Conditions: Polycystic Kidney, Autosomal Dominant
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 478
Healthy volunteers: no

Brief summary:
Primary Objective:

To determine the effect of venglustat on the rate of total kidney volume (TKV) growth (Stage 1) and estimated glomerular filtration rate (eGFR) decline in participants at risk of rapidly progressive Autosomal Dominant Polycystic Kidney Disease (ADPKD) (Stage 2).

Secondary Objectives:

* To determine the effect of venglustat on the rate of renal function decline (Stage 1) and on the rate of TKV growth (Stage 2).
* To evaluate the pharmacokinetics (PK) of venglustat in ADPKD participants (Stages 1 and 2).
* To determine the effect of venglustat on pain and fatigue, based on participant reported diary (Stages 1 and 2).
* Safety/tolerability objectives:
* To characterize the safety profile of venglustat (Stages 1 and 2).
* To evaluate the effect of venglustat on mood using Beck Depression Inventory II (BDI-II) (Stages 1 and 2).
* To evaluate the effect of venglustat on the lens by ophthalmological examination (Stages 1 and 2).

Detailed description:
Study duration per participant was 26 months (maximal) that included a screening period of 15 days, run-in period of 2 weeks, a 24-month treatment period, and a follow-up 30 days after final dose of investigational medicinal product (IMP).

Arms:
arm 1: Participants from Stage 1 were randomized to receive 2 capsules of placebo matched to venglustat once daily for treatment period of 24 months. arm 2: Participants from Stage 1 were randomized to receive venglustat 8 milligrams (mg) (i.e., 2 capsules of 4 mg) once daily for treatment period of 24 months. arm 3: Participants from Stage 1 were randomized to receive 1 capsule of venglustat 15 mg and 1 capsule of placebo matched to venglustat once daily for treatment period of 24 months. arm 4: Participants from Stage 2 were randomized to receive 1 capsule of placebo matched to venglustat once daily for treatment period of 24 months. arm 5: Participants from Stage 2 were randomized to receive 1 capsule of venglustat 15 mg once daily for treatment period of 24 months.

Interventions: intervention 1: Venglustat intervention 2: Placebo
Intervention descriptions: intervention 1: Pharmaceutical form: capsule; Route of administration: oral intervention 2: Pharmaceutical form: capsule; Route of administration: oral

Protocol document:
Prot_000.pdf: 


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NAMES AND ADDRESSES OF 
COORDINATING 
INVESTIGATOR 
 
Name: 
Address: 
 
 
 
Tel: 
Fax: 
E-mail: 
 
 
MONITORING TEAM’S 
REPRESENTATIVE 
  
Name: 
Address: 
 
 
 
Tel: 
Fax: 
E-mail: 
 
 
SPONSOR 
  
Company: 
Address: 
 
 
 
 
Genzyme Corporation  
50 Binney Street Cambridge, MA 02142 USA 
 
 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
 
 
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
DOCUMENT HISTORY 
Document 
Country/Countries 
impacted by amendment 
Date, version 
Amended Clinical Trial Protocol 07 
All 
19 April 2021, version 1 (electronic 7.0) 
Amended Clinical Trial Protocol 06 
NL, USA, CAN 
16 December 2020, version 1 (electronic 6.0) 
Amended Clinical Trial Protocol 05 
All 
17 August 2020, version 1 (electronic 5.0) 
Amended Clinical Trial Protocol 04 
All 
14 August 2019, version 1 (electronic 4.0) 
Amended Clinical Trial Protocol 03 
All 
01 October 2018, version 1 (electronic 3.0) 
Amended Clinical Trial Protocol 02 
All 
25 May 2018, version 1 (electronic 2.0) 
Amended Clinical Trial Protocol 01 
All 
19 April 2018, version 1 (electronic 1.0) 
Original Protocol 
All 
08 February 2018, version 1 (electronic 1.0) 
AMENDED PROTOCOL 07 (19 April 2021)  
This amended protocol 07 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 
This amendment is made to optimize the scope and frequency of ophthalmological examination in 
the EFC15392 study based on the recommendations of the Ophthalmological Advisory Board 
(March 2021). The other main change is the conduct of the Measured Glomerular Filtration Rate 
(mGFR) substudy that has been extended to all countries participating in the EFC15392 study. 
Additional clarifications to the text of the protocol are described in the summary of changes table. 
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Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Clinical trial summary, Study 
objective(s), Stage 1, Stage 2 
Section 5.1.3 (Exploratory 
objectives) 
Section 5.2.3 (Exploratory 
objectives) 
Section 9.3.2 (Stages 1 and 
2) 
Section 9.4.4 (Adverse 
events) 
Exploratory objectives and corresponding 
endpoints were updated to consider all-cause 
hospitalization. 
Clarification 
Clinical trial summary, 
Assessment schedule, 
Stage 1, Stage 2, 
Section 1.3 (Study flow chart 
for Stage 1) - footnote p, 
Section 1.4 (Study flow chart 
for Stage 2) - footnote p, 
Section 9.4.10 
(Ophthalmological 
examination) 
Section 10.1.2.2 (Visit 4, 6, 8, 
10, 12/Months 1, 6, 12, 18, 
24 (Day 30, 180, 360, 540, 
720), 
Section 10.1.2.3 (Visit 5, 7, 9, 
11/Month 3, 9, 15, 21 
(Day 90, 270, 450, 630) 
Pupil dilation was added to the non-dilated 
pupil slit-lamp examination at Visit 6 
(Month 6) (Stage 1 and Stage 2) and Visit 10 
(Month 18) (Stage 2). The visual acuity 
examination was removed from Visits 5, 7, 9, 
11/Months 3, 9, 15, 21. 
Rules about when to perform 
ophthalmological examinations with pupil 
dilation after the decline in ≥2 lines of BCVA 
or after a change of WHO Grade ≥1.0 were 
optimized: 
If at any time during study participation 
patient experiences a decline of ≥2 lines in 
BCVA compared with that at baseline or 
previous assessment, a slit-lamp examination 
with pupil dilation must be performed. A slit-
lamp examination with pupil dilation must be 
performed again in 3 months. If no new 
cataract is seen during this examination, a 
normal schedule of ophthalmological 
examinations with pupil dilation can be 
resumed. 
If patient had a change of WHO Grade ≥1 in 
any of the 3 features (nuclear, cortical, and 
posterior subcapsular opacification) of the 
lens, the next scheduled ophthalmic 
assessment (in 3 months) in this patient must 
include pupil dilation and evaluation of 
observed cataract(s) and observations 
graded with the WHO simplified cataract 
grading system. If no new change of WHO 
Grade ≥1 is seen during this examination, a 
normal schedule of ophthalmological 
examinations with pupil dilation can be 
resumed. 
The Ophthalmological Advisory Board 
(March 2021) did not identify safety signals 
related to development of new, or worsening of 
the existing, cataract in adult patients treated 
with venglustat in the completed and ongoing 
studies. 
The board recommended continuing every 
6-month ophthalmological assessments with 
slit-lamp examination with pupil dilation and 
measurement of BCVA. 
Considering as low utility of the non-dilated pupil 
slit lamp examination for the examination of the 
lens and the fundus of the eye, slit lamp 
examinations at Month 6 (Visit 6) (Stage 1 and 
Stage 2) and Month 18 (Visit 10)(Stage 2) were 
supplemented with pupil dilation. 
In line with recommendations of the 
Ophthalmological Advisory Board, the schedule 
of ophthalmological examinations and rules 
about when to perform unscheduled 
ophthalmological examinations with pupil dilation 
were optimized. 
Sections 1.3 (Study flow 
chart for Stage 1) - 
footnote b, 
Section 1.4 (Study flow chart 
for Stage 2) - footnote b. 
Added clarification that for patients to be 
screened for the long-term extension study 
after Month 24 (Visit 12) and prior to 
Month 13 (Visit 13), the last in 
Study EFC15392 should coincide with the 
first visit in the long-term extension study. 
Clarification. 
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Section # and Name 
Description of Change 
Brief Rationale 
Sections 1.3 (Study flow 
chart for Stage 1) - footnote t, 
Section 1.4 (Study flow chart 
for Stage 2) - footnote t. 
The following information was added in 
footnote t. For patients enrolled or screened 
for the long-term extension study prior to 
30 days after the last dose of IMP, all SAEs, 
AEs, and AEs of special interest (AESIs) will 
be collected up to the last visit in 
Study EFC15392, which will coincide with the 
first visit in the long-term extension study.  
Details of ongoing AEs and ongoing 
medications at the time of the last visit in 
Study EFC15392 will be duplicated as such 
into the long-term extension study. 
Clarification. 
Section 1.4 (Study flow chart 
for Stage 2) - footnote i and l. 
Clinical trial summary, 
assessment schedule, 
Stage 2. 
Section 10.1.2.2 (Visit 4, 6, 8, 
10, 12/Month 1, 6, 12, 18, 24 
(Day 30, 180, 360, 540, 720). 
Added information that samples for 
exploratory biomarkers analysis collected in 
Stage 2 of the study will be analyzed only if 
results of this analysis during Stage 1 are 
considered as useful for further investigation. 
Removed collection of serum/plasma and 
urine biomarker samples at Visit 4 (Month 1) 
in Stage 2.  
Optimization, clarification. 
Section 7.2.3 (Exclusion 
criteria related to the current 
knowledge of venglustat 
investigational medicinal 
product) 
Relevant medical history and surgical history 
(if available) and previous and concomitant 
medications (if available) were deleted from 
the list of data to be entered into the 
database for screen failure patients. 
Clarification 
Section 8.8 (Concomitant 
medication) 
Section was supplemented with new 
subsection 8.8.2 COVID-19 vaccine. 
Section was updated with assessments and 
recommendations related to the use of an 
approved COVID-19 vaccine for study patients. 
Section 9.4.13 
(Pharmacodynamic and 
exploratory biomarkers) 
Numbers of patients and samples for 
pharmacodynamics and exploratory 
biomarkers were updated. 
Correction 
Section 9.4.14.1 (Sampling 
time) 
Numbers of patients and samples for 
pharmacokinetics were updated 
Correction 
Section 10.1.1.2 (Visit 2: run-
in Day -15). 
Section 10.1.2.2 (Visit 4, 6, 8, 
10, 12/Month 1, 6, 12, 18, 24 
(Day 30, 180, 360, 540, 720)) 
Clarified at what study visits ophthalmological 
examination includes measurement of the 
corneal thickness (or endothelial cell density) 
and measurement of intraocular pressure. 
Clarification 
Section 10.3.3 (List of criteria 
for permanent treatment 
discontinuation) 
Text changed from “stop the treatment” or 
“discontinuation from the study” to “study 
treatment will be discontinued”. 
“Two visits apart” as 2 points of time, when if 
a patient experiences a reduction in eGFR 
below 30 mL/min/1.73 m2, the treatment will 
be discontinued, was replaced with 
“2 occasions separated by a period of 
3 months during the course of this study”. 
Correction, clarification. 
 
 
Clarification and harmonization with the 
provisions of the long-term extension study. 
Section 11.4.3 (Analyses of 
safety data) 
The definition of residual treatment period 
was updated. 
Clarification 
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Section # and Name 
Description of Change 
Brief Rationale 
Appendix C (General 
guidance for the follow-up of 
laboratory abnormalities by 
Sanofi), Acute Kidney Injury 
Defined ‘abrupt’ reduction in kidney function. 
Correction and clarification. 
Appendix L 
Changes in previous amendment 06 
(Appendix N) that were specific to the USA, 
the Netherlands, and Canada will be now 
applicable for all the countries for this 
amendment 07, with the exception of the 
additional inclusion criteria asking for an 
eGFR between 45 and 89.9 mL/min/1.73 m2 
that is no longer applicable for participants 
enrolling to the sub-study. 
To extend the conduct of the Measured 
Glomerular Filtration Rate (mGFR) substudy to 
all countries participating in the EFC15392 
study. 
Correction (all patients, patients with any 
screening eGFR value, in Stage 2 can be 
potentially eligible for mGFR study). 
Appendix N (Protocol 
amendment history) 
Added protocol amendment 06 
Administrative update 
Throughout 
Typos have been corrected where necessary. 
Minor editorial and document formatting 
revisions were made. 
To provide clarifications. 
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CLINICAL TRIAL SUMMARY 
COMPOUND: 
venglustat/GZ402671 
STUDY No.: EFC15392 
STUDY NAME: STAGED-PKD 
TITLE 
Multicenter, randomized, double-blind, placebo-controlled two stage study to 
characterize the efficacy, safety, tolerability and pharmacokinetics of 
GZ/SAR402671 in patients at risk of rapidly progressive Autosomal Dominant 
Polycystic Kidney Disease (ADPKD) 
INVESTIGATOR/TRIAL LOCATION International, multi-center trial 
PHASE OF DEVELOPMENT 
Phase 2/3 
STUDY OBJECTIVE(S) 
Stage 1 
Primary objective:  
• 
To determine the effect of venglustat on the rate of total kidney volume 
(TKV) growth in patients at risk of rapidly progressive ADPKD.  
Secondary objectives: 
• 
To determine the effect of venglustat on the rate of renal function 
(estimated glomerular filtration rate [eGFR]) decline.  
• 
To determine the effect of venglustat on pain and fatigue, based on 
patient reported diary 
• 
To evaluate the pharmacokinetics (PK) of venglustat in ADPKD patients. 
• 
Safety/tolerability objectives: 
- 
To characterize the safety profile of venglustat. 
- 
To evaluate the effect of venglustat on mood using Beck Depression 
Inventory-II (BDI-II). 
- 
To evaluate the effect of venglustat on the lens by ophthalmological 
examination. 
Exploratory objectives: 
• 
To explore the impact of venglustat on total liver volume (TLV) 
(in patients with height adjusted TLV [htTLV] >2 L/m). 
• 
To explore the effect of venglustat on kidney concentrating ability by 
assessing urine osmolality (in patients not on diuretic). 
• 
To explore the effect of venglustat on nocturia, based on patient reported 
diary 
• 
To explore the effect of venglustat on systolic blood pressure (SBP) and 
diastolic BP (DBP). 
• 
To explore the effect of venglustat on biomarkers associated with ADPKD 
(eg, Fibroblast Growth Factor 23 [FGF23], Asymmetric Dimethylarginine 
[ADMA]). 
• 
To explore the effect of venglustat on pain and fatigue based on Brief 
Pain Inventory [BPI] and Brief Fatigue Inventory [BFI] questionnaires, and 
general health status (based on EuroQoL 5-dimension 5-level [EQ-5D-5L] 
questionnaire). 
• 
To explore the effect of venglustat on type, frequency and dosage of 
analgesic/over the counter (OTC) pain medication administration.  
• 
To explore the effect of venglustat on all-cause hospitalization. 
• 
To explore the pharmacodynamic (PD) effects of venglustat by 
measuring downstream metabolites of glucosylceramide synthase (GCS) 
in plasma and urine. 
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Stage 2 
Primary objective: 
• 
To determine the effect of venglustat on rate of renal function (eGFR) 
decline as compared to placebo in patients at risk of rapidly progressive 
ADPKD. 
Secondary objectives: 
• 
To determine the effect of venglustat on the rate of TKV growth. 
• 
To determine the effect of venglustat on pain and fatigue, based on 
patient reported diary 
• 
To evaluate the PK of venglustat in ADPKD patients. 
• 
Safety/tolerability objectives:  
- 
To characterize the safety profile of venglustat. 
- 
To evaluate the effect of venglustat on mood using BDI-II. 
- 
To evaluate the effect of venglustat on the lens by ophthalmological 
examination.  
Exploratory objectives: 
• 
To explore the impact of venglustat on TLV (in patients with 
htTLV >2 L/m). 
• 
To explore the effect of venglustat on kidney concentrating ability by 
assessing urine osmolality (in patients not on diuretic). 
• 
To explore the effect of venglustat on nocturia, based on patient reported 
diary. 
• 
To explore the effect of venglustat on SBP and DBP. 
• 
To explore the effect of venglustat on measured GFR (mGFR) 
(substudy). 
• 
To explore the effect of venglustat on biomarkers associated with ADPKD 
(eg, FGF23, ADMA). 
• 
To explore the effect of venglustat on pain and fatigue based on Brief 
Pain Inventory [BPI] and Brief Fatigue Inventory [BFI] questionnaires, and 
general health status (based on EuroQoL 5-dimension 5-level [EQ-5D-5L] 
questionnaire). 
• 
To explore the effect of venglustat on type, frequency and dosage of 
analgesic/over-the-counter (OTC) pain medication administration.  
• 
To explore the effect of venglustat on all-cause hospitalization. 
• 
To explore the PD effects of venglustat by measuring downstream 
metabolites of GCS in plasma and urine. 
• 
To explore the effect of venglustat on eGFR (CKD-EPI equation) from 
baseline to 24 months in patients with a screening eGFR between 30 and 
44.9 mL/min/1.73 m2. 
STUDY DESIGN 
This is an international, multicenter, randomized, double-blind, placebo-controlled 
two-stage study in adult patients at risk of rapidly progressive ADPKD aged 18 to 
50 years in Stages 1 and 2 (and aged 18 to 55 years for patients with a screening 
eGFR between 30 and 44.9 mL/min/1.73 m2 in Stage 2). 
The study is divided into 2 stages: 
Stage 1: An up to 30-day screening period including a 2-week single-blind placebo 
run-in (to identify patients who are unlikely to follow the assigned treatment 
regimen), followed by a randomized double-blind comparative placebo-controlled 
core treatment period of 24 months duration. 
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After run-in, eligible patients will be randomized with a 1:1:1 ratio to placebo, 8 mg 
venglustat, or 15 mg venglustat.  
Patients will be stratified based on their predicted ADPKD progression rate 
(1C versus 1D versus 1E) according to Mayo Imaging Classification and by 
geographic region (North America, Europe, China, Japan, Republic of Korea, Rest 
of the World). If after reviewing the unblinded aggregate safety data from Stage 1 
(after at least 1 month of treatment of the first 150 randomized patients from 
Stage 1), the Data Monitoring Committee (DMC) recommends the 8 mg dose for 
Stage 2, then the DMC may recommend switching patients on 15 mg treatment 
arm, in Stage 1, to the 8 mg arm. 
Stage 2: After the first 150 randomized patients from Stage 1 have completed at 
least 1 month of treatment (or have prematurely discontinued), the DMC will review 
in an unblinded fashion the aggregate safety data from Stage 1 and will select the 
venglustat dose 8 mg or 15 mg for Stage 2 patients. The selected dose will be the 
highest dose determined to be safe and well tolerated in Stage 1.  
Stage 2 will start with an up to 30-day screening period including a 2-week single-
blind placebo run-in (to identify participants who are unlikely to follow the assigned 
treatment regimen), followed by a randomized double-blind comparative core 
treatment period of 24 months duration.  
After run-in, patients will be randomized with a 1:1 ratio to placebo and venglustat 
(dose to be determined in Stage 1). Patients will be stratified based on their 
predicted progression rate (1C versus 1D versus 1E) and by geographic region 
(North America, Europe, China, Japan, Republic of Korea, Rest of the World). 
STUDY POPULATION  
Main selection criteria 
Inclusion criteria: 
• 
Male or female adult with ADPKD with an age at the time the consent is 
signed: 
- 
between 18 and 50 years (inclusive) for patients in Stage 1 
- 
between 18 and 50 years (inclusive) for patients in Stage 2 with an 
eGFR between 45 and 89.9 mL/min/1.73 m2 during the screening 
period* 
- 
between 18 and 55 years (inclusive) for patients in Stage 2 with an 
eGFR between 30 and 44.9 mL/min/1.73 m2 during the screening 
period* 
Diagnosis of ADPKD in patients with a family history, will be based 
on unified Pei criteria. In the absence of a family history, the 
diagnosis will be based on the presence of renal cysts bilaterally, 
totaling at least 20, in the absence of findings suggestive of other 
cystic renal diseases. 
• 
Mayo Imaging Classification of ADPKD Class 1C, 1D, or 1E**.  
**TKV volume must be confirmed by a central reader prior to Visit 3. 
• 
Estimated glomerular filtration rate between 45 and 89.9 mL/min/1.73 m2 
during the screening period* (Chronic Kidney Disease Epidemiology 
Collaboration [CKD EPI] equation) for Stage 1. Estimated glomerular 
filtration rate between 30 and 89.9 mL/min/1.73 m2 during the screening 
period* (CKD-EPI equation) for Stage 2. 
*Eligibility will be confirmed by the eGFR value from one of the two first 
pre-randomization eGFR measurements (Visit 1 or Visit 2 measurements 
or Visit 1 and an additional measurement performed at the Investigator’s 
discretion between Visit 1 and Visit 2). 
• 
Stable treatment regimen of antihypertensive therapy for at least 30 days 
prior to the screening visit for hypertensive patients. 
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• 
Able to read, comprehend and respond to the study questionnaires. 
• 
Patient has given voluntary written informed consent before performance 
of any study related procedures not part of standard medical care. 
• 
Patient does not have access to tolvaptan at the time of study start or 
tolvaptan is not indicated for treatment of patient according to treating 
physician (patient does not meet recommended criteria for treatment, 
refuses to initiate or does not tolerate treatment with tolvaptan). 
Exclusion criteria: 
• 
Systolic BP >160 mmHg* at run-in and baseline visits. 
*mean value of three or five systolic BP measurements 
(See Section 9.4.5). 
• 
Administration within 3 months prior to the screening visit of tolvaptan or 
other Polycystic Kidney Disease-modifying agents (somatostatin 
analogues). 
• 
The patient, in the opinion of the Investigator, is unable to adhere to the 
requirements of the study or unable to undergo study assessments 
(eg, has contraindications to pupillary dilation or unable to undergo 
magnetic resonance imaging [MRI]) [For example: patient’s weight 
exceeds weight capacity of the MRI, ferromagnetic metal prostheses, 
aneurysm clips, severe claustrophobia, large abdominal/back tattoos]). 
• 
The patient has, according to World Health Organization (WHO) Grading, 
a cortical cataract ≥1-quarter of the lens circumference (Grade cortical 
cataract-2 [COR-2]) or a posterior subcapsular cataract ≥2 mm 
(Grade posterior subcapsular cataract-2 [PSC-2]). Patients with nuclear 
cataracts will not be excluded. 
• 
The patient is currently receiving potentially cataractogenic medications, 
including a chronic regimen (more frequently than every 2 weeks) of any 
route of corticosteroids (including medium and high potency topical 
steroids), or any medication that may cause cataract, according to the 
Prescribing Information. 
• 
The patient has received strong or moderate inducers or inhibitors of 
CYP3A4 within 14 days or 5 half-lives, whichever is longer, prior to 
randomization. This also includes the consumption of grapefruit, 
grapefruit juice, or grapefruit containing products within 72 hours of 
starting venglustat administration. 
Total expected number of patients Stage 1: Approximately 240 patients (80 patients per arm). 
Stage 2: Approximately 400 patients (200 patients on venglustat and 200 patients 
on placebo). 
STUDY TREATMENT(S) 
 
Investigational medicinal 
product(s) 
Venglustat, matched placebo. 
Formulation: 
Venglustat is provided in capsule formulation containing 4 mg or 15 mg of 
venglustat (active moiety). 
Matched placebo is provided as a capsule indistinguishable from venglustat. 
Route(s) of administration: 
Oral. 
Dose regimen: 
Run-in period: Placebo. 
Stage 1: Placebo, 8 mg, or 15 mg of venglustat once per day for 24 months. 
Stage 2: Placebo or venglustat once per day (dose to be determined in Stage 1) for 
24 months. 
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ENDPOINT(S) 
Stage 1 
Primary endpoint: 
• 
Annualized rate of change in TKV based on MRI from baseline to 
18 months. 
Secondary endpoints: 
• 
Annualized rate of change in eGFR (CKD-EPI equation) from baseline to 
18 months. 
• 
Change in pain (BPI - Item 3) from baseline to 18 months, from the daily 
symptom diary. 
• 
Change in fatigue (BFI - Item 3) from baseline to 18 months, from the 
daily symptom diary. 
• 
Plasma venglustat concentrations. 
• 
Safety/tolerability endpoints:  
- 
Safety in terms of treatment-emergent adverse events 
(TEAEs)/adverse events (AEs)/serious adverse events (SAEs), 
laboratory parameters, vital signs, electrocardiogram and findings 
from physical examination will be assessed through the study and 
will be reported in the electronic case report form (eCRF). Adverse 
event data will be collected throughout the study. 
Treatment-emergent AEs are defined as AEs that develop, worsen 
(according to the Investigator opinion), or become serious during the 
treatment period. The treatment period is defined as the time from 
first dose of study treatment up to 30 days after last dose of study 
treatment. Full details of safety reporting and AE monitoring 
procedures are provided in Section 10.1. 
- 
Change in score of BDI-II during the treatment-emergent period. 
- 
Change in the lens clarity by ophthalmological examination during 
the treatment-emergent period.  
Exploratory endpoints: 
• 
Annualized rate of change in total liver volume based on MRI (in patients 
with htTL >2 L/m) from baseline to 18 months: 
Change in: 
- 
Urine osmolality from baseline to 18 months (in patients not on 
diuretic). 
- 
Systolic BP during the treatment-emergent period. 
- 
Diastolic BP during the treatment-emergent period. 
- 
Pain (BPI), fatigue (BFI), and health status (EQ-5D-5L) from 
baseline to 18 months.  
- 
Nocturia from baseline to 18 months based on patient reported diary. 
- 
Type, frequency, and dosage of analgesic/over the counter (OTC) 
pain medication administration from baseline to 18 months. 
- 
Biomarkers associated with ADPKD (eg, FGF23 and ADMA) from 
baseline to 18 months. 
- 
Glucosylceramide (GL-1) and monosialodihexosylganglioside (GM3) 
from baseline to 18 months.  
• 
Rate of all-cause hospitalization. 
• 
Time to confirmed 30% reduction in eGFR. 
• 
Time to confirmed 40% reduction in eGFR. 
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Stage 2 
Primary endpoint: 
• 
Annualized rate of change in eGFR (CKD-EPI equation) from baseline to 
24 months. 
Secondary endpoints: 
• 
Annualized rate of change in TKV based on MRI from baseline to 
18 months.  
• 
Change in Pain (BPI - Item 3) from baseline to 24 months, from the daily 
symptom diary. 
• 
Change in fatigue (BFI - Item 3) from baseline to 24 months, from the 
daily symptom diary. 
• 
Plasma venglustat concentrations. 
• 
Safety/tolerability endpoints: 
- 
Safety in terms of TEAEs/AEs/SAEs, laboratory parameters, vital 
signs, electrocardiogram and findings from physical examination will 
be assessed through the study and will be reported in the eCRF. 
Adverse event data will be collected throughout the study. 
Treatment-emergent AEs are defined as AEs that develop, worsen 
(according to the Investigator opinion), or become serious during the 
treatment period. The treatment period is defined as the time from 
first dose of study treatment up to 30 days after last dose of study 
treatment. Full details of safety reporting and AE monitoring 
procedures are provided in Section 10.1. 
- 
Change in score of BDI-II during treatment-emergent period. 
- 
Change in the lens clarity by ophthalmological examination during 
treatment-emergent periods.  
Exploratory endpoint(s): 
• 
Annualized rate of change in total liver volume based on MRI (in patients 
with htTL >2 L/m) from baseline to 18 months. Change in: 
• 
Systolic BP during treatment-emergent period. 
- 
Diastolic BP during treatment-emergent period. 
- 
Pain (BPI), fatigue (BFI), and health status (EQ-5D-5L) from 
baseline to 24 months. 
- 
Nocturia from baseline to 24 months based on patient reported diary. 
- 
Urine osmolality from baseline to 24 months (in patients not on diuretic). 
- 
Type, frequency, and dosage of analgesic/OTC pain medication 
administration from baseline to 24 months. 
- 
Biomarkers associated with ADPKD (eg, FGF23 and ADMA) from 
baseline to 24 months. 
- 
Glucosylceramide (GL-1) and GM3 from baseline to 24 months. 
• 
Rate of all-cause hospitalization. 
• 
Time to confirmed 30% reduction in eGFR. 
• 
Time to confirmed 40% reduction in eGFR. 
• 
Annualized rate of change in mGFR from baseline to 24 months 
(substudy). 
• 
Annualized rate of change in eGFR (CKD-EPI equation) from baseline to 
24 months in patients with a screening eGFR between 30 and 
44.9 mL/min/1.73 m2. 
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ASSESSMENT SCHEDULE 
Stage 1 
Efficacy assessments: MRI during screening period (at Visit 1 or Visit 2), Months 1, 
9, and 18. eGFR (CKD-EPI) at screening, run-in, baseline, Month 1, Month 3, and 
then every 3 months. 
Safety/tolerability assessments: Vital signs, physical examination, clinical laboratory 
evaluation will be performed at all visits. Ophthalmological assessments will be 
performed at Months -0.5, 6, 12, 18, and 24. Beck Depression Inventory-II will be 
assessed at Months -0.5, 3, and then every 3 months. 
Biomarker assessments: Screening, Months 1, 6, 12, 18, 24, and at 30 days follow-
up (Month 25).  
PK assessments: Blood samples for plasma venglustat concentrations assessment 
will be collected in all patients at following visits: 
• 
Day 1: 3 (±1) hour post dose. 
• 
Month 1: pre-dose and 3 (±1) hours post dose. 
• 
6 months and 18 months: pre-dose sample.  
Patient Reported Outcome (PRO) Assessments:  
Pain (BPI) and fatigue (BFI) data will be collected at the baseline visit and at each 
study visit prior to administration of procedures and the disease and treatment 
discussion with the patients. Patient global impression of severity will be collected 
at run-in, baseline and Months 3, 12, 18, and 24. Patient global impression of 
change will be collected at Months 3, 12, 18, and 24. Health status (EQ-5D-5L) will 
be collected at baseline and Months 3, 6, 12, 18, and 24. 
Daily diary data on symptoms of ADPKD (pain: BPI Item 3, fatigue: BFI Item 3,and 
nocturia) will be entered by the patients for specified consecutive days during the 
administration period prior to Baseline visit, from Baseline visit to Month 3, and prior 
to the site visit at Months 12, 18, and 24.  
Patients who prematurely and permanently discontinue study medication should 
complete rapidly (within 7 days) an end of treatment assessment visit. End-of-
treatment visit should include all procedures of Visit 12 and additionally a PK 
sample should be collected. In 30 days, a Follow-up visit should be performed. 
Investigator should ask patient to continue study visits for safety and efficacy 
assessments up to and including the last scheduled visit, if possible. If the patient 
refuses to attend all scheduled visits and to continue answering all PRO 
questionnaires, Investigator should ask the patient to continue answering questions 
of “Daily symptoms of ADPKD” diary, and also return to the site at Month 18 to 
have at least MRI performed, and at Month 24 to have at least blood sample (for 
eGFR) collected. Other assessments planned at Month 18 and/or Month 24 should 
also be done if possible. 
Stage 2 
Efficacy assessments: MRI during screening period (at Visit 1 or Visit 2) and 
Month 18. eGFR (CKD-EPI) at screening, run-in, baseline, Month 1, Month 3, and 
then every 3 months. 
Iohexol will be administered in a substudy in approximately 15% of patients at the 
baseline visit, Months 12 and 24 to evaluate mGFR. 
Safety/tolerability assessments: Vital signs, physical examination, clinical laboratory 
evaluation will be performed at all visits. Ophthalmological assessments will be 
performed at Months -0.5, 6, 12, 18, and 24. BDI-II will be assessed at Months -0.5, 
3, and then every 3 months.  
Biomarkers: Screening, Months 6, 12, 18, 24, and at 30 days follow-up (Month 25). 
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PK assessments: Blood samples for plasma venglustat concentrations assessment 
will be collected from all patients at following visits: 
• 
Month 1: Pre-dose and 3 (±1) hours post dose. 
• 
Month 24: Pre-dose sample. 
Patient Reported Outcome (PRO) Assessments:  
Pain (BPI) and fatigue (BFI) data will be collected at the baseline visit and at each 
study visit prior to administration of procedures and the disease and treatment 
discussion with the patients. Patient global impression of severity will be collected 
at run-in, baseline and Months 3, 12, 18, and 24. Patient global impression of 
change will be collected at Months 3, 12, 18 and 24. Health status (EQ-5D-5L) will 
be collected at baseline and Months 3, 6, 12, 18, and 24.  
Daily diary data on symptoms of ADPKD (pain: BPI Item 3, fatigue: BFI Item 3, and 
nocturia) will be entered by the patients for specified consecutive days during the 
administration period at screening, baseline to Month 3 and prior to the site visit at 
Months 12, 18, and 24. 
Patients who permanently discontinue study medication should complete rapidly 
(within 7 days) an end-of-treatment assessment visit. End-of-treatment visit should 
include all procedures of Visit 12. In 30 days, a Follow-up visit should be 
performed. Investigator should ask patient to continue study visits for safety and 
efficacy assessments up to and including the last scheduled visit, if possible. If the 
patient refuses to attend all scheduled visits and to continue answering all PRO 
questionnaires, Investigator should ask the patient to continue answering questions 
of “Daily symptoms of ADPKD” diary, and also return to the site at Month 18 to 
have at least MRI performed, and at Month 24 to have at least blood sample (for 
eGFR) collected and samples for mGFR measurement (for patients participating in 
the mGFR substudy) collected. Other assessments planned at Month 18 and/or 
Month 24 should also be done if possible. 
STATISTICAL CONSIDERATIONS 
Sample size determination: 
In Stage 1, approximately 240 patients will be randomized (with randomization ratio 
1:1:1) to placebo (n=80) or venglustat 8 mg (n=80) or venglustat 15 mg (n=80). In 
Stage 2, approximately 320 patients with an eGFR between 45 and 
89.9 mL/min/1.73 m2 at screening will be randomized (with randomization ratio 1:1) 
to placebo (n=160) or venglustat (n=160). In addition, 80 patients with an eGFR 
between 30 and 44.9 mL/min/1.73 m2 at screening will be randomized (with 
randomization ratio 1:1) to placebo (n=40) or venglustat (n=40). The patients from 
Stage 2 with an eGFR between 30 and 44.9 mL/min/1.73 m2 will not be included in 
the primary efficacy and safety analyses populations but the data from these 
patients will be analyzed separately. 
This sample size will provide approximately 89% power to detect a 50% reduction 
in annualized rate of change in TKV at end of Stage 1 and approximately 
87% power to detect a 30% reduction in annualized rate of change in eGFR 
between venglustat and placebo at end of Stage 2. Overall, the total sample size 
will provide approximately 87% power to detect an effect on both TKV and eGFR. 
Sample size and power calculations were based on simulations, assuming different 
scenarios regarding the dose-response relationship. The following model 
parameters were estimated based on available databases from the similar patient 
population (patients aged 18 to 50 years with Mayo Class 1C-1E and baseline 
eGFR from 45 to 90 mL/min/1.73 m²) in 2 historical studies (Consortium for 
Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) and the 
Polycystic Kidney Disease Treatment Network [HALT-PKD]): 
• 
A slope of log10(TKV) of 0.02591, 0.02832 and 0.03141 in patients from 
Mayo Class 1C, 1D and 1E respectively (corresponding to 6.1%, 6.7% 
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and 7.5% increase per year in TKV), and average slope of 
0.02764 (6.6%/year) assuming 50% of 1C, 33% of 1D and 17% of 1E. 
• 
Standard deviation for the residual error of TKV (on the log10 scale) of 
0.02566 and standard deviation for the random effect of slope of 0.01477. 
• 
A slope of eGFR of -3.16, -3.88 and -4.69 mL/min/1.73 m² per year in 
patients from Mayo Class 1C, 1D and 1E respectively and average slope 
of -3.66 mL/min/1.73 m² per year assuming 50% of 1C, 33% of 1D and 
17% of 1E. 
• 
Standard deviation for the residual error of eGFR of 6.34 and standard 
deviation for the random effect of slope of 1.98. 
In addition, sample size and power calculations assumed an overall significance 
level of 0.05 (2-sided), 10% dropout rate and included adjustments for handling of 
multiplicity of tests and futility analysis (as described in later sections). 
A sample size of 80 patients (40 per arm) with an eGFR between 30 and 
44.9 mL/min/1.73 m2 at screening will provide approximately 80% probability to 
detect a treatment effect in this subgroup at the 0.20 significance level (two-sided), 
based on a model evaluating the dependence of the treatment effect on baseline 
eGFR. 
Analysis population: 
Stage 1: 
Stage 1 intent-to-treat (ITT) population will include all patients who are randomized 
in Stage 1.  
Primary analysis in Stage 1 will include all data from Stage 1 available at the cut-off 
date (ie, including data reported up to Month 24, if any). The cut-off date will be 
defined as the date all patients from Stage 1 have completed the Month 18 visit (or 
have discontinued the study).  
Stage 2: 
The combined Stage 1 and Stage 2 ITT population will include all patients with an 
eGFR between 45 and 89.9 mL/min/1.73 m2 at screening who are randomized in 
Stage 1 or Stage 2, analyzed according to the treatment group allocated by 
randomization (venglustat 15 mg, venglustat 8 mg, or placebo). Patients from 
Stage 2 with an eGFR between 30 and 44.9 mL/min/1.73 m2 at screening will not 
be included in the primary efficacy and safety analyses population but the data from 
these patients will be analyzed separately. 
Primary analysis in the combined Stage 1 and Stage 2 will include all data available 
from baseline to the end of the 24-month double-blind core treatment period. 
Primary analysis: 
A linear mixed effect model will be fitted to the log10-transformed TKV, which will 
include fix effects of treatment (venglustat 15 mg, venglustat 8 mg or placebo), 
Mayo Imaging classification (as per randomization: Class 1C versus 1D versus 1E), 
time (as continuous variable), treatment * time interaction and Mayo Imaging 
classification * time interaction, and will include random intercept and slope. Time 
will be based on actual TKV assessment date relative to randomization date (in 
years). Overall effect of venglustat will be assessed using a Multiple Comparison 
Procedure (MCP). Multiple trend tests will be performed using optimal contrasts 
determined from a set of pre-specified candidate models for the dose-response 
relationship. Optimal contrasts will apply to the treatment * time interaction term in 
the linear mixed effect model. P-value will be adjusted for multiple trend tests. 
The same analysis will be performed for annualized rate of change in eGFR. No 
log-transformation will be used for eGFR. 
Analysis will be based on randomized treatment group, regardless of the treatment 
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actually received and regardless of whether or not patients completed the treatment 
period (treatment policy strategy). Patients who prematurely and permanently 
discontinue study medication will be requested to undergo MRI scan and obtain 
eGFR up to the planned end of study. All efforts will be made to minimize the 
amount of missing data for the primary and secondary efficacy endpoints.  
Missing data will be handled using a multiple imputation method, that will include 
separate slopes of log10 (TKV) during the on-treatment period and after permanent 
treatment discontinuation. Patients with missing data after permanent treatment 
discontinuation will have their data imputed based on the mean slope estimated 
during the post-treatment period in patients from the same treatment arm, who 
discontinued the treatment but had TKV data available during the post-treatment 
period. After imputation, data will be analyzed using the proposed linear mixed 
effect model. 
Analysis of secondary endpoints: 
In Stage 1, the annualized rate of change in eGFR (CKD-EPI equation) is a 
secondary efficacy endpoint. The analysis eGFR in Stage 1 will be identical to 
those of Stage 2. 
In Stage 1, change from baseline to Month 18 in pain (BPI Item 3) and change from 
baseline to Month 18 in fatigue (BFI Item 3) are secondary endpoints and will be 
analyzed using a mixed effect model with repeated measures (MMRM). 
In Stage 2, the annualized rate of change in TKV is a secondary efficacy endpoint. 
The analysis of TKV in Stage 2 will be identical to those of Stage 1. 
In Stage 2, change from baseline to Month 24 in pain (BPI Item 3) and change from 
baseline to Month 24 in fatigue (BFI Item 3) are secondary endpoints and will be 
analyzed using MMRM. 
Multiplicity of endpoints and multiplicity of analyses (at end of Stage 1 and end of 
Stage 2) will be handled using a weighted Bonferroni-based closed test procedure, 
ensuring a strong control of the type I error rate for the entire study. 
Safety analysis: 
Treatment-emergent AEs (TEAEs) will be tabulated (counts and percentages). 
Adverse event of special interest (AESI), SAEs, and discontinuations due to AEs 
will be summarized.  
Additional safety data including clinical laboratory tests, vital signs, and 
ophthalmological tests will be summarized descriptively by treatment/dosing 
groups. 
All safety analyses will be performed on the safety population, defined as all 
patients who are randomized and received at least one dose or part of a dose of 
the double-blind investigational medicinal product (IMP), analyzed according to the 
treatment actually received. 
Pharmacodynamic and pharmacokinetic analysis:  
Pharmacodynamics (PD) parameters will be summarized and compared between 
venglustat 15 mg, venglustat 8 mg and placebo using descriptive statistics at each 
time point, including assessment of observed values and percent change from 
baseline.  
For PK analysis: Trough concentrations will be summarized separately using 
descriptive stats, along with other single time-point plasma concentration data by 
dose and visit.  
Plasma concentrations will be reported for individual patients and summarized 
using descriptive statistics by dose and visit separately for Stage 1 and Stage 2. 
Plasma venglustat concentration data might be used for population PK modeling if 
considered necessary and the results of population PK modeling will be reported 
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separately from the study report. The population PK analyses will characterize the 
inter- and intra-subject variability in PK parameters and evaluate the effect of 
covariates such as, renal function status (creatinine clearance) on the venglustat 
PK. 
An evaluation of the correlation between exposure and efficacy (in particular TKV 
and eGFR) and safety may be performed to evaluate exposure-response 
relationships. 
Patient reported outcome analysis: 
Both total scores and subscale scores of PROs will be calculated. Each PRO will 
be scored according to their scoring guidelines, including handling the missing 
items. The daily diaries baseline average scores and thereafter the average score 
over the assessment prior to the visits will be calculated. The calculation of a diary 
score requires less than 50% of missing data.  
The Least Square Mean (LSM) changes from baseline to Month 18 (Stage 1) and 
Month 24 (Stage 2) for each score on PRO questionnaires and the daily diary will 
be calculated. 
Interim analysis:  
An interim analysis for futility will be performed under the supervision of the DMC 
when all patients from Stage 1 have completed the first 9 months of treatment and 
approximately 30% have completed 18 months of treatment with TKV available 
(or have prematurely discontinued). 
Final analysis: 
The analysis will be conducted in 2 steps: 
• 
First step: conducted when all patients from Stage 1 have been 
randomized and have completed the Month 18 visit (or have discontinued 
the study). This analysis will be conducted after a partial database lock. 
First step analysis in Stage 1 will include all collected and validated data 
from Stage 1 population, up to the cut-off date (including data reported up 
to Month 24 visit, if any). 
• 
Second step: conducted when all patients from Stage 2 have completed 
the study and will consist of the final analysis of the combined Stage 1 
and Stage 2 study. This analysis will be conducted after the final 
database lock. 
The results of the first step analysis will not be used to change the conduct of the 
ongoing study in any aspect. This first analysis will be used for the submission of 
the registration dossier to health authorities accepting TKV growth rate change as a 
surrogate endpoint reasonably likely to predict changes in eGFR slope.  
First step analysis will be conducted before all patients from Stage 1 have 
completed the 24-month treatment period. However, treatment allocated to each 
individual patient will not be released to anyone who is directly involved in the 
conduct of Stage 1 of the study until Stage 1 is fully completed. 
DURATION OF STUDY PERIOD  
(per patient)  
Stage 1 
Total study duration: 26 months (maximal). 
• 
Screening period:  
- 
Initial screening: up to 15 (+3) days. 
- 
Placebo run-in period: 15 days ±3 days. 
• 
Core treatment period: 24 months. 
• 
Follow-up: 30 days after final dose of IMP. Not applicable for patients 
who may be eligible for a potential long-term extension study after 
completion of 24 months of treatment. 
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Stage 2 
Total study duration: 26 months (maximal). 
• 
Screening period:  
- 
Initial screening: up to 15 (+3) days. 
- 
Placebo run-in period: 15 days ±3 days. 
• 
Core treatment period: 24 months. 
• 
Follow-up: 30 days after final dose of IMP. Not applicable for patients 
who may be eligible for a potential long-term extension study after 
completion of 24 months of treatment 
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1 
FLOW CHARTS 
1.1 
GRAPHICAL STUDY DESIGN FOR STAGE 1 
 
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1.2 
GRAPHICAL STUDY DESIGN FOR STAGE 2  
 
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1.3 
STUDY FLOW CHART FOR STAGE 1 
 
 
Screening period 
Blinded treatment perioda 
Follow-up 
(off-treatment)  
 
Initial 
screening 
Run-in 
Visit 
1 
2 
3 
(Baseline)
4 
5 
6 
7 
8 
9 
10 
11 
12a, w 
(End of 
treatment) 
13b 
Months 
-1 
-0.5 
0 
1 
3 
6 
9 
12 
15 
18 
21 
24 
25 
Day (window [days]) -30 to -16u 
(+3) 
-15 (±3) 
1 
(±3) 
30 (±7) 
90 
(±7) 
180 
(±7) 
270 
(±7) 
360 
(±7) 
450 
(±7) 
540 
(±7) 
630 
(±7) 
720 
(±7) 
750 
(-7 to +21) 
Informed consent (for 
Stage 1) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Exclusion criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medication history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight, heightc 
X 
X 
 
 
 
 
 
X 
 
 
 
 
X 
Vital signsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
Complete  
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
Physical examination 
Abbreviatede 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Laboratory testingf 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy test (WOCBP)g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
FSH and/or estradiol as 
neededg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Viral serologyh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
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Screening period 
Blinded treatment perioda 
Follow-up 
(off-treatment)  
 
Initial 
screening 
Run-in 
Visit 
1 
2 
3 
(Baseline)
4 
5 
6 
7 
8 
9 
10 
11 
12a, w 
(End of 
treatment) 
13b 
Months 
-1 
-0.5 
0 
1 
3 
6 
9 
12 
15 
18 
21 
24 
25 
Day (window [days]) -30 to -16u 
(+3) 
-15 (±3) 
1 
(±3) 
30 (±7) 
90 
(±7) 
180 
(±7) 
270 
(±7) 
360 
(±7) 
450 
(±7) 
540 
(±7) 
630 
(±7) 
720 
(±7) 
750 
(-7 to +21) 
Urinalysis w/microscopyi 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
GSL markers 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Serum/plasma biomarkers 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
venglustat plasma 
concentration (PK)j 
 
 
X 
X 
 
X 
 
 
 
X 
 
 
 
Urinary markers, urine 
spotk, l 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Collection of home urine 
based on 24 h collectionl 
 
 
X 
X 
(X) 
X 
(X) 
X 
 
X 
 
X 
 
12-lead ECGm 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
MRIn 
Xo 
 
X 
 
 
X 
 
 
X 
 
 
 
BDI-II 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Ophthalmological 
examinationp 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
Diaries 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense diary 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Collect/review diary 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Complete daily symptom 
diaryq 
 
X (7 days 
prior to 
baseline 
visit) 
X 
(daily) 
 
 
X 
(7 days 
prior to 
visit) 
 
X 
(14 days 
prior to 
visit) 
 
X 
(14 days prior 
to visit) 
 
Randomization 
 
 
X  
 
 
 
 
 
 
 
 
 
 
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Screening period 
Blinded treatment perioda 
Follow-up 
(off-treatment)  
 
Initial 
screening 
Run-in 
Visit 
1 
2 
3 
(Baseline)
4 
5 
6 
7 
8 
9 
10 
11 
12a, w 
(End of 
treatment) 
13b 
Months 
-1 
-0.5 
0 
1 
3 
6 
9 
12 
15 
18 
21 
24 
25 
Day (window [days]) -30 to -16u 
(+3) 
-15 (±3) 
1 
(±3) 
30 (±7) 
90 
(±7) 
180 
(±7) 
270 
(±7) 
360 
(±7) 
450 
(±7) 
540 
(±7) 
630 
(±7) 
720 
(±7) 
750 
(-7 to +21) 
PROr 
 
 
 
 
 
 
 
 
 
 
 
 
 
BPI 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
BFI 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PGIS 
 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
PGIC 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
EQ-5D-5L 
 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
Dispense IMP/placebo 
 
Xv 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Call IXRS/IWRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IMP accounting & 
compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Biobankings 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
Pharmacogenetic sample 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEs/SAEt 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEs = adverse events; AESI = adverse events of special interest; BCVA = best corrected visual acuity; BDI-II = Beck Depression Inventory-II; BFI = Brief Fatigue Inventory; BP = blood pressure; BPI = Brief Pain 
Inventory; CT = computed tomography; ECG = electrocardiogram; EQ-5D-5L = EuroQoL 5-dimension 5-level; FSH = follicle stimulating hormone; GSL = glycosphingolipid; IMP = investigational medicinal product; 
MRI = magnetic resonance imaging; PGIC = Patient Global Impression of Change; PGIS = Patient Global Impression of Severity; PK = pharmacokinetic; PRO = Patient Reported Outcome; SAEs = serious AEs; 
TKV = total kidney volume; US = ultrasonography; WHO = World Health Organization; WOCBP = women of childbearing potential. 
a If a patient discontinues treatment with IMP early during the core treatment period, the patient will have an End-of-Treatment/Early Withdrawal (EOT/EW) Visit within 7 days and a Follow-up Visit 30 days after the 
last dose of IMP. In addition, every effort will be made to have the patients return to the site at the time corresponding to their scheduled visits, particularly the Month 18 Visit and the Month 24 Visit. If the patient 
does not agree to a site visit, they will be contacted by telephone to inquire about safety status. 
b 30 days after the last dose of IMP will be evaluated. Not applicable for patients screening for the long-term extension study within 30 days after Month 24 (Visit 12). For patients to be screened for the long-term 
extension study after Month 24 (Visit 12) and prior to Month 13 (Visit 13), the last visit in Study EFC15392 should coincide with the first visit in the long-term extension study. 
c Height to be measured only at Visit 1. 
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d Vital sign measurements (sitting BP and heart rate): For all measurements 3 separate seated BP measurements should be taken with at least 1 minute between readings, following at least 10-minute rest period 
and prior to phlebotomy. The arm with the higher pressure at the initial screening visit should be used for all subsequent BP measurements. 
e The abbreviated physical examination should focus on areas important for assessment of AEs if necessary. 
f 
All laboratory assessments occur prior to intake of double-blind IMP. Samples should be collected in fasting conditions. Some assessments done at the beginning of screening may have to be repeated, 
Investigator will need to receive and evaluate results of repeated tests prior to Visit 3. 
g Serum pregnancy testing only at Visit 1; urine pregnancy testing subsequently. Serum pregnancy test results must be reviewed prior to the run-in phase for all WOCBP unless there is documented history of 
menopause (based on documented FSH and estradiol levels - if results not documented then FSH and estradiol will be tested at screening) or they are surgically sterile. Any positive urine test results must be 
confirmed based on serum pregnancy test. The Investigator may perform additional tests at their discretion or as required by local regulations. Patients will perform monthly urine pregnancy at home and report to 
the site. 
h Viral serology (central lab) includes hepatitis B surface antigen (HBs Ag), hepatitis B core antibody (HBc Ab) anti-hepatitis C virus (anti-HCV) antibodies, anti-human immunodeficiency Virus 1 and 2 antibodies 
(anti-HIV1 and anti-HIV2 Ab). 
i 
Urinalysis includes urine dipstick and microscopy. Dipstick includes assessment of specific gravity, pH, protein, glucose, blood, ketones, bilirubin, urobilinogen, nitrite, and leukocyte esterase. Microscopy (central 
lab) includes detection of formed cellular elements, casts, bacteria, yeast, parasites, and crystals in centrifuged urine sediment. Dipstick will be done locally, if any parameter on the dipstick is abnormal, a urine 
sample should be sent to the central laboratory for quantitative measurement.  
j 
Plasma samples for PK to be collected on Day 1 (3 ±1 hours, post dose), Month 1 (pre-dose and 3 ±1 hours post dose), Months 6 and 18 (pre-dose). At visits when a post-dose PK sample is to be collected, 
patients should take the study drug on site. 
k Spot urine will be collected based on 3 samples from the Day -2, morning of the day of the site visit and from 24 hour urine sample (or sample provided for urinalysis on the day of the visit - for visits when 
collection of 24 hour sample is not required) (see Section 9.4.3). 
l 
Urine will be collected to evaluate exploratory biomarkers, albumin, total protein, creatinine, electrolyte and osmolality. At selected sites, urinary exosomes will be isolated from the urine at Visits 3, 4, 5, and 7. 
Please refer to laboratory manual for collection instructions. Collection of 24-hour urine sample at Visits 5 and 7 will be performed only at selected sites that participate in isolation of urinary exosomes. 
m The 12-lead ECG recordings should be performed before blood samplings. Investigator should evaluate V2 ECG reading prior to run-in medication administration; V2 ECG central reader’s assessment should be 
evaluated prior to IMP administration at Visit 3. The ECG will be evaluated as “normal” or “abnormal”. 
n Using a central reader, liver volume and combined renal volume of both kidneys will be measured. Combined renal cyst volume and renal parenchyma may be determined at a later date for a subset of patients. 
o If a patient has documented CT/MRI/US kidneys imaging test results obtained prior to the study, Investigator may use this data for preliminary evaluation of a patient`s eligibility based on massively enlarged 
kidneys at Visit 1. First study MRI for confirmation of TKV Imaging Classification Class will be performed at Visit 2 (Run-in visit). If a patient has no documented CT/MRI/US kidneys imaging test results obtained 
prior to the study, Investigator will perform MRI for confirmation of TKV Imaging Classification Class at Visit 1 (initial screening visit). TKV volume must be confirmed by a central reader prior to Visit 3. 
p The patient is required to have an ophthalmological examination with pupil dilation before randomization, at Month 6 (Visit 6), Month 12 (Visit 8), Month 18 (Visit 10), and at Month 24 (Visit 12) (or upon withdrawal 
or discontinuation). Ophthalmological examinations at Visit 2, Month 12 (Visit 8), Month 18 (Visit 10), and Month 24 (Visit 12) will also include measurement of the corneal thickness (or endothelial cell density) and 
measurement of intraocular pressure. If at any time during study participation a patient experiences a decline of ≥2 lines in BCVA compared with that at baseline or previous assessment, a slit-lamp examination 
with pupil dilation should be performed. Observed lens opacities must be graded with the WHO simplified cataract grading system. A slit-lamp examination with pupil dilation must be performed again in 3 months. 
If no new cataract is seen during this examination, a normal schedule of ophthalmological examinations with pupil dilation can be resumed. If patient had change of WHO Grade ≥1 in any of the 3 features (nuclear, 
cortical, and posterior subcapsular opacification) of the lens, the next scheduled ophthalmological examination (in 3 months) in this patient must include pupil dilation and evaluation of observed cataract(s) and 
observations graded with the WHO simplified cataract grading system. If no new change of WHO Grade ≥1 is seen during this examination, a normal schedule of ophthalmological examinations with pupil dilation 
can be resumed. Pupil dilation and full ophthalmological examination can be performed at any time if deemed medically necessary; observed lens opacities must be graded with the WHO simplified cataract 
grading system (see Section 9.4.10). 
q The daily diaries will be filled out by patients at home for 7 days prior to baseline visit and after that at home for consecutive days for the specified administration period before the study visits and will be collected 
at the time of visit. 
r 
The PROs will be administered to patients at study visit according to the listed schedule. 
s Prior to the start of IMP at Baseline Visit. In subjects who have consented to it, samples of serum will be collected and archived for future analysis. 
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t 
All SAEs, AEs and AEs of special interest (AESIs) will be collected starting with signing informed consent and continue until 30 days after the last dose of IMP or study end, whichever comes later. All AEs that 
occurred during treatment should be followed for at least 30 days following the last dose of IMP or until the event has resolved, the condition has stabilized, the etiology of the event is determined to be not related 
to IMP, or the patient is lost to follow-up. All patients should be followed to collect safety information up to 30 days after the last IMP administration or up to the first visit of the long-term extension study, whichever 
occurs first. For patients enrolled or screened into the long-term extension study prior to 30 days after the last dose of IMP, all SAEs, AEs, and AESIs will be collected up to the last visit in Study EFC15392, which 
will coincide with the first visit in the long-term extension study. Details of ongoing AEs and ongoing medications at the time of the last visit in Study EFC15392 will be duplicated as such into the long-term 
extension study. 
u The initial screening period (Visit 1) can last up to 15 days (+3 days). Visit 2 can be performed as soon as results of all assessments performed at Visit 1 are available. 
v During the run-in period the patient will receive single-blind placebo. 
w At Visit 12 patients may be offered to enter long-term extension study. For patients who will agree and will be eligible to enter into a potential long-term extension study without any discontinuation between the 
EFC15392 and the LTS15823 studies, Visit 12 (end of treatment visit) of EFC15392 study will correspond to Visit 1 of LTS15823 study including all planned evaluations to be performed at Visit 12 of EFC15392 
study and an additional MRI that will be performed in the frame of Visit 1 of the LTS15823 study.  
1.4 
STUDY FLOW CHART FOR STAGE 2 
 
 
Screening period 
Blinded treatment perioda 
Follow-up 
(off-treatment)  
 
Initial 
screening 
Run-in 
Visit 
1 
2 
3 
(Baseline) 
4 
5 
6 
7 
8 
9 
10 
11 
12a, y 
(End of 
treatment)  
13b 
Months 
-1 
-0.5 
0 
1 
3 
6 
9 
12 
15 
18 
21 
24 
25 
Day (window [days]) -30 to -16w 
(+3) 
-15 (±3) 
1  
(±3) 
30 
(±7) 
90 
(±7) 
180 
(±7) 
270 
(±7) 
360 
(±7) 
450 
(±7) 
540 
(±7) 
630 
(±7) 
720 
(±7) 
750 
(-7 to +21) 
Informed consent (for 
Stage 2) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Exclusion criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medication history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight, heightc 
X 
X 
 
 
 
 
 
X 
 
 
 
 
X 
Vital signsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
Complete  
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
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Screening period 
Blinded treatment perioda 
Follow-up 
(off-treatment)  
 
Initial 
screening 
Run-in 
Visit 
1 
2 
3 
(Baseline) 
4 
5 
6 
7 
8 
9 
10 
11 
12a, y 
(End of 
treatment)  
13b 
Months 
-1 
-0.5 
0 
1 
3 
6 
9 
12 
15 
18 
21 
24 
25 
Day (window [days]) -30 to -16w 
(+3) 
-15 (±3) 
1  
(±3) 
30 
(±7) 
90 
(±7) 
180 
(±7) 
270 
(±7) 
360 
(±7) 
450 
(±7) 
540 
(±7) 
630 
(±7) 
720 
(±7) 
750 
(-7 to +21) 
Physical examination 
Abbreviatede 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Laboratory testingu 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy test (WOCBP)f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
FSH and/or estradiol as 
neededf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Viral serologyg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis w/microscopyh 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
GSL markers 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Serum/plasma biomarkersi 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
venglustat plasma 
concentration (PK)j 
 
 
 
X 
 
  
 
 
 
 
 
X 
 
Urinary markers, urine 
spoti, k, l  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Collection of home urine 
based on 24 h collectionl 
 
 
X 
X 
(X) 
X 
(X) 
X 
 
X 
 
X 
 
mGFRv 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
12-lead ECGm 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
MRIn 
Xo 
 
 
 
 
 
 
 
X 
 
 
 
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Screening period 
Blinded treatment perioda 
Follow-up 
(off-treatment)  
 
Initial 
screening 
Run-in 
Visit 
1 
2 
3 
(Baseline) 
4 
5 
6 
7 
8 
9 
10 
11 
12a, y 
(End of 
treatment)  
13b 
Months 
-1 
-0.5 
0 
1 
3 
6 
9 
12 
15 
18 
21 
24 
25 
Day (window [days]) -30 to -16w 
(+3) 
-15 (±3) 
1  
(±3) 
30 
(±7) 
90 
(±7) 
180 
(±7) 
270 
(±7) 
360 
(±7) 
450 
(±7) 
540 
(±7) 
630 
(±7) 
720 
(±7) 
750 
(-7 to +21) 
BDI-II 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Ophthalmological 
examinationp 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
Diaries 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense diary 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Collect/review diary 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Complete daily symptom 
diaryq 
 
X (7 days 
prior to 
baseline visit) 
X (daily) 
 
 
X 
(7 days 
prior to 
visit) 
 
X 
(14 days 
prior to 
visit) 
 
X 
(14 days prior 
to visit) 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
PROr 
 
 
 
 
 
 
 
 
 
 
 
 
 
BPI 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
BFI 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PGIS 
 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
PGIC 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
EQ-5D-5L 
 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
Dispense IMP/placebo 
 
Xx 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Call IXRS/IWRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IMP accounting & 
compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Biobankings 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
Pharmacogenetic sample 
 
 
X 
 
 
 
 
 
 
 
 
 
 
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Screening period 
Blinded treatment perioda 
Follow-up 
(off-treatment)  
 
