Clinical trial NCT03236311
Conditions: Microvascular Coronary Artery Disease
Sponsor: Sanofi
Start date: 2017-10-12; Completion date: 2018-07-23
Enrollment: 10 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary Objective:

To assess the effects of SAR407899 on coronary vasomotor function using the coronary flow reserve (CFR) in participants with microvascular angina (MVA) and/or persistent stable angina despite angiographically successful percutaneous coronary intervention (PCI).

Secondary Objectives:

* To assess the effects of SAR407899 on quality of life using Seattle Angina Questionnaire physical limitation scale (SAQ-PL) in participants with MVA and/or persistent stable angina despite angiographically successful PCI.
* To assess the safety of SAR407899 in participants with MVA and/or persistent stable angina despite angiographically successful PCI with a focus on identified risks such as hypotension and orthostatic hypotension.
* To assess SAR407899 plasma concentrations in MVA participants and/or persistent stable angina despite angiographically successful PCI.

Detailed description:
The total duration of study per participant was:

\- up to 9 weeks for participants with previous coronary artery angiography or coronary computed tomography angiography (CCTA) within 24 months prior to screening with up to 4 weeks screening period, 3 weeks titration phase, 1 week maintenance period, and 1 week follow-up after the last investigational medicinal product administration.

or

\- up to 11 weeks for participants with previous coronary artery angiography or CCTA between 24 months and 5 years prior to screening who need CCTA during screening period with up to 6 weeks screening period, 3 weeks titration phase, 1 week maintenance period, and 1 week follow-up after the last investigational medicinal product administration.

Arms: arm 1: Matching placebo for 4 weeks. arm 2: SAR407899 with dose titration over 4 weeks administration (3 week titration phase + 1 week maintenance phase).
Interventions: intervention 1: SAR407899 intervention 2: Placebo intervention 3: Adenosine intervention 4: Regadenoson intervention 5: 13N-ammonia intervention 6: 82Rubidium
Intervention descriptions: intervention 1: Pharmaceutical form: Capsule Route of administration: Oral intervention 2: Pharmaceutical form: Capsule Route of administration: Oral intervention 3: Pharmaceutical form: Solution for injection Route of administration: Intravenous intervention 4: Pharmaceutical form: Solution for injection Route of administration: Intravenous intervention 5: Pharmaceutical form: Solution for injection Route of administration: Intravenous intervention 6: Pharmaceutical form: Solution for injection Route of administration: Intravenous

Protocol documents:
Prot_000.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity
According to template: QSD-003152 VERSION N°3.0 (04-FEB-2016)
Page 1
AMENDED CLINICAL TRIAL PROTOCOL NO 03
COMPOUND: SAR407899
A randomized, double-blind, placebo-controlled parallel arm dose titration study to 
assess the effects of SAR407899 in patients with microvascular angina and/or 
persistent stable angina despite angiographically successful percutaneous 
coronary intervention
STUDY NUMBER: ACT14656
VERSION DATE / STATUS: Approval date (18-Apr-2018) / Approved
Protocol Amendment 04
Version number: 1 (electronic 1.0)
Date : 18-Apr-2018
Amended Clinical Trial Protocol 03 (local 
for Sweden)
Version number: 1 (electronic 3.0)
Date : 05-Dec-2017
Amended Clinical Trial Protocol 02
Version number: 1 (electronic 3.0)
Date : 05-Dec-2017
Protocol Amendment 03
Version number: 1 (electronic 2.0)
Date : 05-Dec-2017
Amended Clinical Trial Protocol 02 (local 
for Sweden)
Version number: 1 (electronic 1.0)
Date : 11-Sep-2017
Protocol Amendment 02 (local for Sweden)
Version number: 1 (electronic 1.0)
Date : 11-Sep-2017
Amended Clinical Trial Protocol 01
Version number: 1 (electronic 1.0)
Date : 31-Mar-2017
Protocol Amendment 01
Version number: 1 (electronic 1.0)
Date : 31-Mar-2017
Clinical Trial Protocol
Version number: 1 (electronic 1.0)
Date : 07-Jul-2016
Version Number:
1
EudraCT Number:
2016-000629-38
IND Number:
129855
WHO Universal Trial Number:
U1111-1182-1709
Date:
18-Apr-2018
Total number of pages:
108
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NCT Number: NCT03236311


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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:
To be filled in by each CSU participating in the 
study
SPONSOR
Company:
Address:
sanofi-aventis Recherche & Développement
1, Avenue Pierre Brossolette
91385 Chilly Mazarin - France
OTHER EMERGENCY 
TELEPHONE NUMBERS
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CLINICAL TRIAL SUMMARY
COMPOUND: SAR407899
STUDY No.: ACT14656
TITLE
A randomized, double-blind, placebo-controlled parallel arm dose 
titration study to assess the effects of SAR407899 in patients with 
microvascular angina and/or persistent stable angina despite 
angiographically successful percutaneous coronary intervention (PCI).
INVESTIGATOR/TRIAL LOCATION
Europe, Asia and US
PHASE OF DEVELOPMENT
Phase 2a
STUDY OBJECTIVE(S)
Primary objective:

Assess the effects of SAR407899 on coronary vasomotor 
function using coronary flow reserve (CFR) in patients with 
microvascular angina and/or persistent stable angina despite 
angiographically successful PCI.
Secondary objectives:

Assess the effects of SAR407899 on quality of life using 
SAQ-PL in patients with microvascular angina and/or 
persistent stable angina despite angiographically successful
PCI.

Assess the safety of SAR407899 in patients with 
microvascular angina and/or persistent stable angina despite 
angiographically successful PCI with a focus on identified 
risks such as hypotension and orthostatic hypotension.

Assess SAR407899 plasma concentrations in microvascular 
angina patients and/or persistent stable angina despite 
angiographically successful PCI.
STUDY DESIGN
A Phase 2a, multi-center, randomized with 1:1 ratio, double-blind, 
placebo-controlled parallel group study with weekly titration up to 
maintenance dose, based on individual patient tolerability, particularly 
symptomatic or asymptomatic blood pressure (BP) decreases.
STUDY POPULATION 
Male and female patients with microvascular angina and/or persistent 
stable angina despite angiographically successful PCI.
Main selection criteria
Main Inclusion criteria:

Male or female patient not at childbearing potential 
≥18 year-old or legal age of majority.

Female patient if she has undergone sterilization at least 
3 months earlier or is postmenopausal.
-
Post-menopausal status is defined by having no 
menses for 12 months without an alternative medical 
cause.
-
In females not treated with hormonal replacement 
therapy (HRT), menopausal status is confirmed by a 
high follicle stimulating hormone (FSH) level greater 
than 40 IU/L.
-
In females on HRT and whose menopausal status is in 
doubt (ie, in women aged less than 45 years), a highly 
effective contraception methods will be required.
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Contraception should be used during the whole study 
and for at least seven days corresponding to time 
needed to eliminate study treatment.

Symptomatic stable angina pectoris (typical or atypical 
symptoms with an average of at least bi-weekly episodes 
over the past month),

Patients with non-obstructive (<50% stenosis) coronary 
arteries or intermediate stenosis (between 50 and 70%) 
should have fractional flow reserve (FFR) >0.80 or
instantaneous wave-free ratio (iFR) >0.89 on angiogram 
documented within the previous 24 months*. In patients with 
stenting, a minimum diameter stenosis of <10% is required.
or
Coronary computed tomography angiography (CCTA) with 
finding of non-obstructive coronary arteries within the past 
24 months* in patients without previous PCI.
*Note: in cases of clinically suspected progression of 
atherosclerosis as per the Investigator, a more contemporary 
(ie, 6 months) evidence should be provided.
or
CCTA performed during screening period, with finding of non-
obstructive coronary arteries, in patients diagnosed with MVA 
and stable angina without previous PCI who did not have a 
coronary angiogram or CCTA in the previous 24 months but 
between 24 months to 5 years.

Baseline global CFR (measured during the study) assessed 
by 13N-ammonia or 82Rubidium PET scan <2.0.
Main Exclusion criteria:

Esophageal dysmotility or esophagitis.

Any use of nitrates (except short-acting nitrates) and/or 
dipyridamole and/or phosphodiesterase type 5 (PDE5) 
inhibitors within one week prior to baseline PET scan or 
anticipated to be used during the study.

Patients with acute coronary syndrome (ACS) [myocardial 
infarction (MI) and/or unstable angina] in previous 3 months.

Unsuccessful or incomplete coronary revascularization with 
residual obstructive stenosis or coronary artery disease
(CAD) progression in native vessels as documented on 
invasive coronary angiography (≥50% stenosis) within 
24 months of enrollment.

Patients with history of coronary artery bypass grafting 
(CABG).

Percutaneous coronary intervention performed at the time of 
an ACS (MI or unstable angina) in the previous 12 months.

Recent PCI within the past 3 months.

Contraindication to vasodilator stress PET scan and/or CCTA 
if CCTA needed during screening.

Regional local flow abnormal perfusion defects at baseline 
PET scan*.
*Note: if contemporary evidence with invasive coronary 
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angiography or CCTA demonstrates non-obstructive 
coronary arteries or if the regional local flow abnormal 
perfusion defect on PET scan is consistent with previous 
studies then patient qualifies for the study.

Recent (≤3 months) major surgery (ie, valvular surgery, 
surgery for congenital heart disease), stroke, transient 
ischemic attack (TIA), sustained ventricular arrhythmia, 
clinically significant structural heart disease (moderate-
severe valvular disease, hypertrophic cardiomyopathy, 
congenital heart disease, pulmonary hypertension).

Patients with cardiac conduction abnormalities (second or 
third degree atrioventricular [AV] block, sick sinus syndrome, 
symptomatic bradycardia, sinus node disease) except in 
patients fitted with a functioning pacemaker.

History or known carotid stenosis:
-
Carotid stenosis (>50%)
or
-
History of carotid stenosis in patients with previous 
symptoms.

Contraindication or known hypersensitivity to adenosine (or 
regadenoson).

Contraindication to aminophylline.

Inability to discontinue treatment with methylxanthines 
treatment within 24 hours prior to PET scan.

Patient unable to read, understand and fill a questionnaire 
without any help (eg, partially visually impaired or blind).

Systolic Blood Pressure (SBP) <110 mmHg at baseline.

Presence at baseline of symptomatic orthostatic 
hypotension (SBP decrease of 20 mmHg or more at Minute 3 
or Minute 5 between seated and standing position), or 
asymptomatic orthostatic hypotension with a decrease in 
SBP equal or greater than 30 mmHg at Minute 3 or Minute 5 
when changing from the seated to the standing position.

