.2 Packaging and labeling, handling and accountability  
Lademirsen (SAR339375) and placebo will be supplied in a single use glass vial packed in a kit 
box. Each kit box will be labeled as required per country requirements.  
All drug supplies will be provided by the Sponsor, and the logistics of supply will be managed by 
the Sponsor or an appropriate designee.  
Investigators or other authorized persons (eg, pharmacists) are responsible for receiving and 
storing the IMP in a secure and safe place in accordance with local regulations, labeling 
specifications, policies and procedures. 
The Investigator or designee, care giver for home injection, must confirm appropriate temperature 
conditions have been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention. 
Only subjects enrolled in the study may receive study intervention and only authorized site staff 
may supply or administer study intervention. All study intervention must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the Investigator and authorized site staff. Study 
intervention shipment and storage for subjects who will have home injections are provided in the 
Pharmacy Manual. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance. 
Under no circumstances will the Investigator supply IMP to a third party (except for direct to 
patient (DTP) shipment, for which a courier company has been approved by the Sponsor), allow 
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the IMP to be used other than as directed by this clinical trial protocol, or dispose of IMP in any 
other manner. 
A separate Pharmacy Manual will be provided detailing instructions for preparation, handling 
storage and accountability.  
4.2 
TREATMENT ASSIGNMENT  
Once all the screening data become available, the Investigator will perform the final evaluation of 
the subject’s eligibility. If a subject is not eligible, the reason will be recorded. Treatment 
assignment and randomization will be performed using a centralized treatment allocation 
system/IRT. The IRT (centralized treatment allocation system) generates the patient 
randomization list and allocates the treatment number and the corresponding treatment kits to the 
subjects accordingly.  
Before randomizing a patient, the Investigator or designee will have to contact the centralized 
treatment allocation system/IRT. 
For the double-blind, placebo-controlled treatment period, approximately 45 eligible subjects will 
be centrally randomized in a 2:1 ratio to lademirsen (SAR339375) 110 mg or placebo SC QW for 
48 weeks, with stratification by screening eGFR (<60 mL/min/1.73 m2 versus ≥60 mL/min/1.73 m2). 
For the open-label extension, all subjects will receive lademirsen (SAR339375) 110 mg SC QW 
for up to 48 weeks. Subjects who require dose reduction to 110 mg Q2W during the blinded 
period of the study will receive the same dose in the open-label period of the study. 
4.3 
TREATMENT ADMINISTRATION  
A subject’s platelet count will be obtained weekly before dose administration. Platelet counts may 
be measured from a central laboratory and can exceptionally be measured from a local laboratory. 
The most recent subject’s platelet counts, but not older than 10 days will be reviewed by the 
Investigator/physician before drug administration.  
Qualified and trained personnel will prepare the study drug on the day of administration and SC 
injection and administer all study drug injections. The study drug should be administered as a 
bolus in the anterior lower abdominal wall. The time of dosing and the region of the abdomen 
used should be recorded for doses administered. A separate document will provide additional 
details on the preparation and administration of study drug.  
4.4 
HOME INJECTION  
Home injection may be possible where permitted by national and local regulations.  
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Subjects must meet the eligibility requirements outlined below. Subject’s underlying 
comorbidities and ability to adhere to the requirements of the study need to be taken into account 
when evaluating subjects for eligibility to receive home injection. Any identified risk of 
noncompliance to monitoring of study requirements or potential for loss to follow up should lead 
to this subject not being eligible for home injection. 
Home injection might begin at Week 1 for subjects agreed by the Investigator and meet the 
required criteria. 
The following criteria must be documented in the subject’s medical record: 
• The Investigator must agree in writing that home injection is appropriate for the subject. 
• The subject must be willing and able to comply with home injection procedures. 
• The subject must have no ongoing (not yet recovered) SAEs that, in the opinion of the 
Investigator, may affect the subject’s ability to tolerate the injection. 
• Home injection infrastructure, resources, and procedures must be established and available 
according to applicable regional and local regulations. 
• Subject has not experienced a severe AE or SAE considered related to lademirsen 
(SAR339375). 
• Subject experiencing a severe AE or an SAE moderate or severe ISR while being injected 
at home will return to the study site for their following injection and will continue to 
receive injections at the study site until no such events are present for at least after 
2 injections. 
• In the event of manufacturing scale change, the subject will be required to receive the 
first injection at the site. All criteria for return to home injection will apply. 
The subject must agree to report to the site staff (by email or by phone) all events that occurred 
between 2 injections prior to the next planned injection. 
Prior to beginning home injections, training will be provided to the healthcare professional 
according to the protocol dosing requirements and pharmacy manual. Any new healthcare 
professional must be trained prior to resuming home injection. 
During the 48 weeks double – blind randomized period, for subjects who are eligible and agree 
for home injection, the drug injections will be performed by a trained healthcare professional. 
Prior to each home visit, the Investigator or delegate will review a subject’s most recent platelets 
count (not older than 10 days) then will contact the healthcare professional to confirm 
administration and the dose of the study drug.  
• Before each injection: the healthcare professional will collect and will review safety 
assessments (AEs, with specific assessments about petechiae, gingival bleeding, bruising, 
and any new concomitant medications) with the Investigator or delegate to confirm or to 
change the study drug dosing. The requested blood sampling and other assessments (per 
Table 1) will be done. 
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• After each injection: the healthcare professional will confirm administration of the study 
drug to the site staff and will monitor the subject’s injection site for 15 minutes. The site 
staff will contact the subjects the day following each injection to collect any safety events 
including ISR. 
During the last 6 months (from Week 24) of the double-blind period, the subject will be trained on 
self-administration and handling of the study drug in preparation for the open-label extension 
period. The patient will be observed in self-administration technique during the training period. 
During the open-label extension period, it is expected that the subjects will practice self-
administration unless the Investigator or delegate deems that the subject is unable to do so or self-
administration is not suitable by the subject. In the latter case, the drug injection will be done at 
home or at the site by qualified and trained personnel.  
For subject who will practice self-administration during the open-label extension period: 
• Before each injection: the requested blood sampling will be drawn by an assigned 
healthcare professional. The Investigator or delegate will contact the subject at the planned 
day of injection and will review and collect safety assessments (AEs, with answers to 
specific assessments about petechiae, gingival bleeding, bruising, and any new 
concomitant medications). The Investigator or delegate will confirm or change 
administration of the lademirsen (SAR339375) dose based on the most recent platelets 
count (not older than 10 days) and the reported AEs. The injection will only be done 
after obtaining confirmation from the Investigator and after blood sampling. 
• After each injection: the subject will complete the “home dosing diary”, including 
reporting of ISRs, and send a copy to the site via e-mail or fax. The original will be 
provided to the site during the next site visit. The site staff will contact the subject the day 
following the injection to monitor and collect safety events, including ISRs, and will 
schedule with the subject the next injection. Any ISRs will be assessed and graded by the 
Investigator or delegate. 
For subjects who do not wish to perform self-injection, the home injection procedure will be the 
same as for double-blind period. 
4.5 
DOSE REDUCTION  
Before administering each dose of study drug, the Investigator or delegate will review a subject’s 
most recent safety data. A subject’s platelet count will be obtained weekly before dose 
administration. Platelet counts will be measured from a central laboratory and can exceptionally 
be measured from a local laboratory. The most recent subject’s platelet counts, but not older than 
10 days, will be reviewed by the Investigator/physician before drug administration. Following the 
resolution of a Grade 2 AE or increase in aminotransferases (return to normal or ≤ Grade 1 for 
AE) that does not otherwise trigger a stopping rule (see Section 3.4), the Investigator in 
consultation with the Sponsor Medical Manager may reduce an individual subject’s dose to 
110 mg Q2W. Dose reductions should be discussed with the Sponsor Medical Manger before 
implementation.  
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Grade 2 thrombocytopenia (platelet count from <100 000 to 50 000/microL) will result in 
suspension of dosing pending a return of platelet count to > LLN and review by the Investigator 
and the Sponsor Medical Manager. If dosing is to resume, it will be reduced to 110 mg Q2W.  
For actions related to laboratory abnormalities that are indicative of potential hepatotoxicity, any 
subject experiencing a moderate (Grade 2) alkaline phosphatase, or bilirubin elevation will have a 
dose suspension and related laboratory test should be done weekly until the value(s) return to the 
normal range. For actions related to elevation of aminotransferases, please refer to Section 10.3.2. 
If dosing is to resume, it will be reduced to 110 mg Q2W.  
Injection site reactions will be graded according to Table 6. Any Grade 2 (except 
erythema/redness) or Grade 3 ISR must have resolved or reached Grade 1 (“Mild”, eg, limited 
tenderness, and/or induration, except erythema/redness) prior to the next dose or subsequent 
dosing will be suspended. Consideration of resumed dosing at dose 110 mg Q2W will be based on 
review of the AE and time course to resolution in consultation with the Sponsor Medical 
Manager.  
Once a subject’s dose has been reduced, it will not be increased. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Section 10.6.  
4.6 
RANDOMIZATION CODE BREAKING DURING THE STUDY  
In case of an AE, the code should only be broken in circumstances when knowledge of the IMP is 
required for treating the subject. If the Investigator decides that unblinding is warranted, he/she 
may, at his/her discretion, contact the Sponsor to discuss the situation prior to unblinding a 
subject’s treatment assignment unless this could delay emergency treatment for the subject. 
Code breaking can be performed at any time by using the proper module of the IRT and/or by 
calling any other phone number provided by the Sponsor for that purpose. The code-breaking can 
also be performed by contacting the “24-hour alert system”. A patient card, including the relevant 
“24-hour alert system” telephone number will be provided to every patient who will participate in 
the study. 
If a subject’s treatment assignment is unblinded, the Sponsor must be notified within 24 hours of 
this occurrence. The Investigator should document the date, time of day and reason for code 
breaking in the source documentation and case report form. 
Subject will only be withdrawn from IMP administration when the code break call is made at the 
site level. That means if the Emergency Unblinding transaction is performed by the Investigator 
(ie, at the site level), then the subject will be withdrawn from the treatment. Please refer to 
Section 3.3.1 of the protocol for details on handling of patient treatment discontinuation. 
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4.7 
TREATMENT COMPLIANCE  
Appointed team members will be identified at each center who will be responsible for the receipt, 
handling, and accountability of the study drug. Records of the study drug used, dosages 
administered, and intervals between visits will be kept during the study. Further details are 
provided in the Pharmacy Manual and relevant monitoring plan. 
4.8 
PRIOR AND CONCOMITANT MEDICATIONS  
Prior medications/therapy (eg, given within 30 days before signing the ICF) and ongoing 
medications/therapy will be recorded on the eCRF Prior/Concomitant Medications Page. If 
additional concomitant medication becomes necessary during the study treatment period, this 
must also be documented and appropriately listed on the eCRF Prior/Concomitant Medications 
Page. 
Subjects must agree to the following restrictions regarding concomitant medications during the 
study: 
• To inform the site of any new prescription medication or dose adjustment to existing 
medication. 
• To inform the site of any over-the-counter medication or herbal supplement. 
• Not to participate in any other investigational drug trial. 
Concomitant medications should be maintained at a stable dose and regimen during the study. 
Investigators should take particular care to avoid changing medications that affect blood pressure 
or renal function, including angiotensin-converting enzyme (ACE) inhibitors, angiotensin II 
receptor blockers (ARBs), statins, diuretics, and calcium channel blockers. Concomitant 
medications may be adjusted to maintain standard of care. Any change in concomitant 
medications after signing the ICF must be recorded in the eCRF, with the type of medication, 
dose, duration, and indication. 
Vaccination for coronavirus disease 2019 (COVID-19) will not have an impact on subject 
enrollment or study drug treatment. No wash-out period is required between vaccination and 
initiation of study drug. Nevertheless, it is preferred that the COVID-19 vaccination and the study 
drug injection are separated by at least 48 hours to allow an adequate evaluation of potential AEs. 
4.9 
DIETARY GUIDANCE  
Investigators should encourage subjects to maintain a consistent renal diet throughout the study, 
as significant changes may affect key outcome measures. In particular, subjects should be 
counseled to avoid atypically high protein meals in the days prior to visits that include serum 
chemistry and urinalysis assessments. 
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5 
STUDY PROCEDURES  
The timing of the procedures and assessments to be performed is outlined in Table 1 for screening 
and the double-blind, placebo-controlled treatment period and in Table 2 for the open-label 
treatment period and study follow-up. Additional details of the study procedures are given in 
Section 6. Rescreening of subjects is permitted with consultation of the Study Medical Manager. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Section 10.6.  
5.1 
SCREENING  
The following assessments, procedures, and data collection will be performed during screening 
prior to drug administration:  
• Obtain written informed consent before performing any study-related procedure 
• Demographics data collection (age, gender, ethnicity) 
- 
For study conducted in France, see Section 10.5.3. 
• Medical history 
• Family history relevant to Alport syndrome and renal disease 
• Type IV collagen alpha chain gene 1 (COL4A3/4/5) genotyping 
• Prior medications/therapy (given within 30 days prior to signing the ICF) 
• Concomitant medications (eg, any medication taken after signing the ICF) 
• Vital signs (systolic and diastolic blood pressure, pulse rate, body temperature, and 
respiratory rate) and body weight 
• Complete physical examination and height measurement 
• 12-lead ECG 
• Drug and alcohol screen 
• HbsAG, HCV antibody, and HIV-1/2 antibody screen 
• 24-hour urine sample 
• Urinalysis 
• CBC with differential 
• Serum chemistry (including creatinine and Cystatin C for calculation of eGFR per the 
CKD-EPI; see Section 10.5.3 for study conducted in France) 
• Lipid panel 
• High-sensitivity C-reactive protein (hs-CRP) 
• Coagulation panel 
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• Blood pregnancy 
• AE assessment beginning after the ICF is signed 
5.2 
DOUBLE-BLIND, PLACEBO-CONTROLLED TREATMENT PERIOD  
Eligible subjects will be randomized in a 2:1 ratio to receive QW subcutaneous (SC) doses of 
lademirsen (SAR339375) 110 mg or placebo for 48 weeks. Once randomized, the subject should 
be treated within 3 calendar days maximum. Details of the procedure for randomization will be 
provided in a separate document. 
The Schedule of Events for the double-blind, placebo-controlled treatment period is provided in 
Table 1. Study drug injections will be administered by study personnel during scheduled study 
site visits or (as deemed acceptable by the Investigator) at home visits. Certain visits outlined in 
the Schedule of Events (see Table 1) may be performed at an alternate location by trained, 
qualified study personnel, to which the Investigator has delegated responsibility. 
The following assessments, procedures, and data collection will be performed prior to drug 
administration, if not otherwise specified, at the study visits during the double-blind, placebo-
controlled treatment period:  
Day 1 - Baseline/Dosing Site Visit 
Tests that are common between screening and baseline visits will not have to be repeated at 
baseline if done within 7 days prior to first dosing. 
• Complete physical examination 
• 12-lead ECG 
• Urinalysis 
• Coagulation panel 
• Lipid panel 
• hs-CRP 
The following tests should be performed on baseline visit prior to the first injection: 
• Concomitant medications 
• Hearing assessment 
• Biomarkers from blood and urine samples (for study conduct in China, see 
Section 10.5.2.2) 
• Blood sampling for PK (4 hours pre-dose and 4 hours post dose) 
• Blood sampling for complement (C3, C3a, C4, and Bb) at 0.5 hours pre-dose; 0.5 hours 
and 4 hours post-dose 
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• Blood sampling for markers of inflammation (quantitative immunoglobulins: γ-globulin, 
IgM, IgG) 
• Plasma/serum for storage to support exploratory objective on biomarker (for study conduct 
in China, see Section 10.5.2.3) 
• Vital signs (0.5 to 1 hours pre- and 4 hours post-dose) and body weight 
• 24-hour urine sample 
• CBC with differential 
• Serum chemistry 
• ADA 
• Injection of study drug 
• Assessment of AEs including ISRs (Minimum of 2 hours post-injection observation 
period) 
• miR-21 
• Urine Pregnancy 
• Assignment to treatment group 
Weeks: 1, 2 and 3 (±2 days) - *Option for Alternative Location Visit 
• Concomitant medications 
• CBC with differential 
• Serum chemistry at Week 2 only 
• Assessment of AEs including ISRs 
• Injection of study drug 
• ADA 
Week 4 (±2 days) - Site Visit 
• Concomitant medications 
• Vital signs (systolic and diastolic blood pressure, pulse rate, body temperature, and 
respiratory rate) and body weight 
• Urinalysis 
• Spot UPCR 
• CBC with differential 
• Coagulation panel 
• Serum chemistry 
• Lipid panel 
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• hs-CRP 
• Urine pregnancy 
• PK (up to 4 hours before dose administration) 
• ADA 
• Assessment of AEs including ISRs 
• Injection of study drug 
Weeks: 5, 6, 7, 9, 10, 11, 13, 14, 15, 17, 18, 19, 21, 22, 23, 25, 26, 27, 29, 30, 31, 33, 34, 35, 37, 
38, 39, 41, 42, 43, 45, 46 and 47 (all ±2 days) - *Option for Alternative Location Visit 
• Concomitant medications 
• CBC with differential 
• Assessment of AEs including ISRs 
• Injection of study drug 
Weeks: 8, 16, 20, 28, 32, 40, 44 (all ±2 days) - *Option for Alternative Location Visit 
• Concomitant medications 
• CBC with differential 
• Coagulation panel 
• Serum chemistry 
• Urine pregnancy 
• Spot UPCR 
• Assessment of AEs including ISRs 
• Injection of study drug 
Weeks: 12, 24, 36, 48 (all ±2 days) - * Site visits 
• Concomitant medications 
• Complete physical examination (Week 24 and Week 48); limited physical examination 
(Week 12 and Week 36) 
• Vital signs (systolic and diastolic blood pressure, pulse rate, body temperature, and 
respiratory rate) and body weight. At Week 48, vital signs will be done at 0.5 to 1 hour 
pre- and 4 hour post-dose) 
• 12-lead ECG 
• 24-hour urine sample 
• Urinalysis 
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• CBC with differential 
• Coagulation panel 
• Serum chemistry 
• Lipid panel 
• hs-CRP 
• Urine pregnancy 
• Blood pregnancy (on Week 48 only) 
• Hearing assessment (on Week 48 only) 
• ADA 
• Biomarkers from blood and urine samples (for study conduct in China, see 
Section 10.5.2.2) 
• Blood sampling for PK (up to 4 hours before dose administration and 4 hours post-dose at 
W24 and W48) 
• Blood sampling for complement (C3, C3a, C4, and Bb) at 0.5 hour pre-dose 
• Blood sampling for markers of inflammation (quantitative immunoglobulins: γ-globulin, 
IgM, IgG) 
• Plasma/serum for storage (for study conduct in China, see Section 10.5.2.3) 
• miR-21 
• Injection of study drug 
• Assessment of AEs including ISRs 
5.3 
OPEN-LABEL EXTENSION TREATMENT PERIOD  
Subjects who complete the 48-week double-blind, placebo-controlled treatment period will be 
rolled over into the 48-week open-label extension period in which all subjects will receive active 
treatment with lademirsen (SAR339375) 110 mg QW. Subjects who complete the double-blind, 
placebo-controlled treatment period but who will not continue with the open-label extension will 
enter directly into the post-treatment follow-up period (see Section 5.5).  
The open-label treatment period allows all the subjects to benefit from exposure to lademirsen 
(SAR339375) after the randomized period of the treatment. In addition, this allows us to gain 
long-term safety and efficacy data in Alport subjects. Procedures for study visits in the 48-week 
open-label extension will be nearly identical to those for the 48-week double-blind, 
placebo-controlled treatment period.  
The following assessments, procedures, and data collection will be performed prior to dose 
administration, if not specify, at the study visits during the open-label extension treatment period:  
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Week 48 (±2 days) - Site Visit 
The Week 48 visit of the double-blind, placebo-controlled treatment period will serve as the 
baseline visit of the open-label extension. Subjects continuing on to the open-label extension will 
receive their first open-label dose of lademirsen (SAR339375) at this visit. In addition to the 
procedures specified for this visit in Section 5.2, vital signs will be taken both pre- and post-dose 
and AEs including information related to ISRs will be assessed for at least 2 hours after injection 
at Week 48. 
Weeks: 49, 50, 51, 53, 54, 55, 57, 58, 59, 61, 62, 63, 65, 66, 67, 69, 70, 71, 73, 74, 75, 77, 78, 79, 
81, 82, 83, 85, 86, 87, 89, 90, 91, 93, 94 and 95 (±2 days) - *Option for Alternative Location 
Visit 
• CBC with differential 
• Assessment of AEs including ISRs 
• Injection of study drug 
Week 52 (±2 days) - Site Visit 
• Concomitant medications 
• Vital signs and body weight 
• Urinalysis 
• Spot UPCR 
• CBC with differential 
• Coagulation panel 
• Serum chemistry 
• Lipid panel 
• hs-CRP 
• Urine pregnancy 
• Assessment of AEs including ISRs 
• Injection of study drug 
Weeks: 56, 64, 68, 76, 80, 88, 92 (all ±2 days) - *Option for Alternative Location Visit 
• Concomitant medications 
• CBC with differential 
• Urine pregnancy 
• Spot UPCR 
• Serum chemistry 
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• Coagulation panel 
• Assessment of AEs including ISRs 
• Injection of study drug 
Weeks: 60, 72, 84, and 96 (all ±2 days) - Site Visits 
• Concomitant medications 
• Vital signs and body weight 
• Limited physical exam (symptom-directed, at Weeks 60 and 84) or complete physical 
exam (at Weeks 72 and 96) 
• Hearing Assessment at Week 96 
• 12-lead ECG 
• 24-hour urine sample 
• Urinalysis 
• CBC with differential 
• Coagulation panel 
• Urine pregnancy 
• Serum chemistry 
• Lipid panel 
• hs-CRP 
• Blood sample for PK (pre-dose) 
• Blood sample for complement (C3, C3a, C4 and Bb) (pre-dose) 
• Blood sampling for markers of inflammation (quantitative immunoglobulins: γ-globulin, 
IgM, IgG) 
• ADA 
• Biomarkers from blood and urine samples (see Section 10.5.2.2 for study conduct in 
China) 
• miR-21 
• Assessment of AEs including ISRs 
• Injection of study drug (not Week 96) 
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5.4 
EARLY TERMINATION  
Any subject who discontinues before completing either active treatment period (double-blind 
placebo or open-label extension periods) should be encouraged to return to the study site to 
complete the following end-of-study procedures. With the exception of CBC, serum and urine 
chemistry, and coagulation panel, the specified laboratory assessments do not need to be 
completed if they were completed as part of a study visit within the 4 previous weeks. 
• Concomitant medications 
• Vital signs and body weight 
• Complete physical exam 
• Hearing Assessment 
• 12-lead ECG 
• Assessment of AEs including ISRs 
• 24-hour urine sample 
• Urinalysis 
• CBC with differential 
• Serum chemistry 
• Lipid panel 
• hs-CRP 
• Coagulation panel 
• Blood sample for PK and complement (C3, C3a, C4, and Bb) 
• Blood sampling for markers of inflammation (quantitative immunoglobulins: γ-globulin, 
IgM, IgG) 
• ADAs 
• Biomarkers from blood and urine samples (for study conduct in China, see 
Section 10.5.2.2) 
• miR-21, plasma/serum storage (for study conduct in China, see Section 10.5.2.3), record 
adverse events 
• Urine pregnancy 
5.5 
FOLLOW-UP PERIOD  
Subjects who complete the open-label treatment extension period or subjects who discontinue 
early and have completed the early termination visit will enter the post-treatment follow-up 
period, which will be the same for all subjects. Follow-up weeks are numbered starting from the 
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last scheduled study visit in the active treatment period (eg, Follow-up Week 2 will occur 2 weeks 
after Week 96 or after ET). 
Follow-up Weeks 2 and 4 (both ±3 days) - *Option for Alternative Location Visit 
• Concomitant medications 
• Collection of information related to potential AEs including ISRs 
• CBC with differential 
Follow-up Week 10 (±3 days) - Site Visit 
• Concomitant medications 
• Vital signs and body weight 
• Complete physical exam 
• Collection of information related to potential AEs including ISRs 
• Complement (C3, C3a, C4, and Bb) 
• Blood sampling for markers of inflammation (quantitative immunoglobulins: γ-globulin, 
IgM, IgG) 
• miR-21 
• Urinalysis 
• CBC with differential 
• Serum chemistry 
• Lipid panel 
• hs-CRP 
• Coagulation panel 
• ADAs 
5.6 
UNSCHEDULED VISITS  
Unscheduled visits are those visits that occur beyond regularly scheduled visits and are performed 
in order to assess a previously noted AE (especially if the AE is considered by the Investigator to 
be possibly related to the use of study drug), abnormal/alarming laboratory values, and/or clinical 
findings. In such cases, the Investigator may at his/her discretion arrange for a subject to have an 
unscheduled visit. The subject will be contacted to arrange an unscheduled visit to assess the 
noticed abnormalities. Only focused assessments (guided by the reason for the visit) are 
foreseen for these visits, and there will be no need to collect very extensive additional laboratory 
or other safety and efficacy data.  
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The unscheduled visits could be done at alternative location (including at home), and at the 
Investigator’s discretion, for the assessment of AEs related to abnormal/alarming laboratory 
values. 
The Unscheduled Visit Page in the eCRF must be completed (Table 1, Table 2). 
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5.7 
ALTERNATE LOCATION VISIT  
Subjects will be seen at the Investigational site, or at an Alternate Location including subject’s 
home by trained, qualified personnel to whom the Investigator has delegated responsibility. All 
staff performing activities at an Alternate Location will be appropriately trained in the protocol, 
study drug administration, study assessments and procedures to be performed. They will be 
documented in the delegation of duties log. The purpose of this flexibility, where available, is to 
offer subjects the option of having their visits performed at a more convenient location (including 
the subject’s home), due to the frequency of study visits and length of study, and the potential for 
subjects to live a significant distance from their main Investigational site. 
5.8 
END OF STUDY DEFINITION  
The end of the study is defined as the date of the last visit of the last subject in the trial globally. 
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6 
BACKGROUND, SAFETY, EFFICACY, PHARMACODYNAMIC, AND 
PHARMACOKINETIC ASSESSMENTS  
The timing of procedures and assessments to be performed is provided in Table 1 (for screening 
and the double-blind, placebo-controlled treatment period), Table 2 (for the open-label treatment 
period), and Section 5.  
6.1 
MEDICAL HISTORY AND FAMILY HISTORY  
A subject’s significant prior (eg, occurring before signing the ICF) and ongoing illnesses, 
surgeries, and smoking history should be documented on the eCRF Medical History Page. 
Medical history relevant to Alport syndrome will include past lab tests related to disease 
progression and should be documented on the appropriate eCRF page. Family history relevant to 
Alport syndrome and renal disease should be documented on the eCRF Family History Page. 
Medical history and family history data collected in the ATHENA study may be used for this 
study. Additional illnesses present from the time when the ICF is signed until the completion of 
the last follow-up visit are to be documented as AEs on the eCRF Adverse Event Page.  
6.2 
SAFETY ASSESSMENTS  
Safety assessments will consist of monitoring and recording all AEs, including SAEs, physical 
examination, vital sign assessment, ECG recording, clinical laboratory results (hematology, serum 
chemistry, lipids, coagulation, complement, urinalysis), and regular monitoring of ISRs. 
6.2.1 Adverse events  
An AE is any undesirable sign, symptom, or medical condition occurring after signing the ICF. 
Information about all AEs, regardless of seriousness or relationship to study treatment, whether 
volunteered by the subject, discovered by questioning, or detected through physical examination, 
laboratory testing, or other means, will be collected and recorded on the AE eCRF page and 
followed as appropriate.  
Medical conditions present prior to study entry will be documented in the Medical History eCRF. 
However, medical conditions occurring after signing the ICF are to be recorded as AEs. 
Treatment-emergent adverse events (TEAEs) are defined as AEs with onset after the first dose of 
study drug or existing AEs that worsened after the first dose of study drug until the last 
administration of study medication plus 10 weeks follow up. 
The Investigator (or delegate) is obliged to interview subjects at each visit and clarify/discuss any 
abnormality that may indicate a potential AE. 
Subjects should be encouraged to report AEs that occur between scheduled visits to the 
Investigator or between home injections to the nurse.  
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AEs will be recorded from the time of signing the ICF until the end of the safety follow-up. If any 
AE is ongoing at the time of subject withdrawal, the subject will be asked to return for clinic visits 
or to respond to follow-up by telephone (if the AE is considered not related or unlikely related to 
study drug) until resolution or stabilization of this AE. 
Whenever possible, diagnosis or single syndrome should be reported instead of symptoms. The 
Investigator should specify the date of onset, intensity, action taken with respect to study 
treatment, corrective treatment/therapy given, additional investigations performed, outcome, and 
his/her opinion as to whether there is a reasonable possibility that the AE was caused by the study 
treatment. When AEs occur on the day of study drug administration, the approximate time of day 
should be provided. 
Any AE that occurs during the study must be monitored and followed up until one or more of the 
following criteria have been met: 
• It has resolved to ≤ Grade 1 or baseline level 
• Pathological laboratory findings have returned to normal 
• Steady state has been achieved 
A subset of AEs will be closely monitored (ie, events identified as AESIs; see Section 6.2.2 and 
Table 3). 
It is the responsibility of the Investigator to ensure that any necessary additional therapeutic 
measures and follow-up procedures are performed. 
As far as possible, each AE will also be described by: 
• Duration (start and end dates) 
• Severity grade 
• Relationship to the study drug 
• Action(s) taken and, as relevant, the outcome 
6.2.2 Adverse event of special interest  
An adverse event of special interest (AESI) is an AE (serious or non-serious) of scientific and 
medical concern specific to the Sponsor’s product or program, for which ongoing monitoring and 
immediate notification by the Investigator to the Sponsor is required. Such events may require 
further investigation in order to characterize and understand them. Adverse events of special 
interest may be added, modified or removed during a study by protocol amendment. 
• Pregnancy of a female participant entered in a study as well as pregnancy occurring in a 
female partner of a male participant entered in a study with IMP: 
- 
Pregnancy occurring in a female participant entered in the clinical trial or in a female 
partner of a male participant entered in the clinical trial. It will be qualified as an SAE 
only if it fulfills one of the seriousness criteria (see Appendix 1 [Section 10.1]). 
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- 
In the event of pregnancy in a female participant, IMP should be discontinued.  
- 
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined (see Appendix 4 
[Section 10.4]). 
• Symptomatic overdose (serious or non-serious) with IMP: 
- 
An overdose (accidental or intentional) with the IMP is an event suspected by the 
Investigator or spontaneously notified by the participant and defined as increase of at 
least 30% above the intended dose at each administration or any two doses separated 
by <5 days. 
• Other specific AESIs subject to close monitoring:  
- 
All Grade ≥2 events listed in Table 3, except for eGFR 
- 
Grade ≥3 events of eGFR 
6.2.3 Adverse events grading  
Table 3 - Grading system for the definition of AESIs  
Parameter 
Mild 
(Grade 1)  
Moderate 
(Grade 2) 
Severe (Grade 3) 
Life threatening event 
(Grade 4) 
Platelets 
125 000 to 
100 000 cells/μL 
<100 000 to 
50 000 cells/μL 
<50 000 to 25 000 cells/μL 
<25 000 cells/μL 
ALT or ASTa 
1.25 to <2.5 x ULN 
2.5 to <5.0 x ULN 
5.0 to <10.0 x ULN 
≥10.0 x ULN 
Direct 
Bilirubin 
NA 
NA 
> ULN with signs and 
symptoms of 
hepatotoxicity 
> ULN with life-threatening 
consequences (eg, signs and 
symptoms of liver failure) 
Total Bilirubin 
1.1 to <1.6 x ULN 
1.6 to <2.6 x ULN 
2.6 to <5.0 x ULN 
≥5.0 x ULN 
Alkaline 
phosphatase 1.25 to <2.5 x ULN 
2.5 to <5.0 x ULN 
5.0 to <10.0 x ULN 
≥10.0 x ULN 
eGFR 
NA 
10 to <30% decrease 
from participant’s 
baseline 
30 to <50% decrease from 
participant’s baseline 
≥50% decrease from 
participant’s baseline or 
dialysis needed 
ALT: alanine aminotransferase; AST: aspartate aminotransferase; eGFR: estimated glomerular filtration rate; NA: not applicable; ULN: upper 
limit of normal 
Grading criteria are based on the DAIDS grading system (30). All deaths related to an AE are to be classified as Grade 5. 
a For management of elevated aminotransferases, please refer to Section 10.3.2. 
For events not defined in Table 3, the following guidelines are to be used to classify adverse 
events (see Table 4). 
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Table 4 - Classification of adverse events by severity  
Parameter 
Mild (Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Life threatening 
(Grade 4) 
Grade 5 
Clinical AE 
NOT 
identified in 
Table 3  
Mild symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional activities 
with intervention not 
indicated 
Moderate symptoms 
causing greater 
than minimal 
interference with 
usual social & 
functional activities 
with intervention 
indicated 
Severe symptoms 
causing inability to 
perform usual social 
& functional 
activities with 
intervention or 
hospitalization 
indicated 
Potentially life-threatening 
symptoms causing 
inability to perform basic 
self-care functions with 
intervention indicated to 
prevent permanent 
impairment, persistent 
disability, or death 
Death 
related to 
AE 
AE: adverse event 
Grading criteria are based on the DAIDS grading system (30). 
If there is an increase in severity of an AE, it will be recorded as a single event. The worst grade 
of severity for the AE should be recorded in the source data and eCRF. 
An AE that is assessed as severe (having a “severe” or Grade 3 classification) should not be 
confused with an SAE. “Severe” is a category in rating the intensity of an event. An event is 
defined as “serious” when it meets one of the pre-defined outcomes described in Section 6.2.5. 
The Investigator will assess any causal relationship of an AE to study drug not related to treatment 
or related to treatment. 
6.2.4 Adverse event outcome  
If the same AE occurs several times in the same subject, and the previous AE has 
“recovered/resolved” or “recovering/resolving” as an outcome, then the subsequent AE must be 
documented and assessed as a new AE each time unless the event is considered to be a 
continuation of the previously reported event rather than reoccurrence of the event.  
Outcome of the AE will be recorded as defined below in Table 5. 
Table 5 - Adverse event outcome  
Not recovered/not resolved - One of the possible results of an AE outcome that indicates that the event has not improved or 
recuperated. 
Recovered/resolved - One of the possible results of an AE outcome that indicates that the event has improved or recuperated. 
The subject recovered from the AE. Record the AE stop date. 
Recovering/resolving - One of the possible results of an AE outcome that indicates that the event is improving. No AE stop 
date should be recorded when an AE is recovering/resolving. 
Recovered/resolved with sequelae - One of the possible results of an AE outcome where the subject recuperated but 
retained pathological conditions resulting from the prior disease or injury. Record the AE stop date. The AE stop date will 
represent the date the AE stabilized with no change in event outcome anticipated. 
Unknown - There is an inability to access the subject or the subject’s records to determine the outcome (eg, subject withdraws 
consent or is lost to follow-up). No AE stop date should be recorded. 
Fatal - The AE directly caused death. Record the date of death as the AE stop date. 
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6.2.5 Serious adverse events  
An AE is considered “serious” if, in the view of either the Investigator or Sponsor, it meets one or 
more of the following criteria:  
• Is fatal 
• Is life-threatening 
• Results in subject hospitalization or prolongation of existing hospitalization 
• Results in a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• Is a congenital anomaly/birth defect 
• Is an important medical event 
Important medical events that may not be immediately life-threatening or result in death or 
hospitalization are considered SAEs, based upon appropriate medical judgment, if they are 
thought to jeopardize the subject or require intervention to prevent one of the other outcomes 
listed in the definition above. Since SAEs are critically important for the identification of 
significant safety problems, it is important to take into account both the Investigator’s and the 
Sponsor’s assessment. If either the Sponsor or the Investigator believes that an event is serious, 
the event must be considered serious and evaluated by the Sponsor for expedited reporting.  
Information about all SAEs will be collected and recorded on the Serious Adverse Event Report 
Form and reported to the Sponsor within 24 hours of learning of its occurrence. 
Events not to be reported as SAEs are hospitalizations for the following:  
• Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• Treatment that was elective or pre-planned, for a pre-existing condition that is unrelated to 
the indication under study and did not worsen 
• Admission to a hospital or other institution for general care, not associated with any 
deterioration in condition 
• Treatment on an emergency, outpatient basis for an event not fulfilling any of the 
definitions of SAE given above and not resulting in hospital admission 
Any SAE occurring after signing the ICF to the end of a patient’s study participation must be 
reported to the Sponsor. SAEs occurring after study participation have to be reported only if 
considered related to study drug as per Investigator judgment.  
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study treatment. 
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Instructions about completing initial and follow-up SAE Report Forms and sending them to the 
Sponsor/CRO are given in Section 9.1.1. 
6.2.6 Follow-up of AEs and SAEs  
After the initial AE/AESI/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. At the pre-specified study end-date, all SAEs and AESIs 
(as defined in Section 6.2.2), will be followed until resolution, stabilization, the event is otherwise 
explained, or the participant is lost to follow-up (as defined Section 3.3.1). Further information on 
follow-up procedures is provided in Appendix 1 (Section 10.1). 
6.2.7 Procedures in case of pregnancy  
COLLECTION OF PREGNANCY INFORMATION:  
Male subjects with partners who become pregnant  
• The Investigator will attempt to collect pregnancy information on any male subject’s 
female partner who becomes pregnant while the male subject is in this study. This applies 
only to male subjects who receive lademirsen (SAR339375). 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the Sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure.  
Female subjects who become pregnant  
• The Investigator will collect pregnancy information on any female subject who becomes 
pregnant while participating in this study. Information will be recorded on the appropriate 
form and submitted to the Sponsor within 24 hours of learning of a subject's pregnancy. 
The subject will be followed to determine the outcome of the pregnancy. The Investigator 
will collect follow-up information on the subject and the neonate and the information will 
be forwarded to the Sponsor. Generally, follow-up will not be required for longer than 6 to 
8 weeks beyond the estimated delivery date. Any termination of pregnancy will be 
reported, regardless of fetal status (presence or absence of anomalies) or indication for the 
procedure. 
• Any pregnancy complication or elective termination of a pregnancy will be reported as an 
AE or SAE. A spontaneous abortion (occurring at <22 weeks gestational age) or stillbirth 
(occurring at >22 weeks gestational age) are always considered to be an SAE and will be 
reported as such. Any post-study pregnancy related SAE considered reasonably related to 
the study intervention by the Investigator will be reported to the Sponsor as described in 
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Section 10.1 of the protocol. While the Investigator is not obligated to actively seek this 
information in former study subjects, he or she may learn of an SAE through spontaneous 
reporting.  
• Any female subject who becomes pregnant while participating in the study will 
discontinue study intervention or be withdrawn from the study.  
6.2.8 Regulatory reporting requirements for SAEs  
• Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. 
• The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and Investigators. 
• Adverse events that are considered expected will be specified by the reference safety 
information (lademirsen [SAR339375] Investigator’s Brochure). 
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary.  
• An Investigator who receives an Investigator safety report describing an SAE, SUSAR or 
any other specific safety information (eg, summary or listing of SAEs) from the Sponsor 
will review and then file it along with the [Investigator's Brochure/IDFU/package insert or 
state other documents] and will notify the IRB/IEC, if appropriate according to local 
requirements. It is the responsibility of the Sponsor to assess whether an event meets the 
criteria for a SUSAR, and therefore, is expedited to regulatory authorities. 
6.2.9 Guidelines for reporting product complaints (lademirsen [SAR339375])  
Any defect in the lademirsen (SAR339375) must be reported as soon as possible by the 
Investigator to the monitoring team that will complete a product complaint form within required 
timelines. 
• Appropriate information (eg, samples, labels or documents like pictures or photocopies) 
related to product identification and to the potential deficiencies may need to be gathered. 
The Investigator will assess whether or not the quality issue has to be reported together 
with an AE or SAE. 
6.2.10 Physical examination/body system assessments  
Complete or limited physical examinations or body system assessments will be performed by 
qualified study personnel (eg, physician, nurse practitioner, nurse). Height should be measured at 
screening. Limited examinations will be symptom-directed. Body system assessments will 
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evaluate general appearance, HEENT (head, ears, eyes, nose, throat), the cardiovascular system, 
the respiratory system, the abdomen, the musculoskeletal system, and the skin. Any confirmed 
clinically significant examination findings occurring after signing the ICF are to be recorded as 
AEs.  
6.2.11 Vital signs and body weight  
Vital signs (systolic and diastolic blood pressure measurements, pulse rate, body temperature, and 
respiratory rate) and body weight will be evaluated at each on site visit. Moreover, on Day 1 of 
the double-blind, placebo-controlled treatment period and at Week 48 if the subject is continuing 
into the open-label treatment extension period, vital signs should be assessed both 0.5 to 1 hour 
pre- and 4 hours post-dose. 
Where feasible, vital signs should be measured before blood is drawn and after the subject has 
been sitting comfortably for 5 minutes with the blood pressure cuff in place on the nondominant 
arm. Blood pressure, and pulse rate measurements will be taken first and may be done manually 
or by automated recorder. Temperature will be obtained. Respiratory rate will be determined by 
observation for at least 30 seconds. 
Vital sign measurements will be repeated if clinically significant or machine/equipment errors 
occur. Out-of-range blood pressure and heart rate measurements will be repeated at the 
Investigator’s discretion. Any confirmed clinically significant vital sign measurements occurring 
before signing the ICF are to be designated as medical history. Any confirmed clinically 
significant vital sign measurements occurring after signing the ICF are to be recorded as AEs. 
6.2.12 Electrocardiogram assessment  
A standard 12-lead ECG will include a general diagnostic impression as well as measurement of 
the heart rate, PR interval, QRS duration, QT interval, and the Fridericia-corrected QT interval 
(QTcF). ECGs will be centrally read for results.  
Any ECG measurement determined by the Investigator to be clinically significant (occurring after 
signing the ICF) will be noted as an AE on the appropriate eCRF page(s). Such abnormalities will 
be closely monitored until their resolution.  
6.2.13 Hearing assessment  
Hearing will be assessed during the Treatment Period and Extension Period using a pure tone 
audiometry (air only) test at defined frequencies at baseline, Week 48 and 96.  
6.2.14 Laboratory assessments  
All analyses must be done with the minimally required blood amount, and the number of needle 
insertions should be minimized during the blood collection.  
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All hematology (including CBC with differential), serum chemistry, serology parameters 
(HBsAg, HCV antibody, HIV-1/2 antibody), COL4A3/4/5 genotyping, and urine analyses will be 
done centrally. Samples for PK analysis will be sent to the contract research organization (CRO). 
Samples for ADA analysis will be sent to the CRO. 
Laboratory management details, including preparation, labeling, and storage of aliquots, will be 
described in a separate document.  
Clinical laboratory results, not including PK, pharmacodynamics, and biomarker results (except 
for BUN, UPCR, UACR, creatinine and Cystatin C), will be sent back to the Investigator after 
completion of analyses. 
All laboratory reports must be reviewed, signed, and dated by the Investigator or delegated 
co-Investigator. A legible copy of all reports must be filed in a subject medical record (source 
document) for that visit and the exact data must be recorded in the eCRF.  
Hematology 
CBC with differential will comprise the following parameters: hemoglobin, hematocrit, RBC 
count, WBC count with differential (neutrophils, eosinophils, basophils, monocytes, and 
lymphocytes), and platelet count. 
Serum chemistry 
Serum chemistry will comprise the following parameters: total protein, glucose (in fasting 
condition as per site habit), Cystatin C, creatinine for calculation of eGFR per the CKD-EPI 
creatinine equation (for study conducted in France, see Section 10.5.3), uric acid, lactate 
dehydrogenase, sodium, potassium, chloride, bicarbonate, calcium, iron, phosphate, BUN, and hs-
CRP. A hepatic function panel will also be evaluated as part of serum chemistry. 
Hepatic function panel 
The hepatic function panel will comprise the following parameters: albumin, total bilirubin, direct 
bilirubin, ALT, AST, ALP, and GGT. 