Initial 
screening 
Run-in 
Visit 
1 
2 
3 
(Baseline) 
4 
5 
6 
7 
8 
9 
10 
11 
12a, y 
(End of 
treatment)  
13b 
Months 
-1 
-0.5 
0 
1 
3 
6 
9 
12 
15 
18 
21 
24 
25 
Day (window [days]) -30 to -16w 
(+3) 
-15 (±3) 
1  
(±3) 
30 
(±7) 
90 
(±7) 
180 
(±7) 
270 
(±7) 
360 
(±7) 
450 
(±7) 
540 
(±7) 
630 
(±7) 
720 
(±7) 
750 
(-7 to +21) 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEs/SAEst 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEs = adverse events; AESI = adverse events of special interest; BCVA = best corrected visual acuity; BDI-II = Beck Depression Inventory-II; BFI = Brief Fatigue Inventory; BP = blood pressure; BPI = Brief Pain 
Inventory; CT = computed tomography; ECG = electrocardiogram; EQ-5D-5L = EuroQoL 5-dimension 5-level; FSH = follicle stimulating hormone; GSL = glycosphingolipid; IMP = investigational medicinal product; 
mGFR = measured GFR; MRI = magnetic resonance imaging; PGIC = Patient Global Impression of Change; PGIS = Patient Global Impression of Severity; PK = pharmacokinetic; PRO = Patient Reported Outcome; 
SAEs = serious AEs; TKV = total kidney volume; US = ultrasonography; WHO = World Health Organization; WOCBP = women of childbearing potential. 
a If a patient discontinues treatment with IMP early during the core treatment period, the patient will have an End-of-Treatment/Early Withdrawal (EOT/EW) Visit within 7 days and a Follow-up Visit 30 days after the 
last dose of IMP. In addition, every effort will be made to have the patients return to the site at the time corresponding to their scheduled visits, particularly the Month 24 Visit. If the patient does not agree to a site 
visit, they will be contacted by telephone to inquire about safety status. 
b 30 days after the last dose of IMP will be evaluated. Not applicable for patients screening for the long-term extension study within 30 days after Month 24 (Visit 12). For patients to be screened for the long-term 
extension study after Month 24 (Visit 12) and prior to Month 13 (Visit 13, the last visit in Study EFC15392 should coincide with the first visit in the long-term extension study. 
c Height to be measured only at Visit 1. 
d Vital sign measurements (sitting BP and heart rate): For all measurements 3 separate seated BP measurements should be taken with at least 1 minute between readings, following at least 10-minute rest period 
and prior to phlebotomy. The arm with the higher pressure at the initial screening visit should be used for all subsequent BP measurements. 
e The abbreviated physical examination should focus on areas important for assessment of AEs if necessary. 
f 
Serum pregnancy testing only at Visit 1; urine pregnancy testing subsequently. Serum pregnancy test results must be reviewed prior to the run-in phase for all WOCBP unless there is documented history of 
menopause (based on documented FSH and estradiol levels - if results not documented then FSH and estradiol will be tested at screening) or they are surgically sterile. Any positive urine test results must be 
confirmed based on serum pregnancy test. The Investigator may perform additional tests at their discretion or as required by local regulations. Patients will perform monthly urine pregnancy at home and report to 
the site. 
g Viral serology (central lab) includes hepatitis B surface antigen (HBs Ag), hepatitis B core antibody (HBc Ab) anti-hepatitis C virus (anti-HCV) antibodies, anti-human immunodeficiency Virus 1 and 2 antibodies 
(anti-HIV1 and anti-HIV2 Ab). 
h Urinalysis includes urine dipstick and microscopy. Dipstick includes assessment of specific gravity, pH, protein, glucose, blood, ketones, bilirubin, urobilinogen, nitrite, and leukocyte esterase. Microscopy 
(central lab) includes detection of formed cellular elements, casts, bacteria, yeast, parasites, and crystals in centrifuged urine sediment. Dipstick will be done locally, if any parameter on the dipstick is abnormal, a 
urine sample should be sent to the central laboratory for quantitative measurement. 
i 
Serum/plasma and urine samples for exploratory biomarkers analysis collected in Stage 2 of the study, will be analyzed only if results of this analysis during Stage 1 are considered as useful for further 
investigation. 
j 
PK sample collection time for Month 1 (pre-dose and 3[±1] hours post dose, Month 24 [pre-dose]). At visits when a post-dose PK sample is to be collected, patients should take the study drug on site. 
k Spot urine will be collected based on 3 samples from the Day -2, morning of the day of the site visit and from 24 hour urine sample (or sample provided for urinalysis on the day of the visit - for visits when 
collection of 24 hour sample is not required) (see Section 9.4.3). 
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l 
Urine will be collected to evaluate exploratory biomarkers (except at Month 1 visit), albumin, total protein, creatinine, electrolyte and osmolality. At selected sites, urinary exosomes will be isolated from the urine at 
Visits 3, 4, 5, and 7. Please refer to laboratory manual for collection instructions. Collection of 24-hour urine sample at Visits 5 and 7 will be performed only at selected sites that participate in isolation of urinary 
exosomes. 
m The 12-lead ECG recordings should be performed before blood samplings. Investigator should evaluate V2 ECG reading prior to run-in medication administration; V2 ECG central reader’s assessment should be 
evaluated prior to IMP administration at Visit 3. The ECG will be evaluated as “normal” or “abnormal”. 
n Using a central reader, liver volume and combined renal volume of both kidneys will be measured. Combined renal cyst volume and renal parenchyma may be determined at a later date for a subset of patients. 
o If a patient has documented CT/MRI/US kidneys imaging test results obtained prior to the study, Investigator may use this data for preliminary evaluation of a patient`s eligibility based on massively enlarged 
kidneys at Visit 1. First study MRI for confirmation of TKV Imaging Classification Class will be performed at Visit 2 (Run-in visit). If a patient has no documented CT/MRI/US kidneys imaging test results obtained 
prior to the study, Investigator will perform MRI for confirmation of TKV Imaging Classification Class at Visit 1 (initial screening Visit). TKV volume must be confirmed by a central reader prior to Visit 3. 
p The patient is required to have an ophthalmological examination with pupil dilation before randomization, at Month 6 (Visit 6), Month 12 (Visit 8), Month 18 (Visit 10), and at Month 24 (Visit 12) (or upon withdrawal 
or discontinuation). Ophthalmological examinations at Visit 2, Month 12 (Visit 8), and Month 24 (Visit 12) will also include measurement of the corneal thickness (or endothelial cell density) and measurement of 
intraocular pressure. If at any time during study participation a patient experiences a decline of ≥2 lines in BCVA compared with that at baseline or previous assessment, a slit-lamp examination with pupil dilation 
should be performed. Observed lens opacities must be graded with the WHO simplified cataract grading system. A slit-lamp examination with pupil dilation must be performed again in 3 months. If no new cataract 
is seen during this examination, a normal schedule of ophthalmological examinations with pupil dilation can be resumed. If patient had change of WHO Grade ≥1 in any of the 3 features (nuclear, cortical, and 
posterior subcapsular opacification) of the lens, the next scheduled ophthalmological examination (in 3 months) in this patient must include pupil dilation and evaluation of observed cataract(s) ad observations 
graded with the WHO simplified cataract grading system. If no new change of WHO Grade ≥1 is seen during this examination, a normal schedule of ophthalmological examinations with pupil dilation can be 
resumed. Pupil dilation and full ophthalmological examination can be performed at any time if deemed medically necessary; observed lens opacities must be graded with the WHO simplified cataract grading 
system (see Section 9.4.10). 
q The daily diaries will be filled out by patients at home for 7 days prior to baseline visit and after that at home for consecutive days for the specified administration period before the study visits and will be collected 
at the time of visit. 
r 
The PROs will be administered to patients at study visit according to the listed schedule. 
s Prior to the start of IMP at Baseline Visit. In subjects who have consented to it, samples of serum will be collected and archived for future analysis. 
t 
All SAEs, AEs and AEs of special interest (AESIs) will be collected starting with signing informed consent and continue until 30 days after the last dose of IMP or study end, whichever comes later. All AEs that 
occurred during treatment should be followed for at least 30 days following the last dose of IMP or until the event has resolved, the condition has stabilized, the etiology of the event is determined to be not related 
to IMP, or the patient is lost to follow-up. All patients should be followed to collect safety information up to 30 days after the last IMP administration or up to the first visit of the long-term extension study, whichever 
occurs first. For patients enrolled or screened into the long-term extension study prior to 30 days after the last dose of IMP, all SAEs, AEs, and AESIs will be collected up to the last visit in the Study EFC15392, 
which will coincide with the first visit in the long-term extension study. Details of ongoing AEs and ongoing medications at the time of the last visit in EFC15392 study will be duplicated as such into the long-term 
extension study. 
u All laboratory assessments occur prior to intake of double-blind IMP. Samples should be collected in fasting conditions. Some assessments done at the beginning of screening may have to be repeated, 
Investigator will need to receive and evaluate results of repeated tests prior to Visit 3. 
v A subset of patients will be evaluated with iohexol for mGFR. 
w The initial screening period (Visit 1) can last up to 15 days (+3 days). Visit 2 can be performed as soon as results of all assessments performed at Visit 1 are available. 
x During the run-in period the patient will receive single-blind placebo. 
y At Visit 12 patients may be offered to enter long-term extension study. For patients who will agree and will be eligible to enter into a potential long-term extension study without any discontinuation between the 
EFC15392 and the LTS15823 studies, Visit 12 (end of treatment visit) of EFC15392 study will correspond to Visit 1 of LTS15823 study including all planned evaluations to be performed at Visit 12 of EFC15392 
study and an additional MRI that will be performed in the frame of Visit 1 of the LTS15823 study.
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2 
TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 07 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 3 
1 
FLOW CHARTS ............................................................................................................................. 19 
1.1 
GRAPHICAL STUDY DESIGN FOR STAGE 1 ............................................................................. 19 
1.2 
GRAPHICAL STUDY DESIGN FOR STAGE 2 ............................................................................. 20 
1.3 
STUDY FLOW CHART FOR STAGE 1 ......................................................................................... 21 
1.4 
STUDY FLOW CHART FOR STAGE 2 ......................................................................................... 25 
2 
TABLE OF CONTENTS ................................................................................................................ 30 
2.1 
LIST OF TABLES ........................................................................................................................... 37 
2.2 
LIST OF FIGURES ......................................................................................................................... 37 
3 
LIST OF ABBREVIATIONS .......................................................................................................... 38 
4 
INTRODUCTION AND RATIONALE ............................................................................................. 41 
4.1 
BACKGROUND: VENGLUSTAT AND AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY 
DISEASE ........................................................................................................................................ 41 
4.1.1 
Venglustat ...................................................................................................................................... 41 
4.1.2 
Autosomal dominant polycystic kidney disease ............................................................................. 42 
4.1.3 
Autosomal dominant polycystic kidney disease and venglustat .................................................... 43 
4.2 
CLINICAL TRIALS OF VENGLUSTAT IN HUMANS ..................................................................... 44 
4.3 
BENEFIT/RISK OF VENGLUSTAT ............................................................................................... 45 
5 
STUDY OBJECTIVES ................................................................................................................... 50 
5.1 
STAGE 1 ........................................................................................................................................ 50 
5.1.1 
Primary objective ............................................................................................................................ 50 
5.1.2 
Secondary objectives ..................................................................................................................... 50 
5.1.3 
Exploratory objectives .................................................................................................................... 50 
5.2 
STAGE 2 ........................................................................................................................................ 51 
5.2.1 
Primary objective ............................................................................................................................ 51 
5.2.2 
Secondary objectives ..................................................................................................................... 51 
5.2.3 
Exploratory objectives .................................................................................................................... 51 
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6 
STUDY DESIGN ............................................................................................................................ 52 
6.1 
DESCRIPTION OF THE STUDY ................................................................................................... 52 
6.2 
DURATION OF STUDY PARTICIPATION .................................................................................... 53 
6.2.1 
Duration of study participation for each patient ............................................................................. 53 
6.2.2 
Determination of end of clinical trial (all patients) .......................................................................... 53 
6.3 
INTERIM ANALYSIS ...................................................................................................................... 53 
6.4 
STUDY COMMITTEES .................................................................................................................. 54 
6.4.1 
Data monitoring committee ............................................................................................................ 54 
6.4.2 
Steering committee ........................................................................................................................ 54 
6.5 
DISCUSSION OF STUDY DESIGN AND CHOICE OF CONTROL GROUPS ............................. 54 
6.5.1 
Rationale for selection of dose ....................................................................................................... 54 
6.5.2 
Rationale for study design and control groups .............................................................................. 55 
7 
SELECTION OF PATIENTS .......................................................................................................... 58 
7.1 
INCLUSION CRITERIA .................................................................................................................. 58 
7.2 
EXCLUSION CRITERIA ................................................................................................................ 59 
7.2.1 
Exclusion criteria related to study methodology ............................................................................ 59 
7.2.2 
Exclusion criteria related to mandatory background therapies ...................................................... 61 
7.2.3 
Exclusion criteria related to the current knowledge of venglustat investigational medicinal 
product ........................................................................................................................................... 61 
7.2.4 
Criteria for temporarily delaying of randomization or administration of study treatment ............... 62 
8 
STUDY TREATMENTS ................................................................................................................. 63 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) .......................................................................... 63 
8.1.1 
Pharmaceutical form ...................................................................................................................... 63 
8.1.2 
Dose of drug per administration ..................................................................................................... 63 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) .................................................................. 64 
8.3 
BLINDING PROCEDURES ............................................................................................................ 64 
8.3.1 
Methods of blinding ........................................................................................................................ 64 
8.3.2 
Randomization code breaking during the study ............................................................................. 65 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP .............................................. 65 
8.5 
INVESTIGATIONAL MEDICINAL PRODUCT PACKAGING AND LABELING ............................. 66 
8.6 
STORAGE CONDITIONS AND SHELF LIFE ................................................................................ 66 
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8.7 
RESPONSIBILITIES ...................................................................................................................... 66 
8.7.1 
Treatment accountability and compliance...................................................................................... 67 
8.7.2 
Return and/or destruction of treatments ........................................................................................ 68 
8.8 
CONCOMITANT MEDICATION ..................................................................................................... 68 
8.8.1 
List of forbidden concomitant medication ...................................................................................... 68 
8.8.2 
COVID-19 vaccine ......................................................................................................................... 69 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT .............................................. 70 
9.1 
PRIMARY ENDPOINTS ................................................................................................................. 70 
9.1.1 
Stage 1 ........................................................................................................................................... 70 
9.1.2 
Stage 2 ........................................................................................................................................... 70 
9.2 
SECONDARY ENDPOINTS .......................................................................................................... 70 
9.2.1 
Stage 1 ........................................................................................................................................... 70 
9.2.2 
Stage 2 ........................................................................................................................................... 70 
9.2.3 
Safety/tolerability endpoints ........................................................................................................... 71 
9.3 
EXPLORATORY ENDPOINTS ...................................................................................................... 71 
9.3.1 
Stage 2 only ................................................................................................................................... 71 
9.3.2 
Stages 1 and 2 ............................................................................................................................... 71 
9.4 
ASSESSMENT METHODS ........................................................................................................... 72 
9.4.1 
Magnetic resonance imaging ......................................................................................................... 72 
9.4.2 
Estimated glomerular filtration rate ................................................................................................ 72 
9.4.3 
Urine osmolality .............................................................................................................................. 73 
9.4.4 
Adverse events .............................................................................................................................. 73 
9.4.5 
Vital signs ....................................................................................................................................... 73 
9.4.6 
Physical examination ..................................................................................................................... 74 
9.4.7 
Laboratory safety variables ............................................................................................................ 75 
9.4.8 
Electrocardiogram variables .......................................................................................................... 75 
9.4.9 
Beck Depression Inventory, second edition ................................................................................... 76 
9.4.10 
Ophthalmological examination ....................................................................................................... 76 
9.4.11 
Patient reported outcomes ............................................................................................................. 77 
9.4.11.1 Overall pain .................................................................................................................................... 78 
9.4.11.2 Overall fatigue ................................................................................................................................ 78 
9.4.11.3 Global impression of severity ......................................................................................................... 78 
9.4.11.4 Global impression of change ......................................................................................................... 78 
9.4.11.5 Quality of life/health status ............................................................................................................. 79 
9.4.11.6 Daily symptoms of autosomal dominant polycystic kidney disease .............................................. 79 
9.4.12 
Analgesic/over the counter pain medication administration........................................................... 79 
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9.4.13 
Pharmacodynamic and exploratory biomarkers ............................................................................ 79 
9.4.13.1 Biomarkers associated with autosomal dominant polycystic kidney disease ................................ 80 
9.4.13.2 Glycosphingolipids: glucosylceramide, monosialodihexosylganglioside ....................................... 80 
9.4.14 
Pharmacokinetics ........................................................................................................................... 80 
9.4.14.1 Sampling time ................................................................................................................................ 80 
9.4.14.2 Pharmacokinetics handling procedure ........................................................................................... 81 
9.4.14.3 Bioanalytical method ...................................................................................................................... 81 
9.4.14.4 Pharmacokinetics parameters ....................................................................................................... 81 
9.4.15 
Pharmacogenetic assessment ....................................................................................................... 81 
9.4.15.1 Optional stored deoxyribonucleic acid sample .............................................................................. 81 
9.4.16 
Future use of samples ................................................................................................................... 82 
9.4.17 
Isolation of urinary exosomes ........................................................................................................ 83 
9.5 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 83 
10 
STUDY PROCEDURES ................................................................................................................ 84 
10.1 
VISIT SCHEDULE .......................................................................................................................... 84 
10.1.1 
Screening period ............................................................................................................................ 85 
10.1.1.1 Visit 1: screening from Day -30 to Day -16 .................................................................................... 85 
10.1.1.2 Visit 2: run-in Day -15..................................................................................................................... 86 
10.1.2 
Treatment period - Month 0 to Month 24 ....................................................................................... 87 
10.1.2.1 Visit 3: randomization at Month 0/Day 1 ........................................................................................ 87 
10.1.2.2 Visit 4, 6, 8, 10, 12/Month 1, 6, 12, 18, 24 (Day 30, 180, 360, 540, 720) ...................................... 88 
10.1.2.3 Visit 5, 7, 9, 11/Month 3, 9, 15, 21 (Day 90, 270, 450, 630) .......................................................... 90 
10.1.3 
Follow-up visit - Visit 13/Month 25 (Day 750) ................................................................................ 91 
10.2 
DEFINITION OF SOURCE DATA .................................................................................................. 92 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION ....................................... 92 
10.3.1 
Temporary treatment discontinuation with investigational medicinal product(s) ........................... 92 
10.3.2 
Permanent treatment discontinuation with investigational medicinal product ............................... 93 
10.3.3 
List of criteria for permanent treatment discontinuation ................................................................. 93 
10.3.4 
Handling of patients after permanent treatment discontinuation ................................................... 94 
10.3.5 
Procedure and consequence for patient withdrawal from study .................................................... 95 
10.3.6 
Lost to follow-up ............................................................................................................................. 96 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING .......................... 96 
10.4.1 
Definitions of adverse events ......................................................................................................... 96 
10.4.1.1 Adverse event ................................................................................................................................ 96 
10.4.1.2 Serious adverse event ................................................................................................................... 96 
10.4.1.3 Adverse event of special interest ................................................................................................... 97 
10.4.2 
General guidelines for reporting adverse events ........................................................................... 98 
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10.4.3 
Instructions for reporting serious adverse events .......................................................................... 99 
10.4.4 
Guidelines for reporting adverse events of special interest ......................................................... 100 
10.4.5 
Guidelines for management of specific laboratory abnormalities ................................................ 100 
10.4.6 
Guidelines for reporting product complaints (investigational medicinal product) ........................ 101 
10.5 
OBLIGATIONS OF THE SPONSOR ........................................................................................... 101 
10.6 
SAFETY INSTRUCTIONS ........................................................................................................... 101 
10.7 
ADVERSE EVENTS MONITORING ............................................................................................ 101 
11 
STATISTICAL CONSIDERATIONS ............................................................................................ 102 
11.1 
DETERMINATION OF SAMPLE SIZE ......................................................................................... 102 
11.2 
DISPOSITION OF PATIENTS ..................................................................................................... 103 
11.3 
ANALYSIS POPULATIONS ......................................................................................................... 103 
11.3.1 
Efficacy populations ..................................................................................................................... 103 
11.3.1.1 Intent-to-treat population .............................................................................................................. 103 
11.3.2 
Safety population ......................................................................................................................... 104 
11.3.3 
Pharmacokinetics/pharmacodynamics analysis population......................................................... 104 
11.4 
STATISTICAL METHODS ........................................................................................................... 104 
11.4.1 
Extent of study treatment exposure and compliance ................................................................... 104 
11.4.1.1 Extent of investigational medicinal product exposure .................................................................. 105 
11.4.1.2 Compliance .................................................................................................................................. 105 
11.4.2 
Analyses of efficacy endpoints ..................................................................................................... 105 
11.4.2.1 Analysis of primary efficacy endpoint(s) ...................................................................................... 105 
11.4.2.2 Analyses of secondary efficacy endpoints ................................................................................... 109 
11.4.2.3 Multiplicity considerations ............................................................................................................ 111 
11.4.2.4 Secondary analysis including patients from Stage 2 with eGFR between 30 and 
44.9 mL/min/1.73 m2 at screening ............................................................................................... 112 
11.4.3 
Analyses of safety data ................................................................................................................ 112 
11.4.3.1 Adverse events ............................................................................................................................ 113 
11.4.3.2 Laboratory data and vital signs .................................................................................................... 114 
11.4.4 
Analyses of pharmacokinetic and pharmacodynamic variables .................................................. 115 
11.4.5 
Analyses of patient reported outcomes (health-related quality of life/health economics 
variables) ...................................................................................................................................... 115 
11.5 
INTERIM AND FINAL ANALYSIS ................................................................................................ 116 
11.5.1 
Dose selection safety review ....................................................................................................... 116 
11.5.2 
Interim futility analysis .................................................................................................................. 116 
11.5.3 
Two-step final analysis ................................................................................................................. 117 
12 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................................. 118 
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12.1 
ETHICAL AND REGULATORY STANDARDS ............................................................................ 118 
12.2 
INFORMED CONSENT ............................................................................................................... 118 
12.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC) ................................................................................................. 118 
13 
STUDY MONITORING................................................................................................................. 120 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S) ..................................................................... 120 
13.2 
RESPONSIBILITIES OF THE SPONSOR ................................................................................... 120 
13.3 
SOURCE DOCUMENT REQUIREMENTS .................................................................................. 121 
13.4 
USE AND COMPLETION OF ELECTRONIC CASE REPORT FORMS (ECRFS) AND 
ADDITIONAL REQUEST ............................................................................................................. 121 
13.5 
USE OF COMPUTERIZED SYSTEMS ........................................................................................ 121 
14 
ADDITIONAL REQUIREMENTS ................................................................................................. 122 
14.1 
CURRICULUM VITAE.................................................................................................................. 122 
14.2 
RECORD RETENTION IN STUDY SITES .................................................................................. 122 
14.3 
CONFIDENTIALITY ..................................................................................................................... 122 
14.4 
PROPERTY RIGHTS ................................................................................................................... 123 
14.5 
DATA PROTECTION ................................................................................................................... 123 
14.6 
INSURANCE COMPENSATION .................................................................................................. 124 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES ............................... 124 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE .......................................................................................................................................... 124 
14.8.1 
By the Sponsor ............................................................................................................................. 124 
14.8.2 
By the Investigator ....................................................................................................................... 125 
14.9 
CLINICAL TRIAL RESULTS ........................................................................................................ 125 
14.10 
PUBLICATIONS AND COMMUNICATIONS ............................................................................... 125 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS ........................................................................ 126 
16 
BIBLIOGRAPHIC REFERENCES ............................................................................................... 127 
17 
APPENDICES .............................................................................................................................. 130 
APPENDIX A 
CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION ............................................................................................................................ 131 
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APPENDIX B 
LIST OF KNOWN CYP3A4 INDUCERS/INHIBITORS ...................................................... 134 
APPENDIX C 
GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY 
ABNORMALITIES BY SANOFI .................................................................................................... 135 
APPENDIX D 
BECK DEPRESSION INVENTORY-II ............................................................................... 140 
APPENDIX E 
BRIEF PAIN INVENTORY (SHORT FORM) ..................................................................... 142 
APPENDIX F 
BRIEF FATIGUE INVENTORY .......................................................................................... 144 
APPENDIX G 
PATIENT GLOBAL IMPRESSION OF SEVERITY (PGIS) ............................................... 145 
APPENDIX H 
PATIENT GLOBAL IMPRESSION OF CHANGE (PGIC) ................................................. 146 
APPENDIX I 
EUROQOL (EQ-5D-5L) ....................................................................................................... 147 
APPENDIX J 
STATISTICAL TECHNICAL DETAILS ............................................................................... 148 
APPENDIX K 
ISOLATION OF URINARY EXOSOMES ........................................................................... 157 
APPENDIX L 
MEASURED GLOMERULAR FILTRATION RATE SUBSTUDY ....................................... 160 
APPENDIX M 
COUNTRY-SPECIFIC REQUIREMENTS ........................................................................ 164 
APPENDIX N 
PROTOCOL AMENDMENT HISTORY ............................................................................. 165 
APPENDIX O 
CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL EMERGENCY 
THAT IS DECLARED BY A GOVERNMENTAL AGENCY .......................................................... 188 
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2.1 
LIST OF TABLES 
Table 1 - Patient reported outcome (PRO) concepts and questionnaires .................................................... 77 
Table 2 - Summary of plasma pharmacokinetics samples handling for venglustat ...................................... 81 
Table 3 - Summary of handling procedures for stored DNA samples ........................................................... 82 
Table 4 - Summary of adverse event reporting instructions ........................................................................ 100 
Table 5 - Optimal contrasts for the 3 prespecified candidate of dose-response models ............................ 106 
Table 6 - Highly effective contraceptive methods ....................................................................................... 132 
Table 7 - Operating characteristics of the study design assuming the dose 15 mg is selected for Stage 2
 ..................................................................................................................................................................... 149 
Table 8 - Operating characteristics of the study design assuming the dose 8 mg is selected for Stage 2 . 150 
 
2.2 
LIST OF FIGURES 
Figure 1 - Dose-dependent glucosylceramide synthase lowering and efficacy in the jck mouse model of 
polycystic kidney disease .............................................................................................................................. 43 
Figure 2 - Prespecified candidate of dose-response models ...................................................................... 106 
Figure 3 - Graphical illustration of the procedure for handling multiplicity .................................................. 111 
Figure 4 - Schematic representation of imputation of missing data - primary analysis ............................... 151 
Figure 5 - Schematic representation of imputation of missing data - sensitivity analysis using control based 
multiple imputation ....................................................................................................................................... 155 
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3 
LIST OF ABBREVIATIONS 
 
ADMA: 
asymmetric dimethylarginine 
ADPKD: 
autosomal dominant polycystic kidney disease 
AE: 
adverse event 
AEs: 
adverse events 
AESI: 
adverse event of special interest 
ALP: 
alkaline phosphatase 
ALT: 
alanine aminotransferase 
anti-HCV: 
anti-hepatitis C 
anti-HIV1: 
anti-human immunodeficiency virus 1 antibody 
anti-HIV2 Ab: 
anti-human human immunodeficiency virus 2 antibody 
AST: 
aspartate aminotransferase 
AUC: 
area under the concentration-time curve 
BCVA: 
best corrected visual acuity 
BDI-II: 
beck depression inventory II 
BFI-SF: 
brief fatigue inventory short form 
BPI-SF: 
brief pain inventory short form 
BUN: 
blood urea nitrogen 
CDMS: 
clinical data management system 
CI: 
confidence intervals 
CKD: 
chronic kidney disease 
CKD-EPI: 
Chronic Kidney Disease Epidemiology Collaboration 
CLss: 
clearance at steady state 
Cmax: 
maximum observed concentration 
CNS: 
central nervous system 
COR-2: 
cortical cataract-2 
DBP: 
diastolic blood pressure 
DMC: 
Data Monitoring Committee 
DNA: 
deoxyribonucleic acid 
eCRF: 
electronic case report form 
eGFR: 
estimated glomerular filtration rate 
EOT: 
end-of-treatment 
EQ-5D-5L: 
European quality of life 5-dimension 5-level 
EU: 
European Union 
FD: 
Fabry disease 
fe: 
mean fraction of dose excreted unchanged in urine 
FGF23: 
fibroblast growth factor 23 
FSH: 
follicle stimulating hormone 
GBA: 
glucocerebrosidase 
GBA-PD: 
Parkinson's disease with a confirmed acid-β-glucosidase gene mutation, 
glucocerebrocidase in Parkinson Disease 
GCP: 
Good Clinical Practice 
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GCS: 
glucosylceramide synthase 
GD: 
Gaucher disease 
GD3: 
Gaucher Disease Type 3 
GGT: 
gamma-glutamyl transferase 
GI: 
gastrointestinal 
GL-1: 
glucosylceramide 
GL-2: 
lactosylceramide 
GL-3: 
globotriaosylceramide 
GM3: 
monosialodihexosylganglioside 
GSL: 
glycosphingolipids 
GSL: 
glycosphingolipid 
HBcAb: 
hepatitis C core antibody 
HBsAb: 
hepatitis B surface antibody 
HBsAg: 
hepatitis B surface antigen 
hERG: 
human ether-a-go-go-related gene 
HLGT: 
high-level group term 
HLT: 
high level term 
IB: 
investigator's brochure 
IEC: 
Independent Ethics Committee 
IMP: 
investigational medicinal product 
INR: 
International Normalized Ratio 
IRB: 
Institutional Review Board 
IRT: 
interactive response technology 
ITT: 
Intent-to-treat 
LC-MS/MS: 
liquid chromatography tandem mass spectrometry 
LLOQ: 
lower limit of quantification 
MCP-1: 
monocyte chemoattractant protein-1 
MedDRA: 
Medical Dictionary for Regulatory Activities 
mGFR: 
measured glomerular filtration rate 
MMRM: 
mixed effect model with repeated measures 
MMSE: 
mini mental state examination 
MRI: 
magnetic resonance imaging 
NOAEL: 
no observed adverse effect level 
NRS: 
numeric rating scale 
NYHA: 
New York Heart Association 
PCSA: 
potentially clinically significant abnormality 
PD: 
pharmacodynamic 
PGIC: 
patient global impression of change 
PGIS: 
patient global impression of severity 
PK: 
pharmacokinetic(s) 
PR interval: 
the time from the onset of the P wave to the start of the QRS complex 
PRO: 
patient reported outcome 
PSC-2: 
posterior subcapsular cataract-2 
PT: 
prothrombin time, preferred term 
PTT: 
partial thromboplastin time 
QD: 
once daily 
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QRS interval: 
time from ECG Q wave to the end of the s wave corresponding to ventricular 
depolarization 
RAAS: 
renin-angiotensin-aldosterone system 
SA: 
statistical analysis plan 
SAEs: 
serious adverse events 
SAR: 
suspected adverse reaction 
SBP: 
systolic blood pressure 
SC: 
Steering Committee 
SE: 
standard errors 
SMQ: 
standardized MedDRA query 
SOC: 
system organ class, system organ class 
SRT: 
substrate reduction therapy 
ST deviation: 
ECG ST-segment deviation 
SUSAR: 
Suspected Unexpected Serious Adverse Reaction 
TEAE: 
treatment-emergent adverse event 
TKV: 
total kidney volume 
tmax: 
time to maximum observed concentration 
ULN: 
upper limit of normal 
US: 
United States 
WHO: 
World Health Organization 
WOCBP: 
women of childbearing potential 
β-hCG: 
beta human chorionic gonadotropin 
 
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4 
INTRODUCTION AND RATIONALE 
4.1 
BACKGROUND: VENGLUSTAT AND AUTOSOMAL DOMINANT POLYCYSTIC 
KIDNEY DISEASE 
4.1.1 Venglustat 
GZ402671, also referred to as venglustat, SAR402671 is a glucosylceramide synthase (GCS) 
inhibitor that decreases the synthesis of glucosylceramide (GL-1), a central building block for 
more complex glycosphingolipids (GSLs). Substrate reduction therapy (SRT) with GCS inhibitors 
is expected to have broad therapeutic applicability across a number of disorders, including 
lysosomal storage diseases, as well as other disorders associated with increased GL-1 or increased 
levels of glycosphingolipids that contain GL-1 at their core. 
Sanofi is investigating venglustat as a potential SRT for treating patients with Fabry disease (FD), 
Gaucher disease Type 3 (GD3), Parkinson’s disease patients with a confirmed acid-β-glucosidase 
(glucocerebrosidase gene [GBA]) mutation (GBA-PD), GM2 gangliosidosis, and autosomal 
dominant polycystic kidney disease (ADPKD). A novel GCS inhibitor, venglustat inhibits the 
enzymatic conversion of ceramide to GL-1, the first step in glycosphingolipid biosynthesis. By 
reducing the production of GL-1, the central building block for the synthesis of more complex 
glycosphingolipids (including globotriaosylceramide [GL-3], GM1, GM2, and 
monosialodihexosylganglioside [GM3]), SRT with venglustat offers a potential therapeutic 
strategy for FD, GD, GBA-PD, and ADPKD.  
Venglustat is a potent and selective inhibitor of murine and human GCS in biochemical and 
cell-based in vitro assays. In vivo pharmacology studies in rodents and dogs showed reduction in 
plasma GL-1 concentrations as a pharmacodynamic (PD) marker of GCS inhibition. Reductions 
of GL-1 concentrations in plasma (rodents and dogs) and tissue (rodents only) were observed 
following oral venglustat administration. In both species, the effects of venglustat on plasma GL-1 
were dose-dependent and correlated with plasma concentrations of the compound. Based on 
multiple preclinical studies following a single oral administration to rats, venglustat distributed 
extensively in kidney, liver, lung, spleen, intestine, and heart tissues and crossed the blood brain 
barrier.  
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4.1.2 Autosomal dominant polycystic kidney disease 
Autosomal dominant polycystic kidney disease (ADPKD) is a life-threatening genetic disease 
caused by mutations in PKD1 and PKD2 genes characterized by the formation of multiple kidney 
cysts that enlarge with disease progression to result in end-stage renal disease and dialysis in 
~50% of patients (1). Cysts may also develop in liver and other organs (eg, seminal vesicle, 
pancreas). At least 60% of ADPKD patients report pain (back pain and abdominal pain) and up to 
one third of patients report severe symptoms. The target population is those patients with ADPKD 
at high risk of progressing to end-stage renal disease (1C, 1D, and 1E of the Mayo Imaging 
Classification). Classes 1C, 1D, and 1E represent 30% to 40% of the diagnosed ADPKD 
population who can be identified by imaging measures of kidney size (2, 3). In the United States 
(US), the diagnosed patient population is estimated to be between 1 in 2500 to 1 in 3000 or 
roughly 120 000 people which qualifies for an orphan designation (prevalence of less than 
200 000). In the European Union (EU), the population is estimated to be approximately 
170 000 people or 3.2 in 10 000 people. This is below the EU ceiling for orphan designation 5 in 
10 000 (1). 
Tolvaptan is approved in Japan, EU, US, and Canada to slow the progression of cyst development 
and renal insufficiency. The liver toxicity led to the requirement in the EU for a risk management 
plan which includes 18 months of monthly monitoring of the liver function (4). Tolvaptan safety 
(risk of idiosyncratic liver toxicity) and tolerability (eg, thirst, polyuria, and nocturia in ~55%, 
38%, and 29% of patients, respectively) make it a suboptimal chronic treatment. In clinical 
studies, treatment discontinuation rates were 23% for tolvaptan and 14% for placebo, primarily 
due to adverse events (AEs).  
The completion of the HALT-PKD study provided important insights to the management of 
hypertension in ADPKD (5). The HALT-PKD study, a US multicenter trial conducted on more 
than 1000 ADPKD patients with up to 8 years of follow-up, advised strict blood pressure control. 
In patients with estimated glomerular filtration rate (eGFR]) above 60 mL/min/1.73 m2, a target 
blood pressure of 110/70 mmHg was suggested, especially in young patients with a high 
progression risk. In chronic kidney disease (CKD) Stage 3, the target blood pressure should be 
below 120/80 mmHg. Double renin-angiotensin-aldosterone system (RAAS) blockade with 
a target blood pressure of 120/80 mmHg or less had no beneficial effects but did increase 
complications among older ADPKD patients (6). There is a significant variation in the local 
standard of care for blood pressure target and the use of therapeutic agent to achieve that. 
It is generally advised to reduce dietary sodium intake to within limits recommended for the 
general healthy population, and general CKD population (<100 mmol/d). Increased fluid intake 
has been hypothesized to reduce the progression of ADPKD, but there is no direct evidence to 
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support this as a conclusive recommendation for use in clinical practice (7). In addition, since 
urinary osmolality is an endpoint in this trial, increase in fluid intake has not been recommended 
beyond normal daily fluid intake. 
4.1.3 Autosomal dominant polycystic kidney disease and venglustat 
Human and murine ADPKD is associated with increased GCS activity, leading to a pathogenic 
accumulation of GSLs such as GL-1, lactosylceramide (GL-2), and GM3 (8, 9). Several 
structurally distinct GCS inhibitors have significantly reduced cyst growth and preserved renal 
function in 3 different preclinical ADPKD models: the orthologous model with conditionally 
inactivated PKD1 gene (aggressive course of ADPKD), the jck mouse model (moderately 
progressive phenocopy of human disease), and the pcy mouse model (slowly progressive disease) 
(10) (and unpublished data). Efficacy is consistently observed when kidney GL-1 lowering 
exceeds 70% (10). Kidney and serum GL-1 lowering is well-correlated in the mouse, suggesting 
that either can be used as a PD marker. 
Efficacy of venglustat has been confirmed in the jck mouse model of ADPKD (Figure 1). 
Treatment with venglustat (and the related molecule, Genz-667161) significantly reduced 
cystogenesis, as demonstrated by the decreased kidney to body weight ratio and cyst volume. 
Reduced blood urea nitrogen (BUN) measurements suggest preserved kidney function, since the 
experiment was not sufficiently powered to achieve statistical significance for this disease 
parameter. Kidney and serum GL-1 measurements show a strong correspondence between serum 
and kidney GL-1 lowering.  
Figure 1 - Dose-dependent glucosylceramide synthase lowering and efficacy in the jck mouse 
model of polycystic kidney disease 
 