Renal impairment [estimated glomerular filtration rate (eGFR)
<50 milliliter (mL)/min/1.73m2 at screening and baseline].

Drug-induced liver injury related criteria: 
-
Underlying hepatobiliary disease,
-
ALT >3 times the upper limit of normal (ULN).
Total expected number of patients:
78 patients to be randomized (39 per arm).
Expected number of sites:
Approximately 20 sites.
Stratification on the presence of angiographically successful PCI 
(YES/NO) will be performed.
STUDY TREATMENT(s)
Investigational medicinal product(s)
SAR407899, 2.5 mg and 5mg capsules.
SAR407899 matching placebo.
Formulation:
Capsules.
Route(s) of administration:
Oral administration, twice per day: in the morning and at bedtime.
Dose may be taken with or without food as per preference of the 
patient.
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Dose regimen:
Starting dose: 
.
Individual dose titration based on BP tolerability at scheduled visits 
with the following rules:

 
if well tolerated over a period of 3 weeks followed
by a maintenance period of 1 week (total duration of treatment 
4 weeks including titration).
 
 
 
 
 
 
 

If 
 dose is not tolerated, the study drug will be 
discontinued.
Stopping criterion based on creatinine level:

Stop study drug if creatinine blood level >150 µmol/L and 
increase from baseline >30%.
. When 
19 patients will have completed first week after randomization, the 
Data Monitoring Committee (DMC) will review the clinical safety data 
including adverse events of special interests (AESIs). During the safety 
evaluation of the first 19 enrolled patients, these patients will continue 
to receive IMPs as per the titration schedule described above and 
enrolment will continue.
Non investigational medicinal product(s)

PET radiopharmaceuticals (13N-ammonia and 82Rubidium).

Vasodilator stressors (adenosine and regadenoson).
The NIMPs for PET scan should be used according to their approved 
labeling.
ENDPOINTS
Primary efficacy endpoint:

Change from baseline to Week 4 in uncorrected global CFR
assessed by 13N-ammonia or 82Rubidium PET scan.
Secondary efficacy endpoint:

Change from baseline to Week 4 on angina-induced physical 
limitation using SAQ-PL (disease-specific health-related 
quality of life).
Exploratory endpoints:

Rate of diary angina episodes at baseline and Week 4

Rate of diary angina episodes requiring use of short-acting 
nitrates at baseline and Week 4

Change from baseline to Week 4 in the other dimensions of 
the SAQ.

Change from baseline to Week 4 in the SAQ-7 score.

Patients’ perceptions of treatment and symptoms assessed 
at baseline and Week 4.
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Safety:

Adverse events (AEs) / treatment-emergent adverse events 
(TEAEs).

Blood pressure and orthostatic blood pressure.

Blood creatinine and cystatin C.
Pharmacokinetics:

Peak and trough SAR407899 concentrations at specific time 
points.
ASSESSMENT SCHEDULE
Coronary Flow Reserve assessed by 13N-ammonia or 82Rubidium PET 
scan and SAQ will be assessed at baseline and the end of Week 4.
Safety will be monitored during the whole study with special focus on 
BP and renal function (creatinine and Cystatin C).
Pharmacokinetics: sparse sampling will be performed on Day 1 at 
1 hour and 3 hour post-dosing, pre-dose on Day 8, Day 15 and 
Day 22, and pre-dose and in the 1-3 hour interval post-dose on 
Day 29.
Number of angina episodes and short acting NTG intake per week 
using a diary from baseline to Week 4.
STATISTICAL CONSIDERATIONS
Sample size determination:
Estimated as 78 patients (39 per group). Based on a large study of 
2783 patients referred for rest/stress PET (1) which suggested a SD of 
0.65 for CFR at baseline. Under the hypothesis of a correlation of 
0.6 between baseline assessment and week 4-assessment the SD for 
the change from baseline to Week 4 could be estimated at 0.58.
35 patients per group will be needed to detect with 1 sided test alpha 
0.05 and 80% power, a clinically significant relevant difference versus 
placebo of 0.35 in the change from baseline in PET CFR to Week 4. 
To reach this number of patients 78 patients need to be included in this 
study with the hypothesis of 10% inevaluable.  
Analysis population:
The efficacy population will be the modified intend-to-treat population, 
defined as all randomized patients analyzed according to the treatment 
group allocated by randomization, receiving at least one dose or part of 
a dose of the investigational medicinal product and having a baseline  
PET scan CFR assessment available.
The safety population will include all randomized patients who received 
at least one dose or part of a dose of the IMP. In the safety analysis, 
patients will be analyzed in the treatment group as actually received.
Primary analysis: efficacy analyses will be performed on ITT 
population.
The change in CFR from baseline to week 4 will be analyzed using an 
ANCOVA model. The model will include the two fixed categorical effect 
of treatment group (pooled SAR407899 doses versus placebo) and of 
the presence of angiographically successful PCI (YES/NO) as well as 
a continuous fixed covariate of baseline CFR. The corresponding 
interaction of order two will be also included in the model.
The final model will provide adjusted least-squares means (LS means) 
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estimates of the change from baseline to Week 4 in both treatment 
groups and their corresponding 95% confidence intervals. The 
difference of these estimates will be tested at the 5% 1-sided alpha 
level and the 95% confidence interval of the difference will be provided.
To evaluate the impact of missing values on treatment effect 
estimation, a multiple imputation method will be used. 
Analysis of the key secondary endpoint:
The secondary analysis will use a similar model as primary analysis 
applied to the change from baseline to Week 4 in SAQ PL.  The final 
model will provide adjusted least-squares means (LS means) 
estimates of the change from baseline to Week 4 in both treatment 
groups and their corresponding 95% confidence intervals. The 
difference of these estimates will be tested at the 
10% 1-sided alpha level and the 95% confidence interval of the 
difference will be provided. 
A safety review with a DMC meeting will start as soon as the first 
19 patients will have been randomized and have finished the first week 
of treatment. Additional analyses for safety may be performed in this 
study.
Safety analysis: 
Safety analyses will be descriptive, based on the safety population with 
a focus on BP, creatinine and cystatin C.
The safety analysis will focus on the TEAE period. This period is 
defined as the time from the first administration of the IMP to the last 
administration of the IMP +5 times the half-life. The half-life being from 
20 to 31 hours depending on the age of the patients, a conservative 
estimate of 31 hours is used for all patients (thus 5 times the half-life 
corresponds to 5 times 31 hours ie, approximately 7 days).
Pharmacokinetic analysis:
Descriptive statistics will be provided by SAR407899 dose and 
time-point for observed concentrations.
Pharmacokinetic/pharmacodynamic analysis:
Scatter plots of concentrations versus primary/secondary endpoints will 
be provided. If relevant, some models will be provided to fit the 
relationship between concentrations and endpoint(s).
DURATION OF STUDY PERIOD (per patient) 
Screening: up to 4 weeks before the first dosing (Day -28 to Day -
1) and up to 6 weeks in patients diagnosed with MVA and stable 
angina without previous PCI who did not have a coronary artery 
angiography or CCTA in the previous 24 months but between 24 
months and 5 years prior to screening and requiring CCTA in this 
screening period.

Titration phase: 3 weeks.

Maintenance phase: 1 week.

Total duration of treatment: 4 weeks (including titration).

Follow-up: 1 week.

Total study duration: 9 weeks (+/- 2 days) and up to 11 weeks (+/-
2 days) in patients requiring CCTA in screening period.
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1
FLOW CHARTS
1.1
GRAPHICAL STUDY DESIGN
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1.2
POTENTIAL TITRATION SCHEDULES & DECISION RULES STUDY
In case a patient does not tolerate a dose, he/she call the investigator to have an on-site visit. Based on the tolerability assessed at this visit, the investigator could decide to stop or modify study drug dose.
Dose titration based on BP tolerability at visits as per Section 9.2.4.3 with the following recommendations:
 
Stopping criterion based on creatinine level: 