Lipid panel 
The lipid panel will comprise the following parameters: total cholesterol, triglycerides, 
high-density lipoprotein (HDL), and low-density lipoprotein (LDL).  
Coagulation panel 
The coagulation panel will comprise the following parameters: prothrombin time, aPTT, 
international normalized ratio (INR), and fibrinogen. 
Serology parameters 
All subjects will be tested for HBsAg, HCV antibody, and HIV-1/2 antibodies at screening visit. 
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Genotype 
All subjects will be tested for COL4A3/4/5 genotype at screening visit.  
Drug and alcohol screen 
The drug and alcohol screen will include measurement of opiates, cocaine, heroin, phencyclidine, 
amphetamines (including ecstasy), barbiturates, benzodiazepines, cannabinoids, and alcohol. 
Urine analysis 
Urinalysis reports will include the following: color, appearance, specific gravity, pH, total protein, 
glucose, ketones, leukocyte esterase, nitrate, bilirubin, urobilinogen, urine sediment, 
microalbuminuria, creatinine, hematuria, and microscopy.  
The 24-hour urine assessment will provide accurate measures of creatinine clearance, fractional 
excretion of sodium, total protein, and total albumin, in addition to standard urinalysis. 
Anti-drug antibodies 
Anti-drug antibodies (IgG) will be evaluated with a direct-binding ELISA method. 
Complement 
Complement C3, C3a, C4, and Bb will be measured on Day 1 in samples obtained 0.5 hour 
pre-dose and 0.5 and 4 hours post-dose and pre-dose for other visits as specified in Tables 1 and 2.  
Abnormal Laboratory Results 
Any abnormal laboratory test result (after signing the ICF) considered by the Investigator to be 
clinically significant will be recorded as an AE. Clinically significant laboratory values include 
those that require an intervention. Clinically significant laboratory values will be graded by 
severity as outlined in Table 4. Clinically significant abnormal values occurring during the study 
will be followed until repeat test results return to normal, stabilize, or are no longer clinically 
significant.  
6.2.15 Monitoring of platelet count  
Because of the potential for thrombocytopenia associated with the administration of an 
oligonucleotide drug, a subject’s platelet count will be obtained weekly before dose 
administration. Platelet counts may be measured from a central laboratory and can exceptionally 
be measured from a local laboratory. The most recent subject’s platelet counts, but, not older than 
10 days, will be reviewed by the Investigator/physician before each drug administration. 
6.2.16 Injection site reactions  
Qualified study personnel (eg, physician, nurse practitioner, nurse) will assess the injection site 
and surrounding area. Injection site reactions will be rated according to the Food and Drug 
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Administration (FDA) Guidance for Industry: Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (31) as summarized in 
Table 6. Any reaction meeting the criteria for an AE (Section 6.1) should also be recorded as an 
AE. 
For self-administrations during the open-label period, ISRs will be reported as described in 
Section 4.4. 
Table 6 - Injection site grading (local reaction)  
Local Reaction 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Pain 
Does not interfere with activity 
Repeated use of non-narcotic 
pain reliever >24 hours or 
interferes with activity 
Any use of narcotic pain 
reliever or prevents daily 
activity 
Tenderness 
Mild discomfort to touch 
Discomfort with movement 
Significant discomfort at rest 
Erythema/Redness* 
2.5 - 5 cm 
5.1 - 10 cm 
>10 cm 
Induration/Swelling** 
2.5 - 5 cm and does not 
interfere with activity 
5.1 - 10 cm or interferes with 
activity 
>10 cm or prevents daily 
activity 
* 
In addition to grading the measured local reaction at the greatest single diameter, the measurement should be recorded as a continuous 
variable. 
** 
Induration/swelling should be evaluated and graded using the functional scale as well as the actual measurement. 
6.2.17 Safety oversight  
An independent Data Monitoring Committee (DMC) will be comprised of individuals with 
expertise in the diseases under study, biostatistics, or clinical research. The DMC members are 
independent of the project/study teams and are not involved in the study conduct. The primary 
responsibilities of the DMC are to review and evaluate the study data during the course of the trial 
and make appropriate recommendations regarding the conduct of the clinical trial to project/study 
team as detailed in the DMC charter. 
The DMC will review data every six months and on an ad hoc basis as necessary throughout the 
study. The DMC will conduct a review of the relevant safety data outputs, PK, and will closely 
monitor AESIs (eg, platelet counts, eGFR). 
The DMC may be consulted whenever the Investigator considers that worsening of eGFR and 
UPCR values are medically relevant. 
The DMC will also review data at a planned interim analysis (IA), as described in Section 7.2.7. 
The roles and responsibilities of the DMC, as well as, the DMC meeting timelines will be 
described in detail in a separate charter. 
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6.3 
EFFICACY ASSESSMENTS  
6.3.1 Estimated GFR  
Estimated GFR will be calculated using the CKD-EPI creatinine equation (32).  
eGFR = 141 × min(Scr/κ, 1)α × max(Scr/κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 [if 
black], where Scr is serum creatinine in mg/dL, κ is 0.7 for females and 0.9 for males, 
α is -0.329 for females and -0.411 for males. 
For study conducted in France, see Section 10.5.3. 
6.4 
PHARMACODYNAMIC ASSESSMENTS AND BIOMARKERS  
Pharmacodynamics will be assessed by measurement of the following:  
• Circulating miR-21. 
Renal injury and function biomarkers: 
• In blood only: BUN 
• In urine only: protein/creatinine ratio, albumin/creatinine ratio, and EGF 
• In both blood and urine: creatinine, Cystatin C, NGAL, and TGF-β 
The UPCR will be performed every 4 weeks (using first morning void urine), either using spot 
urine or 24h-h urine collection at D1, W12, W24, W36, W48, W60, W72, W84, W96). In case of 
worsening of UPCR, the Investigator could repeat the UPCR before the next scheduled test.  
Exploratory biomarkers to be evaluated may include but are not necessarily limited to the 
following: 
• In blood only: microRNAs (miRs) other than miR-21 
• In urine only: KIM-1 and calbindin-D28k  
• In both blood and urine: β-2 microglobulin and CTGF 
For study conduct in China, see Section 10.5.2.2 for pharmacodynamic assessments and biomarkers. 
6.5 
PHARMACOKINETIC ASSESSMENTS  
Plasma PK samples will be collected 4 hours post-dose on Day 1, Week 24, and Week 48 of the 
Treatment Period, for determination of maximum plasma concentrations (approximate Cmax) of 
lademirsen (SAR339375), RG0005, and SUM. In addition, pre-dose plasma PK samples will be 
collected (up to 4 hours before dose administration) on Day 1 and Weeks 4, 12, 24, 36, 48, 60, 72, 
84 and 96 for determination of minimum plasma concentrations (Ctrough) of SUM (see Table 1). 
No PK samples will be withdrawn on Weeks 4, 12, 24, 36, 48, 60, 72, 84 and 96 if injection is not 
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administered. In case visit is performed without injection administered, only pre-dose PK sample 
will be withdrawn. Time and date of PK sampling, as well as the date of the last prior 
administration of study drug should be recorded in the eCRF. 
A manual for blood sampling, collection, processing, and shipment will be provided. 
6.6 
DISPOSITION OF SAMPLES AFTER STUDY COMPLETION  
Collected blood and urine samples (except PK and ADA samples) may be stored and used in the 
future for the discovery, analysis, verification and/or validation of other biomarkers or tests for 
renal disease. The samples will be kept for a prolonged period of time (eg, up to 5 years). Each 
sample will be identified by its barcode number and will not directly identify the subject on the 
label. Consent from the subject to store the samples will be requested, and subjects may elect to 
opt out of prolonged sample storage at any time by indicating so in the ICF. PK samples will be 
disposed of following completion of CSR. ADA samples may be disposed of following 
completion of CSR or may be kept for additional ADA characterization and/or method 
development, if warranted based on the ADA data obtained in this study.  
For study conduct in China, see Section 10.5.2.3. 
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7 
STATISTICAL ANALYSIS  
7.1 
ENDPOINTS  
7.1.1 Efficacy endpoints  
• Annualized change in estimated glomerular filtration rate (eGFR) from baseline during the 
placebo-controlled treatment period 
• Absolute and percentage change in eGFR values from baseline at Week 24 and 48 
• Number and proportion of subjects who reach ESRD as defined by an eGFR 
≤15 mL/min/1.73 m2 or initiation of hemodialysis or renal transplantation during the 
placebo-controlled treatment period 
• Absolute and percent change in eGFR values from baseline at Week 96  
• Proportion of subjects with a reduction from baseline in eGFR of <10%, <20%, <30%, or 
<40% reduction at Week 24, 48 and 96 
7.1.2 Safety endpoints  
• Incidence and severity of treatment-emergent AEs and serious adverse events (SAEs) 
• Observed values and changes from baseline in clinical laboratory parameters 
(eg, hematology, chemistry, complement, and urinalysis) 
• Observed values and changes from baseline in vital signs 
• Observed changes from baseline in 12-lead ECG 
• Observed changes from baseline in physical examinations 
• Incidence and titer of ADAs 
• Association of AEs with ADAs 
7.1.3 Pharmacodynamic endpoints  
• Changes in circulating miR-21 at Weeks 24, 48, and 96 
• Change in renal injury and function biomarkers from baseline at Weeks 24, 48, and 96: 
- 
In blood only: BUN;  
- 
In urine only: protein/creatinine ratio, albumin/creatinine ratio, and EGF;  
- 
In both blood and urine: creatinine, Cystatin C, TGF-β, and NGAL. 
7.1.4 Exploratory endpoints  
• Changes in exploratory biomarkers, which may include but are not necessarily limited to: 
- 
In blood only: microRNAs (miRs) other than miR-21 
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- 
In both blood and urine: β-2 microglobulin and CTGF 
- 
In urine only: KIM-1 and calbindin-D28k  
• Please see Section 10.5.2.1.2 for study conduct in China. 
7.1.5 Pharmacokinetic endpoint  
• Plasma concentrations of lademirsen (SAR339375), RG0005, and SUM in Cmax samples 
and SUM only in Ctrough samples. 
7.2 
STATISTICAL METHODS AND ANALYSES  
The statistical analysis plan will be developed and finalized before database lock and will describe 
the subject populations to be included in the analyses. This section is a summary of the planned 
primary and secondary analyses. 
7.2.1 Determination of sample size  
An approximate 45 total subjects will be randomized in 2:1 ratio to lademirsen (SAR339375) 
versus placebo. The sample size will provide approximately 75% power to detect a reduced rate of 
decline of 5 mL/min/1.73 m2/year (~50% reduction) in eGFR annualized rate under lademirsen 
(SAR339375) treatment, in comparison to placebo.  
Power calculations were based on simulations. The following model parameters were obtained 
from preliminary analysis of the ATHENA Natural History Study (OBS16374) data: 
• Average linear decline in eGFR of 10 mL/min/1.73 m2/year in placebo arm 
• Standard deviation (SD) for the residual error of eGFR of 
 mL/min/1.73 m2 and SD for 
random effect of slope to be 
 mL/min/1.73 m2/year 
• Mean and SD for intercept to be 
 mL/min/1.73 m2 and 
mL/min/1.73 m2, 
respectively  
In addition, power calculations were based on a success criterion defined in Section 7.2.5 and a 
10% dropout rate was assumed. 
7.2.2 Analysis populations  
The Intent-to-Treat (ITT) Population will consist of all randomized subjects analyzed 
according to the treatment group allocated by randomization. The ITT Population will be the 
primary efficacy analysis population. 
The Safety Population will consist of all subjects who receive at least one dose or partial of a 
dose of the IMP, analyzed according to the treatment actually received.  
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The PK Population will consist of all subjects who receive at least one dose of the IMP and have 
at least one post-dose PK sample to determine plasma concentrations of lademirsen 
(SAR339375). 
7.2.3 Demographic and baseline characteristics  
Demographics will be presented using descriptive statistics (eg, mean, standard deviation, median, 
and range for continuous variables; number and percentage of subjects for categorical variables). 
No hypothesis tests will be performed on demographic and baseline characteristics.  
7.2.4 Safety analysis  
The summary of safety results will be presented by treatment group. All safety analyses will be 
performed on the Safety Population. The baseline value is defined generally as the last available 
value before randomization. The treatment-emergent adverse event (TEAE) period is defined as 
the time between the first administration of study medication to the last administration of study 
medication plus 10 weeks follow up. 
Adverse events will be presented by System Organ Class (SOC) and Preferred Term (PT) for each 
treatment group, the number (n) and percentage (%) of subjects experiencing an AE. The numbers 
and percentages of subjects with at least one TEAE, treatment-emergent SAE, TEAE leading to 
death, and TEAE leading to permanent treatment discontinuation will be tabulated by treatment 
group. In addition, TEAEs will be described according to maxim intensity and relation to the 
study drug.  
• The following deaths summaries will be generated 
Death in nonrandomized subjects or randomized and not treated subjects 
• Treatment-emergent AE leading to death (death as an outcome on the AE eCRF page as 
reported by the Investigator) by primary SOC, HLGT, HLT, and PT showing number (%) 
of subjects sorted by internationally agreed order of SOC and alphabetic order of HLGT, 
HLT, and PT 
• AESI will be summarized by treatment group 
Results and change from baseline for the laboratory parameters will be summarized by treatment 
group for baseline and each post baseline time point, endpoint, minimum and maximum value. 
Summary statistics will include number of subjects, mean, standard deviation, median, Q1, Q3, 
minimum, and maximum.  
The following definitions will be applied to laboratory parameters. 
• The potentially clinically significant abnormality (PCSA) values are defined as abnormal 
values considered medically important by the Sponsor according to predefined 
criteria/thresholds based on literature review and defined by the Sponsor for clinical 
laboratory tests. 
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• PCSA criteria will determine which subjects had at least 1 PCSA during the on-treatment 
period, taking into account all evaluations performed during the on-treatment period, 
including unscheduled or repeated evaluations. The number of all such subjects will be the 
numerator for the on-treatment PCSA percentage.  
The proportion of subjects who had at least one incidence of PCSA at any time during the TEAE 
period will be summarized by treatment group. Shift tables showing changes with respect to the 
baseline status will be provided. Vital signs, ECG and physical examinations will be summarized 
using descriptive statistics. 
7.2.5 Efficacy analysis  
Estimated GFR will be calculated using the CKD-EPI creatinine equation as described by (32). 
For French subjects, see Section 10.5.3. 
Annualized rate of change in eGFR during the placebo-controlled treatment period will be 
compared between lademirsen (SAR339375) and placebo using a linear mixed effect model. 
ATHENA Natural History Study (OBS16374) data will be used as prior information 
supplementing the placebo arm, using a Bayesian approach.  
The model will include eGFR measurements from baseline to Week 48 as response variables, and 
it will include fix effects of treatment (lademirsen [SAR339375] or placebo), screening eGFR 
stratification factor, time, and treatment-by-time interaction. In addition, it will include random 
intercept and random slope for time to account for the between subject variability. Time will be 
treated as continuous variable based on actual eGFR assessment date relative to the randomization 
date. 
A prior distribution for the slope of the placebo group was determined based on the annualized 
rate of change in eGFR observed in a subgroup of subjects from ATHENA Natural History Study, 
who are considered as rapid progressors meeting renal function criteria similar to I 05 in 
Section 3.2.1. The prior distribution assumes a normal distribution for the slope of eGFR in the 
placebo group, with a mean of -10 and standard deviation of 2.22. Non-informative priors will be 
used for other parameters in the model. Efficacy of lademirsen (SAR339375) will be based on the 
posterior probability that the slope of the lademirsen (SAR339375) group is greater than the slope 
of the placebo group. A posterior probability of at least 95% will be considered significant. 
The primary estimand will be the difference in mean slope of eGFR estimated from baseline to 
Week 48 in ITT population, regardless of whether or not subjects completed the study period of 
48 weeks.  
Change and percent change from baseline in eGFR at Week 24 and 48 will be analyzed using 
mixed effects model with repeated measures (MMRM), based on eGFR measurements up to 
Week 48.  
The number and proportion of subjects who reach ESRD or initiation of hemodialysis or renal 
transplantation will be summarized by treatment group. The proportion will be estimated based on 
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total subjects in ITT population, as well as the Kaplan-Meier estimate taking consideration of lost 
to follow-up during the study. 
Efficacy endpoints that include data from the open-label extension period will be summarized 
using descriptive statistics. 
Exploratory analyses will be described in the statistical analysis plan finalized before database 
lock. 
7.2.6 Other analyses  
PK, pharmacodynamic, and exploratory biomarker analyses (see Section 10.5.2.2 for study 
conduct in China) will be described in the statistical analysis plan finalized before database lock. 
Measured plasma concentrations (observed PK parameters Cmax and Ctrough) for lademirsen 
(SAR339375), RG0005, and SUM (as applicable) will be summarized using descriptive statistics 
(eg, mean, standard deviation (SD), median, min-max, and coefficient of variation [%CV]. 
The incidence and titer of ADA will be provided by treatment groups. Association between ADA 
status and safety may be explored.  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
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8 
DATA MANAGEMENT  
8.1 
DATA HANDLING  
Data will be collected by means of eCRFs. The eCRF must be kept current to reflect subject status 
during the course of the study. A subject identification number will be used to identify the subject. 
Completion instructions will be provided.  
The study will use an Internet-Based Remote Data Entry System or electronic data capture (EDC) 
system to collect the clinical trial data at the investigational sites. The system complies with 
21 Code of Federal Regulations (CFR) Part 11 and International Conference on Harmonisation 
(ICH) E6 Good Clinical Practice (GCP). Queries are generally sent to the investigational site 
using an electronic data query system that provides an automatic audit trail of the corrections 
made by designated Investigator staff. All changes to the data have an electronic audit trail, in 
accordance with 21 CFR 11.10(e). Electronic signatures will be used in conformance with 21 CFR 
Part 11. 
Source documents are to be retained to enable a reconstruction and evaluation of the trial. No 
original observations will be entered directly into the computerized system without source 
documentation. Laboratory data will be processed centrally. 
Access to the EDC is controlled with user ID and password and can only be granted to 
appropriately trained users. Different types of users have different privileges assigned in the EDC 
system. A user access list is maintained throughout the study. 
The Investigator will receive subject data for archiving at the investigational site following 
database lock. 
8.2 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS  
The Investigator and institutions involved in this study will agree to allow study monitors from 
the Sponsor or its designee(s) direct access to all source data, CRFs, and documents, including a 
subject’s complete medical record if necessary. Access must also be granted to authorized 
auditors, IRB/IEC reviewers, and all applicable regulatory bodies as necessary. 
Source documents are considered to be all information in original records and certified copies of 
original records of clinical findings, observations, data, or other activities in a clinical study 
necessary for the reconstruction and evaluation of the study. 
8.3 
PROTECTION OF PERSONAL DATA  
The completion of the study involves the collection and processing of personal data. All 
processing of personal data at the clinic and by the Sponsor must be carried out in accordance 
with national legislation concerning the protection of personal data. 
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The Investigator must ensure that the subject’s privacy is maintained. On the CRF or other 
documents submitted to the Sponsor, subjects will be identified by a subject identification number 
only. Documents that are not submitted to the Sponsor (eg, signed ICFs) should be kept in a 
strictly confidential file by the Investigator. 
As part of the required content of the ICF, subjects will be informed that their records may be 
reviewed by the Sponsor or its designee and by regulatory agencies. Should access to medical 
records require a separate waiver or authorization, it is the Investigator’s responsibility to obtain 
such permission from the subject in writing before the subject is entered into the study. 
8.4 
CODING DICTIONARIES  
Concomitant medications entered into the database will be coded using the most current World 
Health Organization Drug Dictionary, which employs the Anatomical Therapeutic Chemical 
classification system. Coexistent diseases and AEs will be coded using Medical Dictionary for 
Regulatory Activities (MedDRA).  
8.5 
DATABASE MANAGEMENT AND QUALITY CONTROL  
Data queries will be reviewed by site and by data type to highlight any data issues that may be 
addressed through additional training or enhancements to the data validation programs. 
A formal quality control review will also be conducted prior to database lock. 
Any required changes to the database design and programming will be managed through a 
detailed change control process. 
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9 
STUDY MANAGEMENT/PROCEDURES AND INSTRUCTIONS  
9.1 
SAFETY-RELATED PROCEDURES  
9.1.1 Rapid notification on serious adverse events  
All AEs that meet any seriousness criteria and AESI must be reported within 24 hours of 
awareness of the AE. 
SAEs and complementary report forms will be reported via eCRF; any additional information will 
be reported to the contact address on the Sponsor Contact List.  
The photocopy of all examinations carried out and the dates on which these examinations were 
performed should be reported to the representative of the monitoring team (refer to the Sponsor 
Contact List). Care should be taken to ensure that the subject's identity is protected and the 
subject's identifiers in the clinical trial are properly mentioned on any copy of source document 
provided to the Sponsor. For laboratory results, include the laboratory normal ranges. 
Do not delay reporting SAEs. Investigators should not wait to receive additional information to 
fully document the event before reporting the SAE. The SAE report should provide the known 
information at the time of awareness that an SAE has occurred. A follow-up report should be sent 
when additional details are known. 
All further data updates should be recorded in the eCRF as appropriate, and further documentation 
as well as additional information (for laboratory data, concomitant medication, subject status, etc) 
should be sent (by fax or e-mail) to the monitoring team within 24 hours of knowledge. In addition, 
any effort should be made to further document within the week (7 days) following initial 
notification any SAE that is fatal or life threatening. 
A back-up plan is used (using paper flow) when the eCRF system does not work. 
9.1.2 Dosing deviations  
Over- or under-dosing are considered protocol deviations. The Investigator must notify Genzyme 
Corporation within 24 hours of any occurrence of overdose with study drug by telephone and by 
faxing/emailing a completed Protocol Deviation Form. 
Symptomatic overdose (serious or non-serious) with IMP: In case of accidental or intentional 
overdose with the study treatment, even not fulfilling a seriousness criterion, is to be reported to 
the Sponsor immediately (within 24 hours) using the AE form together with the SAE 
complementary form to be entered in the eCRF. 
Overdose is defined as increase of at least 30% above the intended dose at each administration or 
any two doses separated by <5 days. 
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9.2 
REGULATORY ISSUES, ETHICS, AND GOOD CLINICAL PRACTICE  
9.2.1 Regulatory guidelines  
This study will be conducted in accordance with the accepted version of the Declaration of 
Helsinki in the version of 1996 and the applicable amendments, and/or all relevant federal 
regulations, as set forth in Parts 50, 54, 56 of Title 21 of the CFR, in compliance with GCP 
guidelines, and as per all applicable local regulatory guidelines and Directive of the European 
Parliament, guidelines set out in Volume 10 of the publication “The rules governing medicinal 
products in the European Union”, and other applicable European Medicines Agency regulations. 
9.2.2 Ethical review  
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant documents 
(eg, advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of changes 
made to the study design, except for changes necessary to eliminate an immediate hazard to study 
subjects. 
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC. 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
• Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European Regulation 536/2014 for clinical 
studies (if applicable), and all other applicable local regulations. 
9.2.3 Informed consent  
• The Investigator or his/her representative will explain the nature of the study to the subject 
or his/her legally authorized representative (defined as an individual or juridical or other 
body authorized under applicable law to consent, on behalf of a prospective subject, to the 
subject's participation in the clinical trial) and answer all questions regarding the study. 
• Subjects must be informed that their participation is voluntary. Subjects or their legally 
authorized representative will be required to sign a statement of informed consent that 
meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act (HIPAA) requirements, where applicable, and the 
IRB/IEC or study center. 
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• The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF. 
• Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
• A copy of the ICF(s) must be provided to the subject or the subject’s legally authorized 
representative. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Section 10.6. 
9.2.4 Regulatory and ethical considerations  
• This study will be conducted in accordance with the protocol and with the following: 
- 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki in the version of 1996 and the applicable amendments and 
Council for International Organizations of Medical Sciences (CIOMS) International 
Ethical Guidelines. 
- 
Applicable ICH Good Clinical Practice (GCP) Guidelines. 
- 
Applicable laws and regulations. 
• The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the Investigator and 
reviewed and approved by the IRB/IEC before the study is initiated. 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study subjects. 
• The Investigator will be responsible for the following: 
- 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC. 
- 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
- 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local regulations.  
9.2.5 Sponsor obligation  
The Sponsor will report all safety observations made during the conduct of the trial in the CSR. 
The Sponsor or its designee (eg, contract research organization [CRO]) will provide protocol 
training to the site study personnel, as appropriate. Clinical monitors will conduct site visits, as 
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needed, to ensure the site procedures are being carried out in accordance with the protocol and 
GCP. Throughout the study period, the clinical monitor will be available to address any issues that 
may arise. This availability includes access by phone, fax, and e-mail. 
Injury in subjects possibly arising from participating in this trial is covered by the liability 
insurance of the Investigator or Sponsor. This insurance provides coverage for damage to the 
subjects through injury or death caused by the trial. 
The Investigator, the clinical site pharmacist, or other personnel allowed to store and dispense 
lademirsen (SAR339375) will be responsible for ensuring that the lademirsen (SAR339375) used 
in the clinical trial is securely maintained as specified by the Sponsor and in accordance with the 
applicable regulatory requirements. 
All lademirsen (SAR339375) shall be dispensed in accordance with the Investigator’s prescription 
and it is the Investigator’s responsibility to ensure that an accurate record of lademirsen 
(SAR339375) issued and returned is maintained. 
Any quality issue noticed with the receipt or use of lademirsen (SAR339375) provided by the 
Sponsor (deficiency in condition, packaging, appearance, pertaining documentation, labeling, 
expiration date, etc) should be promptly notified to the Sponsor, who will initiate a complaint 
procedure (see Section 9.2.7). 
A potential defect in the quality of lademirsen (SAR339375) provided by the Sponsor may be 
subject to initiation of a recall procedure by the Sponsor. In this case, the Investigator will be 
responsible for promptly addressing any request made by the Sponsor, in order to recall 
lademirsen (SAR339375) and eliminate potential hazards. 
Under no circumstances will the Investigator supply lademirsen (SAR339375) provided by the 
Sponsor to a third party, allow the lademirsen (SAR339375) provided by the Sponsor to be used 
other than as directed by this clinical trial protocol, or dispose of lademirsen (SAR339375) 
provided by the Sponsor in any other manner. 
9.2.6 Principal Investigator  
The Principal Investigator has the overall responsibility for the conduct and compliance of this 
clinical trial according to this protocol and GCP. 
Investigators and other key personnel shall provide curriculum vitae or equivalent that will 
confirm their suitability for the clinical study. All Investigators and key personnel should be listed 
together with their responsibilities in the study on a signature and delegation log. 
It is the responsibility of the Investigator to ensure that all personnel involved in the study are 
fully informed of all relevant aspects of the study, including detailed knowledge of and training in 
all procedures to be followed. 
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9.2.7 Guidelines for reporting product complaints (lademirsen [SAR339375])  
Any defect in the lademirsen (SAR339375) must be reported as soon as possible by the 
Investigator to the monitoring team that will complete a product complaint form within required 
timelines. 
Appropriate information (eg, samples, labels or documents like pictures or photocopies) related to 
product identification and to the potential deficiencies may need to be gathered. The Investigator 
will assess whether or not the quality issue has to be reported together with an AE or SAE. 
9.3 
ADMINISTRATIVE PROCEDURES  
9.3.1 Protocol amendment and protocol deviations  
Protocol Amendment 
Amendments to the protocol that entail corrections of typographical errors, clarifications of 
confusing wording, changes in study personnel, and minor modifications that have no impact on 
the safety of subjects or the conduct of the study will be classed as administrative amendments 
and will be submitted to the IRB/IECs and Regulatory Authorities for information only. The 
Sponsor (or designee) will ensure that acknowledgement is received and filed. Amendments that 
are classed as substantial amendments must be submitted to the appropriate Regulatory 
Authorities and the IRBs/IECs for approval. 
Protocol Deviations 
Should protocol deviations that affect a subject’s safety occur, the Sponsor must be informed as 
soon as possible. Protocol deviations will be included in the Clinical Study Report. Reporting of 
protocol deviations to the IRB/IEC and in accordance with applicable Regulatory Authority 
mandates is an Investigator responsibility. 
9.3.2 Monitoring procedures  
The study will be monitored to ensure that it is conducted and documented properly according to 
the protocol, GCP, and all applicable regulatory requirements. 
Before the study start, during the initiation visit, a Sponsor representative will review the protocol 
and the eCRF with the Investigator(s) and their staff. 
During the study, monitoring visits will be made at appropriate times. Clinical monitors will 
monitor the site regularly to check the completeness of subject records, the accuracy of entries on 
the eCRF, the adherence to the protocol and to GCP, the progress of enrollment, and to ensure that 
study drug is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the clinical monitor during these visits. 
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The Investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the eCRF entries. Full verification for the presence of informed consent, 
adherence to the inclusion/exclusion criteria, documentation of SAEs, and the recording of data 
that will be used for all primary and safety variables will be checked. Additional checks of the 
consistency of the source data with the eCRFs are performed according to the study-specific 
monitoring plan. No information in source documents about the identity of the subjects will be 
disclosed. 
9.3.3 Study documentation, confidentiality, and records retention  
Subjects will be assigned a unique identifier by the Sponsor. Any subject records or datasets that 
are transferred to the Sponsor will contain the identifier only; subject names or any information 
which would make the subject identifiable will not be transferred. 
The subject must be informed that his/her personal study-related data will be used by the Sponsor 
in accordance with local data protection law. The level of disclosure must also be explained to the 
subject. 
The subject must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the Sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
9.3.4 Data quality control and quality assurance  
9.3.4.1 Data handling  
Source documents provide evidence for the existence of the subject and substantiate the integrity 
of the data collected. Source documents are filed at the Investigator’s site. 
Data reported or entered in the eCRF that are transcribed from source documents must be 
consistent with the source documents or the discrepancies must be explained. The Investigator 
may need to request previous medical records or transfer records, depending on the study. Also, 
current medical records must be available. 
All subject data relating to the study will be recorded on printed or eCRF unless transmitted to the 
Sponsor or designee electronically (eg, laboratory data). The Investigator is responsible for 
verifying that data entries are accurate and correct by physically or electronically signing the 
eCRF. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 
The Sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
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9.3.5 Audits and inspections  
Periodically, the Sponsor or its authorized representatives audit clinical investigative sites as an 
independent review of core trial processes and documents to determine whether these activities 
were conducted, and data were recorded, analyzed, and accurately reported according to the 
protocol, GCP guidelines of the ICH, and any applicable regulatory requirements. A regulatory 
authority, an IEC or an IRB may visit the site to perform audits or inspections, including source 
data verification. The Investigator should contact the Sponsor, or its designee, immediately if 
contacted by a regulatory agency, an IEC or an IRB about an inspection. 
9.3.6 Financing and insurance  
Prior to the commencement of the study, the Sponsor (or its designee) and the Investigator (or the 
institution, as applicable) will agree on costs necessary to perform the study. This agreement will 
be documented in a financial agreement that will be signed by the Investigator (or the institution 
signatory) and the Sponsor (or its designee).  
The Investigator is required to have adequate current insurance to cover claims for negligence 
and/or malpractice. The Sponsor will provide insurance coverage for the clinical study as required 
by national regulations. 
9.3.7 Publication policy  
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission. 
This allows the Sponsor to protect proprietary information and to provide comments. 
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a coordinating 
Investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 
9.3.8 Dissemination of clinical study data  
The Sponsor shares information about clinical trials and results on publically accessible websites, 
based on company commitments, international and local legal and regulatory requirements, and 
other clinical trial disclosure commitments established by pharmaceutical industry associations. 
These websites include www.clinicaltrials.gov, www.clinicaltrialregister.eu, and 
www.sanofi.com, as well as some national registries. 
In addition, results from clinical trials in subjects are required to be submitted to peer-reviewed 
journals following internal company review for accuracy, fair balance and intellectual property. 
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For those journals that request sharing of the analyzable data sets that are reported in the 
publication, interested researchers are directed to submit their request to 
www.clinicalstudydatarequest.com. 
Individual subject data and supporting clinical documents are available for request at 
www.clinicalstudydatarequest.com. While making information available we continue to protect 
the privacy of subjects in our clinical trials. Details on data sharing criteria and process for 
requesting access can be found at this web address: www.clinicalstudydatarequest.com. 
9.3.9  Data protection   
All personal data collected related to subjects, Investigators, or any person involved in the study, 
which may be included in the Sponsor’s databases, shall be treated in compliance with all 
applicable laws and regulations including the Global Data Protection Regulation (GDPR). 
Data collected must be adequate, relevant and not excessive, in relation to the purposes for which 
they are collected. Each category of data must be properly justified and in line with the study 
objective. 
Subject race will be collected in this study to calculate eGFR (for study conducted in France, see 
Section 10.5.3). Subject ethnicity will also be collected in this study, where permitted by local 
regulations, as a requirement for some regulatory agencies (eg, in the African American 
population for the FDA in the US, or Japanese population for the Pharmaceuticals and Medical 
Devices Agency in Japan). 
• Subjects will be assigned a unique identifier by the Sponsor. Any subject records or 
datasets that are transferred to the Sponsor will contain the identifier only; subject names 
or any information which would make the subject identifiable will not be transferred. 
• The subject must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the subject. 
• The subject must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
• When archiving or processing personal data pertaining to the Investigator and/or to the 
subjects, the Sponsor shall take all appropriate measures to safeguard and prevent access 
to this data by any unauthorized third party. 
9.3.10  Data quality assurance   
• All subject data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
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• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in separate study documents. 
• The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• The Sponsor assumes accountability for actions delegated to other individuals 
(eg, Contract Research Organizations). 
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of subjects are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements. 
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 25 years after the signature of the final study 
report unless local regulations or institutional policies require a longer retention period. No 
records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor. 
9.3.11 Source documents  
• Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site. 
• Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The Investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
9.3.12 Study and site closure  
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
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Reasons for study termination by the Sponsor, as well as reasons for the early closure of a study 
site by the Sponsor or Investigator may include but are not limited to: 
• For study termination: 
- 
Information on the product leads to doubt as to the benefit/risk ratio, 
- 
Discontinuation of further study intervention development. 
• For site termination: 
- 
Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor's procedures, or GCP guidelines, 
- 
Inadequate or no recruitment (evaluated after a reasonable amount of time) of subjects 
by the Investigator, 
- 
Total number of subjects included earlier than expected. 
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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS  
10.1 
APPENDIX 1: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING  
DEFINITION OF AE 
AE definition 
• An AE is any untoward medical occurrence in a subject or clinical study subject, 
temporally associated with the use of study intervention, whether or not considered related 
to the study intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
Events meeting the AE definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the Investigator (eg, not related to progression of underlying 
disease): 
- 
Symptomatic and/or 
- 
Requiring either corrective treatment or consultation, and/or 
- 
Leading to IMP discontinuation or modification of dosing, and/or 
- 
Fulfilling a seriousness criterion, and/or 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. 
• The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE. Also, “lack of 
efficacy” or “failure of expected pharmacological action” also constitutes an AE or SAE. 
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Events NOT meeting the AE definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the subject’s condition.  
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s 
condition. 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
DEFINITION OF SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
A) Results in death 
B) Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
C) Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the subject has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment 
that would not have been appropriate in the physician’s office or outpatient setting. 
Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as 
to whether “hospitalization” occurred or was necessary, the AE should be considered 
serious.  
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
D) Results in persistent disability/incapacity 
- 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
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- 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
E) Is a congenital anomaly/birth defect 
F) Other situations: 
- 
Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious. 
- 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
RECORDING AND FOLLOW-UP OF AE AND/OR SAE 
AE and SAE recording 
• When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• The Investigator will then record all relevant AE/SAE information in the CRF. 
• It is not acceptable for the Investigator to send photocopies of the subject’s medical 
records to the Sponsor’s representative in lieu of completion of the AE/SAE CRF page. 
• There may be instances when copies of medical records for certain cases are requested by 
the Sponsor’s representative. In this case, all subject identifiers, with the exception of the 
subject number, will be redacted on the copies of the medical records before submission to 
the Sponsor’s representative. 
• The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to 1 of the following categories: 
• Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not 
interfering with everyday activities. 
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• Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities. 
• Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with a SAE. Severe is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE, NOT when it is rated as severe. 
Assessment of causality 
• The Investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. 
• A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• The Investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• The Investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
• For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to the Sponsor’s representative. However, it is 
very important that the Investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to the Sponsor’s 
representative. 
• The Investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of AEs and SAEs 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor’s 
representative to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
• If a subject dies during participation in the study or during a recognized follow-up period, 
the Investigator will provide the Sponsor’s representative with a copy of any post-mortem 
findings including histopathology. 
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• New or updated information will be recorded in the originally completed CRF. 
• The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
REPORTING OF SAES 
SAE reporting to the Sponsor’s representative via an electronic data collection tool 
• The primary mechanism for reporting an SAE to the Sponsor’s representative will be the 
electronic data collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data collection 
tool (see next section) in order to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes available. 
• After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study subject or receives updated data on a 
previously reported SAE after the electronic data collection tool has been taken offline, 
then the site can report this information on a paper SAE form (see next section) or to the 
Sponsor’s representative by telephone. 
• Contacts for SAE reporting can be found on the Sponsor Contact List. 
SAE reporting via paper CRF (if eCRF is not available) 
• Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to the Sponsor. 
• In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the SAE data collection tool sent by overnight mail or courier 
service. 
• Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the SAE CRF pages within the designated reporting time frames. 
• Contacts for SAE reporting can be found on the Sponsor Contact List. 
10.2 
APPENDIX 2: CLINICAL LABORATORY  
The tests detailed in Table 7 will be performed by the central laboratory.  
• Local laboratory results are only required in the event that the central laboratory results are 
not available in time for either IMP administration and/or response evaluation. 
Additionally, if the local laboratory results are used to make either an IMP decision or 
response evaluation, the results and normal ranges must be entered into the CRF. 
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• Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Section 3.2.1 and Section 3.2.2 of the protocol. 
• Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or required by local regulations. 
Table 7 - Protocol required safety laboratory assessments  
Laboratory 
assessments 
Parameters 
Hematology 
To include hemoglobin, hematocrit, platelet count, total white blood cell (WBC) count with 5-part differential 
count, and total red blood cell count.  
Clinical chemistry 
To include creatinine, blood urea nitrogen, glucose, uric acid, total cholesterol, total protein, albumin, total 
and direct bilirubin, ALT, AST, alkaline phosphatase, GGT, lactate dehydrogenase, sodium, potassium, 
chloride, bicarbonate, calcium, iron, phosphate, total cholesterol, triglycerides, HDL, LDL, prothrombin time 
(PT), activated partial thromboplastin time (aPTT), international normalized ratio (INR), and fibrinogen. 
Routine 
urinalysis 
To include specific gravity, pH, glucose, ketones, blood, protein, nitrate, leukocyte esterase, urobilinogen, 
and bilirubin. If specific gravity, PH, glucose, ketones, nitrate, leukocyte esterase, urobilinogen, and 
bilirubin parameters on the dipstick are abnormal, the investigation will be done by the Investigator as per 
local practice.  
Other tests 
Clinical laboratory testing at Screening Visit 1 will include hepatitis screen covering HBs Ag, hepatitis B 
surface antibody (HBs Ab), HBc Ab, hepatitis C virus antibodies (HCV Ab), HIV screen (Anti-HIV-1 and 
HIV-2 antibodies) and anti-nuclear antibody (ANA). In case of results showing HBs Ag (negative) and HBc 
Ab (positive), an HBV DNA testing may be performed prior to randomization to rule out a false positivity if 
the Investigator believes the subject is a false positive, or to clarify the serological status if the Investigator 
finds it unclear to interpret in absence of known HBV infection. In case of results showing HCV Ab 
(positive), an HCV RNA testing may be performed to rule out a false positivity, if the Investigator believes 
the subject is a false positive.  
Note: Anti-ds DNA antibody will be tested if ANA is positive (≥1:160 titer).  
 