BUN = blood urea nitrogen; BW = body weight; GL-1 = glucosylceramide; K/BW = kidney/body weight; SEM = standard error of the mean. 
Jck mice were administered venglustat or the reference compound Genz-667161 in feed ad libitum from 26 days of age until sacrificed at 
64 days of age. Data shown are mean +/- SEM.  
Percentage of glucosylceramide lowering is indicated above the corresponding bars. 
*p <0.05. 
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In completed clinical studies in healthy subjects, venglustat was observed to be safe and well 
tolerated. Overall, the AE profile of subjects in the venglustat dosing groups was similar to that 
observed in the placebo groups. 
More information on the safety of venglustat and on the clinical program can be found in the 
Investigator Brochure (IB). 
4.3 
BENEFIT/RISK OF VENGLUSTAT 
Venglustat significantly reduced GSL levels, reduced cyst growth, and preserved renal function in 
3 different preclinical ADPKD models (8, 9, 10). These results strongly support the hypothesis 
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that GCS inhibition using venglustat could be a viable treatment to slow cyst growth and preserve 
renal function in individuals with ADPKD. 
Venglustat is currently being investigated for FD, GD3, GM2, and Parkinson’s disease patients 
with a confirmed acid-β-glucosidase GBA mutation (GBA-PD). Overall, in the clinical program, 
the majority of reported AEs were assessed as mild to moderate; most of which resolved 
spontaneously. Serious adverse events (SAEs) and discontinuations due to adverse events (AE) 
have been limited in Phase 2 studies. Based on an evaluation of the cumulative safety data from 
the clinical program, venglustat is generally safe and well tolerated.  
Potential risks have been identified mostly based on data from the nonclinical toxicology studies 
(IB). 
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More detailed efficacy and safety information is provided in the IB. 
The anticipated improvement in progression of ADPKD (the rate of total kidney volume [TKV] 
growth and the rate of renal function [estimated glomerular filtration rate] decline), with its 
associated reductions in blood pressure, and the tolerability and safety profile of venglustat to 
date, predict a favorable benefit-risk assessment for venglustat in ADPKD. 
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5 
STUDY OBJECTIVES 
5.1 
STAGE 1 
5.1.1 Primary objective 
• To determine the effect of venglustat on the rate of TKV growth in patients at risk of 
rapidly progressive ADPKD. 
5.1.2 Secondary objectives 
• To determine the effect of venglustat on the rate of renal function (eGFR) decline. 
• To determine the effect of venglustat on pain and fatigue, based on patient reported diary. 
• To evaluate the PK of venglustat in ADPKD patients. 
• Safety/tolerability objectives: 
- 
To characterize the safety profile of venglustat, 
- 
To evaluate the effect of venglustat on mood using BDI-II, 
- 
To evaluate the effect of venglustat on the lens by ophthalmological examination. 
5.1.3 Exploratory objectives 
• To explore the impact of venglustat on total liver volume (TLV) (in patients with 
height-adjusted total liver volume [htTLV] >2 L/m). 
• To explore the effect of venglustat on kidney concentrating ability by assessing urine 
osmolality (in patients not on diuretic). 
• To explore the effect of venglustat on nocturia, based on patient reported diary. 
• To explore the effect of venglustat on systolic blood pressure (SBP) and diastolic blood 
pressure (DBP). 
• To explore the effect of venglustat on biomarkers associated with ADPKD (eg, Fibroblast 
Growth Factor 23 [FGF23], Asymmetric Dimethylarginine [ADMA]). 
• To explore the effect of venglustat on pain and fatigue based on Brief Pain Inventory 
[BPI] and Brief Fatigue Inventory [BFI] questionnaires, and general health status (based 
on EuroQoL 5-dimension 5-level [EQ-5D-5L] questionnaire). 
• To explore the effect of venglustat on type, frequency and dosage of analgesic/over-the-
counter (OTC) pain medication administration. 
• To explore the effect of venglustat on all-cause hospitalization. 
• To explore the PD effects of venglustat by measuring downstream metabolites of GCS in 
plasma and urine. 
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5.2 
STAGE 2 
5.2.1 Primary objective 
• To determine the effect of venglustat on rate of renal function (eGFR) decline as compared 
to placebo in patients at risk of rapidly progressive ADPKD.  
5.2.2 Secondary objectives 
• To determine the effect of venglustat on the rate of TKV growth. 
• To determine the effect of venglustat on pain and fatigue, based on patient reported diary 
• To evaluate the PK of venglustat in ADPKD patients. 
• Safety/tolerability objectives: 
- 
To characterize the safety profile of venglustat, 
- 
To evaluate the effect of venglustat on mood using BDI-II, 
- 
To evaluate the effect of venglustat on the lens by ophthalmological examination. 
5.2.3 Exploratory objectives 
• To explore the impact of venglustat on TLV (in patients with htTLV >2 L/m). 
• To explore the effect of venglustat on kidney concentrating ability by assessing urine 
osmolality (in patients not on diuretic). 
• To explore the effect of venglustat on nocturia, based on patient reported diary. 
• To explore the effect of venglustat on SBP and DBP. 
• To explore the effect of venglustat on measured GFR (mGFR) (substudy) Appendix L. 
• To explore the effect of venglustat on biomarkers associated with ADPKD (eg, FGF23, 
ADMA). 
• To explore the effect of venglustat on pain and fatigue based on Brief Pain Inventory 
[BPI] and Brief Fatigue Inventory [BFI] questionnaires, and general health status (based 
on EuroQoL 5-dimension 5-level [EQ-5D-5L] questionnaire). 
• To explore the effect of venglustat on type, frequency and dosage of analgesic/over-the-
counter (OTC) pain medication administration. 
• To explore the effect of venglustat on all-cause hospitalization. 
• To explore the PD effects of venglustat by measuring downstream metabolites of GCS in 
plasma and urine. 
• To explore the effect of venglustat on eGFR (CKD-EPI equation) from baseline to 
24 months in patients with a screening eGFR between 30 and 44.9 mL/min/1.73 m2. 
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6 
STUDY DESIGN 
6.1 
DESCRIPTION OF THE STUDY 
This is an international, multicenter, randomized, double-blind, placebo-controlled, two-stage 
study in adult patients at risk of rapidly progressive ADPKD aged 18 to 50 years in Stages 1 and 
2 (and aged 18 to 55 years for patients with a screening eGFR between 30 and 
44.9 mL/min/1.73 m2 in Stage 2). 
The study is divided into 2 stages: 
Stage 1: An up to 30-day screening period including a 2-week single-blind placebo run-in 
(to identify patients who are unlikely to follow the assigned treatment regimen), followed by 
a randomized double-blind comparative placebo-controlled core treatment period of 24 months 
duration. 
After run-in, eligible patients will be randomized with a 1:1:1 ratio to placebo, 8 mg venglustat, or 
15 mg venglustat.  
Patients will be stratified based on their predicted ADPKD progression rate (1C versus 1D versus 
1E) according to Mayo Imaging Classification and by geographic region (North America, Europe, 
China, Japan, Republic of Korea, Rest of the World). If after reviewing the unblinded aggregate 
safety data from Stage 1 (after at least 1 month of treatment of the first 150 randomized patients 
from Stage 1), the DMC recommends the 8 mg dose for Stage 2, then the DMC may recommend 
switching patients on 15 mg treatment arm, in Stage 1, to the 8 mg arm. 
Stage 2: After the first 150 randomized patients from Stage 1 have completed at least 1 month of 
treatment (or have prematurely discontinued), the DMC will review in an unblinded fashion the 
aggregate safety data from Stage 1 and will select the venglustat dose 8 mg or 15 mg for Stage 2 
patients. The selected dose will be the highest dose determined to be safe and well tolerated in 
Stage 1. If after reviewing the unblinded aggregate safety data from Stage 1, the DMC 
recommends the 8 mg dose for Stage 2, then the DMC may recommend switching patients on the 
15 mg treatment arm, in Stage 1, to the 8 mg arm. 
Stage 2 will start with an up to 30-day screening period including a 2-week single-blind placebo 
run-in (to identify participants who are unlikely to follow the assigned treatment regimen), 
followed by a randomized double-blind comparative core treatment period of 24 months duration. 
After run-in, patients will be randomized with a 1:1 ratio to placebo and venglustat (dose to be 
determined in Stage 1). 
Patients will be stratified based on their predicted progression rate (1C versus 1D versus 1E) and 
by geographic region (North America, Europe, China, Japan, Republic of Korea, Rest of the 
World). 
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6.2 
DURATION OF STUDY PARTICIPATION 
6.2.1 Duration of study participation for each patient 
The maximum study duration per patient will be approximately 26 months. 
This will consist of a screening period of up to 30 +3 days (initial screening period of up to 
15 +3 days and single-blind placebo run-in period of 15 ±3 days), followed by a blinded study 
core treatment period of 24 months and a 30-day follow-up visit (for patients not participating in 
the potential long-term extension study) after the final dose of investigational medicinal product 
(IMP).  
Patients who completed 24 months of treatment in EFC15392 study may be given the option to 
enroll into an open-label long-term extension study LTS15823 (additional 24 months of treatment 
with 15 mg venglustat [ie, as specified in the EFC15392 protocol the dose selected for Stage 2 of 
EFC15392 study during unblinded review by the DMC of the aggregated safety data for 
150 patients who have completed at least 1 month of treatment in EFC15392 study]). 
The last study visit: 
1. for patients who elect to enter the potential long-term extension study upon completion of 
24 months of treatment in EFC15392 study will be Visit 12 (Month 24)  
2. for patients who complete the treatment in EFC15392 study and elect not to enter this 
potential extension study will be Visit 13 (Month 25) 
3. for patients who permanently discontinue medication and continue for all the remaining 
visits will be Visit 12 (Month 24) if they continue for all the remaining visits, or it will be 
their premature follow-up visit. 
6.2.2 Determination of end of clinical trial (all patients) 
The end of the study is defined as being the day the last patient completes his/her last visit 
planned in the protocol. 
The Sponsor reserves the right to discontinue the study at any time. 
6.3 
INTERIM ANALYSIS 
The dose selection safety review will be performed by the DMC when the first 150 patients from 
Stage 1 have completed 1 month of treatment (or have prematurely discontinued). Based on this 
safety review, the DMC will select the venglustat dose for Stage 2 (8 mg or 15 mg). The selected 
dose will be the highest dose determined to be safe and well tolerated. 
An interim analysis for futility will be performed when all patients from Stage 1 have completed 
the first 9 months of treatment and approximately 30% have completed 18 months of treatment 
with TKV available (or have prematurely discontinued). 
Further details are provided in Section 11.5. 
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6.4 
STUDY COMMITTEES 
6.4.1  Data monitoring committee 
A DMC, operating independently from the Sponsor and Clinical Investigators, will be responsible 
for overseeing the safety of patients and the risk/benefit ratio throughout the study. This 
committee is composed of externally-based individuals with expertise in the disease under study, 
biostatistics, and/or clinical research. The primary responsibilities of the DMC are to ensure the 
patients welfare as well as to evaluate and review the safety and other applicable data throughout 
the course of the study by conducting formal regular reviews of unblinded safety data and make 
appropriate recommendations to the Sponsor regarding the conduct of the clinical trial. 
The DMC will review, in an unblinded fashion, the aggregate safety data from Stage 1 to select 
the venglustat dose for Stage 2. It will also supervise the interim futility analysis (Section 6.3). 
The specific responsibilities of the DMC will be described in the DMC charter. 
6.4.2 Steering committee 
The Steering Committee (SC) is composed of field experts and Sponsor-based scientists with 
clinical and methodological expertise. This Committee, led by a Chairperson, selected by the 
Sponsor, will provide advice to the Sponsor regarding scientific issues and operational conduct of 
the study. The SC will also review any amendments and provide input regarding interpretation of 
study results. The members will remain blinded until completion of the study.  
Among its responsibilities, the SC will receive blinded study status reports from the Sponsor, and 
will review the recommendations from the DMC throughout the study. 
Moreover, the SC will also be responsible for the primary publication(s) emanating from the 
study. The Principal Investigators (PI) of the study will be selected by the Sponsor and will be the 
first authors for the primary publication(s). Principal Investigators at the 3 first sites enrolling the 
most patients will also be included as authors for the primary publication, in addition to the other 
SC members.  
Detailed activities and responsibilities of the SC will be provided in the SC charter. 
6.5 
DISCUSSION OF STUDY DESIGN AND CHOICE OF CONTROL GROUPS 
6.5.1 Rationale for selection of dose 
The 8 mg and 15 mg QD doses of venglustat resulted in about 70% and 75% reduction in plasma 
GL-1 from baseline, respectively in the healthy volunteers (repeated dose study TDR12768). This 
is in the similar range of plasma GL-1 reduction where efficacy was demonstrated in the 
nonclinical disease animal model of ADPKD by oral treatment of GCS inhibitors. Therefore, 
8 mg and 15 mg QD doses of venglustat in ADPKD patients are anticipated to translate into 
ADPKD efficacy and have been selected for Stage 1 in this study. Since 26.3% to 33.1% of the 
drug is excreted unchanged in urine, there is a potential for increased exposure in patients with 
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renal impairment. However, the Sponsor does not anticipate that the renal impairment status of 
ADPKD patients in Stage 1 of this study (mild to moderate renal impairment with eGFR 
>45 mL/min/1.73 m2 baseline) will have any potential implications for patient safety, as indicated 
by a PBPK model that predicted a mean venglustat plasma steady state exposure in a moderate RI 
population (GFR 30-60 mL/min/1.73 m2) following 15 mg QD dose, normal CYP abundance and 
age (matching the age of ADPKD patients in the current study) to be within the range of steady 
state exposures observed in Phase 1 (TDR12768 in healthy volunteers) and Phase 2 studies 
(ACT13739 in FD patients). This was further confirmed with results from a clinical study 
conducted to assess the impact of renal impairment on venglustat PK (POP14499), where, 
following a single 15 mg dose, venglustat exposure (AUC) was similar in subjects with mild RI 
but was estimated to be higher in subjects with moderate and severe RI by as much as 1.33-fold 
(90% CI: 1.09 to 1.62) and 1.59-fold (90% CI: 1.15 to 2.20), respectively. To provide 
a conservative estimate of effect of moderate RI on venglustat PK, the upper end of 90% CI 
(1.62-fold) was taken into account at the lower limit of moderate RI (GFR: 30 mL/min). 
Given the current exposure margin from NOAEL in 26-week adult rat toxicology study of 
approximately 3.7-fold relative to the to human steady state exposure following 15 mg dose 
(2420 ng.hr/mL obtained from healthy subjects in study TDR12768 and NOAEL exposure of 
8890 ng.hr/mL in female rats in adult rat 26-week toxicology study), venglustat exposure in 
moderate renal impaired subjects with eGFR up to 30 mL/min following a 15 mg QD dose, is 
anticipated to be below this NOAEL exposures. In addition, venglustat exposure in moderate 
renal impaired subjects with eGFR up to 30 mL/min following a 15 mg QD dose, is also 
anticipated to be below the NOAEL exposure estimate for spermatid degeneration from adult 
mouse precarcinogenicity study (7780 ng.hr/mL). Considering the totality of this information, no 
dose adjustment is warranted in patients with eGFR ≥30 mL/min. 
The patients in Stage 1 will finish 24 months on placebo or 8 mg or 15 mg venglustat. In Stage 2, 
patients will be randomized to placebo or either 8 mg or 15 mg venglustat. The dose of 8 mg or 
15 mg will be selected during unblinded review by the DMC of the aggregated safety data from 
Stage 1. The selected dose will be the highest dose determined to be safe and well tolerated in 
Stage 1 (based on DMC review of safety data for 150 patients who have completed at least 
1 month of treatment). 
If during Stage 1 the 8 mg and 15 mg doses of venglustat have similar safety and tolerability 
profiles, then the 15 mg dose will be selected. This is because based on the human healthy 
volunteer plasma PK/PD in the repeat-dose study TDR12768 and rodent ADPKD efficacy studies, 
better efficacy is anticipated with 15 mg dose due to higher plasma GL-1 reduction as compared 
to the 8 mg dose. Only minimal safety concerns were observed for the 15 mg dose based on the 
present safety data of FD patients who have received the 15 mg dose for up to 24 months. 
6.5.2 Rationale for study design and control groups 
This study is designed to demonstrate the efficacy by slowing the progression of kidney volume 
and concomitantly evaluate the effect on worsening renal function, patient reported outcome 
(PRO) and liver volume in patients with ADPKD. Due to the high variability of eGFR, the 
primary endpoint of Stage 1 is TKV growth rate while the primary endpoint in Stage 2 is the slope 
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of eGFR. Safety, tolerability, PK, and PD effects of venglustat are supported by Phase 1 and 
Phase 2 studies and animal toxicology data in rodents up to 26 weeks and dogs up to 39 weeks. 
In vitro and in vivo genotoxicity studies have been conducted and are negative. Carcinogenicity 
studies have not yet been conducted.  
A prognostic enrichment approach is used to select patients for primary analysis population who 
will be at risk for rapid progression of disease based on those aged between 18 to 50 years, CKD 
Stages 2-3A, and Mayo Imaging Classification of ADPKD Class 1C-E. This enrichment allows 
the detection of treatment benefit on both TKV and GFR in the same population thus 
circumventing the need for performing separate trials in "early" and "late" ADPKD patients. 
Patients with eGFR <45 mL/min/1.73 m2 aged 18 to 55 years old recruited in Stage 2 of the study 
will be not included in primary analysis population but the data from these patients will be 
analyzed separately. 
Patients with CKD Stage 3b (eGFR 30 - 45 mL/min/1.73 m2) aged 18 to 55 years old will be 
recruited in Stage 2 of the study to permit gathering information on venglustat in this severely 
affected patient population. However, this patient population will not be included in the Stage 2 
primary analysis but will be analyzed separately. The rationale for including these patients in the 
study is to obtain further information on venglustat exposure, safety and efficacy in patients with 
lower renal function.  
Based on the mode of action of venglustat the benefit of disease modification is expected to 
decrease whereas the exposures of venglustat increase with declining renal function. For this 
reason, CKD Stage 4 patients (eGFR <30 mL/min/1.73 m2) will not be included into the study. 
The seamless design of this two-stage trial is based on the similarities of the endpoints of the 
2 stages and the identical inclusion/exclusion criteria of the primary analysis population of the 
2 stages. This design ensures faster results of the effect of venglustat on TKV with confirmatory 
results on eGFR so that effective and safe compounds can be provided to the ADPKD patients.  
To achieve balanced distribution of factors influencing the progression of the disease between 
treatment arms, randomization will be stratified based on the Mayo Imaging Classification of 
progression rate (1C, 1D, and 1E).  
The control group will be treated with placebo to allow for an unbiased assessment of treatment 
effects and safety data. Bias will be minimized by randomizing the patients to treatment groups, 
blinding the patients, the Investigators, and the Sponsor to the treatment allocations. Tolvaptan, 
though approved in several regions, is not being used as control due to the following reasons:  
• Tolvaptan is not available in all countries due to lack of regulatory approval or market 
access.  
• Even in regions where tolvaptan is available, poor tolerability and safety has led to low 
levels of uptake of the drug due to patient discontinuation or failure to start therapy.  
• Treatment with tolvaptan is associated with acute diuresis which can lead to substantial 
unblinding resulting in a compromise of the integrity of the trial ie, failure to conduct 
a randomized controlled trial.  
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• Even if a blinded study is attempted with tolvaptan by ignoring the effect of acute diuresis, 
the need for recommending substantially increased water intake to patients in the trial to 
minimize the risk of dehydration in the blinded tolvaptan arm can lead to an erroneous 
attribution of excess diuresis in the venglustat arm leading to a suboptimal assessment of 
treatment benefit. 
A parallel-group, randomized, controlled design was selected because trial participants are 
exposed to a single treatment and assignment to that treatment is based solely on chance. 
This design is free of the limitations of competing designs such as crossover in which there may 
be a carryover effect from one treatment to the second treatment. Although this carryover effect 
can be minimized with a washout period, it is possible that some longer-term effects may persist. 
While the sample size of the parallel group design is larger to account for more variability when 
participants cannot serve as their own control, the above-mentioned limitations of the crossover 
design have led the randomized parallel-group controlled trial design to be the standard for 
therapeutic trials for regulatory approval such as this trial. 
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7 
SELECTION OF PATIENTS 
Note: A patient should not be randomized more than once. One-time rescreening is allowed at the 
Investigator’s medical judgment for any manageable reasons that caused the screening failure and 
the patient is likely to be eligible before the enrollment completion. For patients agreeing to 
participate in the mGFR substudy of the Stage 2 of the EFC15392 study, additional eligibility 
criteria are listed in Appendix L. 
7.1 
INCLUSION CRITERIA 
I 01. Male or female adult with ADPKD with an age at the time the consent is signed: 
a) between 18 and 50 years (inclusive) for patients in Stage 1 
b) between 18 and 50 years (inclusive) for patients in Stage 2 with an eGFR between 
45 and 89.9 mL/min/1.73 m2 during the screening period* 
c) between 18 and 55 years (inclusive) for patients in Stage 2 with an eGFR between 
30 and 44.9 mL/min/1.73 m2 during the screening period* 
Diagnosis of ADPKD in patients with a family history, will be based on unified Pei criteria 
(12). In the absence of a family history, the diagnosis will be based on the presence of 
renal cysts bilaterally, totaling at least 20, in the absence of findings suggestive of other 
cystic renal diseases. 
I 02. Mayo Imaging Classification of ADPKD Class 1C, 1D, or 1E** (3). 
**TKV volume must be confirmed by a central reader prior to Visit 3. 
I 03. Estimated glomerular filtration rate between 45 and 89.9 mL/min/1.73 m2 during the 
screening period* (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] 
equation) for Stage 1.  
Estimated glomerular filtration rate between 30 and 89.9 mL/min/1.73 m2 during the 
screening period* (CKD-EPI equation) for Stage 2. 
*Eligibility will be confirmed by the eGFR value from one of the two first pre-
randomization eGFR measurements (Visit 1 or Visit 2 measurements or Visit 1 and an 
additional measurement performed at the Investigator’s discretion between Visit 1 and 
Visit 2). 
I 04. Stable treatment regimen of antihypertensive therapy for at least 30 days prior to the 
screening visit for hypertensive patient. 
I 05. Able to read, comprehend, and respond to the study questionnaires. 
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I 06. Patient has given voluntary written informed consent before performance of any study 
related procedures not part of standard medical care. 
I 07. Patient does not have access to tolvaptan at the time of study start or tolvaptan is not 
indicated for treatment of patient according to treating physician (patient does not meet 
recommended criteria for treatment, refuses to initiate or does not tolerate treatment with 
tolvaptan). 
I 08. The patient, if female of childbearing potential, must have a negative blood pregnancy test 
(β-human chorionic gonadotropin [β-hCG]) at the screening visit and a negative urine 
pregnancy test at the baseline visit. 
I 09. Female patients of childbearing potential and male patients must agree to practice true 
abstinence in line with their preferred and usual lifestyle or to use double-contraceptive 
methods (including a highly effective method of contraception for female patients of 
childbearing potential) for the entire duration of the study and for at least 6 weeks for 
females and 90 days for males following their last dose of study drug (see contraceptive 
guidance in Appendix A). 
7.2 
EXCLUSION CRITERIA 
Patients who have met all the above inclusion criteria listed in Section 7.1 will be screened for the 
following exclusion criteria which are sorted and numbered in the following subsections:  
7.2.1 Exclusion criteria related to study methodology 
E 01. Systolic BP >160 mmHg* at run-in and baseline visits. 
*mean value of three or five systolic BP measurements (See Section 9.4.5). 
E 02. Administration within 3 months prior to the screening visit of tolvaptan or other Polycystic 
Kidney Disease-modifying agents (somatostatin analogues). 
E 03. The patient, in the opinion of the Investigator, is unable to adhere to the requirements of 
the study or unable to undergo study assessments (eg, has contraindications to pupillary 
dilation or unable to undergo magnetic resonance imaging [MRI] [For example: patient’s 
weight exceeds weight capacity of the MRI, ferromagnetic metal prostheses, aneurysm 
clips, severe claustrophobia, large abdominal/back tattoos, etc]). 
E 04. Current participation in another investigational interventional study or use of 
investigational medicinal product (IMP), within 3 months or 5 half-lives, whichever is 
longer, before randomization. 
E 05. The patient has a positive result of any of the following tests: hepatitis B surface antigen 
(HBsAg), anti-hepatitis C virus (anti-HCV) antibodies, anti-human immunodeficiency 
Virus 1 and 2 antibodies (anti-HIV1 and anti-HIV2 Ab). Patients with a positive 
hepatitis B surface antibody (HBsAb) test are eligible if other criteria are met (ie, negative 
tests for: HBsAg, hepatitis B core antibody [HBcAb]). 
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Patients immune due to natural infection (positive HBsAb, negative HBsAg, and positive 
HBcAb) are eligible if they have a negative HBV DNA test.  
E 06. A history of drug and/or alcohol abuse within the past year prior to the screening visit. A 
history of alcohol dependence within the 5 years prior to the screening visit. 
E 07. Any patient who is the Investigator or any Subinvestigator, research assistant, pharmacist, 
study coordinator, other staff, or relative thereof directly involved in the conduct of the 
study. 
E 08. The patient is scheduled for in-patient hospitalization including elective surgery, during the 
study. 
E 09. The patient has a clinically significant, uncontrolled medical condition that, in the opinion 
of the investigator, would put the safety of the patient at risk through participation, or 
which would affect the efficacy or safety analysis if the condition exacerbated during the 
study, or that may significantly interfere with study compliance, including all prescribed 
evaluations and follow-up activities. The list of medical conditions that should be taken 
into account includes, but is not limited to the following: 
congestive heart failure New York Heart Association (NYHA) Grade III/IV 
clinically significant cardiac arrhythmia 
severe unstable angina pectoris within 6 months of Visit 1 
hypertensive emergency within 6 months of 
Visit 1a  
stroke or transient ischemic attack within 3 months of Visit 1 
current malignancyb 
myocardial infarction within 3 months of Visit 1 
tuberculosis (current or untreatedc) 
Cushing's disease 
uncontrolled diabetes mellitus 
Addison's disease 
uncontrolled thyroid disorder 
a Systolic blood pressure >180 mm Hg or diastolic blood pressure >120 mm Hg, and acute target organ damage. (Aronow WS. Treatment of 
hypertensive emergencies. Ann Transl Med 2017;5:S5).  
b A current malignancy or previous history of cancer in remission for <5 years prior to Visit 1 (localized basal cell or squamous cell carcinoma 
of the skin that has been resected is not exclusionary). 
c Patients with a history of tuberculosis who have received an approved prophylactic treatment regimen or an approved active treatment 
regimen and who have had no evidence of active disease for a minimum of 2 years may be enrolled (American Thoracic Society/Centers for 
Disease Control and Prevention/Infectious Diseases Society of America: Controlling Tuberculosis in the United States. Am J Respir Crit Care 
Med. 2005;172:1169-27.) 
E 10. Any country-related specific regulation that would prevent the patient from entering the 
study. 
For patients in Germany:  
- 
The patient concerned has been committed to an institution by virtue of an order issued 
either by the judicial or the administrative authorities, 
- 
The patient is an employee of the sponsor or investigator or otherwise dependent on 
them. 
E 11. The patients did not adhere to treatment (<70% compliance rate) in the run-in. 
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7.2.2 Exclusion criteria related to mandatory background therapies  
E 12. The patient has, according to World Health Organization (WHO) Grading (13), a cortical 
cataract ≥1-quarter of the lens circumference (Grade cortical cataract-2 [COR-2]) or 
a posterior subcapsular cataract ≥2 mm (Grade posterior subcapsular cataract-2 [PSC-2]). 
Patients with nuclear cataracts will not be excluded. 
E 13. The patient is currently receiving potentially cataractogenic medications, including 
a chronic regimen (more frequently than every 2 weeks) of any route of corticosteroids 
(including medium and high potency topical steroids), or any medication that may cause 
cataract, according to the Prescribing Information. 
E 14. The patient has received strong or moderate inducers or inhibitors of CYP3A4 
(See Appendix B) within 14 days or 5 half-lives, whichever is longer, prior to 
randomization. This also includes the consumption of grapefruit, grapefruit juice, or 
grapefruit containing products within 72 hours of starting venglustat administration. 
7.2.3 Exclusion criteria related to the current knowledge of venglustat investigational 
medicinal product 
E 15. The patient is pregnant, or lactating. 
E 16. Liver enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST]) or 
total bilirubin >2 times the upper limit of normal (ULN) unless the patient has the 
diagnosis of Gilbert syndrome. Patients with the Gilbert syndrome should have no 
additional symptoms or signs which suggest hepatobiliary disease and serum total bilirubin 
level no more than 3 mg/dl (51 μmol/L) with conjugated bilirubin less than 20% of the 
total bilirubin fraction. 
E 17. Presence of severe depression as measured by BDI-II >28 and/or a history of a major 
affective disorder within 1 year of the screening visit. 
E 18. Known hypersensitivity to venglustat or any component of the excipients. 
If the patient is a screen failure, all data obtained at screening including laboratory results of 
screening tests must be available in the patient’s medical records. For screening failures, the 
following data obtained during screening will be transferred to the electronic case report form 
(eCRF) and entered into the database: informed consent date, visit date, patient’s demographic 
data, inclusion and exclusion criteria, AE data (if available), and reason for failure. 
Note: Rescreening is possible in this study in cases where the original screening failure was due to 
reasons expected to change at rescreening and based upon the Investigator’s clinical judgment. 
The patient may be rescreened once while the screening period is still open to check whether or 
not they then meet all of the inclusion and none of the exclusion criteria.  
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Patients who were rescreened in Stage 1 of the study under protocol versions preceding 
amendment 04 and failed screening because of eGFR <45 mL/min/1.73 m2, can be screened in 
Stage 2. 
A patient cannot be randomized more than once in the study. Patients who fail screening may be 
rescreened once during the recruitment period; a different patient identification will be issued. 
There is no requirement for a waiting period between the screen-failure date and the rescreening 
date. The interactive response technology (IRT) report will flag rescreened patients. Patients that 
are rescreened must sign a new consent form and all Visit 1 procedures must be repeated except of 
certain assessments when for rescreened patients the Investigator may use the initial screening 
visit results: 
• chemistry, hematology, and urinalysis (within 2 weeks of the initial screening visit), 
• MRI (obtained within 1 months prior to randomization), 
• neurological and ophthalmic exams (obtained within 3 months prior to randomization). 
There is no need to repeat collection of already collected at initial screening biomarkers. 
To have adequate representation of patients across eGFR spectrum a minimum of 20% of patients 
will be enrolled within each of the following categories: 
• Patients with eGFR at screening from 45.0 to 59.9 mL/min/1.73 m2. 
• Patients with eGFR at screening from 60.0 to 74.9 mL/min/1.73 m2. 
• Patients with eGFR at screening from 75.0 to 89.9 mL/min/1.73 m2. 
In case one of the above categories is over-represented in the study, enrollment of additional 
patients in this category may be stopped in order to achieve good representativeness of the study 
population. 
7.2.4 Criteria for temporarily delaying of randomization or administration of study 
treatment  
During a regional or national emergency declared by a governmental agency that results in travel 
restrictions, confinement, or restricted site access, if the site is unable to adequately follow 
protocol mandated procedures, contingency measures proposed in Appendix O should be 
considered for enrollment, randomization, or administration of study treatment. 
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8 
STUDY TREATMENTS 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) 
8.1.1 Pharmaceutical form 
Venglustat or matching placebo will be supplied for oral administration, as opaque hard gelatin 
capsules: 
• Venglustat 4 mg or 15 mg (calculated with reference to the active moiety) or, 
• Placebo matching venglustat. 
Venglustat and matching placebo will be packaged in blister packs. 
8.1.2 Dose of drug per administration 
In Stage 1, during the run-in period the patient will receive placebo matching venglustat 
(2 capsules) once daily for 2 weeks. 
During the double-blind core treatment period, the patient will receive once daily doses of 
venglustat or matching placebo for 24 months:  
• Venglustat 8 mg (2 capsules of venglustat 4 mg). 
• Venglustat 15 mg (1 capsule of venglustat 15 mg, 1 capsule of placebo). 
• Placebo matching venglustat (2 capsules of placebo). 
In Stage 2, during the run-in period the patient will receive placebo matching venglustat once 
daily for 2 weeks (1 or 2 capsules depending on the dose of venglustat selected for Stage 2 during 
unblinded review by the DMC of the aggregated safety data from Stage 1).  
The dose of venglustat determined in Stage 1 or placebo will be administered once per day for 
24 months: 
• Venglustat 8 mg or 15 mg. 
• Placebo matching venglustat. 
Venglustat or matching placebo is to be taken daily, around the same time each day throughout 
the study and can be administered without restriction to food, except for the consumption of 
grapefruit, grapefruit juice, and/or grapefruit containing products within 72 hours of starting 
venglustat administration. At visits when a post-dose PK sample is to be collected, patients should 
take the study drug on site. 
Between the protocol-scheduled on-site visits, interim visits may be required for IMP dispensing. 
As an alternative to these visits, venglustat may be supplied from the site to the patient via 
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a Sponsor-approved courier company where allowed by local regulations and approved by the 
patient. This includes the Direct-to-Patient supply of venglustat during national or regional 
emergency declared by a governmental agency that results in travel restrictions, confinement, or 
restricted site access (See Appendix O). 
Both regular on-site IMP dispensation and Direct-to-Patient supply of IMP are not contingent on 
availability of contemporaneous laboratory results or other study specific assessments. 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) 
Not applicable. 
8.3 
BLINDING PROCEDURES 
8.3.1 Methods of blinding 
Venglustat and placebo to match venglustat will be indistinguishable from one another and be 
provided in identically matched packaging which includes labeling to protect the blind. 
In addition to maintain the blind, the same number of capsules will be taken daily by the patient 
for each dosing group in Stage 1 and Stage 2. 
In Stage 1, patients on 8 mg dosing group will receive 2 capsules of 4 mg. Patients on 15 mg 
dosing group will receive 1 capsule of 15 mg, plus 1 placebo capsule. Patients on placebo dosing 
group will receive 2 capsules of placebo. Likewise, in Stage 2, patients on venglustat or on 
placebo will receive the same number of capsules. 
In accordance with the double-blind design, study patients, Investigators and study site personnel 
will remain blinded to study treatment and will not have access to the randomization list 
(treatment codes) except under circumstances described in Section 8.3.2. At the assay institutions 
charged for PK measurements, only samples collected from patients on active drug will be 
analyzed leading to unblinding of responsible bioanalysts prior to data base lock. Bioanalysts are 
excluded from the clinical study operation’s team and a process will be set up to prevent any 
potential unblinding ie, no unblinded data will be shared with the clinical study operational team 
prior to database lock and unblinding of the study. The Investigators and the Sponsor will also be 
blinded to PK and biomarkers data. A Sanofi Clinical Supplies representative will remain 
unblinded throughout the study with respect to the study medication kits in order to provide the 
appropriate study drug to patients; however, sites and study teams must be blinded to PK and 
biomarker data throughout the study.  
Refer to Section 10.5 for suspected unexpected serious adverse drug reaction unblinding by the 
Sponsor. 
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8.3.2 Randomization code breaking during the study 
In case of an AE, the code must only be broken in circumstances when knowledge of the IMP is 
required for treating the patient, or when required by local regulatory authorities. If possible, 
contact should be initiated with the monitoring team before breaking the code. 
In case of an emergency, the code breaking can be performed at any time by the Investigator by 
using the appropriate module of the IRT and/or by contacting any phone number or system 
provided by the Sponsor for that purpose.  
In case of Suspected Unexpected Serious Adverse Reaction (SUSAR), the Pharmacovigilance 
department of the Sponsor will contact the IRT to reveal the IMP assignment for regulatory 
reporting requirements for the particular case. The IRT unblinding procedures should be followed 
as outlined in the IRT manual. 
If the blind is broken by the Investigator or designee, the date, time of day, and reason for code 
breaking must be documented.  
If the emergency unblinding transaction is performed by the Investigator (ie, at the site level), 
then the patient will be withdrawn from treatment. The withdrawal will be discussed on a 
case-by-case basis. However, if the emergency unblinding transaction is performed by the 
Sponsor (ie, at the study level), then the patient will not be withdrawn from treatment.  
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP  
A randomized treatment kit number list will be generated centrally by the Sponsor. The IMP 
(venglustat or placebo) will be packaged in accordance with this list.  
The Sanofi Clinical Supplies team will provide the randomized list of treatment kit numbers and 
the Study Biostatistician will provide the randomization scheme to the centralized treatment 
allocation system provider. The IRT (centralized treatment allocation system) will generate the 
patient randomization list and allocates the randomization number and the corresponding 
treatment kit(s) to the patients accordingly.  
Patients who comply with all inclusion/exclusion criteria will be assigned before the IMP 
administration: 
• A patient number according to the chronological order of inclusion. 
• A randomization number in a preplanned order following the randomization list. 
Randomization will be performed at the baseline visit (Month 0) by the centralized randomization 
procedure of the IRT. 
In Stage 1, patients will be randomized to receive venglustat 8 mg or 15 mg or placebo during the 
double-blind core treatment period using a ratio 1:1:1. 
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In Stage 2, patients will be randomized with a 1:1 ratio into placebo, or the selected dose of 
venglustat. 
The treatment kit numbers will be allocated by the centralized treatment allocation system on 
randomization visit (baseline visit/Month 0), Month 1, Month 3, and every 3 months up to 
Month 21 in Stage 1 and Stage 2. 
A randomized patient is defined as a patient who is registered and assigned with a treatment kit 
number from the centralized treatment allocation system, as documented from its log file. 
A patient cannot be randomized more than once in the study.  
The details of the centralized randomization procedure and IRT are provided in a separate manual. 
8.5 
INVESTIGATIONAL MEDICINAL PRODUCT PACKAGING AND LABELING 
Venglustat and matching placebo are packaged and labeled to protect the blind in Stage 1 and 
Stage 2.  
Packaging is in accordance with the administration schedule. The content of the labeling is in 
accordance with GMP requirements and the local regulatory specifications and requirements. 
8.6 
STORAGE CONDITIONS AND SHELF LIFE 
Investigators or other authorized persons (eg, pharmacists) are responsible for storing the IMP in a 
secure and safe place in accordance with local regulations, labeling specifications, policies, and 
procedures. The IMP should be stored between +2°C and +30°C (36°F and 86°F). 
Control of IMP storage conditions, especially control of temperature (eg, refrigerated storage) and 
information on in-use stability and instructions for handling the Sanofi compound must be 
managed according to the rules provided by the Sponsor. 
Batch and expiry date management will be assisted with IRT.  
NOTE: Exceptionally, after discussion between site and Sponsor some IMP kits could be 
supplied, when feasible, directly from site to patient via a Sponsor-approved courier company. 
This process would be implemented at selected sites/countries (where certain conditions would be 
fulfilled, and where permitted locally) and for patients who would consent to such a process. 
This direct-to-patient process will be described in detail in a separate document and would be 
implemented after appropriate training of monitoring teams and investigational sites.  
8.7 
RESPONSIBILITIES 
The Investigator, the site pharmacist, or other personnel allowed to store and dispense the IMP 
will be responsible for ensuring that the IMP used in the clinical trial is securely maintained as 
specified by the Sponsor and in accordance with applicable regulatory requirements. 
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All IMP will be dispensed in accordance with the Investigator's prescription and it is the 
Investigator's responsibility to ensure that an accurate record of IMP issued and returned is 
maintained. 
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) must be promptly notified to the Sponsor. 
Some deficiencies may be recorded through a complaint procedure (see Section 10.4.6). 
A potential defect in the quality of IMP 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 the IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party (except for DTP 
shipment, for which a courier company has been approved by the Sponsor), allow the IMP to be 
used other than as directed by this clinical trial protocol, or dispose of IMP in any other manner. 
8.7.1 Treatment accountability and compliance 
The Investigator or designee will keep an accurate record of all IMP that is received, dispensed, 
and returned on a per patient basis using an IMP accountability log. 
Measures taken to ensure and document treatment compliance and IMP accountability include: 
• The Investigator or designee will obtain via IRT the treatment kit number(s) and he/she 
will dispense the treatment kit(s) to the patient. 
• Accurate recording of treatment kit number or packaging number as required on 
appropriate eCRF page for accounting purposes; 
• All medication treatment kits (whether empty or unused) are returned by the patient at 
each visit. 
• The Investigator or designee tracks treatment accountability/compliance by diary 
(by counting missing doses reported by the patient), and by counting the number of used 
treatment kits and fills in the appropriate page of the patient treatment log. 
• The monitor in charge of the study then checks the data entered on the IMP administration 
page by comparing them with the IMP that has been retrieved and the patient treatment log 
form. 
A patient diary will be issued to the patient at run-in visit with instructions to record missing 
doses. A brief explanation should be provided if a dose is missed. The patient should bring their 
diary and any remaining capsules to each clinic visit.  
The site staff will collect and review the patient diary during each clinic visit and record 
excursions from treatment into the eCRF. The patient diary will be retrieved when the patient 
finishes their participation in the study. 
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8.7.2 Return and/or destruction of treatments 
Whenever possible all partially used, used, or unused investigational product will be destroyed 
on-site according to the standard practices and capabilities of the site after reconciliation 
verification by the monitor. 
A detailed treatment log of the destroyed investigational product will be established with the 
Investigator (or the pharmacist) and countersigned by the Investigator and the monitoring team. 
The Investigator will not destroy any investigational product unless the Sponsor provides written 
authorization. When destruction at site cannot be performed, all IMPs will be retrieved by the 
Sponsor or designee for destructions. 
8.8 
CONCOMITANT MEDICATION 
A concomitant medication is any treatment received by the patient concomitantly to the IMP. 
Concomitant medications should be kept to a minimum during the study. Furthermore, changes in 
concomitant medications should be kept to a minimum and only occur if considered to be 
absolutely necessary in the medical judgment of the Investigator. However, if these are considered 
necessary for the patient's welfare and are unlikely to interfere with the IMP, they may be given as 
rescue medication at the discretion of the Investigator and must be recorded in the eCRF. 
Concomitant medications, including OTC, dietary supplements (eg, herbal remedies) or 
prescriptions, are permitted during the study period, except for tolvaptan use which is forbidden 
throughout the study and the medications listed in the following section. 
8.8.1 List of forbidden concomitant medication 
During the study treatment periods, the following medications are prohibited: 
• Use of investigational medication in any other clinical study. 
• Chronic use of strong or moderate CYP3A inducers or inhibitors.  
• Tolvaptan. 
• Polycystic Kidney Disease-modifying agents (eg, somatostatin analogues). 
• Alpha-adrenergic receptor agonist glaucoma medications because they can worsen the 
vision of patients with cataracts. 
Venglustat interruptions are permitted for those patients who require temporary use (≤2 weeks) of 
strong or moderate inhibitors or inducers of CYP3A (per FDA classification) 
(http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio
nsLabeling) for the treatment of acute illness. Such medications must not be used on more than 
a total of 2 occasions (ie, up to 2 weeks per occasion for a maximum of 30 days of 
venglustat interruptions) during the study treatment periods. 
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Given nonclinical lens findings (see IB), a chronic regimen (ie, more frequent than once every 
2 weeks) of the following medications is forbidden during the clinical trial: 
• Corticosteroids: 
- 
May be used on a restricted basis in patients who require temporary use (≤1 week) for 
the treatment of any acute condition for which no appropriate substitute is found. Such 
medications must not be used on more than a total of 4 occasions (ie, up to 1 week per 
occasion) during the study treatment periods. 
- 
Patients with chronic skin diseases can use low and least potent (Class VI to VII) 
topical steroids. Application to eyelids and periorbital region should be avoided. 
• Psoralens used in dermatology with ultraviolet light therapy. 
• Typical antipsychotics. 
• Amiodarone. 
• Allopurinol. 
The Investigator should consider substituting medications listed in the previous paragraphs and 
other medications that have cataractogenic potential according to their Prescribing Information for 
noncataractogenic treatments, as appropriate.  
Atypical antipsychotics are allowed. 
Other medications which are unlikely to interfere with the PK or PD of the IMP or confound 
interpretation of the study endpoints are allowed as needed and discussed with the Investigator. 
However, doses of chronically administered medicines should be kept fixed during the trial if at 
all possible. 
8.8.2 COVID-19 vaccine 
Immunotoxicology-related parameters (e.g., immunophenotyping, total immunoglobulin levels) 
were not evaluated in the repeat-dose toxicology studies.  Based on the available preclinical data 
(venglustat-related hematological and histopathological changes to immune system tissues/ 
organs) and data from clinical studies, it is unlikely that venglustat has immunomodulatory 
properties and would have an impact on the immune system. 
The coronavirus disease 2019 (COVID-19) vaccines that have been authorized for use are 
considered as a concomitant medication with no interaction that requires advice on timing or other 
aspects of the vaccination. 
If the COVID 19 vaccine is authorized, available, and recommended by the local regulatory 
authority and/or health authority for patients like those in this study, the vaccine can be 
administered during the study and should be administered according to the label or 
recommendations of the local regulatory authority and/or health authority. 
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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT 
Scales and questionnaires should be completed before dosing and before clinical procedures are 
performed by the study Investigator or other healthcare provider(s). Moreover, if possible, the 
patient completed instruments should be done prior to clinical interaction in order to try to 
minimize any influence this may have on the patient (either positive or negative). 
The scales/questionnaires will be administered by individuals who will be blinded to study 
treatment and who are trained in the administration of standardized questionnaires. 
The scales/questionnaires are provided in the appendices. Specific instructions for the 
administration of each scale/questionnaire are provided on each of the scales/questionnaires. 
9.1 
PRIMARY ENDPOINTS 
9.1.1 Stage 1 
• Annualized rate of change in TKV based on MRI from baseline to 18 months. 
9.1.2 Stage 2 
• Annualized rate of change in eGFR (CKD-EPI equation) from baseline to 24 months.  
9.2 
SECONDARY ENDPOINTS 
9.2.1 Stage 1 
• Annualized rate of change in eGFR (CKD-EPI equation) from baseline to 18 months. 
• Change in Pain (BPI - Item 3) from baseline to 18 months, from the daily symptom diary. 
• Change in fatigue (BFI - Item 3) from baseline to 18 months, from the daily symptom 
diary. 
• Plasma venglustat concentrations. 
9.2.2 Stage 2 
• Annualized rate of change in TKV based on MRI from baseline to 18 months. 
• Change in Pain (BPI - Item 3) from baseline to 24 months, from the daily symptom diary. 
• Change in fatigue (BFI - Item 3) from baseline to 24 months, from the daily symptom 
diary. 
• Plasma venglustat concentrations. 
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9.2.3 Safety/tolerability endpoints 
• Safety in terms of TEAEs/AEs/SAEs, laboratory parameters, vital signs, 
electrocardiogram and findings from physical examination will be assessed through the 
study and will be reported in the eCRF. Adverse event data will be collected throughout 
the study. Treatment-emergent AEs are defined as AEs that develop, worsen (according to 
the Investigator opinion), or become serious during the treatment period. The treatment 
period is defined as the time from first dose of study treatment up to 30 days after last dose 
of study treatment. Full details of safety reporting and AE monitoring procedures are 
provided in Section 10.1. 
• Change in score of BDI-II during the treatment-emergent period.  
• Change in the lens clarity by ophthalmological examination during the treatment-emergent 
period. 
9.3 
EXPLORATORY ENDPOINTS 
9.3.1 Stage 2 only 
• Annualized rate of change in mGFR from baseline to 24 months (substudy). 
• Annualized rate of change in eGFR (CKD-EPI equation) from baseline to 24 months in 
patients with a screening eGFR between 30 and 44.9 mL/min/1.73 m2. 
9.3.2 Stages 1 and 2 
• Annualized rate of change in total liver volume based on MRI (in patients with htTLV 
>2 L/m) from baseline to 18 months, Change in: 
- 
Systolic BP during the treatment-emergent period, 
- 
Diastolic BP during the treatment-emergent period, 
- 
Pain (BPI), fatigue (BFI), and health status (EQ-5D-5L) from baseline to 18 months in 
Stage 1 and 24 months in Stage 2, 
- 
Nocturia from baseline to 18 months in Stage 1 and 24 months in Stage 2, based on 
patient reported diary, 
- 
Urine osmolality from baseline to 18 months in Stage 1 and 24 months in Stage 2 (in 
patients not on diuretic), 
- 
Type, frequency, and dosage of analgesic/OTC pain medication administration from 
baseline to 18 months in Stage 1 and 24 months in Stage 2, 
- 
Biomarkers associated with ADPKD (eg, FGF23 and ADMA) from baseline to 
18 months in Stage 1 and 24 months in Stage 2, 
- 
Glucosylceramide (GL-1) and GM3 from baseline to 18 months in Stage 1 and 
24 months in Stage 2.  
• Rate of all-cause hospitalization. 
• Time to confirmed 30% reduction in eGFR. 
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• Time to confirmed 40% reduction in eGFR. 
9.4 
ASSESSMENT METHODS 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix O. 
9.4.1 Magnetic resonance imaging 
• Magnetic resonance imaging will be performed at certified facilities and liver and kidney 
volumes calculated according to a separate protocol. Images will be reviewed/assessed by 
a central reader.  
Magnetic resonance imaging will be performed at the following time points: 
• Stage 1: During the screening period (at Visit 1 or Visit 2) and at Months 1, 9, and 18. 
• Stage 2: During the screening period (at Visit 1 or Visit 2) and at Month 18. 
9.4.2 Estimated glomerular filtration rate 
Estimated glomerular filtration rate will be calculated from the creatinine result from the general 
chemistry laboratory assessments according to the study flow charts (Section 1.3 and Section 1.4). 
The CKD-EPI equation will be used: 
eGFR = 141 × min (SCr/κ, 1)α x max (SCr/κ, 1)-1.209 x 0.993Age x 1.018 (if female) x 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. 
• Min indicates the minimum of SCr/κ or 1, and 
• Max indicates the maximum of SCr/κ or 1. 
• For calculation of eGFR in Asian population of patients (except Japanese patients), the 
Asian-modified CKD-EPI (aCKD-EPI) equation will be used (14): 
Female and SCr ≤0.7: 151 × (SCr / 0.7)−0 328 × (0.993)age 
Female and SCr >0.7: 151 × (SCr / 0.7)−1.210 × (0.993)age 
Male and SCr ≤0.9: 149 × (SCr / 0.9)−0.412 × (0.993)age 
Male and SCr >0.9: 149 × (SCr / 0.9)−1.210 × (0.993)age 
• For calculation of eGFR in Japanese patients, CKD-EPI Study equation multiplied by a 
Japanese coefficient of 0.813 will be used (15). 
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9.4.3 Urine osmolality 
Urine will be analyzed for urine osmolality during the blinded treatment period (Months 0, 1, 3, 6, 
9, 12, 15, 18, 21, and 24) and at the final study visit (Month 25). 
Procedure for the urine (spot) collection: 
1. Patient will fast after 10 pm (Day -3 pm). 
2. Sample before the sleep will be discarded (Day -3 pm). 
3. First morning void will be discarded (Day -2 am). 
4. The second urine void shall be collected as first spot (Day -2 am). 
5. First morning void will be discarded (Day -1 am). 
6. Collection of 24-hour urine (whole day) - before visits that include 24-hour urine sample 
collection (Visits 3, 4, 6, 8, 10 and 12). 
7. Patient will fast after 10 PM (Day -1 am). 
8. First morning void will be included in 24-hour collection (day of the visit) - for visits that 
include 24-hour urine sample collection (Visits 3, 4, 6, 8, 10 and 12). 
9. The second urine void shall be collected as second spot (day of the visit). 
10. The third urine spot sample will be collected from 24-hour urine sample at site (Visits 3, 4, 
6, 8, 10 and 12) or from urine sample provided by patient for urinalysis during the visit 
(Visits 5, 7, 9, 11 and 13). 
9.4.4 Adverse events 
Refer to Section 10.4 to Section 10.7 for details. 
The rate of all-cause hospitalization will be assessed as exploratory endpoints. 
9.4.5 Vital signs 
Vital signs including respiratory rate, heart rate (in bpm), blood pressure (systolic/diastolic in 
mmHg), and temperature (in Celsius; °C) will be recorded at every visit during the screening and 
double-blind core treatment periods and at the final visit.  
Heart rate, SBP and DBP will be recorded after 10 minutes in the sitting position. The arm with 
the higher pressure at the initial screening visit should be used for all subsequent BP 
measurements (16). Blood pressure will be measured under standardized conditions using the 
same method for a given patient. It will be determined at each study visit using a well calibrated 
apparatus.  
For all seated BP measurements, 3 separate measurements should be taken with at least 1 minute 
between readings, following at least 10-minute rest period and prior to phlebotomy.  
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After sitting quietly for at least 10 minutes with the arm resting at heart level, three readings will 
be obtained at least 1 minute apart. If there is a difference of more than 10 mm Hg (systolic) 
between the second and third readings in one sitting, a fourth and fifth reading will be recorded 
for that sitting. 
Body temperature (auricular or oral body temperature [°C]) will be collected using the same 
method for a given patient. Any hyperthermia should be evaluated by Investigator and if it meets 
criteria for AE reporting (see Section 10.4.2), it should be recorded as an AE and the Investigator 
should perform all investigations necessary to rule out infection. 
If a change from baseline is noted that meets the definition of an AE (see Section 10.4.1), the AE 
should be documented on the eCRF. 
Changes from baseline in SBP and DBP will also be assessed as other endpoints. 
9.4.6 Physical examination 
Whenever possible, the same physician or appropriately trained member of the site study team (in 
countries/states which permit nurse practitioners or physician assistants to perform physical 
examinations under the supervision of a physician) should perform the physical examination at all 
study visits. The findings of each examination will be recorded.  
A complete physical examination will include a thorough review of all body systems to collect 
physical observations/measurements. 
A mental status evaluation will be performed as a part of the complete physical examination and 
should include a Mini Mental State Examination (MMSE) or an equivalent local standard method 
for assessment of the cognitive state of a patient, provided the method covers all the areas 
assessed by MMSE. 
A full standard basic neurological examination will be performed as a part of the complete 
physical examination. Results will be documented in the eCRF pages dedicated to neurological 
examination. For details, please refer to the Study Reference Manual. 
The Investigator will evaluate and access clinical findings as normal, abnormal but not clinically 
significant, or abnormal and clinically significant. 
Complete physical examination will be performed at screening, Months 18 and 24. At screening, 
height will be measured without shoes and body weight will be measured without shoes or heavy 
clothing (see Section 1.3 and Section 1.4). 
Abbreviated physical examinations will focus on areas important for assessment of AEs if 
necessary. 
Abbreviated physical examinations will be performed at the run-in visit, Months 0, 1, 3, 6, 9, 12, 
15, 21, and 25 (see Section 1.3 and Section 1.4). 
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9.4.7 Laboratory safety variables 
All laboratory data listed in this section will be measured at a central laboratory. The laboratory 
data will be collected at designated visits as shown in Section 1.3 and Section 1.4. The clinical 
laboratory data consist of blood analysis (including hematology, clinical chemistry, and 
urinalysis). Clinical laboratory values will be analyzed after conversion into standard international 
units. International units will be used in all listings and tables. 
The following laboratory safety variables will be analyzed: 
• Hematology: red blood cell count, hematocrit, hemoglobin, white blood cell count with 
differential count (neutrophils, eosinophils, basophils, monocytes, and lymphocytes), 
platelets, prothrombin time (PT), partial thromboplastin time (PTT), and international 
normalized ratio (INR).  
• Chemistry:  
- 
Plasma/serum electrolytes: sodium, potassium, chloride, calcium, bicarbonate, 
- 
Liver function: ALT, AST, gamma-glutamyl transferase (GGT), alkaline phosphatase 
(ALP), total and conjugated bilirubin, 
- 
Renal function: urea, serum creatinine, serum cystatin C, 
- 
Metabolism: glucose, albumin, total proteins. 
• Urinalysis and microscopy.  
• At screening, serum β-HCG test for women of childbearing potential (WOCBP). 
9.4.8 Electrocardiogram variables 
Heart rate, ECG recordings, including time from ECG Q wave to the end of the S wave 
corresponding to ventricular depolarization (QRS interval), the time from the onset of the P wave 
to the start of the QRS complex (PR interval), QT interval, ECG ST-segment deviation 
(ST deviation), T wave morphology, and U wave presence or absence will be determined per local 
site procedure using automated and manual readings of all ECGs. All ECG recordings will be 
centrally read by independent experts. Refer to central ECG reading manual for more details.  
Any clinically significant abnormality (eg, corrected QT or QTc >450 msec in males/>470 msec 
in females) observed at the run-in visit (Day -15 to Day -1) upon Investigator review will be 
immediately rechecked for confirmation before making a determination regarding patient 
exclusion from the study. Additional ECGs may be performed if deemed clinically necessary by 
the Investigator (eg, diagnosis of AE) and will be documented in the eCRF. 
A 12-lead ECG will be performed prior to randomization (at Visit 2), at Month 6 and at Month 24. 
Electrocardiogram recordings should be performed before blood samplings. 
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9.4.9 Beck Depression Inventory, second edition  
Depression will be monitored during the study by using the BDI-II according to the study flow 
chart (see Section 1.3 and Section 1.4 and Appendix D) Beck Depression Inventory-II is a 
21-question, multiple choice, self-report inventory. It is composed of items relating to symptoms 
of depression such as hopelessness and irritability, cognitions such as guilt or feelings of being 
punished, as well as physical symptoms such as fatigue, weight loss, and disinterest in sex. 
The wording of the BDI-II is clear and concise. The test contains 21 items, most of which assess 
depressive symptoms on a Likert scale of 0-3. The two exceptions to this are Questions 16 and 18. 
Question 16 addresses changes in sleeping pattern, while question 18 addresses changes in 
appetite. Patients will be asked to report their own feelings over the past 2 weeks instead of 
1 week, as in the BDI and BDI-IA. The reason for this is to be consistent with the Diagnostic and 
Statistical Manual of Mental Disorders, 4th Edition criteria for depression. There were also 2 items 
added to indicate any directional changes in eating and sleeping patterns. Finally, all forms of the 
inventory are written at the 5th grade reading level. 
Clinical interpretation of scores is accomplished through criterion-referenced procedures utilizing 
the following interpretive ranges: total BDI-II scores of 0 to 13 indicate minimal depression, 
scores of 14 to 19 indicate mild depression, scores of 20 to 28 indicate moderate depression, and 
scores of 29 to 63 indicate severe depression.  
If a patient has a score of ≥20, the patient must be referred to his or her health care professional 
for psychiatric evaluation. If the patient has any score but picks out statement 2 or 3 for 
Question 9, the local suicide assessment and management protocol must be followed and patient 
must be supervised until appropriate mental health personnel is available. This will be captured as 
an AE. The patient may continue on the study, but this is dependent on the outcome of psychiatric 
evaluation and judgment of the PI.  
9.4.10 Ophthalmological examination 
The effect of venglustat on the lens will be closely monitored throughout the study. The 
ophthalmological examination will include the measurement of visual acuity with current 
correction (or without correction as applicable), best corrected distance and near visual acuity 
after correction for refractive errors using the Snellen chart, and slit-lamp examination including 
examination of the cornea, lens, and retina after pupil dilation. Details of the ophthalmological 
examination are described in the study reference manual. When a cataract is detected, it must be 
graded according to the WHO simplified cataract grading system. If a new or worsening lens 
abnormality is found, documentation of finding with lens photography using standard local 
photographic methods is recommended. For opacities present at baseline/previous visit, changes 
in WHO Grade ≥1 for nuclear, cortical, or posterior subcapsular opacification compared with 
baseline or previous assessment will be considered as a worsening. 
In countries where the Latin alphabet is not used, the Snellen chart could be substituted with the 
Tumbling E distance chart based on the Snellen fraction. 
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An ophthalmological examination with pupil dilation will be performed prior to randomization 
(Visit 2), at Month 6 (Visit 6), Month 12 (Visit 8), Month 18 (Visit 10), and at Month 24 
(Visit 12) (or upon withdrawal or discontinuation) of the blinded treatment period. 
Prior to randomization (Visit 2), at Month 12 (Visit 8), Month 18 (Visit 10), and Month 24 
(Visit 12) in Stage 1, and prior to randomization (Visit 2), at Month 12 (Visit 8), and Month 24 
(Visit 12) in Stage 2, ophthalmological examinations will also include measurement of the corneal 
thickness (or endothelial cell density) and measurement of intraocular pressure. 
If at any time during study participation a patient experiences a decline of ≥2 lines in best 
corrected visual acuity (BCVA) compared with that at baseline or previous assessment, a 
slit-lamp examination with pupil dilation should be performed. Observed lens opacities must be 
graded with the WHO simplified cataract grading system. A slit-lamp examination with pupil 
dilation must be performed again in 3 months. If no new cataract is seen during this examination, 
a normal schedule of ophthalmological examinations with pupil dilation can be resumed. 
If patient had change of WHO Grade ≥1 in any of the 3 features (nuclear, cortical, and 
posterior subcapsular opacification) of the lens, the next scheduled ophthalmological 
examination (in 3 months) in this patient must include pupil dilation and evaluation of observed 
cataract(s) graded with the WHO simplified cataract grading system. If no new change of WHO 
Grade ≥1 is seen during this examination, a normal schedule of ophthalmological examinations 
with pupil dilation can be resumed. 
Pupil dilation and full ophthalmological examination can be performed at any time if deemed 
medically necessary; observed lens opacities must be graded with the WHO simplified cataract 
grading system. 
The examination should be performed by the same ophthalmologist (optometrist if allowed 
according to local regulations) throughout the study, if possible. Abnormal findings reported by 
the clinical sites will be reviewed by the DMC and/or the clinical site to adjudicate these findings 
as AE of special interest (AESI) and assess their seriousness/severity. 
9.4.11  Patient reported outcomes 
Table 1 shows the concepts of measurement and their related PRO questionnaires to be used in the 
trial. Patient reported outcomes performed on site will be completed prior to any procedures or 
discussions about the treatment and disease. 
Table 1 - Patient reported outcome (PRO) concepts and questionnaires 
Concept 
PRO questionnaire 
Overall pain 
BPI-SF (Appendix E) 
Overall fatigue 
BFI- (Appendix F) 
Global impression of severity 
PGIS (Appendix G) 
Global impression of change 
PGIC (Appendix H)  
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Concept 
PRO questionnaire 
Health status 
EQ-5D-5L (Appendix I) 
Daily symptoms of ADPKD (worst pain: BPI, Item 3, worst fatigue: 
BFI, Item 3, nocturia) 
Daily diary 
ADPKD = Autosomal dominant polycystic kidney disease; BFI = Brief Fatigue Inventory: BPI-SF = Brief Pain Inventory short-form; 
EQ-5D-5L = EuroQoL 5-dimension 5-level; PGIC = Patient global impression of change; PGIS = Patient global impression of severity; 
PRO = Patient reported outcome.  
9.4.11.1 Overall pain 
Overall pain will be measured using the BPI short-form (BPI-SF [17]); one of the most widely 
used instruments for measuring pain in clinical trials (Appendix E). The BPI-SF comprises 
15 questions related to pain severity, location, treatment and pain interference in the previous 
24 hours; and 1 item asks about pain “right now”. Most items provide an 11-point numeric rating 
scale (NRS) to indicate severity of pain (n=4), pain interference (n=7) and treatment relief (n=1). 
A binary categorical response is given to a single item about pain incidence, and a body diagram 
is completed to indicate pain location. Scores are by items and by dimensions; the global score 
ranges from 0 to 10. Lower scores indicate lower pain. The BPI-SF will be administered at the 
baseline and Months 1, 3, 6, 9, 12, 15, 18, 21, and 24 visits.  
9.4.11.2 Overall fatigue 
The Brief Fatigue Inventory- (BFI [18]) has been used widely in clinical research in both drug 
development and observational studies (Appendix F). It will be used in the current study to 
measure overall fatigue. The BFI comprises 10 questions related to fatigue incidence in the past 
week (1 item; yes/no), fatigue severity (3 items; two recalling the past 24 hours, one “right now”, 
all on an 11-point NRS) and fatigue impact in the past 24 hours (6 items on 11-point NRS). 
Scores are by dimension, 1-item and the global score ranging from 0 to 10. Lower scores indicate 
lower fatigue. The BFI will be administered at the baseline and Months 1, 3, 6, 9, 12, 15, 18, 21, 
and 24 visits.  
9.4.11.3 Global impression of severity 
Patient global impression of severity (PGIS) is a single item scale in which patients indicate 
an overall assessment of their APKD symptoms (none, mild, moderate, and severe). The PGIS 
will be administered at the run-in visit, baseline visit, and Months 3, 12, 18 and 24 visits 
(Appendix G). 
9.4.11.4 Global impression of change 
The Patient Global Impression of Change (PGIC) consists of one item adapted to the patient that 
evaluates all aspects of patients' health and assesses if there has been an improvement or decline 
in clinical status since they started taking the study medication (7-category scale from “very much 
better” to “very much worse”). The PGIC will be administered at Months 3, 12, 18 and 24 visits 
(Appendix H). 
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9.4.11.5 Quality of life/health status 
The EuroQoL 5-dimension 5-level (EQ-5D-5L) is used widely in clinical trials to assess 
5 dimensions of health outcome (mobility, self-care, usual activities, pain/discomfort, 
anxiety/depression) from a wide variety of interventions on a common scale, for purposes of 
evaluation, allocation and monitoring. The EQ-5D-5L will be measured at baseline and Months 3, 
6, 12, 18 and 24 visits (Appendix I). 
9.4.11.6 Daily symptoms of autosomal dominant polycystic kidney disease  
A daily diary will be included in the study to measure pain, fatigue and nocturia with a 24-hour 
recall. The diary will be completed for 7 days prior to baseline visit and for the specified 
administration period before the study visits (see Section 1.3 and Section 1.4). The diary will be 
comprised of 3 items plus an additional item that will direct to the medication entry log: 
• A nocturia item: “Last night, how many times did you wake up because you had to 
urinate? (if you did not wake up, please write 0)”. 
• Item 3 of the BFI-SF to measure worst fatigue in the past 24 hours; “Please rate your 
fatigue (weariness, tiredness) by circling the one number that best describes your WORST 
level of fatigue in the last 24 hours”. Response options are given on an 11-point NRS from 
0 (No Fatigue) to 10 (As bad as you can imagine).  
• Item 3 of the BPI-SF to measure worst pain in the past 24 hours; “Please rate your pain by 
marking the box beside the number that best describes your pain at its worst in the last 
24 hours”. Response options are given on an 11-point NRS from 0 (no pain) to 10 (pain as 
bad as you can imagine). 
• Medication log entry item; "Have you taken any medication for your pain in the past 
24 hours? Yes/No".  
If the response to the medication log entry item is "Yes" patients will enter the pain medication 
log.  
An average score for each item will be taken for each administration period.  
9.4.12 Analgesic/over the counter pain medication administration 
Analgesic use will be captured at baseline and at each pain assessment period using a medication 
log. Patients will report pain medication use in their daily diary. 
9.4.13 Pharmacodynamic and exploratory biomarkers 
Plasma, serum, and urine samples will be collected at the times specified in the study flow chart 
(see Section 1.3 and Section 1.4). Based on collection from an anticipated 640 patients at 7 time 
points, up to 4480 samples are expected per assessed biomarker. 
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9.4.13.1 Biomarkers associated with autosomal dominant polycystic kidney disease 
Pharmacodynamic biomarkers associated with ADPKD such as FGF23 and ADMA in plasma will 
be analyzed using appropriate bioanalytical platforms at the Sponsor’s laboratory or at a 
subcontracted laboratory. Other analytes may also be assessed if available data during the course 
of the study suggest a relationship to disease course in ADPKD patients or to venglustat. 
Urine samples (24-hour urine collections) will be analyzed for markers of kidney injury such as 
monocyte chemoattractant protein-1 (MCP-1) using an appropriate bioanalytical platform at the 
Sponsor’s laboratory or at a subcontracted laboratory. Additional exploratory biomarkers in urine 
(eg, Kidney Injury Molecule-1 [KIM-1], neutrophil gelatinase-associated lipocalin [NGAL], or 
GL-1, GM3) may be assessed. 
9.4.13.2 Glycosphingolipids: glucosylceramide, monosialodihexosylganglioside 
Plasma samples for GL-1 and GM3 will be analyzed using validated liquid chromatography 
tandem mass spectrometry (LC-MS/MS) methods at the Sponsor’s laboratory or at a 
subcontracted laboratory.  
9.4.14 Pharmacokinetics 
9.4.14.1 Sampling time 
Blood samples for plasma venglustat assessment will be collected from all patients according to 
the time points described below and as shown in the study flow charts (see Section 1.3 and 
Section 1.4): 
Based on collection of PK samples from an anticipated 640 patients (5 samples per patient in 
Stage 1 for 240 patients and 3 samples per patient in Stage 2 for 400 patients), approximately 
2400 PK samples are expected from the study. 
• Stage 1: 
- 
Day 1: 3 (±1) hours post dose, 
- 
Month 1: Pre-dose and 3 (±1) hours post dose, 
- 
Months 6 and 18: Pre-dose. 
• Stage 2: 
- 
Month 1: Pre-dose and 3 (±1) hours post dose, 
- 
Month 24: Pre-dose. 
At visits when a post-dose PK sample is to be collected, patients should take the study drug on 
site. 
For PK sample collected at end-of-treatment visit in case of premature treatment discontinuation, 
time of last dose and time of PK sample collected should be accurately recorded. 
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9.4.14.2 Pharmacokinetics handling procedure 
Special procedures for collection, storage, and shipment of plasma samples collected for 
venglustat concentrations will be provided in a separate laboratory manual provided by the central 
laboratory. An overview of PK sample handling procedure is provided in Table 2. 
Table 2 - Summary of plasma pharmacokinetics samples handling for venglustat  
Sample type 
venglustat 
Matrix 
Plasma 
Blood sample volume 
See study specific laboratory manual 
Anticoagulant 
K2EDTA  
Blood handling procedures 
See study specific laboratory manual 
Aliquot split 
See study specific laboratory manual 
Storage conditions 
Keep in upright position at -70°C 
Shipment conditions 
Frozen, on dry ice 
K2EDTA = dipotassium ethylenediamine tetraacetic acid. 
9.4.14.3 Bioanalytical method 
Venglustat plasma concentrations will be determined using a validated liquid chromatography 
tandem mass spectrometry (LC-MS/MS) method (DMPK15-R012) with a lower limit of 
quantification (LLOQ) of 0.5 ng/mL under the responsibility of QPS, Newark, Delaware, USA. 
9.4.14.4 Pharmacokinetics parameters 
Only sparse plasma pharmacokinetic samples will be collected at clinical visits (see study 
flowchart in protocol Section 1.1). As a result, no pharmacokinetic parameters will be generated. 
Pharmacokinetic variables will include plasma venglustat concentrations. 
Exploratory venglustat metabolite profiling and/or metabolite exposure analysis may be 
conducted in the collected plasma samples. 
9.4.15 Pharmacogenetic assessment 
9.4.15.1 Optional stored deoxyribonucleic acid sample 
Once enrollment is confirmed, patients will be asked if they are willing to consent to long-term 
storage of deoxyribonucleic acid (DNA) samples for future use. For those patients who provided 
written consent to the collection of the optional pharmacogenetic samples, blood samples for 
exploratory genetic analysis of DNA will be collected at Day 1 (Section 1.3 and Section 1.4) for 
the purpose of pharmacogenetic analysis and this sample will be stored. This sample may be used 
for genetic analysis related to ADPKD and/or to venglustat. 
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This blood sample will be transferred to a Sanofi site (or a subcontractor site) which could be 
located outside of the country where the study is conducted. Sanofi or its subcontractor will 
extract DNA from the sample.  
This blood sample, and the DNA that is extracted from it, will be assigned a second number, a 
Genetic ID that is different from the Patient ID. This “double coding” is performed to separate a 
patient’s medical information and DNA data.  
The clinical study data (coded by Patient ID) will be stored in the clinical data management 
system (CDMS), which in a distinct database in a separate environment from the database 
containing the genetic data (coded by Genetic ID). The key linking Patient ID and Genetic ID will 
be maintained by a third party, under appropriate access control. The matching of clinical data and 
pharmacogenetic data, for the purpose of data analysis, will be possible only by using this key, 
which will be under strict access control. All data will be reported only in coded form in order to 
maintain confidentiality.  
The DNA will be stored for up to 15 years from the completion of the clinical study report.  
If a patient, via written request, asks for destruction of his/her samples and the samples have not 
yet been double coded, the Sponsor will destroy the samples per applicable guidelines; however, 
any data already generated will not be destroyed. The Sponsor will notify the Investigator in 
writing that the samples have been destroyed. However, any analyses of the sample(s) that have 
already been performed or data generated prior to patient’s request will continue to be used as part 
of the research in this project and will be kept by the Sponsor. 
Special procedures for collection, storage, and shipping of DNA samples are summarized in 
Table 3 and will be described in detail in the laboratory manual provided to the study sites. 
Table 3 - Summary of handling procedures for stored DNA samples 
Sample type(s) 
Pharmacogenetics 
Blood sample volume 
6 mL 
Tube type 
Tube provided by central laboratory for DNA sample storage 
Anticoagulant 
See laboratory manual for specific instructions 
Blood handling procedures 
Shipping conditions 
See laboratory manual for specific instructions 
See laboratory manual for specific instructions 
Blood sample storage conditions 
-20°C or colder; See laboratory manual for specific instructions 
DNA: deoxyribonucleic acid. 
9.4.16 Future use of samples  
For patients who have consented to it, serum samples will be collected at Visits 3, 8, and 12 and 
these samples will be stored (Biobanking).  
Not all of the samples collected during this study may be required for the tests planned in this 
clinical trial. For patients who have consented to it, the samples that are unused or left over after 
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testing and samples collected for Biobanking may be used for other research purposes (excluding 
genetic analysis) related to ADPKD than those defined in the present protocol. 
These other research analyses will help to understand either disease subtypes or drug response, or 
to develop and/or validate a bioassay method, or to identify new drug targets or biomarkers.  
These samples will remain labelled with the same identifiers used during the study (ie, patient 
ID). They will be transferred to a Sanofi site (or a subcontractor site) which can be located outside 
of the country where the study is conducted. The Sponsor has included safeguards for protecting 
patient confidentiality and personal data (see Section 14.3 and Section 14.5). 
9.4.17 Isolation of urinary exosomes 
Urinary exosomes will be isolated from the urine of patients at selected sites. Exosomes isolation 
will be done on the 24-hour samples of urine already collected in the study (Appendix K). 
9.5 
APPROPRIATENESS OF MEASUREMENTS  
For details please refer to Section 4 and Section 6.5.  
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10 
STUDY PROCEDURES 
The staff of each study center will include the following physicians: a primary nephrologist and a 
Subinvestigator. The primary nephrologist, who can serve as the PI, will have overall 
responsibility to lead the site study team (physicians, pharmacists, technicians, nurses, and clinical 
coordinators) in all aspects of the study. The Subinvestigator can back up the PI when/if needed. 
The clinical coordinator may be a qualified individual who will be responsible for coordinating 
and assisting all study site staff, including patient scheduling and completion and monitoring of 
all patients’ case report forms. He/she will be responsible for coordinating IMP administration, 
and collect, process, and send all blood and other forms of biological samples and requests to the 
central laboratory. Additionally, he/she will be responsible for administering the patient-reported 
questionnaires and coordinating the conduct of the MRIs. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix O. 
10.1 
VISIT SCHEDULE 
This is an outpatient study consisting of on-site visits. Additional, optional phone-call visits to 
monitor safety should be scheduled as often as deemed necessary by the Investigator. If a patient 
does not attend a scheduled visit, the study site personnel should contact the patient by telephone 
as soon as possible for rescheduling. 
Scales and questionnaires should be completed before dosing and before clinical assessments by 
the Study Investigator or other healthcare provider(s). 
Before any screening assessment is performed, information regarding the aims and methods of the 
study, its constraints and risks will be explained to the patient and a written summary in the form 
of an informed consent will be provided. The patient must sign and date the informed consent 
before screening and before patient demography is recorded. 
Although the screening assessments for this study are grouped under the heading of a single visit 
in this protocol, it is possible for these to be performed over more than one site visit if necessary, 
as long as the screening visit window prior to Day -15 (run-in/Visit 2) is respected. Rescreening is 
possible in this study. 
The study visits occur on the planned dates (relative to the first administration of IMP), as 
scheduled. The visit schedule should be adhered to within ±3 days for the run-in period, ±7 days 
for the double-blind core treatment period, and -7 to +21 days for the follow-up (off-treatment) 
period. If one visit date is skipped/missed/changed, the next visit should take place according to 
the original schedule. 
Further details of procedures/assessments listed in the following sections are captured in the study 
flow charts (Section 1.3 and Section 1.4). 
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10.1.1 Screening period 
10.1.1.1 Visit 1: screening from Day -30 to Day -16 
The initial screening period (Visit 1) can last up to 15 days (+3 days). Visit 2 can be performed as 
soon as results of all assessments performed at Visit 1 are available. 
The following activities will be performed: 
• An explanation of the purpose, procedures, potential risks, and benefits of this study will 
be provided to the patient. 
• Informed consent signature and date will be collected. 
• Patient demography will be recorded. 
• Confirmation of eligibility by the Investigator. 
• MRI (if the patient has no documented CT/MRI/US kidneys imaging test results obtained 
prior to the study) 
- 
If the patient has documented CT/MRI/US kidneys imaging test results obtained prior 
to the study, the Investigator may use this data for preliminary evaluation of the 
patient`s eligibility (massively enlarged kidneys) at Visit 1. First study MRI for 
confirmation of TKV Imaging Classification Class will be performed at Visit 2 (run-in 
visit). 
• Medical/surgical history. 
• Review of current medical conditions, with AE/SAE reporting (if any). 
• Review of current and prior medications. 
• Complete physical examination. 
• Record of height and body weight measurements. 
• Vital signs. 
• Laboratory assessments. 
- 
Chemistry and hematology. 
• Viral serology (to be performed by a central laboratory: HBsAg, HBcAb, anti-HCVAb, 
anti-HIV1 Ab and anti-HIV2 Ab). 
• Blood sampling for GSL marker analysis. 
• Blood sampling for biomarker analysis in Stage 1. In Stage 2, only if to be done following 
analysis of Stage 1 samples. 
• Urinalysis (local dipstick test) including glucose, protein, bilirubin, urobilinogen, pH, 
specific gravity, blood, ketones, nitrite, and leukocyte esterase. Central urinalysis will be 
performed if any abnormality is observed in the urinalysis dipstick test. 
• Urinalysis with microscopy (to be performed by a central laboratory). 
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• Serum β-HCG pregnancy test (for women of childbearing potential [WOCBP]). 
• Blood sampling for follicle stimulating hormone (FSH)/estradiol levels (in post-
menopausal females, if not previously documented). 
10.1.1.2 Visit 2: run-in Day -15 
Visit window: The run-in visit (Day -15) can be performed up to 15 (±3) days after the initial 
screening visit or as soon as results of all assessments performed at Visit 1 are available. 
The following activities will be performed:  
• Whenever possible, the BDI-II (Appendix D) and PGIS (Appendix G) should be done 
prior to clinical interaction with the Investigator. At screening, patients with BDI-II of 
20 to 28, inclusive, should be evaluated by a mental health specialist before the 
Investigator can determine if the patient would be able to fully participate in the trial. 
Patients with a BDI-II of >28 (severe depression) at screening will be excluded. 
• Review of current medical conditions, with AE/SAE reporting (if any). 
• Review of current medications. 
• Abbreviated physical examination (focus on areas important for assessment of AEs if 
necessary). 
• Record of body weight measurement. 
• Vital signs. 
• 12-lead ECG (print out of ECG recording should be evaluated by Investigator prior to IMP 
administration). 
• Laboratory assessments (Chemistry only). 
• Urine pregnancy test (for WOCBP). 
• Ophthalmological examination with pupil dilation including measurement of the corneal 
thickness (or endothelial cell density) and measurement of intraocular pressure. 
• MRI (if MRI for confirmation of TKV Imaging Classification Class was not performed at 
Visit 1). 
• Confirmation of eligibility by the Investigator. 
• Issue daily symptom diary and remind the patient that this should be completed for the 
7 days before the next visit. 
Following confirmation of eligibility (based on results of assessments performed at the screening 
visit, including evaluation of liver enzymes at the screening visit and blood pressure at the run-in 
visit), patients will receive once daily, 2 placebo capsules for 2 weeks in Stage 1 (1 or 2 placebo 
capsules in Stage 2). 
A patient diary will be issued with instructions to record any missing doses of IMP and pain 
medication used. The patient should bring their diary and any remaining capsules to the next 
clinic visit. The site staff will review the patient diary during the clinic visit and record excursions 
from treatment into the eCRF.  
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The patient should be given suitable containers in which to collect the 24-hour urine and the urine 
spot, required prior to the next visit and to be returned at that visit. 
10.1.2 Treatment period - Month 0 to Month 24 
Visit window: The randomization visit (Day 1) should be performed 15 days after Visit 2 with the 
acceptable window of ±3 days. Using Day 1 as reference, a time frame of ±7 days is acceptable 
for Visits 4 to 12. (If one visit date is skipped/missed/changed, the next visit should take place 
according to the original schedule.) 
10.1.2.1 Visit 3: randomization at Month 0/Day 1 
Screening assessments will be completed within the 30-day screening period. Eligibility will be 
reconfirmed prior to randomization/first dose IMP administration on Day 1 (based on results of 
assessments performed during the screening period, including evaluation of liver enzymes at the 
run-in visit and blood pressure at the baseline visit). 
Patients will receive either placebo or venglustat, orally, at the clinic.  
Patients will be instructed to record any missing doses of IMP and pain medication used in their 
patient diary. The patient should bring their diary and any remaining capsules to each clinic visit. 
The site staff will review the patient diary during each clinic visit and record excursions from 
treatment into the eCRF. The patient diary will be retrieved when the patient finishes their 
participation in the study. 
The Randomization visit (Day 1) will include assessments and activities as listed in the study flow 
chart, Section 1.3 and Section 1.4, which should be done in the following order: 
• Whenever possible, the following scales and questionnaires should be done prior to 
clinical interaction with the Investigator:  
- 
BPI (Appendix E), 
- 
BFI (Appendix F), 
- 
PGIS (Appendix G), 
- 
EQ-5D-5L (Appendix H). 
• Review of concomitant medications. 
• Review of current medical conditions, with AE/SAE reporting (if any). 
• Collection of spot urine sample. 
• Collection of home urine based on 24-hour collection. 
• Reconfirmation of eligibility by the Investigator. 
• Review daily symptom diary for completeness. 
• Review of missed dose log for eligibility compliance. 
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• Abbreviated physical examination (focus on cardiac and respiratory systems, as well as 
any areas important for assessment of AEs if necessary). 
• Vital signs. 
• Laboratory assessments. 
- 
Chemistry and hematology. 
• Biobanking blood sample (optional) collected prior to the start of IMP. 
• Pharmacogenetic sample (optional). 
• Urine pregnancy test (for WOCBP). 
• Randomization via IRT. 
• Dispense study medication. 
• Blood sampling for PK analysis 3 hours post dose (Stage 1 only). 
• If the patient is participating in the mGFR substudy, perform iohexol infusion and collect 
blood samples according to Appendix L. 
• Issue daily symptom diary and remind the patient that this should be completed daily until 
Visit 5. 
Remind patient to return to the clinic for next visit, bring their diary and any remaining capsules. 
Remind patient to not take the dose at home on the next clinic visiting day. 
The patient should be given suitable containers in which to collect the 24-hour urine and the urine 
spot (see Section 9.4.3), required prior to the next visit and to be returned at that visit. 
10.1.2.2 Visit 4, 6, 8, 10, 12/Month 1, 6, 12, 18, 24 (Day 30, 180, 360, 540, 720) 
Patients will receive either placebo or venglustat, orally, at the clinic.  
Patients will be instructed to record any missing doses and pain medication used in their diary. 
The patient should bring their diary and any remaining capsules to each clinic visit. The site staff 
will review the patient diary during each clinic visit and record excursions from treatment into the 
eCRF. 
The following activities will be performed: 
• Whenever possible, the following scales and questionnaires should be done prior to 
clinical interaction with the Investigator:  
- 
BDI-II (Visits 6, 8, 10, 12), 
- 
BPI (Visits 4, 6, 8, 10, 12), 
- 
BFI (Visits 4, 6, 8, 10, 12), 
- 
PGIS (Visits 8, 10, 12), 
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- 
PGIC (Visits 8, 10, 12), 
- 
EQ-5D-5L (Visits 6, 8, 10, 12). 
• Review of concomitant medications. 
• Review of current medical conditions, with AE/SAE reporting (if any). 
• Collection of spot urine sample. 
• Collection of home urine based on 24-hour collection. 
• Review daily symptom diary for completeness. 
• Review of missed dose log for compliance. 
• Abbreviated physical examination (focus on areas important for assessment of AEs if 
necessary; Visits 4, 6, and 8). 
• Complete physical examination at Visits 10 and 12. 
• Record of body weight measurement at Visit 8. 
• Vital signs. 
• 12-lead ECG at Visits 6 and 12. 
• Laboratory assessments. 
- 
Chemistry and hematology. 
• Blood sampling for GSL markers. 
• Blood sampling for biomarker analysis (not collected at Month 1 in Stage 2). 
• Blood sampling for PK analysis: 
- 
Stage 1: pre-dose and 3 hours post-dose at Visit 4; pre-dose at Visits 6 and 10, 
- 
Stage 2: pre-dose and 3 hours post-dose at Visit 4; pre-dose at Visit 12. 
• Biobanking blood sample (optional) at Visits 8 and 12. 
• Urinalysis (local dipstick test) including glucose, protein, bilirubin, urobilinogen, pH, 
specific gravity, blood, ketones, nitrite, and leukocyte esterase. Central urinalysis will be 
performed if any abnormality is observed in the urinalysis dipstick test. 
• Urinalysis with microscopy; (to be performed by a central laboratory). 
• Ophthalmological examination 
- 
At Month 6 (Visit 6), Month 12 (Visit 8), Month 18 (Visit 10), and Month 24 
(Visit 12): ophthalmological examination with pupil dilation 
- 
At Month 12 (Visit 8), Month 18 (Visit 10) and Month 24 (Visits 12) in Stage 1, and at 
Month 12 (Visit 8) and Month 24 (Visits 12) in Stage 2, ophthalmological examination 
will also include measurement of the corneal thickness (or endothelial cell density) and 
measurement of intraocular pressure. 
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• MRI at: 
- 
Stage 1: Visits 4 and 10, 
- 
Stage 2: Visit 10. 
• Urine pregnancy test (for WOCBP). 
• If the patient is participating in the mGFR substudy, perform iohexol infusion and collect 
blood samples according to Appendix L, at Visits 8 and 12. 
• Dispense study medication at Visits 4, 6, 8, and 10. 
• Remind the patient that the patient daily symptom diary should be completed daily until 
Visit 5 and for 7 days before Visit 8. 
Remind patient to return to the clinic for next visit, bring their diaries and any remaining capsules. 
Provide WOCBP with at-home pregnancy tests and remind them to administer the pregnancy test 
monthly between visits. 
Remind patient to not take the dose at home on the clinic visiting day at Visits 6 and 10 during 
Stage 1, and at Visit 12 during Stage 2. 
The patient should be given suitable containers in which to collect the spot urine, to be returned at 
that visit (see Section 9.4.3). 
10.1.2.3 Visit 5, 7, 9, 11/Month 3, 9, 15, 21 (Day 90, 270, 450, 630) 
Patients will receive either placebo or venglustat, orally, at the clinic.  
Patients will be instructed to record any missing doses and pain medication used in their diary. 
The patient should bring their diary and any remaining capsules to each clinic visit. The site staff 
will review the patient diary during each clinic visit and record excursions from treatment into the 
eCRF. 
The following activities will be performed: 
• Whenever possible, the following scales and questionnaires should be done prior to 
clinical interaction with the Investigator:  
- 
BDI-II (Appendix D), 
- 
BPI (Appendix E), 
- 
BFI (Appendix F), 
- 
PGIS (Visit 5 only; Appendix G), 
- 
PGIC (Visit 5 only; Appendix H), 
- 
EQ-5D-5L (Visit 5 only; Appendix I). 
• Review of concomitant medications. 
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• Review of current medical conditions, with AE/SAE reporting (if any). 
• Collection of spot urine sample. 
• Review daily symptom diary for completeness. 
• Review of missed dose log for compliance. 
• Abbreviated physical examination (focus on areas important for assessment of AEs if 
necessary). 
• Vital signs. 
• Laboratory assessments. 
- 
Chemistry and hematology. 
• Urinalysis (local dipstick test) including glucose, protein, bilirubin, urobilinogen, pH, 
specific gravity, blood, ketones, nitrite, and leukocyte esterase. Central urinalysis will be 
performed if any abnormality is observed in the urinalysis dipstick test. 
• Urinalysis (microscopy; to be performed by a central laboratory). 
• Urine pregnancy test (for WOCBP). 
• MRI (at Visit 7 of Stage 1). 
• Dispense study medication. 
• Remind the patient that the patient daily symptom diary should be completed for the 
14 days before Visit 10 and Visit 12. 
Remind patient to return to the clinic for next visit, bring their diaries and any remaining capsules. 
Provide WOCBP with at-home pregnancy tests and remind them to administer the pregnancy test 
monthly between visits.  
The patient should be given a suitable container in which to collect the 24-hour urine and the spot 
urine, required prior to the next visit and to be returned at that visit. 
10.1.3 Follow-up visit - Visit 13/Month 25 (Day 750)  
Not applicable for patients who may be eligible for a potential long-term extension study after 
completion of 24 months of treatment. 
Visit window: The Follow-up Visit (Day 750) can be performed within a -7 to +21 days window. 
The following activities will be performed: 
• Review of current medical conditions, with AE/SAE reporting (if any). 
• Review of current and prior medications. 
• Collection of spot urine sample. 
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• Abbreviated physical examination (focus on areas important for assessment of AEs if 
necessary). 
• Record of body weight measurement. 
• Vital signs. 
• Laboratory assessments (Chemistry only). 
• Blood sampling for GSL markers. 
• Blood sampling for biomarker analysis in Stage 1. In Stage 2, only if to be done following 
analysis of Stage 1 samples.  
10.2 
DEFINITION OF SOURCE DATA 
Source data are defined as original documents, data, and records. This includes, but is not limited 
to the following: hospital records, clinic and office charts, study-specific source document 
worksheets, phone logs, memoranda, evaluation checklists, laboratory requisitions and reports, 
ECG tracings, ophthalmological images and results and reports, local laboratory reports 
(if applicable), medication dispensing records, patient questionnaires, MRI images, computer 
printouts, electronic data/information sources including IRT notifications, and any other 
documentation regarding the patient. 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION  
The IMP should be continued whenever possible. In case the IMP is stopped, it should be 
determined whether the stop can be made temporarily; permanent IMP discontinuation should be 
a last resort. Any IMP discontinuation must be fully documented in the eCRF. In any case, the 
patients who permanently discontinue IMP during the double-blind treatment period should 
complete an end-of-treatment visit and have selected assessments performed at Month 18 and 
Month 24 (refer to Section 10.3.4). 
Pregnancy will lead to definitive treatment discontinuation in all cases. 
10.3.1 Temporary treatment discontinuation with investigational medicinal product(s) 
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 (Appendix O). After close and appropriate clinical and/or laboratory 
monitoring, once the Investigator considers, according to his/her best medical judgment that the 
occurrence of the concerned event was unlikely due to the IMP, the safety of the patient is not 
affected, and if the selection criteria for the study are still met (refer to Section 7.1 and 
Section 7.2), treatment with the IMP may be re-initiated. 
For all temporary treatment discontinuations, duration should be recorded by the Investigator in 
the appropriate pages of the eCRF. 
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10.3.2 Permanent treatment discontinuation with investigational medicinal product 
Permanent treatment discontinuation is any treatment discontinuation associated with the 
definitive decision from the Investigator not to re-expose the patient to the IMP at any time during 
the study, or from the patient not to be re-exposed to the IMP, whatever the reason. 
10.3.3 List of criteria for permanent treatment discontinuation 
The patients may withdraw from treatment with the IMP if they decide to do so, at any time and 
irrespective of the reason, or this may be the Investigator’s decision. All efforts should be made to 
document the reason(s) for treatment discontinuation and this should be documented in the eCRF. 
The patients who develop loss of 3 or more lines of BCVA in either eye due to posterior 
subcapsular cataract could be discontinued from study treatment if recommended by DMC (if 
DMC will decide that benefit/risk ratio is not favorable for this patient). 
If a patient experiences a 50% reduction in eGFR compared to the screening value on at least 
2 occasions separated by a period of at least 30 days during the course of this trial, the study 
treatment will be discontinued and alternative therapy will have to be discussed by the 
Investigator. 
If a patient experiences a reduction in eGFR below 30 mL/min/1.73 m2 on 2 occasions separated 
by a period of 3 months during the course of this study, the study treatment will be discontinued. 
If a patient experiences a reduction in eGFR below 25 mL/min/1.73 m2, a repeated test must be 
performed after 30 days: 
• If the result of the eGFR test (repeated in 30 days) is below 30 mL/min/1.73 m2, the study 
treatment will be discontinued. 
The following may be justifiable reasons for the Investigator or Sponsor to discontinue a patient 
from treatment. 
Patient specific: 
• The patient experiences two similar SAE or one life-threatening SAE (assessed as related 
by the Investigator and/or the Sponsor). 
• The patient meets criteria for Hy's law (confirmed ALT >5 × upper limit of normal (ULN) 
range or confirmed ALT >3 × ULN and bilirubin >2 × ULN). 
• The patient becomes pregnant. 
Trial specific: 
• Any AEs, per Investigator judgment, that may jeopardize the patient's safety. 
• Any unblinding of the study treatment by the Investigator. 
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Any use of prohibited concomitant treatment (see Section 8.8). 
• At patient’s request, ie, withdrawal of the consent for treatment. 
After the company representatives have been made aware of the suspected adverse reactions 
(SARs), relevant safety/laboratory data will be submitted to the DMC within 72 hours by 
Global Pharmacovigilance, Clinical, and other related departments as designated by the Company. 
Any abnormal laboratory value or imaging reports will be immediately rechecked by the Sponsor 
and the central reader, respectively, for confirmation before making a decision of permanent 
discontinuation of the IMP for the concerned patient.  
The DMC will also review data if applicable to assist in determining if AEs should preclude 
continued treatment with venglustat.  
If a patient decides to discontinue participation in the study, he/she should be contacted by the 
Study Investigator in order to obtain information about the reason(s) for discontinuation and 
collection of any potential AEs. 
If possible, and after the permanent discontinuation of treatment, the patients will be assessed 
using the procedure normally planned for the Month 18 and Month 24 Visits.  
All cases of permanent treatment discontinuation should be recorded by the Investigator in the 
appropriate pages of the eCRF when considered as confirmed. 
10.3.4 Handling of patients after permanent treatment discontinuation 
Patients will be followed-up according to the study procedures specified in this protocol up to the 
scheduled date of study completion, or up to recovery or stabilization of any AE to be 
followed-up as specified in this protocol, whichever comes last. 
All cases of permanent treatment discontinuation must be recorded by the Investigator in the 
appropriate pages of the eCRF when considered as confirmed. 
Patients who prematurely and permanently discontinue study medication should complete rapidly 
(within 7 days) an end-of-treatment (EOT) assessment visit. 
Stage 1: EOT visit should include all procedures of Visit 12 and additionally a PK sample should 
be collected. In 30 days, a premature Follow-up visit (all procedures of Visit 13) should be 
performed. 
Stage 2: EOT visit should include all procedures of Visit 12. In 30 days, a premature Follow-up 
visit (all procedures of Visit 13) should be performed.  
In addition, for both Stage 1 and Stage 2: 
1. Investigator should ask patient who prematurely and permanently discontinued study 
medication to continue study visits for safety and efficacy assessments (including PRO 
questionnaires) up to and including the last scheduled visit, if possible. 
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2. If the patient refuses to attend all scheduled visits and to continue answering all PRO 
questionnaires, Investigator should ask the patient to continue answering questions of 
“Daily symptoms of ADPKD” diary and to return to the site at 18 months (to have at least 
an MRI, blood sample for eGFR evaluation, urine analysis [for urine protein and 
osmolality], as well as safety assessments performed) and at 24 months (to have blood 
sample for eGFR evaluation, urine analysis [for urine protein and osmolality], and safety 
assessments performed).  
For patients participating in mGFR substudy of the Stage 2, mGFR measurement should be 
performed at 24 months. 
Patients who withdraw from the study due to pregnancy should be followed throughout the 
pregnancy up to approximately 6 to 8 weeks beyond the estimated delivery date so that the 
outcome of the pregnancy is determined. Additional follow-up information may be requested 
about the baby until at least one year after the birth of the baby, due to potential risk of 
abnormalities not present at birth. See Appendix A for guidance. 
10.3.5 Procedure and consequence for patient withdrawal from study 
The patients may withdraw from the study before study completion if they decide to do so, at any 
time and irrespective of the reason without any effect on their care. However, if patients 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. 
Patients who withdraw from the study treatment should be explicitly asked about the contribution 
of possible AEs to their decision, and any AE information elicited must be documented.  
All study withdrawals must be recorded by the Investigator in the appropriate screens of the eCRF 
and in the patient’s medical records when considered as confirmed. In the medical record, at least 
the date of the withdrawal and the reason should be documented. 
In addition, a patient may withdraw his/her consent to stop participating in the study. Withdrawal 
of consent for treatment should be distinguished from withdrawal of consent for follow-up visits 
and from withdrawal of consent for non-patient contact follow-up, eg, medical record checks. The 
site should document any case of withdrawal of consent. 
For patients who fail to return to the site, unless the patient withdraws consent for follow-up, the 
Investigator must make the best effort to recontact the patient (eg, contact patient’s family or 
private physician, review available registries or health care databases), and to determine his/her 
health status, including at least his/her vital status. Attempts to contact such patients must be 
documented in the patient’s records (eg, times and dates of attempted telephone contact, receipt 
for sending a registered letter). 
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All data collected up to the patient's withdrawal will be included in the analyses. The statistical 
analysis plan (SAP) will specify how early withdrawals from treatment will be accounted for in 
the analyses of efficacy endpoints. 
Patients who have withdrawn from the study cannot be rerandomized (treated) in the study. Their 
inclusion and treatment numbers must not be reused.  
10.3.6 Lost to follow-up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
• Before a participant is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING 
10.4.1 Definitions of adverse events  
10.4.1.1 Adverse event 
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. 
10.4.1.2 Serious adverse event 
A SAE is any untoward medical occurrence that at any dose: 
• Results in death, or 
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• Is life-threatening, or 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which 
the patient 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. 
• Requires inpatient hospitalization or prolongation of existing hospitalization, or 
• Results in persistent or significant disability/incapacity, or 
• Is a congenital anomaly/birth defect 
• Is a medically important event 
Medical and scientific judgment should be exercised in deciding whether expedited 
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 
patient or may require medical or surgical intervention (ie, specific measures or corrective 
treatment) to prevent one of the other outcomes listed in the definition above. 
Note: The following list of medically important events is intended to serve as a guideline 
for determining which condition has to be considered a medically important event. The list 
is not intended to be exhaustive: 
- 
Intensive treatment in an emergency room or at home for: 
- 
Allergic bronchospasm, 
- 
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc), 
- 
Convulsions (seizures, epilepsy, epileptic fit, absence, etc). 
- 
Development of drug dependence or drug abuse, 
- 
ALT >3 x ULN + total bilirubin >2 x ULN or asymptomatic ALT increase 
>10 x ULN, 
- 
Suicide attempt or any event suggestive of suicidality, 
- 
Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling), 
- 
Bullous cutaneous eruptions, 
- 
Cancers diagnosed during the study or aggravated during the study. 
10.4.1.3 Adverse event of special interest 
An AESI is an AE (serious or nonserious) 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. 
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The definition of AESI for this study are as follows: 
• Pregnancy: 
- 
Pregnancy occurring in a female patient entered in the clinical trial or in a female 
partner of a male patient entered in the clinical trial. It will be qualified as an SAE only 
if it fulfills one of the seriousness criteria (see Section 10.4.1.2), 
- 
In the event of pregnancy in a female patient, IMP should be discontinued,  
- 
Follow-up of the pregnancy in a female patient or in a female partner of a male patient 
is mandatory until the outcome has been determined (See Appendix A).  
• Symptomatic overdose (serious or nonserious) with IMP: 
- 
An overdose (accidental or intentional) with the IMP is an event suspected by the 
Investigator or spontaneously notified by the patient (not based on systematic pills 
count) and defined as at least twice the intended dose within the intended therapeutic 
interval, adjusted according to the tested drug, 
- 
Of note, asymptomatic overdose has to be reported as a standard AE, 
- 
The circumstances (ie, accidental or intentional) should be clearly specified in the 
verbatim and symptoms, if any, entered on separate AE forms. 
• Increase in ALT (see the “Increase in ALT” flow diagram in Appendix C of the protocol).  
• Other project specific AESI(s): 
- 
New or worsening lenticular opacities and cataracts. 
For opacities present at baseline/previous visit, changes in WHO Grade ≥1 for nuclear, cortical 
opacification, or posterior subcapsular opacification compared with baseline or previous 
assessment will be considered as a worsening. 
10.4.2 General guidelines for reporting adverse events  
• All AEs, regardless of seriousness or relationship to IMP, spanning from the signature of 
the informed consent form until the end of the study as defined by the protocol for that 
patient, are to be recorded on the corresponding page(s) or screen(s) of the eCRF. 
• 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 
IMP, 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 IMP or by the study procedure(s).  
• The Investigator should take appropriate measures to follow all AEs until clinical recovery 
is complete and laboratory results have returned to normal, or until progression has been 
stabilized, or until death, in order to ensure the safety of the patients. This may imply that 
observations will continue beyond the last planned visit per protocol, and that additional 
investigations may be requested by the monitoring team up to as noticed by the Sponsor. 
At the prespecified study end-date, patients who experience an ongoing SAE or an AESI 
should be followed until resolution, stabilization, or death and related data will be 
collected.  
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• When treatment is prematurely discontinued, the patient’s observations will continue until 
the end of the study as defined by the protocol for that patient. 
• Laboratory, vital signs, ECG, or ophthalmic examination abnormalities are to be recorded 
as AEs only if:  
- 
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, 
- 
Defined as an AESI, and or, 
- 
Leading to unscheduled full ophthalmological examination with or without WHO 
simplified cataract grading system evaluation. 
Instructions for AE reporting are summarized in Table 4. 
10.4.3 Instructions for reporting serious adverse events 
In the case of occurrence of an SAE, the Investigator or any designees must immediately: 
• ENTER (within 24 hours) the information related to the SAE in the appropriate screens of 
the eCRF; the system will automatically send a notification to the monitoring team after 
approval of the Investigator within the eCRF or after a standard delay. 
• There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In such a case, care should be taken to ensure that the patient's identity is 
protected and the patient's identifiers in the study are properly mentioned on any copy of a 
source document provided to the Company. For laboratory results, include the laboratory 
normal ranges. 
• All further data updates should be recorded in the eCRF as appropriate, and further 
documentation as well as additional information (for laboratory data, concomitant 
medications, patient status, etc) should be sent (by fax or e-mail) to the monitoring team 
within 24 hours of knowledge of the SAE. In addition, every effort should be made to 
further document any SAE that is fatal or life-threatening within a week (7 days) of the 
initial notification. 
• A back-up plan (using a paper CRF process) is available and should be used when the 
eCRF system does not work. 
• Any SAE brought to the attention of the Investigator at any time after the end of the study 
for the patient and considered by him/her to be caused by the IMP with a reasonable 
possibility, should be reported to the monitoring team. 
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10.4.4 Guidelines for reporting adverse events of special interest  
For AESIs, the Sponsor must be informed immediately (ie, within 24 hours), as per SAE 
notification guidelines described in Section 10.4.3, even if not fulfilling a seriousness criterion, 
using the corresponding screens in the eCRF. 
Instructions for AE reporting are summarized in Table 4. 
10.4.5 Guidelines for management of specific laboratory abnormalities 
Decision trees for the management of certain laboratory abnormalities by Sanofi are provided in 
Appendix C. 
The following laboratory abnormalities should be monitored, documented, and managed 
according to the related flow chart in protocol appendices.  
• Neutropenia. 
• Thrombocytopenia. 
• ALT increase. 
• Acute renal insufficiency. 
• Suspicion of rhabdomyolysis. 
Table 4 - Summary of adverse event reporting instructions 
Event 
category 
Reporting 
timeframe 
Specific events in this category 
Case report form completion 
AE form 
Other specific 
forms 
Adverse Event 
(non-SAE, 
non-AESI) 
Routine 
Any AE that is not SAE or AESI 
Yes 
No 
Serious Adverse 
Event (non-AESI 
or AESI) 
Expedited (within 
24 hours) 
Any AE meeting seriousness criterion per 
Section 10.4.1.2 
Yes 
No 
 