Stop study drug if creatinine blood level >150 μmol/L and increase from baseline >30%. In specific circumstances where creatinine blood level can be obtained only in the afternoon the day of the visit, the 
patient will be titrated according to titration scheme and if creatinine blood level meets stopping rules, the investigator will need to contact the patient before bedtime study drug intake as study drug should 
be permanently discontinued and a premature study drug discontinuation visit will be planned as per Section 8.1.1.
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1.3
STUDY FLOW CHARTS
1.3.1
Study flow chart for patients with previous coronary artery angiography or CCTA within 24 months prior to screening
Phase
Screening
Titration Phase
Maintenance 
Phase
End-of-study
D-28 to D-1
D1
(see separate 
flow chart for this 
visit)
D8
(+/-2days)
D15
(+/-2days)
D22
(+/-2days)
D29
(+2days)
EOT/early 
discontinuation
D36
(+/-2days)
Informed consent 
X
Visit at clinical site
X
Xa
X
X
X
Xa
X
Data of previous coronary artery angiography  
or CCTA
Xb
Inclusion/exclusion criteria
X
X
Medical/surgical history
X
Prior/concomitant medicationsc
<---
----
----
----
----
----
--->
IVRS/IWRS
Xo
Xp
Xp
Xp
Xp
X
Randomization
X
IMP administrationd
<---
----
----
----
--->
IMP dispensation
X
X
X
X
Xq
Safety
Physical examination
X
X
X
Height
X
Body weight
X
X
X
Vital signse (including search for  orthostatic 
BP), ECGs
X
Xf,g
Xf
Xf
Xf
Xf,g
X
Body temperature
X
X
Hematology, biochemistry, urinalysis
X
X
Xs
Xns
Xns
X
Xs
Renal function (blood  creatinine and cystatin
C)
X
X
X
X
X
X
X
Plasma FSHm
X
Adverse event collection
<---
----
----
----
----
----
--->
Pharmacodynamics
Data of previous CFR assessment whatever 
the method
Xb
CFR assessed by vasodilator stress PET 
Xi
Xi
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Phase
Screening
Titration Phase
Maintenance 
Phase
End-of-study
D-28 to D-1
D1
(see separate 
flow chart for this 
visit)
D8
(+/-2days)
D15
(+/-2days)
D22
(+/-2days)
D29
(+2days)
EOT/early 
discontinuation
D36
(+/-2days)
scanh
NIMP administration
X i,r
Xr
Patient’s diary dispensation and/or review 
(angina episodes and short-acting 
nitroglycerin intakes)
X
X
X
X
X
X
X
SAQj
X
X
Resources Utilizationk
X
Patients’ perception of treatment and 
symptomsj
X
X
Pharmacokinetics
SAR407899 pharmacokinetic plasma 
samples
Xl
Xl
Xl
Xl
Xl
DNA
Pharmacogenetic DNA sample
X
Biomarkers
Blood samples for 
 and 
X
Future use of samples
Blood sample if specific consent signed
X
ECG = electrocardiogram; EOT = End of Treatment; FSH = follicle-stimulating hormone; IMP = investigational medicinal product; CCTA: Coronary Computed Tomography Angiography.
a
Whole day stay due to assessment duration process.
b
If assessment done within 24 months prior to screening.
c
Concomitant medication (if those are not allowed during the study, see exclusion criterion 3 in Section 7.2.1) needs to be stopped 1 week before baseline CFR assessed by PET scan and during the whole study.
d
Capsules in the morning and at bedtime. If PET assessment on Day 29 no administration at bedtime. If PET assessment delayed, last IMP administration should be done in the morning of the PET assessment.
e
Vital signs: BP & heart rate measurements including search of hypotension (orthostatic or not).
f
Before morning administration, vital signs should be assessed by the investigator or designee except on Day 1 which requires before morning administration, at T1H and T3H. For any safety reasons additional 
physical examination, vital signs, ECG may be performed at the investigator’s discretion.
g
At Day 1 & Day 29 PET assessments, continuous monitoring of heart rate, BP and ECG should be performed throughout the stressor infusion.
h
Restriction rules for CFR assessed by vasodilator stress PET scan (detailed in Section 10.1.2 and Section 10.1.4) to follow.
i
On Day 1 (or, if not otherwise possible, up to 14 days prior to Day 1) CFR assessed by vasodilator stress PET scan should be performed before the IMP administration. On Day 29 or up to 2 days after (if not 
otherwise possible) CFR assessed by vasodilator stress PET scan should be performed approximately 1 to 2 hours after morning IMP intake. Prior to baseline PET assessment (on day 1 or up to 14 days prior to 
day 1), the eligibility criteria must be carefully reviewed (including review of the screening labs), and if the patient no longer qualifies for the study, then he/she should not undergo the PET assessment.
j
To be completed before any other assessment and without any help.
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k
Health care resources will include number of out-patients visits by type physician (specialists, general practitioner, other) and impact on working status.
l
Two PK samplings on Day 1 (1h and 3 h post-dose), one PK sampling (pre-dose) at Day 8, Day 15 and Day 22, two PK samplings on Day 29 (pre-dose and 1-3 hours post-dose). The patient will have to come at 
the site without having taken his morning dose of IMP if the visit occurs in the morning.
m Only in post-menopausal female patient not receiving hormone replacement therapy.
n
Except hematology.
o
To assign patient number.
p
To obtain the treatment number after specifying the chosen titration.
q
Only if not enough IMP for PET scan scheduled on Day 30 or Day 31.
r
Only for PET scan.
s
Except urinalysis.
1.3.2
Study flow chart for patients diagnosed with MVA and stable angina without previous PCI and with previous coronary artery 
angiography or CCTA between 24 months and 5 years prior to screening, who need CCTA during screening period
Phase
Screening
Titration Phase
Maintenance 
Phase
End-of-study
Up to 6 weeks
D-42 to D-1
D1
(see separate 
flow chart for this 
visit)
D8
(+/-2days)
D15
(+/-2days)
D22
(+/-2days)
D29
(+2days)
EOT/early 
discontinuation
D36
(+/-2days)
Informed consent 
X
Visit at clinical site
X
Xa
X
X
X
Xa
X
Data of previous coronary artery angiography 
or CCTA
Xb
CCTA
Xs
Inclusion/exclusion criteria
X
X
Medical/surgical history
X
Prior/concomitant medicationsc
<---
----
----
----
----
----
--->
IVRS/IWRS
Xo
Xp
Xp
Xp
Xp
X
Randomization
X
IMP administrationd
<---
----
----
----
--->
IMP dispensation
X
X
X
X
Xq
Safety
Physical examination
X
X
X
Height
X
Body weight
X
X
X
Vital signse (including search for  orthostatic 
X
Xf,g
Xf
Xf
Xf
Xf,g
X
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Phase
Screening
Titration Phase
Maintenance 
Phase
End-of-study
Up to 6 weeks
D-42 to D-1
D1
(see separate 
flow chart for this 
visit)
D8
(+/-2days)
D15
(+/-2days)
D22
(+/-2days)
D29
(+2days)
EOT/early 
discontinuation
D36
(+/-2days)
BP), ECGs
Body temperature
X
X
Hematology, biochemistry, urinalysis
X
X
Xt
Xnt
Xnt
X
Xt
Renal function (blood  creatinine and cystatin
C)
X
X
X
X
X
X
X
Plasma FSHm
X
Adverse event collection
<---
----
----
----
----
----
--->
Pharmacodynamics
Data of previous CFR assessment whatever 
the method
Xu
CFR assessed by vasodilator stress PET 
scanh
Xi
Xi
NIMP administration
Xr
Xr
Patient’s diary dispensation and/or review 
(angina episodes and short-acting 
nitroglycerin intakes)
X
X
X
X
X
X
X
SAQj
X
X
Resources Utilizationk
X
Patients’ perception of treatment and 
symptomsj
X
X
Pharmacokinetics
SAR407899 pharmacokinetic plasma 
samples
Xl
Xl
Xl
Xl
Xl
DNA
Pharmacogenetic DNA sample
X
Biomarkers
Blood samples for 
 and 
X
Future use of samples
Blood sample if specific consent signed
X
ECG = electrocardiogram; EOT = End of Treatment; FSH = follicle-stimulating hormone; IMP = investigational medicinal product; CCTA: Coronary Computed Tomography Angiography.
a
Whole day stay due to assessment duration process.
b
If assessment done between 24 months and 5 years prior to screening.
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c
Concomitant medication (if those are not allowed during the study, see exclusion criterion 3 in Section 7.2.1) needs to be stopped 1 week before baseline CFR assessed by PET scan and during the whole study.
d
Capsules in the morning and at bedtime. If PET assessment on Day 29 no administration at bedtime. If PET assessment delayed, last IMP administration should be done in the morning of the PET assessment.
e
Vital signs: BP & heart rate measurements including search of hypotension (orthostatic or not).
f
Before morning administration, vital signs should be assessed by the investigator or designee except on Day 1 which requires before morning administration, at T1H and T3H. For any safety reasons additional 
physical examination, vital signs, ECG may be performed at the investigator’s discretion.
g
At Day 1 & Day 29 PET assessments, continuous monitoring of heart rate, BP and ECG should be performed throughout the stressor infusion.
h
Restriction rules for CFR assessed by vasodilator stress PET scan (detailed in Section 10.1.2 and Section 10.1.4) to follow.
i
Up to 4 weeks before Day 1, CFR assessed by vasodilator stress PET scan should be performed before the IMP administration. On Day 29 or up to 2 days after (if not otherwise possible) CFR assessed by 
vasodilator stress PET scan should be performed approximately 1 to 2 hours after morning IMP intake. Prior to baseline PET assessment, the eligibility criteria must be carefully reviewed (including review of the 
screening labs), and if the patient no longer qualifies for the study, then he/she should not undergo the PET assessment or CCTA. 
j
To be completed before any other assessment and without any help.
k
Health care resources will include number of out-patients visits by type physician (specialists, general practitioner, other) and impact on working status.
l
Two PK samplings on Day 1 (1h and 3 h post-dose), one PK sampling (pre-dose) at Day 8, Day 15 and Day 22, two PK samplings on Day 29 (pre-dose and 1-3 hours post-dose). The patient will have to come at 
the site without having taken his morning dose of IMP if the visit occurs in the morning.
m Only in post-menopausal female patient not receiving hormone replacement therapy.
n
Except hematology.
o
To assign patient number.
p
To obtain the treatment number after specifying the chosen titration.
q
Only if not enough IMP for PET scan scheduled on Day 30 or Day 31.
r
Only for PET scan.
s
CCTA after PET scan (if CFR <2.0) in order to have CCTA results available for inclusion.
t
Except urinalysis.
u
If assessment done within 24 months prior to screening.
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1.4
DAY 1 FLOW CHART
1.4.1
Flow chart with PET scan on Day 1 (not applicable for patients diagnosed with MVA and stable angina without previous PCI and 
with previous coronary artery angiography or CCTA between 24 months and 5 years prior to screening, who need CCTA during 
screening period)
Day
D1
Time (hour/minute)a
-4H
-3H
-2H30
-0H30 
0H
1H
3H
Visit start
X
End of visit
Xi
Concomitant medicationsb
----------------------------------------------------------------------------------------------------------------------------------------
SAQ 
X
Resources Utilization
X
Patients’ perception of treatment and symptoms 
X
Patient’s diary
---------------------------------------------------------------------------------------------------------------------------------------
Inclusion/Exclusion criteria
X
X
CFR assessed by vasodilator stress PET scanc
Xd
NIMP administration
Xh
IVRS/IWRS
X
Randomization
X
IMP administration
X
Safetye
Physical examination
X
Body temperature
X
Body weight
X
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Day
D1
Time (hour/minute)a
-4H
-3H
-2H30
-0H30 
0H
1H
3H
Vital signsg, 12 lead-ECGf
X
X
X
X
Hematology, biochemistry, urinalysis
X
Renal function (blood creatininej, and cystatin C)
X
Adverse event collection
--------------------------------------------------------------------------------------------------------------------------------------
Pharmacokinetics
SAR407899 plasma samples
X
X
DNA
Pharmacogenetic DNA sample
X
Biomarkers
Blood samples for 
 and 
X
Future use of samples
Blood sample if specific consent signed
X
DME = drug metabolizing enzymes; ECG = electrocardiogram; IMP = investigational medicinal product.
Note: when several items take place at the same time, the following order should be respected: questionnaires, ECG, vital signs, blood sampling, pharmacodynamics, drug administration, meal.
In order to respect exact timing of pharmacokinetic samples, the other measures will be done ahead of the scheduled time.
a
Time (hour/minute) is expressed in reference to the first administration of SAR407899 (T0H). The times expressed prior to T0H are approximate.
b
Concomitant medication (if those are not allowed during the study, see exclusion criterion 3 in Section 7.2.1) needs to be stopped 1 week before CFR assessed by PET scan. 
c
Restriction rules for CFR assessed by vasodilator stress PET scan (detailed in Section 10.1.2) to follow.
d
Prior to the Day 1 PET assessment, the eligibility criteria must be carefully reviewed (including review of the screening labs), and if the patient no longer qualifies for the study, then he/she should not undergo the 
PET assessment.
e
Refer to Safety Section 9.2 for detailed safety investigations.
f
Vital signs should be performed by the investigator or designee. Continuous monitoring of heart rate, BP and 12-lead ECG should be performed throughout the stressor infusion.
g
Vital signs: BP & heart rate measurements including search of hypotension (orthostatic or not).
h
Only for PET scan.
i
The patient may be discharged later on Day 1 to guarantee patient’s safety based upon the opinion of the Investigator.
j
Mandatory to check criterion E 25. Alternatively for practical reasons, blood creatinine results should be obtained within 2 days prior to Day 1 to check the exclusion criterion E25.
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1.4.2
Flow chart with PET scan prior to Day 1
This flow chart is displayed as follows:
-
PET scan up to 28 days if patient with MVA and stable angina without previous PCI and with previous coronary artery angiography or
CCTA between 24 months and 5 years prior to screening
-
or PET scan up to 14 days prior to D1 if previous coronary artery angiography or CCTA within 24 months prior to screening
Day
PET scan up to 28 days or up to 
14 days
D1
Time (hour/minute)a
Prior dosing
0H
1H
3H
Visit start
X
X
End of visit
X
Xi
Concomitant medicationsb
----------------------------------------------------------------------------------------------------------------------------------------------------------------
SAQ 
X
Resources Utilization
X
Patients’ perception of treatment and 
symptoms 
X
Patient’s diary
----------------------------------------------------------------------------------------------------------------------------------------------------------------
Inclusion/Exclusion criteria
X
X
CFR assessed by vasodilator stress 
PET scanc,f
Xd
NIMP administration
Xh
IVRS/IWRS
X
Randomization
X
IMP administration
X
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Day
PET scan up to 28 days or up to 
14 days
D1
Time (hour/minute)a
Prior dosing
0H
1H
3H
Safetye
Physical examination
X
Body temperature
X
Body weight
X
Vital signsg, 12 lead-ECGf
Xk
X
X
Hematology, biochemistry, urinalysis
X
Renal function (blood creatininej, and 
cystatin C)
X
Adverse event collection
----------------------------------------------------------------------------------------------------------------------------------------------------------------
Pharmacokinetics
SAR407899 plasma samples
X
X
DNA
Pharmacogenetic DNA sample
X
Biomarkers
Blood samples for 
 and 
X
Future use of samples
Blood sample if specific consent 
signed
X
DME = drug metabolizing enzymes; ECG = electrocardiogram; IMP = investigational medicinal product.
Note: when several items take place at the same time, the following order should be respected: questionnaires, pharmacodynamics, ECG, vital signs, blood sampling, drug administration, meal.
In order to respect exact timing of pharmacokinetic samples, the other measures will be done ahead of the scheduled time.
a
Time (hour/minute) is expressed in reference to the first administration of SAR407899 (T0H). Prior dosing at the arrival on site, if it takes eg. 3 hours to get creatinine result after the blood sampling, to check that 
the patients do not meet the exclusion criterion E25, vital signs and 12-lead ECG may have to be repeated closer before dosing. Otherwise, blood creatinine result may be obtained within 2 days prior to Day 1.
b
Concomitant medication (if those are not allowed during the study, see exclusion criterion 3 in Section 7.2.1) needs to be stopped 1 week before CFR assessed by PET scan. 
c
Restriction rules for CFR assessed by vasodilator stress PET scan (detailed in Section 10.1.2) to follow.
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d
Prior to the PET assessment, the available eligibility criteria must be carefully reviewed (including review of the screening labs), and if the patient no longer qualifies for the study, then he/she should not undergo 
the PET assessment.
e
Refer to Safety Section 9.2 for detailed safety investigations.
f
Vital signs should be performed by the investigator or designee. Continuous monitoring of heart rate, BP and 12-lead ECG should be performed throughout the stressor infusion.
g
Vital signs: BP & heart rate measurements including search of hypotension (orthostatic or not).
h
Only for PET scan.
i
The patient may be discharged later on Day 1 to guarantee patient's safety based upon the opinion of the Investigator.
j
Mandatory before dosing to check criterion E 25.
k
To be repeated as close as possible and before to the study drug administration if the turnaround time to get the results of creatinine before dosing is approximately 3 hours.
1.5
DAY 29 FLOW CHART SUGGESTED TIME FRAME (CAN BE ADAPTED BY SITE)
Day
D29
Time (hour/minute)a
At arrival 
at the site
0H Study 
drug intake
1H
2H
3H before 
leaving 
the site
Additional hours 
at Investigator’s 
discretion
Visit start
X
End of visit
Xi
Concomitant medications
--------------------------------------------------------------------------------------------------------------------
SAQ 
X
Patients’ perception of treatment and symptoms 
X
Patient’s diary
--------------------------------------------------------------------------------------------------------------------
IMP administration
Xg
CFR assessed by vasodilator stress PET scanb, e
Xc
NIMP administration
Xh
Safetyd
Physical examination
X
Body temperature
X
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Day
D29
Time (hour/minute)a
At arrival 
at the site
0H Study 
drug intake
1H
2H
3H before 
leaving 
the site
Additional hours 
at Investigator’s 
discretion
Body weight
X
Vital signsf, 12 lead-ECGe
X
Hematology, biochemistry, urinalysis, 
X
Renal function (blood creatinine and cystatin C)
X
Adverse event collection
--------------------------------------------------------------------------------------------------------------------
Pharmacokinetics
SAR407899 plasma samples
X
Xj
DME = drug metabolizing enzymes; ECG = electrocardiogram; IMP = investigational medicinal product.
Note: when several items take place at the same time, the following order should be respected: questionnaires, ECG, vital signs, blood sampling, drug administration, pharmacodynamics, meal.
In order to respect exact timing of pharmacokinetic samples, the other measures will be done ahead of the scheduled time.
a
Time (hour/minute) is expressed in reference to the last administration of SAR407899 (T0H).
b
Restriction rules for CFR assessed by vasodilator stress PET scan (detailed in Section 10.1.4) to follow.
c
On Day 29 or up to 2 days after (at the latest if not otherwise possible) CFR assessed by vasodilator stress PET scan should be performed approximately 1 to 2 hours after morning IMP intake.
d
Refer to Safety section for detailed safety investigations.
e
Vital signs should be performed by the investigator or designee. Continuous monitoring of heart rate, BP and 12-lead ECG should be performed throughout the stressor infusion.
f
Vital signs: BP & Heart rate measurements including search of hypotension (orthostatic or not). 
g
IMP administration should be continued until the day of the CFR assessment by vasodilator PET scan.
h
Only for PET scan.
i
Based on Investigator’s judgement, the patient may be discharged later for safety reasons.
j
To be performed 1 to 3 hours after dosing.
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2
TABLE OF CONTENTS
1
FLOW CHARTS...............................................................................................................................9
1.1
GRAPHICAL STUDY DESIGN ........................................................................................................9
1.2
POTENTIAL TITRATION SCHEDULES & DECISION RULES STUDY........................................10
1.3
STUDY FLOW CHARTS................................................................................................................11
1.3.1
Study flow chart for patients with previous coronary artery angiography or CCTA within 24 
months prior to screening ..............................................................................................................11
1.3.2
Study flow chart for patients diagnosed with MVA and stable angina without previous PCI 
and with previous coronary artery angiography or CCTA between 24 months and 5 years 
prior to screening, who need CCTA during screening period........................................................13
1.4
DAY 1 FLOW CHART....................................................................................................................16
1.4.1
Flow chart with PET scan on Day 1 (not applicable for patients diagnosed with MVA and 
stable angina without previous PCI and with previous coronary artery angiography or 
CCTA between 24 months and 5 years prior to screening, who need CCTA during 
screening period) ...........................................................................................................................16
1.4.2
Flow chart with PET scan prior to Day 1........................................................................................18
1.5
DAY 29 FLOW CHART SUGGESTED TIME FRAME (CAN BE ADAPTED BY SITE).................20
2
TABLE OF CONTENTS ................................................................................................................22
2.1
LIST OF TABLES...........................................................................................................................27
2.2
LIST OF FIGURES.........................................................................................................................27
3
LIST OF ABBREVIATIONS ..........................................................................................................28
4
INTRODUCTION AND RATIONALE.............................................................................................30
4.1
GENERAL BACKGROUND ...........................................................................................................30
4.1.1
Background on patient population .................................................................................................30