Investigators must document their review of each laboratory safety report. 
Laboratory/analyte results that could unblind the study will not be reported to investigative sites 
or other blinded personnel until the study has been unblinded. 
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10.3 
APPENDIX 3: SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP ASSESSMENTS  
10.3.1 Neutropenia  
 
Neutropenia is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting adverse events in Section 10.1 is met. 
Neutrophils < 1500/mm3 or according to ethnic 
group
NEUTROPENIA
Repeat immediately a full blood count if value 
close to 1500/mm3
Neutrophils < 1500/mm3 confirmed 
with signs of infection  
Neutrophils < 1500/mm3 confirmed 
with no signs of infection  
1.
DISCONTINUE
Investigational Medicinal 
Product, hospitalization 
should be considered
2.
PERFORM biological 
investigations for infection
1.
DISCONTINUE
Investigational 
Medicinal Product
2.
INVESTIGATE for 
infection
In both situations
3.
INFORM the local monitor
4.
INVESTIGATE previous treatments particularly long-term, even a long time ago, 
exposure to toxic agents, e.g., benzene, X-rays, etc.
5.
PERFORM and collect the following investigations (results): 
•
RBC and platelet counts
•
Serology: EBV, (HIV), mumps, measles, rubella
6.
DECISION for bone marrow aspiration: to be taken in specialized unit
7.
COLLECT/STORE one sample following handling procedures described in PK 
sections (for studies with PK sampling) and freeze one serum sample (5 mL) on 
Day 1 (cessation of investigational medicinal product) and Day 5 (for further 
investigations)
8.
MONITOR the leukocyte count 3 times per week for at least one  week, then twice a 
month until it returns to normal
Note: 
•The procedures described in the above flowchart are to be discussed with the patient only in case 
the event occurs. If applicable (according to local regulations), an additional consent (e.g., for 
HIV testing) will only be obtained in the case the event actually occurs.
•For individuals of African descent, the relevant value of concern is <1000/mm3
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10.3.2 Abnormal liver function  
AT > 3 ULN
Monitor LFTs every 72 hours
AT ≤ 5 ULN
AT > 3 ULN & 
Total Bilirubin > 2 ULN 
Permanent Discontinuation of IMP
AT > 5 ULN 
In ANY CASE, FOLLOW the instructions listed in the box below: 
1.
INFORM the Site Monitor who will forward the information to the Study Manager
2.
INVESTIGATE specifically, for malaise with or without loss of consciousness, dizziness, and/or 
hypotension and/or episode of arrhythmia in the previous 72 hours; rule out muscular injury
3.
PERFORMthe following tests:
- LFTs: AST, ALT, alkaline phosphatase, total and conjugated bilirubin and prothrombin time / INR
- CPK, serum creatinine, complete blood count
- Anti-HAV IgM, anti-HBc IgM, (HBV-DNA if clinically indicated), anti-HCV and HCV RNA, anti-
CMV IgM and anti-HEV IgM antibodies
- Depending on the clinical context, check for recent infection with EBV, herpes viruses, and toxoplasma
- Hepatobiliary ultrasonography (or other imaging investigations if needed)
4.
CONSIDER Auto-antibodies: antinuclear, anti-DNA, anti-smooth muscle, anti-LKM
5.
CONSIDERconsulting with hepatologist
6.
CONSIDERpatient hospitalization if INR>2 (or PT<50%) and/or central nervous system disturbances 
suggesting hepatic encephalopathy
7.
MONITOR LFTs after discontinuation of IMP:
- As closely as possible(or every 48 hours) until stabilization, then every 2 weeks until return to 
normal/baseline or clinicalresolution.
COMPLETE the specific CRF forms 
for „ALT Increase” and inform the 
Monitoring Team within 24 hours
Confirm AT > 3 ULN
Retest within 72 hours of initial sample*
Temporary Interruption of 
IMP until AT return to 
baseline or ≤ 2 × ULN
INCREASE IN AT (ALT or AST)
Notes: Upon resumption of study drug, transaminases and bilirubin should be assessed
weekly for 4 weeks and the dose will be reduced to 110 mg Q2W. If a protocol-defined
transaminase elevation interruption threshold recurs within 4 weeks of rechallenge with
the study drug (with confirmation of the initial elevation by repeat testing within 48 to
72 hours), then the study drug must be permanently discontinued, regardless of the
presumed etiology.
 