 
 
 
 
Adverse Event of 
Special Interest  
Expedited (within 
24 hours) 
New or worsening lens opacities and 
cataracts 
Yes 
No 
 
 
Pregnancy 
Yes 
Yes 
 
 
Symptomatic overdose 
Yes 
No 
 
 
ALT increase as defined in the protocol 
Yes 
Yes 
AE = adverse event; AESI = adverse event of special interest; ALT = alanine aminotransferase; SAE = serious adverse event. 
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10.4.6 Guidelines for reporting product complaints (investigational medicinal product) 
Any defect in the IMP 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. 
10.5 
OBLIGATIONS OF THE SPONSOR 
During the course of the study, the Sponsor will report in an expedited manner: 
• All SAEs that are both unexpected and at least reasonably related to the IMP (SUSAR), to 
the regulatory authorities, independent ethics committee (IECs)/institutional review boards 
(IRBs) as appropriate and to the Investigators.  
• All SAEs that are expected and at least reasonably related to the IMPs to the regulatory 
authorities, according to local regulations. 
Adverse events that are considered expected will be specified by the reference safety information 
in the IB.  
The Sponsor will report all safety observations made during the conduct of the trial in the clinical 
study report. 
10.6 
SAFETY INSTRUCTIONS 
At any time during the study, patients who develop ≥ Grade 3 cataracts will be discontinued from 
treatment. 
In order to closely monitor the liver function, assessment of total protein, albumin, total bilirubin, 
AST, ALT, and ALP are measured as part of the clinical laboratory testing. Patients with a 
positive medical history of hepatitis B or hepatitis C antibody at the screening visit will be 
excluded from the study. 
Guidance for the investigation of elevated liver function tests is provided in Appendix C. 
Venglustat is not known to be associated with any renal effect. See Appendix C; this algorithm is 
provided for informational purposes regarding the assessment of acute renal failure. 
Investigator should follow local standards of care if during the study patient will require 
modification of antihypertensive therapy. 
10.7 
ADVERSE EVENTS MONITORING 
All events will be managed and reported in compliance with all applicable regulations and 
included in the final clinical study report. 
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11 
STATISTICAL CONSIDERATIONS 
11.1 
DETERMINATION OF SAMPLE SIZE 
In Stage 1, approximately 240 patients will be randomized (with randomization ratio 1:1:1) to 
placebo (n=80) or venglustat 8 mg (n=80) or venglustat 15 mg (n=80). In Stage 2, approximately 
320 patients with an eGFR between 45 and 89.9 mL/min/1.73 m² at screening will be randomized 
(with randomization ratio 1:1) to placebo (n=160) or venglustat (n=160). In addition, 80 patients 
with an eGFR between 30 and 44.9 mL/min/1.73 m² at screening will be randomized (with 
randomization ratio 1:1) to placebo (n=40) or venglustat (n=40). The patients from Stage 2 with 
an eGFR between 30 and 44.9 mL/min/1.73 m2 will not be included in the primary efficacy and 
safety analyses populations but the data from these patients will be analyzed separately. 
This sample size will provide approximately 89% power to detect a 50% reduction in annualized 
rate of change in TKV at end of Stage 1 and approximately 87% power to detect a 30% reduction 
in annualized rate of change in eGFR between venglustat and placebo at the end of Stage 2. 
Overall, the total sample size will provide approximately 87% power to detect an effect on both 
TKV and eGFR.  
Sample size and power calculations were based on simulations, assuming different scenarios 
regarding the dose-response relationship (see Appendix J for additional details). The following 
model parameters were estimated based on available databases from a similar patient population 
(patients aged 18 to 50 years with Mayo Class 1C-1E and baseline eGFR from 
45 to 90 mL/min/1.73 m²) in 2 historical studies (Consortium for Radiologic Imaging Studies of 
Polycystic Kidney Disease (CRISP) and the Polycystic Kidney Disease Treatment Network 
[HALT-PKD]): 
• A slope of log10(TKV) of 0.02591, 0.02832 and 0.03141 in patients from Mayo Class 1C, 
1D, and 1E respectively (corresponding to 6.1%, 6.7% and 7.5% increase per year in 
TKV), resulting in average slope of 0.02764 (6.6%/year) assuming 50% of 1C, 33% of 
1D and 17% of 1E. 
• Standard deviation for the residual error of TKV (on the log10 scale) of 0.02566 and 
standard deviation for the random effect of slope of 0.01477. 
• A slope of eGFR of -3.16, -3.88 and -4.69 mL/min/1.73 m² per year in patients from Mayo 
Class 1C, 1D, and 1E respectively, resulting in average slope of -3.66 mL/min/1.73 m² per 
year assuming 50% of 1C, 33% of 1D, and 17% of 1E. 
• Standard deviation for the residual error of eGFR of 6.34 and standard deviation for the 
random effect of slope of 1.98. 
In addition, sample size and power calculations assumed an overall significance level of 
0.05 (2-sided), 10% dropout rate and included adjustments for handling of multiplicity of tests and 
futility analysis (as described in Section 11.4.2.3 and Section 11.5.1). A sample size of 80 patients 
(40 per arm) with an eGFR between 30 and 44.9 mL/min/1.73 m² at screening will provide 
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approximately 80% probability to detect a treatment effect in this subgroup at the 
0.20 significance level (two-sided), based on a model evaluating the dependence of the treatment 
effect on baseline eGFR. 
11.2 
DISPOSITION OF PATIENTS 
Screened patients are defined as any patient who signed the informed consent.  
Randomized patients consist of all patients who have been allocated a treatment kit based on a 
randomization process. It will consist of all patients with a treatment kit number allocated and 
recorded in the IRT database, and regardless of whether the treatment kit was used or not. 
Patients treated without being randomized will not be considered as randomized and will not be 
included in any efficacy population.  
For any patient randomized more than once, only the data associated with the first randomization 
will be used in any analysis population. The safety experience associated with any later 
randomization will be assessed separately. 
The safety experience of patients treated and not randomized will be reported separately, and 
these patients will not be in the safety population. 
11.3 
ANALYSIS POPULATIONS 
11.3.1 Efficacy populations 
11.3.1.1 Intent-to-treat population 
Stage 1 
The Stage 1 Intent-to-treat (ITT) population will be defined as all patients who are randomized in 
Stage 1, analyzed according to the treatment group allocated by randomization (venglustat 15 mg, 
venglustat 8 mg, or placebo). 
Primary analysis in Stage 1 will include all data from Stage 1 available at the cut-off date 
(ie, including data reported up to Month 24, if any). The cut-off date will be defined as the date all 
patients from Stage 1 have completed the Month 18 visit (or have discontinued the study). 
Stage 2 
The combined Stage 1 and Stage 2 ITT population will include all patients with an eGFR between 
45 and 89.9 mL/min/1.73 m² at screening who are randomized in Stage 1 or Stage 2, analyzed 
according to the treatment group allocated by randomization (venglustat 15 mg, venglustat 8 mg, 
or placebo). 
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Primary analysis in the combined Stage 1 and Stage 2 will include all data available from baseline 
to the end of the 24-month double-blind core treatment period. Patients from Stage 2 with an 
eGFR between 30 and 44.9 mL/min/1.73 m² at screening will not be included in the primary 
efficacy analysis population but the data from these patients will be analyzed separately. 
11.3.2 Safety population 
The Stage 1 Safety population will be defined as all patients who are randomized in Stage 1 and 
received at least one dose or part of a dose of the double-blind IMP, analyzed according to the 
treatment actually received (venglustat 15 mg, venglustat 8 mg, or placebo) 
The combined Stage 1 and Stage 2 Safety population will be defined as all patients with an eGFR 
between 45 and 89.9 mL/min/1.73 m² at screening who are randomized in Stage 1 or Stage 2 and 
received at least one dose or part of a dose of the double-blind IMP, analyzed according to the 
treatment actually received (venglustat 15 mg, venglustat 8 mg, or placebo). Patients from Stage 2 
with an eGFR between 30 and 44.9 mL/min/1.73 m² at screening will not be included in the 
primary safety analysis population but the data from these patients will be analyzed separately. 
A secondary safety analysis population will include patients who are randomized in Stage 2 with 
an eGFR between 30 and 44.9 mL/min/1.73 m² at screening and received at least one dose or part 
of a dose of the double-blind IMP. 
In addition:  
• Nonrandomized but treated patients will not be part of the safety population, but their 
safety data will be presented separately.  
• Randomized patients for whom it is unclear whether they took the study medication will 
be included in the safety population as randomized. 
• For patients receiving more than 1 study treatment during the trial, the treatment group 
allocation for as-treated analysis will be the one to which the patient was treated with the 
longest duration. 
11.3.3 Pharmacokinetics/pharmacodynamics analysis population 
The PK and PD populations will be defined as all patients who were randomized, received at least 
one dose of the double-blind IMP and who have at least one PK or PD assessment, respectively. 
11.4 
STATISTICAL METHODS 
11.4.1 Extent of study treatment exposure and compliance 
The extent of study treatment exposure and compliance will be assessed and summarized by 
actual treatment received within the safety population. 
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11.4.1.1 Extent of investigational medicinal product exposure 
Duration of IMP exposure is defined as: last dose date – first dose date +1 day, regardless of 
unplanned intermittent discontinuations. 
11.4.1.2 Compliance 
A given administration will be considered noncompliant if the patient did not take the planned 
dose of treatment as required by the protocol. No imputation will be made for patients with 
missing or incomplete data. 
Treatment compliance will be summarized descriptively (N, mean, SD, median, min, and max). 
The percentage of patients with compliance <80% will be summarized. 
11.4.2 Analyses of efficacy endpoints 
11.4.2.1 Analysis of primary efficacy endpoint(s) 
11.4.2.1.1 Stage 1 
In Stage 1, the primary efficacy endpoint is the annualized rate of change in TKV. TKV will be 
measured with MRI. 
Estimands 
The primary estimand will be the difference in mean slope of log10-transformed TKV estimated 
from baseline to 18 months in all randomized patients, regardless of whether or not patients 
completed the treatment period. This estimand corresponds to a “treatment policy strategy”. This 
estimand will be considered primary for supporting regulatory decision making. 
A secondary estimand will be the difference in mean slope of log10-transformed TKV estimated 
during the on-treatment period (from baseline to end of treatment). This estimand corresponds to a 
“while on treatment strategy”. This estimand will be considered for describing the effect of 
treatment as long as patients adhere to their randomized treatment. 
Primary analysis 
A linear mixed effect model will be fitted to the log10-transformed TKV, which will include fix 
effects of treatment (venglustat 15 mg, venglustat 8 mg or placebo), Mayo Imaging Classification 
(as per randomization stratification factor: Class 1C versus 1D versus 1E), time (as continuous 
variable), treatment * time interaction and Mayo Imaging Classification * time interaction, and 
will include random intercept and slope. Time will be based on actual TKV assessment date 
relative to randomization date (in years).  
Within group mean slope of log10-transformed TKV will be obtained from the linear mixed effect 
model, using weights for each stratum (Mayo Class 1C, 1D and 1E) equal to the overall 
proportion of patients in each stratum in the Stage 1 ITT population (ie, “population weight”). A 
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back-transformation will be applied to obtain annualized rate of change in TKV (in % per year) 
within each treatment arm, along with their 95% confidence intervals: 
(
) 100
1
10
 
 
year)
per 
 
(%
 
TKV
in 
 
change
 
of
 
rate
 
Annualized
TKV
 
log10
 
of
 
slope

−
=
 
Overall effect of venglustat will be assessed using a Multiple Comparison Procedure (19). 
Multiple trend tests will be performed using optimal contrasts determined from a set of 
3 prespecified candidate models for the dose-response relationship described in Figure 2.  
Figure 2 - Prespecified candidate of dose-response models 
Dose
Relative reduction (%)
0
10
20
30
40
50
0
5
10
15
emax
0
5
10
15
linear
0
5
10
15
sigEmax
 
Optimal contrasts for each candidate model were derived using the R add-on package 
DoseFinding (20) and are presented in Table 5. Contrasts will apply to the treatment * time 
interaction term in the linear mixed effect model. Multiplicity adjusted p-value will be presented. 
Table 5 - Optimal contrasts for the 3 prespecified candidate of dose-response models 
Dose 
Emax model 
Linear model 
Sigmoid Emax model 
Placebo 
-0.8131 
-0.7223 
-0.6615 
venglustat 8 mg 
0.3424 
0.0314 
-0.0838 
venglustat 15 mg 
0.4707 
0.6909 
0.7453 
Relative reduction in annualized rate of change in TKV will be estimated for each dose of 
venglustat versus placebo and defined as: 
100
arm
 
placebo
in 
 
TKV
in 
 
change
 
of
 
rate
 
Annualized
arm
 
71
GZ/SAR4026
in 
 
TKV
in 
 
change
 
of
 
rate
 
Annualized
 - 1
 
 
(%)
reduction 
 
Relative







=
 
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Relative reduction for each dose of venglustat will be presented with 95% confidence intervals 
obtained using a first-order Taylor approximation. In addition, p-values for the comparison of 
each dose of venglustat versus placebo will be presented for descriptive purpose. 
Primary analysis in Stage 1 will include all data from Stage 1 available at the cut-off date 
(including data reported up to Month 24, if any). The cut-off date will be defined as the date all 
randomized patients from Stage 1 have completed the Month 18 visit (or have discontinued the 
study).  
Handling of missing data 
The primary analysis will include all observed TKV data in randomized patients, regardless of 
whether or not patients completed the treatment period (treatment policy strategy). Patients who 
prematurely and permanently discontinue study medication will be requested to obtain an MRI 
scan at 18 months and their data collected after treatment discontinuation will be included in the 
primary analysis. All efforts will be made to minimize the amount of missing data. 
Missing data will be handled using a multiple imputation method. Missing data will be imputed 
using a linear mixed effect model that will include separate slopes of log10 (TKV) during the 
on-treatment period and after permanent treatment discontinuation, for each treatment arm 
(venglustat 15 mg, venglustat 8 mg, or placebo). The imputation model will also include 
adjustment for Mayo class (1C versus 1D versus 1E) as well as random intercept and slope.  
Imputations will be based on the following assumptions: 
• Patients with missing data during the on-treatment period will have their data imputed 
based on the mean slope estimated during the on-treatment period in patients from the 
same treatment arm. 
• Patients with missing data after permanent treatment discontinuation will have their data 
imputed based on the mean slope estimated during the post-treatment period in patients 
from the same treatment arm, who discontinued the treatment but had TKV data available 
during the post-treatment period. 
Additional details about the multiple imputation procedure, including a sample SAS code, are 
included in Appendix J. 
If the number of patients who permanently discontinue the treatment but have TKV data available 
during the post-treatment period is insufficient to estimate the imputation model (less than 
3 patients per treatment arm), then the control based multiple imputation (later described as 
sensitivity analysis) will be used as the primary method to handle missing data. 
After multiple imputations, the imputed datasets will be analyzed using the linear mixed effect 
model described above. Results from the model, including within group mean slopes and contrasts 
will be combined using Rubin’s formula.  
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Sensitivity analysis 
Different sensitivity analyses will be performed, in order to evaluate the robustness of the primary 
analysis to alternative assumptions about missing data. These sensitivity analyses will target the 
same estimand as the primary analysis. 
Analysis of observed data 
In this sensitivity analysis, no imputation of missing data will be performed. The linear mixed 
effect model described above will be run on all observed data, including data collected after 
treatment discontinuation. This sensitivity analysis will be based on the assumption that the rate of 
progression in TKV is the same before and after treatment discontinuation.  
Control based multiple imputation 
In this sensitivity analysis, missing data will be handled using a control based multiple imputation 
method. Imputations will be based on a model that will assume that after permanent treatment 
discontinuation, the slope of log10(TKV) for patients in the venglustat arms will be the same as the 
slope of log10(TKV) for patients in the placebo arm. The imputation model will also include 
adjustment for Mayo class (1C versus 1D versus 1E) as well as random intercept and slope. 
Imputations will be based on the following assumptions: 
• Patients with missing data during the on-treatment period will have their data imputed 
based on the mean slope estimated during the on-treatment period in patients from the 
same treatment arm. 
• Patients with missing data after permanent treatment discontinuation will have their data 
imputed based on the mean slope estimated in patients from the placebo arm. 
Additional details about the control based multiple imputation procedure are included in 
Appendix J. 
Secondary analysis 
A secondary analysis will estimate the difference in mean slope of log10-transformed TKV during 
the on-treatment period (while on treatment strategy). In this secondary analysis, TKV assessed 
more than 30 days after the last IMP administration will be excluded from the analysis. 
TKV assessed in randomized but not treated patients will also be excluded from the analysis. Any 
missing data during the on-treatment period will be considered “at random” in this secondary 
analysis, therefore no imputation will be required since the linear mixed effect model provides 
valid inference under missing at random assumption. 
Another secondary analysis will explore a potential acute hemodynamic effect. In this 
secondary analysis, only TKV assessed from 1 month to 18 months will be included in the linear 
mixed effect model. TKV at baseline will be excluded from this secondary analysis. 
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11.4.2.1.2 Stage 2 
In Stage 2, the primary efficacy endpoint is the annualized rate of change in eGFR 
(CKD-EPI equation). 
The analysis of eGFR will be similar to those of TKV, with the exception that no log 
transformation will be used for eGFR. Baseline eGFR will be defined for each patient as the 
average of eGFR values assessed prior to randomization. 
Primary analysis in Stage 2 will combine all data from Stage 1 and Stage 2 available from 
baseline to the end of the 24-month double-blind core treatment period. Primary analysis will 
include all observed eGFR data in randomized patients, regardless of whether or not patients 
completed the treatment period (treatment policy strategy). Patients who prematurely and 
permanently discontinue study medication will be requested to obtain eGFR at 24 months. 
All efforts will be made to minimize the amount of missing data. 
Missing data will be handled using methods similar to those of TKV. Additional details are 
included in Appendix J. 
A secondary analysis will estimate the effect of venglustat while patients are still on treatment. 
11.4.2.2 Analyses of secondary efficacy endpoints 
11.4.2.2.1 Stage 1: Annualized rate of change in eGFR 
In Stage 1, the annualized rate of change in eGFR (CKD-EPI equation) is a secondary efficacy 
endpoint. 
The analysis of eGFR in Stage 1 will include all data from Stage 1 available at the cut-off date 
(ie, including data reported up to Month 24, if any). The cut-off date will be defined as the date all 
patients from Stage 1 have completed the Month 18 visit (or have discontinued the study).  
The analysis of eGFR in Stage 1 will be identical to those of Stage 2 (see Section 11.4.2.1.2) 
11.4.2.2.2 Stage 1: Change in pain (BPI- Item 3) from baseline to 18 months 
In Stage 1, change in pain from baseline to 18 months is a secondary efficacy endpoint. Pain score 
will be based on BPI Item 3, assessed from the daily symptom diary. 
Daily diaries scores will be averaged over 7 consecutive assessments prior to the baseline, 
Month 3 and Month 12 visit and over the 14 consecutive days prior to the planned Month 18 visit. 
At least 50% of the days in the observation period (ie, 4 or more of the 7 days for baseline, 
Month 3 and Month 12; 7 or more of the 14 days for Month 18) are required to calculate the 
average score on-missing data. 
Change in pain from baseline will be analyzed using a mixed effect model with repeated measures 
(MMRM). The model will include the fixed categorical effects of treatment (venglustat 15 mg, 
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venglustat 8 mg, or placebo), Mayo Imaging Classification (as per randomization stratification 
factor: Class 1C versus 1D versus 1E), time point (Month 3, Month 12, Month 18), treatment-by-
time point interaction, randomization strata-by-time point interaction as well as the continuous 
fixed covariates of baseline and the baseline-by-time point interaction.  
This model will be run using SAS Mixed procedure with an unstructured correlation matrix to 
model the within-patient errors. Parameters will be estimated using restricted maximum likelihood 
method. Denominator degrees of freedom will be estimated using Kenward-Roger approximation. 
This model will provide baseline adjusted least-squares means estimates at Month 18 for each 
treatment groups with their corresponding standard errors (SE) and 95% confidence intervals (CI). 
Within group mean change in pain will be obtained from the MMRM, using weights for each 
stratum (Mayo Class 1C, 1D and 1E) equal to the overall proportion of patients in each stratum in 
the Stage 1 ITT population (ie, “population weight”). 
Overall effect of venglustat will be assessed using a Multiple Comparison Procedure similar to 
those of the primary endpoint (see Section 11.4.2.1). In addition, p values for the comparison of 
each dose of venglustat versus placebo will be presented for descriptive purpose. 
11.4.2.2.3 Stage 1: Change in fatigue (BFI- Item 3) from baseline to 18 months 
In Stage 1, change in fatigue from baseline to 18 months is a secondary efficacy endpoint. Fatigue 
score will be based on BFI Item 3, assessed from the daily symptom diary. 
Change in fatigue will be analyzed using the same method as change in pain. 
11.4.2.2.4 Stage 2: Annualized rate of change in TKV 
In Stage 2, the annualized rate of change in TKV is a secondary efficacy endpoint. 
The analysis of TKV in Stage 2 will combine all data from Stage 1 and Stage 2 available from 
baseline to the end of the double-blind core treatment period. 
The analysis of TKV in Stage 2 will be identical to those of Stage 1 (see Section 11.4.2.1.1). 
11.4.2.2.5 Stage 2: Change in pain (BPI- Item 3) from baseline to 24 months 
In Stage 2, change in pain from baseline to 24 months is a secondary efficacy endpoint. Pain score 
will be based on BPI Item 3, assessed from the daily symptom diary. 
Change in pain in Stage 2 will be analyzed using the same method as change in pain in Stage 1, 
with the exception that an additional time-point at Month 24 will be included. 
11.4.2.2.6 Stage 2: Change in fatigue (BFI- Item 3) from baseline to 24 months 
In Stage 2, change in fatigue from baseline to 24 months is a secondary efficacy endpoint. Fatigue 
score will be based on BFI Item 3, assessed from the daily symptom diary. 
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Change in fatigue in Stage 2 will be analyzed using the same method as change in fatigue in 
Stage 1, with the exception that an additional time-point at Month 24 will be included. 
11.4.2.3 Multiplicity considerations 
A weighted Bonferroni-based closed test procedure will be used in order to control the Type I 
error rate for the entire study. This procedure will handle both multiplicity of endpoints (primary 
and secondary endpoints) and multiplicity of analysis (analysis at end of Stage 1 and analysis at 
end of Stage 2). Multiplicity of doses will be handled using the Multiple Comparison Procedure 
described in Section 11.4.2.1.1. 
The statistical procedure is illustrated using a graphical approach (19) and is shown in Figure 3. 
This procedure will ensure a strong control of the overall Type-I error rate at the 0.05 level for the 
entire study. No further adjustments will be made for sensitivity analyses, secondary analyses or 
analyses of other secondary efficacy endpoints, for which p-values will be provided for 
descriptive purpose only. In addition, p-values for the comparison of each dose of venglustat 
versus placebo will be presented for descriptive purpose. 
Figure 3 - Graphical illustration of the procedure for handling multiplicity 
TKV growth rate
End of stage 1
eGFR rate of decline
End of stage 1
eGFR rate of decline
End of stage 2
a = 0.04
0.975
0.025
a = 0.01
1
TKV growth rate
End of stage 2
Change in pain
End of stage 2
1
Change in fatigue
End of stage 2
1
Analysis at 
end of Stage 1
Primary endpoint
Secondary endpoints
Analysis at 
end of Stage 2
Change in pain
End of stage 1
1
Change in fatigue
End of stage 1
1
 
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Note: Analysis at end of Stage 1 includes all data from Stage 1 available at the cut-off date 
(defined as the date all patients from Stage 1 have completed the Month 18 visit or have 
discontinued the study) including data reported up to Month 24, if any. Analysis at end of Stage 2 
includes all data from Stage 1 and Stage 2 available from baseline to the end of the 24-month 
double-blind core treatment period. Analysis of each endpoint is based on a Multiple Comparison 
Procedure. 
11.4.2.4 Secondary analysis including patients from Stage 2 with eGFR between 30 and 
44.9 mL/min/1.73 m2 at screening 
A secondary analysis of eGFR will include the following patients: 
• Patients from Stage 1 randomized to placebo or to the selected dose of venglustat (N=160) 
• Patients from Stage 2 with eGFR between 45 and 89.9 mL/min/1.73 m2 at screening 
(N=320) 
• Patients from Stage 2 with eGFR between 30 and 44.9 mL/min/1.73 m2 at screening 
(N=80) 
The purpose of this secondary analysis will be to make model-based inferences about the 
dependence of the treatment effect on baseline eGFR. 
A linear mixed effect model will be fitted to the eGFR, which will include fix effects of treatment 
(venglustat or placebo), Mayo Imaging Classification (as per randomization stratification factor: 
Class 1C versus 1D versus 1E), eGFR at screening (as a continuous variable), time (as a 
continuous variable), treatment * time interaction, Mayo Imaging Classification * time 
interaction, eGFR at screening * time interaction, as well as the treatment * eGFR at screening * 
time interaction. The model will also include random intercept and slope. 
Mean eGFR slopes within each treatment group (venglustat or placebo), as well as the difference 
in eGFR slopes, will be estimated for the following patient categories: 
• Patients with eGFR at screening of 30 to 44.9 mL/min/1.73 m2 
• Patients with eGFR at screening of 45 to 59.9 mL/min/1.73 m2 
• Patients with eGFR at screening of 60 to 74.9 mL/min/1.73 m2 
• Patients with eGFR at screening of 75 to 89.9 mL/min/1.73 m2 
Estimates within each category will be calculated from the linear mixed effect model, using the 
center of each category as eGFR at screening in the model. Difference in slopes will be presented 
with 80% CI. 
11.4.3 Analyses of safety data 
The observation period will be divided into 4 periods: 
• The pretreatment period is defined as the time from the signed informed consent date up to 
the day prior to the first double-blind IMP administration. 
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• The on-treatment period is defined as the time from the first administration of the IMP to 
the last administration of the IMP +1, including any temporary treatment discontinuation 
period, if any. 
• The residual treatment period is defined as the time from the day after the last IMP 
administration plus 30 days or up to the first visit in the long-term extension study, 
whichever comes earlier: 
- 
The treatment-emergent period will include both the on-treatment and the residual 
treatment periods. 
• The post-treatment period is defined as the period of time starting the day after the end of 
the TEAE period up to the end of the study. 
All safety analyses will be performed on the safety population using the following common rules: 
The baseline value is defined generally as the last available value before first IMP administration. 
The following definitions will be applied to laboratory parameters, vital signs and ECG. 
• 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, vital signs, and ECG.  
• Potentially clinically significant abnormality criteria will determine which patients had at 
least 1 PCSA during the treatment-emergent period, taking into account all evaluations 
performed during the treatment emergent period, including unscheduled or repeated 
evaluations, local and central evaluations. The number of all such patients will be the 
numerator for the treatment emergent period PCSA percentage.  
11.4.3.1 Adverse events 
Adverse events will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA). The AEs will be classified into predefined standard categories according to 
chronological criteria: 
• Pretreatment AEs: AEs that occurred or worsened during the pre-treatment period. 
• Treatment emergent AEs: AEs that occurred or worsened during the treatment-emergent 
period. 
• Post-treatment AEs: AEs that occurred or worsened during the post-treatment period. 
Adverse event incidence tables will present by system organ class (SOC) (sorted by 
internationally agreed order), high-level group term (HLGT), high level term (HLT) and preferred 
term (PT) sorted in alphabetical order for each treatment group, and the number (n) and 
percentage (%) of patients experiencing an AE. Multiple occurrences of the same event in the 
same patient will be counted only once in the tables within a treatment phase. The denominator 
for computation of percentages is the safety population within each treatment group. 
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Death:  
The following deaths summaries will be generated: 
• Number (%) of patients who died by study period (treatment emergent period, on-study) 
summarized on the safety population by treatment received. 
• Death in nonrandomized patients or randomized and not treated patients. 
• TEAE leading to death (death as an outcome on the AE eCRF page as reported by the 
Investigator) by primary SOC and PT. 
11.4.3.2 Laboratory data and vital signs 
The summary statistics (including mean, standard deviation, median, Q1, Q3, minimum, and 
maximum) of all laboratory variables and all vital signs parameters (raw data and changes from 
baseline) will be calculated for each visit, last and worst value assessed during the treatment 
period, and presented by treatment group.  
The incidence of PCSAs at any time during the treatment emergent period will be summarized by 
treatment group whatever the baseline level and/or according to the following baseline categories: 
• Normal/missing. 
• Abnormal according to PCSA criterion or criteria. 
For laboratory parameters for which PCSA criterion is not defined, similar table(s) using the 
normal range could be provided. 
Liver tests 
The liver function tests, namely ALT, AST, alkaline phosphatase, and total bilirubin, are used to 
assess possible drug-induced liver toxicity. The proportion of patients with PCSA values at any 
postbaseline visit by baseline status will be displayed by treatment group for each parameter. 
The proportion of patients with PCSA values at any postbaseline visit will also be displayed by 
duration of exposure for each treatment group. 
A graph of distribution of peak values of ALT versus peak values of total bilirubin will also be 
presented. Note that the ALT and total bilirubin values are presented on a logarithmic scale. The 
graph will be divided into 4 quadrants with a vertical line corresponding to 3 x ULN for ALT and 
a horizontal line corresponding to 2 x ULN for total bilirubin. 
The normalization (to 1 x ULN or return to baseline if baseline > ULN) of elevated liver 
function tests will be summarized by categories of elevation (3 x ULN, 5 x ULN, 10 x ULN, 
20 x ULN for ALT and AST; 1.5 x ULN for alkaline phosphatase; and 1.5 x ULN and 2 x ULN 
for total bilirubin), with the following categories of normalization: return to baseline PCSA status 
before last IMP dose, return to baseline PCSA status after last IMP dose, never returned to 
baseline PCSA status, no assessment after elevation. Note that a patient will be counted only 
under the maximum elevation category.  
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The incidence of liver-related AEs will be summarized by treatment group. The selection of 
preferred terms will be based on standardized MedDRA query (SMQ) Hepatic disorder. Time to 
liver-related treatment discontinuation and time to liver death may also be provided based on 
hepatic disorder SMQ. 
11.4.4 Analyses of pharmacokinetic and pharmacodynamic variables 
Each PD variable will be summarized and compared between venglustat 15 mg, venglustat 8 mg, 
and placebo using descriptive statistics at each time point, including assessment of observed 
values and percent change from baseline.  
For PK analysis: Trough concentrations (pre-dose) along with other single time point plasma 
concentration data will be summarized by dose and visit. The data will be reported for individual 
patients and summarized using descriptive statistics. Plasma concentrations data will be reported 
separately for Stage 1 and Stage 2. 
Exploratory metabolite analysis may be performed on selected plasma samples. If data permit, 
PK parameters will be estimated for metabolites using noncompartmental methods. These will be 
summarized using descriptive statistics. 
Plasma venglustat concentration data might be used for population PK modeling if considered 
necessary and the results of population PK modeling will be reported separately from the study 
report. The population PK analyses will characterize the inter- and intra- subject variability in PK 
parameters and evaluate the effect of covariates such as, but not limited to, demographics (eg, age, 
gender, body weight, race), and disease status on oral clearance and volume. 
Exploratory PK-PD analyses may be performed as deemed necessary to evaluate 
exposure-response relationships (in particular TKV, eGFR and safety parameters). 
11.4.5 Analyses of patient reported outcomes (health-related quality of life/health 
economics variables) 
Both total scores and subscale scores of PROs will be calculated. Each PRO will be scored 
according to their scoring guidelines, including handling the missing items. The daily diaries 
baseline scores and thereafter the average score over 14 days prior to the quarterly visits will be 
calculated and correlations between these scores and their respected questionnaires will be 
calculated. The calculation of a diary score requires least 50% of non-missing data (ie, 4 or more 
of the 7 days for baseline, Month 3 and Month 12; 7 or more of the 14 days for Month 18 and 
Month 24) (21, 22) 
Change from baseline to Month 18 and Month 24 in pain and fatigue is described in 
Section 11.4.2.2. Change from baseline to Month 18 and Month 24 in other PROs’ total score and 
their subscales will be analyzed using an MMRM similar to pain and fatigue.  
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11.5 
INTERIM AND FINAL ANALYSIS 
11.5.1 Dose selection safety review 
The dose selection safety review will be performed when the first 150 patients from Stage 1 have 
completed 1 month of treatment (or have prematurely discontinued). 
The dose selection safety review will be performed by the DMC. An unblinded safety report will 
be prepared by the external independent DMC statistician and will be reviewed by the DMC. 
Safety data will include AEs (including SAEs and AEs leading to permanent treatment 
discontinuation), clinical laboratory evaluation, ECG, physical and ophthalmological examination, 
and BDI-II data. 
Based on this safety review, the DMC will select the venglustat dose for Stage 2 (8 mg or 15 mg). 
The selected dose will be the highest dose determined to be safe and well tolerated. 
11.5.2 Interim futility analysis 
An interim analysis for futility will be performed when all patients from Stage 1 have completed 
the first 9 months of treatment and approximately 30% have completed 18 months of treatment 
with TKV available (or have prematurely discontinued). 
The interim analysis will be performed by the external independent statistician and will be 
reviewed under the supervision of the DMC. The interim analysis will primarily focus on the 
primary endpoint in Stage 1 (annualized rate of change in TKV) and stopping rules will be based 
on this primary endpoint. Data monitoring committee will also review secondary efficacy 
endpoint (annualized rate of change in eGFR) and safety data (AEs, laboratory data, vital signs) 
available at the time of the interim analysis. 
Futility may be declared if the one-sided p-value of the primary endpoint at the interim analysis is 
>0.30. The one-sided p-value will be determined from the Multiple Comparison Procedure 
described in Section 11.4.2.1.1. Based on simulations, it is expected that futility may be declared 
if the relative reduction versus placebo in TKV growth rate estimated at the interim analysis is 
approximately less than 15%. Probability to declare futility under different scenarios is presented 
in Appendix J. 
Of note, the futility rule is provided as a guideline for the DMC but should not be considered as a 
strict stopping rule. In case the one-sided p-value observed at the interim analysis is close to the 
pre-specified threshold, the DMC will review the totality of data available at the time of interim 
analysis, including safety data (AEs, laboratory data, vital signs), and based on these data, may 
decide to overrule the futility rule. 
In order to protect the global type one error in case the decision is taken to overrule the futility 
rule, nonbinding futility rules will be used for determination of alpha. 
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11.5.3 Two-step final analysis 
The analysis will be conducted in two steps: 
• First step: conducted when all patients from Stage 1 have been randomized and have 
completed the Month 18 visit (or have discontinued the study). This analysis will be 
conducted after a partial database lock. First step analysis in Stage 1 will include all 
collected and validated data from Stage 1 population, up to the cut-off date (including data 
reported up to Month 24 visit, if any). 
• Second step: conducted when all patients from Stage 2 have completed the study and will 
consist of the final analysis of the combined Stage 1 and Stage 2 study. This analysis will 
be conducted after the final database lock. 
The results of the first step analysis will not be used to change the conduct of the ongoing study in 
any aspect. This first analysis will be used for the submission of the registration dossier to health 
authorities accepting TKV growth rate change as a surrogate endpoint reasonably likely to predict 
changes in eGFR slope.  
First step analysis will be conducted before all patients from Stage 1 have completed the 
24-month treatment period. However, treatment allocated to each individual patient will not be 
released to anyone who is directly involved in the conduct of Stage 1 of the study until Stage 1 is 
fully completed. 
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12 
ETHICAL AND REGULATORY CONSIDERATIONS 
12.1 
ETHICAL AND REGULATORY STANDARDS 
This clinical trial will be conducted by the Sponsor, the Investigator, and delegated Investigator 
staff and Subinvestigator, in accordance with consensus ethics principles derived from 
international ethics guidelines, including the Declaration of Helsinki, and the ICH guidelines for 
Good Clinical Practice (GCP), all applicable laws, rules and regulations. 
This clinical trial will be recorded in a free, publicly accessible, internet-based registry, no later 
than 21 days after the first patient enrollment, in compliance with applicable regulatory 
requirements and with Sanofi public disclosure commitments.  
12.2 
INFORMED CONSENT 
The Investigator (according to applicable regulatory requirements), or a person designated by the 
Investigator, and under the Investigator's responsibility, should fully inform the patient of all 
pertinent aspects of the clinical trial including the written information giving approval/favorable 
opinion by the ethics committee (IRB/IEC). All patients should be informed to the fullest extent 
possible about the study, in language and terms they are able to understand. 
Prior to a patient’s participation in the clinical trial, the written informed consent form should be 
signed, name filled in and personally dated by the patient, and by the person who conducted the 
informed consent discussion. A separate informed consent form will be used in Stage 1 and 
Stage 2 of the study. A copy of the signed and dated written informed consent form will be 
provided to the patient.  
The informed consent form used by the Investigator for obtaining the patient's informed consent 
must be reviewed and approved by the Sponsor prior to submission to the appropriate ethics 
committee (IRB/IEC) for approval/favorable opinion. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix O. 
12.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC)  
As required by local regulation, the Investigator or the Sponsor must submit this clinical trial 
protocol to the health authorities (competent regulatory authority) and the appropriate IRB/IEC 
and is required to forward to the respective other party a copy of the written and dated 
approval/favorable opinion signed by the chairman with IRB/IEC composition. 
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The clinical trial (study number, clinical trial protocol title and version number), the documents 
reviewed (clinical trial protocol, informed consent form, and IB, Investigator’s curriculum vitae 
[CV], etc) and the date of the review should be clearly stated on the written (IRB/IEC) 
approval/favorable opinion. 
The IMP will not be released at the study site and the Investigator will not start the study before 
the written and dated approval/favorable opinion is received by the Investigator and the Sponsor. 
During the clinical trial, any amendment or modification to the clinical trial protocol should be 
submitted to the health authorities (competent regulatory authority), as required by local 
regulation, in addition to the IRB/IEC before implementation, unless the change is necessary to 
eliminate an immediate hazard to the patients, in which case the health authorities (competent 
regulatory authority) and the IRB/IEC should be informed as soon as possible. They should also 
be informed of any event likely to affect the safety of patients or the continued conduct of the 
clinical trial, in particular any change in safety. All updates to the IB will be sent to the IRB/IEC 
and to health authorities (competent regulatory authority), as required by local regulation. 
A progress report is sent to the IRB/IEC at least annually and a summary of the clinical trial’s 
outcome at the end of the clinical trial.  
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13 
STUDY MONITORING 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S) 
The Investigator is required to ensure compliance with all procedures required by the clinical trial 
protocol and with all study procedures provided by the Sponsor (including security rules). 
The Investigator agrees to provide reliable data and all information requested by the clinical trial 
protocol (with the help of the eCRF, Discrepancy Resolution Form [DRF] or other appropriate 
instrument) in an accurate and legible manner according to the instructions provided and to ensure 
direct access to source documents by Sponsor representatives. 
If any circuit includes transfer of data particular attention should be paid to the confidentiality of 
the patient's data to be transferred. 
The Investigator may appoint such other individuals as he/she may deem appropriate as 
Subinvestigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol. All Subinvestigators shall be appointed and listed in a timely manner. 
The Subinvestigators will be supervised by and work under the responsibility of the Investigator. 
The Investigator will provide them with a copy of the clinical trial protocol and all necessary 
information. 
13.2 
RESPONSIBILITIES OF THE SPONSOR 
The Sponsor of this clinical trial is responsible to regulatory authorities for taking all reasonable 
steps to ensure the proper conduct of the clinical trial as regards ethics, clinical trial protocol 
compliance, and integrity and validity of the data recorded on the eCRFs. Thus, the main duty of 
the monitoring team is to help the Investigator and the Sponsor maintain a high level of ethical, 
scientific, technical and regulatory quality in all aspects of the clinical trial. 
At regular intervals during the clinical trial, the site will be contacted, through monitoring visits, 
letters or telephone calls, by a representative of the monitoring team to review study progress, 
Investigator and patient compliance with clinical trial protocol requirements and any emergent 
problems. These monitoring visits will include but not be limited to review of the following 
aspects: patient informed consent, patient recruitment and follow-up, SAE documentation and 
reporting, AESI documentation and reporting, AE documentation, IMP allocation, patient 
compliance with the IMP regimen, IMP accountability, concomitant therapy use and quality of 
data. 
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. 
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13.3 
SOURCE DOCUMENT REQUIREMENTS 
According to the ICH GCP, the monitoring team must check the eCRF entries against the source 
documents, except for the pre-identified source data directly recorded in the eCRF. The informed 
consent form will include a statement by which the patient allows the Sponsor’s duly authorized 
personnel, the ethics committee (IRB/IEC), and the regulatory authorities to have direct access to 
original medical records which support the data on the eCRFs (eg, patient's medical file, 
appointment books, original laboratory records). These personnel, bound by professional secrecy, 
must maintain the confidentiality of all personal identity or personal medical information 
(according to confidentiality and personal data protection rules). 
13.4 
USE AND COMPLETION OF ELECTRONIC CASE REPORT FORMS (eCRFs) AND 
ADDITIONAL REQUEST 
It is the responsibility of the Investigator to ensure that the previous use of tolvaptan is 
documented (physician assessment, intolerant, unwilling or naïve patient with no access) and to 
maintain adequate and accurate eCRFs (according to the technology used) designed by the 
Sponsor to record (according to Sponsor instructions) all observations and other data pertinent to 
the clinical investigation in a timely manner. All eCRFs should be completed in their entirety in a 
neat, legible manner to ensure accurate interpretation of data. 
Should a correction be made, the corrected information will be entered in the eCRF overwriting 
the initial information. An audit trail allows identifying the modification.  
Data are available within the system to the Sponsor as soon as they are entered in the eCRF. 
The computerized handling of the data by the Sponsor may generate additional requests (DRF) to 
which the Investigator is obliged to respond by confirming or modifying the data questioned. 
The requests with their responses will be managed through the eCRF. 
13.5 
USE OF COMPUTERIZED SYSTEMS 
The complete list of computerized systems used for the study is provided in a separate document 
which is maintained in the Sponsor trial master file. 
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14 
ADDITIONAL REQUIREMENTS 
14.1 
CURRICULUM VITAE 
A current copy of the curriculum vitae describing the experience, qualification, and training of 
each Investigator and Subinvestigator will be signed, dated, and provided to the Sponsor prior to 
the beginning of the clinical trial. 
14.2 
RECORD RETENTION IN STUDY SITES 
The Investigator must maintain confidentiality of all study documentation and take measures to 
prevent accidental or premature destruction of these documents. 
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. 
If the Investigator's personal situation is such that archiving can no longer be ensured by him/her, 
the Investigator shall inform the Sponsor and the relevant records shall be transferred to a 
mutually agreed upon designee.  
14.3 
CONFIDENTIALITY 
All information disclosed or provided by the Sponsor (or any company/institution acting on their 
behalf), or produced during the clinical trial, including, but not limited to, the clinical trial 
protocol, personal data in relation to the patients, the eCRFs, the IB and the results obtained 
during the course of the clinical trial, is confidential, prior to the publication of results. The 
Investigator and any person under his/her authority agree to undertake to keep confidential and 
not to disclose the information to any third party without the prior written approval of the 
Sponsor.  
However, the submission of this clinical trial protocol and other necessary documentation to the 
ethics committee (IRB/IEC) is expressly permitted, the IRB/IEC members having the same 
obligation of confidentiality. 
The Subinvestigators shall be bound by the same obligation as the Investigator. The Investigator 
shall inform the Subinvestigators of the confidential nature of the clinical trial. 
The Investigator and the Subinvestigators shall use the information solely for the purposes of the 
clinical trial, to the exclusion of any use for their own or for a third party's account. 
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14.4 
PROPERTY RIGHTS 
All information, documents and IMP provided by the Sponsor or its designee are and remain the 
sole property of the Sponsor. 
The Investigator shall not and shall cause the delegated Investigator staff/Subinvestigator not to 
mention any information or the Product in any application for a patent or for any other intellectual 
property rights. 
All the results, data, documents and inventions, which arise directly or indirectly from the clinical 
trial in any form, shall be the immediate and exclusive property of the Sponsor. 
The Sponsor may use or exploit all the results at its own discretion, without any limitation to its 
property right (territory, field, continuance). The Sponsor shall be under no obligation to patent, 
develop, market or otherwise use the results of the clinical trial. 
As the case may be, the Investigator and/or the Subinvestigators shall provide all assistance 
required by the Sponsor, at the Sponsor's expense, for obtaining and defending any patent, 
including signature of legal documents. 
14.5 
DATA PROTECTION 
• The patient's personal data, which are included in the Sponsor database shall be treated in 
compliance with all applicable laws and regulations. 
• When archiving or processing personal data pertaining to the Investigator and/or to the 
patients, the Sponsor shall take all appropriate measures to safeguard and prevent access to 
this data by any unauthorized third party. 
• The Sponsor also collects specific data regarding Investigator as well as personal data 
from any person involved in the study which may be included in the Sponsor’s databases, 
shall be treated by both the Sponsor and the Investigator in compliance with all applicable 
laws and regulations. 
Patient race or ethnicity (eg, "American Indian or Alaska Native, Asian, Black/Black or African 
American, Native Hawaiian or Other Pacific Islander, White, Not Reported or Unknown") will be 
collected in this study if permitted by local regulations, because these data are required by several 
regulatory authorities (eg, on afro American population for FDA or on Japanese population for the 
PMDA in Japan). 
Analyses of patient genetic data will be conducted as described in the protocol as this is needed 
for pharmacogenetics analyses required for the purposes of the study or by regulatory authorities. 
The data collected in this study will only be used for the purpose(s) of the study and to document 
the evaluation of the benefit/risk ratio, efficacy, and safety of the product(s). They may be further 
processed if they have been anonymized. 
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14.6 
INSURANCE COMPENSATION 
The Sponsor certifies that it has taken out a liability insurance policy covering all clinical trials 
under its sponsorship. This insurance policy is in accordance with local laws and requirements. 
The insurance of the Sponsor does not relieve the Investigator and the collaborators from any 
obligation to maintain their own liability insurance policy. An insurance certificate will be 
provided to the IECs/IRBs or regulatory authorities in countries requiring this document.  
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES 
For the purpose of ensuring compliance with the clinical trial protocol, good clinical practice, and 
applicable regulatory requirements, the Investigator should permit auditing by or on the behalf of 
the Sponsor and inspection by regulatory authorities. 
The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel is bound by professional secrecy, and as 
such will not disclose any personal identity or personal medical information. 
The Investigator will make every effort to help with the performance of the audits and inspections, 
giving access to all necessary facilities, data, and documents. 
As soon as the Investigator is notified of a planned inspection by the authorities, he will inform 
the Sponsor and authorize the Sponsor to participate in this inspection. 
The confidentiality of the data verified and the protection of the patients should be respected 
during these inspections. 
Any result and information arising from the inspections by the regulatory authorities will be 
immediately communicated by the Investigator to the Sponsor. 
The Investigator shall take appropriate measures required by the Sponsor to take corrective 
actions for all problems found during the audit or inspections. 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE 
14.8.1 By the Sponsor  
The Sponsor has the right to terminate the participation of either an individual site or the study at 
any time, for any reason, including but not limited to the following:  
• The information on the product leads to doubt as to the benefit/risk ratio. 
• Patient enrollment is unsatisfactory. 
• The Investigator has received from the Sponsor all IMP, means, and information necessary 
to perform the clinical trial and has not included any patient after a reasonable period of 
time mutually agreed upon. 
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• Noncompliance of the Investigator or Subinvestigator, delegated staff with any provision 
of the clinical trial protocol, and breach of the applicable laws and regulations or breach of 
the ICH GCP. 
• The total number of patients are included earlier than expected. 
• If the study no longer meets the development needs of the compound or business needs of 
the company. 
In any case the Sponsor will notify the Investigator of its decision by written notice. 
14.8.2 By the Investigator 
The Investigator may terminate his/her participation upon 30 days' prior written notice if the study 
site or the Investigator for any reason becomes unable to perform or complete the clinical trial.  
In the event of premature discontinuation of the study or premature close-out of a site, for any 
reason whatsoever, the appropriate IRB/IEC and regulatory authorities should be informed 
according to applicable regulatory requirements. 
14.9 
CLINICAL TRIAL RESULTS 
The Sponsor will be responsible for preparing a clinical study report and to provide a summary of 
study results to the Investigator. 
14.10 PUBLICATIONS AND COMMUNICATIONS 
The Investigator undertakes not to make any publication or release pertaining to the study and/or 
results of the study prior to the Sponsor’s written consent, being understood that the Sponsor will 
not unreasonably withhold its approval. 
As the study is being conducted at multiple sites, the Sponsor agrees that, consistent with 
scientific standards, a primary presentation or publication of the study results based on global 
study outcomes shall be sought. However, if no multicenter publication is submitted, underway, 
or planned within 12 months of the completion of this study at all sites, the Investigator shall have 
the right to publish or present independently the results of this study in agreement with other 
Investigators and stakeholders. The Investigator shall provide the Sponsor with a copy of any such 
presentation or publication for review and comment at least 30 days in advance of any 
presentation or submission for publication. In addition, if requested by the Sponsor, any 
presentation or submission for publication shall be delayed for a limited time, not to exceed 
90 days, to allow for filing of a patent application or such other justified measures as the Sponsor 
deems appropriate to establish and preserve its proprietary rights.  
The Investigator shall not use the name(s) of the Sponsor and/or its employees in advertising or 
promotional material or publication without the prior written consent of the Sponsor. The Sponsor 
shall not use the name(s) of the Investigator and/or the collaborators in advertising or promotional 
material or publication without having received his/her and/or their prior written consent(s). 
The Sponsor has the right at any time to publish the results of the study. 
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15 
CLINICAL TRIAL PROTOCOL AMENDMENTS 
All appendices attached hereto and referred to herein are made part of this clinical trial protocol. 
The Investigator should not implement any deviation from, or changes to the clinical trial protocol 
without agreement by the Sponsor and prior review and documented approval/favorable opinion 
from the IRB/IEC and/or notification/approval of health authorities (competent regulatory 
authority) of an amendment, as required by local regulation, except where necessary to eliminate 
an immediate hazard(s) to clinical trial patients, or when the change(s) involves only logistical or 
administrative aspects of the trial. Any change agreed upon will be recorded in writing, the 
written amendment will be signed by the Investigator and by the Sponsor and the signed 
amendment will be filed with this clinical trial protocol. 
Any amendment to the clinical trial protocol requires written approval/favorable opinion by the 
IRB/IEC prior to its implementation, unless there are overriding safety reasons. 
In case of substantial amendment to the clinical trial protocol, approval from the health authorities 
(competent regulatory authority) will be sought before implementation. 
In some instances, an amendment may require a change to the informed consent form. The 
Investigator must receive an IRB/IEC approval/favorable opinion concerning the revised informed 
consent form prior to implementation of the change and patient signature should be re-collected if 
necessary. 
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16 
BIBLIOGRAPHIC REFERENCES 
1. Willey CJ, Blais JD, Hall AK, Krasa HB, Makin AJ, Czerwiec FS. Prevalence of autosomal 
dominant polycystic kidney disease in the European Union. Nephrol Dial Transplant. 
2017;32(8):1356-63. 
2. Irazabal MV, Abebe KZ, Bae KT, Perrone RD, Chapman AB, Schrier RW, et al. Prognostic 
enrichment design in clinical trials for autosomal dominant polycystic kidney disease: the 
HALT-PKD clinical trial. Nephrol Dial Transplant. 2017;32(11):1857:65. 
3. Irazabal MV, Rangel LJ, Bergstralh EJ, Osborn SL, Harmon AJ, Sundsbak JL, et al. Imaging 
classification of autosomal dominant polycystic kidney disease: a simple model for selecting 
patients for clinical trials. J Am Soc Nephrol. 2015;26(1):160-72. 
4. Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Grantham JJ, Higashihara E, et al. 
Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 
2012;367(25):2407-18. 
5. Schrier RW, Abebe KZ, Perrone RD, Torres VE, Braun WE, Steinman TI, et al; HALTPKD 
Trial Investigators: Blood pressure in early autosomal dominant polycystic kidney disease. N 
Engl J Med. 2014;371(24):2255-66. 
6. Sommerer C, Zeier M. Clinical manifestation and management of ADPKD in western 
countries. Kidney Dis (Basel). 2016;(3):120-7. 
7. Campbell KL, Rangan GK, Lopez-Vargas P, Tong A. KHA-CARI Autosomal Dominant 
Polycystic Kidney Disease Guideline: Diet and Lifestyle Management. Semin Nephrol. 
2015;35(6):572-81. 
8. Deshmukh GD, Radin NS, Gattone VH 2nd, Shayman JA. Abnormalities of 
glycosphingolipid, sulfatide, and ceramide in the polycystic (cpk/cpk) mouse. J Lipid Res. 
1994;35(9):1611-8. 
9. Chatterjee S, Shi WY, Wilson P, Mazumdar A. Role of lactosylceramide and MAP kinase in 
the proliferation of proximal tubular cells in human polycystic kidney disease. J Lipid Res. 
1996;37(6):1334-44. 
10. Natoli TA, Smith LA, Rogers KA, Wang B, Komarnitsky S, Budman Y, et al. Inhibition of 
glucosylceramide accumulation results in effective blockade of polycystic kidney disease in 
mouse models. Nat Med. 2010;16(7):788-92. 
11. Cole AL, Lee PJ, Hughes DA, Deegan PB, Waldek S, Lachmann RH. Depression in adults 
with Fabry disease: a common and under-diagnosed problem. J Inherit Metab Dis. 
2007;30(6):943-51. 
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12. Pei Y, Obaji J, Dupuis A, Paterson AD, Magistroni R, Dicks E, et al. Unified criteria for 
ultrasonographic diagnosis of ADPKD. J Am Soc Nephrol. 2009;20(1):205-12. 
13. Thylefors B, Chylack LT Jr, Konyama K, Sasaki K, Sperduto R, Taylor HR, et al. WHO 
Cataract Grading Group. A simplified cataract grading system. Ophthalmic Epidemiol. 
2002;9(2):83-95. 
14. Hongwei Ji et al. GFRs from Asian-modified CKD-EPI and Chinese-modified CKD-EPI 
equations were associated better with hypertensive target organ damage in the community-
dwelling elderly Chinese: the Northern Shanghai Study. Clin Interv Aging. 2017;12:1297-308. 
15. Horio M, Imai E, Yasuda Y, Watanabe T, Matsuo S, et al. Modification of the CKD 
epidemiology collaboration (CKD-EPI) equation for Japanese: accuracy and use for 
population estimates. Am J Kidney Dis. 2010;56(1):32-8. 
16. Pickering TG, Hall JE, Appel LJ, Falkner BE, Graves J, Hill MN, et al. Recommendations for 
blood pressure measurement in humans and experimental animals: part 1: blood pressure 
measurements in humans: a statement for professionals from the Subcommittee of 
Professional and Public Education of the American Heart Association Council on High Blood 
Pressure Research. Circulation 2005;111(5):697-716. 
17. Cleeland C.S. The brief pain inventory: User guide. 2009. 
18. Mendoza TR, Wang XS, Cleeland CS, Morrissey M, Johnson BA, Wendt JK, et al. The rapid 
assessment of fatigue severity in cancer patients: use of the Brief Fatigue Inventory. Cancer. 
1999;85(5):1186-96. 
19. Bretz F, Pinheiro JC, Branson M. Combining multiple comparisons and modeling techniques 
in dose-response studies. Biometrics. 2005;61(3):738-48. 
20. Bornkamp B, Pinheiro J, Bretz F. DoseFinding: planning and analyzing dose finding 
experiments. R package. 2018. 
21. Kammerman LA, Cappelleri J, Bartlett J. Patient-Reported Outcomes. [Online]. Wiley 
StatsRef: Statistics Reference Online. 2017 [cited 2021 Apr]; Available from: 
URL:https://onlinelibrary.wiley.com/doi/pdf/10.1002/9781118445112.stat07929 
22. Sloan JA, Dueck AC, Erickson PA, Guess H, Revicki DA, Santanello NC, et al. Analysis and 
interpretation of results based on patient-reported outcomes. Value Health. 2007;10 Suppl 
2:S106-15. 
23. Pisitkun T, Johnstone R, Knepper MA. Discovery of urinary biomarkers. Mol Cell 
Proteomics. 2006;5(10):1760-71. 
24. Stevens LA, Levey AS. Measured GFR as a confirmatory test for estimated GFR. J Am Soc 
Nephrol. 2009;20(11):2305-13. 
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25. Gaspari F, Perico N, Ruggenenti P, Mosconi L, Amuchastegui CS, Guerini E, et al. Plasma 
clearance of nonradioactive Iohexol as a measure of glomerular filtration rate. J Am Soc 
Nephrol. 1995;6(2):257-63.  
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17 
APPENDICES 
 