4.1.1.1
Patients with persistent angina despite angiographically successful PCI .....................................30
4.1.1.2
Patients with microvascular angina (MVA) ....................................................................................30
4.1.1.3
Pathophysiology and purported beneficial mechanism of Rho-Kinase inhibition: .........................30
4.2
BACKGROUND ON SAR407899 ..................................................................................................32
4.3
RATIONALE FOR THE STUDY.....................................................................................................32
4.4
DESIGN RATIONALE AND RISK ASSESSMENT........................................................................32
5
STUDY OBJECTIVES ...................................................................................................................36
5.1
PRIMARY.......................................................................................................................................36
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5.2
SECONDARY ................................................................................................................................36
6
STUDY DESIGN ............................................................................................................................37
6.1
DESCRIPTION OF THE STUDY...................................................................................................37
6.2
DURATION OF STUDY PARTICIPATION ....................................................................................37
6.2.1
Duration of study participation for each patient .............................................................................37
6.2.2
Determination of end of clinical trial (all patients) ..........................................................................37
6.3
INTERIM ANALYSIS......................................................................................................................37
6.4
STUDY COMMITTEES..................................................................................................................38
6.4.1
Data Monitoring Committee ...........................................................................................................38
7
SELECTION OF PATIENTS..........................................................................................................39
7.1
INCLUSION CRITERIA..................................................................................................................39
7.2
EXCLUSION CRITERIA ................................................................................................................40
7.2.1
Exclusion criteria related to study methodology ............................................................................40
7.2.2
Additional exclusion criteria during or at the end of screening before randomization ...................42
8
STUDY TREATMENTS .................................................................................................................43
8.1
INVESTIGATIONAL MEDICINAL PRODUCT(S) / NON INVESTIGATIONAL MEDICINAL 
PRODUCT(S).................................................................................................................................43
8.1.1
INVESTIGATIONAL MEDICINAL PRODUCT(S) ..........................................................................43
8.1.2
NON INVESTIGATIONAL MEDICINAL PRODUCT(S) .................................................................44
8.1.2.1
13N-ammonia and 82Rubidium........................................................................................................44
8.1.2.2
Adenosine and regadenoson.........................................................................................................44
8.2
BLINDING PROCEDURES............................................................................................................44
8.2.1
Methods of blinding........................................................................................................................44
8.2.2
Randomization code breaking during the study.............................................................................44
8.3
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP ..............................................45
8.4
PACKAGING AND LABELING ......................................................................................................45
8.5
STORAGE CONDITIONS AND SHELF LIFE................................................................................46
8.6
RESPONSIBILITIES ......................................................................................................................46
8.6.1
Treatment accountability and compliance......................................................................................46
8.6.2
Return and/or destruction of treatments ........................................................................................47
8.7
CONCOMITANT MEDICATION.....................................................................................................47
9
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ..............................................49
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9.1
EFFICACY ENDPOINTS ...............................................................................................................49
9.1.1
Primary efficacy endpoint...............................................................................................................49
9.1.2
Secondary efficacy endpoint..........................................................................................................49
9.1.3
Exploratory endpoints ....................................................................................................................49
9.1.4
Assessment methods and activity parameters ..............................................................................49
9.1.4.1
13N-ammonia or 82Rubidium PET scan ..........................................................................................49
9.1.4.2
Analysis of rest and stress myocardial perfusion PET images......................................................50
9.1.4.3
Angina episodes and short-acting nitrates:....................................................................................51
9.1.4.4
Patient Reported Outcomes...........................................................................................................51
9.1.4.5
Coronary computed tomography angiography ..............................................................................53
9.2
SAFETY ENDPOINTS ...................................................................................................................53
9.2.1
Adverse events ..............................................................................................................................53
9.2.2
Physical examination .....................................................................................................................53
9.2.3
Laboratory safety variables............................................................................................................54
9.2.4
Vital signs.......................................................................................................................................54
9.2.4.1
Technical aspects ..........................................................................................................................54
9.2.4.2
Screening visit (determination of reference arm)...........................................................................55
9.2.4.3
Measurements for assessing presence or not of orthostatic hypotension.....................................55
9.2.5
Electrocardiogram variables ..........................................................................................................55
9.3
PHARMACOKINETIC ENDPOINT ................................................................................................56
9.3.1
Pharmacokinetics...........................................................................................................................56
9.3.1.1
Sampling time ................................................................................................................................56
9.3.1.2
Pharmacokinetics handling procedure...........................................................................................56
9.3.1.3
Bioanalytical method......................................................................................................................56
9.3.1.4
Pharmacokinetics parameters .......................................................................................................57
9.3.2
Pharmacogenetic assessment.......................................................................................................57
9.3.2.1
Drug metabolizing enzymes DNA sample .....................................................................................57
9.3.2.2
Optional stored DNA sample .........................................................................................................57
9.4
BIOMARKER ENDPOINTS ...........................................................................................................57
9.4.1
Sampling / handling procedures ....................................................................................................58
9.4.2
Biomarker assay methods .............................................................................................................58
9.5
FUTURE USE OF SAMPLES FOR BIOMARKER SAMPLES ......................................................58
9.6
SAMPLE BLOOD VOLUME...........................................................................................................59
9.7
APPROPRIATENESS OF MEASUREMENTS ..............................................................................59
10
STUDY PROCEDURES ................................................................................................................61
10.1
VISIT SCHEDULE..........................................................................................................................61
10.1.1
Visit 0: Screening visit....................................................................................................................61
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10.1.2
Visit 1: Baseline / Randomization / Day 1......................................................................................62
10.1.3
Visits 2, 3, and 4: Days 8, 15, and 22 (+/- 2 days).........................................................................65
10.1.4
Visit 5: End of treatment: Day 29 (or up to 2 days after at the latest) even in case of early 
IMP discontinuation........................................................................................................................65
10.1.5
Visit 6: End of study: Day 36 (+/- 2 days) ......................................................................................67
10.2
DEFINITION OF SOURCE DATA..................................................................................................67
10.3
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION.......................................68
10.3.1
Temporary treatment discontinuation with investigational medicinal product(s) ...........................68
10.3.2
Permanent treatment discontinuation with investigational medicinal product(s) ...........................68
10.3.3
Handling of patients after permanent treatment discontinuation ...................................................69
10.3.4
Procedure and consequence for patient withdrawal from study....................................................70
10.4
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ..........................70
10.4.1
Definitions of adverse events.........................................................................................................70
10.4.1.1 Adverse event ................................................................................................................................70
10.4.1.2 Serious adverse event ...................................................................................................................71
10.4.1.3 Adverse event of special interest...................................................................................................72
10.4.2
Serious adverse events waived from expedited regulatory reporting to regulatory 
authorities.......................................................................................................................................73
10.4.3
General guidelines for reporting adverse events ...........................................................................73
10.4.4
Instructions for reporting serious adverse events ..........................................................................73
10.4.5
Guidelines for reporting adverse events of special interest...........................................................74
10.4.6
Guidelines for management of specific laboratory abnormalities ..................................................74
10.5
OBLIGATIONS OF THE SPONSOR .............................................................................................75
10.6
SAFETY INSTRUCTIONS .............................................................................................................76
10.7
ADVERSE EVENTS MONITORING..............................................................................................76
11
STATISTICAL CONSIDERATIONS..............................................................................................77
11.1
DETERMINATION OF SAMPLE SIZE...........................................................................................77
11.2
DISPOSITION OF PATIENTS .......................................................................................................77
11.3
ANALYSIS POPULATIONS...........................................................................................................78
11.3.1
Efficacy populations .......................................................................................................................78
11.3.1.1 Modified intent-to-treat population .................................................................................................78
11.3.2
Safety population ...........................................................................................................................78
11.3.3
Pharmacokinetic and biomarker analysis population.....................................................................78
11.4
STATISTICAL METHODS .............................................................................................................78
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11.4.1
Extent of study treatment exposure and compliance.....................................................................78
11.4.1.1 Extent of investigational medicinal product exposure....................................................................78
11.4.1.2 Compliance ....................................................................................................................................79
11.4.2
Analyses of efficacy endpoints.......................................................................................................79
11.4.2.1 Analysis of primary efficacy endpoint.............................................................................................79
11.4.2.2 Analyses of secondary efficacy endpoints.....................................................................................80
11.4.2.3 Multiplicity considerations ..............................................................................................................80
11.4.3
Analyses of safety data..................................................................................................................80
11.4.3.1 Adverse events ..............................................................................................................................81
11.4.3.2 Laboratory data..............................................................................................................................82
11.4.3.3 Potential drug-induced liver injury..................................................................................................82
11.4.3.4 Vital signs data...............................................................................................................................83
11.4.3.5 Electrocardiogram data..................................................................................................................83
11.4.4
Analyses of pharmacokinetic and pharmacodynamic variables ....................................................83
11.5
INTERIM ANALYSIS......................................................................................................................83
12
ETHICAL AND REGULATORY CONSIDERATIONS...................................................................84
12.1
ETHICAL AND REGULATORY STANDARDS ..............................................................................84
12.2
INFORMED CONSENT .................................................................................................................84
12.3
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC)...................................................................................................84
13
STUDY MONITORING...................................................................................................................86
13.1
RESPONSIBILITIES OF THE INVESTIGATOR(S).......................................................................86
13.2
RESPONSIBILITIES OF THE SPONSOR.....................................................................................86
13.3
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST......................................................................................................................................87
13.4
USE OF COMPUTERIZED SYSTEMS..........................................................................................87
14
ADDITIONAL REQUIREMENTS...................................................................................................88
14.1
CURRICULUM VITAE....................................................................................................................88
14.2
RECORD RETENTION IN STUDY SITES ....................................................................................88
14.3
CONFIDENTIALITY .......................................................................................................................88
14.4
PROPERTY RIGHTS.....................................................................................................................89
14.5
DATA PROTECTION.....................................................................................................................89
14.6
INSURANCE COMPENSATION....................................................................................................89
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14.7
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES .................................90
14.8
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE............................................................................................................................................90
14.8.1
By the Sponsor...............................................................................................................................90
14.8.2
By the Investigator .........................................................................................................................91
14.9
CLINICAL TRIAL RESULTS ..........................................................................................................91
14.10
PUBLICATIONS AND COMMUNICATIONS .................................................................................91
15
CLINICAL TRIAL PROTOCOL AMENDMENTS ..........................................................................92
16
BIBLIOGRAPHIC REFERENCES.................................................................................................93
17
APPENDICES................................................................................................................................96
APPENDIX A
GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY 
ABNORMALITIES BY SANOFI......................................................................................................97
APPENDIX B
PROCEDURE FOR COLLECTION, HANDLING, STORAGE, AND SHIPMENT OF
SAR407899 SPECIMENS FOR PHARMACOGENETIC SAMPLES...........................................102
APPENDIX C
PATIENT REPORTED OUTCOMES ................................................................................105
2.1
LIST OF TABLES
Table 1 - Summary of sampling/handling procedures for 
.....................................................................58
Table 2 - Summary of sampling/handling procedures for 
.............................................................58
Table 3 - Summary of sampling/handling procedures for future use of samples..........................................58
Table 4 - Sampled blood volume...................................................................................................................59
Table 5 - Summary of adverse event reporting instructions..........................................................................75
2.2
LIST OF FIGURES
Figure 1 - Rho kinase pathway......................................................................................................................31
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3
LIST OF ABBREVIATIONS
ACS:
acute coronary syndrome
AE:
adverse event
AESI:
adverse event of special interest
AV:
atrioventricular
BP:
blood pressure
CABG:
coronary artery bypass grafting
CAD:
coronary artery disease
CCBs:
calcium channel blockers
CCTA:
coronary computed tomography angiography
CFR:
coronary flow reserve
CVR:
coronary vascular resistance
DBTP:
double blind treatment package
DMC:
data monitoring committee
eGFR:
estimated glomerular filtration rate
eNOS:
endothelial nitric oxide synthase
FFR:
fractional flow reserve
FSH:
follicle stimulating hormone
HRT:
hormonal replacement therapy
IAG:
imaging acquisition guidelines
IEC:
independent ethics committee
iFR:
instantaneous wave-free ratio
IMP:
investigational medicinal product
IRB:
institutional review board
IRT:
interactive response technology
LAD:
left anterior descending
LCX:
left circumflex
LV:
left ventricle
LVEF:
left ventricular ejection fraction
MAPK:
mitogen-activated protein kinases
MBF:
myocardial blood flow
MI:
myocardial infarction
mL:
milliliter
NIMP:
non investigational medicinal product
OCT2:
organic cation transporter-2
PCI:
percutaneous coronary intervention
RCA:
right coronary artery
 