“Baseline” refers to ALT sampled at baseline visit; or if baseline value unavailable, to the latest ALT sampled before the baseline 
visit. The algorithm does not apply to the instances of increase in ALT during screening. 
See Section 10.1 for guidance on safety reporting. 
 
Normalization is defined as ≤ULN or baseline value, if baseline value is >ULN. 
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10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION  
DEFINITIONS: 
Woman of childbearing potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
- 
Documented hysterectomy 
- 
Documented bilateral salpingectomy 
- 
Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, mullerian agenesis, androgen insensitivity), Investigator discretion 
should be applied to determining study entry. 
Note: Documentation can come from the site personnel’s: review of the subject’s medical 
records, medical examination, or medical history interview. 
3. Postmenopausal female 
- 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
- 
A high follicle stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception or 
hormonal replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, confirmation with more than one FSH measurement is required. 
- 
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
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COLLECTION OF PREGNANCY INFORMATION: 
Male subjects with partners who become pregnant 
• The Investigator will attempt to collect pregnancy information on any male subject’s 
female partner who becomes pregnant while the male subject is in this study. This applies 
only to male subjects who receive lademirsen (SAR339375). 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within [24 hours] of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the Sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure. 
Female subjects who become pregnant 
• The Investigator will collect pregnancy information on any female subject who becomes 
pregnant while participating in this study. Information will be recorded on the appropriate 
form and submitted to the Sponsor within 24 hours of learning of a subject’s pregnancy. 
The subject will be followed to determine the outcome of the pregnancy. The Investigator 
will collect follow-up information on the subject and the neonate and the information will 
be forwarded to the Sponsor. Generally, follow-up will not be required for longer than 6 to 
8 weeks beyond the estimated delivery date. Any termination of pregnancy will be 
reported, regardless of fetal status (presence or absence of anomalies) or indication for the 
procedure. 
• Any pregnancy complication or elective termination of a pregnancy will be reported as an 
AE or SAE. A spontaneous abortion (occurring at <22 weeks gestational age) or stillbirth 
(occurring at >22 weeks gestational age) are always considered to be an SAE and will be 
reported as such. Any post-study pregnancy related SAE considered reasonably related to 
the study intervention by the Investigator will be reported to the Sponsor as described in 
Section 10.1. While the Investigator is not obligated to actively seek this information in 
former study subjects, he or she may learn of an SAE through spontaneous reporting. 
• Any female subject who becomes pregnant while participating in the study will 
discontinue study intervention or be withdrawn from the study. 
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10.5 
APPENDIX 5: COUNTRY-SPECIFIC REQUIREMENTS  
10.5.1 Germany  
10.5.1.1 Additional details regarding potential risks associated with study participation  
More detailed information about the potential risks associated with study participation are 
provided below. Additional details about the known and expected benefits and risks associated 
with lademirsen (SAR339375), and the reasonably expected adverse events of lademirsen 
(SAR339375), may be found in the Investigator’s Brochure. 
As stated in Section 1.3.1, potential side effects of lademirsen (SAR339375) fall into three broad 
categories: 1) class effects, 2) nonclinical toxicology findings, and 3) clinical data with lademirsen 
(SAR339375). Side effects observed with other oligonucleotide drugs include reductions in 
complement and platelet counts and abnormalities in liver function tests. Nonclinical toxicity 
studies have identified reduced albumin, hemoglobin, other red blood cell (RBC) parameters, and 
platelets; activation of the alternative complement pathway; prolongation of activated partial 
thromboplastin time (aPTT), and weight loss as side effects. In the RG012-05 Phase 1 multiple 
ascending dose study a Grade 1 thrombocytopenia AE occurred in a single subject which 
spontaneously resolved while the subject continued to receive lademirsen (SAR339375). Injection 
site reactions observed in both the single ascending dose and multiple ascending studies were 
generally mild and infrequently moderate and did not lead to discontinuation of study drug.  
10.5.1.1.1 Immune system effects  
Chronic administration of lademirsen (SAR339375) was associated with dose-related pro-
inflammatory effects in both mice and monkeys, as expected for this drug class. Findings included 
1) decreased platelet counts (as discussed in IB Section 7.1.3), 2) increased serum globulin 
concentrations, 3) changes in lymphoid organ weight, 4) infiltration of histiocytes/mononuclear 
cells/lymphocytes into tissues, and/or 5) lymphoid tissues changes such as hematopoiesis, white 
pulp development in spleen, germinal center hyperplasia, decreased cellularity in spleen and 
lymph nodes, sinus plasmacytosis in lymph nodes, and/or decreased cortical cellularity in thymus. 
However, oligonucleotide-related complement activation is considered to be species specific and 
not translatable to humans. The likelihood of complement activation by lademirsen (SAR339375) 
and/or its active N-1 metabolite (RG0005) in clinical trials is low because the plasma SUM 
(SAR339375 + RG0005) Cmax at 110 mg QW (Study RG012-05) was 2.27 μg/mL, which is 
substantially lower than the plasma concentrations (≥~26 μg/mL) required for complement 
activation in monkeys. Furthermore, humans are less sensitive to oligonucleotide-related 
complement activation than monkeys (Shen et al, 2014; listed in Section 10.5.1.1.5). 
10.5.1.1.2 Injection site effects  
Lademirsen (SAR339375)-related injection site observations seen in a few 100 and 
300 mg/kg/week male mice included hair loss and/or skin scab/crust of the back, neck, shoulder, 
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or injection (dose) site. In monkeys in the 13- and 39-week studies, lademirsen (SAR339375)-
related changes at the injection site were observed in a few 30 and 100 mg/kg/week animals 
(discoloration, erythema, scab/crust, and lump/swollen) and typically occurred after the first dose 
and/or were transient. Microscopically in the 39-week study, epidermal hyperplasia, fibroplasia, 
mononuclear/mixed cell infiltrates, and SC hemorrhage were observed at injection sites in test 
article-treatment monkeys. 
In addition to the nonclinical findings, mild ISRs occurred commonly with lademirsen 
(SAR339375) in clinical studies; 43% and 46% of subjects in the healthy volunteer studies 
RG012-02 and RG012-05, respectively, experienced mild ISRs. Moderate ISRs occurred in 30% 
and 21% of subjects in RG012-02 and RG012-05 studies, respectively. In the PDY16327 
(RG012-06) study, conducted in patients with Alport syndrome, all patients reported mild and/or 
moderate ISRs during the study. No severe ISRs have been reported in the clinical studies. 
10.5.1.1.3 Anti-drug antibody effects  
Anti-drug antibodies were evaluated in the 39-week monkey study. In all lademirsen 
(SAR339375)-treatment groups (ie, 3 to 100 mg/kg/week), confirmed positive ADA responses 
were observed with the time of onset in animals ranging from 2-9 months after the start of 
treatment. ADAs were also present in the recovery phase. ADA responses generally resulted in 
highly elevated (several-fold) plasma trough concentrations but had no meaningful impact on 
plasma Cmax and AUC values for lademirsen (SAR339375), RG0005, and SUM, except in animals 
with titers of 12 800 or higher. In these animals (titers ≥12 800) several-fold increases in Cmax and 
AUC were also observed, in addition to increases in Ctrough. Although ADAs correlated with 
increases in serum IgG, IgM, and gamma globulin concentrations, microscopic examination did 
not indicate any changes indicative of antibody-mediated effects. However, high ADA titers 
(>100 000) were observed in five of the eight monkeys with glomerulopathy; the causal 
relationship is unclear, particularly since IHC staining suggests a mechanism mediated by 
complement activation rather than by immune complex deposition.  
The results of ADA testing in healthy volunteers (study RG012-05) show a low incidence of 
confirmed antibody responses to lademirsen (SAR339375) treatment that are transient. In patients 
with Alport syndrome (study PDY16327), 2 of 4 subjects developed low titers of ADAs (but 
without associated AEs suggestive of systemic hypersensitivity reactions). Due to the limited 
number of subjects in the PDY16327 study, a potential association between ADAs and ISR could 
not be established. ADAs have also been reported in clinical trials with other oligonucleotides. As 
the presence of high titers of ADAs was associated with changes in the overall exposure of 
lademirsen (SAR339375) and glomerulopathy in the chronic monkey toxicity study, monitoring 
of ADA is warranted and is planned for ACT16248. 
It is not known whether the ADA observed in 2 of 4 subjects in study PDY16327 were 
neutralizing antibodies (NAb) or not. However, it is known from literature data that 
oligonucleotide therapeutics distribute rapidly to intracellular sites of action. Thus, even if an 
immune response occurred proximal to the site of action, the majority of the targeted drug is 
likely to be inaccessible to the ADA. Because of this, it is unlikely that the ADA would be able to 
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bind to enough of the drug to have a clinically relevant neutralizing effect (Stebbins et al, 2019; 
listed in Section 10.5.1.1.5). 
10.5.1.1.4 Drug accumulation effects  
Oligonucleotides generally accumulate in liver and kidneys; thus there is a theoretical risk of liver 
and/or kidney toxicity following repeated administration of oligonucleotide therapeutics. 
Concentrations of lademirsen (SAR339375), RG0005, and SUM (SAR339375 + RG0005) were 
measured in mouse liver and kidney (24 h post-dose) following the first and last doses in a 
26-week mouse toxicity study (RG012.Tox.004). Accumulation of SUM in mouse liver and 
kidney at doses of 50 to 300 mg/kg ranged from 3.5 to 5.0-fold (liver) and 1.8 to 2.9-fold 
(kidney).  
10.5.1.1.5  References supporting the additional details regarding potential risks  
Shen L, Frazer-Abel A, Reynolds PR, Giclas PC, Chappell A, Pangburn MK, et al. Mechanistic 
understanding for the greater sensitivity of monkeys to antisense oligonucleotide-mediated 
complement activation compared with humans. J Pharmacol Exp Ther. 2014;351(3):709-17. 
Stebbins CC, Petrillo M, Stevenson LF. Immunogenicity for antisense oligonucleotides: a risk-
based assessment. Bioanalysis. 2019 Nov;11(21):1913-6. 
10.5.2 China  
10.5.2.1 Study objectives and endpoints  
10.5.2.1.1 Exploratory objectives  
There are no exploratory objectives for Chinese subjects.  
The content of this section supersedes the content of Section 2.3 for study conduct in China. 
10.5.2.1.2 Pharmacodynamic and exploratory endpoints  
No exploratory endpoints will be evaluated for Chinese subjects.  
The content of this section supersedes the content of Section 7.1.3 for study conduct in China. 
10.5.2.2 Pharmacodynamic assessments and biomarkers  
No exploratory biomarkers will be evaluated for Chinese subjects. The following assessments will 
not be evaluated for Chinese subjects: β2-microglobulin, calbindin-D28k, CTGF, microRNAs 
(other than miR-21, as listed above), and KIM-1. 
The content of this section supersedes the content of Section 6.4 for study conduct in China. 
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10.5.2.3 Sample storage and disposition of samples after study completion  
Plasma/serum samples for storage to support exploratory objectives (listed in Table 1, Section 5.2, 
and Section 5.4) will not be collected for Chinese subjects. 
All residual mandatory samples from Chinese subjects have to be destroyed upon CSR 
completion, at the latest. 
The content of this section supersedes the content of Section 6.6 for study conduct in China. 
10.5.3 France  
Race will not be collected and will not be used in the eGFR calculation for French subjects. For 
these subjects, the eGFR will be calculated using the new CKD-EPI creatinine equation (2021) 
which does not have a race variable (33): 
eGFR = 142 × min(Scr/κ, 1)α × max(Scr/κ, 1)-1.200 × 0.9938Age × 1.012 [if female], where Scr is 
serum creatinine in mg/dL, κ is 0.7 for females and 0.9 for males, α is -0.241 for females 
and -0.302 for males, and min indicates the minimum of Scr/κ and 1 and max indicates the 
maximum of Scr/κ and 1. 
10.6 
APPENDIX 6: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY  
A regional or national emergency declared by a governmental agency (eg, public health 
emergency, natural disaster, pandemic, terrorist attack) may prevent access to the clinical trial 
site. 
Contingency procedures are suggested below for an emergency that prevents access to the study 
site, to ensure the safety of the participants, to consider continuity of the clinical study conduct, 
protect trial integrity, and assist in maintaining compliance with Good Clinical Practice in 
Conduct of Clinical Trials Guidance. Sponsor agreement MUST be obtained prior to the 
implementation of these procedures for the duration of the emergency; this agreement must be 
provided in writing by the Sponsor and will be kept in the Investigator file. 
During the emergency, if the site will be unable to adequately follow protocol mandated 
procedures, screening and enrollment may be temporarily delayed/halted.  
Attempts should be made to perform all assessments in accordance with the approved protocol to 
the extent possible. In case this is not possible due to a temporary disruption caused by an 
emergency, focus should be given to assessments necessary to ensure the safety of participants 
and those important to preserving the main scientific value of the study. 
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10.6.1 Informed consent   
For a regional or national emergency declared by a governmental agency, contingency procedures 
may be implemented for the duration of the emergency. The participant or their legally authorized 
representative should be verbally informed prior to initiating any changes that are to be 
implemented for the duration of the emergency (eg, study visit delays/treatment extension, use of 
local labs), and the verbal information given to the patient should be documented in the subject’s 
medical record.  
10.6.2 Study procedures  
Procedures to be considered in the event of a regional or national emergency declared by a 
governmental agency: 
1. New screenings during a regional or national emergency declared by a governmental 
agency can be performed only if allowed by local competent authorities and after 
Sponsor’s agreement is obtained. Rescreening will be permitted when the situation 
normalizes and only if allowed by local competent authorities and after Sponsor’s 
agreement is obtained.  
2. If onsite visits or alternative location (out of subject’s home) are not possible, all visits 
from week 1 (including those planned to be done onsite) will be performed at home by a 
trained healthcare professional and if allowed by local competent authorities for: 
- 
Treatment administration  
- 
Blood sampling for safety (at least hematology, hepatic function panel, coagulation 
panel) and efficacy assessment (at least serum creatinine for eGFR calculation), and 
pregnancy test (if applicable) 
- 
Measuring vital signs 
- 
Monitoring of ISR, AEs and SAEs  
The use of a local laboratory may be allowed for safety follow up in case the central lab cannot be 
used. 
The Investigator or delegate will perform a phone-call visit at each onsite planned visit to collect 
safety data and concomitant treatment. All data collected remotely will be properly documented in 
the subject’s medical record and the study CRF. 
For all assessments which will not be performed remotely, the assessment windows will be 
extended until subjects may access the site.  
If onsite visit and home visit are not possible, a temporary treatment discontinuation may be 
considered. The Investigator or delegate will perform a phone-call visit at each onsite planned 
visit to collect safety data and concomitant treatment. 
Contingencies implemented due to emergency will be documented in the subject’s medical 
record. 
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10.6.3 Temporary discontinuation  
A temporary treatment discontinuation may be considered by the Investigator because of 
suspected AEs or disruption of the clinical trial due to a regional or national emergency declared 
by a governmental agency.  
Reinitiation of study drug can only occur once the Investigator has determined, according to 
his/her best judgement, that the study drug did not contribute to the occurrence of the epidemic 
event (eg, COVID-19). 
For all temporary intervention discontinuations, duration should be recorded by the Investigator in 
the appropriate pages of the CRF or eCRF.  
10.6.4 Statistical analysis  
The impact of the regional or national emergency declared by a governmental agency on study 
conduct will be summarized (eg, study discontinuation or discontinuation/delay/omission of the 
intervention due to the emergency). Any additional analyses and methods required to evaluate the 
impact on efficacy (eg, missing data due to the emergency) and safety will be detailed in the SAP. 
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10.7 
APPENDIX 7: ABBREVIATIONS  
 
%: 
percentage 
ACE: 
angiotensin-converting enzyme 
ACR: 
albumin to creatinine ratio 
ADAs: 
anti-drug antibodies 
ADAS: 
autosomal dominant Alport syndrome 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALP: 
alkaline phosphatase 
ALT: 
alanine aminotransferase 
ANA: 
anti-nuclear antibody 
aPTT: 
activated partial thromboplastin time 
ARAS: 
autosomal recessive Alport syndrome 
ARB: 
angiotensin II receptor blocker 
AST: 
aspartate aminotransferase 
AUC: 
area under the concentration-time curve 
BUN: 
blood urea nitrogen 
CBC: 
complete blood count 
CFR: 
Code of Federal Regulations 
CKD-EPI: 
Chronic Kidney Disease Epidemiology Collaboration 
COL1A1: 
Type I collagen alpha chain gene 1 
COL3A1: 
Type III collagen alpha chain gene 1 
COL4A3/4/5: 
Type IV collagen alpha chain gene 1 
CONSORT: 
Consolidated Standards of Reporting Trials 
COVID-19: 
coronavirus disease 2019 
CRO: 
contract research organization 
CSR: 
clinical study report 
CTGF: 
connective tissue growth factor 
CV: 
coefficient of variation 
DMC: 
Data Monitoring Committee 
DTP: 
direct to patient 
ECG: 
electrocardiogram 
eCRF: 
electronic case report form 
EDC: 
electronic data capture 
EGF: 
epidermal growth factor 
eGFR: 
estimated glomerular filtration rate 
ESRD: 
end-stage renal disease 
ET: 
early termination 
FDA: 
Food and Drug Administration 
FSH: 
follicle stimulating hormone 
GCP: 
Good Clinical Practice 
GDPR: 
Global Data Protection Regulation 
GFR: 
glomerular filtration rate 
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GGT: 
gamma-glutamyl transferase 
GLP: 
Good Laboratory Practice 
HAV: 
hepatitis A virus 
HBs Ab: 
hepatitis B surface antibody 
HBsAg: 
hepatitis B surface antigen 
HCV: 
hepatitis C virus 
HDL: 
high-density lipoprotein 
HEENT: 
head, ears, eyes, nose, throat 
HIPAA: 
Health Insurance Portability and Accountability Act 
HIV: 
human immunodeficiency virus 
HRT: 
hormonal replacement therapy 
hs-CRP: 
high-sensitivity C-reactive protein 
IA: 
interim analysis 
IB: 
Investigator's Brochure 
ICF: 
informed consent form 
ICH: 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IMP: 
investigational medicinal product 
IND: 
investigational new drug 
INR: 
international normalized ratio 
IRB: 
Institutional Review Board 
IRT: 
Interactive Response Technology 
ISR: 
injection site reaction 
ITT: 
intent-to-treat 
KIM-1: 
kidney injury molecule-1 
LDL: 
low-density lipoprotein 
LLN: 
lower limit of normal 
MedDRA: 
Medical Dictionary for Regulatory Activities 
miR: 
microRNA 
MMRM: 
mixed effects model with repeated measures 
n: 
number 
NGAL: 
neutrophil gelatinase-associated lipocalin 
NHP: 
non-human primates 
NOAEL: 
no-observed-adverse-effect levels 
PCSA: 
potentially clinically significant abnormality 
PK: 
pharmacokinetic 
PPARα: 
peroxisome proliferator-activated receptor alpha 
PT: 
preferred term 
Q2W: 
every two weeks 
QTcF: 
Fridericia-corrected QT interval 
QW: 
every week 
RBC: 
red blood cell 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SC: 
subcutaneous(ly) 
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SD: 
standard deviation 
SEC: 
Safety Evaluation Committee 
SOC: 
System Organ Class 
SUM: 
SAR339375 + RG0005 
TEAE: 
treatment-emergent adverse event 
TGF-β: 
transforming growth factor-β 
TK: 
toxicokinetic 
UACR: 
urine albumin-to-creatinine 
ULN: 
upper limit of normal 
UPCR: 
urine protein-to-creatinine ratio 
UUO: 
unilateral ureteral obstruction 
WBC: 
white blood cell 
WOCBP: 
woman of childbearing potential 
XLAS: 
X-linked Alport syndrome 
 
10.8 
APPENDIX 8: PROTOCOL AMENDMENT HISTORY  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the names and addresses of the monitoring team’s representative. 
10.8.1 Amended protocol 11 (10 August 2021)  
This amended protocol (amendment 11) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
The purpose of this amendment is to clarify the action to be taken with study drug dosing for 
adverse events and injection site reactions, to revise the stopping criteria for study drug dosing, 
and to revise the definition of adverse events of special interest. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Protocol Synopsis / Individual Treatment 
Stopping Criteria 
AND 
3.3.1.1 Individual Treatment Stopping 
Criteria 
The phrase “except for renal function 
parameters related to the underlying 
disease process including eGFR, 
creatinine, BUN, and urinalysis” was added 
in parenthesis in the first paragraph. 
To clarify the action to be taken 
with study drug dosing for Grade 2 
adverse events associated with 
renal function parameters and 
considered by the Investigator to 
be at least possibly related to study 
drug. 
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Section # and Name 
Description of Change 
Brief Rationale 
The following sentence was added to the 
first paragraph regarding the grading of 
injection site reactions and the action to be 
taken for study drug dosing: “Injection site 
reactions (ISRs) will be graded according to 
Table 6. Any Grade 2 (except 
erythema/redness) or Grade 3 ISRs which 
had not resolved or reached Grade 1 
(“Mild”, eg, limited tenderness, and/or 
induration, except erythema/redness) prior 
to the next dose, would result in a pausing 
of dosing.” 
For alignment with the update in 
Section 4.5. 
The event “eGFR” was added to the 
parenthesis in the first sentence of the 
second paragraph. 
For clarification. 
In the list of adverse events for which study 
drug should be discontinued, the third bullet 
regarding unintended weight loss was 
revised to increase the threshold for 
change to ≥20% from baseline. In addition, 
the fourth bullet regarding estimated 
glomerular filtration rate and its decline was 
revised to include a decline of ≥50% from 
the last measurement, and not from 
baseline, or confirmed end-stage renal 
disease. 
To reflect that 1) estimated 
glomerular filtration rate decrease 
is the expected progression of the 
underlying disease (as a reminder, 
change in estimated glomerular 
filtration rate is the primary efficacy 
endpoint of this study), and 2) mild 
or moderate weight loss is an 
expected manifestation of the 
underlying disease. 
Protocol Synopsis / Study Suspension 
and Stopping Criteria 
AND 
3.4 Discontinuation of the Study 
The phrase “except for ISRs and renal 
function parameters related to the 
underlying disease process including 
eGFR, creatinine, BUN, and urinalysis” was 
added in parenthesis to the first paragraph. 
To align with the revised guidance 
for study drug dosing with regard to 
injection site reactions or adverse 
events associated with renal 
function parameters. 
Protocol Synopsis / Table 1 
Schedule of events revised to include 1 day 
post injection follow-up assessments to be 
performed on a weekly basis. 
For clarification. 
Serum chemistry, lipid panel, and 
high-sensitivity C-reactive protein 
assessments included for unscheduled 
visits. 
For consistency with the 
assessments to be performed at 
unscheduled visits during the 
open-label treatment extension 
period and follow-up period. 
Protocol Synopsis / Table 2 
Schedule of events revised to (1) remove 
blood sampling for pharmacokinetic 
(pre-dose) assessments at unscheduled 
visits, and (2) include 1 day post injection 
follow-up assessments to be performed on 
a weekly basis from Week 48 to Week 96 
(corresponding footnote [cc] added to 
describe purpose/scope of follow-up 
assessment).  
Pharmacokinetic sampling at 
unscheduled visits removed for 
consistency with the assessments 
to be performed during the 
double-blind, placebo-controlled 
treatment period.  
Post injection follow-up 
assessments added for 
clarification.  
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Section # and Name 
Description of Change 
Brief Rationale 
Blood sampling for complement removed 
from unscheduled visits. 
For consistency with the 
assessments to be performed at 
unscheduled visits during the 
double-blind, placebo-controlled 
treatment period. 
Protocol Synopsis / Table 1  
AND 
Protocol Synopsis / Table 2 
Footnote “q” in Table 1 and footnote “i” in 
Table 2 describing urinalysis parameters 
revised to the following “Urinalysis: 
assessment of colour and appearance, and 
dipstick test for specific gravity, 
erythrocytes, pH, protein, glucose, ketones, 
leukocyte esterase, nitrate, bilirubin, and 
urobilinogen will be done locally. 
Microscopic examination of urine sediment, 
microalbuminuria, urine creatinine, and 
urine protein will be a laboratory test.” 
To clarify which urinalysis 
parameters will be performed 
locally (and with a dipstick test) and 
which will be performed by central 
laboratory. 
1.3.1 Potential Risks 
Section 1.3.1 title and content revised to 
describe both identified and potential risks 
associated with lademirsen (in accordance 
with this change, Section 1.3 title revised to 
“Risks and Benefits”). 
For alignment with the language in 
the current Investigator’s Brochure. 
4.5 Dose Reduction 
The fourth paragraph was revised to the 
following “Any Grade 2 (except 
erythema/redness) or Grade 3 ISRs which 
had not resolved or reached Grade 1 
(“Mild”, eg, limited tenderness, and/or 
induration, except erythema/redness) prior 
to the next dose, would result in a pausing 
of dosing.” 
To clarify the grading of injection 
site reactions and the action to be 
taken with study drug dosing for 
Grade 2 and Grade 3 injection site 
reactions. 
4.6 Randomization Code Breaking During 
the Study 
The first paragraph was revised to the 
following “If the Investigator decides that 
unblinding is warranted, he/she may, at 
his/her discretion, contact the Sponsor to 
discuss the situation prior to unblinding a 
subject’s treatment assignment unless this 
could delay emergency treatment for the 
subject.” 
To align with standardized template 
language.  
Minor revisions were made to the third 
paragraph as follows “If a subject’s 
treatment assignment is unblinded, the 
Sponsor must be notified within 24 hours of 
this occurrence.” 
Second sentence of final paragraph revised 
to include “then the subject will be 
withdrawn from the treatment”. 
For clarification. 
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Section # and Name 
Description of Change 
Brief Rationale 
4.8 Prior and Concomitant Medications 
Statement regarding coronavirus 
disease 2019 vaccination added: 
“Vaccination for coronavirus disease 2019 
(COVID-19) will not have an impact on 
subject enrollment or study drug treatment. 
No wash-out period is required between 
vaccination and initiation of study drug. 
Nevertheless, it is preferred that the COVID-
19 vaccination and the study drug injection 
are separated by at least 48 hours to allow 
an adequate evaluation of potential AEs.” 
To clarify that coronavirus 
disease 2019 vaccination is not 
deemed to impact study conduct. 
6.2.1 Adverse Events 
Phrase “Grade ≥2” removed from 
description of adverse events of special 
interest in parenthesis. 
For alignment with revised 
definition of adverse events of 
special interest added in 
Sections 6.2.2 and 6.2.3. 
6.2.2 Adverse Event of Special Interest 
For other specific adverse events of special 
interest to be closely monitored, text 
updated to include all Grade ≥2 events 
listed in Table 3 (except for estimated 
glomerular filtration rate) and Grade ≥3 
events of estimated glomerular filtration 
rate. 
To reflect that adverse events of 
special interest subject to close 
monitoring have been revised to 
include all Grade ≥2 events (as per 
Table 3), except for estimated 
glomerular filtration rate, and 
Grade ≥3 events of estimated 
glomerular filtration rate.  
Estimated glomerular filtration rate 
decrease is the expected 
progression of the underlying 
disease (as a reminder, change in 
estimated glomerular filtration rate 
is the primary efficacy endpoint of 
this study). 
6.2.3 Adverse Events Grading 
Table 3 revised as follows: 
Unintentional weight loss parameter 
removed 
Footnote a: deleted 
Footnote b: renumbered to footnote a. 
Weight loss observed in animal 
studies occurred with a 
substantially higher dose of 
lademirsen than that used in the 
current study. Significant 
unintentional weight loss has not 
been observed in any clinical 
studies to date. 
6.2.4 Adverse Event Outcome 
Description of adverse event outcomes 
revised from “recovered” and “recovering”, 
to “recovered/resolved” and 
“recovering/resolving”. 
For alignment with the adverse 
event outcome definitions 
presented in Table 5. 
6.2.7 Procedures in Case of Pregnancy 
AND 
10.4 Appendix 4: Contraceptive Guidance 
and Collection of Pregnancy Information 
For female subjects who become pregnant, 
the phrase “occurring at <22 weeks 
gestational age) or stillbirth (occurring at 
>22 weeks gestational age” was added to 
the description of spontaneous abortion.  
To clarify the definition of 
spontaneous abortion and to 
add/define the term stillbirth. 
6.2.14 Laboratory Assessments 
The statement “except for BUN, UPCR, 
UACR, creatinine and Cystatin C” was 
added in parenthesis to the fourth 
paragraph. 
For clarification. 
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Section # and Name 
Description of Change 
Brief Rationale 
7.2.5 Efficacy Analysis 
Third paragraph revised to include 
screening eGFR as a stratification factor in 
the linear mixed effect modelling of 
annualized rate of change in eGFR during 
the placebo-controlled treatment period. 
To reflect the stratification factors 
included, as standard, in this 
statistical model. 
Sentence stating “However, those data 
collected after the study drug 
discontinuation or the initiation of non-study 
treatment (eg, renal transplantation) will not 
be included.” deleted from fifth paragraph. 
For alignment with Regulatory 
Agency guidance for reporting 
primary estimands. 
7.2.7 Interim Analysis 
The numerical value assigned as the 
pre-specified threshold for declaring study 
futility at the interim analysis was removed 
(“eg, 30%” was removed from the first 
sentence of the fourth paragraph). 
This information will be specified in 
the statistical analysis plan.  
9.1.1 Rapid Notification on Serious 
Adverse Events 
Study procedures revised to state that 
1) any serious adverse events or adverse 
events of special interest must be reported 
within 24 hours of awareness of the 
adverse event, and 2) to specify the 
location of the study team contact list. 
For clarification. 
9.3.2 Monitoring Procedures 
Text revised to remove references to site 
visits and on-site monitoring. 
Procedures revised to permit 
remote monitoring of study sites. 
9.3.9 Data Protection 
New paragraph added: “Subject race will be 
collected in this study to calculate eGFR. 
Subject ethnicity will also be collected in 
this study, where permitted by local 
regulations, as a requirement for some 
regulatory agencies (eg, in the African 
American population for the FDA in the US, 
or Japanese population for the 
Pharmaceuticals and Medical Devices 
Agency in Japan).” 
To specify that subject race and 
ethnicity will be collected during the 
study, and to clarify the rationale 
for collecting these data. 
10.1 Appendix 1: Adverse Events: 
Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
Procedures revised to specify the location 
of the study team contact list for reporting 
serious adverse event (either via electronic 
data collection tool or via paper CRF). 
For clarification. 
10.5.2.3 Sample Storage and Disposition 
of Samples after Study Completion 
Procedures for storing samples from 
Chinese subjects revised to the following 
“All residual mandatory samples from 
Chinese subjects have to be destroyed 
upon CSR completion, at the latest.” 
To clarify that samples from 
Chinese subjects must be 
destroyed by the time of clinical 
study report completion. 
10.8.1 Amended Protocol 10 
(22 January 2021) 
New section created to contain the prior 
amendment’s history, and subsequent 
sections renumbered accordingly. Minor 
formatting updates applied. 
To conform with the usual process 
for amendment history. 
In addition, minor editorial, stylistic, and/or grammatical changes were made throughout this 
document. 
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10.8.2 Amended protocol 10 (22 January 2021)  
This amended protocol (amendment 10) is considered to be nonsubstantial based on the criteria 
set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of 
the European Union because it does not significantly impact the safety or physical/mental 
integrity of participants, nor the scientific value of the study. 
OVERALL RATIONALE FOR THE AMENDMENT 
To implement updated guidance for management of liver function abnormalities, and other 
clarifications, following Regulatory Agency feedback. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Protocol Amendment Summary of 
Changes 
The section is updated to reflect Amended 
Protocol 10. 
This action is taken to conform with 
the usual Sanofi process for 
amended protocols.  
Protocol Synopsis / Study Design and 
Methodology 
  