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Appendix A 
Contraceptive guidance and collection of pregnancy information 
DEFINITIONS 
Nonreproductive potential 
1. Premenopausal female with 1 of the following: 
NOTE: Documentation can come from the review of patient’s medical records, medical 
examination, or medical history interview. 
- 
Documented hysterectomy. 
- 
Documented bilateral salpingectomy. 
- 
Documented bilateral oophorectomy. 
2. Postmenopausal 
- 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH)/estradiol 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, a single FSH/estradiol measurement is 
insufficient.  
- 
Females on HRT and whose menopausal status is in doubt will be required to use 1 of 
the 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. 
Reproductive potential (WOCBP) 
A woman is considered of reproductive potential (WOCBP), ie, fertile, following menarche and 
until becoming postmenopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. 
CONTRACEPTIVE GUIDANCE 
Male patients 
• Male patients with heterosexual partners of reproductive potential (WOCBP) are eligible 
to participate if they agree to use the following for the duration of the study and for 
90 days following their last dose of study drug: 
- 
Refrain from donating sperm. 
and 
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- 
At least 1 of the following conditions applies: 
- 
Are and agree to remain abstinent from penile-vaginal intercourse on a long-term 
and persistent basis, when this is their preferred and usual lifestyle.  
or 
- 
Agree to use a male condom plus an additional contraceptive method with a failure 
rate of 1% per year (see Table 6 for female patients). 
• Men with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom for the time defined in the protocol. 
Female patients: 
Female patients of childbearing potential are eligible to participate if they agree to use a highly 
effective method of contraception consistently and correctly for the duration of the study and for 
at least 6 weeks following their last dose of study drug as described in Table 6. 
Table 6 - Highly effective contraceptive methods 
Highly Effective Contraceptive Methods That Are User Dependenta 
• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation: 
- 
Oral. 
- 
Intravaginal. 
- 
Transdermal. 
• 
Progestogen-only hormone contraception associated with inhibition of ovulation: 
- 
Oral. 
- 
Injectable. 
Highly Effective Methods That Are User Independent 
• 
Implantable progestogen-only hormone contraception associated with inhibition of ovulationb 
- 
Intrauterine device. 
- 
Intrauterine hormone-releasing system.  
• 
Bilateral tubal occlusion. 
Vasectomized partner. 
A vasectomized partner is a highly effective contraceptive method provided that the partner is the sole sexual partner of the 
WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should 
be used. 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during 
the entire period of risk associated with the study treatment. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the study and the preferred and usual lifestyle of the patient. 
Note:  
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with local regulations 
regarding the use of contraceptive methods for patients participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the efficacy of the contraceptive 
method. In this case 2 highly effective methods of contraception should be utilized during the treatment period and for at least 6 weeks for 
females and 90 days for males following their last dose of study drug. 
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Male patients with partners of reproductive potential who become pregnant:  
• The Investigator will attempt to collect pregnancy information on any female partner of 
a male study patient who becomes pregnant while participating in this study. This applies 
only to patients who receive study treatment. 
• 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.  
• 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, 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 procedure.  
Female patients who become pregnant: 
• The Investigator will collect pregnancy information on any female patient, 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 patient's pregnancy.  
• Patient will be followed to determine the outcome of the pregnancy. The Investigator will 
collect follow-up information on patient and neonate, which 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.  
• Additional follow-up information may be requested about the baby until at least 1 year 
after the birth of the baby, due to potential risk of abnormalities not present at birth. 
• Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.  
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
or elective termination of a pregnancy will be reported as an AE or SAE.  
• A spontaneous abortion is always considered to be an SAE and will be reported as such. 
• Any poststudy pregnancy-related SAE considered reasonably related to the study 
treatment by the Investigator will be reported to the Sponsor as described in 
Section 10.4.3. While the Investigator is not obligated to actively seek this information in 
former study patients, he or she may learn of an SAE through spontaneous reporting. 
• Any female patient who becomes pregnant while participating in the study will 
discontinue study treatment and will be withdrawn from the study. 
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Appendix B 
List of known CYP3A4 inducers/inhibitors 
Please always check/confirm against the Prescribing Information/Summary of Product 
Characteristics and the most up-to-date information on the FDA site: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio
nsLabeling 
CYP3A4 inducers 
Aminoglutethimide 
Nevirapine 
Bexarotene 
Oxcarbazepine 
Bosentan 
Phenobarbital 
Carbamazepine 
Phenytoin 
Dexamethasone 
Primidone 
Efavirenz 
Rifabutin 
Fosphenytoin 
Rifampin 
Griseofulvin 
Rifapentine 
Modafinil 
St. John’s wort 
Nafcillin 
 
CYP3A4 inhibitors 
Amiodarone 
Imatinib 
Amprenavir 
Indinavir 
Atazanavir 
Isoniazid 
Chloramphenicol 
Itraconazole 
Clarithromycin 
Ketoconazole 
Conivaptan 
Lapatinib 
Cyclosporine 
Miconazole 
Darunavir 
Nefazodone 
Dasatinib 
Nelfinavir 
Delavirdine 
Posaconazole 
Diltiazem 
Ritonavir 
Erythromycin 
Quinupristin 
Fluconazole 
Saquinavir 
Fluoxetine 
Tamoxifen 
Fluvoxamine 
Telithromycin 
Fosamprenavir 
Verapamil 
Grapefruit juice 
Voriconazole 
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Appendix G 
Patient global impression of severity (PGIS) 
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Appendix H 
Patient global impression of change (PGIC) 
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Appendix J 
Statistical technical details 
Operating characteristics of the study design 
Operating characteristics were assessed through extensive simulations. All simulations used the 
following assumptions on design and parameters: 
• Sample size of 80 patients per arm in Stage 1 (randomized 1:1:1 to placebo, venglustat 
8 mg or venglustat 15 mg) and of 160 patients per arm in Stage 2 (randomized 1:1 to 
placebo or venglustat). 
• TKV assessed at screening, 1 month, 9 months, and 18 months in Stage 1; at screening and 
24 months in Stage 2. 
• eGFR assessed at baseline, 1 month, 3 months, and then every 3 months, both in Stage 1 
and Stage 2. 
• Mean slope of log10(TKV) of 0.02764 (6.6%/year) in the placebo arm. 
• Standard deviation for the residual error of TKV (on the log10 scale) of 0.02566 and 
standard deviation for the random effect of slope of 0.01477. 
• Mean slope of eGFR of -3.66 mL/min/1.73 m² per year in the placebo arm. 
• Standard deviation for the residual error of eGFR of 6.34 and standard deviation for the 
random effect of slope of 1.98. 
• Correlation between log10(TKV) slope and eGFR slope of -0.35. 
• Dropout rate of 10% at 2 years, assuming an exponential distribution for time to dropout. 
Simulations were based on different scenarios regarding the true effect of venglustat on TKV and 
eGFR. Most scenarios assumed a 50% relative reduction in TKV growth rate and a 30% relative 
reduction in eGFR rate of decline for the venglustat 15 mg, and varying effect of venglustat 8 mg. 
They also assumed that the 15 mg dose was selected in Stage 2. These scenarios are presented in 
Table 7. Additional scenarios assuming that the 8 mg dose was selected in Stage 2 were 
considered and are presented in Table 8. 
For each scenario, 10 000 trials were simulated. Each simulated trial was analyzed according to 
the procedure described in Section 11.4.2. 
• An interim analysis was performed when all patients from Stage 1 had TKV at baseline, 
1 month and 9 months and 30% of patients also had TKV at 18 months (or had 
discontinued). Futility was declared at the interim analysis if the one-sided p-value from 
Multiple Comparison Procedure was >0.30. 
• If no futility was declared at interim analysis, the analysis at end of Stage 1 was performed 
when all patients from Stage 1 had TKV available up to 18 months (or have discontinued). 
It was also assumed that at the cut-off date, 50% of patients from Stage 1 had eGFR 
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available at 21 months and 30% had eGFR available at 24 months. According to the 
procedure for handling multiplicity of test (see Figure 3), the following rules applied: 
- 
A significant effect on TKV at end of Stage 1 was declared if 2 * one-sided p-value 
from Multiple Comparison Procedure was <0.04. 
- 
If a significant effect on TKV was declared, a significant effect on eGFR at end of 
Stage 1 was declared if 2 * one-sided p-value from Multiple Comparison Procedure 
was <0.001. 
• Analysis at end of Stage 2 was performed when all patients from Stage 1 and Stage 2 had 
TKV available up to 18 months and eGFR available up to 24 months (or have 
discontinued). According to the procedure for handling multiplicity of test, the following 
rules applied: 
- 
If a significant effect on TKV was declared at end of Stage 1: A significant effect on 
eGFR at end of Stage 2 was declared if 2 * one-sided p-value from Multiple 
Comparison Procedure was <0.049. 
- 
If no significant effect on TKV was declared at end of Stage 1: A significant effect on 
eGFR at end of Stage 2 was declared if 2 * one-sided p-value from Multiple 
Comparison Procedure was <0.01. 
The probabilities to detect an effect on TKV and eGFR are presented in Table 7 assuming the 
15 mg dose was selected in Stage 2. Under the expected scenario that venglustat 15 mg would 
provide 50% reduction on TKV growth rate and 30% reduction in eGFR rate of decline, and that 
the venglustat 8 mg would provide a slightly reduced efficacy of 40% reduction in TKV and 
25% reduction in eGFR (scenario 2), the study would have approximately 89% power to detect an 
effect on TKV and 87% power to detect an effect on eGFR. It is to be noted that thanks to the 
Multiple Comparison Procedure, the power on TKV and eGFR would remain >80% whatever the 
efficacy of venglustat 8 mg. 
Table 7 - Operating characteristics of the study design assuming the dose 15 mg is selected for 
Stage 2 
Scenario 
 
Probability to 
detect an 
effect on TKV 
at the end of 
Stage 1 
Probability to 
detect an effect 
on eGFR at the 
end of Stage 1 
Probability to 
detect an effect 
on eGFR at end of 
Stage 1 and/or 
end of Stage 2 
Probability to 
declare 
futility at 
interim 
analysis 
Scenario 1 
15 mg: 50% on TKV, 30% on eGFR 
8 mg: 50% on TKV, 30% on eGFR 
92.6% 
6.4% 
90.1% 
2.3% 
Scenario 2 
15 mg: 50% on TKV, 30% on eGFR 
8 mg: 40% on TKV, 25% on eGFR 
89.0% 
5.1% 
87.0% 
3.1% 
Scenario 3 
15 mg: 50% on TKV, 30% on eGFR 
8 mg: 30% on TKV, 20% on eGFR 
86.0% 
4.4% 
84.6% 
3.7% 
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Scenario 
 
Probability to 
detect an 
effect on TKV 
at the end of 
Stage 1 
Probability to 
detect an effect 
on eGFR at the 
end of Stage 1 
Probability to 
detect an effect 
on eGFR at end of 
Stage 1 and/or 
end of Stage 2 
Probability to 
declare 
futility at 
interim 
analysis 
Scenario 4 
15 mg: 50% on TKV, 30% on eGFR 
8 mg: 20% on TKV, 15% on eGFR 
84.6% 
3.9% 
83.2% 
4.2% 
Scenario 5 
15 mg: 50% on TKV, 30% on eGFR 
8 mg: 10% on TKV, 10% on eGFR 
85.1% 
3.7% 
83.0% 
4.3% 
Scenario 6 
15 mg: 70% on TKV, 50% on eGFR 
8 mg: 50% on TKV, 30% on eGFR 
99.3% 
26.4% 
99.7% 
0.3% 
eGFR = estimated glomerular filtration rate; TKV = total kidney volume. 
It is expected that venglustat 15 mg would be well tolerated in Stage 1 and therefore selected in 
Stage 2. However, in case of safety concern, the DMC may recommend the use of venglustat 
8 mg for Stage 2. The probabilities to detect an effect on TKV and eGFR in such a case are 
presented in Table 8. Assuming that venglustat 8 mg would provide 50% reduction on TKV 
growth rate and 30% reduction in eGFR rate of decline, the power to detect an effect on TKV and 
eGFR would be >80%. 
Table 8 - Operating characteristics of the study design assuming the dose 8 mg is selected for 
Stage 2 
Scenario 
 
Probability to 
detect an 
effect on TKV 
at the end of 
Stage 1 
Probability to 
detect an effect 
on eGFR at the 
end of Stage 1 
Probability to 
detect an effect 
on eGFR at end of 
Stage 1 and/or 
end of Stage 2 
Probability to 
declare 
futility at 
interim 
analysis 
Scenario 7 
15 mg: 50% on TKV, 30% on eGFR 
8 mg: 50% on TKV, 30% on eGFR 
92.6% 
6.4% 
80.1% 
2.3% 
Scenario 8 
15 mg: 70% on TKV, 50% on eGFR 
8 mg: 50% on TKV, 30% on eGFR 
99.3% 
26.4% 
98.3% 
0.3% 
eGFR = estimated glomerular filtration rate; TKV = total kidney volume. 
Multiple imputation of missing data for TKV - Primary analysis 
In the primary analysis, missing data will be imputed using a linear mixed effect model that will 
include separate slopes of log10(TKV) during the on-treatment period and after permanent 
treatment discontinuation, for each treatment arm (venglustat 15 mg, venglustat 8 mg or placebo). 
The imputation model will also include adjustment for Mayo class (1C versus 1D versus 1E) as 
well as random intercept and slope.  
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Imputations will be based on the following assumptions: 
• Patients with missing data during the on-treatment period will have their data imputed 
based on the mean slope estimated during the on-treatment period in patients from the 
same treatment arm. 
• Patients with missing data after permanent treatment discontinuation will have their data 
imputed based on the mean slope estimated during the post-treatment period in patients 
from the same treatment arm, who discontinued the treatment but had TKV data available 
during the post-treatment period. 
In both cases, measurements history of patients with missing data will be accounted for in the 
imputation process, via within-patients intercept and slope. Imputation model will also be adjusted 
for Mayo class. Figure 4 provides a schematic representation of imputation of missing data for 
a Mayo 1C patient randomized to venglustat 15 mg who would permanently discontinue treatment 
at 12 months, with no TKV available at 18 months. It will be assumed that from 12 to 18 months, 
TKV would have increased at the same rate as other Mayo 1C patients in the venglustat 15 mg 
arm who discontinued treatment but had TKV measured after treatment discontinuation. The 
on-treatment period will be defined as the period from the first IMP administration to the last IMP 
administration, regardless of temporary treatment discontinuations. The post-treatment period will 
be defined as the period from last IMP administration +1 day. 
Figure 4 - Schematic representation of imputation of missing data - primary analysis 
 
Uncertainty in the imputation model’s parameters will be taken into account using a Bayesian 
approach. A noninformative prior distribution will be used for the parameters of the model. For 
fixed effects parameters, a normal distribution with mean of 0 and standard deviation of 1000 will 
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be used as noninformative prior distribution. For variance parameters, the following estimates 
were obtained from the CRISP and HALT-PKD studies: 
• Variance for the random intercept: 0.017647. 
• Variance for the random slopes: 0.000218. 
• Covariance between random intercept and slopes: 0.000105. 
• Variance for the residual error: 0.000658. 
These estimates will be used to construct a non-informative prior distribution, corresponding to 
the distribution that would have been derived if these estimates had been obtained from a sample 
of 1 patient. 
The Bayesian mixed effect model will be fitted using a Markov chain Monte Carlo (MCMC) 
procedure. Missing values will be treated as unknown parameters and incorporated in the 
sampling process. A minimum of 100 imputations will be generated for each missing data. The 
number of imputations may be increased to obtain stable estimates. The number of burn-in 
iterations and thinning rate may be adjusted in order to improve convergence. The seed will be 
arbitrarily set to 15392 (study code). 
A sample SAS code is provided below.  
 
proc mcmc data=datain seed=15392 nbi=100 nmc=1000 thin=10; 
 array u[2]; 
 array S[2,2] (0.017647 0.000105 0.000105 0.000218); 
 array mu[2] (0 0); 
 array cov[2,2]; 
 
 parms int diffint8 diffint15 diffint1D diffint1E slope0ontrt slope8ontrt slope15ontrt slope0posttrt 
slope8posttrt slope15posttrt diffslope1D diffslope1E cov Vres; 
 
 prior int   ~ normal(mean=0, sd=1000); 
 prior diffint8  ~ normal(mean=0, sd=1000); 
 prior diffint15  ~ normal(mean=0, sd=1000); 
 prior diffint1D  ~ normal(mean=0, sd=1000); 
 prior diffint1E  ~ normal(mean=0, sd=1000); 
 prior slope0ontrt ~ normal(mean=0, sd=1000); 
 prior slope8ontrt ~ normal(mean=0, sd=1000); 
 prior slope15ontrt ~ normal(mean=0, sd=1000); 
 prior slope0posttrt ~ normal(mean=0, sd=1000); 
 prior slope8posttrt ~ normal(mean=0, sd=1000); 
 prior slope15posttrt ~ normal(mean=0, sd=1000); 
 prior diffslope1D ~ normal(mean=0, sd=1000); 
 prior diffslope1E ~ normal(mean=0, sd=1000); 
 
 prior Vres ~ igamma(1/2, scale=0.000658/2); 
 prior cov ~ iwish(2,S); 
 
 random u ~ mvn(mu, cov) subject=subject nooutpost; 
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 mean = int + diffint8*arm8 + diffint15*arm15 
  + diffint1D*mayo1D + diffint1E*mayo1E 
  + slope0ontrt*timeontrt*arm0 + slope0posttrt*timeposttrt*arm0 
  + slope8ontrt*timeontrt*arm8 + slope8posttrt*timeposttrt*arm8 
  + slope15ontrt*timeontrt*arm15 + slope15posttrt*timeposttrt*arm15 
  + diffslope1D*time*mayo1D + diffslope1E*time*mayo1E 
  + u[1] + u[2]*time; 
  
 model logtkv ~ normal(mean=mean, var=Vres); 
 
 ods output PosteriorSample=Sample; 
run; 
In the above SAS code: 
• Dataset datain is the input dataset, with one record per patient and planned assessment. 
Records will be created for patients with missing TKV at a planned time point. 
• Variables arm0, arm8 and arm15 are dummy variables indicating the randomized 
treatment arm: 
- 
arm0=1, arm8=0 and arm1=0 for patients in the placebo arm. 
- 
arm0=0, arm8=1 and arm15=0 for patients in the venglustat 8 mg arm. 
- 
arm0=0, arm8= 0 and arm15=1 for patients in the venglustat 15 mg arm. 
• Variables Mayo1D and Mayo1E are dummy variables indicating the Mayo class: 
- 
Mayo1D=0 and Mayo1E=0 for Mayo 1C patients. 
- 
Mayo1D=1 and Mayo1E=0 for Mayo 1D patients. 
- 
Mayo1D=0 and Mayo1E=1 for Mayo 1E patients. 
• Variable time is a continuous variable indicating the time (in years) of actual assessment 
(if TKV was observed) or the planned time of assessment (if TKV was missing). For 
example, for the hypothetical patient described in Figure 4: 
- 
At Month 0: time=0. 
- 
At Month 1: time=0.0833. 
- 
At Month 9: time=0.75. 
- 
At Month 18: time=1.5. 
• Variable timeontrt is a continuous variable indicating the cumulative duration of the 
on-treatment period (in years) at the time of actual assessment (if TKV was observed) or at 
the planned time of assessment (if TKV was missing). For example, for the hypothetical 
patient having discontinued treatment after 12 months described in Figure 4: 
- 
At Month 0: timeontrt=0. 
- 
At Month 1: timeontrt=0.0833. 
- 
At Month 9: timeontrt=0.75. 
- 
At Month 18: timeontrt=1. 
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• Variable timeposttrt is a continuous variable indicating the cumulative duration of the 
post-treatment period (in years) at the time of actual assessment (if TKV was observed) or 
at the planned time of assessment (if TKV was missing). For example, for the hypothetical 
patient having discontinued treatment after 12 months described in Figure 4: 
- 
At Month 0: timeposttrt=0. 
- 
At Month 1: timeposttrt=0. 
- 
At Month 9: timeposttrt=0. 
- 
At Month 18: timeposttrt=0.5. 
• Parameter int is the parameters modelling the intercept of log10(TKV) in Mayo 1C patients 
randomized to placebo. 
• Parameters diffint8 and diffint15 are the parameters modelling the difference in intercept in 
patients randomized to 8 mg and 15 mg arms respectively. 
• Parameters diffint1D and diffint1E are the parameters modelling the difference in intercept 
in Mayo 1D and Mayo 1E patients respectively. 
• Parameters slope0ontrt, slope8ontrt and slope15ontrt, are the parameters modelling the 
slope of log10(TKV) during the on-treatment period in the placebo, 8 mg and 15 mg arms 
respectively. 
• Parameters slope0posttrt, slope8posttrt and slope15posttrt, are the parameters modelling 
the slope of log10(TKV) during the post-treatment period in the placebo, 8 mg and 15 mg 
arms respectively. 
• Parameters diffslope1D and diffslope1E are the parameters modelling the difference in 
slope in patients of Mayo Class 1D and 1E respectively (versus Mayo 1C). 
Multiple imputation of missing data for TKV - Sensitivity analysis using a control based 
multiple imputation 
In this sensitivity analysis, missing data will be handled using a control based multiple imputation 
method. Imputations will be based on a model that will assume that after permanent treatment 
discontinuation, the slope of log10(TKV) for patients in the venglustat arms will be the same as the 
slope of log10(TKV) for patients in the placebo arm. The imputation model will also include 
adjustment for Mayo class (1C versus 1D versus 1E) as well as random intercept and slope. 
Imputations will be based on the following assumptions: 
• Patients with missing data during the on-treatment period will have their data imputed 
based on the mean slope estimated during the on-treatment period in patients from the 
same treatment arm. 
• Patients with missing data after permanent treatment discontinuation will have their data 
imputed based on the mean slope estimated in patients from the placebo arm. 
Figure 5 provides a schematic representation of imputation of missing data for a Mayo 1C patient 
randomized to venglustat 15 mg who would permanently discontinue treatment at 12 months, with 
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no TKV available at 18 months. It will be assumed that from 12 to 18 months, TKV would have 
increased at the same rate as other Mayo 1C patients in the placebo arm. 
Figure 5 - Schematic representation of imputation of missing data - sensitivity analysis using 
control based multiple imputation 
 
A sample SAS code is provided below.  
 
proc mcmc data=datain seed=15392 nbi=1000 nmc=1000 thin=10; 
 array u[2]; 
 array S[2,2] (0.017647 0.000105 0.000105 0.000218); 
 array mu[2] (0 0); 
 array cov[2,2]; 
 
 parms int diffint8 diffint15 diffint1D diffint1E slope0 slope8 slope15 diffslope1D diffslope1E cov Vres; 
 
 prior int   ~ normal(mean=0, sd=1000); 
 prior diffint8 ~ normal(mean=0, sd=1000); 
 prior diffint15 ~ normal(mean=0, sd=1000); 
 prior diffint1D ~ normal(mean=0, sd=1000); 
 prior diffint1E ~ normal(mean=0, sd=1000); 
 prior slope0  ~ normal(mean=0, sd=1000); 
 prior slope8  ~ normal(mean=0, sd=1000); 
 prior slope15  ~ normal(mean=0, sd=1000); 
 prior diffslope1D ~ normal(mean=0, sd=1000); 
 prior diffslope1E ~ normal(mean=0, sd=1000); 
 
 prior Vres ~ igamma(1/2, scale=0.000658/2); 
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 prior cov ~ iwish(2,S); 
 
 random u ~ mvn(mu, cov) subject=subject nooutpost; 
 
 mean = int + diffint8*arm8 + diffint15*arm15 
  + diffint1D*mayo1D + diffint1E*mayo1E 
  + slope0*time*arm0 
  + slope8*timeontrt*arm8 + slope0*timeposttrt*arm8  
  + slope15*timeontrt*arm15 + slope0*timeposttrt*arm15 
  + diffslope1D*time*mayo1D + diffslope1E*time*mayo1E 
  + u[1] + u[2]*time; 
  
 model logtkv ~ normal(mean=mean, var=Vres); 
 
 ods output PosteriorSample=Sample; 
run; 
In the above SAS code, variable and parameters have the same interpretation as in the previous 
model, except: 
• Parameters slope0, slope8 and slope15, are the parameters modelling the slope of 
log10(TKV) during the on-treatment period in the placebo, 8 mg and 15 mg arms 
respectively. Of note, in the placebo arm, slope is assumed to be the same during the 
on-treatment and during the post-treatment periods. 
A consequence of this model is that after treatment discontinuation, patients from the venglustat 
arms will have a slope equal to the slope of patients in the same Mayo class treated with placebo. 
For example, for the hypothetical patient described in Figure 5: 
• Between Month 0 and Month 12: the slope will be slope15 (slope of Mayo 1C patients 
treated with dose 15 mg). 
• Between Month 12 and Month 18: the slope will be slope0 (slope of Mayo 1C patients 
treated with placebo). 
Multiple imputation of missing data for eGFR 
Missing data for GFR will be handled using a similar approach, with the exception that no log 
transformation will be used for eGFR. Prior distribution of variance parameters was derived 
following a similar approach. The following estimates were obtained from the CRISP and 
HALT-PKD studies: 
• Variance for the random intercept: 106.81. 
• Variance for the random slopes: 3.90. 
• Covariance between random intercept and slopes: 5.36. 
• Variance for the residual error: 40.26. 
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Appendix K 
Isolation of Urinary Exosomes 
1 
INTRODUCTION 
Exosomes are membrane vesicles, which are secreted from their cells of origin into surrounding 
body fluids and contain proteins and mRNA which are protected from digestive enzymes by a cell 
membrane. Exosomes can mediate cell-cell communication and affect signal transduction in 
recipient cells in both normal and pathological conditions. In the kidney, and other organs, 
exosomes have been suggested to carry disease-specific biomarkers (23). Analysis of urinary 
exosomes may therefore provide a method to noninvasively assess disease progression or 
treatment effects in the kidney. 
Urinary exosomes isolation will be done from the 24-hour samples of urine at selected sites. 
2 
OBJECTIVES 
2.1 
PRIMARY OBJECTIVES 
The primary objectives of this substudy are: 
• To isolate and study urinary exosomes as a source of kidney dysfunction biomarkers in 
patients with ADPKD. 
• To study the response of kidney dysfunction biomarkers to treatment. 
3 
PRIMARY ENDPOINTS 
Not applicable. 
4 
STUDY DESIGN 
Urinary exosomes will be isolated from the 24-hour samples of urine in patients randomized in 
the multinational, multicenter, double-blind, placebo-controlled, two stage EFC15392 study at 
selected sites. 24-hour urine samples of up to 60 patients at Visit 3 (baseline visit) will be 
screened for expression of the biomarkers of interest. 
Urine samples of up to 30 patients that had a high level of expression of the biomarkers of interest 
at Visit 3 will be further analyzed at Month 1, 3, and 9 to follow changes in biomarker expression. 
Samples of urine will be processed and analyzed as noted below. 
5 
SELECTION OF PATIENTS 
Patients who consented to participation in the EFC15392 study at selected sites. 
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6 
STUDY PROCEDURES 
A) An aliquot from the 24-hour urine collection will be taken. 
B) Study staff will process the urine as follows: 
a) Record the date and the total volume of urine for each sample. 
b) Thoroughly mix urine prior to aliquoting. 
c) Aliquot 100 mL into two 50 mL tubes. 
d) Add one protease inhibitor cocktail tablet (Sigma; cat# 4693132001) per 50 mL of 
urine, dissolve completely. 
e) Centrifuge 4 000× g (15 minutes; 4°C) to sediment cells and cellular debris. 
f) Using pipette, transfer supernatant into the new 50 mL tube (do not disturb the pellet!).  
g) Freeze supernatant at -80°C. 
h) Ship frozen on dry ice. 
7 
WITHDRAWAL OF CONSENT 
Patients who wish to withdraw their participation in this additional research may do so at any 
time. If they do so, they may continue participation in the main study. Patients, who discontinue 
the main study, must also discontinue participation in this additional research. 
8 
STATISTICAL ANALYSIS 
Not applicable. 
9 
SAFETY REPORTING 
Adverse events and serious adverse events will be captured and reported in accordance with the 
main EFC15392 study (see Section 10 in the main protocol). 
10 
ADMINISTRATION 
10.1 
INFORMED CONSENT 
Urinary exosomes are part of ADPKD biomarkers assessment (required tests of the protocol) and 
are covered by the informed consent of EFC15392 study. 
10.2 
CONFIDENTIALITY 
Data collection and handling by the Sponsor for this substudy will be in accordance with that 
described in the main EFC15392 protocol (see Section 14.3 in the main protocol), and every effort 
will be made to protect patient confidentiality. In case the results are published, they will be done 
so anonymously. 
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10.3 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE 
Urinary exosomes isolation is a required test of the protocol and is covered by the informed 
consent of EFC15392 study that will be submitted for review and approval to the IRB/EC charged 
with this responsibility. 
10.4 
RECORDS RETENTION 
Investigators must retain records pertaining to this substudy as described in the main EFC15392 
study protocol (see Section 14.2 in the main protocol). 
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Appendix L 
Measured glomerular filtration rate substudy 
1 
INTRODUCTION 
The primary endpoint in the Stage 2 of the study EFC15392 is annualized rate of change in 
estimated glomerular filtration rate (eGFR; CKD-EPI equation) from baseline to 24 months. 
Estimated glomerular filtration rate may be inaccurate in the nonsteady state and in people in 
whom non-GFR determinants differ greatly from those in whom the estimating equation was 
developed. Measured GFR (mGFR) using urinary or plasma clearance of exogenous filtration 
markers is considered the gold standard for evaluation of kidney function (24). To determine the 
effect of venglustat on mGFR, GFR will be measured with iohexol in approximately 15% of 
patients randomized in Stage 2 of the EFC15392 study. Glomerular filtration rate will be 
calculated by plasma iohexol clearance (25). 
2 
OBJECTIVE 
2.1 
PRIMARY OBJECTIVE 
The primary objective of this substudy is: 
• To determine the effect of venglustat on mGFR. 
3 
PRIMARY ENDPOINT 
The primary endpoint of this substudy is the annualized rate of change in mGFR from baseline to 
24 months. 
4 
STUDY DESIGN 
Patients randomized in Stage 2 of the international, multicenter, double-blind, placebo-controlled, 
two stage EFC15392 study will be asked to participate in this optional substudy. Once written 
informed consent is obtained, glomerular filtration rate will be measured at Months 0, 12, and 24. 
Plasma samples will be processed and analyzed as noted below. 
5 
SELECTION OF PATIENTS 
Patients will be selected from those agreeing to participate in Stage 2 of the EFC15392 study, 
with the additional criteria below. 
5.1.1 Additional inclusion criterion 
• A written signed acknowledgment for mGFR substudy of EFC15392 protocol in the 
consent of the Stage 2 of the EFC15392 study indicating patient’s agreement. 
5.1.2 Additional exclusion criterion 
• Known hypersensitivity to iohexol or other contrast media, known sensitivity to iodine. 
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Patients who are not eligible for the substudy based on the additional eligibility criteria may still 
take part in the main study of the EFC15392 protocol. 
6 
STUDY PROCEDURES 
Commercial iohexol will be sourced by the study site for this substudy. Refer to the iohexol 
Prescribing Information for full information about its properties and the conditions attached to its 
use. 
Iohexol will be stored at the temperature specified in the package insert in a secure location at the 
site. 
Omnipaque 300 mg iodine per milliliter contains 647 mg/mL iohexol. Exactly 5 mL of iohexol 
solution (drawn in a 5 mL syringe), containing 3.235 g of iohexol will be injected intravenously 
(IV) through an injection catheter. 
The following should be considered prior to performing GFR measurements: 
• Patients will have their study visit in the morning in fasted condition (eat nothing and 
drink only water) 
• This procedure should be performed after all other scheduled blood samples for the visit 
are collected. 
• Adequate hydration should be assured before and after administration of iohexol. 
• If not obtained within 72 hours of the GFR measurement procedure, the patient’s weight 
and height should be measured and recorded. 
6.1 
Patient preparation 
After a 10-hour fast (eating nothing and drinking only water), 2 IV catheters, one in each arm, will 
then be placed in the patient’s antecubital vein. One line will be used for the single dose injection 
of nonradioactive iohexol. The second line will be used for intermittent blood sampling. 
6.2 
Iohexol injection (time -2 to 0 minutes) 
Exactly 5 mL of iohexol solution (drawn in a 5 mL syringe), containing 3.235 g of iohexol, will 
be injected slowly into the injection catheter. 
• The 5 mL solution should be injected over a period of 2 minutes. 
• The exact time of the injection will be recorded in the eCRF and in the source document. 
For consistency, the same digital clock should be used throughout the procedure. 
• The total, exact, volume of the solution injected must be recorded on the central laboratory 
requisition form and in the source document. 
• Blood samples must not be taken from the arm receiving the iohexol solution. 
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6.3 
Blood collection 
Blood samples for the determination of GFR by plasma clearance of iohexol will be collected 
prior the injection of the iohexol solution as well as during the last 4 hours of the procedure. 
Initiation of the GFR procedure will occur at time -2 minutes and is defined as the time at 
which the iohexol solution is injected. Time 0 represents the end of the iohexol injection. The 
timing for the blood samples are relative to the end of the iohexol injection (Time 0). 
Blood samples will be taken at 120, 150, 180, 210, and 240 minutes (2, 2.5, 3, 3.5, and 4 hours) 
after injection of iohexol. Plasma iohexol concentrations will be measured by a central laboratory. 
The procedure for measuring mGFR is described in detail in the laboratory manual. 
7 
WITHDRAWAL OF CONSENT 
Patients who wish to withdraw their participation in this substudy may do so at any time. If they 
do so, they may continue participation in the main study. Patients, who discontinue the main 
study, must also discontinue participation in the substudy. 
Patients, who prematurely discontinue study treatment (regardless of the reason) and continue the 
main study, should be encouraged to complete the scheduled Month 24 mGFR assessment. 
8 
STATISTICAL ANALYSIS 
8.1 
Sample size determination 
No formal sample size calculations have been performed for this substudy, sample size was based 
upon empirical considerations. It is expected that approximately 60 patients (15% of patients 
randomized in Stage 2) will participate in the mGFR substudy. 
8.2 
Primary analysis 
A linear mixed effect model will be fitted to the mGFR, which will include fix effects of treatment 
(venglustat or placebo), Mayo Imaging Classification (as per randomization stratification factor: 
Class 1C versus 1D versus 1E), time (as continuous variable), treatment * time interaction and 
Mayo Imaging Classification * time interactions, and will include random intercept and slope. 
Within group mean slope of mGFR will be obtained from the linear mixed effect model, using 
weights for each stratum (Mayo Class 1C, 1D and 1E) equal to the overall proportion of patients 
in each stratum in the Stage 2 population (ie “population weight”). Difference in mean slope will 
be calculated and presented with its 95% confidence interval. p-value will be presented for 
descriptive purpose. 
No imputation of missing data will be performed. The linear mixed effect model described above 
will be run on all observed data, including data collected after treatment discontinuation. 
9 
SAFETY REPORTING 
Adverse events and serious adverse events will be captured and reported in accordance with the 
main EFC15392 study (see Section 10 in the main protocol).  
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10 
ADMINISTRATION 
10.1 
INFORMED CONSENT 
Information about the substudy will be included in the main informed consent for the Stage 2 of 
EFC15392 study. A separate informed consent where required by local regulations shall be 
obtained from patients who voluntarily agree to participate in the substudy. A separate informed 
consent form will be used in Stage 1 and Stage 2 of the study. The informed consent form 
reflecting this substudy will be submitted for review and approval to the IRB/EC charged with 
this responsibility. 
10.2 
CONFIDENTIALITY 
Data collection and handling by the Sponsor for this substudy will be will be in accordance with 
that described in the main EFC15392 protocol (see Section 14.3 in the main protocol), and every 
effort will be made to protect patient confidentiality. In case the results are published, they will be 
done so anonymously. 
10.3 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE 
This substudy, the Informed Consent Form for this substudy, and any advertisement for patient 
recruitment will be submitted for review and approval to the IRB/EC charged with this 
responsibility. 
10.4 
RECORDS RETENTION 
Investigators must retain records pertaining to this substudy as described in the main EFC15392 
study protocol. (see Section 14.2 in the main protocol). 
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Appendix M 
Country-specific requirements 
Not applicable. 
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Appendix N 
Protocol amendment history 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the clinical trial summary. 
The primary reasons for each protocol amendment are summarized below. 
AMENDED PROTOCOL 06 (16 December 2020)  
This amended protocol 06 (Amendment 06) was considered to be non-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 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 
This amendment was to update Appendix L, which describes the Measured Glomerular Filtration 
Rate (mGFR) substudy. This substudy is planned to be conducted in selected centers in the USA, 
the Netherlands, and Canada. This amendment will further clarify inclusion and exclusion criteria 
and study procedures as described in the summary of changes table. 
The full history of protocol amendments is included in Appendix N. 
Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
Appendix L, Section 1, 
Introduction 
Added clarification that GFR will be measured 
with iohexol in patients with the screening eGFR 
between 45 and 89.9 mL/min/1.73 m2. 
Clarification 
Appendix L, 
Section 5.1.1 Additional 
inclusion criteria 
Added inclusion criterion related to the screening 
eGFR value in patients eligible for the mGFR 
substudy. 
Clarification 
Appendix L, 
Section 5.1.2, 
Additional exclusion 
criteria 
Deletion of the exclusion criterion related to the 
request of the washout periods of 2 weeks for 
angiotensin converting enzyme (ACE) inhibitors 
or angiotensin II receptor blockers (ARBs) and of 
3 days for non-steroidal anti-inflammatory drugs 
(NSAIDs) prior to the mGFR assessment visit. 
To match testing conditions for eGFR and mGFR 
Appendix L, 
Section 6.0, Study 
Procedures 
Added the clarification that “Patients will have 
their study visit in the morning in fasted condition 
(eat nothing and drink only water)”. 
Removed the washout periods related to the 
temporary discontinuation of ACE inhibitors or 
ARBs and non-steroidal anti-inflammatory drugs. 
Added the clarification that “Adequate hydration 
should be assured before and after administration 
of iohexol”. 
Clarifications 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Appendix L, 
Section 6.1, Patient 
preparation 
Added the clarification that the 10-hour fast 
means “eating nothing and drinking only water”. 
Clarification 
Appendix N, Protocol 
amendment history 
Added protocol amendment summary-of-changes 
table for amended protocol 05 
Update 
Protocol Amendment 05 Version number 1 (electronic 5.0) Date 17-Aug-2020 
Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
Sections 1.3 Study flow 
chart for STAGE 1 - 
footnote p, 
Section 1.4 Study flow 
chart for STAGE 2 - 
footnote p, 
Section 9.4.10 
Ophthalmological 
examination, 
Section 10.1.2.2 Visit 4, 
6, 8, 10, 12/Months 1, 
6, 12, 18, 24 (Day 30, 
180, 360, 540, 720), 
Section 10.4.2 General 
guidelines for reporting 
adverse events 
Replacement of LOCSIII with WHO 
simplified cataract grading system. 
The LOCSIII requirement of recertification every 6 months 
renders the utilization of LOCSIII in the study extremely 
challenging.  
To ensure continuity of lens changes monitoring and to avoid 
the risk of losing data related to ophthalmologists potentially 
not performing the required LOCSIII certification every 6 
months during the study, we are replacing LOCSIII with the 
WHO simplified cataract grading system. Going forward 
changes in the lens clarity in patients will be evaluated by 
using the WHO simplified cataract grading system. The 
replacement of LOCSIII used to grade lens opacities with the 
WHO simplified cataract grading system in this study will 
have no impact on the safety monitoring of the lens for the 
following reasons: 
1. The protocol safety rules (increase in the frequency of 
dilated lens examination or IMP discontinuation) are based 
on the decrease in BCVA lines and not on the degree of lens 
opacity progression 
2. In the current protocol, pre-treatment opacities detected at 
Visit 2 (= Run-In) are assessed and characterized with WHO 
simplified cataract grading system. Therefore, we will be able 
to compare the future WHO assessments throughout the 
study (Month 12, 18 & 24) with the WHO grade established 
at Visit 2 
3. Lens opacity progression in small increments with LOCSIII 
(<1.0 grade) does not trigger the increase of frequency of 
dilated lens examination.   
Clinical Trial Summary 
- Study objectives, 
Endpoints 
Section 5.1 STAGE 1: 
Section 5.1.2 
Secondary objectives 
Section 5.1.3 
Exploratory objectives 
Section 5.2 STAGE 2: 
Section 5.2.2 
Secondary objectives 
Updated the hierarchy of the 
secondary and exploratory objectives 
and endpoints: 
STAGE 1: 
1. pain and fatigue are moved from 
exploratory to secondary objectives 
and endpoints  
2. nocturia is moved from secondary to 
exploratory objectives and endpoints  
 
Data from venglustat clinical studies do not suggest that 
venglustat causes urinary frequency or nocturia. For this 
reason, the change in nocturia was moved from secondary to 
exploratory endpoints. 
Pain and fatigue were moved from exploratory to secondary 
endpoints as they are fit in ADPKD as the concepts for which 
a positive effect can be shown. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 5.2.3 
Exploratory objectives 
Section 9.2 Secondary 
endpoints 
Section 9.3 Exploratory 
endpoints 
Section 11.4.2.2 
Analyses of secondary 
efficacy endpoints 
STAGE 2: 
1. pain and fatigue are moved from 
exploratory to secondary objectives 
and endpoints  
2. urine osmolality and nocturia are 
moved from secondary to exploratory 
objectives and endpoints. 
Clinical Trial Summary 
- Duration of study 
period (per patient), 
Section 1.3 Study flow 
chart for STAGE 1 - 
footnote b, Section 1.4 
Study flow chart for 
STAGE 2 - footnote b, 
Section 10.1.3 Follow-
up visit -Visit 13/ 
Month 25 (Day 750) 
Added clarification that follow-up visit 
after V12 (Month 24, end of treatment) 
visit is applicable for patients who 
completed the treatment period and 
elected not to participate in the 
potential long-term extension study. 
Clarification 
Section 4.2 Clinical 
trials of venglustat in 
humans 
Section updated with new and 
completed clinical trials of venglustat in 
humans. 
Updated information 
Section 4.3 Benefit/risk 
of venglustat 
Section updated based on Investigator 
Brochure ed12 related to new 
information from nonclinical studies. 
The toxicity finding in sexually mature 
dogs was removed based on two 
external experts' opinions. 
Updated information 
Section 6.2.1 Duration 
of study participation 
for each patient 
Added clarification regarding the last 
study visit in Stage 1 and Stage 2 to 
allow for patients, upon completion of 
study EFC15392, to enter into a 
potential long-term open-label 
extension (LTS15823). 
Clarification 
Section 7.2.1 Exclusion 
criteria related to study 
methodology - E06 
A History of alcohol dependency within 
the five years prior to the screening 
visit was added to the exclusion 
criterion E06. 
To exclude cases of potential alcoholic relapse during the 
study. 
Section 7.2.1 Exclusion 
criteria related to study 
methodology - E09 
Resistant hypertension as an example 
of clinically significant, uncontrolled 
medical condition in exclusion criterion 
E09 was replaced with hypertensive 
emergency within 6 month of Visit 1. 
Correction and clarification. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 7.2 Exclusion 
criteria, 
Appendix O 
Contingency Measures 
for a regional or 
national emergency 
that is declared by a 
governmental agency. 
Clarified use of initial screening results 
for rescreened patients:  
• 
MRI (obtained within 
1 months prior to 
randomization), 
• 
neurological and ophthalmic 
exams (obtained within 
3 months prior to 
randomization). 
• 
already collected at initial 
screening biomarkers. 
To reduce the burden of assessments on the rescreened 
patients, certain initial screening exam results that are still 
clinically actual (no changes are expected during a particular 
period of time) can be used for rescreening Visit 1 or Visit 2. 
Section 7.2.4 Criteria 
for Temporarily 
Delaying of 
Randomization or 
Administration of Study 
Treatment  
Added section referring to contingency 
measures proposed in Appendix O for 
situation if the site is unable to 
adequately follow protocol mandated 
procedures during a regional or 
national emergency declared by a 
governmental agency that results in 
travel restrictions, confinement, or 
restricted site access. 
Set up of contingency measures for a regional or national 
emergency that can be declared by a governmental agency. 
Section 8.1.2 Dose of 
drug per administration 
Section updated with information that 
venglustat may be supplied from the 
site to the patient during national 
emergency declared by a 
governmental agency that results in 
travel restrictions, confinement, or 
restricted site access. 
Clarification. 
Section 8.8.1 List of 
forbidden concomitant 
medications 
Allopurinol was added to the list of 
medications prohibited during the 
study. 
Clarification added that Investigator 
should consider substituting any 
concomitant medication that has 
cataractogenic potential according to 
its Prescribing Information for 
noncataractogenic medication. 
Link between allopurinol use and cataract development is 
described in the literature, cataract is reported as adverse 
event in Prescribing Information for allopurinol.  
The list of medications with cataractogenic potential in 
section 8.8.1 is not exhaustive. Investigator should consider 
substituting any concomitant medication with cataractogenic 
potential according to its Prescribing Information for 
noncataractogenic medication. 
Section 9.4 
Assessments methods, 
Section 10 Study 
procedures, Section 
10.3.1 Temporary 
treatment 
discontinuation with 
investigational 
medicinal product(s), 
Section 12.2 Informed 
consent 
Added reference to the Appendix O. 
 