SAE:
serious adverse event
SBP:
systolic blood pressure
TEAE:
treatment-emergent adverse events
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TIA:
transient ischemic attack
TPD:
total perfusion deficit
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4
INTRODUCTION AND RATIONALE
4.1
GENERAL BACKGROUND
4.1.1
Background on patient population
Patients who have microvascular dysfunction as demonstrated by a reduced CFR in the absence of 
obstructive CAD and who continue to have angina pectoris are an important group of patients 
with high unmet medical need as there is no currently approved specific pharmacologic therapy.
4.1.1.1
Patients with persistent angina despite angiographically successful PCI
Coronary revascularization procedures by means of PCI are performed routinely for the 
symptomatic treatment of patients with myocardial ischemia.   Percutaneous coronary intervention
has not been shown to reduce mortality in patients with stable CAD. Data from large trials 
investigating the use of PCI in patients with stable CAD show that angina is still experienced in a 
large number of patients one year after the procedure and that this proportion increases over time.  
In a select group of these patients who have no current obstructive CAD but with evidence of 
myocardial ischemia, are thought to be due coronary microvascular dysfunction as a possible 
cause of persistent stable angina (2, 3).
4.1.1.2
Patients with microvascular angina (MVA)
Patients who present with angina and a positive noninvasive test may undergo a diagnostic 
coronary angiography.  The yield of elective coronary angiography in such patients is 
unsatisfactory with no coronary artery disease (defined as <20% stenosis in all vessels) reported in 
close to 40% of the patients (4). Amongst them a significant proportion of patients have coronary 
microvascular dysfunction (CMD), a disease that affects the walls and inner lining of tiny 
coronary artery blood vessels that branch off from the larger coronary arteries (5).  Accordingly, 
this type of angina is categorized as microvascular angina (MVA).  Irrespective of the degree of 
coronary artery disease, higher angina episodes frequencies are associated with lower physical 
functioning, quality of life (QoL) (6), angina stability, treatment satisfaction and higher 
prevalence of anxiety and depression, hospital re-admission (7, 8) and  repeat coronary 
angiography (9).
4.1.1.3
Pathophysiology and purported beneficial mechanism of Rho-Kinase inhibition: 
Abnormalities in vascular smooth muscle cell (VSMC) as well as vascular endothelial cells in the 
heart’s smallest arterioles have been widely discussed as major contributor in the pathophysiology 
of MVA (10, 11). The finding that a reduced coronary blood flow response to direct arteriolar 
dilator agents like adenosine, dipyridamole or papaverine has been shown in patients with angina 
pectoris and normal coronary angiograms suggests abnormalities of smooth muscle cell relaxation 
in MVA (12, 13, 14). In addition, an impairment of endothelium-dependent coronary 
microvascular dilation is also described in patients with MVA (13, 14, 15).
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Physiologic levels of rho-kinase activity are important for vascular homeostasis, whereas on the 
opposite, enhanced rho-kinase activity could causes vascular diseases through VSMC 
hypercontractility/proliferation, endothelial cell damage and promotion of pro-inflammatory 
pathways (16).
Figure 1 - Rho kinase pathway
Myosin-binding subunit myosin light chain phosphatase (MBS) is one of the major endogenous 
substrates for Rho-kinase, and its phosphorylation is acknowledged as a marker for Rho-kinase 
activity in various tissues including kidney (17), vasculature (18) and cardiac tissue (19). Thus 
using a pMBS/totMBS, a statistically significant 1.5-fold higher Rho kinase activity was 
considered in circulating neutrophils of patients with pulmonary arterial hypertension (PAH) 
compared to healthy controls (20) and a 1.9-fold higher activity in patients with cardiovascular 
diseases compared healthy controls (21). Moreover, a statistically significant reduction from 
baseline of pMBS/totMBS ratio was observed in patients with vasospastic angina after treatment 
with CCBs (22).
SAR407899 is a potent ATP-competitive rho-kinase inhibitor (23) and has, based on this MoA, 
the potential to improve patient conditions with MVA through endothelium dependent [prevention 
of ROCK induced inhibition of endothelial nitric oxide synthase (eNOS) expression] and 
endothelium independent effects (prevention of hypervasoconstriction) (24). Such beneficial 
effects could therefore potentially lead to an improvement in symptoms and quality of life, and a 
decreased burden of CV procedures/hospitalization for patients with microvascular dysfunction 
and/or non-obstructive coronary artery disease.
Based on the above described patient needs and the therapeutic potential of SAR407899, patients 
with microvascular angina and/or persistent angina despite successful PCI will be evaluated in the 
POC-study ACT14656.
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4.2
BACKGROUND ON SAR407899
SAR407899 is an inhibitor of Rho kinase (ROCK), a broadly expressed serine/threonine protein 
kinase. 
SAR407899 has already been studied in healthy adult volunteers, healthy elderly subjects, patients 
with chronic kidney disease (CKD) and patients with erectile dysfunction. Although SAR407899 
was generally well-tolerated, dose-related symptomatic orthostatic hypotension occurred in some 
subjects, primarily after administration of the first dose, and particularly in patients who had renal 
dysfunction and who were treated with concomitant anti-hypertensive drugs.  Orthostatic 
hypotension is considered to be a mechanism-related effect and will be mitigated in the current 
study by using an individual dose titration approach.  In healthy young subjects, a few cases of 
serum creatinine increase >30% were observed however the values remain within normal range.
This effect was not observed in elderly subjects or in patients with CKD.
4.3
RATIONALE FOR THE STUDY
This study will evaluate SAR407899 compared with placebo in a population of patients with 
microvascular angina and/or persistent angina despite angiographically successful PCI (typical or 
atypical symptoms of angina pectoris), non-obstructive (<50% stenosis) coronary arteries on 
angiogram or intermediate stenosis with FFR >0.80 or iFR >0.89, and microvascular dysfunction 
documented by a global CFR <2.0 measured by PET. Angiographically successful balloon 
angioplasty with a reduction of a minimum stenosis diameter to <50% or for coronary stents a 
minimum diameter stenosis of <10%, with a final TIMI flow Grade 3 (visually assessed by 
angiography) without side branch loss, flow-limiting dissection, distal embolization, or 
angiographic thrombus.
This study will assess whether SAR407899 improves PET scan global CFR (25) before and after 
administration of a pharmacologic stressor (ie, vasodilator). Low CFR is considered as a hallmark 
of microvascular dysfunction. An improvement in CFR observed after interventions in this patient 
population would suggest an improvement in the underlying causal vascular biological 
abnormalities.  Assessment of patient-reported outcome using the Seattle Angina Questionnaire 
physical limitation scale (SAQ-PL) due to its sensitivity will be used as secondary endpoint.
Change in angina episodes and short-acting nitrate intakes will be collected in the patient’s diary.
4.4
DESIGN RATIONALE AND RISK ASSESSMENT