The language regarding the participation of 
subjects in the open-label treatment 
extension period was revised by replacing 
"all subjects will have the opportunity to 
enter the 48-week open-label extension 
period” with “all subjects will enter the 
48-week open-label extension period”.  
Clarification due to Regulatory 
Agency feedback since the open-
label treatment extension period is 
a required part of the study. 
Protocol Synopsis / Double-Blind, 
Placebo-Controlled Treatment Period 
The second paragraph regarding home 
injections was reworded to match the 
language of Section 3.1 (Overall Study 
Design/Double-Blind, Placebo-Controlled 
Treatment Period). 
Clarification for consistent 
presentation between sections.  
Protocol Synopsis / Open-Label 
Treatment Extension Period 
As above, the text in the first paragraph “will 
be eligible to roll over into” was replaced by 
“will be rolled over into”. 
Clarification due to Regulatory 
Agency feedback since the open-
label treatment extension period is 
a required part of the study. 
The second paragraph in the prior version 
of the protocol regarding subjects who 
complete the double-blind treatment period 
but who will not enter the open-label 
treatment extension period was removed. In 
addition, the last paragraph in the prior 
version regarding those who did not 
complete the double-blind period and early 
terminate was deleted. 
For clarification and simplification 
regarding when patients proceed to 
the follow-up period.  
Protocol Synopsis / Follow-up Period 
In the second paragraph: the phrase “or 
subjects who discontinue early and have 
completed the early termination visit” was 
added. In addition, “Week 48” and “of the 
double-blind part” were removed from the 
parentheses. 
For clarification regarding the 
procedure for advancing to the 
follow-up period. 
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Section # and Name 
Description of Change 
Brief Rationale 
Protocol Synopsis / Dose Reduction 
 
The phrase “or increase in 
aminotransferases” was added in the first 
sentence of the second paragraph 
In accordance with the new  
guidance for management of 
elevated aminotransferases 
(Section 10.3.2) and the update in 
Section 4.5. 
Protocol Synopsis / Individual Treatment 
Stopping Criteria 
And  
3.3.1.1 Individual treatment stopping 
criteria 
In the list of situations in which study drug 
should be discontinued, the second bullet 
regarding liver function abnormality was 
revised to include specific thresholds for 
ALT, AST, and total bilirubin. 
Added for further clarification in 
accordance with the new guidance 
in Section 10.3.2, per Regulatory 
Agency request. 
Protocol Synopsis / Pharmacokinetic 
Assessment 
The words “lademirsen (SAR339375), 
RG0005, and” were added to the first 
sentence describing which Cmax 
concentrations will be determined.  
For consistency with Section 6.5 
and other sections of the protocol. 
Protocol Synopsis / Table 1 
In footnotes b & e, the language regarding 
subjects being “eligible” and “choosing” to 
roll over to the open-label treatment 
extension period was revised to say that the 
subjects “will be rolled” and “will enter” into 
the open-label treatment extension period, 
respectively. 
Clarification due to Regulatory 
Agency feedback since the open-
label treatment extension period is 
a required part of the study. 
In footnote d: the second sentence was 
simplified to say for subjects who 
“discontinue early …”, and the timing of 
follow-up week 2 was clarified. 
For clarification. 
Protocol Synopsis / Tables 1 and 2 
The last sentence regarding the timeframe 
of the ET visit was added to footnotes c of 
Table 1 and b of Table 2. 
For clarification. 
Footnotes t of Table 1 (double-blind period 
schedule of events) and k of Table 2 (open-
label treatment extension period schedule 
of events) were updated with a sentence 
containing a link to Section 10.3.2. 
For guidance in the event of 
elevated aminotransferases. 
Protocol Synopsis / Table 2 
The tick marks for the hearing assessment 
and exploratory biomarkers at USV in the 
schedule of events were removed. 
These assessments at USV should 
have been removed in the prior 
amendment (consistent with 
Table 1); this action represents a 
correction of the schedule of events 
table only. 
“ET visit” was added in footnote c. 
For clarification on the timing of 
follow-up Week 2.  
1.2.2 Justification of study design 
And 
3.1 Overall Study Design 
And 
5.3 Open-Label Extension Treatment 
Period 
Similar changes to those made in the 
Protocol Synopsis/ Study design and 
Methodology and Protocol synopsis/ Open-
label treatment extension period sections 
were made regarding the language for 
participation of subjects in the open-label 
treatment extension period. 
Clarification due to Regulatory 
Agency feedback since the open-
label treatment extension period is 
a required part of the study. 
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Section # and Name 
Description of Change 
Brief Rationale 
3.1 Overall Study Design 
Under the subsection “Double-Blind, 
Placebo-Controlled Treatment Period”: the 
phrase “or at an alternate location” was 
added to the third paragraph. 
Clarification for consistency with 
the Protocol Synopsis.  
Under the subsection “Open-Label 
Treatment Extension Period”: The third 
paragraph in the prior version of the 
protocol (regarding subjects who did not 
complete the double-blind treatment period) 
was removed. 
For clarification and simplification 
regarding when patients proceed to 
the follow-up period. 
Under the subsection “Open-Label 
Treatment Extension Period”: The phrase 
“or an alternate location” was added. 
Clarification.  
Under the subsection “Dose Reduction”: the 
phrase “or increase in aminotransferases” 
was added in the first sentence of the 
second paragraph 
In accordance with the new  
guidance for management of 
elevated aminotransferases 
(Section 10.3.2) and the update in 
Section 4.5. 
Under the subsection “Dose Reduction”: the 
words “Medical Manager” were added in the 
first paragraph. 
For clarification and consistency 
with Section 4.5. 
Under the “Follow-up Period” subsection: 
“Week 48” was removed from the last 
paragraph. 
For clarification since the open-
label treatment extension period is 
a required part of the study. 
4.5 Dose reduction 
The text “or increase in aminotransferases” 
was added to the following sentence in the 
first paragraph: “The most recent subject’s 
platelet counts, but not older than 10 days, 
will be reviewed by the 
Investigator/physician before drug 
administration. Following the resolution of a 
Grade 2 AE (return to normal or ≤ Grade 1 
for AE) that does not otherwise trigger a 
stopping rule (see Section 3.4), …”. In 
addition, the word “transaminase” was 
removed from the first sentence of the third 
paragraph, and a sentence with link to 
Section 10.3.2 was added in the third 
paragraph for further information about 
aminotransferases. 
In accordance with the new  
guidance for management of 
elevated aminotransferases 
(Section 10.3.2). 
The abbreviation “AE” was removed from 
the second sentence in the paragraph 
beginning “Injection Site Reactions 
(ISRs)…”. 
Minor clarification that the 
paragraph is about ISRs, and not 
other adverse events. 
5.4 Early termination 
The clarification “(double-blind placebo or 
open-label extension periods)” was added 
to the first sentence. 
Clarification of the treatment 
period. 
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Section # and Name 
Description of Change 
Brief Rationale 
5.5 Follow-up period 
The first sentence was revised to refer to 
subjects “who discontinue early and have 
completed the early termination visit” 
instead of referring to subjects who 
complete the double-blind period but who 
do not continue to the open-label period. In 
addition, “Week 48” and “of the double-blind 
part” were removed from the parenthesis in 
the first paragraph. 
For clarification regarding the 
procedure for advancing to the 
follow-up period. 
6.2.2 Adverse event of special interest 
And 
9.1.2 Dosing deviations 
The definition of overdose was updated: the 
timeframe between two doses was revised 
from ≤5 days to <5 days. 
Clarification for consistency with 
the allowed visit window (5-9 days). 
6.2.3 Adverse events grading 
Footnote b was added to Table 3. 
For guidance in the event of 
elevated aminotransferases. 
6.2.8 Regulatory reporting requirements 
for SAEs 
The section was retitled from “Sponsor 
obligation” in the prior version, and all prior  
content except the 3rd bullet in the current 
version were removed. The rest of the 
content was added for the current version. 
The deleted information is 
duplicated in Section 9.2.5 and/or 
did not align to current Sanofi 
standard wording.  
9.2.5 Sponsor obligation 
The first two paragraphs (including sub-
bullets) were removed.  
The deleted information was 
duplicated in Section 6.2.8, which 
was updated as described above. 
10.3 Appendix 3: Safety: Suggested 
Actions and Follow-up Assessments 
In the sentence following the neutropenia 
decision tree, the link to Section “10.3” (in 
Amended Protocol 09) was revised to 
Section “10.1”. 
Typographical error in prior version. 
Headers 10.3.1 (Neutropenia) and 10.3.2 
(Abnormal liver function) were created. 
To organize the content of this 
appendix. 
In Section 10.3.2 (abnormal liver function), 
safety guidance was added for the 
identification, management and follow-up of 
treatment-emergent abnormal liver function 
tests. 
Due to Regulatory Agency request. 
Section 10.8.1 Amended protocol 09 
(11 September 2020) 
New section is created to contain the prior 
amendment’s history, and subsequent 
sections are renumbered accordingly. Minor 
formatting updates are applied. 
This action is taken to conform with 
the usual process for amendment 
history. 
In addition, minor editorial, stylistic, and/or grammatical changes were made throughout this 
document. 
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10.8.3 Amended protocol 09 (11 September 2020)  
This amended protocol (amendment 09) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
The purpose of this amendment is to align the protocol globally with country specific 
requirements applicable to all country participants, to clarify the process of home injection and of 
subject drug delivery and to provide contingency measurements for regional or national 
emergency context. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Throughout document 
Updated protocol numbering, dates, and headers. 
This action is taken to conform with 
the usual Sanofi process for 
amended protocols, in accordance 
with Amended Protocol 09.  
The term “RG456070” is replaced with “SAR339375”. 
To align with the change in the 
product code due to change in 
Sponsor (Regulus Therapeutics to 
Sanofi). 
Title, title page, and 
throughout the protocol 
Added “Lademirsen” to the Investigational Medicinal 
Product row and to the occurrences of “SAR339375” 
throughout the protocol. 
Lademirsen is the INN for this 
compound. 
Protocol Amendment 
Summary of Changes 
The section is updated to reflect Amended Protocol 09. 
This action is taken to conform with 
the usual Sanofi process for 
amended protocols.  
Protocol Synopsis - Study 
Objectives; 
Section 2.2 Secondary 
Objectives; and Section 2.3 
Exploratory Objectives 
The secondary objective related to pharmacodynamic 
effects is applied globally, and the China-specific 
reference is removed. 
These changes are in line with the 
changes in the classification of the 
endpoints (see below for details) 
and align objectives globally. 
The exploratory objective of renal function assessment 
is removed. 
Protocol Synopsis - Study 
Endpoints; and 
Section 7.1.1 Efficacy 
endpoints 
The endpoints “absolute and percent change in eGFR 
from baseline at Week 96, and proportion of subjects 
with a reduction from baseline in eGFR of <10%, <20%, 
<30%, or <40% reduction at Week 24, 48, and 96” are 
moved from exploratory endpoints to efficacy endpoints 
and this classification is applied globally.  
These changes are in line with the 
changes in the classification of the 
endpoints, and regroup these 
two relevant clinical endpoints with 
the other efficacy endpoints. 
The reference to the China-specific efficacy endpoints is 
removed. 
These changes are made to align 
endpoints globally. 
Protocol Synopsis - Study 
Endpoints; and 
Section 7.1.2 Safety 
endpoints 
The words “treatment-emergent” are added to the first 
safety endpoint. 
These changes are made to better 
define the AEs to be analyzed. 
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Section # and Name 
Description of Change 
Brief Rationale 
Protocol Synopsis - Study 
Endpoints; Section 7.1.3 
Pharmacodynamic 
endpoints; and 
Section 7.1.4 Exploratory 
endpoints 
The “Exploratory endpoints: Efficacy, Pharmacodynamic 
and Biomarker Endpoints” section is split into 
two separate sections, “Pharmacodynamic Endpoints” 
and “Exploratory endpoints” (corresponding to the same 
changes in Sections 7.1.3 and 7.1.4, respectively), in 
addition to the movement of two endpoints (absolute 
and percent change in eGFR and reduction in eGFR) to 
efficacy endpoints.  
Other changes are made with respect to the endpoints 
in the initial section, which include: revision of the list of 
renal biomarkers (KIM-1 and β2-microglobulin removed; 
EGF and TGF-β added); addition of β2-microglobulin 
and KIM-1 as exploratory endpoints; removal of EGF 
and TGF-β from the exploratory endpoints list; and the 
exploratory “microRNAs” is qualified with “other than 
miR-21”. 
These changes are in line with the 
changes in the classification of 
endpoints, and align endpoints 
globally. 
Protocol Synopsis - Follow-
up Period and Study 
Duration  
The last visit during the follow-up period is revised to 
occur at Week 10 instead of Week 6, and the link to the 
UK-specific section is consequently removed. In 
addition, in the Study Duration section, the link to the 
Germany-specific section regarding the end of study 
clarification is removed. Accordingly, the planned length 
of participation in the study for each subject was revised 
to say up to approximately “110” weeks. 
For the purpose of harmonization, 
the duration of follow-up and end of 
study specifications are applied 
globally. 
Protocol Synopsis - 
Individual Treatment 
Stopping Criteria; and 
Section 3.3.1.1 Individual 
Treatment Stopping Criteria 
The sentence “With regard to AEs of interest, study 
drug…” is revised to “With regard to AEs, study drug…”.  
For clarification. 
Protocol Synopsis - Analysis 
Populations; and 
Section 7.2.2 Analysis 
Populations 
The definition of PK Population is revised in 
Section 7.2.2 and is added to the Protocol Synopsis: the 
specification “analyzed according to the treatment 
actually received” is removed, and the sample is 
clarified as “post-dose”. 
Only samples from patients who 
received drug are analyzed, so this 
specification is not needed. “Post-
dose” is added to clarify the timing 
post-baseline. The definition is 
missing in the Protocol Synopsis in 
the prior version. 
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Section # and Name 
Description of Change 
Brief Rationale 
Protocol Synopsis - Table 1 
(Schedule of events for 
screening and double-blind, 
placebo-controlled treatment 
period and follow-up period) 
The visit days at Follow-up Weeks 2, 4, and 10 are 
revised from Days 14, 28, and 70 to Days 15, 29, and 
71 respectively. 
For consistency in calculation of 
study days. 
The last follow-up visit is revised from Week 6 (Day 42) 
to Week 10 (Day 71), and the UK-specific links and 
notations in the Table and footnotes contained in the 
prior version of the protocol are removed. 
For the purpose of harmonization, 
the duration of the post-treatment 
follow-up period is applied globally. 
The hearing assessment, complement, miR-21, and 
exploratory biomarkers assessments are removed from 
the USV. 
The aim of the unscheduled visit is 
to follow up for safety such as 
abnormal values for parameters 
(eg, laboratory tests, vital signs) 
which have an impact on the drug 
injection continuation; these 
assessments are not relevant in 
this regard.  
Footnote n is revised to state that vital signs are 
collected prior to drug administration throughout the 
study (except as specified in the footnote). 
For clarification. 
Footnote r is clarified to indicate that the full hematology 
panel is performed at each visit during the follow-up 
period. 
This change is made to align with 
the updated follow-up visit 
schedule.  
“urea” is removed from footnote t (regarding serum 
chemistry).  
This assessment is a duplicate with 
blood urea nitrogen. 
Footnote aa: KIM-1, β2-microglobulin and creatinine are 
removed, Cystatin C is specified as “urine Cystatin C”, 
and TGF-β and EGF are added. 
To align with updates in endpoints. 
Creatinine removed because it is 
already among the serum 
chemistry test.  
Footnote bb: KIM-1 and β2-microglobulin are added, 
and TGF-β and EGF are removed. 
To align with updates in endpoints. 
Footnote jj from the prior version (regarding UK-
specificities) is removed. 
The duration of the post-treatment 
follow-up period is applied globally. 
The alternate location option is selected for unscheduled 
visits (USV). Footnotes jj and kk are added regarding 
USVs. 
To allow flexibility of the visit at 
alternate location and for 
clarification.  
Protocol Synopsis - Table 1 
(Schedule of events for 
screening and double-blind, 
placebo-controlled treatment 
period and follow-up period); 
and Section 5.2 Double-
blind, placebo-controlled 
treatment period 
The ADA assessment is added to the assessment 
schedule for Weeks 1, 2, and 3. 
To better understand the timeframe 
for potential ADA development. 
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Section # and Name 
Description of Change 
Brief Rationale 
Protocol Synopsis - Table 2 
(Schedule of events for 
open-label treatment 
extension period and follow-
up period) 
The footnote on the “ET” header is corrected from “a” to 
“b”. 
Typographical error in the prior 
edition. 
The visit days at Follow-up Weeks 2, 4, and 10 are 
revised from Days 14, 28, and 70 to Days 15, 29, and 
71 respectively. 
For consistency in calculation of 
study days. 
The last follow-up visit is revised from Week 6 (Day 42) 
to Week 10 (Day 71), and the UK-specific links and 
notations in the Table and footnotes contained in the 
prior version of the protocol are removed. 
For the purpose of harmonization, 
the duration of the post-treatment 
follow-up period is applied globally. 
“urea” is removed from footnote k (regarding serum 
chemistry). 
This assessment is a duplicate with 
blood urea nitrogen. 
Footnote r: KIM-1, creatinine, and β2-microglobulin are 
removed, Cystatin C is specified as “urine Cystatin C”, 
and TGF-β and EGF are added. 
To align with updates in endpoints. 
Creatinine is removed because it is 
already among the serum 
chemistry test.  
Footnote s: KIM-1 and β2-microglobulin are added, and 
TGF-β and EGF are removed. 
To align with updates in endpoints. 
Footnote u: the second bullet is clarified to indicate that 
the drug administration should follow blood sampling. 
To provide precision on the time of 
drug administration. 
Footnote w is clarified to indicate that the full 
hematology panel is performed at each visit during the 
follow-up period. 
This change is made to align with 
the updated follow-up visit 
schedule.  
Footnote aa from the prior version (regarding UK-
specificities) is removed. 
The duration of the post-treatment 
follow-up period is applied globally. 
An alternate location option is selected for unscheduled 
visits (USV). Footnotes aa and bb are added regarding 
USVs. 
To allow flexibility of the visit at 
alternate location and for 
clarification. 
Section 1.1.2 Lademirsen 
(SAR339375) 
The INN lademirsen is added to the title of this section. 
To align with the change in the 
product code related to the 
Sponsor (Sanofi), and to introduce 
lademirsen as the INN recently 
assigned to this compound. 
The first sentence is revised to introduce lademirsen as 
the INN for SAR339375. 
Section 1.1.4.3 Study 
PDY16327 
The section is added. 
To reflect current clinical 
experience, as the PDY16327 
study has completed. 
Section 1.2.3 Justification of 
route and dose regimen 
The first bullet under the nonclinical kidney SUM 
concentration data is revised.  
To reflect nonclinical pharmacology 
data. 
Section 3.1 Overall Study 
Design 
In the first paragraph of the “Open-Label Treatment 
Extension Period” section, the words “will continue” are 
removed from the second sentence. 
To correct contradictory language 
in this paragraph and for 
consistency with the Protocol 
Synopsis.  
In the “Follow-up Period” section: the last visit during the 
follow-up period is revised to occur at week follow-up 
Week 10, and the link to the UK-specific section is 
removed. 
For the purpose of harmonization, 
the duration of the post-treatment 
follow-up period is applied globally. 
Section 3.2.1 Inclusion 
criteria and Section 
3.2.2 Exclusion criteria 
Aligned numbering to protocol synopsis. 
Corrected typographical errors in 
numbering in prior version. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 4.1 Investigational 
Products 
The sentence regarding supply by courier is added. 
To provide flexibility regarding 
provision of supplies to study 
participants. 
Section 4.4 Home injection 
The statement regarding the reporting of all events 
between 2 injections (after the list of documentation 
criteria) is added. 
To ensure that patients who will 
have home injection(s) will report 
all adverse events. 
The statement “Prior to beginning home injections…” is 
revised and the subsequent sentence is added. 
To clarify the training requirement 
for healthcare professionals. 
The details of home injections during both the double-
blind and open label periods are expanded. 
To provide clarifications regarding 
the home injection. 
Clarifications are made to the paragraph “During the last 
6 months…”. 
For clarification. 
Section 4.5 Dose reduction, 
Section 5 Study Procedures, 
Section 7.2.7 Interim 
analysis, and 
Section 9.2.3 Informed 
consent 
The sentence regarding emergency declarations is 
added. 
To anticipate actions in case of 
national or regional emergency. 
Section 5 Study Procedures 
The link to the German-specific section is removed. 
For the purpose of harmonization, 
the he end of study definition is 
applied globally (Section 5.8 is 
created). 
Section 5.2 Double-Blind, 
Placebo-Controlled 
Treatment Period 
For Day 1: concomitant medications reporting is moved 
from the list of tests not to be repeated at baseline if 
done within 7 days prior to first dosing to the list of tests 
to be done at the baseline visit prior to the first injection. 
To collect concomitant treatment 
medications at each visit. 
Section 5.5 Follow-up Period 
The last visit during the follow-up period is revised to 
occur at Week 10 (from Week 6), and the link to the UK-
specific section is removed 
For the purpose of harmonization, 
the duration of the post-treatment 
follow-up period is applied globally. 
Section 5.6 Unscheduled 
Visits 
The statement “The unscheduled visits could be done at 
alternative location (including at home), and at the 
Investigator’s discretion, for assessment of AEs related 
to abnormal/alarming laboratory values.” is added. 
To provide flexibility regarding the 
unscheduled visits. 
Section 5.8 End of Study 
Definition 
This section is created. 
To provide the definition of the end 
of study. 
Section 6.1 Medical History 
and Family History 
The timeframe for documenting additional illnesses for a 
patient (last sentence) is updated from the end of study 
to the completion of the last follow-up visit.  
To clarify the timeframe of all 
additional illnesses to be as AEs. 
The clarification for Germany is removed from the last 
sentence. 
The end of study definition is 
applied globally (not only in 
Germany) in this amended 
protocol. 
Section 6.2.1 Adverse 
events 
The statement “until the last administration of study 
medication plus 10 weeks follow up” is added to the 
definition of TEAEs in the second paragraph. 
To provide clarification on the 
definition of TEAEs. 
The statement that a subset of AEs (Grade ≥2 AESIs) 
will be closely monitored is added. 
For clarification. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.2.2 Adverse event 
of special interest 
This section is created, and subsequent sections are 
renumbered accordingly. 
To provide definitions and 
clarifications regarding AESIs. 
Section 6.2.3 Adverse 
events grading 
The section header is added. Subsequent sections are 
renumbered accordingly.  
For clarification. 
Tables 3 and 4 (located in Section 6.2.1 of the prior 
protocol version) are modified to more closely align with 
the DAIDS criteria. The DAIDS criteria reference is 
added to Section 11, accordingly. 
For clarification. 
Section 6.2.4 Adverse event 
outcome 
The section header is added. Subsequent sections are 
renumbered accordingly. Minor revisions are made to 
the text to align with Table 5 (located in Section 6.2.1 of 
the prior protocol version). 
For clarification and alignment with 
terminology in Table 5. 
Section 6.2.5 Serious 
adverse events 
The paragraph regarding SAEs occurring after signing 
the ICF to the end of the study is revised to any SAE 
occurring after the ICF signing “to the end of a patient’s 
study participation”, and the link to the German-specific 
end of study definition is removed. 
For clarification. 
The paragraph regarding Investigator responsibility for 
AEs and SAEs is added. 
For clarification. 
Section 6.2.6 Follow-up of 
AEs and SAEs 
This section is created, and subsequent sections are 
renumbered accordingly. 
To provide clarity for the AE/SAE 
follow-up procedure. 
Section 6.2.14 Laboratory 
assessments 
“urea” is removed from the list of serum chemistry.  
This assessment is a duplicate with 
blood urea nitrogen. 
“IgG” is added to the description of ADAs. 
For clarification. 
Section 6.2.16 Injection site 
reactions 
The sentence preceding Table 6 was added regarding 
ISR reporting for self-administrations. 
For clarification. 
Section 6.2.17 Safety 
oversight 
The second paragraph is revised to say “and will closely 
monitor AESIs” and platelet counts and eGFR are 
added as examples. 
For clarification. 
Section 6.4 
Pharmacodynamic 
assessments and 
biomarkers 
Circulating miR-21 is added as a pharmacodynamics 
assessment. 
For clarification. 
The list of renal injury and function biomarkers is revised 
(KIM-1 and β2-microglobulin are removed; EGF and 
TGF-β are added). In the list of exploratory biomarkers, 
β2-microglobulin and KIM-1 are added, and TGF-β and 
EGF are removed. The exploratory “microRNAs” is 
clarified as microRNAs “other than miR-21”. 
These changes are made to align 
assessments globally. 
Section 7.1.5 
Pharmacokinetic endpoints 
This section (7.1.4 in the prior version) was renumbered 
to 7.1.5. 
The preceding section was split 
into two (7.1.3 and 7.1.4) as 
described above. 
Section 7.2.4 Safety analysis 
The first paragraph is updated to indicate “plus 
10 weeks” and to remove the link to UK-specifications 
for follow-up. 
For the purpose of harmonization, 
the duration of the post-treatment 
follow-up period is applied globally. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 10.2 Appendix 2: 
Clinical Laboratory 
Neutrophil and eosinophil counts are removed from 
Table 7 because they are not study biomarkers. 
For consistency with other sections 
of the protocol. 
The clinical chemistry parameters in Table 7 are revised 
to align with the coagulation panel, serum chemistry, 
and lipid panel assessments specified in the Schedule 
of Activities (Tables 1 & 2). 
For clarification. 
Section 10.5 Appendix 5: 
Country-specific 
Requirements 
The section for the United Kingdom (10.5.1 in Amended 
Protocol 08) is removed, and subsequent sections are 
renumbered accordingly. 
For the purpose of harmonization, 
the duration of the post-treatment 
follow-up period is applied globally. 
Section 10.5.1 Germany 
The section for the end of study definition (10.5.2.1 End 
of study definition in Amended Protocol 08) is removed, 
and subsequent sections are renumbered accordingly. 
The end of study definition is 
applied globally (Section 5.8 is 
created). 
Section 10.5.2 China 
The section for the secondary objectives 
(10.5.3.1.1 Secondary objectives in Amended 
Protocol 08) and efficacy endpoints (10.5.3.1.3 Efficacy 
endpoints) are removed, and subsequent sections are 
renumbered accordingly. 
The secondary objectives and 
efficacy endpoints are aligned 
globally. 
Section 10.5.2.1.2 
Pharmacodynamic and 
exploratory endpoints 
China-specific pharmacodynamic endpoints are 
removed. 
The pharmacodynamic endpoints 
are aligned globally. 
Section 10.5.2.2 
Pharmacodynamic 
assessments and 
biomarkers 
China-specific pharmacodynamic assessments are 
removed. 
The pharmacodynamic 
assessments are aligned globally. 
Section 10.6 Appendix 6: 
Contingency measures for a 
regional or national 
emergency that is declared 
by a governmental agency 
The entire section is added, and subsequent sections 
are renumbered accordingly. 
To describe actions to be set up in 
case of a regional or national 
emergency. 
Section 10.8.1 Amended 
protocol 08 (18 March 2020) 
New section is created to contain the prior amendment’s 
history, and subsequent sections are renumbered 
accordingly. Minor formatting updates are applied. 
This action is taken to conform with 
the usual process for amendment 
history. 
Section 11 References 
Reference 30 (DAIDS Table for Grading the Severity of 
Adult and Pediatric Adverse Events) is added in 
accordance with the revisions in Section 6.2.3, and 
subsequent references were renumbered accordingly. 
For clarification. 
In addition, minor editorial, stylistic, and/or grammatical changes were made throughout this 
document. 
10.8.4 Amended protocol 08 (18 March 2020)  
This amended protocol (amendment 08) is considered to be nonsubstantial based on the criteria 
set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of 
the European Union because it does not significantly impact the safety or physical/mental 
integrity of participants, nor the scientific value of the study. 
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OVERALL RATIONALE FOR THE AMENDMENT 
The purpose of this amendment is to align with the requirements of the Human Genetics 
Resources Administration of China (HGRAC). 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Throughout document 
Updated protocol numbering, dates, 
and headers. 
This action was taken to conform with the 
usual Sanofi process for amended protocols, 
in accordance with Amended Protocol 08.  
Protocol Amendment Summary of 
Changes 
The section was updated to reflect 
Amended Protocol 08. 
This action was taken to conform with the 
usual Sanofi process for amended protocols.  
Protocol Synopsis (Study Objectives 
and Study Endpoints subsections), 
2.2 Secondary Objectives, 
2.3 Exploratory Objectives, 
7.1.1 Efficacy endpoints, 
7.1.3 Exploratory endpoints: efficacy, 
pharmacodynamic and biomarker 
endpoints 
Links to the Section 10.5.3.1 
subsections were added. 
These links were added because the 
subsection was created in accordance with 
country-specific requirements. 
Protocol Synopsis (Tables 1 & 2), 
5.2 Double-Blind, Placebo-Controlled 
Treatment Period, 5.3 Open-Label 
Extension Treatment Period, 
5.4 Early Termination, 
6.4 Pharmacodynamic Assessments 
and Biomarkers 
Links to Section 10.5.3.2 were added 
to Table 1 footnotes aa and bb, 
Table 2 footnotes r and s, the 
relevant visits of Sections 5.2 and 
5.3, and Sections 5.4 and 6.4. 
These links were added because the 
subsection was created in accordance with 
country-specific requirements. 
Section 7.2.6 Other analyses 
A link to Section 10.5.3.2 was added. 
This link was added because the subsection 
was created in accordance with country-
specific requirements. 
Protocol Synopsis (Disposition of 
Samples after Study Completion 
subsection), Table 1, 
5.2 Double-Blind, Placebo-Controlled 
Treatment Period,  
5.4 Early Termination, 
6.6 Disposition of Samples After 
Study Completion 
Links to 10.5.3.3 were added. 
These links were added because the 
subsection was created in accordance with 
country-specific requirements. 
10.5 Appendix 5: Country-specific 
requirements 
Subsection 10.5.3 and subsections 
were created for study conduct in 
China. 
This change is due to HGRAC requirements: 
modifications in study objectives/endpoints 
and sample storage/disposition with 
consideration of the Chinese country-specific 
requirements for Chinese patients. 
Section 10.7.1 Amended protocol 07 
(20 February 2020) 
New section was created to contain 
the prior amendment’s history, and 
subsequent sections were 
renumbered accordingly. Minor 
formatting updates were applied. 
This action was taken to conform with the 
usual process for amendment history. 
Please note that no other changes were made throughout this document. 
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10.8.5 Amended protocol 07 (20 February 2020)  
This amended protocol (amendment 07) is considered to be nonsubstantial based on the criteria 
set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of 
the European Union because it does not significantly impact the safety or physical/mental 
integrity of participants, nor the scientific value of the study. 
OVERALL RATIONALE FOR THE AMENDMENT 
The purpose of this amendment is to respond to requests from the German health authority. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Throughout document 
Updated protocol numbering, dates, and 
headers. 
This action was taken to conform with the usual 
Sanofi process for amended protocols, in 
accordance with Amended Protocol 07.  
Protocol Amendment 
Summary of Changes 
The section was updated to reflect 
Amended Protocol 07. 
This action was taken to conform with the usual 
Sanofi process for amended protocols.  
Protocol Synopsis (Study 
Duration) 
A link to Section 10.5.2.1 was added. 
To provide the clarification relating to the end of 
study requested by the German health authority. 
1.3.1 Potential risks 
A link to Section 10.5.2.2 was added. 
To more clearly present the risks associated with 
participation in ACT16248, in accordance with the 
regulatory agency request. 
5 Study Procedures, 
6.1 Medical History and 
Family History, and 6.2.2 
Serious adverse events 
A link to Section 10.5.2.1 was added. 
To provide the clarification relating to the end of 
study requested by the German health authority. 
10.5 Appendix 5: Country-
specific requirements 
Subsection 10.5.2 and subsections were 
created for Germany. 
This change is due to regulatory requests: to more 
clearly define the end of the study, and to more 
clearly present the potential risks associated with 
participation in ACT16248. 
Section 10.7.1 Amended 
protocol 06 (15 January 
2020) 
New section was created to contain the 
prior amendment’s history, and 
subsequent sections were renumbered 
accordingly. Minor formatting updates 
were applied. 
This action was taken to conform with the usual 
process for amendment history. 
Please note that no other changes were made throughout this document. 
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10.8.6 Amended protocol 06 (15 January 2020)  
This amended protocol (amendment 06) is considered to be nonsubstantial based on the criteria 
set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of 
the European Union because it does not significantly impact the safety or physical/mental 
integrity of participants, nor the scientific value of the study. 
OVERALL RATIONALE FOR THE AMENDMENT 
The duration of follow-up was updated to 10 weeks for patients in the United Kingdom due to 
regulatory agency request. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Title page 
Updated to reflect Amended Clinical Trial Protocol 
06. 
This action was taken to conform with the 
usual Sanofi process for amended 
protocols. 
Throughout document 
Headers were updated. 
This change is in accordance with 
Amended Protocol 06.  
Protocol Synopsis (Follow-Up 
Period section) 
A reference to Section 10.5.1 was added to the 
second paragraph.  
This change is due to regulatory request. 
Protocol Synopsis (Study 
Duration) 
References to Section 10.5.1 were added. 
This change is due to regulatory request. 
Protocol Synopsis (Tables 1 
and 2) 
In the “Follow-up” column, “10 (UK)” and “70 
(UK)” were added to Week 6 and Study Day 42, 
respectively, with a clarification in footnotes jj and 
aa (newly added to Tables 1 and 2, respectively) 
to refer to Section 10.5.1 for UK specifications. 
This change is due to regulatory request. 
For footnotes o and r in Table 1 and footnotes g, 
p, and w in Table 2, clarifications were added to 
refer to Section 10.5.1 for UK specifications. 
Clarifications were added in accordance 
with the regulatory request. 
3.1 Overall Study Design 
(Follow-up Period subsection)  
A reference to Section 10.5.1 was added to the 
second paragraph. 
This change is due to regulatory request. 
5.5 Follow-up Period 
A reference to Section 10.5.1 was added to the 
“Follow-up Week 6” subheading.  
This change is due to regulatory request. 
7.2.4 Safety analysis 
A reference to Section 10.5.1 was added to the 
first paragraph.  
This change is due to regulatory request. 
10.5 Country-specific 
requirements 
Subsection 10.5.1 was created for the United 
Kingdom, and the duration of follow-up specific to 
the UK was described.  
This change is due to regulatory request. 
Section 10.7.1 Amended 
protocol 05 (07 November 
2019) 
New section was created to contain the prior 
amendment’s history, and subsequent sections 
were renumbered accordingly. Minor formatting 
updates were applied. 
This action was taken to conform with the 
usual process for amendment history. 
Please note that no other changes were made throughout this document. 
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10.8.7 Amended protocol 05 (07 November 2019)  
This amended protocol (amendment 05) is considered to be nonsubstantial based on the criteria 
set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of 
the European Union because it does not significantly impact the safety or physical/mental 
integrity of participants, nor the scientific value of the study. 
OVERALL RATIONALE FOR THE AMENDMENT 
A new EudraCT number was issued for this study, as the prior number had reflected study 
completion. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Title Page 
The EudraCT number was updated. 
A new EudraCT number was issued for this study. 
Section 10.7.1 Amended 
protocol 04 (01 August 
2019) 
New section was created to contain the 
prior amendment’s history, and 
subsequent sections were renumbered 
accordingly. 
This action was taken to conform with the usual 
process for amendment history. 
Please note that no other changes were made throughout this document. 
10.8.8 Amended protocol 04 (01 August 2019)  
This amended protocol (amendment 04) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT  
Changes were made to the protocol to implement several updates listed in the following table. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Title Page 
Title was updated to reflect Amended 
Clinical Trial Protocol 04. 
The change was made to reflect the update of the 
amended clinical trial protocol.  
Title Page 
Protocol Date was changed to reflect 
01-Aug-2019. 
The change was made to reflect the updated date of 
approval of the document. 
Protocol Amendment 
Summary of Changes 
The document history was updated to 
include the Amended Clinical Trial 
Protocol 04 with date, and version of 
01 August 2019, version 2. 
The change was made to reflect the update of the 
amended clinical trial protocol, approval date, and 
version.  
 