Set up of contingency measures for a regional or national 
emergency that can be declared by a governmental agency. 
 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 10.3.4 
Handling of patients 
after permanent 
treatment 
discontinuation 
Added clarification that in patients who 
prematurely and permanently 
discontinued study medication, a follow 
up visit required in 30 days after the 
premature end-of-treatment visit 
includes all assessment of the Visit 13. 
Clarification. 
Section 10.3.6 Lost to 
Follow-up 
 
Added section describing the actions 
that must be taken if a participant fails 
to return to the clinic for a required 
study visit. 
Clarification. 
Section 10.4.3 
Instructions for 
reporting serious 
adverse events  
Requirement to send a photocopy of all 
examinations related to SAE to the 
representative of the monitoring team 
was changed to the requirement to send 
copies of medical records only when 
they are requested by the Sponsor. 
Simplification and standardization of the clinical safety data 
flow (to minimize risk of non-secured transmission and non-
secured storage). 
Section 11.3.1.1 Intent-
to-treat population 
Primary analysis of Stage 1 will include 
data available at the cut-off date, 
including data reported up to Month 24, 
if any 
Clarification. 
Section 11.3.4 Patient-
reported outcome 
population 
PRO population deleted 
PRO analysis will be performed on ITT population 
Section 11.4.2.1 
Analysis of primary 
efficacy endpoint(s): 
Section 11.4.2.1.1 
Stage 1 
Removal of sentence “Time of baseline 
TKV will be set to 0.” 
Time of baseline TKV will be calculated as relative time since 
randomization date. 
Section 11.4.2.2 
Analyses of secondary 
efficacy endpoints 
Description of analysis of change in 
pain and change in fatigue 
Removal of description of analysis of 
change in urine osmolality and change 
in nocturia 
Change in pain and fatigue considered as secondary 
endpoints. Change in urine osmolality and change in nocturia 
considered as exploratory endpoints 
Section 11.4.2.3 
Multiplicity 
considerations 
Change in hierarchy of secondary 
endpoints as illustrated in Figure 3. 
Change in pain and fatigue considered as secondary 
endpoints. Change in urine osmolality and change in nocturia 
considered as exploratory endpoints 
Section 11.4.3 
Analyses of safety data 
Change in definition of on-treatment 
period and treatment-emergent period 
Clarification. 
Section 11.4.3.1 
Adverse events  
Presentation of statistical tables by 
SOC and PT 
Clarification. 
Section 11.4.3.2 
Laboratory data and 
vital signs 
Statistical analysis of liver test data 
was updated 
Clarification. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 11.4.5 
Analyses of patient 
reported outcomes 
(health-related quality 
of life/health economics 
variables) 
The text regarding statistical analysis 
of PRO data using MMRM was 
updated 
Clarification. 
Section 11.5.3 Two-
step final analysis 
Primary analysis of Stage 1 will include 
data available at the cut-off date, 
including data reported up to Month 24, 
if any. 
Clarification. 
Section 13.2 
Responsibilities of the 
Sponsor 
Section supplements with information 
that monitoring details are located in 
separate study documents. 
Clarification. 
Appendix C General 
guidance for the follow-
up of laboratory 
abnormalities by 
Sanofi, chart ‘Acute 
Renal Failure’ 
Definition of acute renal failure was 
replaced with the definition of acute 
kidney injury based on the % of 
change in creatine from baseline. 
Study population patients have already increased creatinine 
at baseline. Definition of acute kidney injury based on the % 
of change in creatine from baseline and urine output is more 
suitable for patients with CKD in this study. 
Appendix K Isolation of 
Urinary Exosomes, 
Section 1.4 Study flow 
chart for STAGE 2 - 
footnote l 
Urine exosomes sub-study will be 
performed at selected sites in Stage 1 
and Stage 2. 
To ensure that site initially selected for this sub-study will 
have time to complete the substudy. 
Appendix O 
Contingency Measures 
for a regional or 
national emergency 
that is declared by a 
governmental agency. 
Addition of contingency measures for a 
regional or national emergency that 
can be declared by a governmental 
agency. 
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 during an 
emergency that prevents access to the study site. 
Protocol Amendment 04 Version number: 1 (electronic 4.0) Date: 14-Aug-2019 
 
Section # and Name 
Description of Change 
Brief Rationale 
Clinical trial summary; study 
objective(s), 
5.2.3 Stage 2, Exploratory 
objectives 
To explore the effect of venglustat on eGFR (CKD-EPI equation) 
from baseline to 24 months in patients with a screening eGFR 
between 30 and 44.9 mL/min/1.73 m2. 
With the inclusion in Stage 2 
of the study patients with a 
screening eGFR between 
30 and 44.9 mL/min/1.73 m2, 
this exploratory endpoint has 
been added. 
Clinical trial summary; study 
design,  
6.1 Description of the study 
This is an international, multicenter, randomized, double-blind, 
placebo controlled two stage study in adult patients at risk of 
rapidly progressive ADPKD aged 18 to 50 years in Stages 1 and 
2 (and aged 18 to 55 years for patients with a screening eGFR 
between 30 and 44.9 mL/min/1.73 m2 in Stage 2). 
With the inclusion of patients 
with an eGFR 30 - 
44.9 mL/min/1.73 m2, the 
upper age limit was 
increased to 55 years as 
advanced disease occurs at 
a more advanced age. 
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Section # and Name 
Description of Change 
Brief Rationale 
Clinical trial summary; study 
design; Stage 1 
If after reviewing the unblinded aggregate safety data from 
Stage 1 (after at least 1 month of treatment of the 
first 150 randomized patients from Stage 1), the Data Monitoring 
Committee (DMC) recommends the 8 mg dose for Stage 2, then 
the DMC may recommend switching patients on 15 mg treatment 
arm, in Stage 1, to the 8 mg arm. 
Clarification: Clinical trial 
summary was supplemented 
with information already 
present in Section 6.1 of the 
protocol. 
Clinical trial summary; study 
design; Stage 2 
After the first 150 randomized patients from Stage 1 have 
completed at least 1 month of treatment (or have prematurely 
discontinued), the Data Monitoring Committee (DMC) will review 
in an unblinded fashion the aggregate safety data from Stage 1 
and will select the venglustat dose for Stage 2 (8 mg or 15 mg) 
for Stage 2 patients. 
Clarification. 
Clinical trial summary: study 
population, inclusion criteria 
7.1 Inclusion criteria 
Male or female adult with ADPKD diagnosed by unified Pei 
criteria with an age at the time the consent is signed: 
between the ages of 18 to and 50 years (both inclusive) at 
screening for patients in Stage 1 
between 18 and 50 years (inclusive) for patients in Stage 2 with 
an eGFR between 45 and 89.9 mL/min/1.73 m2 during the 
screening period* 
between 18 and 55 years (inclusive) for patients in Stage 2 with 
an eGFR between 30 and 44.9 mL/min/1.73 m2 during the 
screening period* 
Diagnosis of ADPKD in patients with a family history, will be 
based on unified Pei criteria. In the absence of a family history, 
the diagnosis will be based on the presence of renal cysts 
bilaterally, totaling at least 20, in the absence of findings 
suggestive of other cystic renal diseases. 
Mayo Imaging Classification of ADPKD Class 1C, 1D, or 1E**.  
**TKV volume must be confirmed by a central reader prior to 
Visit 3. 
Estimated glomerular filtration rate between 45 to and 
90 89.9 mL/min/1.73 m2 at during the screening period*(Chronic 
Kidney Disease Epidemiology Collaboration [CKD-EPI] equation) 
for Stage 1. Estimated glomerular filtration rate between 30 and 
89.9 mL/min/1.73 m2 during the screening period* (CKD-EPI 
equation) for Stage 2. 
*Eligibility will be confirmed by the eGFR value from one of the 
two first pre-randomization eGFR measurements (Visit 1 or Visit 2 
measurements, or Visit 1 and an additional measurement 
performed at the Investigator’s discretion between Visit 1 and 
Visit 2) 
Inclusion in Stage 2 of the 
study patients with a 
screening eGFR between 
30 and 44.9 mL/min/1.73 m2. 
For confirmation of eligibility, 
Investigator will use eGFR 
value from one of the 
two first pre-randomization 
eGFR measurements.  
Criteria for diagnosis of 
ADPKD was additionally 
clarified for patients without 
family history of ADPKD. 
Clinical trial summary: study 
population, inclusion criteria 
7.2 Exclusion criteria 
Systolic BP >160 mmHg* at run in and baseline visits.  
*mean value of three or five systolic BP measurements (See 
Section 9.4.5) 
The patient has, according to World Health Organization (WHO) 
Grading, a cortical cataract > ≥1 quarter of the lens 
circumference (Grade cortical cataract 2 [COR 2]) or a posterior 
subcapsular cataract > ≥2 mm (Grade posterior subcapsular 
cataract 2 [PSC 2]). Patients with nuclear cataracts will not be 
excluded. 
Clarification 
 
 
Correction 
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Section # and Name 
Description of Change 
Brief Rationale 
Clinical trial summary: Total 
expected number of patients 
Stage 2: Approximately 320 400 patients (160 200 patients on 
venglustat and 200 patients on placebo per arm). 
Added information that an 
additional 80 patients will be 
enrolled in Stage 2 of the 
study. 
Clinical trial summary: 
Stage 2 exploratory 
endpoints 
9.3.2 Stage 2 only 
Annualized rate of change in eGFR (CKD-EPI equation) from 
baseline to 24 months in patients with a screening eGFR between 
30 and 44.9 mL/min/1.73 m2 
Added to assess exploratory 
endpoint for Stage 2 patients 
with eGFR between 25 and 
44.9 mL/min/1.73 m2 
Clinical trial summary: 
assessment schedule, 
Stage 1, Stage 2 
Biomarker assessments: Month -1 and Months 1, 6, 12, 18, 24, 
and at 1 month30 days follow-up (Month 25). 
Clarification: Adjusted 
1 month to 30 days 
Clinical trial summary: 
assessment schedule, PRO 
assessments; Stage 1 
End-of-treatment visit should include all procedures of Visit 12 
and additionally a PK sample should be collected. In 
4 weeks30 days, a Follow-up visit should be performed. 
Clarification: Adjusted 
4 weeks to 30 days.  
Clinical trial summary: 
assessment schedule, PRO 
assessments: Stage 2 
Patients who prematurely and permanently discontinue study 
medication should complete rapidly (within 7 days) an end-of-
treatment assessment visit. 
End-of-treatment visit should include all procedures of Visit 12. In 
4 weeks30 days, a Follow-up visit should be performed. 
Clarification: Adjusted 
4 weeks to 30 days. 
Clinical trial summary: 
Statistical considerations; 
Sample size determination; 
11.1 Determination of 
sample size 
In Stage 2, approximately 320 patients with an eGFR between 
45 and 89.9 mL/min/1.73 m2 at screening will be randomized 
(with randomization ratio 1:1) to placebo (n = 160) or venglustat 
(n = 160). In addition, 80 patients with an eGFR between 30 and 
44.9 mL/min/1.73 m2 at screening will be randomized (with 
randomization ratio 1:1) to placebo (n = 40) or venglustat 
(n = 40). The patients from Stage 2 with an eGFR between 
30 and 44.9 mL/min/1.73 m2 will not be included in the primary 
efficacy and safety analyses populations but the data from these 
patients will be analyzed separately. 
A sample size of 80 patients (40 per arm) with an eGFR between 
30 and 44.9 mL/min/1.73 m2 at screening will provide 
approximately 80% probability to detect a treatment effect in this 
subgroup at the 0.20 significance level (two-sided), based on a 
model evaluating the dependence of the treatment effect on 
baseline eGFR. 
Added statistical 
consideration related to 
probability of detecting a 
treatment effect in an 
additional 80 patients with 
screening eGFR between 
25 and 44.9 mL/min/1.73 m2. 
Clinical trial summary: 
Statistical considerations, 
Analysis population Stage 2 
The combined Stage 1 and Stage 2 ITT population will include all 
patients with an eGFR 45 and 89.9 mL/min/1.73 m2 at screening 
who are randomized in Stage 1 or Stage 2, analyzed according to 
the treatment group allocated by randomization (venglustat 
15 mg, venglustat 8 mg, or placebo). Patients from Stage 2 with 
an eGFR between 30 and 44.9 mL/min/1.73 m2 at screening will 
not be included in the primary efficacy and safety analyses 
population but the data from these patients will be analyzed 
separately. 
Added information that 
patients in Stage 2 with an 
eGFR between 30 and 
44.9 mL/min/1.73 m2 at 
screening will be described 
separately from the primary 
analysis population. 
Clinical trial summary: 
Duration of study period; 
Stage 1 and Stage 2 
Screening period 
Initial screening: up to 15 (+3) days. 
Placebo run-in period: 15 days ±3 days 2 weeks. 
Clarified maximum duration 
of initial screening period; 
2 weeks to 15 days 
clarification for placebo 
run-in period, and 
specification of its minimum 
and maximum duration. 
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Section # and Name 
Description of Change 
Brief Rationale 
1.2 Graphical study design 
for Stage 2 
New graphical study design for Stage 2 patients with an eGFR 
between 30 and 44.9 mL/min/1.73 m2 added 
Added revised graphical 
study design for patients with 
an eGFR between 30 and 
44.9 mL/min/1.73 m2 at 
screening. 
1.3 and 1.4 Study flowchart 
for Stage 1 and Stage 2 
Call IXRS/IWRS included in the flowchart for Visits 1-12. 
Clarification. 
1.3 and 1.4 Study flowchart 
for Stage 1, Stage 2: 
footnote “a” 
If a patient discontinues treatment with IMP early during the core 
treatment period, the patient will have an End-of-Treatment/Early 
Withdrawal (EOT/EW) Visit within 7 days and a Follow-up Visit 
4 weeks 30 days after the last dose of IMP.  
4 weeks to 30-day 
clarification. 
1.3 and 1.4 Study flowchart 
for Stage 1 and Stage 2: 
footnote “e” 
The abbreviated physical examination should focus on cardiac 
and respiratory systems, as well as any areas important for 
assessment of AEs if necessary. 
Clarification. 
1.3 and 1.4 Study flowchart 
for Stage 1 and Stage 2: 
footnote “j” 
8.1.2 Dose of drug per 
administration 
9.4.14.1 Sampling time 
Plasma samples for PK to be collected on Day 1 (3 ±1 hours post 
dose), Month 1 (pre dose and 3 ±1 hours post dose), Months 6 
and 18 (pre dose). At visits when a post-dose PK sample is to be 
collected, patients should take the study drug on site. 
Clarification that at visits 
when a PK sample is to be 
collected, patients should 
take the study drug on site. 
1.3 and 1.4 Study flowchart 
for Stage 1 and Stage 2: 
footnote “o” 
TKV volume must be confirmed by a central reader prior to 
Visit 3. 
Clarification. 
1.3 and 1.4 Study flowchart 
for Stage 1 and Stage 2: 
footnote “s” 
Prior to the start of IMP at Baseline Visit. In subjects who have 
consented to it, samples of serum will be collected and archived 
for future analysis. 
Footnote “s” added for 
clarification 
1.3 and 1.4 Study flowchart 
for Stage 1 and Stage 2: 
footnote “t” 
All SAEs, AEs and AEs of special interest (AESIs) will be 
collected starting with signing informed consent and continue until 
30 days 4 weeks after the last dose of IMP or study end, 
whichever comes later. All AEs that occurred during treatment 
should be followed for at least 30 days 4 weeks following the last 
dose of IMP or until the event has resolved, the condition has 
stabilized, the etiology of the event is determined to be not related 
to IMP, or the patient is lost to follow-up. All patients will have a 
follow-up visit 30 days 4 weeks after the last dose of IMP to 
collect safety information. 
4 weeks to 30-day 
clarification. 
1.3 and 1.4 Study flowchart 
for Stage 1: footnote “u”; 
Stage 2: footnote “w”; 
10.1.1.1 Visit 1: Screening 
from Day -30 to Day -16 
The initial screening period (Visit 1) can last up to 15 days 
(+3 days). Visit 2 can be performed as soon as results of all 
assessments performed at Visit 1 are available. 
Clarification that initial 
screening period could last 
up to 15 days and that it 
could be completed and V2 
could be performed as soon 
as results of all V1 
assessments are available. 
4.3 Benefit/risk of venglustat 
Infertility in adult males due to venglustat exposure in childhood 
(<12 years of age) 
Testicular degeneration was observed in juvenile toxicity study in 
the rat. There were no similar findings in any other nonclinical 
(adult animal) study. The finding could be related to the 
development stage of the animals, and is considered to be a 
potential risk for pediatric patients <12 years of age only. As 
Described preclinical 
testicular toxicity findings 
and theoretical implications. 
Added clarification that 
neurological AEs are closely 
monitored in venglustat 
studies by means of 
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Section # and Name 
Description of Change 
Brief Rationale 
pediatric patients are not included in the current study, there will 
be no measure for clinical monitoring for this risk. 
The finding of degeneration of testicular germinal epithelium, 
which was restricted to juvenile rats only, could be related to the 
development stage of the animals, and is currently considered to 
be a potential risk only for patients exposed to venglustat below 
the age of 12 years. Exposure under 12 years of age has a 
potential to negatively impact male fertility, an effect which would 
manifest at the time of sexual maturity. There is no measure for 
clinical monitoring in patients under 12 years of age.  
The two toxicity findings in sexually mature mice and dogs were 
of minimal severity and considered likely to be reversible, while 
there were no findings in any of the adult rat studies. Taken 
together the relevance of these findings is of unknown clinical 
significance in adult male patients. The exposures reached in 
juvenile and adult animal studies are not predicted to be achieved 
in human when receiving chronic treatment with venglustat at the 
15 mg dose. 
Theoretical risk of adverse neurological and psychiatric effects 
given the compound’s access to the CNS 
Neurological and psychiatric AEs are being closely monitored and 
evaluated in the clinical trials, and will be monitored in this study, 
including a complete physical examination that includes a 
standard neurological examination and the use of BDI-II 
instrument for assessment of the existence and severity of 
symptoms of depression. 
Concomitant administration with CYP3A inhibitors or inducers 
In the completed clinical drug-drug interaction study (INT14339), 
concomitant administration of venglustat with itraconazole, a 
strong inhibitor of CYP3A, resulted in an increase in venglustat 
exposure. 
standard neurological 
examination (part of 
complete physical 
examination). 
6.1 Description of the study; 
Stage 2 
Stage 1: If after reviewing the unblinded aggregate safety data 
from Stage 1 (after at least 1 month of treatment of the first 
150 randomized patients from Stage 1), the Data Monitoring 
Committee (DMC) recommends the 8 mg dose for Stage 2, then 
the DMC may recommend switching patients on 15 mg treatment 
arm, in Stage 1, to the 8 mg arm. 
Stage 2: After the first 150 randomized patients from Stage 1 
have completed at least 1 month of treatment (or have 
prematurely discontinued), the DMC will review in an unblinded 
fashion the aggregate safety data from Stage 1 and will select the 
venglustat for Stage 2 dose 8 mg or 15 mg for Stage 2 patients. 
The selected dose will be the highest dose determined to be safe 
and well tolerated in Stage 1. If after reviewing the unblinded 
aggregate safety data from Stage 1, the DMC recommends the 
8 mg dose for Stage 2, then the DMC may recommend switching 
patients on the 15 mg treatment arm, in Stage 1, to the 8 mg arm, 
if the DMC considers that there is a safety concern with the 
15 mg dose. 
Additionally, described in this 
section possible course of 
action with regard to the 
study drug dose in ongoing 
patients in Stage 1 that could 
be recommended by DMC to 
Sponsor after dose selection 
for Stage 2. 
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6.2.1 Duration of study 
participation for each patient 
This will consist of a screening period of up to 30 +3 days (initial 
screening period of up to 15 +3 days and single-blind placebo 
run-in period of 2 weeks)15 ±3 days), followed by a blinded study 
core treatment period of 24 months and a 30-day follow-up visit 
after the final dose of IMP. 
Clarified maximum duration 
of initial screening period; 
2 weeks to 15 days 
clarification for placebo run-
in period, and specification of 
its minimum and maximum 
duration. 
6.5.1 Rationale for selection 
of dose 
However, the Sponsor does not anticipate that the renal 
impairment status of ADPKD patients in Stage 1 of this study 
(mild to moderate renal impairment with eGFR 
>45 mL/min/1.73 m2 baseline) will have any potential implications 
for patient safety, as indicated by a PBPK model that predicted a 
mean venglustat plasma steady state exposure in a moderate RI 
population (GFR 30-60 mL/min/1.73 m2) following 15 mg QD 
dose, normal CYP abundance and age (matching the age of 
ADPKD patients in the current study) to be within the range of 
steady state exposures observed in Phase 1 (TDR12768 in 
healthy volunteers) and Phase 2 studies (ACT13739 in FD 
patients).  
The patients in Stage 1 will finish 24 months on placebo, 8 mg or 
15 mg. In Stage 2, patients will be randomized to placebo and 
This was further confirmed with results from a clinical study 
conducted to assess the impact of renal impairment on venglustat 
PK (POP14499), where, following a single 15 mg dose (8 mg or 
15 mg) selected during unblinded review by the DMC of the 
aggregated safety data from Stage 1. The selected dose will be 
the highest dose determined, venglustat exposure (AUC) was 
similar in subjects with mild RI but was estimated to be safe and 
well tolerated higher in Stage subjects with moderate and severe 
RI by as much as 1.33-fold (90% CI: 1.09 to 1.62) and 1.59-fold 
(90% CI: 1.15 to 2.20), respectively. To provide a conservative 
estimate of effect of moderate RI on venglustat PK, the upper end 
of 90% CI (1.62-fold) was taken into account at the lower limit of 
moderate RI (GFR: 30 mL/min).  
Given the current exposure margin from NOAEL in 26-week adult 
rat toxicology study of approximately 3.7-fold relative to the to 
human steady state exposure following 15 mg dose 
(2420 ng.hr/mL obtained from healthy subjects in study 
TDR12768 and NOAEL exposure of 8890 ng.hr/mL in female rats 
in adult rat 26-week toxicology study), venglustat exposure in 
moderate renal impaired subjects with eGFR up to 30 mL/min 
following a 15 mg QD dose, is anticipated to be below this 
NOAEL exposures. In addition, venglustat exposure in moderate 
renal impaired subjects with eGFR up to 30 mL/min following a 
15 mg QD dose, is also anticipated to be below the NOAEL 
exposure estimate for spermatid degeneration from adult mouse 
precarcinogenicity study (7780 ng.hr/mL). Considering the totality 
of this information, no dose adjustment is warranted in patients 
with eGFR ≥30 mL/min. 
The patients in Stage 1 will finish 24 months on placebo or 8 mg 
or 15 mg venglustat. In Stage 2, patients will be randomized to 
placebo or either (8 mg or 15 mg venglustat. The dose of 8 mg or 
15 mg will be selected during unblinded review by the DMC of the 
Clarification 
Provided information from 
the completed study of the 
assessment of renal 
impairment on venglustat PK 
and rationale for no dose 
adjustment in patients with 
eGFR ≥30 mL/min. 
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aggregated safety data from Stage 1. The selected dose will be 
the highest dose determined to be safe and well tolerated in 
Stage 1 (based on DMC review of safety data for 150 patients 
who have completed at least 1 month of treatment). 
If both during Stage 1 the 8 mg and 15 mg doses of venglustat 
have similar safety and tolerability profiles, during Stage 1, then 
the 15 mg dose will be selected. because, This is because based 
on the human healthy volunteer plasma PK/PD in the repeat dose 
study TDR12768 and rodent ADPKD efficacy studies, better 
efficacy is anticipated with 15 mg dose due to higher plasma 
GL-1 reduction as compared to the 8 mg dose. There are Only 
minimal safety concerns were observed for the 15 mg dose 
based on the present safety data of FD patients who have 
received the 15 mg dose for up to 24 months. 
6.5.2. Rationale for study 
design and control groups 
A prognostic enrichment approach is used to select patients for 
primary analysis population who will be at risk for rapid 
progression of disease based on those aged between 18 to 
50 years, CKD stages 2-3A, and Mayo Imaging Classification of 
ADPKD Class 1C-E. 
Patients with eGFR < 45 mL/min/1.73 m2 aged 18 to 55 years old 
recruited in Stage 2 of the study will be not included in primary 
analysis population but the data from these patients will be 
analyzed separately. 
Patients with CKD stage 3b (eGFR 30 - 45 mL/min/1.73 m2) aged 
18 to 55 years old will be recruited in Stage 2 of the study to 
permit gathering information on venglustat in this severely 
affected patient population. However, this patient population will 
not be included in the Stage 2 primary analysis but will be 
analyzed separately. The rationale for including these patients in 
the study is to obtain further information on venglustat exposure, 
safety and efficacy in patients with lower renal function.  
Based on the mode of action of venglustat the benefit of disease 
modification is expected to decrease whereas the exposures of 
venglustat increase with declining renal function. For this reason, 
CKD Stage 4 patients (eGFR <30 mL/min/1.73 m2) will not be 
included into the study. 
The seamless design of this two-stage trial is based on the 
similarities of the endpoints of the 2 stages and the identical 
inclusion/exclusion criteria of the primary analysis population of 
the 2 stages. 
Clarification. 
7.2 Exclusion criteria E1 
Systolic BP >160 mmHg* at run in and baseline visits.  
*mean value of three or five systolic BP measurements (See 
Section 9.4.5) 
The patient has, according to World Health Organization (WHO) 
Grading, a cortical cataract >≥1 quarter of the lens circumference 
(Grade cortical cataract 2 [COR 2]) or a posterior subcapsular 
cataract >≥2 mm (Grade posterior subcapsular cataract 2 [PSC 
2]). Patients with nuclear cataracts will not be excluded. 
Clarification 
 
 
Correction 
7.2 Exclusion criteria E5 
The patient has a documented diagnosis positive result of any of 
the following infections tests: hepatitis B, hepatitis C, human 
immunodeficiency virus 1 or 2 (positive hepatitis B surface 
antigen (HBsAg), anti-hepatitis C virus (anti-HCV) antibodies, 
anti-human immunodeficiency virus 1 and 2 antibodies (anti-HIV1 
Clarification that patients’ 
immune due to natural 
infection (positive HBsAb, 
negative HBs Ag, and 
positive HBcAb) are eligible 
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and anti-HIV2 Ab). Patients with a positive hepatitis B surface 
antibody (HBsAb) test with a history of prior hepatitis B 
immunization are eligible if other criteria are met (ie, negative 
tests for: HBsAg, hepatitis B core antibody [HBcAb]). Patients 
immune due to natural infection (positive HBsAb, negative HBs 
Ag, and positive HBcAb) are eligible if they have a negative HBV 
DNA test. 
if they have a negative HBV 
DNA test. 
7.2.3 Exclusion criteria 
Patients who were rescreened in Stage 1 of the study under 
protocol versions preceding amendment 04 and failed screening 
because of eGFR <45 mL/min/1.73 m2, can be screened in 
Stage 2. 
Patients with eGFR at screening from 75.0 to 
89.9 90 mL/min/1.73 m2. 
Clarification. 
8.8.1 List of forbidden 
concomitant medication 
Alpha-adrenergic receptor agonist glaucoma medications 
because they can worsen the vision of patients with cataracts. 
Glaucoma medications. 
Clarified that among 
glaucoma medications only 
alpha-adrenergic receptor 
agonist glaucoma 
medications are prohibited 
during the study treatment 
period.  
9.4.6 Physical examination 
A complete physical examination (including full neurological 
exam) will include a thorough review of all body systems to collect 
physical observations/measurements. 
A mental status evaluation will be performed as a part of the 
complete physical examination and should include a Mini Mental 
State Examination (MMSE) or an equivalent local standard 
method for assessment of the cognitive state of a patient, 
provided the method covers all the areas assessed by MMSE. 
A full standard basic neurological examination will be performed 
as a part of the complete physical examination. Results will be 
documented on eCRF pages dedicated to neurological 
examination. For details, please refer to the Study Reference 
Manual. 
Abbreviated physical examinations will focus on cardiac and 
respiratory symptoms, as well as any areas important for 
assessment of AEs if necessary. 
Provided reference to the 
Study Reference Manual for 
details of the full standard 
neurological examination 
(including mental status 
evaluation) that is performed 
as a part of the complete 
physical examination. 
9.4.10 Ophthalmological 
examination 
10.4.1.3 Adverse event of 
special interest 
For opacities present at baseline/previous visit, changes in 
LOCSIII score of ≥0.5 for nuclear opalescence, ≥0.8 for cortical 
opacification, or ≥0.5 for posterior subcapsular opacification 
compared with baseline or previous assessment will be 
considered as a worsening. 
To specify threshold for 
minimal significant change in 
LOCSIII score that will be 
considered as a worsening 
of lens opacity. 
In countries where the Latin alphabet is not used, the Snellen 
chart could be substituted with the Tumbling E distance chart 
based on the Snellen fraction. 
Clarification that the 
Tumbling E distance chart 
should be based on the 
Snellen fraction. 
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10.1.1.2 Visit 2; Run-in 
Day -15, Visit window 
The run-in visit (Day -15) can should be performed up to 
approximately 15 (±3) days after the initial screening visit or as 
soon as results of all assessments performed at Visit 1 are 
available. Visit. Using the date of the initial screening visit (date of 
the first study procedure) as reference, a time frame of ±3 days is 
acceptable for this visit. 
Abbreviated physical examination (focus on cardiac and 
respiratory systems, as well as any areas important for 
assessment of AEs if necessary). 
Clarification that the run-in 
visit can be performed up to 
approximately 15 (+3) days 
after the initial screening visit 
or as soon as results of all 
assessments performed at 
Visit 1 are available. 
10.1.2 Treatment Period - 
Month 0 to Month 24 
Visit window: The randomization visit (Day 1) should be 
performed 30 15 days after Visit 2 the initial screening visit with 
the acceptable window of ±3 days. Using Day 1 as reference, a 
time frame of ±7 days is acceptable for Visits 4 to 12. (If one visit 
date is skipped/missed/changed, the next visit should take place 
according to the original schedule.) 
Clarified that the time of the 
randomization visit depends 
on the time frame of Visit 2 
and not on the time frame for 
Visit 1 because the initial 
screening period could be 
completed as soon as results 
of all V1 assessments are 
available. 
10.1.2.1 Visit 3 
Randomization at 
Month 0/Day 1 
Biobanking blood sample (optional) collected prior to the start of 
IMP. 
Remind patient to not take the dose at home on the next clinic 
visiting day. 
Clarification. 
10.1.2.2 Visit 4, 6, 8, 10, 
12/Month 1, 6, 12, 18, 24 
(Day 30, 180, 360, 540, 720) 
Abbreviated physical examination (focus on cardiac and 
respiratory systems, as well as any areas important for 
assessment of AEs if necessary; Visits 4, 6, and 8). 
Biobanking blood sample (optional) at Visits 8 and 12. 
Remind patient to not take the dose at home on the clinic visiting 
day at Visits 6 and 10 during Stage 1, and at Visit 12 during 
Stage 2Visits 4, 8, and 10. 
Correction. 
10.1.2.3 Visit 5, 7, 9, 
11/Month 3, 9, 15, 21 
(Day 90, 270, 450, 630) 
Abbreviated physical examination (focus on cardiac and 
respiratory systems, as well as any areas important for 
assessment of AEs if necessary). 
Clarification. 
10.1.3 Follow-up Visit – Visit 
13/Month 25 (Day 750) 
Abbreviated physical examination (focus on cardiac and 
respiratory systems, as well as any areas important for 
assessment of AEs if necessary). 
Clarification. 
10.3.3 List of criteria for 
permanent treatment 
discontinuation 
If a patient experiences a reduction in eGFR below 
30 mL/min/1.73 m2 on two visits apart, the patient will be 
discontinued from the study. 
If a patient experiences a reduction in eGFR below 
25 mL/min/1.73 m2, a repeated test must be performed in 
4 weeks 30 days: 
if eGFR result repeated in 4 weeks30 days is below 
30 mL/min/1.73 m2, the patient will be discontinued from the 
study. 
Added rules for 
discontinuation for confirmed 
decrease in eGFR. 
10.3.4 Handling of patients 
after permanent treatment 
discontinuation 
Stage 1: EOT visit should include all procedures of Visit 12 and 
additionally a PK sample should be collected. In 4 weeks 
30 days, a Follow-up visit (Visit 13) should be performed. 
Stage 2: EOT visit should include all procedures of Visit 12. In 
4 weeks 30 days, a Follow-up visit (Visit 13) should be performed. 
4 weeks to 30-day 
clarification. 
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10.4.2 General guidelines for 
reporting adverse events 
Laboratory, vital signs, or ECG, or ophthalmic examination 
abnormalities are to be recorded as AEs only if:  
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, 
Defined as an AESI, and or, 
Leading to unscheduled full ophthalmological examination with or 
without LOCSIII evaluation. 
Correction. 
11.3.1.1 Intent–to-treat 
population, Stage 2 
The combined Stage 1 and Stage 2 ITT population will include be 
defined as all patients with an eGFR between 45 and 
89.9 mL/min/1.73 m2 at screening who are randomized in Stage 1 
or Stage 2, analyzed according to the treatment group allocated 
by randomization (venglustat 15 mg, venglustat 8 mg or placebo). 
Primary analysis in the combined Stage 1 and Stage 2 will 
include all data available from baseline to the end of the 
24-month double-blind core treatment period. Patients from 
Stage 2 with an eGFR between 30 and 44.9 mL/min/1.73 m2 at 
screening will not be included in the primary efficacy analysis 
population but the data from these patients will be analyzed 
separately. 
Added clarification to the 
definition of the combined 
Stage 1 and Stage 2 ITT 
population will include all 
randomized patients with 
eGFR between 45 and 
89.9 mL/min/1.73 m2 at 
screening and patients from 
Stage 2 with eGFR between 
30 and 44.9 mL/min/1.73 m2 
at screening will be analyzed 
separately.  
11.3.2 Safety population 
The combined Stage 1 and Stage 2 Safety population will be 
defined as all patients with an eGFR between 45 and 
89.9 mL/min/1.73 m2 at screening who are randomized in Stage 1 
or Stage 2 and received at least one dose or part of a dose of the 
double-blind IMP, analyzed according to the treatment actually 
received (venglustat 15 mg, venglustat 8 mg or placebo). Patients 
from Stage 2 with an eGFR between 30 and 44.9 mL/min/1.73 m2 
at screening will not be included in the primary safety analysis 
population but the data from these patients will be analyzed 
separately. 
A secondary safety analysis population will include patients who 
are randomized in Stage 2 with an eGFR between 30 and 
44.9 mL/min/1.73 m2 at screening and received at least one dose 
or part of a dose of the double-blind IMP. 
Added clarification to the 
definition of the combined 
Stage 1 and Stage 2 Safety 
population will be defined as 
all randomized patients with 
eGFR between 45 and 
89.9 mL/min/1.73 m2 at 
screening and patients from 
Stage 2 with an eGFR 
between 30 and 
44.9 mL/min/1.73 m2 at 
screening will be analyzed 
separately. 
11.4.2.1.1 Stage 1 
Secondary Analysis: In this secondary analysis, TKV assessed 
more than 4 weeks 30 days after the last IMP administration will 
be excluded from the analysis 
4 weeks to 30-day 
clarification. 
11.4.2.4 Secondary analysis 
including patients from 
Stage 2 with eGFR between 
30 and 44.9 mL/min/1.73 m2 
at screening 
New section added; 11.4.2.4 Secondary analysis including 
patients from Stage 2 with eGFR between 30 and 
44.9 mL/min/1.73 m2 at screening 
A secondary analysis of eGFR will include the following patients: 
Patients from Stage 1 randomized to placebo or to the selected 
dose of venglustat (N = 160) 
Patients from Stage 2 with eGFR between 45 and 
89.9 mL/min/1.73 m2 at screening (N = 320) 
Patients from Stage 2 with eGFR between 30 and 
44.9 mL/min/1.73 m2 at screening (N = 80) 
The purpose of this secondary analysis will be to make 
model-based inferences about the dependence of the treatment 
Described secondary 
analysis including patients 
from Stage 2 with eGFR 
between 30 and 
44.9 mL/min/1.73 m2 at 
screening. 
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effect on baseline eGFR. 
A linear mixed effect model will be fitted to the eGFR, which will 
include fix effects of treatment (venglustat or placebo), Mayo 
Imaging Classification (as per randomization stratification factor: 
Class 1C versus 1D versus 1E), eGFR at screening (as a 
continuous variable), time (as a continuous variable), 
treatment * time interaction, Mayo Imaging Classification * time 
interaction, eGFR at screening * time interaction, as well as the 
treatment * eGFR at screening * time interaction. The model will 
also include random intercept and slope. 
Mean eGFR slopes within each treatment group (venglustat or 
placebo), as well as the difference in eGFR slopes, will be 
estimated for the following patient categories: 
Patients with eGFR at screening of 30 to 44.9 mL/min/1.73 m2 
Patients with eGFR at screening of 45 to 59.9 mL/min/1.73 m2 
Patients with eGFR at screening of 60 to 74.9 mL/min/1.73 m2 
Patients with eGFR at screening of 75 to 89.9 mL/min/1.73 m2 
Estimates within each category will be calculated from the linear 
mixed effect model, using the center of each category as eGFR at 
screening in the model. Difference in slopes will be presented 
with 80% CI. 
11.4.3 Analyses of safety 
data 
The residual treatment period is defined as the time from the day 
after the last IMP administration, plus 30 days 4 weeks 
The baseline value is defined generally as the last available value 
before randomization first IMP administration. 
Clarification. 
14.2 Record retention in 
study sites 
The Investigator should retain the study documents at least 
15 years after the completion or discontinuation of the clinical 
trial.  
However, applicable regulatory requirements should be taken into 
account in the event that a longer period is required. 
The Investigator must notify the Sponsor prior to destroying any 
study essential documents following the clinical trial completion or 
discontinuation. 
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. 
Clarification.  
Throughout 
Adjusted 4 weeks to 30 days in running text whenever needed 
Clarification: Adjusted 
4 weeks to 30 days. 
Throughout 
Minor formatting, consistency, and grammar-related changes 
done. 
For consistency and better 
readability. 
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Protocol Amendment 03 Version number: 1 (electronic 3.0) Date: 01 October 2018 
Changes made to the protocol are outlined as follows. 
• To change study acronym. 
In section: Cover Page, Clinical trial summary 
Rationale: change in study acronym. 
• To replace product code with the International Nonproprietary Name venglustat. 
In section: throughout the document. 
Rationale: introduction of the International Nonproprietary Name. 
• To describe objective of mGFR substudy - to explore the effect of GZ/SAR402671 on 
measured GFR. 
In section: Clinical trial summary - Stage 2; Exploratory objectives; 5.2.3 Exploratory 
objectives. 
Rationale: description of objective of mGFR substudy. 
• To describe endpoint that will be assessed in mGFR substudy: annualized rate of 
change in mGFR from baseline to 24 months. 
In section: Clinical Trial Summary - Stage 2; Endpoints; 9.3 Exploratory endpoints; 9.3.2.  
Rationale: description of endpoint that will be assessed in mGFR substudy. 
• To add description of mGFR substudy. 
In section: Clinical Trial Summary - Stage 2; Assessment schedule; 1.3, footnote v; 
10.1.2.1; 10.1.2.2; 10.3.4; Appendix L. 
Rationale: to include details of mGFR substudy. 
• To clarify that collection of 24-hour urine sample at Visits 5 and 7 will take place 
only at selected sites which participate in isolation of urinary exosomes. 
In section: 1.3 footnote l; 9.4.17, Appendix K. 
Rationale: clarification of collection of 24-hour urine sample at Visits 5 and 7. 
• To correct spelling of parameter assessed with the urine dipstick. 
In section: 1.3 footnote i; 1.4 footnote h; 10.1.1.1; 10.1.2.2; 10.1.2.3. 
Rationale: nitrate corrected to nitrite. 
• To clarify timing of evaluation of V2 ECG reading related to run-in medication at V2 
and IMP at V3 administration. 
In section: 1.3; 1.4 footnote m; 10.1.1.2. 
Rationale: clarification added that Investigator should evaluate V2 ECG reading prior to 
run-in medication administration; V2 ECG central reader’s assessment should be 
evaluated prior to IMP administration at for Visit 3 only.  
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• To add information about tolvaptan’s approval in US. 
In section: 4.1.2. 
Rationale: update of the status of tolvaptan’s approval. 
• To add clarification that WOCBP should use a highly effective method of 
contraception during the study. 
In section: 4.3, 7.1 Inclusion Criteria I09. 
Rationale: clarification of requirement for WOCBP to use a highly effective method of 
contraception during the study. 
• To clarify the time point of the follow up visit after the final dose of investigational 
medicinal product. 
In section: 6.2.1. 
Rationale: clarified that the follow-up visit should occur 30 days after the final dose of 
investigational medicinal product. 
• To clarify that for patients agreeing to participate in the mGFR substudy of Stage 2, 
additional entry criteria are listed in Appendix L. 
In section: 7. 
Rationale: description of additional entry criteria for patients who agree to take part in 
mGFR substudy of Stage 2. 
• To emphasize that a complete physical examination includes full neurological 
examination. 
In section: 9.4.6. 
Rationale: emphasis on the neurological component of the complete physical examination. 
• To establish the plan for handling patients who indicate that they have suicidal 
thoughts. 
In section: 9.4.9. 
Rationale: establishing plan for handling patients who indicate that they have suicidal 
thoughts. 
• To clarify the use of Snellen chart in countries where the Latin alphabet is not used. 
In section: 9.4.10. 
Rationale: use of Tumbling E distance chart was allowed in countries where Latin 
alphabet is not used. 
• To remove the phrase that highly effective contraceptive method of birth control may 
be defined according to the local medical practice and regulations. 
In section: Appendix A. 
Rationale: “Highly effective contraception” has a specific meaning as defined the Clinical 
Trial Facilitation Group guidance document on contraception in clinical trials. 
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Protocol Amendment 02 Version number: 1 (electronic 2.0) Date: 25 May 2018 
Changes made to the protocol are outlined as follows. 
• To supplement description of the exploratory objectives of the study. 
In section: clinical trial summary, 5.1.3, 5.2.3 
Rationale: added description of objective to explore the effect of GZ/SAR402671 on type, 
frequency and dosage of analgesic/over the counter pain medication administration. 
• To detail settings of the placebo run-in period. 
In section: clinical trial summary, 6.1, 6.2.1. 
Rationale: single-blind setting added to the description of placebo run-in period in Stage 1 
and Stage 2. 
• To add details of stratification of patients by geographic region. 
In section: clinical trial summary, 6.1. 
Rationale: stratification of patients by region was added to achieve balance between the 
treatment arms across the different regions. 
• To clarify inclusion criteria. 
In section: clinical trial summary, 7.1. 
Rationale:  
- 
Clarification has been made on inclusion criterion I01 related to the timing of 
evaluation of this criterion;  
- 
Clarification has been made on inclusion criterion I07 describing situation when 
patient refuses to initiate treatment with tolvaptan as part of scenario when tolvaptan 
may not be considered by treating physician as indicated for treatment of patient. 
• To clarify exclusion criteria. 
In section: clinical trial summary, 7.2.1 
Rationale:  
- 
Criterion E02 was reworded to emphasize that all Polycystic Kidney 
Disease-modifying agents should not be administered within 3 months prior to the 
screening visit; 
- 
Criterion E05 was supplemented with information when patients with positive hepatitis 
B core antibody, negative HBsAg and negative hepatitis B surface antibody can be 
enrolled in the study (to exclude occult HBV infection in isolated anti-HBc positive 
patients). 
• To apply removal of mGFR substudy to the protocol. 
In section: clinical trial summary, 1.4, 3, 5.2.3, 9.3.2, 10.1.2.1, 10.1.2.2, 10.3.4, 
Appendix A. 
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Rationale: references to mGFR substudy (including collection of blood samples and 
Appendix A) were removed from the protocol.  
• To clarify adjustment on stratification factors in the analysis. 
In section: clinical trial summary, 11.4.2.1.1, 11.4.2.2.3, 11.4.5 
Rationale: to clarify that adjustment on stratification factors in the analysis for Mayo 
imaging classification (Mayo Class 1C, 1D and 1E). 
• To improve the precision and accuracy of the BP measurement. 
In section: 1.3, 1.4, 9.4.5. 
Rationale: 5-minute rest period was changed to 10-minute rest period; additionally 
scenario of short-term blood pressure variability between successive measurements was 
addressed. 
• To clarify screening laboratory assessments. 
In section: 1.3, 1.4 
Rationale: to clarify that some assessments done at the beginning of screening may have to 
be repeated prior to randomization. 
• To detail course of actions when any parameter on the locally performed urinary 
dipstick is abnormal. 
In section: 1.3, 1.4 
Rationale: to specify that in case if any parameter on the urinary dipstick is abnormal, a 
urine sample should be sent to the central laboratory for quantitative measurement 
• To expand the justification of placebo selected as the control arm.  
In section: 6.5.2 
Rationale: Details have been added to justify why tolvaptan is not being used as control 
arm such as the description of potential discontinuation or failure to initiate the therapy 
with tolvaptan due to poor tolerability and safety, and possibility of substantial unblinding 
due to aquaretic effect of tolvaptan.  
• To clarify that enrollment is based on 3 categories of screening eGFR values. 
In section: 7 
Rationale: to have adequate representation of patients across eGFR spectrum a minimum 
of 20% of patients within 3 categories of screening eGFR will be enrolled.  
• To clarify blinding measures related to PK measurements. 
In section: 8.3.1 
Rationale: to clarify that only samples collected from patients on active drug will be 
analyzed and describe measures to ensure blinding at the assay institutions charged for PK 
measurements. 
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• To clarify forbidden concomitant medications. 
In section: 8.8.1 
Rationale: to clarify that Polycystic Kidney Disease-modifying agents (eg, somatostatin 
analogues) are forbidden concomitant medications. 
• To provide details on the method of calculation of eGFR in Asian population of 
patients and separately in Japanese patients. 
In section: 9.4.2 
Rationale: to clarify that for calculation of eGFR in Asian population of patients (except 
Japanese patients) the Asian-modified CKD-EPI equation will be used; the CKD-EPI 
Study equation multiplied by a Japanese coefficient of 0.813 will be used for eGFR 
calculation in Japanese patients. 
• To update and clarify instructions for collection of urine spot. 
In section: 1.3, 1.4, 9.4.3 
Rationale: to clarify instructions for collection of urine spot including collection of third 
spot sample. 
• To provide details on the frequency and scope of ophthalmic examination, to update 
the system for grading the type and severity of cataract, to remove requirement for lens 
photography during each lens assessment and requirement for central reading. 
In section: clinical trial summary, 1.3, 1.4, 9.4.10, 10.1.1.2, 10.1.2.2, 10.1.2.3 
Rationale: to update the frequency and the scope of ophthalmic exam, to replace LOCSII 
with LOCSIII, to remove requirement for mandatory lens photography and central reading 
of lens images. 
• To rename section. 
In section: 9.4.11 
Rationale: to change the name of section to Patient reported outcomes. 
• To update description of Patient Global Impression of Change questionnaire. 
In section: 9.4.11.4. 
Rationale: to specify timing of the start of assessment and categories of scales. 
• To update items of the Daily symptoms of autosomal dominant polycystic kidney 
disease diary.  
In section: 9.4.11.6. 
Rationale: to regroup pain and nocturia items of the diary and to add an additional item 
that will direct to the medication entry log. 
• To update information about PK samples collection. 
In section: clinical trial summary, 1.3, 1.4, 9.4.14.1, 10.1.2.1, 10.1.2.2 
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Rationale: to remove all pre-dose samples on Day1 in Stage 1; to add a post-dose sample 
on Day1 in stage 2; to move the PK sampling from Month 6 to month 1 in Stage 2; to 
specify that the post-dose sample of 3 hours can be collected at 3 + or - 1 hour. 
• To detail stopping rules for individual treatment discontinuation in case of 
ophthalmic examination findings and reduction in eGFR. 
In section:10.3.3  
Rationale: To include a stopping rule for individual treatment discontinuation in case of 
best corrected visual acuity loss due to posterior subcapsular cataract; to modify period 
between 2 assessments with confirmed reduction in eGFR that should lead to study 
treatment discontinuation. 
• To clarify visits and assessments that should be performed if patient prematurely and 
permanently discontinue study medication. 
In section: clinical trial summary, 10.3.4.  
Rationale: to specify visits and assessments that should be performed if patient 
prematurely and permanently discontinue study medication (end-of-treatment and follow-
up visits, PRO assessments, efficacy and safety assessments at visits Month 18 and 
Month 24). 
• To describe secondary analysis that will explore a potential acute hemodynamic 
effect.  
In section: 11.4.2.1.1 
Rationale: to describe secondary analysis that will explore a potential acute hemodynamic 
effect using TKV data assessed from 1 month to 18 months.  
• To correct information of the section. 
In Section: 12.2 
Rationale: to remove requirement that the written informed consent form can be signed 
and dated by the patient’s legally acceptable representative. 
• To clarify information related to highly effective contraceptive method of birth 
control. 
In section: Appendix B. 
Rationale: to specify that highly effective contraceptive method of birth control may be 
defined according to the local medical practice and regulations. 
• To clarify that Isolation of Urinary Exosomes analysis is part of ADPKD biomarkers 
assessment (required tests of the protocol). 
In section: Appendix L. 
Rationale: to specify that isolation of Urinary Exosomes analysis is part of ADPKD 
biomarkers assessment and is covered by informed consent of EFC15392 study. 
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Protocol Amendment 01 Version number: 1 (electronic 1.0) Date: 19 April 2018 
Changes made to the protocol are outlined as follows. 
• To clarify possible course of action with regard to the study drug dose in ongoing 
patients in Stage 1 after DMC review of safety data and dose selection for Stage 2. 
In section: 6.1 
Rationale: described possible course of action with regard to the study drug dose in 
ongoing patients in Stage 1 that could be recommended by DMC to Sponsor after dose 
selection for Stage 2.  
• To clarify inclusion criteria. 
In section: clinical trial summary, 7.1. 
Rationale: clarification has been made on inclusion criteria I01 and I02 to better define the 
targeted population and criterion I07 to describe written ICF collection before any study 
procedure.  
• To clarify exclusion criteria. 
In section: 7.2.1, 7.2.3. 
Rationale: criterion E09 was modified to better detail uncontrolled medical conditions, 
criterion E10 was modified to address country-specific exclusion criteria, criterion E16 
was revised to indicate the limits of total and direct bilirubin that are allowed for inclusion 
of patients with Gilbert`s syndrome. 
• To detail timing of evaluation of the secondary and exploratory endpoints. 
In section(s): clinical trial summary, 9.2.2, 9.2.3.3, 9.3.3. 
Rationale: Details on the time point of evaluation of secondary and exploratory endpoints 
were included. 
• To add a stopping rule for individual treatment discontinuation. 
Section 10.3.3  
Rationale: to include a stopping rule for individual treatment discontinuation in case of 
accelerated disease progression based on eGFR reduction. 
• To include blood pressure control recommendations. 
In Section: 10.6.  
Rationale: Safety management was modified to include blood pressure control 
recommendations if patient requires modification of antihypertensive therapy during study 
participation. 
• To clarify that mGFR substudy is optional for eligible patients. 
In section Appendix A, Section 4.  
Rationale: To clarify that mGFR substudy is optional for eligible patients. 
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Appendix O 
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 and in sections (Section 7.2.4, Section 8.1.2, 
Section 9.4, Section 10, Section 10.3.1, Section 12.2) 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. 
During the emergency, if the site will be unable to adequately follow protocol mandated 
procedures, alternative treatment outside the clinical trial should be proposed, and screening, 
enrollment, randomization and/or administration of study treatment may be temporarily 
delayed/halted.  
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). 
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.  
The following contingencies may be implemented for the duration of the emergency (after 
Sponsor agreement is obtained) to make clinical supplies available to the participant for the 
duration of the emergency: the Direct-to-Patient (DTP) supply of venglustat from the site where 
allowed by local regulations and agreed upon by the participant. Direct-to-Patient supply of IMP 
is not contingent on availability of contemporaneous laboratory results or other study specific 
assessments. 
Procedures to be considered in the event of a regional or national emergency declared by a 
governmental agency (where allowed by local regulations) if onsite visits are not possible: 
• Phone contacts are to be performed in place of an onsite study visits and per study protocol 
schedule. Essential data (that can be checked via interview to evaluate patient safety) to be 
captured via phone contact and documented in the source records include, but is not 
limited to, AEs, SAEs, change in or new concomitant medications, urine pregnancy test 
results, IMP compliance, potential signs of depressed mood, complaints about changes in 
vision, vital signs (if patients can measure temperature and BP at home). Visit ePROs 
(questionnaires) should be completed by the patient in the eDiary as usual. eDiary data can 
still be checked online by the investigator/site team prior to calling the patient to ensure 
any follow-up questions or findings can be discussed. 
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• If it is feasible and there is no additional risk for a patient from the hazard that led to 
declaration of national emergency, consider performing blood tests in local laboratories: 
- 
blood chemistry: at the minimum blood creatinine, AST, ALT, eGFR calculated with 
Chronic Kidney Disease Epidemiology Collaboration equation; 
- 
complete blood count. 
• Patients with a recent eGFR >45 mL/min/1.73 m2, may continue IMP up to 6 months, 
without having an on-site visit.  
Patients with a recent eGFR ≤45 and >30 mL/min/1.73 m2, may continue IMP up to 
3 months, without having an on-site visit. Patient who are not be able to repeat eGFR in 
3 months will have to interrupt the treatment. Temporary IMP discontinuation will need 
to be registered in IRT. 
Patients with a recent eGFR ≤30 and ≥25 mL/min/1.73 m2, who are not be able to repeat 
creatinine in 30 days will have to interrupt the treatment. If eGFR result repeated in 
30 days is below 30 mL/min/1.73 m2, the patient will have to stop the treatment 
permanently. 
• When phone contact is performed in place of an onsite study visits, assessments of 
efficacy and safety data that cannot be obtained remotely [eg, MRI, ECG, 
ophthalmological and neurological examination] will be performed when patients are 
able to resume normal site visits. Safety assessment that cannot be obtained remotely 
may be performed prior to next regular onsite visit if Investigator considers that this is 
clinically indicated and feasible, and that this will not involve an additional risk for a 
patient from the hazard that led to declaration of national emergency. 
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. 
If a rescreened patient was screen-failed during a regional or national emergency for reasons not 
related to eligibility, rescreening shall be permitted when the situation normalizes. 
If eligibility assessment cannot be performed due to department/service shutdowns (MRI, 
ophthalmology, etc) during the screening period, the patient cannot be randomized, and screening 
period can be extended with randomization after site will be able to reopen. In such scenario, 
certain screening assessment will have to be repeated before Visit 3: 
• Blood chemistry (if >2 weeks after Visit 2) 
• CBC (if >4 weeks after Visit 1) 
• BCVA and lens cataract grading according to WHO simplified cataract grading system (if 
>3 months from Visit 2 eye exam) 
• ECG (if >3 months from Visit 2 ECG test) 
• BDII (if >2 weeks after Visit 2) 
• MRI (decision on case by case basis: if >1-3 month before Visit 3) 
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If eligibility was confirmed but patient cannot attend site to perform Visit 3 because of a regional 
or national emergency declared by a governmental agency, a remote Visit 3 (randomization) can 
be performed where allowed by local regulations under condition that the Direct-to-Patient (DTP) 
supply of venglustat from the site is allowed by local regulations and agreed upon by the 
participant, and a home health vendor service is in place to visit patient in 1 month (for Visit 4) to 
collect laboratory samples and assess adverse event after 1 month on the double-blind treatment. 
For a remote Visit 3, a home health vendor should visit the patient at least one day before the 
remote Visit 3 to collect blood pressure measurements, assess run-in medication compliance, 
adverse events, concomitant medications and perform urine pregnancy test (for WOCBP).  
On the day of the remote Visit 3, the Investigator will evaluate assessments performed and 
provided by home health vendor, ePROs completed by the patient in the eDiary, and will 
randomize patient if eligibility is reconfirmed. If patient is randomized, IMP will be sent to patient 
via DTP process. Site will need to follow up via phone with the patient once IMP is delivered. 
Contingencies implemented due to emergency will be documented. 
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Statistical Analysis Plan  
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF TABLES ........................................................................................................................................... 5 
LIST OF FIGURES .......................................................................................................................................... 5 
VERSION HISTORY ....................................................................................................................................... 6 
1 
INTRODUCTION .............................................................................................................................. 8 
1.1 
STUDY DESIGN .............................................................................................................................. 8 
1.2 
OBJECTIVE AND ENDPOINTS ...................................................................................................... 9 
1.2.1 
Estimands ...................................................................................................................................... 12 
2 
SAMPLE SIZE DETERMINATION ................................................................................................ 15 
3 
ANALYSIS POPULATIONS .......................................................................................................... 16 
4 
STATISTICAL ANALYSES ........................................................................................................... 18 
4.1 
GENERAL CONSIDERATIONS .................................................................................................... 18 
4.2 
PARTICIPANT DISPOSITIONS ..................................................................................................... 19 
4.3 
PRIMARY ENDPOINT(S) ANALYSIS ............................................................................................ 20 
4.3.1 
Stage 1 ........................................................................................................................................... 20 
4.3.1.1 
Definition of endpoint(s) ................................................................................................................. 20 
4.3.1.2 
Main analytical approach ............................................................................................................... 20 
4.3.1.3 
Sensitivity analysis ......................................................................................................................... 22 
4.3.1.4 
No sensitivity analysis will be performed due to the discontinuation of the study after the 
futility analysis Supplementary analyses ....................................................................................... 22 
4.3.1.5 
Subgroup analyses ........................................................................................................................ 22 
4.3.1.6 
Description of missing data ............................................................................................................ 23 
4.3.2 
Combined Stage 1 and Stage 2 ..................................................................................................... 23 
4.3.2.1 
Definition of endpoint(s) ................................................................................................................. 23 
4.3.2.2 
Main analytical approach ............................................................................................................... 23 
4.3.2.3 
Sensitivity analysis ......................................................................................................................... 24 
4.3.2.4 
Supplementary analyses ................................................................................................................ 24 
4.3.2.5 
Subgroup analyses ........................................................................................................................ 24 
4.4 
SECONDARY ENDPOINT(S) ANALYSIS ..................................................................................... 25 
4.4.1 
Stage 1 key/confirmatory secondary endpoint(s) .......................................................................... 25 
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4.4.1.1 
Definition of endpoint(s) ................................................................................................................. 25 
4.4.1.2 
Main analytical approach ............................................................................................................... 25 
4.4.2 
Combined Stage 1 and Stage 2 key/confirmatory secondary endpoint(s) .................................... 26 
4.4.2.1 
Definition of endpoint(s) ................................................................................................................. 26 
4.4.2.2 
Main analytical approach ............................................................................................................... 26 
4.4.3 
Supportive secondary endpoint(s) ................................................................................................. 26 
4.5 
TERTIARY/EXPLORATORY ENDPOINT(S) ANALYSIS .............................................................. 27 
4.5.1 
Definition of endpoint(s) ................................................................................................................. 27 
4.5.2 
Main analytical approach ............................................................................................................... 27 
4.6 
MULTIPLICITY ISSUES ................................................................................................................ 28 
4.7 
SAFETY ANALYSES ..................................................................................................................... 29 
4.7.1 
Extent of exposure ......................................................................................................................... 29 
4.7.2 
Adverse events .............................................................................................................................. 30 
4.7.3 
Additional safety assessments ....................................................................................................... 32 
4.7.3.1 
Laboratory variables, vital signs and electrocardiograms (ECGs) ................................................. 32 
4.7.3.2 
Physical examination ..................................................................................................................... 34 
4.7.3.3 
Neurological examination ............................................................................................................... 34 
4.7.3.4 
Ophthalmological examination ....................................................................................................... 35 
4.7.3.5 
Depression (BDI-II) examination .................................................................................................... 36 
4.8 
OTHER ANALYSES....................................................................................................................... 36 
4.8.1 
PK analyses ................................................................................................................................... 36 
4.8.2 
Pharmacodynamic analyses .......................................................................................................... 37 
4.8.3 
Patient reported outcomes analyses.............................................................................................. 37 
4.8.4 
Biomarker analyses........................................................................................................................ 40 
4.8.5 
Hospitalization analyses ................................................................................................................ 41 
4.9 
INTERIM ANALYSES .................................................................................................................... 41 
4.9.1 
Dose selection safety review ......................................................................................................... 41 
4.9.2 
Interim futility analysis .................................................................................................................... 41 
4.9.3 
Two-steps analysis......................................................................................................................... 42 
5 
SUPPORTING DOCUMENTATION .............................................................................................. 43 
5.1 
APPENDIX 1 LIST OF ABBREVIATIONS ..................................................................................... 43 
5.2 
APPENDIX 2 CHANGES TO PROTOCOL-PLANNED ANALYSES ............................................. 45 
5.3 
APPENDIX 3 DEMOGRAPHICS AND BASELINE CHARACTERISTICS, PRIOR OR 
CONCOMITANT MEDICATIONS .................................................................................................. 49 
5.4 
APPENDIX 4 DATA HANDLING CONVENTIONS ........................................................................ 51 
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5.5 
APPENDIX 6 SAMPLE SIZE SIMULATION SAS CODE .............................................................. 54 
5.6 
APPENDIX 7 STATISTICAL TECHNICAL DETAILS .................................................................... 66 
5.6.1 
Operating characteristics of the study design ................................................................................ 66 
5.6.2 
Confidence interval for relative reduction ...................................................................................... 69 
5.6.2.1 
Annualized rate of change in TKV ................................................................................................. 69 
5.6.2.2 
Annualized rate of change in eGFR ............................................................................................... 70 
5.6.3 
P-values from multiple comparison procedure .............................................................................. 70 
6 
REFERENCES ............................................................................................................................... 72 
 
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LIST OF TABLES  
Table 1 - Major changes in statistical analysis plan ........................................................................................ 6 
Table 2 - Objectives and endpoints ................................................................................................................. 9 
Table 3 - Summary of primary estimand for main endpoints ........................................................................ 13 
Table 4 - Populations for analyses ................................................................................................................ 16 
Table 5 - Optimal contrasts for the 3 prespecified candidate of dose-response models .............................. 21 
Table 6 - Sorting of AE tables ....................................................................................................................... 31 
Table 7 - Analyses of adverse events ........................................................................................................... 31 
Table 8 - Selections for AESIs ...................................................................................................................... 32 
Table 9 - Major statistical changes in protocol amendment(s) ...................................................................... 45 
Table 10 - Mayo imaging classification ......................................................................................................... 51 
Table 11 - eGFR values example .................................................................................................................. 52 
Table 12 - Analyses window definition .......................................................................................................... 53 
Table 13 - Analyses window definition for PK analyses - Stage 1 ................................................................ 53 
Table 14 - Analyses window definition for PK analyses - Stage 2 ................................................................ 53 
Table 15 - Operating characteristics of the study design assuming the dose 15 mg is selected for Stage 2
 ....................................................................................................................................................................... 68 
Table 16 - Operating characteristics of the study design assuming the dose 8 mg is selected for Stage 2 . 69 
 
LIST OF FIGURES  
Figure 1 - Prespecified candidate of dose-response models ........................................................................ 21 
Figure 2 - Graphical illustration of the procedure for handling multiplicity .................................................... 28 
Figure 3 - Patient reported outcome (PRO) concepts and questionnaires ................................................... 38 
 
 
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VERSION HISTORY  
This statistical analysis plan (SAP) for study EFC15392 is based on the protocol amendment 5 
dated 17-July-2020. There are no major changes to the statistical analysis features in this SAP. 
The first participant was randomized in the Stage 1 population on 11-Feb-2019. This SAP is 
approved before the futility analysis which is planned when all participants from Stage 1 have 
completed the first 9 months of treatment and approximately 30% have completed 18 months of 
treatment with Total Kidney Volume (TKV) available (or have prematurely discontinued).   
Table 1 - Major changes in statistical analysis plan  
SAP 
Version 
Approval 
Date 
Changes 
Rationale 
1 
19-Jan-2021 
The Population without trial impact (disruption) due to 
COVID-19 has been defined and additional analysis 
performed according to this population  
In order to assess the impact of 
the COVID19 on the study 
2 
22-Jun-2021 
Labels of treatment group updated from GZ/SAR402671 to 
venglustat 
Clarification 
 
 
Added definition of baseline specific to Patient symptom 
diaries parameters and urine osmolality (see Section 4.1 and 
Section 4.8.3) 
Clarification  
 
 
Update of the definition the treatment emergent period for 
patients who participate to the long-term extension 
LTS15823 (see Section 4.1) 
Clarification  
 
 
Update of the tertiary endpoint related to TLV to be analyzed 
in participants with height adjusted total liver volume [htTLV] 
>1 L/m instead of > 2L/m (see Section 1.2 and Section 4.5.1) 
Selection of participant with 
htTLV >2 L/m was to strict. 
According to HALT publication 
(1) it’s acceptable to consider 
moderate PLD as htLV >1 L/m. 
 