This study will be placebo-controlled as no treatment is currently approved in the 
population with microvascular angina and/or persistent stable angina despite 
angiographically successful PCI. The drug will be tested on top of standard treatments for 
angina excluding nitrates (except short-acting nitrates) and PDE 5 inhibitors that should be 
discontinued at least one week before baseline PET assessment and not used during the 
study in order to avoid masking the effects of SAR407899 while increasing the risk of 
orthostatic hypotension.

Beta-blockers act directly on the heart to reduce heart rate, contractility, AV conduction 
and ectopic activity. Additionally, they may increase perfusion of ischemic areas by 
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prolonging the diastole and increasing vascular resistance in non-ischemic areas this is 
why beta-blockers are currently first-line anti-anginal therapy in stable CAD patients 
without contraindications according to ESC 2013 guidelines on stable CAD (26). Hence, 
beta-blockers should be kept at the same dose, as it could potentially impact the 
assessment of efficacy.

SAR407899 will be administered in the morning and at bedtime. As no relevant food-
effect was demonstrated, dose may be taken with or without food as per preference of the 
patient. Twice a day (BID) regimen has been chosen in order to minimize peak 
concentration effects while maintaining sufficient trough levels. 

Decrease in BP (hypotension, orthostatic dysregulation) is considered as a mechanism-
related effect and will be mitigated by using a dose titration approach. 
 
 
 
 
 
  A safety 
review will be performed by the DMC when 19 patients will have completed the first 
week of treatment.  The DMC will review the clinical safety data including AESIs. During 
the safety evaluation of the first 19 enrolled patients, these patients will continue to receive 
IMPs as per the titration schedule described above and enrolment will continue.

If patient does not tolerate a dose level due to hypotension, symptomatic orthostatic 
hypotension with SBP decrease ≥20mmHg, at Minute 3 or Minute 5 after changing 
position from seated to standing, the investigator will decrease the dose level of the 
investigational product to the previous tolerated dose level for the remaining duration of 
the study.

Overall, the exposure to the study drug should last for 4 weeks in total (3 weeks for the 
titration phase and 1 week for the maintenance phase) for all patients. Patients will be 
followed one week after the end of the study treatment to collect any potential AEs during 
the washout period.

Serum creatinine will be monitored. Creatinine is filtered in glomerulus and also partly 
eliminated in urine via an active secretion mediated by organic cation transporter-2
(OCT2). These observed increases in adults could then possibly be explained by inhibition 
of its active secretion by SAR407899 which is a weak in vitro OCT2 inhibitor. Serum 
cystatin C, which is filtered in glomerulus but not subject to tubular secretion, will be 
measured in parallel to serum creatinine to assess glomerular filtration rate.
Specific parameters rationale
Primary endpoint:

Coronary flow reserve (CFR), represents blood flow to the myocardium; the critical 
factor in angina. It is the endpoint with the most abundant clinical data in MVA patients. 
CFR is the ratio of the maximal myocardial blood flow (MBF) after a hyperemic stimulus 
(such as intravenous adenosine injection) to baseline resting blood flow.  In patients with 
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normal endothelial function, adenosine increases MBF by a factor of 2.5 or more while in 
patients with endothelial dysfunction the increase is less than 2.0 (27).
Secondary endpoints:

The Seattle Angina Questionnaire (SAQ) (28) was used in pilot MVA studies. It is 
currently used in clinical trials in MVA populations for ranolazine and thus provided a 
basis for statistical calculations. The SAQ is a self-report instrument with 19 items 
designed to quantify the physical and emotional effects of coronary artery disease. The 
questionnaire has a 4-week recall period. It yields five dimensions, each scored separately: 
physical limitation, angina stability, angina frequency, treatment satisfaction, and disease 
perception. A SAQ-7 summary score can also be derived using 7 items from the physical 
limitation, angina frequency and disease perception domains. The physical limitation 
(SAQ-PL) dimension is the most relevant for defining treatment benefit in this trial and 
was thus specified as a secondary objective. The SAQ-PL dimension measures how 
common daily activities representing low, medium, and high exertional requirements are 
limited by angina (9 items). It is scored by assigning each response an ordinal value, 
beginning with 1 for the response that implies the lowest level of functioning, and 
summing across the 9 items. The score is then transformed to 0-100 range by subtracting 
the lowest possible scale score, dividing by the range of the scale and multiplying by 100. 
The possible range of scores is therefore 0 to 100, with higher scores better. A change of 
10 points is considered to be clinically important. 