Overall rational for the amendment was 
updated. 
This change was made to provide an updated overall 
rational for amended clinical trial protocol 04. 
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Section # and Name 
Description of Change 
Brief Rationale 
Protocol amendment 
summary of changes 
table 
This section was updated to reflect the 
changes to amended clinical trial 
protocol 04.  
This change was made to provide update on summary 
of changes to amended clinical trial protocol 04. 
Protocol Synopsis 
 
Secondary objective was clarified to 
describe terms Cmax and Ctrough. 
This change was made to further develop the 
pharmacokinetic endpoint evaluated. Assay that can 
measure both parent and metabolite (used for Cmax) is 
not sensitive enough to detect very low concentrations 
(Ctrough). The assay used to measure low 
concentrations is very sensitive but cannot distinguish 
between parent and metabolite. 
 
Added time point during the placebo-
controlled treatment period under the 
first bullet of efficacy endpoints. 
 
Clarification of pharmacokinetic endpoint: 
Plasma concentrations of RG456070, 
RG0005, and SUM in Cmax samples and 
SUM only in Ctrough samples was 
provided.  
 
 
eGFR was removed from the exceptions 
of the occurrence of any Grade 3 or 
higher AE from Individual Stopping 
Criteria. 
 
Text was modified with regard to AEs of 
interest to include discontinuation of 
subjects who experience ≥50% decline 
for eGFR from baseline. 
 
Text was modified to include any TEAE 
that in the opinion of the sponsor is of 
potential clinical significance for subject’s 
safety.  
 
Added “adult” to description of the study 
population. 
 
Pharmacokinetic assessment: Removal 
of post baseline visit with PK sampling. 
Addition of statement that no PK samples 
will be withdrawn if injection is not 
administered on Weeks 4, 12, 24, 36, 48, 
60, 72, 84 and 96. 
Removed duplicated sentence under 
pharmacokinetic analysis. 
This change was made to provide clarification of the 
time point for this endpoint. 
 
 
This change was made to further develop the 
pharmacokinetic endpoint evaluated. 
 
 
 
 
This change was made to include eGFR Grade 3 
(eGFR <15) as a stopping criteria. 
 
 
 
This change was made to include the decline eGFR as 
a stopping criteria. 
 
 
The text was modified to include occurrence of events 
suggesting significant safety concern as stopping 
criteria.  
 
 
This change was made to clarify the study population. 
 
 
Changes were made to clarify PK sampling if injection 
is not administered. 
 
 
 
This change was made to correct duplication of 
information in this section.  
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Section # and Name 
Description of Change 
Brief Rationale 
Table 1 Schedule of 
events for screening 
and double-blind, 
placebo-controlled 
treatment period and 
follow-up period 
Urine Pregnancy added testing on ET  
 
 
Assessment of markers of inflammation: 
quantitative immunoglobulins (γ-globulin, 
IgG, IgM) was added with same schedule 
of assessment as complement, on W0, 
W12, W24, W36, W48, on ET and at 
Follow up W6. 
IRT contact was added for W0, W4, W8, 
W12, W16, W20, W24, W28, W32, W36, 
W40, W44, and W48. 
Footnote “m” included collection on a 
weekly basis for changes to the 
medications taken after signing ICF. 
Footnote ”p” removed urinalysis. 
 
 
Footnote “q” added urinalysis, which 
tests will be done by dipstick test, and 
that microscopy urine analysis will be a 
laboratory test. 
Footnote “r” added the following 
statement “during treatment period and 
bi - weekly during follow up period”. 
Footnote “t” removed (SPEP) testing 
stating that If subject experienced low 
protein <1 g the investigation will be 
done by the investigator as per local 
practice. 
Footnote “t” modified text to add: In case 
of worsening of eGFR, the investigator 
could repeat the eGFR before the next 
scheduled test. 
Footnote “x” included 4 hours post-dose 
PK sampling. Removal of Post baseline 
visits with PK sampling and addition that 
no PK samples will be withdrawn if 
injection is not administered on W4, 
W12, W24, W36, and W48.  
Spot urine protein-to-creatinine ratio 
(UPCR) testing was added at W4, W8, 
W16, W20, W28, W32, W40, and W44. 
Footnote “aa” was modified to remove 
Urine protein/Creatinine ratio. And added 
text to describe when urine 
protein/creatinine ration will be 
performed. 
Urine pregnancy testing is necessary at ET to ensure 
that patient will not be pregnant during the study 
intervention and at the end of study intervention.  
 
Changes were made to monitor markers of 
inflammation to be consistent with the investigator 
brochure.  
 
 
This item was added to specify IRT contact timepoints.  
 
 
Changes were made to clarify the timepoint of conmed 
collection.  
 
The language “Urinalysis” was removed to differentiate 
“Urinalysis” to 24 H urine panel (albumin, creatinine, 
sodium, total protein). As sampling is done in same 
visit.  
The language “Urinalysis” was added to specify the 
testing being performed. Clarification of the test to be 
used for urinalysis was also provided.  
 
This change was made to clarify the timepoint during 
the treatment period and follow up period. 
 
This change removes complexity for the conduct of the 
study. 
 
Text was modified to provide Medical Monitors have 
heightened vigilance and the flexibility to increase 
frequency of monitoring based on key outcome 
measures (ie, eGFR, proteinuria). 
 
Changes were made to clarify PK sampling if injection 
is not administered.  
 
 
Changes were made to closely follow up the renal 
function. 
 
 
 
Changes were made to clarify frequency of urine 
protein-to-creatinine ratio.  
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Section # and Name 
Description of Change 
Brief Rationale 
Table 2 Schedule of 
events for open-label 
treatment extension 
period and follow- up 
period 
Assessment of markers of inflammation: 
quantitative immunoglobulins (γ-globulin, 
IgG, IgM) was added with same schedule 
of assessment as complement, on 
Weeks 48, W52, W60, W72, W84, W96 
on ET and at Follow up W6 
 
IRT contact was added for W52, W56, 
W60, W64, W68, W72, W76, W80, W84, 
W88, W92, and W96. 
 
Spot UPCR testing was added to W48, 
W52, W56, W64, W68, W76, W80, W88, 
W92. 
 
Additional testing criteria for W48 for post 
dose PK was added. 
 
 
Footnote “h” removed urinalysis. 
 
 
 
Footnote “i” added urinalysis, which tests 
will be done by dipstick test, and that 
microscopy urine analysis will be a 
laboratory test  
 
Footnote “r” was modified to remove 
Urine protein/Creatinine ratio. And added 
text to describe when urine 
protein/creatinine ration will be 
performed. 
Footnote “x” added that no PK samples 
will be withdrawn if injection was not 
administered on W60, W72, W84, and 
W96. 
Changes were made to monitor markers of 
inflammation to be consistent with the investigator 
brochure.  
 
 
 
 
 
Changes were made to specify IRT contact timepoints. 
 
 
 
Changes were made to closely follow up the renal 
function. 
 
 
Changes were made to keep consistency of the study 
protocol throughout the document.  
 
The language “Urinalysis” was removed to differentiate 
“Urinalysis” to 24 H urine panel (albumin, creatinine, 
sodium, total protein). As sampling is done in same 
visit.  
 
The language “Urinalysis” was added to specify the 
testing being performed. Clarification of the test to be 
used for urinalysis was also provided. 
 
 
Changes were made to clarify frequency of urine 
protein-to-creatinine ratio. 
 
 
Changes were made to clarify PK sampling if injection 
is not administered. 
1.1.3 Nonclinical 
experience 
Clarification of the microscopic findings 
were observations were provided.  
Change of the no-observed-adverse-
effect levels (NOAELs) for monkey 
studies was made.  
Changes were made to this section to clarify where 
observations of microscopic findings occurred.  
Changes were made to correct the NOAELs for 
monkeys.  
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Section # and Name 
Description of Change 
Brief Rationale 
1.2.3 Justification of 
route and dose regimen 
Nonclinical and Clinical data observed 
and target, and Pre-Clinical toxicology 
was edited to reflect reason for therapy 
study design.  
 
 
Pre-clinical toxicology was changed to 
update the NOAELs for monkeys and the 
calculated exposure ratios for 
RG456070; and the following paragraph 
was removed: Mean plasma exposure 
(AUC) at the chronic study NOAELs were 
70.3 ug*hr/mL for mouse and 
172.7 ug*hr/mL for monkey. Plasma 
exposure in clinical study RG012-05 
MAD (110 mg QW x 5) was 24.4 ug*hr/mL. 
Plasma exposure ratios calculated based 
on the nonclinical data are 6X for mouse 
and 15X for monkey. 
Information has been arranged in a more logical order 
than previously recorded. Data which could not be 
verified, or that have no reports, have been deleted. 
References to modeling and predicted data have been 
deleted. No modeling data are used in the revised 
justification for 110 Q1W dose. 
Information in “pre-clinical toxicology” has been 
updated to be consistent with the new version of the 
investigator brochure. These changes are part of the 
update of the “pre-clinical toxicology”. 
2.2 Secondary 
Objectives 
Secondary objective was clarified to 
describe terms Cmax and Ctrough. 
This change was made to further develop the 
pharmacokinetic endpoint evaluated. Assay that can 
measure both parent and metabolite (used for Cmax) is 
not sensitive enough to detect very low concentrations 
(Ctrough). The assay used to measure low 
concentrations is very sensitive but cannot distinguish 
between parent and metabolite. 
3.2 Study Population 
Added “adult” to description of the study 
population. 
This change was made to clarify the study population. 
 
3.2.1 Inclusion Criteria 
I07 changed the use of 2 acceptable 
effective methods of contraception from 
for at least 6 weeks after the last dose, to 
at least 10 weeks after the last dose in 
both female and male subjects. 
Changes were made to be consistent with the latest 
version of the IB. 
 
3.3 Screen Failures 
Subjects may be rescreened if their 
clinical condition changes and a new 
subject number will be assigned. The 
same number previously used will not be 
assigned to the subject.  
Changes were made to clarify rescreening of patients. 
3.3.1.1 Individual 
treatment stopping 
criteria 
eGFR was removed from the exceptions 
of the occurrence of any Grade 3 or 
higher AE from Individual Stopping 
Criteria. 
Text was modified with regard to AEs of 
interest to include discontinuation of 
subjects who experience ≥50% decline 
for eGFR from baseline. 
This change was made to include eGFR Grade 3 
(eGFR <15) as a stopping criteria. 
 
This change was made to include the decline for eGFR 
as stopping criteria.  
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Section # and Name 
Description of Change 
Brief Rationale 
3.4 Discontinuation of 
Study 
Text was modified to include any TEAE 
that in the opinion of the sponsor is of 
potential clinical significance for subject’s 
safety.  
The text was modified to include occurrence of events 
suggesting significant safety concern as stopping 
criteria. 
 
4.2 Treatment 
Assignment 
Treatment assignment and 
randomization will be performed using a 
centralized treatment allocation 
system/IRT. The IRT (centralized 
treatment allocation system) generates 
the patient randomization list and 
allocates the treatment number and the 
corresponding treatment kits to the 
patients accordingly. Before randomizing 
a patient, the Investigator or designee 
will have to contact the centralized 
treatment allocation system/IRT. 
Changes were made to clarify method of treatment 
assignment. 
4.6 Randomization 
Code Breaking During 
The Study 
This entire section was added.  
Changes were made to clarify the code breaking 
procedure and to adhere with Sanofi policy.  
5.2 Double-Blind, 
Placebo-Controlled 
Treatment Period 
Pre-dose and post dose blood sampling 
for PK was added. 
0.5 hours post-dose blood sampling was 
added for complement (C3, C3a, C4, and 
Bb). 
Blood sampling to assess markers of 
inflammation (quantitative 
immunoglobulins: γ-globulin, IgM, IgG) 
was added for Day 1 Baseline/Dosing 
Site Visit, Weeks: 12, 24, 36, 48 (all 
±2 days) * Site visits. 
(all ±2 days) was added for Weeks: 12, 
24, 36, 48. 
Hearing assessment (on Week 48 only) 
was added. 
Testing was added for Spot UPCR for 
Week 4 (±2 days) Site Visit, Weeks: 8, 
16, 20, 28, 32, 40, 44 (all ±2 days) 
*Option for Alternative Location Visit. 
Changes were made to keep consistency of the study 
protocol throughout the document.  
Changes were made to keep consistency of the study 
protocol throughout the document. 
 
 
Changes were made to monitor markers of 
inflammation to be consistent with the investigator 
brochure. 
 
 
Changes were made to clarify the visit windows.  
 
Changes were made to keep consistency of the study 
protocol throughout the document. 
 
Changes were made to closely follow up the renal 
function. 
5.3 Open-Label 
Extension Treatment 
Period 
Blood sampling to assess markers of 
inflammation (quantitative 
immunoglobulins: γ-globulin, IgM, IgG) 
was added for Weeks: 60, 72, 84, and 96 
(all ±2 days) Site Visits. 
 
Testing was added for Spot UPCR for 
Week 52 (±2 days) Site Visit, and 
Weeks: 56, 64, 68, 76, 80, 88, 92 (all 
±2 days) *Option for Alternative Location 
Visit. 
Changes were made to monitor markers of 
inflammation to be consistent with the investigator 
brochure.  
 
 
Changes were made to closely follow up the renal 
function.  
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Section # and Name 
Description of Change 
Brief Rationale 
5.4 Early Termination 
Urine pregnancy test was added. 
 
 
 
Blood sampling to assess markers of 
inflammation (quantitative 
immunoglobulins: γ-globulin, IgM, IgG) 
was added. 
Urine pregnancy testing at ET to ensure that patient will 
not be pregnant during the study intervention and at the 
end of study intervention.  
 
Changes were made to monitor markers of 
inflammation to be consistent with the investigator 
brochure.  
5.5 Follow-up Period 
Blood sampling for markers of 
inflammation (γ-globulin, IgM, IgG) was 
added for Follow-up Week 6 (±3 days) 
Site Visit. 
Changes were made to monitor markers of 
inflammation to be consistent with the investigator 
brochure.  
 
6.2.1 Adverse events 
Removal of following criteria for ending 
AE monitoring: It has been shown to be 
unrelated to the study drug. 
Changes were made to align with standard Genzyme 
Corporation process.  
6.2.6 Physical 
examination/body 
system assessments 
Removal of statement referring to 
schedule of events. 
Changes were made to align with the new design of the 
study.  
6.2.13 Safety oversight 
Text was modified to include that the 
DMC may be consulted at the discretion 
of whenever the investigator considers 
that worsening of eGFR and UPCR 
values are medically relevant. 
Changes were made to allow investigators the 
consultation with the DMC in case of worsening of 
eGFR or UPCR is medically relevant. 
 
6.4 Pharmacodynamic 
Assessments and 
Biomarkers 
Text was modified to include that Urine 
protein/creatinine ratio (UPCR) will be 
performed every 4 weeks (using the first 
morning void urine) either using 24 hours 
spot urine sample or 24 hour urine 
collection (at D1, W12, W24, W36, W48, 
W60, W72, W84, W96). In case of 
worsening of UPCR, the investigator 
could repeat the UPCR before the next 
scheduled test.  
Changes were made to clarify frequency of urine 
protein-to-creatinine ratio and to state possibility of 
investigator to repeat UPCR.  
 
6.5 Pharmacokinetic 
Assessments 
Removal of post baseline visit with PK 
sampling. Addition of statement that no 
PK samples will be withdrawn if injection 
is not administered on Weeks 4, 12, 24, 
36, 48, 60, 72, 84 and 96. 
Changes were made to clarify PK sampling if injection 
is not administered. 
7.1.1 Efficacy endpoints 
Added time point during the placebo-
controlled treatment period under the 
first bullet of efficacy endpoints. 
This change was made to provide clarification of the 
time point for this endpoint. 
7.1.4 Pharmacokinetic 
endpoint 
Clarification of Plasma concentrations of 
RG456070, RG0005, and SUM in Cmax 
samples and SUM only in Ctrough samples 
was provided. 
This change was made to further develop the 
pharmacokinetic endpoint evaluated. 
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Section # and Name 
Description of Change 
Brief Rationale 
7.2.4 Safety analysis 
Clarification of the TEAE period as the 
time between the first administration of 
the study medication to the last 
administration of study medication plus 
6 weeks follow up.  
End of the TEAE period changed from end of study to 
last IMP plus 6 weeks follow up to be more precise.  
7.2.5 Efficacy analysis 
Clarification that the placebo group prior 
distribution assume a normal distribution 
for the slope of eGFR. 
 
Changes to verbiage were made to 
clarify the description of the model for 
analyzed change in eGFR.  
This change was made to state that the placebo group 
has this normal distribution.  
 
 
This change was made to increase clarity of the 
information described.  
9.1.2 Dosing deviations 
Clarification of the definition of an 
overdose was added.  
Changes were made to clarify the definition of the 
overdose. 
10.2 Appendix 2: 
Clinical Laboratory 
Clinical chemistry and routine urinalysis 
parameters removed not applicable 
assessments. 
Changes were made to remove complexity for the 
conduct of the study.  
 