 
Update of tertiary endpoint related to hospitalization to 
analyze rate and time of all-cause hospitalization 
(see Section 1.2, Section 4.5.1 and Section 4.8.5) 
Clarification of endpoint  
 
 
PK populations and PK data analysis time windows have 
been updated (see Section 3 and Section 5.4) 
Correction of time points as per 
protocol 
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SAP 
Version 
Approval 
Date 
Changes 
Rationale 
 
 
The two-step analysis is not applicable anymore and 
replaced by a single analysis of all data available on 
combined Stage 1 & Stage 2 analysis (see Section 1.1 and 
Section 4.9.3) 
Efficacy analyses on Stage 1 ITT population and combined 
Stage 1 and Stage2 population will be conducted on all data 
available up to database lock (see Section 4.1, Section 
4.3.1). No multiple imputation will be done, only analysis on 
observed data will be performed (see Section 1.2.1, 
Section 4.3.1.1, Section 4.3.1.2, and Section 4.3.2.2). 
As no post-baseline MRI data will be available in Stage 2 at 
the time of the study discontinuation, the analysis of TKV and 
TLV in Combined Stage 1 and Stage 2 will not be done 
(see Section 1.2.1, Section 4.4.2.2 & Section 4.5.2). 
Secondary analysis of eGFR on all randomized participants 
will be replaced by descriptive summary across visit on the 
secondary Stage2 ITT population (see Section 3 and 
Section 4.3.2.4) 
For all tertiary endpoints, due to the high number of missing 
data at month18 and month24, MMRM will be replaced by 
only descriptive summary by visits (see Section 4.5.2, 
Section 4.8.2, Section 4.8.3 and Section 4.8.4). For the 
secondary endpoints (BPI-Item3 & BFI Item3), in case the 
MMRM does not converge due to high number of missing 
data, then only descriptive summary by visits will be provided 
(see Section 4.4.1.2 and Section 4.4.2.2) 
As no GM3 sample tested at the time of the study 
discontinuation, the analysis of GM3 will not be done (see 
Section 4.8.2) 
Safety populations and all safety analyses on Stage 1 
populations are removed. All safety analyses will be 
performed on the extended combined Stage 1 and Stage 2 
safety population, including all participants with an eGFR 
between 30 and 89.9 mL/min/1.73 m2 at screening (see 
Section 3 and Section 4.7). 
mGFR analysis has been removed as no data available (see 
Section 4.5.1). 
Following decision to 
discontinue EFC15392 and 
LTS15823 studies based on 
EFC15392 futility analysis 
 
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1 
INTRODUCTION  
1.1 
STUDY DESIGN  
This is an international, multicenter, randomized, double-blind, placebo-controlled, two-stage 
study in adult participants at risk of rapidly progressive Autosomal Dominant Polycystic Kidney 
Disease (ADPKD) aged 18 to 50 years in Stages 1 and 2. In addition, Stage 2 also includes 
participants  aged 18 to 55 years with a screening estimated Glomerular Filtration Rate (eGFR) 
between 30 and 44.9 mL/min/1.73 m2.  
The study is divided into 2 stages: 
Stage 1: an up to 30-days screening period including a 2-week placebo run-in (to identify 
participants who are unlikely to follow the assigned treatment regimen), followed by a 
randomized, double-blind, comparative placebo-controlled core treatment period of 24 months 
duration.  
After run-in, eligible participants, aged 18 to 50 years with an eGFR in (45 to 89.9) are 
randomized with a 1:1:1 ratio to placebo, 8 mg venglustat, or 15 mg venglustat.  
Participants are stratified based on their predicted ADPKD progression rate (1C versus 1D versus 
1E) according to Mayo Imaging Classification and geographical region (North America, Europe, 
China, Republic of Korea, Rest of the World).  
After the interim unblinded aggregate safety review by the DMC of the first 150 randomized 
participants from Stage 1 having completed at least 1 month of treatment (or have prematurely 
discontinued), the DMC determined that the 15 mg dose was the highest dose to be safe and well 
tolerated in Stage 1, and recommended the venglustat 15 mg dose for Stage 2. 
Stage 2: starts with an up to 30-day screening period including a 2-week placebo run-in 
(to identify participants who are unlikely to follow the assigned treatment regimen), followed by a 
randomized, double-blind, comparative core treatment period of 24 months duration. After run-in, 
eligible participants aged 18 to 55 years with an eGFR of 30 to 89.9 are randomized with a 
1:1 ratio to placebo and 15 mg venglustat. Participants are stratified based on their predicted 
progression rate (1C versus 1D versus 1E) according to Mayo Imaging Classification and 
geographical region (North America, Europe, China, Republic of Korea, Rest of the World). 
Participants who completed 24 months of treatment in EFC15392 study may be given the option 
to enroll into an open-label long-term extension study LTS15823 (additional 24 months of 
treatment with 15 mg venglustat). 
As per protocol a first step analysis was planned when all participants from Stage 1 have been 
randomized and have completed the Month 18 visit (or have discontinued the study) for the 
submission to the accelerated approval. Then a second step analysis was planned to be conducted 
after study completion of Stage 1 and Stage 2 participants. 
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Objectives 
Endpoints 
 
• 
To explore the effect of 
venglustat on kidney 
concentrating ability by 
assessing urine osmolality (in 
participants not on diuretic) 
• 
To explore the effect of 
venglustat on nocturia 
• 
To explore the effect of 
venglustat on systolic blood 
pressure (SBP) and diastolic 
blood pressure (DBP) 
• 
To explore the effect of 
venglustat on biomarkers 
associated with ADPKD 
(eg, Fibroblast Growth Factor 23 
[FGF23], Asymmetric 
Dimethylarginine [ADMA]) 
• 
To explore the effect of 
venglustat on pain (Brief Pain 
Inventory [BPI]), fatigue (Brief 
Fatigue Inventory [BFI]), and 
general health status (EuroQoL 
5-dimension 5-level [EQ 5D-5L]) 
to 18 months 
• 
To explore the effect of 
venglustat on type, frequency 
and dosage of analgesic/over the 
counter (OTC) pain medication 
administration 
• 
To explore the effect of 
venglustat on all-cause 
hospitalization  
• 
To explore the 
pharmacodynamic (PD) effects 
of venglustat by measuring 
downstream metabolites of GCS 
in plasma and urine 
• 
Change in urine osmolality from 
baseline to 18 months 
• 
Change in nocturia from baseline to 
18 months, based on patient reported 
diary  
• 
Change in SBP/DBP during the 
treatment emergent period 
• 
Change in biomarkers associated with 
ADPKD (eg, FGF23 and ADMA) from 
baseline to 18 months 
• 
Change in pain (BPI) from baseline to 
18 months 
• 
Change in fatigue (BFI) from baseline 
to 18 months 
• 
Change in health status (EQ 5D 5L) 
from baseline to 18 months 
• 
Type, frequency, and dosage of 
analgesic/over the counter (OTC) pain 
medication administration from 
baseline to 18 months 
• 
Rate of all-cause hospitalization 
• 
Change in Glucosylceramide (GL-1) 
and GM3 from baseline to 18 months 
Stage 2 
 
 
Primary 
 
 
 
• 
To determine the effect of 
venglustat on rate of renal 
function (eGFR) decline as 
compared to placebo in patients 
at risk of rapidly progressive 
ADPKD 
• 
Annualized rate of change in eGFR 
(CKD-EPI equation) from baseline to 
24 months 
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Objectives 
Endpoints 
Secondary 
 
 
• 
Efficacy 
objectives 
• 
To determine the effect of 
venglustat on the rate of TKV 
growth  
• 
To determine the effect of 
venglustat on pain and fatigue, 
based on patient reported diary 
• 
Annualized rate of change in TKV 
based on MRI from baseline to 
18 months 
• 
Change in pain from baseline to 
24 months, based on BPI Item 3 
assessed from the daily symptom diary 
• 
Change in fatigue from baseline to 
24 months, based on BFI Item 3 
assessed from the daily symptom diary 
• 
Safety/tolerability 
objectives 
• 
To evaluate the PK of venglustat 
in ADPKD patients 
• 
To characterize the safety profile 
of venglustat 
• 
Plasma venglustat concentrations 
• 
TEAEs/AEs/SAEs, laboratory 
parameters, vital signs, 
electrocardiogram and findings from 
physical examination 
 
• 
To evaluate the effect of 
venglustat on mood using BDI-II 
• 
To evaluate the effect of 
venglustat on the lens by 
ophthalmological examination 
• 
Change in score of BDI- during the 
treatment emergent period 
• 
Change in the lens clarity by 
ophthalmological examination during 
the treatment emergent period 
Tertiary/exploratory 
 
 
 
• 
To explore the impact of 
venglustat on TLV (in 
participants htTLV >1 L/m) 
• 
Annualized rate of change in TLV 
based on MRI (in participants with 
htTLV >1 L/m) from baseline to 
18 months 
 
• 
To explore the effect of 
venglustat on kidney 
concentrating ability by 
assessing urine osmolality (in 
participants not on diuretic) 
• 
To explore the effect of 
venglustat on nocturia 
• 
To explore the effect of 
venglustat on systolic blood 
pressure (SBP) and diastolic 
blood pressure (DBP) 
• 
To explore the effect of 
venglustat on measured GFR 
(mGFR) (substudy)  
• 
To explore the effect of 
venglustat on biomarkers 
associated with ADPKD 
(eg, Fibroblast Growth Factor 
23 [FGF23], Asymmetric 
Dimethylarginine [ADMA]) 
• 
To explore the effect of 
venglustat on pain (Brief Pain 
Inventory [BPI]), fatigue (Brief 
Fatigue Inventory [BFI]), and 
• 
Change in urine osmolality from 
baseline to 24 months 
• 
Change in nocturia from baseline to 
24 months, based on patient reported 
diary  
• 
Change in SBP/DBP during the 
treatment emergent period 
• 
Annualized rate of change in mGFR 
from baseline to 24 months 
• 
Change in biomarkers associated with 
ADPKD (eg, FGF23 and ADMA) from 
baseline to 24 months 
• 
Change in pain (BPI) from baseline to 
18 months 
• 
Change in fatigue (BFI) from baseline 
to 18 months 
• 
Change in health status (EQ 5D 5L) 
from baseline to 18 months 
• 
Type, frequency, and dosage of 
analgesic/over the counter (OTC) pain 
medication administration from 
baseline to 24 months 
• 
Rate of all-cause hospitalization  
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Objectives 
Endpoints 
general health status (EuroQoL 
5-dimension 5-level [EQ 5D-5L]) 
to 24 months 
• 
To explore the effect of 
venglustat on type, frequency 
and dosage of analgesic/over the 
counter (OTC) pain medication 
administration 
• 
To explore the effect of 
venglustat on all-cause 
hospitalization 
• 
To explore the 
pharmacodynamic (PD) effects 
of venglustat by measuring 
downstream metabolites of GCS 
in plasma and urine 
• 
To explore the effect of 
venglustat on eGFR (CKD-EPI 
equation) from baseline to 24 
months in participants with a 
screening eGFR between 30 and 
44.9 mL/min/1.73 m2 
• 
Change in Glucosylceramide (GL-1) 
and GM3 from baseline to 24 months 
• 
Annualized rate of change in eGFR 
(CKD-EPI equation) from baseline to 
24 months in participants with a 
screening eGFR between 30 and 
44.9 mL/min/1.73 m2 
1.2.1 Estimands  
Primary estimand defined for main endpoints are summarized in below Table 3. More details are 
provided in Section 4. 
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Table 3 - Summary of primary estimand for main endpoints  
Endpoint 
Category 
(estimand) 
Estimands 
Endpoint 
Population 
Intercurrent event(s) handling 
strategy 
Population-level summary  
(Analysis and missing data handling) 
Stage 1 
Primary objective: To determine the effect of venglustat on the rate of TKV growth in patients at risk of rapidly progressive ADPKD 
Primary endpoint 
(treatment policy) 
Annualized rate of change in 
TKV based on MRI from 
baseline to 18 months 
Stage 1 Intent-to-
Treat (ITT) 
regardless of adherence to study intervention 
Difference in mean slope of log10-transformed TKV 
estimated from baseline to 18 months using a linear 
mixed effect model. Overall effect of venglustat 
assessed using a Multiple Comparison Procedure). 
No imputation of missing data 
Secondary objectives:   To determine the effect of venglustat on the rate of renal function (eGFR) decline 
To determine the effect of venglustat on pain and fatigue, based on patient reported diary 
Secondary endpoint 
(treatment policy) 
Annualized rate of change in 
eGFR (CKD-EPI equation) 
from baseline to 18 months 
Stage 1 ITT 
regardless of adherence to study intervention 
Difference in mean slope of eGFR estimated from 
baseline to 18 months using a linear mixed effect 
model. Overall effect of venglustat assessed using a 
Multiple Comparison Procedure). 
No imputation of missing data 
Secondary endpoint 
(treatment policy) 
Change in pain (BPI Item 3) 
from baseline to 18 months 
Stage 1 ITT 
regardless of adherence to study intervention 
Overall effect of venglustat will be assessed using a 
Multiple Comparison Procedure using baseline 
adjusted least-squares means estimates at Month 18 
from Mixed model with repeated measures (MMRM).  
No imputation of missing data 
Secondary endpoint 
(treatment policy) 
Change in fatigue (BFI Item 3) 
from baseline to 18 months 
Stage 1 ITT 
regardless of adherence to study intervention 
Analysis of fatigue will be identical to the one of pain 
Stage 2 
Primary objective: To determine the effect of venglustat on rate of renal function (eGFR) decline as compared to placebo in patients at risk of rapidly progressive ADPKD 
Primary endpoint 
(treatment policy) 
Annualized rate of change in 
eGFR (CKD-EPI equation) 
from baseline to 24 months 
Combined Stage 1 
and Stage 2 ITT 
regardless of adherence to study intervention 
Analysis of eGFR in Stage 2 will be identical to the 
one of Stage 1 
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Endpoint 
Category 
(estimand) 
Estimands 
Endpoint 
Population 
Intercurrent event(s) handling 
strategy 
Population-level summary  
(Analysis and missing data handling) 
Secondary objectives: To determine the effect of venglustat on the rate of TKV growth 
To determine the effect of venglustat on pain and fatigue, based on patient reported diary 
Secondary endpoint 
(treatment policy) 
Annualized rate of change in 
TKV based on MRI from 
baseline to 18 months 
Combined Stage 1 
and Stage 2 ITT 
regardless of adherence to study intervention 
Analysis not done as no post-baseline MRI data 
available on Stage 2 at the time of study 
discontinuation 
Secondary endpoint 
(treatment policy) 
Change in pain (BPI Item 3) 
from baseline to 24 months 
Combined Stage 1 
and Stage 2 ITT 
regardless of adherence to study intervention 
Analysis of pain in Stage 2 will be identical to the one 
of Stage 1 
Secondary endpoint 
(treatment policy) 
Change in fatigue (BFI Item 3) 
from baseline to 24 months 
Combined Stage 1 
and Stage 2 ITT 
regardless of adherence to study intervention 
Analysis of fatigue in Stage 2 will be identical to the 
one of Stage 1 
 
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2 
SAMPLE SIZE DETERMINATION  
In Stage 1, approximately 240 participants will be randomized (with randomization ratio 1:1:1) to 
placebo (n=80) or venglustat 8 mg (n=80) or venglustat 15 mg (n=80mg).  
In Stage 2, approximately 320 participants with an eGFR between 45 and 89.9 mL/min/1.73 m2 at 
screening will be randomized (with randomization ratio 1:1) to placebo (n=160) or venglustat 
(n=160).  
In addition, 80 participants with an eGFR between 30 and 44.9 mL/min/1.73 m2 at screening will 
be randomized (with randomization ratio 1:1) to placebo (n=40) or venglustat (n=40). The 
participants from Stage 2 with an eGFR between 30 and 44.9 mL/min/1.73 m2 will not be 
included in the primary efficacy and safety analyses populations but the data from these 
participants will be analyzed separately. 
This sample size will provide approximately 89% power to detect a 50% reduction in annualized 
rate of change in TKV at end of Stage 1 and approximately 87% power to detect a 30% reduction 
in annualized rate of change in eGFR between venglustat and placebo at the end of Stage 2. 
Overall, the total sample size will provide approximately 87% power to detect an effect on both 
TKV and eGFR.  
Sample size and power calculations were based on simulations, assuming different scenarios 
regarding the dose-response relationship (Section 5.6.1). SAS program is provided in 
(Section 5.5). The following model parameters were estimated based on available datasets from a 
similar participant population (participants aged 18 to 50 years with Mayo class 1C-1E and 
baseline eGFR from 45 to 90 mL/min/1.73 m2) in 2 historical studies (Consortium for Radiologic 
Imaging Studies of Polycystic Kidney Disease (CRISP) and the Polycystic Kidney Disease 
Treatment Network ([HALT-PKD]): 
• A slope of log10(TKV) of 0.02591, 0.02832 and 0.03141 in participants from Mayo class 
1C, 1D and 1E respectively (corresponding to 6.1%, 6.7% and 7.5% increase per year in 
TKV), resulting in average slope of 0.02764 (6.6%/year) assuming 50% of 1C, 33% of 1D 
and 17% of 1E. 
• Standard deviation for the residual error of TKV (on the log10 scale) of 0.02566 and 
standard deviation for the random effect of slope of 0.01477. 
• A slope of eGFR of -3.16, -3.88 and -4.69 mL/min/1.73 m2 per year in participants from 
Mayo class 1C, 1D and 1E respectively, resulting in average slope 
of -3.66 mL/min/1.73 m2 per year assuming 50% of 1C, 33% of 1D and 17% of 1E.  
• Standard deviation for the residual error of eGFR of 6.34 and standard deviation for the 
random effect of slope of 1.98. 
In addition, sample size and power calculations assumed an overall significance level of 
0.05 (2-sided), 10% dropout rate and included adjustments for handling of multiplicity of tests and 
futility analysis. Calculations were made using simulations (Section 5.5 and Section 5.6.1). 
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3 
ANALYSIS POPULATIONS  
The following populations for analyses are defined:  
Table 4 - Populations for analyses  
Population 
Description 
Screened 
All participants who signed the Informed Consent Form (ICF). 
Randomized 
All participants from screened population who have been allocated to a randomized 
intervention by Interactive Response Technology (IRT) regardless of whether the 
intervention was received or not. 
Exposed 
All screened participants who took at least 1 dose of study intervention. 
Population without trial impact 
(disruption) due to COVID-19 
All randomized participants without any critical or major deviation related to COVID19  
and who did not permanently discontinue treatment due to COVID19 and who did not 
permanently discontinue study due to COVID19 
Stage 1 Intent-to-treat (ITT) 
All participants randomized in Stage 1.  
Participants will be analyzed according to the intervention allocated by 
randomization (venglustat 15 mg, venglustat 8 mg or placebo). 
Stage 1 Pharmacokinetic (PK) 
All participants randomized in Stage 1 who took at least 1 dose of study intervention 
and who have at least one post-baseline PK assessment. Participants will be 
analyzed according to the intervention they actually received. 
Stage 1 Pharmacodynamic (PD) 
All participants randomized in Stage 1 who took at least 1 dose of study intervention 
and who have at least one post-baseline PD assessment. Participants will be 
analyzed according to the intervention they actually received. 
Combined Stage 1 and Stage 2 ITT 
All participants with an eGFR between 45 and 89.9 mL/min/1.73 m2 at screening 
who are randomized in Stage 1 or Stage 2.  
Participants will be analyzed according to the intervention allocated by 
randomization (venglustat 15 mg, venglustat 8 mg or placebo).  
Secondary Stage 2 ITT  
All participants with an eGFR between 30 and 44.9 mL/min/1.73 m2 at screening 
who are randomized in Stage 2. Participants will be analyzed according to the 
intervention allocated by randomization (venglustat 15 mg or placebo). 
Extended Combined Stage 1 and Stage 
2 Safety 
All participants with an eGFR between 30 and 89.9 mL/min/1.73 m2 at screening 
who are randomized in Stage 1 or Stage 2 and who took at least 1 dose of study 
intervention. Participants will be analyzed according to the intervention they actually 
received. 
Stage 2 Pharmacokinetic (PK) 
All participants with an eGFR between 45 and 89.9 mL/min/1.73 m2 at screening 
who are randomized in Stage 2, who took at least 1 dose of study intervention and 
who have at least one post-baseline PK assessment. Participants will be analyzed 
according to the intervention they actually received. 
Combined Stage 1 and Stage 2 
Pharmacodynamic (PD) 
All participants with an eGFR between 45 and 89.9 mL/min/1.73 m2 at screening 
who are randomized in Stage 1 or Stage 2, who take at least 1 dose of study 
intervention and who have at least one post-baseline PD assessment. Participants 
will be analyzed according to the intervention they actually received. 
Participants exposed to study intervention before or without being randomized will not be 
considered randomized and will not be included in any analysis population.  The safety 
experience of these participants will be reported separately. 
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Randomized participants for whom it is unclear whether they took the study intervention will be 
considered as exposed and will be included in the safety population as randomized. 
For any participant randomized more than once, only the data associated with the first 
randomization will be used in any analysis population.  The safety experience associated with any 
later randomization will be reported separately. 
For participants receiving more than one study intervention during the study, the intervention 
group for as-treated analyses will be the one to which the participant was treated with the longest 
duration. 
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4 
STATISTICAL ANALYSES  
4.1 
GENERAL CONSIDERATIONS  
In general, continuous data will be summarized using the number of observations available, mean, 
standard deviation (SD), median, [Q1, Q3] minimum, and maximum. Categorical and ordinal data 
will be summarized using the count and percentage of participants. 
The baseline value is defined as the last available value before or equal to the first dose of double-
blind investigational medicinal product (IMP). For participants randomized but not exposed, the 
baseline value is defined as the last available value before or equal to the date and time of 
randomization. 
Baseline eGFR is defined for each participant as the average of eGFR values assessed prior or 
equal to first IMP, or randomization for participants randomized and not exposed. 
Baseline of patient daily diaries scores is defined for each participant as the average of the 
assessments during the 7 days prior the 1st IMP or prior randomization for participants 
randomized and not exposed. 
Baseline of urine osmolality is defined as the average of the 3 separate assessments within the 
3 days prior or equal to the baseline visit (Visit 3). 
Primary efficacy analyses will be conducted on Stage 1 ITT population and on combined Stage 1 
and Stage 2 ITT populations (see Section 3), including all data available at the time of database 
lock from baseline to Month 24: 
• Participants from Stage 2 with an eGFR between 30 and 44.9 mL/min/1.73 m2 at screening 
will not be included in the primary efficacy analysis. A supplemental descriptive efficacy 
analysis on these participants will be performed separately (see Section 3 and 
Section 4.3.2.4).  
Safety analyses will be conducted in the extended combined Stage 1 and Stage 2 population 
(see Section 3) including all data available from baseline to the end of the 24-month double-blind 
treatment period. Unless otherwise specified, analyses will be performed by intervention group 
(and overall for baseline and demographics characteristics). 
Observation period  
The observation period will be divided into 4 segments:  
• The pre-treatment period is defined as the period up to first IMP administration. 
• The treatment-emergent (TE) period is defined as the period from the first IMP 
administration up to the last IMP administration in EFC15392 study +30 days or up to the 
first visit in LTS15823 study, whichever comes earlier. The treatment-emergent period 
includes the following 2 periods:  
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- 
The on-treatment period is defined as the period from the first IMP administration to 
the last administration of the IMP +1 day. 
- 
The residual treatment period is defined as the period from the end of the on-
treatment period to the end of the treatment-emergent period.  
• The post-treatment period is defined as the period from the end of the treatment-
emergent period. 
The on-study observation period is defined as the time from the first administration of the IMP 
until the end of the study (defined as the last scheduled visit for those who completed the study 
and the end-of-study date collected on electronic case report form (e-CRF) page “Completion of 
End of Study” for those who did not complete the study.  If death is the end-of-study reason, date 
of death will be used). 
4.2 
PARTICIPANT DISPOSITIONS  
The number (%) of participants included in each of the analysis populations listed in Table 4 will 
be summarized. The reasons for exclusion from the population without trial impact (disruption) 
due to COVID19 will be also summarized. 
Screen failures are defined as participants who consent to participate in the study but are not 
subsequently randomized. The number (%) of screen failures and reasons for screen failures will 
be provided in the screened population. 
The number (%) of participants in the following categories will be provided:  
• Randomized participants. 
• Randomized but not exposed participants.  
• Randomized and exposed participants. 
• Participants who completed the study treatment period as per protocol. 
• Participants who did not complete the study treatment period as per protocol and main 
reason for permanent intervention discontinuation.  
• Participants who completed the study period as per protocol. 
• Participants who did not complete the study period as per protocol and main reason for 
study discontinuation. 
Reasons for permanent study intervention and study discontinuation “adverse event” and “other 
reasons” will be split as related versus not related to Covid-19, if applicable.  
The number (%) of exposed and not randomized participants will also be summarized.  
In addition, the number (%) of participants screened, screened-failed, randomized, with 
permanent intervention discontinuation and with early study discontinuation will be provided by 
country and site. 
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Protocol deviations 
Critical and major protocol deviations (automatic or manual) will be summarized in the 
randomized population as well as displayed separately as related versus not related to Covid-19. 
Disposition by visit 
Participant disposition by visit will be provided according to trial impact (disruption) due to 
COVID19, as reported in CRF. 
4.3 
PRIMARY ENDPOINT(S) ANALYSIS  
4.3.1 Stage 1  
4.3.1.1 Definition of endpoint(s)  
In Stage 1, the primary efficacy endpoint is the annualized rate of change in TKV based on MRI 
from baseline to 18 months. All the efficacy assessments collected during the study will be used, 
including those obtained after IMP discontinuation. 
The primary estimand will be the difference in mean slope of log10-transformed TKV estimated 
from baseline to 18 months in all randomized participants, regardless of whether or not 
participants completed the treatment period. This estimand corresponds to a “treatment policy 
strategy”. This estimand will be considered primary for supporting regulatory decision making.  
A second estimand will be the difference in the mean slope of log10-transformed TKV estimated 
during the on-treatment period (from baseline to end of treatment). This estimand corresponds to 
“while on-treatment strategy” and will be evaluated for the primary efficacy endpoint only. This 
estimand will be considered for describing the effect of treatment as long as participants adhere to 
their randomized treatment. 
4.3.1.2 Main analytical approach  
A linear mixed effect model will be fitted to the log10-transformed TKV, which will include fix 
effects of treatment (venglustat 15 mg, venglustat 8 mg or placebo), Mayo Imaging Classification 
(as per randomization stratification factor: class 1C versus 1D versus 1E), time (as continuous 
variable), treatment * time interaction and Mayo Imaging Classification * time interaction, and 
will include random intercept and slope. Time will be based on actual TKV assessment date 
relative to randomization date (in years).  
Within group mean slope of log10-transformed TKV will be obtained from the linear mixed effect 
model, using weights for each stratum (Mayo class 1C, 1D and 1E) equal to the overall proportion 
of participants in each stratum in the Stage 1 ITT population (ie, “population weight”). A back-
transformation will be applied to obtain annualized rate of change in TKV (in % per year) within 
each treatment arm, along with their 95% confidence intervals (CI). 
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Overall effect of venglustat will be assessed using a Multiple Comparison Procedure. Multiple 
trend tests will be performed using optimal contrasts determined from a set of 3 prespecified 
candidate models for the dose-response relationship described in Figure 1.  
Figure 1 - Prespecified candidate of dose-response models  
 
Optimal contrasts for each candidate model were derived using the R add-on package 
DoseFinding (2, 3) and are presented in Table 5. Contrasts will apply to treatment * time 
interaction term in the linear mixed effect model. P-value from the Multiple Comparison 
Procedure will be calculated as described in Section 5.6.3. 
Table 5 - Optimal contrasts for the 3 prespecified candidate of dose-response models  
 
Relative reduction in annualized rate of change in TKV will be estimated for each dose of 
venglustat versus placebo and defined as: 
 
 
Relative reduction for each dose of venglustat will be presented with 95% confidence intervals 
obtained using Fieller method (see Section 5.6.2) only if significant change is observed in the 
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placebo arm at the 0.05 level. In addition, p-values for the comparison of each dose of venglustat 
versus placebo will be presented for descriptive purpose. 
Handling of missing data  
The primary analysis will include all observed TKV data in randomized participants, regardless of 
whether or not participants completed the treatment period (treatment policy strategy). 
participants who prematurely and permanently discontinue study intervention will be requested to 
obtain an MRI scan at 18 months and their data collected after permanent intervention 
discontinuation will be included in the primary analysis.  
No imputation of missing data will be performed. The linear mixed effect model described above 
will be run on all observed data, including data collected after intervention discontinuation.  
4.3.1.3 Sensitivity analysis  
4.3.1.4 No sensitivity analysis will be performed due to the discontinuation of the study 
after the futility analysis Supplementary analyses  
While on-treatment estimand 
A supplementary analysis will estimate the difference in mean slope of log10-transformed TKV 
during the on-treatment period. In this secondary analysis, TKV assessed more than 30 days after 
the last IMP administration will be excluded from the analysis. TKV assessed in randomized but 
not treated participants will also be excluded from the analysis.  
Other analysis 
Another analysis will explore a potential acute hemodynamic effect. In this supplementary 
analysis only TKV assessed at least 30 days after the first IMP will be included in the linear 
mixed effect model. TKV at baseline will be excluded from this analysis. 
4.3.1.5 Subgroup analyses  
To assess the homogeneity of the treatment effect across various subgroups, analyses will be 
performed on the primary endpoint across the following subgroups (categories with fewer than 
5 participants may be combined with other categories): 
• Age group (<40, and ≥40 years)  
• Gender (Male, Female) 
• Actual ADPKD progression rate (1C versus 1D versus 1E) at baseline 
• Region (North America, Europe, China, Japan, Republic of Korea, Rest of the World) 
• eGFR (CKD-EPI equation) at screening (45 to <60, 60 to <75, 75 to <90) 
• Prespecified medical history of Hypertension (Yes/No) 
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The linear mixed effect model described as primary analysis will be repeated for each of the 
subgroups as appropriate. Subgroup factor-by-time interaction, treatment-by-subgroup factor 
interaction and treatment-by-subgroup-by-time interaction will be added in the primary model. 
For subgroup analyses by Mayo Imaging Classification, the linear mixed effect model will not 
include the fix effects of Mayo Imaging Classification nor Mayo Imaging Classification * time 
interactions. Forest plots of venglustat 8 mg and venglustat 15 mg relative reduction versus 
placebo and 95% CI will be presented. 
4.3.1.6 Description of missing data  
In order to explore missing data patterns for TKV in the primary efficacy analysis, number and 
percentage of participants in each of the following categories will be presented by study 
intervention group and displayed separately for participants on treatment at the time of Month 18 
visit versus participants with permanent intervention discontinuation prior to Month 18: 
• Pattern 1: Participants without post-baseline TKV assessment. 
• Pattern 2: Participants with at least one post-baseline TKV assessment but not at 
Month 18. 
• Pattern 3: Participants with TKV assessment at Month 18. 
4.3.2 Combined Stage 1 and Stage 2  
4.3.2.1 Definition of endpoint(s)  
In combined Stage 1 and Stage 2, the primary efficacy endpoint is the annualized rate of change in 
eGFR (CKD-EPI equation). 
The primary estimand will be the difference in mean slope of eGFR estimated from baseline to 
24 months in all randomized population, regardless of whether or not participants completed the 
treatment period. This estimand corresponds to a “treatment policy strategy”. 
4.3.2.2 Main analytical approach  
The analysis of eGFR will be similar to those of TKV, with the exception that no log 
transformation will be used for eGFR (see Section 4.3.1.2).  
Primary analysis in Stage 2 will combine all data from Stage 1 and Stage 2 available from 
baseline to the end of the 24-month double-blind core treatment period. Primary analysis will 
include all observed eGFR data in randomized participants, regardless of whether or not 
participants completed the treatment period (treatment policy strategy). Participants who 
prematurely and permanently discontinue study medication will be requested to obtain eGFR at 
24 months.   
No imputation of missing data will be performed. 
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4.3.2.3 Sensitivity analysis  
No sensitivity analysis will be performed due to the discontinuation of the study after the futility 
analysis.  
4.3.2.4 Supplementary analyses  
While on-treatment estimand 
A supplementary analysis will estimate the effect of venglustat while participants are still on 
treatment. eGFR assessed more than 30 days after the last IMP administration will be excluded 
from the analysis. eGFR assessed in randomized but not treated participants will also be excluded 
from the analysis. 
Secondary analysis of eGFR  
Descriptive summary of eGFR by analysis visit will be provided on the secondary Stage 2 ITT 
population (ie, all participants from Stage 2 with eGFR between 30 and 44.9 mL/min/1.73 m2 at 
screening) (see Section 3).  
Time to Event analysis 
Time to confirmed reduction in eGFR (local or central assessment using CKD-EPI formula) will 
be summarized in terms of cumulative incidence probabilities of occurrence with 95% CI as well 
as the number of participants at risk, number of participants censored and number of events at key 
time points (Month 1, Month 3, Month 6, Month 9, Month 12, Month 18, Month 21, Month 24) 
using the Kaplan-Meier estimates. In addition, Kaplan-Meier curves will be provided for each 
treatment arm. 
• Time to confirmed 30% (resp. 40%) reduction in eGFR is defined as: the time from the 
date of randomization to the date of first eGFR assessment in case of 2 consecutive eGFR 
assessment with an observed reduction in eGFR from baseline of at least 30%. 
- 
If reduction in eGFR from baseline is less than 30% (resp. 40%) or if reduction is not 
observed at 2 consecutive visits before end of study, the participant will be censored at 
the date of the last participant’s eGFR assessment for the combined Stage 1 and 
Stage 2 analysis. 
4.3.2.5 Subgroup analyses  
Subgroups analysis and description of missing data will be summarized using methods similar to 
those of TKV, except that eGFR (CKD-EPI equation) at screening will be  (45 to <60, 60 to <75, 
75 to <90) (see Section 4.3.1.5). 
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4.4 
SECONDARY ENDPOINT(S) ANALYSIS  
4.4.1 Stage 1 key/confirmatory secondary endpoint(s)  
4.4.1.1 Definition of endpoint(s)  
In Stage 1, the following endpoints are defined as key secondary endpoints: 
• Annualized rate of change in eGFR (CKD-EPI equation) from baseline to 18 months. 
• Change in pain from baseline to 18 months. Pain score will be based on BPI Item 3, 
assessed from the daily symptom diary. 
• Change in fatigue from baseline to 18 months. Fatigue score will be based on BFI Item 3, 
assessed from the daily symptom diary. 
4.4.1.2 Main analytical approach  
The analysis of eGFR in Stage 1 will be identical to those of Stage 2 (see Section 4.3.2.2). 
Daily diaries scores will be averaged over 7 consecutive assessments prior to the baseline, 
Month 3 and Month 12 visit and over the 14 consecutive days prior to the planned Month 18 visit. 
At least 50% of the days in the observation period (ie, 4 or more of the 7 days for baseline, 
Month 3 and Month 12; 7 or more of the 14 days for Month 18) are required to calculate the 
average score on non-missing data (4, 5). 
Change in pain and change in fatigue from baseline to 18 months will be analyzed on the ITT 
population, regardless of whether or not participants completed the treatment period, using a 
mixed effect model with repeated measures (MMRM). The model will include the fixed 
categorical effects of treatment (venglustat 15 mg, venglustat 8 mg or placebo), Mayo Imaging 
Classification (as per randomization stratification factor: Class 1C versus 1D versus 1E), time 
point (Month 3, Month 12, Month 18), treatment-by-time point interaction, randomization strata-
by-time point interaction as well as the continuous fixed covariates of baseline and the baseline-
by-time point interaction.  
This model will be run using SAS Mixed procedure with an unstructured correlation matrix to 
model the within-patient errors. Parameters will be estimated using restricted maximum likelihood 
method. Denominator degrees of freedom will be estimated using Kenward-Roger approximation. 
This model will provide baseline adjusted least-squares means estimates at Month 18 for each 
study intervention groups with their corresponding standard errors (SEs) and 95% confidence 
intervals (CI). Within group mean change in pain will be obtained from the MMRM, using 
weights for each stratum (Mayo Class 1C, 1D and 1E) equal to the overall proportion of 
participants in each stratum in the Stage 1 ITT population (ie, “population weight”). Population 
weights are considered more appropriate than equal coefficients due to expected unbalances in the 
study population between levels of the randomization stratification factors. 
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Overall effect of venglustat will be assessed using a Multiple Comparison Procedure similar to 
those of the primary endpoint (see Section 4.3.1.2). In addition, p values for the comparison of 
each dose of venglustat versus placebo will be presented for descriptive purpose. 
There will be no imputation of missing data. 
In the case of the model does not converge due to high number of missing data, only descriptive 
summaries by visits will be provided. 
4.4.2 Combined Stage 1 and Stage 2 key/confirmatory secondary endpoint(s)  
4.4.2.1 Definition of endpoint(s)  
In combined Stage 1 and Stage 2, the following endpoints are defined as key secondary endpoints: 
• Annualized rate of change in TKV from baseline to 18 months 
• Change in pain from baseline to 24 months, based on BPI Item 3 assessed from the daily 
symptom diary 
• Change in fatigue pain from baseline to 24 months, based on BFI Item 3 assessed from the 
daily symptom diary 
4.4.2.2 Main analytical approach  
As no post-baseline MRI data will be available in Stage 2 at the time of the study discontinuation 
the analysis of TKV in Combined Stage 1 and Stage 2 will not be done. 
Change in pain and change in fatigue from baseline to 24 months will be analyzed using an 
MMRM similar to the one used in Stage 1, except the time point will include Month 3, Month 12, 
Month 18 and Month 24 (see Section 4.4.1.2). 
In the case of the model does not converge due to high number of missing data, only descriptive 
summaries by visits will be provided. 
4.4.3 Supportive secondary endpoint(s)  
Other safety secondary endpoints will be defined in Section 4.7.3. 
• Change in BDI-II score during the treatment emergent period (Section 4.7.3.5) 
• Change in the lens clarity by ophthalmological examination during the treatment emergent 
period (Section 4.7.3.4) 
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4.5 
TERTIARY/EXPLORATORY ENDPOINT(S) ANALYSIS  
4.5.1 Definition of endpoint(s)  
In Stage 1 and Stage 2, the following endpoints are defined as exploratory efficacy endpoints: 
• Annualized rate of change in TLV based on MRI from baseline to 18 months on 
participants with htTLV >1 L/m 
• Change in: 
- 
Urine osmolality from baseline to 18 months in Stage 1 and 24 months in combined 
Stage 1 and Stage 2 (in participants not on diuretic at baseline) 
- 
Nocturia from baseline to 18 months in Stage 1 and 24 months in combined Stage 1 
and Stage 2, based on the daily symptom diary (see Section 4.8.3)  
- 
Systolic BP during the treatment emergent period (see Section 4.7.3.1) 
- 
Diastolic BP during the treatment emergent period (see Section 4.7.3.1) 
- 
Biomarkers associated with ADPKD (eg, FGF23 and ADMA) from baseline to 
18 months from baseline to 18 months in Stage 1 and 24 months in combined Stage 1 
and Stage 2 (see Section 4.8.4) 
- 
Pain (BPI), fatigue (BFI) and health status (EQ-5D-5L) from baseline to 18 months in 
Stage 1 and 24 months in combined Stage 1 and Stage 2 (see Section 4.8.3) 
- 
Glucosylceramide (GL1) and GM3 from baseline to 18 months in Stage 1 and 
24 months in combined Stage 1 and Stage 2 (see Section 4.8.2) 
• Type, frequency, and dosage of analgesic/over the counter (OTC) pain medication 
administration from baseline to 24 months (see Section 4.8.3) 
• Rate of all-cause hospitalization (see Section 4.8.5) 
4.5.2 Main analytical approach  
As no post-baseline MRI data will be available in Stage 2 at the time of the study discontinuation 
the analysis of TLV in Combined Stage 1 and Stage 2 ITT population will not be done. 
For other quantitative exploratory endpoints only descriptive summaries by visits will be 
provided. 
The urine osmolality will be analyzed using the average of the 3 separate measurements 
performed between visit date - 3 and visit date + 1 at each planned visit performed within analysis 
time windows (see Table 12): 
• first spot at visit day-2 am 
• second spot the day of visit am 
• third spot from the 24-hour urine sample, if any, else sample at the time of visit 
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All participants on oral diuretic medications at the time of the 1st IMP administration (ie, start date 
of medication prior to the 1st administration of IMP and end of medication after the 1st 
administration of IMP or missing) will be excluded from the urine osmolality analysis. 
Analyses of pain medications and hospitalization will be defined in Section 4.8.3 and 
Section 4.8.5. 
4.6 
MULTIPLICITY ISSUES  
A weighted Bonferroni-based closed test procedure will be used in order to control the Type I 
error rate for the entire study. This procedure will handle both multiplicity of endpoints (primary 
and secondary endpoints) and multiplicity of analysis (analysis at end of Stage 1 and analysis at 
end of Stage 2). Multiplicity of doses will be handled using the Multiple Comparison Procedure 
described in Section 4.3.1.2. 
The statistical procedure is illustrated using a graphical approach (6) and is shown in Figure 2. 
This procedure will ensure a strong control of the overall Type-I error rate at the 0.05 level for the 
entire study.  
No further adjustments will be made for supplementary analyses or analyses of other secondary 
efficacy endpoints, for which p-values will be provided for descriptive purpose only. In addition, 
p-values for the comparison of each dose of venglustat versus placebo will be presented for 
descriptive purpose. 
Figure 2 - Graphical illustration of the procedure for handling multiplicity  
 
TKV growth rate
End of stage 1
eGFR rate of decline
End of stage 1
eGFR rate of decline
End of stage 2
a = 0.04
0.975
0.025
a = 0.01
1
TKV growth rate
End of stage 2
Change in pain
End of stage 2
1
Change in fatigue
End of stage 2
1
Analysis at 
end of Stage 1
Primary endpoint
Secondary endpoints
Analysis at 
end of Stage 2
Change in pain
End of stage 1
1
Change in fatigue
End of stage 1
1
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4.7 
SAFETY ANALYSES  
All safety analyses will be performed on the Extended combined Stage 1 and Stage 2 safety 
population as defined in Section 3, unless otherwise specified, using the following common rules: 
• The analysis of the safety variables will be essentially descriptive, and no testing is 
planned.  
• Safety data in participants who do not belong to the safety population (eg, exposed but not 
randomized will be provided separately if any. 
4.7.1 Extent of exposure  
The extent of IMP exposure will be assessed by the duration of IMP exposure and compliance and 
summarized on the Extended combined Stage 1 and Stage 2 safety population. 
In addition, summaries will be provided in the population with trial impact (disruption) due to 
Covid-19. 
Duration of IMP exposure 
Duration of IMP exposure is defined as last IMP administration date – first IMP administration 
date + 1 day, regardless of unplanned intermittent discontinuations. If the date of the last dose of 
IMP is missing, the duration of IMP will be left as missing. 
Duration of IMP exposure will be summarized quantitatively and categorically:  
• ≥1 day 
• ≥1 Month 
• ≥3 months 
• ≥6 months 
• ≥12 months 
• ≥15 months 
• ≥18 months 
• ≥21 months 
• ≥24 months 
Additionally, the cumulative duration of treatment exposure (expressed in participant-years) will 
be provided. 
Treatment compliance 
A given administration will be considered noncompliant if the participant did not receive the 
number of days of IMP as required by the protocol. No imputation will be made for participants 
with missing or incomplete data.  
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Table 6 - Sorting of AE tables  
AE presentation 
Sorting rules 
SOC, HLGT, HLT and PT 
By the internationally agreed SOC order and by alphabetic order of HLGTs, HLTs and PTs.  
SOC, HLT and PT 
By the internationally agreed SOC order and by alphabetic order of HLTs and PTs. 
SOC and PT 
By the internationally agreed SOC order and decreasing frequency of PTsa, b 
SMQ/CMQ and PT 
By decreasing frequency of SMQs/CMQs and PTsa 
PT 
By decreasing frequency of PTsa 
a Sorting will be based on the venglustat 15 mg dose group 
b The table of all TEAEs presented by SOC and PT will define the presentation order for all other tables (eg, treatment-emergent SAE) 
presented by SOC and PT, unless otherwise specified.   
Analysis of all adverse events 
The overview of TEAE with the details below will be generated: 
• Any TEAE  
• Any treatment emergent SAE 
• TEAE leading to death  
• Any TEAE leading to permanent intervention discontinuation  
• Any treatment emergent AESI 
The AE summaries of Table 7 will be generated with number (%) of participants experiencing at 
least one event. The all TEAE summary by Primary SOC and PT (and other safety summaries 
(eg, SAEs, deaths), if deemed needed after TEAE evaluation) will be performed by trial impact 
(disruption) due to Covid-19. 
Table 7 - Analyses of adverse events  
Type of AE 
MedDRA levels 
All TEAE 
Primary SOC, HGLT, HLT and PT 
 
Primary SOC and PT 
Common TEAE (>5% in any group) 
Primary SOC and PT 
TEAE related to IMP as per Investigator’s judgment 
Primary SOC and PT 
TEAE by maximal intensity 
Primary SOC and PT 
Treatment emergent SAE 
Primary SOC and PT 
Treatment emergent AESI 
Primary SOC and PT 
TEAE leading to permanent intervention discontinuation 
Primary SOC and PT 
TEAE leading to death (death as an outcome of the AE as reported 
by the Investigator in the AE page) 
Primary SOC and PT 
Treatment emergent Covid-19 related AE 
Primary SOC and PT 
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Type of AE 
MedDRA levels 
Pretreatment AE 
Overviewa 
Pretreatment AESI 
Primary SOC and PT 
Post-treatment AE 
Overviewa 
a Will include the following AE categories: any AEs, any serious AEs, any AESIs any AEs leading to death, any AEs leading to permanent 
intervention discontinuation 
Analysis of deaths 
In addition to the analyses of deaths included in Table 7 the number (%) of participants in the 
following categories will be provided: 
• Deaths during the treatment-emergent and post-treatment periods by reason for death 
• Deaths in non-randomized participants or randomized but not exposed participants 
Analysis of adverse events of special interest (AESIs)  
Adverse events of special interest (AESIs) and other AEs of interest will be selected for analyses 
as indicated in Table 8. Number (%) of participants experiencing at least one event will be 
provided for each event of interest. Tables will be sorted as indicated in Table 6. 
Table 8 - Selections for AESIs  
AESIs and other AEs of interest 
Selection 
Pregnancy of a female subject or female 
partner of a male subject 
e-CRF specific pregnancy page 
Symptomatic overdose (serious or non-
serious) with IMP 
e-CRF specific symptomatic overdose page 
Increase in alanine transaminase (ALT) 
e-CRF specific AESI tick box on the AE page 
New or worsening lenticular opacities and 
cataracts 
e-CRF specific AESI tick box on the AE page 
AE related to Covid-19 illness 
SMQ COVID19 
4.7.3 Additional safety assessments  
4.7.3.1 Laboratory variables, vital signs and electrocardiograms (ECGs)  
The following laboratory variables, vital signs and electrocardiogram (ECG) variables will be 
analyzed. They will be converted into standard international units. 
• Hematology:  
- 
Red blood cells and platelets and coagulation: hemoglobin, hematocrit, erythrocyte 
count, platelet count, prothrombin time (PT), prothrombin international normalized 
ratio (INR), activated partial thromboplastin time (aPTT). 
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- 
White blood cells: white blood cell count, neutrophils, lymphocytes, monocytes, 
basophils, eosinophils. 
• Clinical chemistry: 
- 
Metabolism: glucose, protein, albumin. 
- 
Electrolytes: sodium, potassium, chloride, bicarbonate, calcium. 
- 
Renal function: creatinine, blood urea nitrogen, serum cystatin C. 
- 
Liver function: alanine aminotransferase, aspartate aminotransferase, alkaline 
phosphatase, gamma glutamyl transferase, total and direct bilirubin. 
- 
Pregnancy test: Serum β-human chorionic gonadotropin (all female participants). 
• Urinalysis: 
- 
Urinalysis for quantitative analysis: pH, specific gravity, proteins, and glucose. 
• Vital signs: heart rate, systolic and diastolic blood pressure, weight. 
- 
For all seated BP measurements, SBP and DBP will be analyzed using the average of 
the 3 to 5 separate measurements at each visit. 
• ECG variables: heart rate, PR, QRS, QT, and corrected QTc (according to 
Bazett/Fridericia). 
Data below the lower limit of quantitation/detection limit (LLOQ) will be replaced by half of the 
LLOQ, data above the upper limit of quantification will be replaced by ULOQ value. 
Quantitative analyses 
For all laboratory variables, vital signs and ECG variables above, descriptive statistics for results 
and changes from baseline will be provided for each visit, the last value and the worst value 
(minimum and/or maximum value depending on the parameter) during the on-treatment period.  
All laboratory parameters (except urinalysis parameters) and vital signs parameters (except weight 
and height) will be summarized using the analysis windows as defined in Table 12. Urinalysis, 
ECG and weight will be summarized by planned visit using central measurements only.  
Analyses according to PCSA 
Potentially clinically significant abnormality (PCSA) analyses will be performed based on the 
PCSA list in effect at Sanofi at the time of the database lock. For parameters for which no PCSA 
criteria are defined, similar analyses will be done using the normal range, if applicable. 
For parameters defined as efficacy endpoints, PCSA summaries will not be provided. 
Analyses according to PCSA will be performed based on the worst value during the treatment-
emergent period, using all measurements (either local or central, either scheduled, nonscheduled 
or repeated). 
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For laboratory variables, vital signs and ECG variables above, the incidence of participants with at 
least one PCSA during the treatment-emergent period will be summarized regardless of the 
baseline level and according to the following baseline status categories: 
• Normal/missing 
• Abnormal according to PCSA criterion or criteria 
For ECG, the incidence of participants with at least one abnormal ECG during the treatment-
emergent period will be summarized regardless of the baseline level and according to the 
following baseline status categories:  
• Normal/missing 
• Abnormal 
Additional analyses for drug-induced liver injury 
The following additional analyses will be performed for drug-induced liver injury:  
• A graph of the distribution of peak values of ALT versus peak values of total bilirubin 
during the treatment-emergent period will be provided.   
• For each liver function test (eg, ALT), participants having experienced a PCSA (eg, ALT 
>5 ULN) will be summarized using the following categories: Returned to baseline PCSA 
status (or returned to value ≤ ULN in case of missing baseline) before last IMP dose, 
Returned to baseline PCSA status after last IMP dose, Never returned to baseline PCSA 
status, No assessment after elevation. This summary will be performed by categories of 
elevation (ALT >3, >5, >10, >20 ULN). 
The incidence of liver related AEs will be summarized by study intervention group. The selection 
of PT will be based on SMQ Hepatic disorder. 
4.7.3.2 Physical examination  
Each physical examination will include the following physical observations/measurements: head, 
heart, lung, abdomen, musculo/skeletal, skin, neurological and mental status. 
Physical examination findings will be assessed as normal or abnormal. 
Number and percentage of participants with complete abnormal physical examination will be 
summarized at each planned visit during the treatment emergent period. 
4.7.3.3 Neurological examination  
Each neurological examination will include, but are not limited to: 
• cranial nerve examination: olfactory, optic, oculomotor, trochlear, trigeminal, abducens, 
facial, vestibulocochlear, glossopharyngeal, vagus, accessory, hypoglossal) 
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• extrapyramidal features: postural tremor, rest tremor, intention tremor, cogwheel rigidity, 
lead pipe rigidity, bradykinesia, postural deficit, dystonia, other 
• gait examination: antalgic, staggering, steppage, waddle, difficulty initiating, glue footed, 
toe walking, other 
• coordination examination: finger to nose test, rapid alternating movements, heel to shin, 
tandem gait 
• motor examination (tone): spasticity, rigidity, paratonia, other, decreased muscle tone 
• peripheral nervous system (sensory disturbances) 
• reflexes examination 
• strength examination: heel walking, sit to stand test, toe walking, other motor abnormality 
These examination findings will be assessed as normal or abnormal. 
Number and percentage of participants with abnormal neurological examination will be 
summarized by location (cranial nerve, Extrapyramidal features, motor, Peripheral nervous 
system strength, reflex, sensory, coordination, gait) at each planned visit during the treatment 
emergent period. 
4.7.3.4 Ophthalmological examination  
The full ophthalmological examination includes best corrected visual acuity (BCVA), slip-lamp 
examination, and examination of the cornea, lens, and retina. The examination should include 
pupil dilation and evaluation of the lens according to the lens opacities classification system III 
(LOCSIII), before implementation of protocol amendment 5. For opacities present at 
baseline/previous visit, changes in LOCSIII score of ≥0.5 (respectively ≥1) for nuclear 
opalescence, ≥0.8 (respectively ≥1) for cortical opacification, or ≥0.5 (respectively ≥1) for 
posterior subcapsular opacification compared with baseline or previous assessment will be 
considered as a worsening. After protocol amendment 5, the LOCSIII examination is replaced by 
the WHO simplified cataract grading system. For opacities present at baseline/previous visit, 
increases in WHO grade ≥1.0 for nuclear opacification, cortical opacification, or posterior 
subcapsular opacification compared with baseline or previous assessment will be considered as a 
worsening. 
Secondary safety endpoints include change in the lens clarity by ophthalmological examination 
during the treatment emergent period. 
Number and percentages of participants with abnormal ophthalmological examination on any eye 
at any time (whether present at screening or not) as well as number and percentages of 
participants with any new onset of abnormal ophthalmological examination on any eye during the 
treatment emergent period as per investigator (site ophthalmologist) assessment will be 
summarized along with a description of lens opacity according to LOCSIII or the WHO 
classification.  
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The decrease in BCVA will also be presented on any eye at any time (whether present at 
screening or not). This decrease will be presented according to 1, 2 or 3 lines (defined as 0.1, 0.2 
or 0.3 increases in LogMAR) (see [7]). 
4.7.3.5 Depression (BDI-II) examination  
Depression will be monitored during the study by using the BDI-II.  
Secondary safety endpoints include change in score of BDI-II during the treatment emergent 
period. 
Descriptive statistics for values and changes from baseline in BDI-II total score will be presented 
for each time point during the on-treatment period (see Section 4.1). All measurements will be 
assigned to analysis windows defined in Table 12.  
The worst (highest) BDI-II total score during the treatment emergent period will be categorized 
and summarized using the number and percentage of participants in each study intervention group 
within each of the following categories: 
• 0-13 (minimal depression) 
• 14-19 (mild depression) 
• 20-28 (moderate depression) 
• 29-63 (severe depression) 
The worst (highest) score for suicidal thoughts (Item 9 of BDI-II) during the treatment emergent 
period will be summarized within each of the following categories: 
• I don't have any thoughts of killing myself 
• I have thoughts of killing myself, but I would not carry them out 
• I would like to kill myself 
• I would kill myself if I had the chance 
In addition, the number of participants with BDI-II worsening from baseline during the treatment 
emergent period will be summarized. 
4.8 
OTHER ANALYSES  
4.8.1  PK analyses  
Plasma venglustat trough concentrations (pre dose) along with other single time point plasma 
concentration data will be summarized on the PK populations by dose and each analysis window 
(see Table 13 and Table 14) using the following descriptive statistics: mean, geometric mean, 
median, standard deviation, coefficient of variation, minimum, and maximum. 
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All concentration values below the lower limit of quantitation (LLOQ) will be treated as zero in 
all summary statistics excepted for the geometric mean and associated coefficient of variation for 
which they will be considered as missing.  
Exploratory metabolite analysis may be performed on selected plasma samples. If data permit, PK 
parameters will be estimated for metabolites using noncompartmental methods. These will be 
summarized using descriptive statistics. 
Plasma venglustat concentration data might be used for population PK modeling if considered 
necessary and the results of population PK modeling will be reported separately from the study 
report.  
Exploratory PK analyses may be performed as deemed necessary to evaluate exposure-response 
relationships (in particular TKV, eGFR and safety parameters). 
4.8.2  Pharmacodynamic analyses   
Exploratory endpoints include change in: 
• GL1 from baseline to 18 months in Stage 1 and 24 months in combined Stage 1 and 
Stage 2 
• GM3 from baseline to 18 months in Stage 1 and 24 months in combined Stage 1 and 
Stage 2 
As no sample tested for GM3 at the time of the study discontinuation, the analysis of GM3 will 
not be done. 
GL1 variable will be summarized on the pharmacodynamics populations using descriptive 
statistics at each time point, including assessment of observed values, change and percent change 
from baseline. 
4.8.3 Patient reported outcomes analyses  
Figure 3 shows the concepts of measurement and their related PRO questionnaires used in the 
trial. 
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Figure 3 - Patient reported outcome (PRO) concepts and questionnaires  
Concept 
PRO questionnaire 
Overall pain 
BPI-SF 
Overall fatigue 
BFI-SF 
Global impression of severity 
PGIS 
Global impression of change 
PGIC 
Health status 
EQ-5D-5L 
Daily symptoms of ADPKD (worst pain, worst fatigue, nocturia) 
Daily diary 
ADPKD = Autosomal dominant polycystic kidney disease; BFI-SF = Brief Fatigue Inventory-short form; BPI-SF = Brief Pain Inventory short-
form; EQ-5D-5L = EuroQoL 5-dimension 5-level; PGIC = Patient global impression of change; PGIS = Patient global impression of severity; 
PRO = Patient reported outcome.  
Overall pain 
Overall pain will be measured using the BPI short-form (BPI-SF). Most BPI-SF items provide an 
11-point numeric rating scale (NRS). Scores are by items and by dimensions; the global score 
ranges from 0 to 10. Lower scores indicate lower pain.  
Exploratory endpoints include change in: 
• Overall pain total score from baseline to 18 months in Stage 1 and 24 months in combined 
Stage 1 and Stage 2 
• Pain severity score from baseline to 18 months in Stage 1 and 24 months in combined 
Stage 1 and Stage 2 
• Pain interference score from baseline to 18 months in Stage 1 and 24 months in combined 
Stage 1 and Stage 2 
• Treatment relief score from baseline to 18 months in Stage 1 and 24 months in combined 
Stage 1 and Stage 2 
Overall fatigue 
The Brief Fatigue Inventory-Short Form (BFI SF) will be used to measure overall fatigue. Scores 
are by dimension and the global score ranging from 0 to 10. Lower scores indicate lower fatigue.  
Exploratory endpoints include change in: 
• Overall fatigue total score from baseline to 18 months in Stage 1 and 24 months in 
combined Stage 1 and Stage 2 
• Fatigue severity score from baseline to 18 months in Stage 1 and 24 months in combined 
Stage 1 and Stage 2 
• Fatigue impact score from baseline to 18 months in Stage 1 and 24 months in combined 
Stage 1 and Stage 2 
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Health status 
The EuroQoL 5-dimension 5-level (EQ-5D-5L) is used to assess the 5 following dimensions of 
health outcome: Mobility, Self-care, Usual activities, Pain/Discomfort, Anxiety/Depression, 
ranged from “1”: no problems to “5”: extreme problems. The EuroQoL-5D index utility score is 
calculated using the crosswalk method based on the UK value set (8). 
Exploratory endpoints include change in: 
• EQ-5D-5L utility score change from baseline to 18 months in Stage 1 and 24 months in 
combined Stage 1 and Stage 2 
• Each of the EuroQol five dimensions (EQ-5D-5L) score from baseline to 18 months in 
Stage 1 and 24 months in combined Stage 1 and Stage 2 
Both total scores and subscale scores of PROs will be calculated according to their scoring 
guidelines, including handling the missing items.  
Daily symptoms of ADPKD  
A daily diary will be included in the study to measure pain, fatigue and nocturia with a 24-hour 
recall. The diary will be completed for 7 days prior to baseline visit and for the specified 
administration period before the study visits. The diary will be comprised of 3 items plus an 
additional item that will direct to the medication entry log: 
• A nocturia item: “Last night, how many times did you wake up because you had to 
urinate? (if you did not wake up, please write 0)”. 
• Item 3 of the BFI-SF to measure worst fatigue in the past 24 hours; “Please rate your 
fatigue (weariness, tiredness) by circling the one number that best describes your WORST 
level of fatigue in the last 24 hours”. Response options are given on an 11-point NRS from 
0 (No Fatigue) to 10 (As bad as you can imagine) (analyzed as secondary endpoint 
see Section 4.4). 
• Item 3 of the BPI-SF to measure worst pain in the past 24 hours; “Please rate your pain by 
marking the box beside the number that best describes your pain at its worst in the last 
24 hours”. Response options are given on an 11 point NRS from 0 (no pain) to 10 (pain as 
bad as you can imagine) (analyzed as secondary endpoint see Section 4.4) 
• Medication log entry item; “Have you taken any medication for your pain in the past 
24 hours? Yes/No”. 
Daily diaries scores will be averaged over 7 consecutive assessments prior to the 1st IMP (or prior 
randomization for participants randomized and not exposed), Month 3 and Month 12 planned visit 
and over the 14 consecutive days prior to the planned Month 18 and Month 24 visits. At least 
50% of the days in the observation period (ie, 4 or more of the 7 days for baseline, Month 3 and 
Month 12; 7 or more of the 14 days for Month 18 and Month 24) are required to calculate the 
average score on non-missing data (4, 5). 
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Exploratory endpoints include change in nocturia from baseline to 18 months in Stage 1 and 
24 months in combined Stage 1 and Stage 2, based on patient reported diary. 
Main analytical approach 
Change from baseline to Month 18 in Stage 1 and Month 24 in combined Stage 1 and Stage 2 in 
pain and fatigue Item 3 are described in Section 4.4.1.1. 
Each other efficacy endpoints will be summarized using descriptive statistics at each time point, 
including assessment of observed values, change and percent change from baseline. 
In addition, any analgesic/over the counter (OTC) medication administered for pain from baseline 
in combined Stage 1 and Stage 2 will be summarized by study intervention group. Medication 
type, frequency, and dosage will be also listed. 
Patient global impression of severity  
The PGIS is a single item scale in which patients indicate an overall assessment of their APKD 
symptoms (none, mild, moderate, and severe). PGIS will be summarized and compared between 
venglustat 15 mg, venglustat 8 mg and placebo using descriptive statistics at each time point, 
including assessment of observed values and change from baseline. 
Patient Global Impression of Change  
The PGIC consists of one item adapted to the patient that evaluates all aspects of patients' health 
and assesses if there has been an improvement or decline in clinical status since they started 
taking the study medication (7-category scale from “very much better” to “very much worse”). 
PGIC will be summarized and compared between venglustat 15 mg, venglustat 8 mg and placebo 
using descriptive statistics at each time point. 
4.8.4  Biomarker analyses   
Pharmacodynamic biomarkers associated with ADPKD such as FGF23 and ADMA in plasma will 
be analyzed using appropriate bioanalytical platforms at the Sponsor’s laboratory or at a 
subcontracted laboratory. Other analytes may also be assessed if available data during the course 
of the study suggest a relationship to disease course in ADPKD patients or to venglustat. 
Exploratory endpoints include change in: 
• FGF23 and ADMA from baseline to 18 months in Stage 1 and 24 months in combined 
Stage 1 and Stage 2 
• ADMA from baseline to 18 months in Stage 1 and 24 months in combined Stage 1 and 
Stage 2 
Each biomarker will be summarized using descriptive statistics at each time point, including 
assessment of observed values, change and percent change from baseline. 
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4.8.5 Hospitalization analyses  
Number and percentage of participants with all cause hospitalization, up to Month 18 visit for 
Stage 1 and up to Month 24 for combined Stage 1 and Stage 2 will be summarized. 
Time to first all-cause hospitalization is defined as the time from randomization to the date of 
hospitalization. Participants who are not hospitalized before the last contact date will be censored 
at the last contact date. Time to hospitalization will be analyzed using Kaplan-Meier method. 
4.9 
INTERIM ANALYSES  
4.9.1 Dose selection safety review  
The dose selection safety review was performed when the first 150 participants from Stage 1 have 
completed 1 month of treatment (or have prematurely discontinued).  
The dose selection safety review was performed by the DMC. An unblinded safety report was 
prepared by the external independent DMC statistician and was reviewed by the DMC. Safety 
data included AEs (including SAEs and AEs leading to permanent intervention discontinuation), 
clinical laboratory evaluation, ECG, physical and ophthalmological examination, and BDI-II data. 
Based on this safety review, the DMC selected the venglustat 15mg dose for Stage 2. The 
venglustat 15 mg dose was the highest dose determined to be safe and well tolerated. 
4.9.2 Interim futility analysis  
An interim analysis for futility was performed when all participants from Stage 1 have completed 
the first 9 months of treatment and approximately 30% have completed 18 months of treatment 
with TKV available (or have prematurely discontinued).  
The interim analysis was performed by the external independent statistician and was reviewed 
under the supervision of the DMC. The interim analysis primarily focused on the primary 
endpoint in Stage 1 (annualized rate of change in TKV) and stopping rules were based on this 
primary endpoint. Data monitoring committee also reviewed secondary efficacy endpoint 
(annualized rate of change in eGFR) and safety data (AEs, laboratory data, vital signs) available at 
the time of the interim analysis.  
As per protocol, futility may be declared if the one-sided p-value of the primary endpoint at the 
interim analysis is >0.30. The one-sided p-value is determined from the Multiple Comparison 
Procedure described in Section 4.3.1.2. Based on simulations, it is expected that futility may be 
declared if the relative reduction versus placebo in TKV growth rate estimated at the interim 
analysis is approximately less than15%. Probability to declare futility under different scenarios is 
presented in Section 5.6.1.  
Of note, the futility rule is non-binding and provided as a guideline for the DMC but should not be 
considered as a strict stopping rule. In case the one-sided p-value observed at the interim analysis 
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is close to the pre-specified threshold, the DMC reviews the totality of data available at the time 
of interim analysis, including safety data (AEs, laboratory data, vital signs), and based on these 
data, may decide to overrule the futility rule. 
If the DMC recommends continuing the study, then the Sponsor is informed of the 
recommendation and have no access to any unblinded results.  
If the DMC recommends stopping the study for futility, then unblinded results are made available 
to a limited number of Sponsor’s senior management team. This limited team makes the final 
decision to stop or continue the study. To prevent internal exposure to unblinded interim data and 
informal or formal discussions that can present a substantial risk to the integrity of the trial and the 
Sponsor’s ability to manage the trial without bias, only a small designated sub team of the 
Sponsor is unblinded, as described in DMC charter. This Sponsor’s sub team is not involved in 
the direct conduct of the remainder of the study and any conduct of external committees related to 
the study to protect the overall integrity of the study. 
In order to protect the global type one error in case the decision is taken to overrule the futility 
rule, non-binding futility rules are used for determination of alpha. 
Based on the futility analysis reviewed by DMC on the 14 May 2021, the DMC recommended to 
stop the analysis for futility. The Sponsor’s senior management team followed this 
recommendation and decided to discontinue the study. 
4.9.3 Two-steps analysis  
Not applicable. 
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5 
SUPPORTING DOCUMENTATION  
5.1 
APPENDIX 1 LIST OF ABBREVIATIONS  
 