Safety will be assessed during the whole study on adverse events with a special focus on 
BP, laboratory data and renal function.  
Exploratory endpoints:
Assessment of angina episodes with or without short-acting nitrate intakes 
Angina episodes and short-acting nitrate intakes collected by the patients in a diary will be 
measured. This will allow assessing the number of angina episodes (and their severity).
Assessment of other dimensions of the SAQ and SAQ-7 score (29)
The SAQ yields five dimensions, each scored separately: physical limitation, angina stability, 
angina frequency, treatment satisfaction, and disease perception. All the dimensions except 
SAQ-PL will be assessed.
The SAQ-7 summary score can also be derived using 7 items from the physical limitation, angina 
frequency and disease perception domains.
Assessment of patient’s perceptions of treatment and symptoms
The patient qualitative self-assessment aims to better understand the patient’s views on their 
treatment and symptoms at baseline and at the end of the study. Three questions assessing the 
patient’s perception will be asked and a free-text box will be provided for patients to give 
qualitative answers. This assessment should take between 5-10 minutes, and the text will later be 
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analyzed using qualitative data analysis software to perform content analysis using text mining. 
The patient will be asked to complete these three questions. The questions are:

Day 1 and at the end of treatment visit/permanent treatment discontinuation or Day 29: 
“Please think back over the past week. In your own words, please describe the symptoms 
you have experienced because of your angina without obstructive coronary artery 
disease.

End of treatment visit/permanent treatment discontinuation or Day 29 only: “Please think 
about the study you have been part of. In your own words, please list the pros and cons of 
study treatment”.

End of treatment visit/permanent treatment discontinuation or Day 29 only: “Please give 
your overall thoughts on the study treatment you have received as part of this study”.
 
 
 
 
 
 
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5
STUDY OBJECTIVES
5.1
PRIMARY 

Assess the effects of SAR407899 on coronary vasomotor function using CFR in patients 
with microvascular angina and/or persistent stable angina despite angiographically 
successful PCI.
5.2
SECONDARY 

Assess the effects of SAR407899 in patients with microvascular angina and/or persistent 
stable angina despite angiographically successful PCI using SAQ-PL.

Assess the safety of SAR407899 in patients with microvascular angina and/or persistent 
stable angina despite angiographically successful PCI with a focus on identified risks such 
as hypotension and orthostatic hypotension.

Assess SAR407899 plasma concentrations in microvascular angina patients and/or 
persistent stable angina despite angiographically successful PCI.
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6
STUDY DESIGN
6.1
DESCRIPTION OF THE STUDY
A Phase 2a, multi-center, randomized with 1:1 ratio, double-blind, placebo-controlled parallel 
group study with weekly titration up to maintenance dose, based on individual patient tolerability, 
particularly symptomatic or asymptomatic BP decreases.
6.2
DURATION OF STUDY PARTICIPATION
6.2.1
Duration of study participation for each patient

Screening: up to 4 weeks before the first dosing (Day -28 to Day -1) and up to 6 weeks in 
patients diagnosed with MVA and stable angina without previous PCI who did not have a 
coronary artery angiography or CCTA in the previous 24 months but between 24 months 
and 5 years prior to screening and requiring CCTA in this screening period.

Titration phase: 3 weeks.

Maintenance phase: 1 week.

Total duration of treatment: 4 weeks (including titration).

Follow-up: 1 week.

Total study duration: 9 weeks (±2 days) and up to 11 weeks (+/- 2 days) in patients 
requiring CCTA in screening period.
6.2.2
Determination of end of clinical trial (all patients)
The end of the clinical trial is defined as the day when the last patient completes her/his last visit 
planned in the protocol.
6.3
INTERIM ANALYSIS
A safety review with a DMC meeting will start as soon as the first 19 patients will have been 
randomized and have finished the first week of treatment. Additional analyses for safety may be 
performed in this study.
Refer to Section 11.5 and to Section 6.4.1 for details on interim analyses.
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6.4
STUDY COMMITTEES
6.4.1
Data Monitoring Committee
A Data Monitoring Committee (DMC) will be charged with monitoring the safety of the patients 
participating in this clinical trial. This committee is comprised of externally-based individuals 
with expertise in the diseases under study, biostatistics, or clinical research. The DMC will review 
all serious adverse events (SAEs), death, and adverse events of special interest (AESIs), in due 
time. The DMC will give appropriate recommendations to the Sponsor on safety aspects during 
the conduct of the study, if needed. The DMC is justified by the early stage of development of 
SAR407899 that has not gathered safety information in patients with microvascular angina or 
persistent angina despite angiographically successful PCI and the identified risk of hypotension. 
The DMC responsibilities and the data review processes are fully described in the DMC charter
that will be developed prior to study start. 
In the above capacities, the DMC is advisory to the Sponsor. The Sponsor is responsible for 
promptly reviewing and for taking into account in a timely manner the recommendations of the 
DMC in terms of trial continuation with or without alterations or of potential trial termination.
Following DMC review of the safety data (of the first 19 patients who will have completed first 
week after randomization) and their recommendations, the Sponsor may have to adjust titration 
schedules and dosing regimen.
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7
SELECTION OF PATIENTS
7.1
INCLUSION CRITERIA
I 01.
MVA and/or persistent stable angina despite angiographically successful PCI male or 
female patients with:
A) Male and female patients not at childbearing potential ≥18 year-old or legal age of 
majority.
B) Female patient if she has undergone sterilization at least 3 months earlier or is 
postmenopausal.
-
Post-menopausal status is defined by having no menses for 12 months without an 
alternative medical cause,
-
In females not treated with HRT, menopausal status is confirmed by a high follicle 
stimulating hormone (FSH) level greater than 40 IU/L,
-
In females on HRT and whose menopausal status is in doubt (ie, in women aged less 
than 45 years), a highly effective contraception methods will be required.
Contraception should be used during the whole study and for at least seven days 
corresponding to time needed to eliminate study treatment.
C) Symptomatic stable angina pectoris (typical or atypical symptoms with an average of at 
least bi-weekly episodes over the past month).
D) Patients with non-obstructive (<50% stenosis) coronary arteries or intermediate stenosis 
(between 50 and 70%) should have FFR >0.80 or iFR >0.89 on angiogram, documented 
within the previous 24 months*. In patients with stenting, a minimum diameter stenosis of 
<10% is required.
or
Coronary computed tomography angiography with finding of non-obstructive coronary 
arteries within the past 24 months* in patients without previous PCI.
*Note: in cases of clinically suspected progression of atherosclerosis as per the 
Investigator, a more contemporary (i.e., 6 months) evidence should be provided.
or
CCTA performed during screening period, with finding of non-obstructive coronary 
arteries, in patients diagnosed with MVA and stable angina without previous PCI who did 
not have a coronary angiogram or CCTA in the previous 24 months but between 24 
months to 5 years .
E) Baseline global CFR (measured during the study) assessed by 13N-ammonia or 82Rubidium 
PET scan <2.0. 
I 02.
Signed written informed consent.
I 03.
Not under any administrative or legal supervision. 
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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 4 subsections: 
7.2.1
Exclusion criteria related to study methodology
E 01.
Any patient who, in the judgment of the Investigator, is likely to be noncompliant during 
the study, or unable to cooperate because of a language problem or poor mental 
development, or cannot be contacted in case of emergency.
E 02.
Patient who has taken other investigational drugs or SAR407899 for this study within 
3 months or 5 half-lives from screening or randomization, whichever is longer.
E 03.
Any use of nitrates (except short-acting nitrates) and/or dipyridamole and/or PDE 5 
inhibitors within one week prior to baseline PET scan or anticipated to be used during the 
study.
E 04.
Conditions/situations such as:

Patients with a short life expectancy (including heart failure New York Heart Association 
[NYHA] III or IV).

Presence or history of drug hypersensitivity that in the opinion of the investigator would 
compromise patient’ safety.

Any history or presence of clinically relevant pulmonary, gastrointestinal, hepatic, renal, 
metabolic, hematological, neurological, osteomuscular, articular, psychiatric, systemic, 
ocular, gynecologic (if female), or infectious disease, or signs of acute illness that 
according to Investigator’s judgment, would adversely affect the patient’s participation in 
the study.
E 05.
Esophageal dysmotility or esophagitis.
E 06.
Patients with acute coronary syndrome (ACS) (MI and/or unstable angina) in previous 
3 months.
E 07.
Unsuccessful or incomplete coronary revascularization with residual obstructive stenosis 
or coronary artery disease progression in native vessels as documented on invasive 
coronary angiography (≥50% stenosis) within 24 months of enrollment.
E 08.
Percutaneous coronary intervention performed at the time of an ACS (MI or unstable 
angina) in the previous 12 months.
E 09.
Recent PCI within the past 3 months.
E 10.
Patients with history of coronary artery bypass grafting (CABG).
E 11.
Recent (≤3 months) major surgery (ie, valvular surgery, surgery for congenital heart 
disease), stroke, TIA, sustained ventricular arrhythmia, clinically significant structural 
heart disease (moderate-severe valvular disease, hypertrophic cardiomyopathy, congenital 
heart disease, pulmonary hypertension).
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E 12.
Regional local flow abnormal perfusion defects at baseline PET scan*.
*Note: if contemporary evidence with invasive coronary angiography or CCTA 
demonstrates non-obstructive coronary arteries or if the regional local flow abnormal 
perfusion defect on PET scan is consistent with previous studies then patient qualifies for 
the study.
E 13.
Patients with cardiac conduction abnormalities (second or third degree AV block, sick 
sinus syndrome, symptomatic bradycardia, sinus node disease) except in patients fitted 
with a functioning pacemaker.
E 14.
History or known carotid stenosis:
-
Carotid stenosis (>50%)
or
-
History of carotid stenosis in patients with previous symptoms.
E 15.
Contraindication or known hypersensitivity to adenosine or regadenoson.
E 16.
Contraindication to aminophylline.
E 17.
Contraindication to vasodilator stress PET scan and/or CCTA if CCTA needed during 
screening.
E 18.
Inability to discontinue treatment with methylxanthines treatment within 24 hours prior to 
PET scan.
E 19.
Patient unable to read, understand and fill a questionnaire without any help (eg, partially 
visually impaired or blind).
E 20.
Blood donation (blood volume to be defined if needed depending on the country), any 
volume, within 2 months before inclusion (duration to be checked according to local 
regulations).
E 21.
Impossibility to meet specific protocol requirements.
E 22.
Patient is the Investigator or any Sub-investigator, research assistant, pharmacist, study 
coordinator, other staff or relative thereof directly involved in the conduct of the protocol.
E 23.
SBP <110 mmHg at baseline.
E 24.
Presence at baseline of symptomatic  orthostatic hypotension (SBP decrease of 20 mmHg 
or more  at Minute 3 or Minute 5 between seated and standing position), or asymptomatic
orthostatic hypotension with a decrease in SBP equal or greater than 30 mmHg at Minute 
3 or Minute 5 when changing from the seated to the standing position.
E 25.
Renal impairment with estimated glomerular filtration rate (eGFR) <50 mL/min/1.73 m2 at 
screening and baseline.
E 26.
Male patient having a female partner of childbearing potential not protected by 
highly-effective method(s) of birth control (as defined in a local protocol amendment in 
case of specific local requirement).
E 27.
Women who are breast feeding.
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E 28.
Drug-induced liver injury related criteria: 

Underlying hepatobiliary disease.