10.2. Appendix 2: 
Clinical Laboratory, 
Table 7 - Protocol 
required safety 
laboratory assessments 
Routine urinalysis text for management 
of abnormal results has been modified.  
Changes were made to this section to clarify 
management of dipstick abnormal results. 
In addition, other minor editorial changes (eg, grammatical, stylistic, and minor typographical error 
corrections) were implemented throughout the protocol. 
10.8.9 Amended protocol 03 (23 April 2019)  
This amended protocol (amendment 03) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
Clinical development and the commercialization rights of RG-012 were granted from Regulus 
Therapeutics Inc. (Regulus) to Genzyme Corporation, which will be assuming responsibility of 
the current clinical program. 
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Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Title page 
The Regulus logo and reference to Regulus 
within the confidentiality statement were deleted.  
These changes were made due to the 
transfer in the development of RG-012. 
The title was updated to reflect the change from 
dosing every other week to weekly dose 
administration. “Every Week in Patients with 
Alport Syndrome”. 
The title was changed to reflect the change in 
study drug administration and the 
amendment. 
The title was updated to reflect “Subcutaneous” 
injection. 
The title was changed to reflect the change in 
study design to indicate the injection route 
and the amendment. 
The sponsor was changed to reflect Genzyme 
Corporation. 
The sponsor was changed to reflect the new 
owner of the product. 
The study number was changed to “ACT16248” 
from RG012-03. 
This change was made due to the transfer in 
the development of RG012-03 from Regulus 
to Genzyme Corporation. 
Investigational Medicinal Product was changed to 
SAR339375. 
This change was made due to the transfer in 
the development of RG-012. 
Study Name HERA was added to title page. 
This addition was made to reflect the name of 
the study which was previously omitted. 
Sponsor address was changed to Genzyme 
Corporation 50 Binney Street Cambridge, 
Massachusetts 02142. 
This change was made reflect the new 
sponsor’s address. 
Sponsor Approval Page 
Removed this page from amended protocol 03. 
Not applicable with the Genzyme Corporation 
standard. 
Investigator Protocol 
Agreement Page 
Removed this page from amended protocol 03. 
Not applicable with the Genzyme Corporation 
standard. 
Protocol Amendment 
Summary of Changes 
Section added to describe document history, 
overall rationale for amendment, and protocol 
amendment summary of changes table. 
This section was inserted to better align with 
the Genzyme Corporation standard, following 
transfer in the development of RG-012. 
Names and Addresses 
A new field for the Monitoring Team’s 
Representative and contact information was 
added. 
This change was made to align with the 
Genzyme Corporation standard.  
List of Abbreviations and 
Acronyms 
The list has been moved to Section 10.6 
Appendix 6 and additional abbreviations have 
been added to the list. Abbreviations for ADUA, 
ANCOVA, CMH, DAP, EC, GMP, IUD, IUS, PP, 
and SOP have been removed from the list of 
abbreviations. 
The changes were made to better align with 
the Genzyme Corporation standard, and to 
remove or add abbreviations that are relevant 
to other revisions made elsewhere in the 
amended protocol 03. 
Throughout the entire 
protocol, including 
headers 
“Regulus” has been changed to “the Sponsor” or 
“Genzyme Corporation,” as appropriate, and the 
Sponsor address and contact details have been 
updated. 
This change was made due to the transfer in 
the development of RG-012. 
 
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Section # and Name 
Description of Change 
Brief Rationale 
Throughout the entire 
protocol, including 
headers 
The Regulus study drug code (RG012-03) has 
been updated to the Genzyme Corporation study 
code (ACT16248) throughout, as has the 
compound code (RG-012, updated to the 
Genzyme Corporation code SAR339375). 
These changes were made due to the 
transfer in the development of RG-012. 
Protocol Synopsis and 
throughout the entire 
protocol 
The primary objective has been presented as 
two points.  
These changes were made to provide 
clarification.  
Protocol Synopsis and 
throughout the entire 
protocol 
The secondary objective has been edited to 
include specific PK parameters (Cmax and Ctrough).  
The secondary objective added PK 
parameters for clarification. 
Protocol Synopsis and 
throughout the entire 
protocol 
Safety endpoint “Association of ADAs with 
adverse events” has been added. 
This change was made to further develop the 
safety endpoint evaluated.  
Protocol Synopsis and 
throughout the entire 
protocol 
Exploratory endpoints for difference in eGFR 
slope between the pretreatment period and 
treatment period were removed from the protocol.  
This change was made as some of the 
subjects may not have eGFR slope available 
on pretreatment period. 
Protocol Synopsis and 
throughout the entire 
protocol 
Exploratory endpoint for absolute and percent 
change in eGFR values from baseline at Week 96 
was added.  
This change was made due to the 
unavailability of some subjects. 
Protocol Synopsis and 
throughout the entire 
protocol 
Exploratory endpoint for the proportion of subjects 
who are treatment responders based on a decline 
in eGFR was removed.  
This change was made to further develop the 
efficacy endpoint evaluated. 
Protocol Synopsis and 
Section 7.1.3 
Exploratory endpoint for the proportion of subjects 
with a reduction from baseline in eGFR of <10%, 
<20%, <30%, or <40%, reduction at Week 24, 48 
and 96 was added. 
This change was made to further develop the 
efficacy endpoint evaluated. 
Protocol Synopsis and 
throughout the entire 
protocol 
Exploratory endpoint to characterize the effect of 
SAR339375 changes in renal biomarkers (BUN), 
albumin/creatinine ratio, and cyctatin C was 
edited. This endpoint removed assessment of 
kidney injury molecule 1 [KIM 1], beta 2 
microglobulin, and neutrophil gelatinase 
associated with lipocalin [NGAL]. 
This change was made to further develop the 
efficacy endpoint evaluated and remove 
complexity for the conduct of the study and 
subjects. 
Protocol Synopsis and 
throughout the entire 
protocol 
Exploratory endpoint for changes in exploratory 
biomarkers (which may include but are not 
necessarily limited to, in blood only: microRNAs 
(miR);in both blood and urine: transforming 
growth factor-β [TGF-β], and connective tissue 
growth factor [CTGF); in urine only: calbindin-
D28k, epidermal growth factor [EGF]). 
This change was made to further develop the 
efficacy endpoint evaluated and remove 
complexity for the conduct of the study and 
subjects. 
Protocol Synopsis and 
throughout the entire 
protocol 
Exploratory endpoint changes in podocyturia as 
measured by analysis of podocyte numbers and 
podocyte specific mRNAs in urine was removed. 
This change was made to further develop the 
efficacy endpoint evaluated and remove 
complexity for the conduct of the study 
subjects. 
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Section # and Name 
Description of Change 
Brief Rationale 
Protocol Synopsis and 
throughout the entire 
protocol 
Exploratory endpoint change over time in quality 
of life (QoL) as measured using the Short Form 
36 Health Survey (SF-36) was removed.  
Removal of exploratory endpoints evaluating 
changes to biomarkers and measurement of 
quality of life (QoL) of subjects was 
considered. The assessment of the effect of 
SAR339375 on QoL would add complexity for 
the conduct of the study and subjects. In 
addition, there was no change in SF36 data 
in early CKD subjects from the ATHENA 
registry (OBS16374, formerly RG012-01), 
thus the analysis has been removed. 
Protocol Synopsis and 
throughout the entire 
protocol 
Pharmacokinetic endpoint plasma concentrations 
added (Cmax and Ctrough) and removed calculated 
PK parameters from this endpoint. 
This change was made to further develop the 
pharmacokinetic endpoint evaluated. 
Protocol Synopsis and 
throughout the entire 
protocol 
Reference to OBS16374, formerly RG012-01, 
ATHENA Natural History Study has been made. 
These changes were made due to the 
transfer in the development of RG-012. 
Protocol Synopsis and 
throughout the entire 
protocol 
The number of subjects was increased from 40 to 
45. 
This change was made to include recruitment 
of approximately 45 adult subjects both male 
and female preventing the exposure of 
children at this early stage of development of 
SAR339375. 
Protocol Synopsis and 
throughout the entire 
protocol 
Removal of the following criteria: a baseline urine 
protein/creatinine ratio ≥300 mg/g, and baseline 
eGFR progression criteria if aged 31-60. 
The study is modified to update inclusion 
criteria to reflect the change in the targeted 
patient population. 
Protocol Synopsis and 
throughout the entire 
protocol 
Change the ratio of randomization from 1:1 to 2:1. 
The change was made to update the dosing 
regimen to increase likelihood of showing a 
statistical difference in the study. 
Protocol Synopsis and 
throughout the entire 
protocol 
Change the dosing from Q2W to QW. 
The change was made because the weekly 
administration of SAR339375 is more likely to 
result in target kidney concentration than 
Q2W administration that would provide 
maximum clinical benefit. This demonstrated 
efficacy was seen in a nonclinical model, 
whilst still maintaining an acceptable safety 
margin.  
The dosing frequency has been increased 
from Q2W to Q1W based on observed drug 
concentrations in human kidney samples. 
(Preliminary data from ongoing open label 
part of the kidney biopsy study PDY16327, 
formerly RG012-06) relative to predicted 
target kidney concentrations based on 
nonclinical kidney PK (mouse and non-
human primates (NHP)) and efficacy 
(mouse). AE profile observed in the open 
label part of PDY16327 within 1 year 
treatment supports the increase in dose. 
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Section # and Name 
Description of Change 
Brief Rationale 
Protocol Synopsis and 
throughout the entire 
protocol 
Addition of criteria in the double-blind, placebo-
controlled treatment period to include the 
statement that: Once randomized, the subject 
should be treated within 3 calendar days 
maximum. 
The change was made to reflect the change 
in the study design.  
Protocol Synopsis and 
throughout the entire 
protocol 
Addition of language in the open-label treatment 
extension period that specifies subjects who do 
not complete the 48-week double-blind, placebo-
controlled treatment period and "early terminate" 
will enter the follow-up period. 
The change was made to reflect the change 
in the study design. 
Protocol Synopsis and 
throughout the entire 
document 
Addition of language in the follow-up period to 
include an example of when the follow up period 
will occur. “Or after ET of the double blind part”. 
The change was made to provide clarity and 
define the follow-up period.  
Protocol Synopsis and 
throughout the entire 
document 
Safety Management language was removed and 
replaced with standard Genzyme Corporation 
language.  
This section was changed to better align with 
the Genzyme Corporation standard, following 
transfer in the development of RG-012. 
Protocol Synopsis and 
throughout the entire 
document 
Safety Management language referencing the 
Safety Review Committee was replaced with Data 
Monitoring Committee. 
The change was made to reflect the standard 
Genzyme Corporation language.  
Protocol Synopsis and 
throughout the entire 
document 
Dose Reduction language was changed to reflect 
a subject’s platelet count will be obtained weekly 
before dose administration. Platelet counts will be 
measured at a central laboratory and can 
exceptionally be measured at a local laboratory. 
The subject’s most recent platelet counts but not 
older than 10 days will be reviewed by the 
Investigator/physician before drug administration.  
This change was made to determine the 
safety of SAR339375 and its effect on 
reducing platelet counts.  
Protocol Synopsis and 
throughout the entire 
document 
Individual Treatment Stopping Criteria changes to 
the reference from the Regulus Medical Monitor 
to the Genzyme Corporation Study Medical 
Manager (SMM) were made. 
This change was made to reflect the standard 
Genzyme Corporation language.  
Protocol Synopsis and 
throughout the entire 
document 
Study Stopping Criteria was changed to Study 
Suspension and Stopping Criteria.  
This change was made to incorporate 
suspension criteria previously omitted.  
Protocol Synopsis and 
throughout the entire 
document 
Study Suspension and Stopping Criteria was 
changed to Grade 3 (or higher) AEs, or any death 
or two SAEs considered at least possibly related 
to participation in the clinical trial, will result in the 
recommendation to suspend all dosing and stop 
recruitment, then will trigger an ad hoc meeting 
with the DMC who will be asked to consider the 
appropriateness of study conduct continuation 
study as unchanged, early study termination or 
modification.  
The criteria have been modified to reflect the 
information that we have for the rate of 
occurrence of AEs and SAEs in the other 
trials. 
Protocol Synopsis and 
throughout the entire 
document 
Study drug dose was changed from 1.5 mg/kg 
every two weeks to 110 mg every week. Study 
drug dose reduction was changed from 
0.75 mg/kg to 110 mg every other week. 
This change was made to standardize the 
dosing regimen in the protocol. 
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Section # and Name 
Description of Change 
Brief Rationale 
Protocol Synopsis and 
throughout the entire 
document 
Study Stopping Criteria is at the discretion of the 
DMC was added to the Study Suspension and 
Stopping Criteria. 
This change was made to reflect the standard 
Genzyme Corporation language.  
Protocol Synopsis and 
throughout the entire 
document 
Investigational Medicinal product removed 
reference to RG-012 and the RG456070 as the 
drug substance. Formulation information was also 
removed and replaced with information about how 
SAR339375 will be supplied. This product will be 
supplied as a 110 mg/mL solution in a 5 mL glass 
vial. Each vial will contain a withdrawable volume 
of 2 mL for single use of administration.  
This change was made further specific the 
IMP in further detail. 
Protocol Synopsis and 
throughout the entire 
document 
Investigational Medicinal Product language 
regarding how the placebo will be supplied was 
removed and replaced with information stating 
that the placebo matching SAR339375 for SC 
administration will be supplied as sodium chloride 
and riboflavin (colorant) solution in 5 mL glass 
vial. Each vial will contain a withdrawable volume 
of 2 mL. 
This change was made further specific the 
placebo in further detail. 
Protocol Synopsis and 
throughout the entire 
document 
Summary of Eligibility Requirements changes to 
Inclusion criteria included the removal of some 
criteria and the addition of other criteria.  
The study added females in the inclusion criteria. 
The study added the need for a confirmed clinical 
diagnosis of Alport syndrome, (hematuria, family 
history, hearing loss, ocular change) and genetic 
confirmation of Alport syndrome in the subject or 
the family member, or kidney biopsy showing 
glomerular basement membrane abnormalities 
consistent with Alport Syndrome.  
The study changed the age from the possibility to 
expand inclusion to 12-60 year olds to exclusively 
including 18-55 years old. The lower limit of the 
eGFR was changed from >40 to 
>35 mL/min/1.73 m2 (based on CKD-EPI) at 
screening. The inclusion criteria also added Renal 
Function Criteria that subjects must meet one of 
the three criteria provided. 
Change to the stability of ACE or ARB treatment 
was included for at least 30 days prior to 
screening.  
Inclusion criteria to address sexually active 
females and women of childbearing potential 
were added. Contraceptive use by men or women 
was also added.  
Hepatitis A virus screening is not required was 
added. 
The study is modified to update inclusion 
criteria to include recruitment of 
approximately 45 adult subjects both male 
and female preventing the exposure of 
children at this early stage of development of 
SAR339375. The updated inclusion criteria 
will allow for expansion of the study 
population and prohibit limitation to X-linked 
Alport Syndrome. In order to better identify 
rapid progressors, additional renal function 
inclusion criteria were added based on the 
baseline eGFR and proteinuria. These new 
criteria are based on the analysis of the 
ATHENA registry data. Inclusion criteria were 
also updated to include ACE/ARB treatment 
at stable dose for at least 30 days since 
ACE/ARB are the current standard of care. 
Inclusion criteria addressing contraceptive 
use for sexually active males, females, and 
women of childbearing potential were added 
to comply with Genzyme Corporation 
standards. Clarification of screening for 
chronic diseases was added. 
 
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Section # and Name 
Description of Change 
Brief Rationale 
Protocol Synopsis and 
throughout the entire 
document 
Summary of Eligibility Requirements changes to 
Exclusion criteria included the addition of 
language to the Exclusion Criteria 01 identifying 
causes of chronic kidney disease aside from 
Alport syndrome (including but not limited to 
“other heritable disorder leading to chronic kidney 
disease” was made.  
Bullet point for Exclusion Criteria 03 was also 
added: “Maintenance mediation known to cause 
QT prolongation” was made. 
The language of Exclusion Criteria 05 was 
modified to add “cervical carcinoma in situ”.  
These changes are for specification of the 
therapy study design. 
Protocol Synopsis and 
throughout the entire 
document 
Exclusion criteria 09 prior treatment with 
Bardoxolone within 90 days prior to screening 
was added. 
These changes were made to prevent 
concomitant action between Bardoxolone and 
SAR339375. 
Protocol Synopsis and 
throughout the entire 
document 
Exclusion criteria 12, 13, and 14 have been 
added. 
These changes are for specification of the 
therapy study design. 
Protocol Synopsis, 
Section 4.2, and 
throughout the entire 
document 
Treatment Assignment change to include 
language that states for open label extension 
period: “Subjects who require dose reduction will 
receive SAR339375 as per the same dose that 
they received in the blinded phase of the study” 
was added.  
These changes are for specification of the 
therapy study design. 
Protocol Synopsis, 
Section 6.5, and 
throughout the entire 
document 
Pharmacokinetic Analysis was changed to 
indicate that Plasma samples will be collected 
4 hours post-dose on Day 1, Week 24, and 
Week 48 of the treatment period for the 
determination of maximum plasma 
concentrations. In addition, pre-dose plasma PK 
samples will be collected (up to 4 hours before 
dose administration) on Day 1 and through 
Weeks 4, 12, 24, 36, and 48 for determination of 
minimum plasma concentrations. The removal of 
PK blood samples was made to this section. Post 
baseline visits with PK sampling should be 
scheduled 7± 3 days after the prior injection of 
study drug during the double blind, placebo-
controlled treatment period. Time and date of PK 
sampling, as well as the date of the last prior 
administration of study drug should be recorded 
in the electronic case report form was added. This 
section removed the reference PK blood sample 
collections according to the visits indicated in 
Table 1 and 2, and also removed the 
measurements of non-compartmental PK 
parameters and the appropriateness of PK 
sampling appropriate, for plasma RG456070, 
RG0005, and SUM. 
These changes are for specification of the 
therapy study design. 
Protocol Synopsis 
Statistical Analyses was changed to Statistical 
Considerations. 
This change was made to reflect the standard 
Genzyme Corporation language. 
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Section # and Name 
Description of Change 
Brief Rationale 
Protocol Synopsis  
Within Statistical Considerations, Sample size 
was changed to Sample Size Determination. 
This change was made to reflect the standard 
Genzyme Corporation language. 
Protocol Synopsis and 
throughout the entire 
document 
Changes were made to Statistical Consideration 
to indicate that: the sample size was changed 
from 40 to 45. The study will randomize the 
subjects in a 2:1 ratio. 
Sample size calculation updated according to 
new primary efficacy analysis and 
randomization ratio.  
Protocol Synopsis 
A section for analysis population was added in 
the protocol synopsis. 
These changes are for specification of the 
therapy study design. 
Protocol Synopsis, 
Section 7.2.5, and 
throughout the entire 
document 
The primary efficacy analysis was added to 
describe that a linear mixed effect model will be 
fitted to the eGFR from baseline to Week 48. 
ATHENA Natural History Study (OBS16374) data 
will be used as prior information supplementing 
the placebo arm, using a Bayesian approach. The 
original two-stage analysis which uses ANCOVA 
model to analyze individual slope obtained from 
simple linear regression for each subject was 
removed. 
The two-stage model was replaced with the 
linear mixed effect model because of the 
advantages of the latter explained in (34). 
Protocol Synopsis 
Statistical Methods: Summary of changes in 
baseline in clinical laboratory parameters and vital 
signs was removed. Description of safety 
analyses in the synopsis were simplified with 
details kept in Section 7.2.4. Description of 
analysis of demographic and baseline 
characteristics were removed from synopsis and 
kept in Section 7.2.3. 
Changes were made to include only key 
information of analysis in the Protocol 
Synopsis.  
Protocol Synopsis 
Statistical Methods: Supportive analysis of the 
primary efficacy endpoint and analysis of 
secondary endpoints were removed from the 
Protocol Synopsis and discussed in Section 7.2.5.  
It was added that pharmacodynamics parameters 
will be summarized and compared between 
treatment groups at each time point using 
descriptive statistics. 
Changes were made to include only key 
information of analysis in the Protocol 
Synopsis. 
Protocol Synopsis and 
throughout the entire 
document 
Statistical Methods: Interim Analysis removal of 
Regulus language and replaced with: A non-
binding interim futility analysis will be performed 
under the supervision of the DMC when 
approximately 24 subjects have completed Week 
48 visit. Further details are provided in 
Section 7.2.7. Additional interim analyses for 
safety assessment only will be performed 
periodically by the DMC.  
These changes are for specification of the 
therapy study design.  
Protocol Synopsis  
Schedule of Events Table 1: Change to title to 
include “and Follow-up Period”  
This change is to include language previously 
omitted. 
Protocol Synopsis 
Schedule of Events Table 1: Changes were made 
to the therapy study design. 
These changes were implemented to 
describe therapy study design and to provide 
clarity of the study design. 
Protocol Synopsis and 
throughout the entire 
document 
Schedule of Events Table 1: Footnotes have 
been changed to include details and information 
to describe the requirement for the study design.  
These changes are for specification of the 
therapy study design. 
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Section # and Name 
Description of Change 
Brief Rationale 
Protocol Synopsis and 
throughout the entire 
document 
Schedule of Events Table 2: Changes were made 
to the therapy study design. 
These changes were implemented to 
describe therapy study design and to provide 
clarity of the study design. 
Section 1.2.3  
Justification of Route and 
Does Regimen 
Justification of Route and Dose Regimen has 
been changed to 110 mg fixed dose, Q1W 
The change was made because the weekly 
administration of SAR339375 is more likely to 
result in target kidney concentration which 
had demonstrated efficacy in a nonclinical 
model, than Q2W administration, whilst still 
maintaining an acceptable safety margin. The 
dosing frequency has been increased 
from Q2W to Q1W based on observed drug 
concentrations in human kidney samples. 
(Preliminary data from ongoing kidney biopsy 
study PDY16327, formerly RG012-06) 
relative to predicted target kidney 
concentrations based on nonclinical kidney 
PK (mouse and NHP) and efficacy (mouse). 
Section 1.2.3 
Justification of Route and 
Does Regimen 
The justification was updated to reflect changes 
related to the study therapy. Determination of 
NHP doses which gave similar kidney SUM 
concentrations (AUC SUM) to those observed in 
the mouse models at pharmacologically active 
doses was added.  
These changes were made to show the 
therapy study design and for clarification.  
Section 1.2.3 
Justification of Route and 
Does Regimen 
Nonclinical and Clinical data observed and target 
and Pre-clinical Toxicology were added to reflect 
reason for therapy study design.  
These changes were made for clarity and to 
describe the rational and basis for the therapy 
study design. 
Section 2.1 
Primary Objectives 
The Primary Objective has been separated into 
two objectives. The first primary objective is to 
assess efficacy of SAR339375 in reducing the 
decline in renal function. The second primary 
objective is to assess the safety and tolerability of 
SAR339375 in subjects with Alport syndrome.  
For clarification the primary objective has 
been separated into two objectives to further 
determine the effects on safety/tolerability, 
and efficacy.  
 