ADMA: 
Asymmetric dimethylarginine 
ADPKD: 
Autosomal dominant polycystic kidney disease 
AE: 
Adverse event 
AESI: 
Adverse event of special interest 
ALT: 
Alanine transaminase 
BCVA: 
Best corrected visual acuity 
BFI: 
Brief fatigue inventory 
BPI: 
Brief pain inventory 
CKD-EPI: 
Chronic kidney disease epidemiologic collaboration 
CRF: 
electronic case report form 
DBP: 
Diastolic blood pressure 
ECG: 
Electrocardiogram 
eGFR: 
estimated glomerular filtration rate 
EQ 5D-5L: 
EuroQol 5 dimensions 5-level 
FGF23: 
Fibroblast growth factor 23 
GCS: 
Glucosylceramide synthase 
GL-1: 
Glucosylceramide 
GM3: 
Monosialodihexosylganglioside 
HGLT: 
High level group term 
HLT: 
High level term 
htTLV: 
height adjusted total liver volume 
ICF: 
Inform consent form 
IRT: 
Interactive response technology 
ITT: 
Intent-to-treat 
LLOQ: 
Lower limit of quantification 
LLT: 
Lower level term 
LOCSIII: 
Lens opacities classification system III 
MedDRA: 
Mecical dictionary for regulatory activities 
mGFR: 
measured glomerular filtration rate 
MMRM: 
Mixed model with repeated measures 
MRI: 
Magnetic resonance imaging 
NRS: 
Numeric rating scale 
OTC: 
Over the counter 
PCSA: 
Potentially clinically significant abnormality 
PD: 
Pharmacodynamic 
PGIC: 
Patient global impression of change 
PGIS: 
Patient global impression of severity 
PK: 
Pharmacokinetic 
PRO: 
Patient reported outcome 
PT: 
Preferred term 
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SAE: 
Serious adverse event 
SBP: 
Systolic blood pressure 
SD: 
Standard deviation 
SE: 
Standard error 
SOC: 
System organ class 
TE: 
Treatment emergent 
TEAE: 
Treatment emergent adverse event 
TKV: 
Total kidney volume 
TLV: 
Total liver volume 
ULOQ: 
Upper limit of quantification 
WHO-DD: 
World Health Organization-drug dictionary 
 
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5.2 
APPENDIX 2 CHANGES TO PROTOCOL-PLANNED ANALYSES  
This section summarizes major statistical changes in the protocol amendment(s). 
Table 9 - Major statistical changes in protocol amendment(s)  
Amendment 
Number 
Approval 
Date 
Changes 
Rationale 
01 
19 April 2018 
Clarification on the timing of evaluation 
of the secondary and exploratory 
endpoints 
To clarify 
 
 
Clarification of possible course of 
action with regard of study dose in 
ongoing participants in Stage 1 after 
DMC review of safety data and dose 
selection for Stage 2 
To clarify 
 
 
Clarification on mGFR stusudy 
To clarify that mGFR substudy is optional 
for eligible participants 
02 
25 May 2018 
Addition of stratification of participants 
by region 
To achieve balance between the treatment 
arms across the different regions 
 
 
Removal of exploratory objective of the 
study on mGFR sub-study 
 
 
 
Addition of exploratory objectives of 
the study on effect of GZ/SAR402671 
on type, frequency and dosage of 
analgesic/over the counter (OTC) pain 
medication administration 
To explore the effect of GZ/SAR402671 on 
type, frequency and dosage of 
analgesic/over the counter pain medication 
administration 
 
 
Update of items of the Daily symptoms 
of autosomal dominant polycystic 
kidney disease diary to regroup pain 
and nocturia items of the diary and to 
add an additional item that will direct to 
the medication entry log 
 
 
 
Addition of secondary analysis on TKV 
assessed from 1 month to 18 months, 
excluding baseline 
To describe secondary analysis that will 
explore a potential acute hemodynamic 
effect using TKV data assessed from 
1 month to 18 months 
03 
01 October 
2018 
Description of objective of mGFR sub-
study 
To explore the effect of GZ/SAR402671 on 
measured GFR (mGFR) substudy 
 
 
Added exploratory endpoint of 
Annualized rate of change in mGFR 
from baseline to 24 months in 
participants within Stage 2 substudy 
 
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Amendment 
Number 
Approval 
Date 
Changes 
Rationale 
04 
14 Aug 2019 
Increase of the sample size for the 
Inclusion in Stage 2 of the study of 
80 participants with a screening eGFR 
between 30 and 44.9 mL/min/1.73 m2 
Addition of exploratory endpoint of 
Annualized rate of change in eGFR 
(CKD-EPI equation) from baseline to 
24 months in participants with a 
screening eGFR between 30 and 
44.9 mL/min/1.73 m2 added 
To explore the effect of venglustat on 
eGFR (CKD-EPI equation) from baseline to 
24 months in participants with a screening 
eGFR between 30 and 
44.9 mL/min/1.73 m2 
 
 
Addition of statistical consideration 
related to probability of detecting a 
treatment effect in an additional 
80 participants with screening eGFR 
between 30 and 44.9 mL/min/1.73 m2 
 
 
 
Addition of clarification to the definition 
of the combined Stage 1 and Stage 2 
Safety population will be defined as all 
randomized participants with eGFR 
between 45 and 89.9 mL/min/1.73 m2 
at screening and participants from 
Stage 2 with an eGFR between 30 and 
44.9 mL/min/1.73 m2 at screening will 
be analyzed separately 
 
 
 
Described secondary analysis 
including participants from Stage 2 with 
eGFR between 30 and 
44.9 mL/min/1.73 m2 at screening 
 
 
 
Clarification of inclusion criteria: 
between the ages of 18 to and 
50 years (both inclusive) at screening 
for participants in Stage 1 
between 18 and 50 years (inclusive) 
for participants in Stage 2 with an 
eGFR between 45 and 
89.9 mL/min/1.73 m2 during the 
screening period* 
between 18 and 55 years (inclusive) 
for participants in Stage 2 with an 
eGFR between 30 and 
44.9 mL/min/1.73 m2 during the 
screening period 
To clarify and add participants with 
screening eGFR between 30 and 
44.9 mL/min/1.73 m2  
 
 
Systolic BP >160 mmHg* at run in and 
baseline visits. 
*mean value of three or five systolic BP 
measurements 
To clarify calculation of SBP 
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Amendment 
Number 
Approval 
Date 
Changes 
Rationale 
 
 
Clarification of the timing of the 
secondary analysis of TKV. TKV 
assessed more than 30 days instead of 
4 weeks after the last IMP 
administration will be excluded from 
the analysis 
To clarify 
 
 
Clarification of the residual treatment 
period defined as the time from the day 
after the last IMP administration, plus 
30 days (instead of 4 weeks) 
To clarify 
 
 
Clarification that the baseline value is 
defined generally as the last available 
value before first IMP administration 
To clarify 
 
 
Clarification that opacities present at 
baseline/previous visit, changes in 
LOCSIII score of ≥0.5 for nuclear 
opalescence, ≥0.8 for cortical 
opacification, or ≥0.5 for posterior 
subcapsular opacification compared 
with baseline or previous assessment 
will be considered as a worsening 
To specify threshold for minimal significant 
change in LOCSIII score that will be 
considered as a worsening of lens opacity 
05 
17 Aug 2020 
Updated the hierarchy of the 
secondary and exploratory endpoints: 
1. 
pain and fatigue are moved 
from exploratory to 
secondary endpoints 
2. 
nocturia and urine osmolality 
(Stage 2) are moved from 
secondary to exploratory 
endpoints 
Data from venglustat clinical studies do not 
suggest that venglustat causes urinary 
frequency or nocturia. For this reason, the 
change in nocturia was moved from 
secondary to exploratory endpoints. 
Pain and fatigue were moved from 
exploratory to secondary endpoints as they 
are fit in ADPKD as the concepts for which 
a positive effect can be shown. 
 
 
PRO population deleted 
PRO analysis will be performed on ITT 
population 
 
 
Removal of sentence “Time of 
baseline TKV will be set to 0.” 
Time of baseline TKV will be calculated 
as relative time since randomization 
date. 
 
 
Change in definition of on-treatment 
period and treatment-emergent 
period 
Clarification 
 
 
Presentation of statistical tables by 
SOC and PT 
Clarification 
 
 
Statistical analysis of liver test data 
Clarification 
 
 
Statistical analysis of PRO data 
using MMRM 
Clarification 
 
 
Primary analysis of Stage 1 will 
include data available at the cut-off 
date, including data reported up to 
Month 24, if any 
Clarification 
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Amendment 
Number 
Approval 
Date 
Changes 
Rationale 
06 
16 Dec 2020 
Added clarification that GFR will be 
measured with iohexol in patients with 
the screening eGFR between 45 and 
89.9 mL/min/1.73 m2 
Clarification 
 
 
Added inclusion criterion related to the 
screening eGFR value in patients 
eligible for the mGFR substudy 
Clarification 
07 
19 Apr 2021 
Exploratory objectives and 
corresponding endpoints were updated 
to consider all-cause hospitalization 
Clarification 
 
 
Added clarification that for patients to 
be screened for the long-term 
extension study after Month 24 
(Visit 12) and prior to Month 13 
(Visit 13), the last in Study EFC15392 
should coincide with the first visit in the 
long-term extension study 
Clarification 
 
 
For patients enrolled or screened for 
the long-term extension study prior to 
30 days after the last dose of IMP, all 
SAEs, AEs, and AEs of special interest 
(AESIs) will be collected up to the last 
visit in Study EFC15392, which will 
coincide with the first visit in the 
long-term extension study 
Clarification 
 
 
Added information that samples for 
exploratory biomarkers analysis 
collected in Stage 2 of the study will be 
analyzed only if results of this analysis 
during Stage 1 are considered as 
useful for further investigation. 
Removed collection of serum/plasma 
and urine biomarker samples at Visit 4 
(Month 1) in Stage 2 
Optimization, clarification 
 
 
Numbers of patients and samples for 
pharmacodynamics and exploratory 
biomarkers were updated. 
Correction 
 
 
The definition of residual treatment 
period was updated. 
Clarification 
 
 
Changes in previous amendment 06 
that were specific to the USA, the 
Netherlands, and Canada will be now 
applicable for all the countries for this 
amendment 07, with the exception of 
the additional inclusion criteria asking 
for an eGFR between 45 and 
89.9 mL/min/1.73 m2 that is no longer 
applicable for participants enrolling to 
the sub-study. 
To extend the conduct of the Measured 
Glomerular Filtration Rate (mGFR) 
substudy to all countries participating in the 
EFC15392 study. 
Correction (all patients, patients with any 
screening eGFR value, in Stage 2 can be 
potentially eligible for mGFR study). 
 
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5.3 
APPENDIX 3 DEMOGRAPHICS AND BASELINE CHARACTERISTICS, PRIOR OR 
CONCOMITANT MEDICATIONS  
The following demographics and baseline characteristics, medical and surgical history and disease 
characteristics will be summarized using descriptive statistics in the randomized population. 
Demographic and baseline characteristics  
• Gender (Male, Female) 
• Age in years (quantitative and categorical variable: <40, and ≥40 years),  
• Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or other Pacific Island, other) 
• Ethnicity (Hispanic, non-Hispanic) 
• Weight in kilograms (quantitative and categorical variable: <50, 50 to <100, ≥100) 
• Body mass index (BMI) in kg/m² (quantitative and categorical variable: <30, ≥30) 
Randomization strata 
The randomization strata of predicted ADPKD progression rate (1C versus 1D versus 1E) 
according to Mayo Imaging Classification and region (North America, Europe, China, Japan, 
Republic of Korea, Rest of the World) as recording in IRT as well as actual strata 
(see Section 5.4). 
Disease characteristics 
eGFR at screening and at baseline (quantitative variable and qualitative variable: <30,30 to <45, 
45 to <60, 60 to <75, 75 to <90, >=90) (see Section 5.4).  
ADPKD gene mutation  
The listing of participants with a genetic testing ever performed will be presented including the 
affected gene, the DNA sequence change and the AA change.  
Medical or surgical history 
Medical (or surgical) history includes previous relevant medical and surgery history collected at 
baseline. Medical and surgical history will be coded to a LLT, PT, HLT, HLGT, and associated 
primary SOC using the MedDRA version currently in effect at Sanofi at the time of database lock. 
Medical/surgical history will be summarized in each treatment arm by primary SOC and PT. 
Events will be sorted by SOC internationally agreed order and decreasing frequency of PT based 
on the incidence in the overall treatment arm. 
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Alcohol habits at baseline  
Alcohol habits include:  
• Frequency of alcoholic drinks in the last 12 months (Never/Occasional/At least 
monthly/At least weekly/At least daily) 
• Number of standard drinks (1 or 2/Greater than 2, where standard drink means 
1 pint/bottle of beer, 1 glass of wine, 1 shot of hard liquor…) per day when drinking 
alcohol 
Baseline safety and efficacy parameters (apart from those listed above) will be presented along 
with the safety and efficacy summaries.  
Prior or concomitant medications 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
using the version currently in effect at Sanofi at the time of database lock: 
• Prior medications are those the participant used prior to first IMP intake.  Prior 
medications can be discontinued before first administration or can be ongoing during 
treatment period. 
• Concomitant medications are any medications received by the participant concomitantly to 
the IMP during the on-treatment period.  
• Post-treatment medications are those the participant took in the period running from the 
end of the concomitant medications period up to the end of the study.  
• A given medication can be classified as a prior medication and/or as a concomitant 
medication and/or as post-treatment medication. If it cannot be determined whether a 
given medication was taken prior or concomitantly or post, it will be considered as prior, 
concomitant, and post-treatment medication. 
The prior and concomitant medications will be summarized for the randomized and exposed 
population, by anatomic and therapeutic level. The summaries for prior medications will be sorted 
by decreasing frequency of anatomic category (ATC) based on the overall incidence across study 
intervention group. The summaries for concomitant medications will be sorted by decreasing 
frequency of ATC based on the incidence the venglustat 15 mg group. In case of equal frequency, 
alphabetical order will be used. 
Participants will be counted once in each ATC category (anatomic or therapeutic) linked to the 
medication.  
In addition, any concomitant pain medication will be summarized. 
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5.4 
APPENDIX 4 DATA HANDLING CONVENTIONS  
General conventions 
The following formulas will be used for computation of parameters. 
Demographic formulas 
• BMI = 
height(m)
weight(kg)
2  
Total kidney volume and total liver volume using MRI 
All TKVs are evaluated by 2 independent reviewers and adjudicated in case of inconsistency 
(percentage difference ≥6%). 
At each visit, the TKV selected by the adjudication, if any, will be used for analyses. Else the 
mean of the TKV provided by the 2 independent reviewers will be considered. 
TLVs were evaluated by 2 independent reviewers at the start of the study for few participants, 
then upon team agreement evaluated by only one reviewer. At each visit, the mean of the TLV 
provided by the 2 independent reviewers, if any, will be considered for analysis. 
Mayo imaging classification strata based on height-adjusted TKV (HtTKV in mL/m) relative to 
age 
Actual Mayo imaging classification strata is based on participant's height adjusted TKV at 
screening (using TKV assessed by the screening radiologist) and age using the TKV growth rate 
per year r defined as (9): 
r = 10**((log10(htTKV) - log10(150)) / age) - 1 
Then the Mayo imaging classification will be defined as follows: 
Table 10 - Mayo imaging classification  
r 
Mayo Imaging classification 
<1.5% 
1A 
1.5% to <3.0% 
1B 
3.0% to <4.5% 
1C 
4.5% to < 6.0% 
1D 
≥6.0% 
1E 
 
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eGFR at screening 
The screening eGFR is defined as the eGFR value that was selected to enroll the participant in the 
study: 
• If eGFR at Visit 1 was between 45 and 89.9 mL/min/1.73 m² (or between 30 and 
89.9 mL/min/1.73 m² for Stage 2), then the value at Visit 1 is considered as the screening 
value 
• Else, if an additional eGFR measurement was done between Visit 1 and Visit 2, then this 
additional value is considered as the screening value 
• Else, the eGFR at Visit 2 is considered as the screening value 
Table 11 - eGFR values example  
Subject 
V1 
Additional (between V1 
and V2) 
V2 
1 
87 
ND 
91 
2 
92 
ND 
85 
3 
95 
86 
93 
4 
92 
95 
88 
eGFR at baseline 
Baseline eGFR is defined for each participant as the average of eGFR values assessed prior or 
equal to 1st IMP or prior or equal to randomization for randomized and not exposed participants. 
Analysis windows for time points 
For efficacy and patient reported outcome endpoints, D1 will be defined as the day of 
randomization. For safety endpoints, D1 will be defined as the day of first IMP intake.  
For endpoints not collected at each visit (including TKV, TLV, weight, height, ECG, complete 
physical examination, neurological examination and daily diaries), analysis by time points will be 
summarized using the protocol planned visits. 
For endpoints collected at almost each visit, the following analysis windows will decide how the 
scheduled and/or unscheduled visits will be used in the by-visit analyses of efficacy data (eGFR, 
urine osmolality), laboratory safety data (except urinalysis parameters), vital signs, (except weight 
and height), ophthalmological examination, patient reported outcome variables as well as PK 
variables. Only central assessments will be taken into account. For each parameter, only analysis 
time windows corresponding to a protocol planned visit for that parameter are applicable. 
A measurement (scheduled or unscheduled) will be used if it is available and measurement date is 
within the analysis window. 
After applying these time windows, if multiple assessments are associated to the same time point, 
the value collected at the scheduled visit will be used, if any. Otherwise the closest from the 
targeted study day will be used. If the difference is a tie, the value after the targeted study day will 
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be used. For all endpoints except PK, if multiple valid values exist within a same day, then the 
first value of the day will be selected.  
If there is no measurement for a given parameter in an analysis window, data will be considered 
missing for the corresponding visit. 
Table 12 - Analyses window definition  
Time point 
Targeted study day 
Analysis window in study days 
Month 1 
D30 
D2 to D60 
Month 3 
D90 
D61 to D135 
Month 6 
D180 
D136 to D225 
Month 9 
D270 
D226 to D315 
Month 12 
D360 
D316 to D405 
Month 15 
D450 
D406 to D495 
Month 18 
D540 
D496 to D585 
Month 21 
D630 
D586 to D675 
Month 24 
D720 
D676 to D765 
Table 13 - Analyses window definition for PK analyses - Stage 1  
Time point 
Target study day 
Analysis window 
Day 1/Post-dose 
Day 1/3 hours Post-dose 
2h00 to 4h00 after Day 1 dose 
Month 1/Pre-dose 
D30/Pre-dose 
Before Month 1/Day 30 dose 
Month 1/Post dose 
D30/3 hours post dose 
2h00 to 4h00 after Month 1/Day 30 
Months 6/Pre-dose 
D180/Pre-dose 
Before Months 6/Day 180 dose 
Months 18/Pre-dose 
D540/Pre-dose 
Before Months 1/Day 540 dose 
Table 14 - Analyses window definition for PK analyses - Stage 2  
Time point 
Target study day 
Analysis window 
Month 1/Pre-dose 
D30/Pre-dose 
Before Month 1/Day 30 dose 
Month 1/Post dose 
D30/3 hours post dose 
2h00 to 4h00 after Month 1/Day 30 
Months 24/Pre-dose 
D720/Pre-dose 
Before Months 24/Day 720 dose 
Unscheduled visits 
Unscheduled visit measurements will be used for computation of baseline, the last on-treatment 
value and worst on-treatment value. For parameters summarized according to analysis time 
windows, unscheduled visit measurements may also be used to provide a measurement for a 
timepoint.  
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%let pM18f = 30; 
 
* Percentage of patients with data at Month 21 and Month 24 at end of Stage 1; 
%let pM21s1  = 50; 
%let pM24s1  = 30; 
 
* Mean slopes of log(TKV) in Placebo; 
%let mStkv_d0 = 0.02764; 
 
* SD of log(TKV): SD of slope and SD of residuals; 
%let sdStkv = 0.01477; 
%let sdRtkv = 0.02566; 
 
* Mean slopes of eGFR in Placebo; 
%let mSgfr_d0 = -3.66; 
 
* SD of eGFR: SD of slope and SD of residuals; 
%let sdSgfr = 1.98; 
%let sdRgfr = 6.34; 
 
* Correlation between slopes log(TKV) and GFR; 
%let corr = -0.35; 
 
* Mean and SD of intercept of log(TKV) - No impact on power, but needed for 
simulations; 
%let mItkv = 3.1693; 
%let sdItkv = 0.13284; 
 
* Mean and SD of intercept of eGFR - No impact on power, but needed for 
simulations; 
%let mIgfr = 75.5963; 
%let sdIgfr = 10.3347; 
 
* List of time-points of TKV and eGFR; 
%let listtime   = 0,0.0833,0.25,0.50,0.75,1.00,1.25,1.50,1.75,2; 
%let timetkv_S1 = 0,0.0833,0.75,1.5; 
%let timetkv_S2 = 0,1.5; 
%let timegfr_S1 = 0,0.0833,0.25,0.50,0.75,1.00,1.25,1.50,1.75,2; 
%let timegfr_S2 = 0,0.0833,0.25,0.50,0.75,1.00,1.25,1.50,1.75,2; 
 
* Seed for random numbers; 
%let seed = 402671; 
 
* Drop out rate (at time tdrop) ; 
%let rdrop = 0.1; 
%let tdrop = 2; 
 
 
/*******************************/ 
/* STEP 1 : Simulation of data */ 
/*******************************/ 
 
data dataSim(keep=sim stage subject dose time logtkv gfr F S1); 
  length sim stage subject dose time logtkv gfr F S1 8; 
 
  retain seed &seed; 
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  do sim=1 to &Nsim; 
 
    do subject=1 to 
&NpatS1_d0+&NpatS1_d1+&NpatS1_d2+&NpatS2_d0+&NpatS2_d1+&NpatS2_d2; 
 
      * Assign subjects to stage 1 or 2 ; 
      if subject <= &NpatS1_d0+&NpatS1_d1+&NpatS1_d2 then stage = 1; else 
stage = 2; 
 
      * Assign subjects to dose 0, 1 or 2 in stage 1 ; 
      if subject <= &NpatS1_d0 then dose = 0; 
      else if subject <= &NpatS1_d0+&NpatS1_d1 then dose = 1; 
      else if subject <= &NpatS1_d0+&NpatS1_d1+&NpatS1_d2 then dose = 2; 
 
      * Assign subjects to dose 0, 1 or 2 in stage 2 ; 
      else if subject <= &NpatS1_d0+&NpatS1_d1+&NpatS1_d2+&NpatS2_d0 then dose 
= 0; 
      else if subject <= 
&NpatS1_d0+&NpatS1_d1+&NpatS1_d2+&NpatS2_d0+&NpatS2_d1 then dose = 1; 
      else if subject <= 
&NpatS1_d0+&NpatS1_d1+&NpatS1_d2+&NpatS2_d0+&NpatS2_d1+&NpatS2_d2 then dose = 
2; 
 
      * Determine if subject has Month 9 data at futility analysis in stage 1; 
      pM9f = .; 
      if 0 < subject <= &NpatS1_d0*&pM9f/100 then pM9f = 1; 
      if &NpatS1_d0 < subject <= &NpatS1_d0+&NpatS1_d1*&pM9f/100 then pM9f = 
1; 
      if &NpatS1_d0+&NpatS1_d1 < subject <= 
&NpatS1_d0+&NpatS1_d1+&NpatS1_d2*&pM9f/100 then pM9f = 1; 
 
      * Determine if subject has Month 18 data at futility analysis in stage 
1; 
      pM18f = .; 
      if 0 < subject <= &NpatS1_d0*&pM18f/100 then pM18f = 1; 
      if &NpatS1_d0 < subject <= &NpatS1_d0+&NpatS1_d1*&pM18f/100 then pM18f = 
1; 
      if &NpatS1_d0+&NpatS1_d1 < subject <= 
&NpatS1_d0+&NpatS1_d1+&NpatS1_d2*&pM18f/100 then pM18f = 1; 
 
      * Determine if subject has Month 21 data at analysis of end of stage 1; 
      pM21s1 = .; 
      if 0 < subject <= &NpatS1_d0*&pM21s1/100 then pM21s1 = 1; 
      if &NpatS1_d0 < subject <= &NpatS1_d0+&NpatS1_d1*&pM21s1/100 then pM21s1 
= 1; 
      if &NpatS1_d0+&NpatS1_d1 < subject <= 
&NpatS1_d0+&NpatS1_d1+&NpatS1_d2*&pM21s1/100 then pM21s1 = 1; 
 
      * Determine if subject has Month 24 data at analysis of end of stage 1; 
      pM24s1 = .; 
      if 0 < subject <= &NpatS1_d0*&pM24s1/100 then pM24s1 = 1; 
      if &NpatS1_d0 < subject <= &NpatS1_d0+&NpatS1_d1*&pM24s1/100 then pM24s1 
= 1; 
      if &NpatS1_d0+&NpatS1_d1 < subject <= 
&NpatS1_d0+&NpatS1_d1+&NpatS1_d2*&pM24s1/100 then pM24s1 = 1; 
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      * Determine mean slope of log(TKV) and GFR (depending on dose) ; 
      if dose = 0 then do; 
        mStkv = &mstkv_d0; 
        mSgfr = &msgfr_d0; 
      end; 
      if dose = 1 then do; 
        mStkv = log10((10**&mstkv_d0-1)*(1-&RRtkv_d1/100)+1); 
        mSgfr = &msgfr_d0*(1-&RRgfr_d1/100); 
      end; 
      if dose = 2 then do; 
        mStkv = log10((10**&mstkv_d0-1)*(1-&RRtkv_d2/100)+1); 
        mSgfr = &msgfr_d0*(1-&RRgfr_d2/100); 
      end; 
 
      * Generate a random intercept of log(TKV) for the current patient ; 
      call rannor(seed,x); 
      inttkv = &mItkv + x*&sdItkv; 
 
      * Generate a random intercept of GFR for the current patient ; 
      call rannor(seed,x); 
      intgfr = &mIgfr + x*&sdIgfr; 
 
      * Generate a random slope of log(TKV) for the current patients ; 
      call rannor(seed,x); 
      slopetkv = mStkv + x*&sdStkv; 
 
      * Generate a random slope of GFR for the current patients ; 
      * Based on the conditional distribution, given slope of log(TKV) ; 
      call rannor(seed,x); 
      slopegfr = mSgfr + &corr*&sdSgfr/&sdStkv*(slopetkv-msTKV) + 
x*&sdSgfr*sqrt(1-(&corr)**2); 
 
      * Simulate time to dropout (assuming exponential time to drop-out and 
rate at time &tdrop is &rdrop) ; 
      call ranuni(seed,x); 
      tdrop = log(x)*&tdrop/log(1-&rdrop); 
 
        * Create observations at each time-point ; 
      do time=&listtime; 
 
        * Create an obsbservation for log(TKV) ; 
        if (stage = 1 and time in (&timetkv_S1)) or (stage = 2 and time in 
(&timetkv_S2)) then do; 
 
          * Generate a residual error for the current observation ; 
          call rannor(seed,x); 
          etkv = &sdRtkv*x; 
 
          * Generate an measurement at the given time-point ; 
          logtkv = inttkv + slopetkv*time + etkv; 
        end; 
        else logtkv = .; 
 
        * Create an obsbservation for GFR ; 
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        if (stage = 1 and time in (&timegfr_S1)) or (stage = 2 and time in 
(&timegfr_S2)) then do; 
 
          * Generate a residual error for the current observation ; 
          call rannor(seed,x); 
          egfr = &sdRgfr*x; 
 
          * Generate an measurement at the given time-point ; 
          gfr = intgfr + slopegfr*time + egfr; 
        end; 
        else gfr = .; 
 
        * Determine if data available at futility analysis in stage 1; 
        F = .; 
        if stage = 1 and time <= 0.75 and pM9f  = 1 then F = 1; 
        if stage = 1 and time <= 1.5  and pM18f = 1 then F = 1; 
 
        * Determine if data available at stage 1 analysis; 
        S1 = .; 
        if stage = 1 and time <= 1.5 then S1 = 1; 
        if stage = 1 and time <= 1.75 and pM21s1 = 1 then S1 = 1; 
        if stage = 1 and time <= 2    and pM24s1 = 1 then S1 = 1; 
 
        * Keep only observations before patient drops out; 
        if time<tdrop then output; 
 
      end; 
    end; 
  end; 
run; 
 
 
/**************************************/ 
/* STEP 2: Analysis of simulated data */ 
/**************************************/ 
 
/* Linear mixed models for different endpoints at different stages*/                  
/* Note: for each contrast, one-sided p-value is requested (lower tail for 
TKV, upper tail for GFR) */ 
 
options nonotes; 
ods listing close; 
 
 
* TKV - Futility analysis ; 
proc mixed data=dataSim noclprint; 
  where stage = 1 and F = 1 and not(missing(logtkv)); 
  by sim; 
  class subject dose; 
  model logtkv = dose time time*dose; 
  estimate "Slope0"  int 0 dose 0 0 0 time 1 time*dose  1 0 0; 
  estimate "Slope1"  int 0 dose 0 0 0 time 1 time*dose  0 1 0; 
  estimate "Slope2"  int 0 dose 0 0 0 time 1 time*dose  0 0 1; 
  estimate "Emax"    int 0 dose 0 0 0 time 0 time*dose -0.8131  0.3424 0.4707 
/ lower; 
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  estimate "Linear"  int 0 dose 0 0 0 time 0 time*dose -0.7223  0.0314 0.6909 
/ lower; 
  estimate "SigEmax" int 0 dose 0 0 0 time 0 time*dose -0.6615 -0.0838 0.7453 
/ lower; 
  random int time / type=un subject=subject; 
  ods output estimates=esttkv_F; 
  ods output covparms=covtkv_F; 
run; 
 
 
* TKV - End of stage 1; 
proc mixed data=dataSim noclprint; 
  where S1 = 1 and not(missing(logtkv)); 
  by sim; 
  class subject dose; 
  model logtkv = dose time time*dose / ddfm=satterthwaite; 
  estimate "Slope0"  int 0 dose 0 0 0 time 1 time*dose  1 0 0; 
  estimate "Slope1"  int 0 dose 0 0 0 time 1 time*dose  0 1 0; 
  estimate "Slope2"  int 0 dose 0 0 0 time 1 time*dose  0 0 1; 
  estimate "Emax"    int 0 dose 0 0 0 time 0 time*dose -0.8131  0.3424 0.4707 
/ lower; 
  estimate "Linear"  int 0 dose 0 0 0 time 0 time*dose -0.7223  0.0314 0.6909 
/ lower; 
  estimate "SigEmax" int 0 dose 0 0 0 time 0 time*dose -0.6615 -0.0838 0.7453 
/ lower; 
  random int time / type=un subject=subject; 
  ods output estimates=esttkv_S1; 
  ods output covparms=covtkv_S1; 
run; 
 
 
* TKV - End of stage 2; 
proc mixed data=dataSim noclprint; 
  where not(missing(logtkv)); 
  by sim; 
  class subject dose; 
  model logtkv = dose time time*dose / ddfm=satterthwaite; 
  estimate "Slope0"  int 0 dose 0 0 0 time 1 time*dose  1 0 0; 
  estimate "Slope1"  int 0 dose 0 0 0 time 1 time*dose  0 1 0; 
  estimate "Slope2"  int 0 dose 0 0 0 time 1 time*dose  0 0 1; 
  estimate "Emax"    int 0 dose 0 0 0 time 0 time*dose -0.8131  0.3424 0.4707 
/ lower; 
  estimate "Linear"  int 0 dose 0 0 0 time 0 time*dose -0.7223  0.0314 0.6909 
/ lower; 
  estimate "SigEmax" int 0 dose 0 0 0 time 0 time*dose -0.6615 -0.0838 0.7453 
/ lower; 
  random int time / type=un subject=subject; 
  ods output estimates=esttkv_S2; 
  ods output covparms=covtkv_S2; 
run; 
 
 
* GFR - End of stage 1; 
proc mixed data=dataSim noclprint; 
  where S1 = 1 and not(missing(gfr)); 
  by sim; 
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  class subject dose; 
  model gfr = dose time time*dose / ddfm=satterthwaite; 
  estimate "Slope0"  int 0 dose 0 0 0 time 1 time*dose  1 0 0; 
  estimate "Slope1"  int 0 dose 0 0 0 time 1 time*dose  0 1 0; 
  estimate "Slope2"  int 0 dose 0 0 0 time 1 time*dose  0 0 1; 
  estimate "Emax"    int 0 dose 0 0 0 time 0 time*dose -0.8131  0.3424 0.4707 
/ upper; 
  estimate "Linear"  int 0 dose 0 0 0 time 0 time*dose -0.7223  0.0314 0.6909 
/ upper; 
  estimate "SigEmax" int 0 dose 0 0 0 time 0 time*dose -0.6615 -0.0838 0.7453 
/ upper; 
  random int time / type=un subject=subject; 
  ods output estimates=estgfr_S1; 
  ods output covparms=covgfr_S1; 
run; 
 
 
* GFR - End of stage 2; 
proc mixed data=dataSim noclprint; 
  where not(missing(gfr)); 
  by sim; 
  class subject dose; 
  model gfr = dose time time*dose / ddfm=satterthwaite; 
  estimate "Slope0"  int 0 dose 0 0 0 time 1 time*dose  1 0 0; 
  estimate "Slope1"  int 0 dose 0 0 0 time 1 time*dose  0 1 0; 
  estimate "Slope2"  int 0 dose 0 0 0 time 1 time*dose  0 0 1; 
  estimate "Emax"    int 0 dose 0 0 0 time 0 time*dose -0.8131  0.3424 0.4707 
/ upper; 
  estimate "Linear"  int 0 dose 0 0 0 time 0 time*dose -0.7223  0.0314 0.6909 
/ upper; 
  estimate "SigEmax" int 0 dose 0 0 0 time 0 time*dose -0.6615 -0.0838 0.7453 
/ upper; 
  random int time / type=un subject=subject; 
  ods output estimates=estgfr_S2; 
  ods output covparms=covgfr_S2; 
run; 
 
ods listing; 
options notes; 
 
/**************************************************************************/ 
/* STEP 3: Calculate distribution of Z statistic from multiple comparison */ 
/* procedure under null hypothesis */ 
/**************************************************************************/ 
 
* Generate 10000000 samples from Z statistic under null hypothesis; 
data simz(keep=z:); 
  retain seed 123; 
 
  do i=1 to 10000000; 
 
    * Generate independent normal for 3 doses ; 
    call rannor(seed,y1); 
    call rannor(seed,y2); 
    call rannor(seed,y3); 
 
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* Calculate all contrasts ;
c1 = -0.8131*Y1+0.3424*Y2+0.4707*Y3;
c2 = -0.7223*Y1+0.0314*Y2+0.6909*Y3;
c3 = -0.6615*Y1-0.0838*Y2+0.7453*Y3;
* Z-statistic : maximum of all contrasts ;
z = round(max(of c1--c3),0.0001);
output; 
  end; 
run; 
* Calculate cumulative distribution of Z statistic;
ods listing close;
proc freq data=simz;
  table z; 
  ods output OneWayFreqs=distz; 
run; 
ods listing; 
* Create all possible values of Z from -5 to +10 (by 0.0001 increment);
data pz(keep=z);
  do x=-5 to 10 by 0.0001; 
z = round(x,0.0001); 
output; 
  end; 
run; 
data pz(keep=z pvalue); 
  merge pz distz; 
  by z; 
  retain lastcum 0; 
  if cumpercent = . then cumpercent = lastcum; 
  lastcum = cumpercent; 
  pvalue = 1-cumpercent/100; 
run; 
* Create a format associating each possible value of Z with its associated p-
value ;
data PZFMT(keep=fmtname start label);
  length FMTNAME $8 START 8 LABEL $20; 
  set pz; 
  fmtname = "PZFMT"; 
  start   = z; 
  label   = put(pvalue,10.8); 
run; 
proc format cntlin=PZFMT; 
run; 
/*******************************************/ 
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/* STEP 4: Combine results of all analyses */ 
/*******************************************/ 
 
* Combine all estimates; 
data allest; 
  length endpoint $3 stage $2 sim 8 label $20; 
  set esttkv_f (in=tkvf) 
      esttkv_s1(in=tkvs1) 
      esttkv_s2(in=tkvs2) 
      estgfr_s1(in=gfrs1) 
      estgfr_s2(in=gfrs2) 
      ; 
  if tkvf or tkvs1 or tkvs2 then endpoint = "TKV"; 
  if gfrs1 or gfrs2 then endpoint = "GFR"; 
  if tkvf then stage = "F"; 
  if tkvs1 or gfrs1 then stage = "S1"; 
  if tkvs2 or gfrs2 then stage = "S2"; 
 
  length id $30; 
  id = compress(lowcase(label)) || "_" || compress(lowcase(endpoint)) || "_" 
|| compress(lowcase(stage)); 
 
  if tails = "Lower" then tvalue = -tvalue; 
  drop tails; 
run; 
 
* Combine all variances; 
data allcov; 
  length endpoint $3 stage $2 sim 8 label $20; 
  set covtkv_f (in=tkvf) 
      covtkv_s1(in=tkvs1) 
      covtkv_s2(in=tkvs2) 
      covgfr_s1(in=gfrs1) 
      covgfr_s2(in=gfrs2) 
      ; 
  if tkvf or tkvs1 or tkvs2 then endpoint = "TKV"; 
  if gfrs1 or gfrs2 then endpoint = "GFR"; 
  if tkvf then stage = "F"; 
  if tkvs1 or gfrs1 then stage = "S1"; 
  if tkvs2 or gfrs2 then stage = "S2"; 
 
  if covparm = "UN(2,2)"  then do; estimate = sqrt(estimate); label = 
"SDslope"; end; 
  if covparm = "Residual" then do; estimate = sqrt(estimate); label = "SDres";   
end; 
 
  length id $30; 
  id = compress(lowcase(label)) || "_" || compress(lowcase(endpoint)) || "_" 
|| compress(lowcase(stage)); 
 
  if covparm in ("UN(2,2)","Residual") then output; 
 
  drop covparm subject; 
run; 
 
 
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* Combine all results ; 
data allMixed; 
  set allest allcov; 
run; 
proc sort data=allMixed; 
  by sim stage; 
run; 
 
 
* Transpose results (one record per simulation) ; 
proc transpose data=allmixed out=estimate(drop=_name_); 
  where label in ("Slope0","Slope1","Slope2","SDslope","SDres"); 
  by sim; 
  var estimate; 
  id id; 
run; 
proc transpose data=allmixed out=zvalue(drop=_name_ _label_) prefix=z_; 
  where label notin ("Slope0","Slope1","Slope2","SDslope","SDres"); 
  by sim; 
  var tvalue; 
  id id; 
run; 
 
 
* Combine all results and calculate p-values from Multiple Comparison 
Procedure ; 
data simResults; 
  merge estimate zvalue; 
  by sim; 
 
  * TKV slope in %/year ; 
  slope0_tkv_f  = 10**slope0_tkv_f-1; 
  slope1_tkv_f  = 10**slope1_tkv_f-1; 
  slope2_tkv_f  = 10**slope2_tkv_f-1; 
  slope0_tkv_s1 = 10**slope0_tkv_s1-1; 
  slope1_tkv_s1 = 10**slope1_tkv_s1-1; 
  slope2_tkv_s1 = 10**slope2_tkv_s1-1; 
  slope0_tkv_s2 = 10**slope0_tkv_s2-1; 
  slope1_tkv_s2 = 10**slope1_tkv_s2-1; 
  slope2_tkv_s2 = 10**slope2_tkv_s2-1; 
 
  * RR on TKV; 
  RR1_tkv_f  = 1-slope1_tkv_f/slope0_tkv_f; 
  RR2_tkv_f  = 1-slope2_tkv_f/slope0_tkv_f; 
  RR1_tkv_s1 = 1-slope1_tkv_s1/slope0_tkv_s1; 
  RR2_tkv_s1 = 1-slope2_tkv_s1/slope0_tkv_s1; 
  RR1_tkv_s2 = 1-slope1_tkv_s2/slope0_tkv_s2; 
  RR2_tkv_s2 = 1-slope2_tkv_s2/slope0_tkv_s2; 
 
  * RR on GFR; 
  RR1_gfr_s1 = 1-slope1_gfr_s1/slope0_gfr_s1; 
  RR2_gfr_s1 = 1-slope2_gfr_s1/slope0_gfr_s1; 
  RR1_gfr_s2 = 1-slope1_gfr_s2/slope0_gfr_s2; 
  RR2_gfr_s2 = 1-slope2_gfr_s2/slope0_gfr_s2; 
 
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  * Z-value of Multiple Comparison Procedure (maximum of z-value of Emax, 
Linear and SigEmax); 
  z_mcp_tkv_f  = max(z_emax_tkv_f ,z_linear_tkv_f ,z_sigemax_tkv_f ); 
  z_mcp_tkv_s1 = max(z_emax_tkv_s1,z_linear_tkv_s1,z_sigemax_tkv_s1); 
  z_mcp_tkv_s2 = max(z_emax_tkv_s2,z_linear_tkv_s2,z_sigemax_tkv_s2); 
  z_mcp_gfr_s1 = max(z_emax_gfr_s1,z_linear_gfr_s1,z_sigemax_gfr_s1); 
  z_mcp_gfr_s2 = max(z_emax_gfr_s2,z_linear_gfr_s2,z_sigemax_gfr_s2); 
 
  * One-sided p-value of Multiple Comparison Procedure; 
  p_mcp_tkv_f  = input(put(round(z_mcp_tkv_f ,0.0001),pzfmt.),best.); 
  p_mcp_tkv_s1 = input(put(round(z_mcp_tkv_s1,0.0001),pzfmt.),best.); 
  p_mcp_tkv_s2 = input(put(round(z_mcp_tkv_s2,0.0001),pzfmt.),best.); 
  p_mcp_gfr_s1 = input(put(round(z_mcp_gfr_s1,0.0001),pzfmt.),best.); 
  p_mcp_gfr_s2 = input(put(round(z_mcp_gfr_s2,0.0001),pzfmt.),best.); 
 
  format slope0_tkv: slope1_tkv: slope2_tkv: percent8.2 slope0_gfr: 
slope1_gfr: slope2_gfr: 6.2 sd: 7.4 p_: 6.4 RR: percentn8.1 z: 6.3; 
run; 
 
 
/****************************************************************************/ 
/*STEP 5:Apply strategy for multiplicity and determine outcome of the study */ 
/****************************************************************************/ 
 
data outcome; 
  set simresults; 
 
  * Futility if one-sided p-value of TKV at interim analysis > 0.30; 
  if p_mcp_tkv_f > 0.30 then do; 
    TKVs1     = 0; 
    GFRs1     = 0; 
    GFRs12    = 0; 
    TKVGFRs12 = 0; 
    Futility  = 1; 
  end; 
 
  else do; 
 
    * Significant effect on TKV at stage 1 if two-sided p-value < 0.04; 
    if 2*p_mcp_tkv_s1 < 0.04 then do; 
 
      * Significant effect on GFR at stage 1 if two-sided p-value < 0.001; 
      if 2*p_mcp_gfr_s1 < 0.001 then do; 
        TKVs1     = 1; 
        GFRs1     = 1; 
        GFRs12    = 1; 
        TKVGFRs12 = 1; 
        Futility  = 0; 
      end; 
 
      * Significant effect on GFR at stage 2 if two-sided p-value < 0.049; 
      else if 2*p_mcp_gfr_s2 < 0.049 then do; 
        TKVs1     = 1; 
        GFRs1     = 0; 
        GFRs12    = 1; 
        TKVGFRs12 = 1; 
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        Futility  = 0; 
      end; 
 
      * Otherwise: no effect on GFR; 
      else do; 
        TKVs1     = 1; 
        GFRs1     = 0; 
        GFRs12    = 0; 
        TKVGFRs12 = 0; 
        Futility  = 0; 
      end; 
    end; 
 
    * If no significant effect on TKV at stage 1; 
    else do; 
 
      * Significant effect on both TKV and GFR at stage 2 if two-sided p-value 
< 0.01 ; 
      if 2*p_mcp_gfr_s2 < 0.01 and 2*p_mcp_tkv_s2 < 0.01 then do; 
        TKVs1     = 0; 
        GFRs1     = 0; 
        GFRs12    = 1; 
        TKVGFRs12 = 1; 
        Futility  = 0; 
      end; 
 
      * Significant effect on GFR at stage 2 if two-sided p-value < 0.01; 
      else if 2*p_mcp_gfr_s2 < 0.01 then do; 
        TKVs1     = 0; 
        GFRs1     = 0; 
        GFRs12    = 1; 
        TKVGFRs12 = 0; 
        Futility  = 0; 
      end; 
 
      * Otherwise, no effect on TKV and GFR; 
      else do; 
        TKVs1     = 0; 
        GFRs1     = 0; 
        GFRs12    = 0; 
        TKVGFRs12 = 0; 
        Futility  = 0; 
      end; 
    end; 
 
  end; 
 
run; 
 
 
* Calculate probability of each outcome; 
proc means data=outcome noprint nway; 
  var TKVs1 GFRs1 GFRs12 TKVGFRs12 Futility; 
  output out=prob(keep=TKVs1 GFRs1 GFRs12 TKVGFRs12 Futility) mean=TKVs1 GFRs1 
GFRs12 TKVGFRs12 Futility; 
run; 
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* Print probabilities; 
options nocenter; 
 
title1 "Operating characteristics of the study design "; 
title2 "Scenario: 15 mg: &RRtkv_d2.% on TKV, &RRgfr_d2% on eGFR"; 
title3 "          8 mg:  &RRtkv_d1.% on TKV, &RRgfr_d1% on eGFR"; 
 
proc print data=prob noobs l; 
  var TKVs1 GFRs1 GFRs12 TKVGFRs12 Futility; 
  format TKVs1 GFRs1 GFRs12 TKVGFRs12 Futility percent8.1; 
  label TKVs1     = "Probability to detect an effect on TKV at the end of 
Stage 1" 
        GFRs1     = "Probability to detect an effect on eGFR at the end of 
Stage 1" 
        GFRs12    = "Probability to detect an effect on eGFR at end of Stage 1 
and/or end of Stage 2" 
        TKVGFRs12 = "Overall probability to detect an effect on TKV and eGFR" 
        Futility  = "Probability to declare futility at interim analysis" 
  ; 
run; 
5.6 
APPENDIX 7 STATISTICAL TECHNICAL DETAILS  
5.6.1 Operating characteristics of the study design  
Operating characteristics were assessed through extensive simulations. All simulations used the 
following assumptions on design and parameters: 
• Sample size of 80 participants per arm in Stage 1 (randomized 1:1:1 to placebo, venglustat 
8 mg or venglustat 15 mg) and of 160 participants per arm in Stage 2 (randomized 1:1 to 
placebo or venglustat). 
• TKV assessed at screening, 1 month, 9 months, and 18 months in Stage 1; at screening and 
24 months in Stage 2. 
• eGFR assessed at baseline, 1 month, 3 months, and then every 3 months, both in Stage 1 
and Stage 2. 
• Mean slope of log10(TKV) of 0.02764 (6.6%/year) in the placebo arm. 
• Standard deviation for the residual error of TKV (on the log10 scale) of 0.02566 and 
standard deviation for the random effect of slope of 0.01477. 
• Mean slope of eGFR of -3.66 mL/min/1.73 m² per year in the placebo arm. 
• Standard deviation for the residual error of eGFR of 6.34 and standard deviation for the 
random effect of slope of 1.98. 
• Correlation between log10(TKV) slope and eGFR slope of -0.35. 
• Dropout rate of 10% at 2 years, assuming an exponential distribution for time to dropout. 
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Simulations were based on different scenarios regarding the true effect of venglustat on TKV and 
eGFR. Most scenarios assumed a 50% relative reduction in TKV growth rate and a 30% relative 
reduction in eGFR rate of decline for the venglustat 15 mg, and varying effect of venglustat 8 mg. 
They also assumed that the 15 mg dose was selected in Stage 2. These scenarios are presented in 
Table 15. Additional scenarios assuming that the 8 mg dose was selected in Stage 2 were 
considered and are presented in Table 16. Sample SAS code of simulations is provided in 
Section 5.5. 
For each scenario, 10 000 trials were simulated. Each simulated trial was analyzed according to 
the procedure described in Section 4.3.1.2: 
•
An interim analysis was performed when all participants from Stage 1 had TKV at
baseline, 1 month and 9 months and 30% of participants also had TKV at 18 months (or
had discontinued). Futility was declared at the interim analysis if the one-sided p value
from Multiple Comparison Procedure was >0.30.
•
If no futility was declared at interim analysis, the analysis at end of Stage 1 was performed
when all participants from Stage 1 had TKV available up to 18 months (or have
discontinued). It was also assumed that at the cut-off date, 50% of participants from
Stage 1 had eGFR available at 21 months and 30% had eGFR available at 24 months.
According to the procedure for handling multiplicity of test (see Section 4.6), the
following rules applied:
-
A significant effect on TKV at end of Stage 1 was declared if 2 * one sided p value
from Multiple Comparison Procedure was <0.04.
-
If a significant effect on TKV was declared, a significant effect on eGFR at end of
Stage 1 was declared if 2 * one-sided p value from Multiple Comparison Procedure
was <0.001.
•
Analysis at end of Stage 2 was performed when all participants from Stage 1 and Stage 2
had TKV available up to 18 months and eGFR available up to 24 months (or have
discontinued). According to the procedure for handling multiplicity of test, the following
rules applied:
-
If a significant effect on TKV was declared at end of Stage 1: A significant effect on
eGFR at end of Stage 2 was declared if 2 * one-sided p value from Multiple
Comparison Procedure was <0.049.
-
If no significant effect on TKV was declared at end of Stage 1: A significant effect on
eGFR at end of Stage 2 was declared if 2 * one sided p value from Multiple
Comparison Procedure was <0.01.
The probabilities to detect an effect on TKV and eGFR are presented in Table 15 assuming the 
15 mg dose was selected in Stage 2. Under the expected scenario that venglustat 15 mg would 
provide 50% reduction on TKV growth rate and 30% reduction in eGFR rate of decline, and that 
the venglustat 8 mg would provide a slightly reduced efficacy of 40% reduction in TKV and 
25% reduction in eGFR (scenario 2), the study would have approximately 89% power to detect an 
effect on TKV and 87% power to detect an effect on eGFR. It is to be noted that thanks to the 
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Multiple Comparison Procedure, the power on TKV and eGFR would remain >80% whatever the 
efficacy of venglustat 8 mg. 
Table 15 - Operating characteristics of the study design assuming the dose 15 mg is selected for 
Stage 2  
Scenario 
Probability to 
detect an 
effect on TKV 
at the end of 
Stage 1 
Probability to 
detect an 
effect on eGFR 
at the end of 
Stage 1 
Probability to 
detect an effect 
on eGFR at end 
of Stage 1 and/or 
end of Stage 2 
Probability to 
declare 
futility at 
interim 
analysis 
Scenario 1 
15 mg: 50% on TKV, 30% on 
eGFR 
8 mg: 50% on TKV, 30% on eGFR 
92.6% 
6.4% 
90.1% 
2.3% 
Scenario 2 
15 mg: 50% on TKV, 30% on 
eGFR 
8 mg: 40% on TKV, 25% on eGFR 
89.0% 
5.1% 
87.0% 
3.1% 
Scenario 3 
15 mg: 50% on TKV, 30% on 
eGFR 
8 mg: 30% on TKV, 20% on eGFR 
86.0% 
4.4% 
84.6% 
3.7% 
Scenario 4 
15 mg: 50% on TKV, 30% on 
eGFR 
8 mg: 20% on TKV, 15% on eGFR 
84.6% 
3.9% 
83.2% 
4.2% 
Scenario 5 
15 mg: 50% on TKV, 30% on 
eGFR 
8 mg: 10% on TKV, 10% on eGFR 
85.1% 
3.7% 
83.0% 
4.3% 
Scenario 6 
15 mg: 70% on TKV, 50% on 
eGFR 
8 mg: 50% on TKV, 30% on eGFR 
99.3% 
26.4% 
99.7% 
0.3% 
eGFR = estimated glomerular filtration rate; TKV = total kidney volume. 
It is expected that venglustat 15 mg would be well tolerated in Stage 1 and therefore selected in 
Stage 2. However, in case of safety concern, the DMC may recommend the use of venglustat 
8 mg for Stage 2. The probabilities to detect an effect on TKV and eGFR in such a case are 
presented in Table 16. Assuming that venglustat 8 mg would provide 50% reduction on TKV 
growth rate and 30% reduction in eGFR rate of decline, the power to detect an effect on TKV and 
eGFR would be >80%. 
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Table 16 - Operating characteristics of the study design assuming the dose 8 mg is selected for 
Stage 2  
Scenario 
Probability to 
detect an 
effect on TKV 
at the end of 
Stage 1 
Probability to 
detect an 
effect on eGFR 
at the end of 
Stage 1 
Probability to 
detect an effect 
on eGFR at end 
of Stage 1 and/or 
end of Stage 2 
Probability to 
declare 
futility at 
interim 
analysis 
Scenario 7 
15 mg: 50% on TKV, 30% on 
eGFR 
8 mg: 50% on TKV, 30% on eGFR 
92.6% 
6.4% 
80.1% 
2.3% 
Scenario 8 
15 mg: 70% on TKV, 50% on 
eGFR 
8 mg: 50% on TKV, 30% on eGFR 
99.3% 
26.4% 
98.3% 
0.3% 
eGFR = estimated glomerular filtration rate; TKV = total kidney volume. 
5.6.2 Confidence interval for relative reduction 
5.6.2.1 Annualized rate of change in TKV 
The relative reduction in annualized rate of change in TKV for venglustat 15 mg dose versus 
placebo is defined as: 
𝑅𝑅15 = (1 −𝜃15
̂
 𝜃0
̂ ) × 100 
where: 
𝜃𝑖̂ = Annualized rate of change in TKV in arm i = 10𝛽𝑖
̂ −1
and 𝛽𝑖̂ is the slope of log10-transformed TKV in arm i (i=0 for the placebo arm and i=15 for the
venglustat 15 mg dose arm), estimated from the linear mixed-effect model. 
Using the properties of the log-normal distribution in base 10, it can be shown that 𝜃𝑖̂ has mean
and variance equal to 𝑚𝑖 and 𝑠𝑖
2:
𝑚𝑖= exp (𝛽𝑖̂ ln 10 + 𝑉𝑎𝑟(𝛽𝑖̂)(ln 10)²
2
) −1 
𝑠𝑖
2 = exp[2𝛽𝑖̂ ln 10 + 𝑉𝑎𝑟(𝛽𝑖̂)(ln 10)²](exp[𝑉𝑎𝑟(𝛽𝑖̂)(ln 10)²] −1)
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Using the Fieller method, the 100 × (1 −𝛼)% confidence interval of the ratio 
 𝜃15
̂
 𝜃0
̂  has lower and 
upper limit equal to 𝐿15 and 𝑈15 : 
𝐿15 =
𝑚0𝑚15 −√(𝑚0𝑚15)2 −(𝑚0
2 −𝑧𝛼/2²𝑠0
2)(𝑚15
2 −𝑧𝛼/2²𝑠15
2 )
𝑚0
2 −𝑧𝛼/2²𝑠0
2
 
𝑈15 =
𝑚0𝑚15 + √(𝑚0𝑚15)2 −(𝑚0
2 −𝑧𝛼/2²𝑠0
2)(𝑚15
2 −𝑧𝛼/2²𝑠15
2 )
𝑚0
2 −𝑧𝛼/2²𝑠0
2
 
where 𝑧𝛼/2 is the quantile of the normal distribution. 
Therefore, the 95% confidence interval for the relative reduction in annualized rate of change in 
TKV for venglustat 15mg dose versus placebo will be calculated as: 
(1 −𝑈15) × 100  ; (1 −𝐿15) × 100 
The same method will be used for the relative reduction of venglustat 8 mg dose versus placebo. 
5.6.2.2 Annualized rate of change in eGFR  
The same method will be used for the relative reduction in annualized rate of change in eGFR, 
with the exception that in absence of log10-transformation, 𝑅𝑅15, 𝑚𝑖 and 𝑠𝑖
2 are defined as: 
𝑅𝑅15 = (1 − 𝛽15
̂
 𝛽0
̂ ) × 100 
𝑚𝑖= 𝛽𝑖̂ 
𝑠𝑖
2 = 𝑉𝑎𝑟(𝛽𝑖̂) 
where 𝛽𝑖̂ is the slope of eGFR in arm i, estimated from the linear mixed-effect model. 
5.6.3 P-values from multiple comparison procedure   
As described in Section 4.3.1.2 , the overall effect of venglustat will be assessed using 3 pre-
specified contrasts Z1, Z2 and Z3. (corresponding to the contrasts associated with the candidate 
models Emax, linear and Sigmoid Emax). The test statistic Z is the maximum of Z1, Z2 and Z3. 
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Assuming the observed statistic is Zobs, the one-sided p-value from the Multiple Comparison 
Procedure can be defined as the probability that Z is greater than Zobs, under the null hypothesis. 
In the asymptotic case, random samples of Z under the null hypothesis can be generated using the 
SAS code below. 
The two-sided p-value will be defined as twice the one-sided p-value, and truncated to 1 in case 
the one-sided p-value is greater than 0.5. 
 
* Observed Z statistic; 
%let Zobs = 2.25; 
 
data pvalue; 
  * Initialization of seed ; 
  retain seed 15392; 
 
  * Initialize the number of samples with Z > Zobs; 
  Ngreater = 0; 
 
  * Generate 1000000 samples from the distribution of the Z statistic 
under the null hypothesis ; 
  do i=1 to 1000000; 
 
    * Generate independent normal for the 3 arms ; 
    call rannor(seed,u0); 
    call rannor(seed,u1); 
    call rannor(seed,u2); 
 
    * Calculate the 3 contrasts ; 
    Z1 = -0.8131*u0 + 0.3424*u1 + 0.4707*u2; 
    Z2 = -0.7223*u0 + 0.0314*u1 + 0.6909*u2; 
    Z3 = -0.6615*u0 - 0.0838*u1 + 0.7453*u2; 
 
    * Z-statistic : maximum of all contrasts ; 
    Z = Max(Z1,Z2,Z3); 
 
    * Increment the number of samples with Z > Zobs; 
    Ngreater = Ngreater + (Z > &Zobs); 
     
  end; 
 
  * One-sided pvalue ; 
  pvalue_onesided = Ngreater/1000000; 
 
  * Two-sided p-value ; 
  pvalue_twosided = min(2*pvalue_onesided,1); 
run; 
 
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6 
REFERENCES  
1. Hogan MC, Abebe K, Torres VE, Chapman AB, Bae KT, Tao C, et al. Liver involvement in 
early autosomal-dominant polycystic kidney disease. Clin Gastroenterol Hepatol. 
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2. Bornkamp B, Pinheiro J, Bretz F. DoseFinding: planning and analyzing dose finding 
experiments. [Online]. R package. 2019 [cited 2021 Jun 22]; Available from: 
URL:https://cran.r-project.org/web/packages/DoseFinding/DoseFinding.pdf 
3. Bretz F, Pinheiro JC, Branson M. Combining multiple comparisons and modeling techniques 
in dose-response studies. Biometrics. 2005;61(3):738‑48. 
4. Kammerman LA, Cappelleri J, Bartlett J. Patient-Reported outcomes. In: Wiley StatsRef: 
Statistics Reference Online. 2017. 
5. Sloan JA, Dueck AC, Erikson PA, Guess H, Revicki DA, Santanello NC, et al. Analysis and 
interpretation of results based on patient-reported outcomes. Value Health. 2007;10 Suppl 
2:S106-15. 
6. Bretz B, Maurer W, Brannath W, Posch M. A graphical approach to sequentially rejective 
multiple test procedures. Stat Med. 2009;28(4):586‑604. 
7. Oduntan OA, Mashige KP, Raliavhegwa-Makhado M. A comparison of two methods of 
logMAR visual acuity data scoring for statistical analysis. S Afr Optom. 2009;68(3):155-63. 
8. Van Hout B, Janssen MF, Feng YS, Kohlmann T, Busschbach J, Golicki D, et al. Interim 
scoring for the EQ-5D-5L: Mapping the EQ-5D-5L to EQ-5D-3L value sets. Value Health. 
2012;15(5):708-15. 
9. Irazabal M, Rangel L, Bergstralh E, Osborn S, Harmon AJ, Sundsbak JL, et al. Imaging 
classification of autosomal dominant polycystic kidney disease: A simple model for selecting 
patients for clinical trials. J Am Soc Nephrol. 2015;26(1):160-72. 
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