Section 2.2 
Secondary Objectives 
The Secondary Objective has been edited to 
include specific PK parameters (Cmax and Ctrough).  
For clarification of the secondary objective 
the addition of the PK parameters has been 
added. 
Section 2.3 
Exploratory Objectives 
Exploratory Objective to assess changes in 
quality of life (QoL) in subject with Alport 
syndrome following administration of RG-012 was 
removed 
Removal of exploratory endpoints evaluating 
changes to biomarkers and measurement of 
quality of life (QoL) of subjects was 
considered. The assessment of the effect of 
SAR339375 QoL would add complexity for 
the conduct of the study and subjects. In 
addition, there was no change in SF36 data 
in early CKD subjects from the ATHENA 
registry (OBS16374, formerly RG012-01), 
thus the analysis has been removed. 
Section 2.3 
Exploratory Objectives 
Exploratory objectives were added and/or 
removed.  
These changes were implemented to 
describe therapy study design and to provide 
clarity of the study design. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 3.1 
Overall Study Design 
The number of subjects was increased from 40 to 
45 
The changes were made to include 
recruitment of approximately 45 adult 
subjects both male and female preventing the 
exposure of children at this early stage of 
development of SAR339375. 
Section 3.1 
Overall Study Design 
The description of the study design was revised 
to include and clarify study treatment design for 
the double-blind, placebo-controlled treatment 
period, the open label treatment extension period, 
for dose reduction, and the follow up period.  
These changes were implemented to 
describe therapy study design and to provide 
clarity of the study design. 
Section 3.2.1 Inclusion 
Criteria 
I01, I02, I03, I04, and I05 were modified to clarify 
the inclusion criteria in the study 
The study is modified to update inclusion 
criteria to include recruitment both male and 
female subjects and preventing the exposure 
of children at this early stage of development 
of SAR339375. The updated inclusion criteria 
will allow for expansion of the study 
population and prohibit limitation to X-linked 
Alport Syndrome. In order to better identify 
rapid progressors, additional renal function 
inclusion criteria were added based on the 
baseline eGFR and proteinuria. These new 
criteria are based on the analysis of the 
ATHENA registry data. Inclusion criteria were 
also updated to include ACE/ARB treatment 
at stable dose for at least 30 days since 
ACE/ARB are the current standard of care.  
Section 3.2.2 Exclusion 
Criteria 
E01, E03, and E05 were modified to provide 
clarity of exclusion criteria of the study, E09, E12, 
E13, E14 were added.  
These changes were implemented to 
describe therapy study design and to provide 
clarity of the study design. 
Section 3.2.3.2 
Follow-up for Drug 
Discontinuation/Subject 
Withdrawal from the 
Study 
Subjects who are withdrawn from the study will 
not be replaced was removed from this section.  
This change was made to provide 
specification to the therapy study design. 
Section 3.3 Screen 
Failures 
This entire section was added in the amended 
protocol. 
These changes were made to align with 
standard Genzyme Corporation process. 
Section 3.4 
Discontinuation of the 
Study 
Study stopping criteria was modified to include 
Grade 3 (or higher) AEs, or any death or 
two SAEs considered at least possibly related to 
participation in the clinical trial.  
This criteria has been modified to reflect the 
information we have for the rate of 
occurrence of AEs and SAEs in the other 
trials and particularly on the ATHENA registry 
study. 
Section 4.1.1 
Identity of Investigation 
Products 
Table 3 Identity of Investigational Products has 
been removed and replaced with descriptive text 
about the study drug dosage form. 
The changes are specifications for the 
therapy study design.  
Section 4.1.2 Packaging 
and Labeling, Handling 
and Accountability  
Details were modified in this section to describe 
how the study drug and placebo dosage forms 
each will be supplied. 
This change was made to provide 
specification to the therapy study design. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 4.2 Treatment 
Assignment 
For open label period, addition of details that 
subjects who require dose reduction will receive 
SAR339375 as per the same dose that they 
received in the blinded. 
This change was made to provide 
specification to the therapy study design. 
Section 4.3 Treatment 
Administration 
Modification to this section was made to describe 
the frequency of obtaining a subject’s platelet 
count and when the platelet count will be 
obtained. 
This change was made to provide 
specification to the therapy study design. 
Section 4.4 Home 
Injection 
This entire section was added in the amended 
protocol. 
These changes were made to align with 
standard Genzyme Corporation process. 
Section 4.5 Dose 
Reduction 
Modification to this section was made to describe 
the frequency of obtaining a subject’s platelet 
count and when the platelet count will be 
obtained. 
This change was made to provide 
specification to the therapy study design. 
Section 4.7 Prior and 
Concomitant Medications 
Removal of text: Prior/concomitant medication 
data collected in the ATHENA study may be used 
for this study. 
The information obtained from the ATHENA 
study about prior or concomitant medications 
will not be used in this study. 
Section 5 Study 
Procedures 
Change to this section to include rescreening of 
subject will be permitted with consultation of the 
Study Medical Manager.  
This change was made for clarification. 
Section 5.1 Screening 
Modification in schedule of events to screenings 
was made to describe screenings required prior 
to drug administration. 
This change was made for clarification. 
Section 5.2 Double-blind, 
placebo-controlled 
treatment period 
Details were added to this section to describe 
dose modifications to IMP dose, and the schedule 
of events for the study drug.  
This change was made for clarification. 
Section 5.3 Open-label 
extension treatment 
period 
Details were added to this section to describe 
dose modifications to IMP dose, and the schedule 
of events for the study drug.  
This change was made for clarification. 
Section 5.4 Early 
termination 
Details were added to this section to describe the 
schedule of events for a subject that discontinues 
before completing the treatment period for the 
study drug.  
This change was made for clarification. 
Section 5.5 Follow up 
period 
Details were added to this section to provide 
clarification of the follow up weeks from the last 
scheduled study visit in the active treatment 
period.  
This change was made for clarification 
Section 6.2.1 Adverse 
events 
Details were added to this section to provide 
clarification on information about collection of 
information about AEs. 
This change was made for clarification.  
Section 6.2.1 Adverse 
events 
Table 4 was modified to include another column 
that addressed Life Threatening Event (Grade 4). 
These changes were implemented align with 
standard Genzyme Corporation data 
collection process. 
Section 6.2.1 Adverse 
events 
Table 6 was removed. 
This change was made to incorporate 
standard Genzyme Corporation processes.  
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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.2.3 Procedures 
in case of pregnancy 
Collection of pregnancy information was added to 
this section.  
These changes were made to align with 
standard Genzyme Corporation process. 
Section 6.2.4 Sponsor 
Obligation 
This section was added and details about the 
Sponsor’ Obligations through the course of the 
study were provided about the storage, 
dispensing, handling, and quality of the 
SAR339375 drug product.  
These changes were made to align with 
standard Genzyme Corporation process. 
Section 6.2.5 Guidelines 
for Reporting Product 
Complaints 
(SAR339375) 
This section was added that provide guidelines 
for reporting product complaints (SAR339375). 
These changes were made to align with 
standard Genzyme Corporation process. 
Section 6.2.11 
Monitoring of Platelet 
Count 
Modification to this section was made to describe 
the frequency of obtaining a subject’s platelet 
count and when the platelet count will be 
obtained. 
This change was made to provide 
specification to the therapy study design. 
Section 6.2.13 Safety 
Oversight 
Details were added to this section to include 
information about the internal Data Monitoring 
Committee and their review of data throughout 
the study. 
These changes were made to align with 
standard Genzyme Corporation process. 
Section 6.3.1 Estimated 
GFR 
Changes to the information about the calculation 
of eGFR were provided. Removed Section 6.3.2 
of SF-36 from previous version of protocol.  
This change was made to provide 
clarification.  
Section 6.4 
Pharmacodynamic 
Assessments and 
Biomarkers  
Modification to this section included the removal 
of several assessments listed in the Schedule of 
Events table.  
This change was made to provide 
specification to the therapy study design. 
Section 6.5 
Pharmacokinetic 
Assessments 
Modifications to this section were made to provide 
details of the changes to the pharmacokinetic 
assessments. 
These changes are for specification of the 
therapy study design. 
Section 6.6 Disposition of 
Samples after Study 
Completion 
Modification to this section was made to provide 
clarity on the disposal of PK samples following 
completion of CSR and the disposal of ADA 
samples.  
These changes were made to align with 
standard Genzyme Corporation process. 
Section 7.1.1 Safety 
Endpoints and Protocol 
Synopsis 
Addition of safety endpoint association of AE with 
ADA was added to this section. 
This change was made to provide 
specification to the therapy study design. 
Section 7.1.2 Efficacy 
Endpoints and Protocol 
Synopsis 
Modifications to this section provided clarity on 
primary endpoint and secondary endpoints. 
Absolute and percentage change in eGFR values 
from baseline at Week 96 was moved to 
Section 7.1.3. 
This change was made to provide clarification 
of the open label extension period of the 
therapy study design. 
Section 7.1.3 Exploratory 
Endpoints: Efficacy, 
Pharmacodynamic and 
Biomarker Endpoints 
Modifications to this section added exploratory 
endpoint of absolute and percentage change in 
eGFR values from baseline at Week 96, and also 
removed assessments no longer performed 
during the treatment period for this study. 
These changes are for specification of the 
therapy study design. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 7.2 Statistical 
Methods and Analyses 
Changes were made to this section to describe 
the statistical analysis plan development. This 
section is modified to include primary and 
secondary analyses.  
These changes were made to align with 
standard Genzyme Corporation process. 
Section 7.2.2 Analysis 
Populations 
Modifications to this section removed the per 
protocol population and also included 
considerations on the subjects who only receive a 
partial dose.  
These changes are for specification of the 
therapy study design. 
Section 7.2.4 Safety 
Analysis 
Changes to this section include information about 
the way safety analyses will be performed on the 
safety population.  
These changes are made to align with the 
standard Genzyme Corporation process. 
Section 7.2.5 Efficacy 
Analysis 
This section has been updated with replacement 
of primary efficacy analysis and changes 
according to the modifications made to efficacy 
endpoint. 
These changes were made to align with 
standard Genzyme Corporation process. 
Section 7.2.6 
Pharmacodynamic 
Analysis 
This section has been removed; information has 
been incorporated into Section 7.2.6 Other 
Analyses. 
These changes were made to align with 
standard Genzyme Corporation process. 
Section 7.2.7 
Pharmacokinetic 
Analysis 
This section has been removed, information has 
been incorporated into Section 7.2.6 Other 
Analyses. 
These changes were made to align with 
standard Genzyme Corporation process. 
Section 7.2.7 Interim 
Analysis 
Modification to this section provide information on 
nonbinding interim futility analysis and when this 
will be performed.  
These changes were made to align with 
standard Genzyme Corporation process. 
Section 9.1.1 Rapid 
Notification on Serious 
Adverse Events 
Slight rewordings and additional details were 
added regarding exam and laboratory information 
to report, and regarding the timeframes in which 
to report. A statement about what to do when the 
eCRF does not work was added. 
These changes were made to align with 
standard Genzyme Corporation process. 
Section 9.1.2 Dosing 
Deviations 
Modification to this section provided information 
on procedure for symptomatic overdose with IMP. 
These changes were made to align with 
standard Genzyme Corporation process. 
Section 9.2.2 Ethical 
Review 
Section Header was changed from “Institutional 
Review Board/Ethics Committee” to “Ethical 
Review”. This section also provides details on 
review by IRB/IEC for approval before 
implementation of changes made to the study 
design.  
These changes were made to align with 
standard Genzyme Corporation process. 
Section 9.2.3 Informed 
Consent 
Changes were made to this section to provide 
information about informed consent for 
participation in this study.  
These changes were made to align with 
standard Genzyme Corporation process. 
Section 9.2.4 Regulatory 
and Ethical 
Considerations  
Section Header was changed from “Ethical 
Considerations” to “Regulatory and Ethical 
Considerations” in order to incorporate 
information about the study being conducted in 
accordance with the protocol.  
These changes were made to align with 
standard Genzyme Corporation process. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 9.2.5 Sponsor 
Obligation 
Section Header was changed from “sponsor” to 
“Sponsor Obligation” additional details were 
added regarding the Sponsor’s reporting 
obligations. IN addition, details were added 
regarding the storage, dispensing, handling and 
quality of SAR339375 drug product. 
These changes were made to align with 
standard Genzyme Corporation process. 
Section 9.2.7 Guidelines 
for reporting product 
complaints (SAR339375) 
This entire section was added in the amended 
protocol. 
These changes were made to align with 
standard Genzyme Corporation process. 
Section 9.3.3 Study 
Documentation, 
Confidentiality, and 
Records Retention 
Section Header was changed from “Records 
Retention” to “Study Documentation, 
Confidentiality, and Records Retention” The 
information in this section was modified to provide 
details about storage of subject data. 
These changes were made to align with 
standard Genzyme Corporation process. 
Section 9.3.4 Data 
Quality Control and 
Quality Assurance 
This entire section and its subsection were 
changed in the amended protocol. 
These changes were made to align with 
standard Genzyme Corporation process. 
Section 9.3.5 Audits and 
Inspections 
This entire section was added in the amended 
protocol. 
These changes were made to align with 
standard Genzyme Corporation process. 
Section 9.3.7 Publication 
Policy 
Section Header was changed from “Publication 
Policy/Disclosure of Data” to Publication Policy” 
and describes that the results of the study may be 
published or presented at scientific meetings. 
These changes were made to align with 
standard Genzyme Corporation process. 
Section 9.3.8 
Dissemination of Clinical 
Study Data 
This entire section was added in the amended 
protocol. 
These changes were made to align with 
standard Genzyme Corporation process. 
Section 9.3.9 Data 
Protection 
This entire section was added in the amended 
protocol. 
These changes were made to align with 
standard Genzyme Corporation process. 
Section 9.3.10 Data 
Quality Assurance 
This entire section was added in the amended 
protocol. 
These changes were made to align with 
standard Genzyme Corporation process. 
Section 9.3.11 Source 
Documents 
This entire section was added in the amended 
protocol. 
These changes were made to align with 
standard Genzyme Corporation process. 
Section 9.3.12 Study and 
site closure 
This entire section was added in the amended 
protocol. 
These changes were made to align with 
standard Genzyme Corporation process. 
Section 10 Supporting 
Documentation and 
operational 
Considerations, and 
Section 11 References  
Section 10 (Supporting Documentation and 
Operational Considerations) was created and the 
prior Section 10 (References) was renumbered to 
Section 11. 
Section 10 was inserted to align with the 
Genzyme Corporation standard, following 
transfer in the development and 
commercialization of RG-012. 
In addition, other minor editorial changes (eg, grammatical, stylistic, and minor typographical 
error corrections) were implemented throughout the protocol. 
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10.8.10 
Clinical study protocol Version 3.0 (16 August 2017)  
Table 8 - Summary of key changes to Protocol RG012-03, Version 3.0  
Heading 
Summary of Change 
CONTACT LIST 
Has been removed from the protocol; A full list of study contacts is provided in 
the Study Reference Manual.  
Removed Clinical Project Manager, Clinical Operations.  
PROTOCOL SYNOPSIS 
Synopsis changes have been made to harmonize the synopsis with the 
multiple changes specified in this summary of changes. 
Section 1.1.4.2 Study RG012-05 
Has been updated to include additional details regarding the changes in 
platelet counts observed in the 220 mg dose cohort.  
Section 1.3.1 Potential Risks 
‘Potential for Thrombocytopenia’, has been updated to include class related 
side effects (decreased complement and elevated liver function tests) and 
added injection site reactions as potential side effects as observed in RG-012 
clinical trials. Thresholds for increased monitoring and dose reduction have 
been removed.  
Section 3.1 Overall Study Design 
Has been modified to state that the threshold for pausing study drug dosing is 
platelets <100 000/microL consistent with the new Grading System for Adverse 
Events of Interest and that AEs must return to normal or >= Grade 1 for injection 
site reactions. 
Section 3.2.2 Exclusion Criteria 
Has been modified to: 
• 
Exclude those with a weight >110 kg (this negates the need for 
two SC injections when study drug is administered). 
Section 3.2.3.1 Individual Treatment 
Stopping Criteria 
Has been modified to: 
• 
Be consistent with the new Grading System for Adverse Events of 
Interest. 
• 
Adjusted the unintended weight loss to >= 9% to be consistent with a 
Grade 3 (severe) severity per the DAIDS Table for Grading Severity 
of Adult and Pediatric Adverse Events, version 2.1, July 2017. 
• 
Added guidance to pausing dosing with any Grade 2 AE that is not 
addressed in the Grading System for Adverse Events of Interest. 
Section 3.3 Discontinuation of Study 
Was modified to clarify the study stopping criteria and the potential outcomes 
from the SRC review of significant AEs.  
Section 4.4 Dose Reduction 
Has been modified to reflect the new Grading System for Adverse Events of 
Interest. Moderate (Grade 2) AEs will result in a pause in dosing. Additional 
details are provided for dose reduction rules for AEs of Interest 
(thrombocytopenia, liver dysfunction, renal function, and injection site 
reactions).  
Section 5.2 Double-Blind, Placebo- 
Controlled Treatment Period 
Has the following modifications: Hearing Assessment added at baseline, 
Week 48, and early termination visits. Hearing loss can occur in Alport 
syndrome.  
• 
For subjects age 12-17, physical exam to include height and Tanner 
stage at baseline, Week 24, and Week 48. In addition, FSH, LH, and 
total testosterone will be measured at baseline, Week 24, and 
Week 48. This is to assess pubertal development. 
• 
Clarified that a 2 hr observation period is required after 
administration of the first dose at the baseline visit.  
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Heading 
Summary of Change 
Section 5.3 Open-Label Extension Treatment 
Period 
Has the following modifications: 
• 
Hearing Assessment added at Week 96 and early termination visits. 
• 
For subjects age 12-17, physical exam to include height and Tanner 
stage at Weeks 48, 72, and 96. In addition, FSH, LH, and total 
testosterone will be measured at Weeks 48, 72, and 96.  
Section 5.4 Early Termination 
Was modified to include: 
• 
Hearing Assessment. 
• 
For subjects age 12-17 physical exam to include height and Tanner 
stage. In addition, FSH, LH, and total testosterone will be measured.  
Section 6.2.1 Adverse Events 
Was modified with: 
• 
A new protocol-defined Grading System for Adverse Events of 
Interest (Table 4) was updated. Thrombocytopenia, liver function 
abnormalities, renal function, and weight loss (Injection site reactions 
are also considered an adverse event of interest but are covered 
separately in Section 6.1.9 and Table 8) were identified as adverse 
events of interest based upon nonclinical toxicology studies with 
RG456070 as well as clinical experience with RG-012 and other 
oligonucleotides. This new grading system is based upon the DAIDS 
Table for Grading Severity of Adult and Pediatric Adverse Events, 
version 2.1, July 2017. This grading system is more conservative 
than the CTCAE grading system for oncology subjects. 
• 
For AEs not considered an event of interest, the Classification of 
Adverse Events by Severity (Table 5) was modified.  
Section 6.2.4 Physical  
Examination/Body System Assessment  
Was modified to add height and Tanner staging for subjects 12 to 17. 
Section 6.2.7 Hearing Assessment 
Added. Hearing will be assessed during the, Treatment Period and Extension 
Period, using a pure tone audiometry (air only) test at defined frequencies at 
baseline, Week 48 and 96.  
Section 6.2.8 Gonadotropins  
Added. For subjects ages 12-17 FSH, LH, and total testosterone will be 
measured.  
Section 6.2.9 Monitoring of Platelet Count 
Common Terminology Criteria for Adverse Events 
[CTCAE] ≥ Grade 1 thrombocytopenia), <125 000/microL was deleted and 
information on Total protein and monitoring platelets was added to 
Section 6.2.8.  
Section 6.4 Pharmacodynamic Assessments 
and Biomarkers 
Was modified to remove the specific podocyte assay. 
Section 7.2.1 Determination of Sample Size 
Changed to: Probability of observing a 50% effect size is provided rather that 
for a 40% effect.  
Section 10 REFERENCES 
Removed reference to CTCAE v4.03 (2010) and added website links.  
 
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10.8.11 
Clinical study protocol Version 2.0 (29 June 2017)  
Table 9 - Summary of key changes to Protocol RG012-03, Version 2.0  
Heading  
Summary of Change 
Protocol Title 
Change was made due and dose regimen from weekly to every two weeks. 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate 
the Safety, Efficacy, Pharmacodynamics, and Pharmacokinetics of RG-012 for 
Injection Administered Every 2 Weeks in Patients with Alport Syndrome 
Synopsis 
Changes have been made to harmonize the synopsis with the multiple 
changes specified in this summary of changes. Additionally, the following 
changes are made: 
• 
Study personnel and contact details were updated including new 
contact details for reporting of Serious Adverse Events and Anti-Drug 
Antibody laboratory. 
• 
The Independent Data Monitoring Committee has been replaced by 
a Safety Review Committee who will review safety data on a monthly 
and ad-hoc basis. Changes to reflect this have been made in the 
Synopsis, Section 3.3 ‘Discontinuation of the Study’, addition of the 
new Section 6.1.9 “Safety Oversight” and deletion of Section 9.1.3 
Independent Data Monitoring Committee. The synopsis section has 
been expanded to include further details to outline Safety 
Management: 
• 
Monitoring of platelet count 
• 
Option for dose reduction 
• 
Individual treatment stopping criteria and study stopping criteria 
added to the synopsis 
Section 1 ‘Introduction’ 
1.1 ‘Background’ 
• 
Additional information provided on Alport Syndrome, RG-012 and its 
target, micro-RNA-21 
• 
More information is provided on the non-clinical studies conducted to 
date, including in vivo studies, and the GLP 26-week mice and 
39-week monkey studies, with the conclusion updated to reflect the 
higher dose implemented with this amendment.  
• 
An update is provided from the ongoing Phase 1 study, RG012-05 in 
healthy subjects, in which dose escalation from fixed doses of 55 mg, 
110 mg (corresponds approximately to 1.5 mg/kg in a 73 kg subject) 
and 220 mg have completed and follow up is ongoing.  
Section 1.2 ‘Rationale’ 
Updated with information on the justification of the target and the study design. 
The justification of the route and dose regimen have also been updated to 
reflect the increased dose and new regimen of 1.5 mg/kg Q2W.  
Section 1.3 ‘Potential Risks and Benefits’ 
New section added. 
Section 2 ‘Study Objectives’ 
 
• 
Efficacy of RG-012 (in reducing the decline in renal function) is now 
included as a primary objective of the study. This is reflected in the 
study title, which is changed on the title page, Investigator protocol 
agreement page and synopsis. 
• 
The secondary objectives have been revised to focus on the plasma 
PK (including the individual concentrations and sum of the parent 
compound and it’s major metabolite) and potential formation of anti-
drug antibodies. As such, the objective “To assess the effect of 
RG-012 on endogenous renal microRNA-21 (miR-21)” has been 
removed. 
• 
The biomarker objective has been moved from a secondary objective 
to be exploratory objective 
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Heading  
Summary of Change 
Section 3 ‘Investigational Plan’ 
• 
The sample size has been increased from 30 to approximately 
40 subjects. 
• 
The double-blind, placebo controlled treatment period has increased 
from 24 to 48 weeks. 
• 
The dose has been changed to be 1.5 mg/kg or placebo (ratio 1:1) 
for 48 weeks (previously was 110 mg or 220 mg RG-012, or placebo 
for 24 weeks). 
• 
RG-012 will be administered every 2 weeks instead of weekly. 
• 
Details of the open-label extension have been added. This is 
available to subjects who complete the original 48-week study. All 
subjects will receive Q2W active treatment with RG-012. As a result 
‘Active treatment period’ has been replaced with ‘Double-Blind, 
Placebo-Controlled Treatment period’ throughout the protocol to 
distinguish from the ‘Open Label Extension Period’. 
• 
Visits previously assigned to be performed as ‘Home visits’ have 
been reassigned as study site visits, with the option for them to be 
performed at an Alternate Location. (Further details as to the training, 
qualification and delegation of the personnel performing these visits 
is provided in Section 5.7 ‘Alternate Location Visits’.) 
• 
Study center information has been updated. 
• 
Information on what and how data from the ATHENA study can be 
used has been updated (some information moved to Section 3.2.1 
Inclusion Criteria) 
• 
Due to the multiple ascending dose study having completing, details 
of the Sentinel cohort and how the study will progress as planned 
have been removed. 
• 
Details of assessments to be performed in the Double-Blind, 
Placebo-Controlled Treatment Period have been removed with 
reference made to Table 1 instead. 
• 
The text was updated to align with changes in the eligibility criteria 
and Section 4.6 Prior and Concomitant Medication, to state that for 
concomitant medication other than ACE and ARBs, the dose can be 
adjusted to maintain standard of care. 
• 
Dose reductions are now allowed in response to a Grade 2 
treatment-emergent adverse event or thrombocytopenia. (Full details 
of this are provided in Section 4.3 ‘Dose Reductions’) 
• 
Patients will be followed up for 6 weeks upon completion of either the 
double-blind, placebo controlled treatment period or the open-label 
extension (previously a 12 week follow up was specified following 
completion of the main part of the study).  
• 
The overall duration is increased from approximately 60 weeks to 
approximately 106 weeks (from screening through completion of 
follow-up). 
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Heading  
Summary of Change 
Section 3.2 ‘Study Population’ 
 
• 
Removed the requirement to be able to provide written informed 
consent 
• 
Women have been excluded from the study. Related eligibility criteria 
have been removed (contraception requirements and exclusion of 
female subjects who are pregnant or lactating) 
• 
The age requirement has been revised to include the option to 
include subjects aged 12 to 60 years following SRC review of the 
data from the first 10 subjects (previously was 18 to 65 years). 
• 
Specified that subjects must have a diagnosis of X-linked Alport 
syndrome (clinical and genetic diagnosis) 
• 
eGFR related inclusion criteria have been simplified and updated to 
reflect the increased age range. Revised to: 
- 
Baseline eGFR value must be between 40 and 90 mL/min/1.73 m2 
(previously was a first screening eGFR of 45 to 90 ml/min/1.73 m2 
and final screening/baseline eGFR >30 ml/min/1.73 m2) 
- 
eGFR Slope criteria are now only applicable for subjects aged 
31-60. For these subjects, the Baseline eGFR progression 
criteria revised to broaden the amount of time the 
measurements can be collected from. 
- 
Changes were also made on how the data from subjects 
participating in the ATHENA study can be used 
• 
The proteinuria limit was reduced from ≥500 mg to ≥300 mg 
protein/g creatinine, which needs to be met at the screening visit 
(previously was initial screening and baseline visits) 
• 
Clarified that subjects currently taking an ACE inhibitor and/or ARB, 
the dosing regimen should be stable for ≥30 days prior to screening. 
• 
Contraception have been simplified, to require the subject to agree to 
use a condom during heterosexual intercourse from screening 
through to 65 days after the last dose of study drug (previously 
additional measures were an option and restriction was applicable for 
30 days after the last dose of study drug) 
• 
Drug screen requirements/options for Investigator discretion updated 
to include cannabinoids. 
• 
Simplified requirements for platelets, hemoglobin and total white cell 
count to be within normal limits 
• 
ALT, AST and GGT must now all be less than 1.5 x ULN (previously 
was 3 x ULN) 
• 
Concomitant medication (prescribed and over the counter) exclusion 
criteria have been updated to reflect that changes to concomitant 
medication are no longer prohibited but must be reported to the study 
staff. 
• 
Greater clarity has been provided to the description clinically 
significant illnesses that would prevent a subject from joining the 
study. Evidence of urinary obstruction or difficulty in voiding and 
history of hypocomplemtemia have been added as exclusionary 
concomitant illnesses.  
• 
Other criteria have been combined and/or reworded for greater 
clarity. 
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Heading  
Summary of Change 
Section 3.2.1 Inclusion Criteria 
 
Information on what and how data from the ATHENA study can be used has 
been updated and some information moved to Section 3.2.1 Inclusion criteria 
Section 3.2.3.1 ‘Individual Treatment 
Stopping Criteria’ 
 
• 
Hyperkalemia (K >6.0 mEq/L) (removed the need to be 
demonstrated at 2 sequential study visits) 
• 
Unexplained decrease in body weight >7% or >5 kg from baseline 
(previously was >10% form baseline) 
• 
Anemia as indicated by hemoglobin ≤10 g/dL (previously was 
<9 g/dL) 
• 
Hypoalbuminemia <2.4 g/dL (previously was <2 g/dL) or a decrease 
in albumin of >1 g/L from baseline (previously this was only 
applicable to subjects with a baseline albumin of <3 g/dL) 
• 
Platelets <50 x 109/L (≥Grade 3 thrombocytopenia) (previously was 
an error in the unit) 
• 
Added: Prothrombin time (PT) and aPTT >2 x ULN* 
Section 3.2.3 ‘Withdrawal, Removal, and 
Replacement of Subjects’ 
 
• 
Section 3.2.3 ‘Withdrawal, Removal, and Replacement of Subjects’ 
has been revised as follows: 
• 
Differentiation has been made between a subject choosing to 
discontinue study drug and to withdraw from the study. Any subject 
who prematurely discontinues study drug should be followed until the 
scheduled end of follow up period, whereas subjects who withdraw 
consent will not be followed. It has been noted that subjects will be 
replaced at the discretion of the Sponsor. 
3.2.3.2 ‘Follow-up for Drug 
Discontinuation/Subject Withdrawal’ 
 
• 
Changes have been made in section 3.2.3.2 Follow-up for Drug 
Discontinuation/Subject Withdrawal from the Study to reflect these 
changes.  
• 
Section 3.2.3.2 ‘Follow-up for Drug Discontinuation/Subject 
Withdrawal’ has also been updated with regards to the need to follow 
up of any subjects that discontinue study drug due to an AE. 
Section 3.3 ‘Discontinuation of the Study’ 
• 
Section 3.3 ‘Discontinuation of the Study’ has been updated to reflect 
that additional enrollment and/or dosing (previously was just 
enrollment) will be suspended pending review and recommendation 
by the SRC. 
Section 4 “Treatment Procedures” 
Section 4.1.2 “Packaging and Labeling” 
• 
Previous Section 4.1.2 and Table 4 ‘Treatments Administered’ has 
been replaced by section (new) 4.3 Treatment Administration, with 
the wording revised 
• 
Packaging and Labeling section (old 4.1.3, new 4.1.2) have been 
updated to state that all labels will be in English and the local 
language will meet CFR 312.6 requirements and meet EudraLex 
Annex 13 requirements specific to each country. 
Section 4.1.3 ‘Study Drug Supply’, Storage, 
and Tracking 
Section 4.1.3 Study Drug Supply, Storage, and Tracking wording has been 
updated to state that the Sponsor or designee is responsible for monitoring the 
logistics of supply, that supplies can only be dispensed in accordance with the 
protocol and more details on the requirement of the drug inventory have been 
added. 
Section 4.2 ‘Treatment Assignment’  
Section 4.2 ‘Treatment Assignment’ has been updated to reflect the changes in 
the new study design. 
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Heading  
Summary of Change 
Section 4.3 ‘Treatment Administration’ 
 
Previous Section 4.1.2 and Table 4 ‘Treatments Administered’ has been 
replaced by section (new) 4.3 Treatment Administration, with the wording 
revised. 
Section 4.4 ‘Dose Reduction’  
 
New Section 4.4 ‘Dose Reduction’ has been introduced to allow dose 
reductions in response to CTCAE Grade 2 treatment-emergent AEs. 
Section 4.5 ‘Medical History and 
Prior/Concomitant Medications’ 
 
Section 4.5 Medical History and Prior/Concomitant Medications has been split, 
with Medical History moved to Section 6 and updated to collect Family History 
relevant to Alport syndrome and renal disease, in addition to the subjects 
significant ongoing illnesses. 
Section 4.6 ‘Prior and Concomitant 
Medications’ 
Prior and Concomitant Medications have been split into their own section, 
Section 4.6. This section has been updated to allow subjects to start taking 
new or adjust the dose of prescription or over-the-counter medications or 
herbal supplements and that any changes need to be reported to the site. 
Concomitant medications should still be maintained at a stable dose and 
regimen, particularly if they affect blood pressure or renal function, however 
they may be adjusted to maintain standard of care. 
Section 5 ‘Study Procedures’ 
Table 1, Table 2 and Section 5 ‘Study Procedures’ have been revised to: 
• 
Remove pregnancy and FSH tests as women are excluded from the 
study. 
• 
Additional visits have been added to reflect the longer study duration. 
• 
Visit windows have been added. 
• 
Week/day numbering has been simplified in Section 5, to just refer to 
the Week number. 
• 
Revise PK and complement profiles on applicable days so only 
collected until 4 hours post dose (was up to 24 hours). 
• 
Biomarkers have been grouped together in Section 5 
Section 5.3 ‘Open Label Extension Period’ 
 
Table 2 and Section 5.3 have been added to describe the assessments 
required for the Open Label Extension Period. 
Section 5.6 ‘Contraception’ 
Section 5.6 ‘Contraception’ has been removed since women are excluded form 
participation in the study and contraception for male subjects has been 
specified in the inclusion criteria as to be required to use a condom. 
Section 6, ‘Background, Safety, Efficacy, 
Pharmacodynamic, and Pharmacokinetic 
Assessments’ 
 
• 
Section 6, ‘Background, Safety, Efficacy, Pharmacodynamic, and 
Pharmacokinetic Assessments’ revised to add ‘Background’ 
assessments. 
• 
Treatment-emergent AEs have been defined. 
• 
Follow up of AEs present at the time of subject withdrawal has been 
defined. 
• 
Table 6 Adverse Event Outcome has been updated to add ‘recover’ 
in the same instances as resolved was recorded. ‘Lost to follow-up’ 
has been changed to ‘Unknown’. ‘Death’ has been changed to 
‘Fatal’. 
• 
Procedures in Case of Pregnancy has been revised considering the 
exclusion of women from the study, but remains to describe 
requirements if the partner of a male subject should become 
pregnant. 
• 
The Renal biopsy has been removed as a study assessment 
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Heading  
Summary of Change 
Section 6.1 ‘Medical History and Family 
History’ 
Medical History and Family History has been added as Section 6.1 described 
above so all section numbers have increased by one. 
Section 6.2.8 ‘Monitoring of Platelet Count 
and Total protein decrease’ 
 
New section 6.1.8 ‘Monitoring of Platelet Count and Total protein decrease’ 
has been added to describe the reflex testing in response to a decrease in total 
protein or platelet count and outline the required monitoring and response to 
changes in platelet count. 
Section 6.2 ‘Safety Assessments’ 
 
(New) Section 6.2 ‘Safety Assessments’ has been updated to provide more 
details as to the areas included in the clinical laboratory tests. 
Section 6.3.1 ‘Estimated GFR’ 
 
Additional information on the options to determine the estimated GFR have 
been added to Section 6.3.1 Estimated GFR. 
Section 6.4 ‘The Biomarker’ 
 
The Biomarker section 6.4 has been updated to detail all pharmacodynamic 
and biomarker assessments. 
Section 6.5 ‘Pharmacokinetic Assessments ‘ 
Section 6.5 Pharmacokinetic Assessments has been updated to reflect the 
reduced PK sampling profiles for the study and to state the Sum of the parent 
and major metabolite will be measured. 
Section 7 ‘Statistical Analysis’ 
Section 7.1.1 ‘Safety Endpoints’ 
Updates were made to the statistical section in response to the change in the 
study design, with the increased sample size, extended treatment period and 
visits, optional extension treatment period, inclusion of Treatment-emergent 
AEs. 
7.1.2 “’Efficacy Endpoints’ 
 
Safety comparisons will be assessed through change from baseline, incidence 
and titer of ADA’s has been reclassified as a safety endpoint. 
7.1.3 ‘Exploratory Endpoints: Efficacy, 
Pharmacodynamic and Biomarker 
Endpoints’ 
Efficacy endpoints have been revised and updated to reflect the new treatment 
duration, with comparisons being made at Weeks 24, 48 and 96. Additional 
efficacy and exploratory efficacy endpoints have been included. 
Section 7.2.8. ‘Interim Analysis’ 
 
• 
Interim Analysis details have been added in a new section, 
Section 7.2.8. 
• 
Exploratory endpoints were updated to reflect the objectives and 
changes in podocyturia was added as an exploratory endpoint 
(updates made to Table 1 and Section 5 ’Study Procedures’ to reflect 
sample collection).  
• 
The efficacy analysis was updated in line with the inclusion of 
efficacy as the primary endpoint of the study. 
• 
Details were added to describe the analysis for the 
pharmacodynamic endpoints. 
• 
The pharmacokinetic analysis section was expanded and PK 
parameter definitions added. 
• 
Interim Analysis details have been added in a new section, 
Section 7.2.8. 
Section 10 ‘References’ 
Section 10, References was updated with new references 
 
 
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11 
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