ALT >3 times the upper limit of normal (ULN).
7.2.2
Additional exclusion criteria during or at the end of screening before randomization
E 29.
Patient who has withdrawn consent before randomization (starting from signed informed 
consent form).
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8
STUDY TREATMENTS
8.1
INVESTIGATIONAL MEDICINAL PRODUCT(S) / NON INVESTIGATIONAL MEDICINAL 
PRODUCT(S)
8.1.1
INVESTIGATIONAL MEDICINAL PRODUCT(S)
Investigational medicinal products: 

SAR407899, 2.5 mg and 5 mg capsules.

SAR407899 matching placebo.
Formulation: Capsules.
Route and method of administration: Oral administration, twice per day, in the morning and at 
bedtime, with or without a meal.
Dose regimen: 2 capsules in the morning and at bedtime. Dose may be taken with or without food 
as per preference of the patient.
Starting dose:
.
 
 
 
 
 
Stopping criterion based on creatinine level:

Stop study drug if creatinine level >150 µmol/L and increase from baseline >30%. In 
specific circumstances where creatinine blood level can be obtained only in the afternoon 
the day of the visit, the patient will be titrated according to titration scheme and if 
creatinine blood level meets stopping rules, the investigator will need to contact the patient 
before bedtime intake to permanently discontinue the study drug and schedule a premature 
study drug discontinuation visit.
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When 19 patients will have completed first week of treatment, 
the DMC will review the clinical safety data. During the safety evaluation of the first 19 enrolled 
patients, these patients will continue to receive IMPs as per the titration schedule described above
and enrolment will continue.
Dosing of SAR407899 is limited to 31 days.
8.1.2
NON INVESTIGATIONAL MEDICINAL PRODUCT(S)
The following classes of drugs are identified as non-investigational medicinal products (NIMP) 
because the medications are used to assess the primary endpoint of the study:

PET radiopharmaceuticals (13N-ammonia and 82Rubidium).

Vasodilator stressors (adenosine and regadenoson).
The NIMPs should be used according to their approved labeling.
8.1.2.1
13N-ammonia and 82Rubidium
13N-ammonia and 82Rubidium are PET radiopharmaceuticals. These NIMPs are administered to 
the patients to assess their primary endpoint using PET scan.
8.1.2.2
Adenosine and regadenoson
Adenosine and regadenoson are vasodilator stressors. These NIMPs are given to the patient to
assess the primary endpoint using PET scan.
8.2
BLINDING PROCEDURES
8.2.1
Methods of blinding
For the double blind treatment package (DBTP), each double-blind SAR407899 treatment kit, 
either SAR407899 or placebo for SAR407899, will be prepared to contain 1 weekly (7 days  
+2 extra days) “child resistant” wallet of 36 capsules in each. In order to protect the blind, all 
SAR407899 double-blind treatment kit boxes (SAR407899 whatever the dose or Placebo for 
SAR407899) will have the same look and feel (identical capsules, same amount of capsules 
whatever the dose, packaging) and therefore will be labeled with a double-blind label.
8.2.2
Randomization code breaking during the study
In case of an adverse event (AE), the code should only be broken in circumstances when 
knowledge of the investigational medicinal product (IMP) is required for treating the patient. 
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If possible, a contact should be initiated with the Sponsor’s monitoring team or medical expert 
before breaking the code.
Code breaking can be performed at any time by using the proper module of the interactive 
response technology (IRT) and/or by calling any other phone number provided by the Sponsor for 
that purpose. If the blind is broken, the Investigator should document the date, time of the day and 
the reason for code breaking. 
If the code is broken, the patient must discontinue IMP administration but he/she continues the
study.
Refer to Section 10.5 for suspected unexpected serious adverse drug reaction requiring unblinding 
by the Sponsor.
8.3
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP
At the screening visit, patients who will sign the informed consent form will be assigned an
incremental subject number according to chronological order. The subject number remains 
unchanged during the study and allows the patient to be identified during the whole study.
Stratification on the presence of angiographically successful PCI (YES/NO) will be performed.
The randomized treatment kit number list is generated centrally by Sanofi.
The IMPs are packaged in accordance with this list. The randomization and the treatment 
allocation (1:1) are performed centrally by an interactive voice/web response system 
(IVRS/IWRS). The IVRS/IWRS allocates treatment kits to the patient according to a prespecified 
randomization list, generated by the company in charge of the IVRS/IWRS.
A patient is considered as randomized as soon as the IVRS/IWRS has assigned a patient to active 
or placebo and indicated a treatment kit to be allocated to the patient, regardless whether the
treatment kit was used or not (ie, patient registered by the IVRS/IWRS).
A patient cannot be randomized more than once in the study.

All screening-failed patients will be entered in database with their subject number 
allocated at screening.
8.4
PACKAGING AND LABELING
For the double-blind treatment package (DBTP), each  double-blind SAR407899 treatment kit, 
containing  either SAR407899 or matching placebo, will be prepared to contain 1 weekly (7 days  
+2 extra days) “child resistant” wallets of 36 capsules in each. 
In order to protect the blind, all SAR407899 double-blind treatment kit boxes (SAR407899 
whatever the dose or Placebo for SAR407899) will have the same look and feel and therefore will 
be labeled with a double-blind label.
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Packaging is in accordance with the administration schedule. One kit will be dispensed for first 
week of treatment. Then several kits will be dispensed according to the number of treatment 
weeks.
The content of the labeling is in accordance with the local regulatory specifications and 
requirements.
8.5
STORAGE CONDITIONS AND SHELF LIFE
The SAR407899 and Placebo kits will be stored at ambient temperature by the site. The 
temperature of the site storage room should be checked at least daily and recorded on a log sheet.
The IMP that will be stored at the investigational site should be kept in an appropriate locked 
room, under the responsibility of the Investigator or designee.
8.6
RESPONSIBILITIES
The Investigator, the hospital 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.
All IMPs 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) should be promptly notified to the 
Sponsor. Some deficiencies may be recorded through a complaint procedure.
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 allow the IMP to be used 
other than as directed by this clinical trial protocol, or dispose of IMP in any other manner.
8.6.1
Treatment accountability and compliance
Compliance of IMP:

The first IMP intake (morning dosing) of each on-site visit will be performed under direct 
medical supervision at each on site visit.

The Investigator or designee records the dosing information on the appropriate page(s) of 
the case report form.
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
The investigator keeps all used/ unused IMPs for monitoring purposes until notice by the 
Sponsor is given to destroy them.

Compliance will be checked by the investigator or designee, through patient’s interview 
and counting of capsules returned by the patient at each study visit versus the number of 
capsules dispensed at the previous visit.  
IMP accountability:

Treatment units are returned by the patient at each visit. 

The Investigator or designee counts the number of capsules remaining in the returned 
treatment kits, and fills in the Treatment Log Form.

The monitoring team in charge of the study then checks the CRF data by comparing them 
with the IMP which he/she has retrieved and treatment log forms.
8.6.2
Return and/or destruction of treatments
Investigational medicinal product reconciliation must be performed on a daily basis at the site by 
the Investigator and the monitoring team using treatment log forms and documented on center 
IMP inventory countersigned by the Investigator and the monitoring team.
A written authorization for destruction will be given by the clinical trial team once the IMP
reconciliation is achieved. This destruction can be performed at site depending on IMP
specificities and local requirements or IMP can be returned to the Sponsor for destruction if kits 
destruction on site is not authorized.
8.7
CONCOMITANT MEDICATION
A concomitant medication is any treatment received by the patient concomitantly to any IMP(s).
An accurate record of all prescription medications must be kept on the appropriate record form, 
including the name of the medication (international nonproprietary name), start of administration, 
daily dosage, and duration for such use.
Prohibited medication:

Nitrates (except short-acting nitrates) should not be used at least one week before 
screening PET scan and during the study as they may mask the vasodilating effects of 
SAR407899 and could increase the risk of hypotension and orthostatic hypotension.

Phosphodiesterase type 5 (PDE5) inhibitors should not be used at least one week before 
screening PET scan and during the study as they may mask the vasodilating effects of 
SAR407899 and could increase the risk of hypotension and orthostatic hypotension.

Dipyridamole should not be used at least one week before screening PET scan and during 
the study as its use is associated with a drug interaction with the vasodilator stressor that is 
utilized during the PET assessment.
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Authorized concomitant medication:

Beta-blockers administered at the recommended dosage for at least four weeks prior to the 
randomization (baseline). No change is permitted unless the patient develops an AE or 
based on the investigator’s judgment. Dose and any change will be recorded on the patient 
e-CRF. Beta-blockers cannot be started during the course of the study.

Calcium channel blockers (CCBs) administered at the recommended dosage for at least 
four weeks prior to the randomization (baseline). No change is permitted unless the patient 
develops an AE or based on the investigator’s judgment. Dose and any change will be 
recorded on the patient e-CRF. CCBs cannot be started during the course of the study.

Short-acting nitrates intakes are authorized as rescue medication at the recommended 
dosage. The use of this medication should be reported in e-CRF.

Any other standard treatments at the recommended dosage for at least one week prior to 
the randomization (baseline). No change is permitted unless the patient develops an AE. 
Dose and any change will be recorded on the patient e-CRF.
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9
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT
9.1
EFFICACY ENDPOINTS
9.1.1
Primary efficacy endpoint

Change from baseline to Week 4 in uncorrected global CFR assessed by 13N-ammonia or 
82Rubidium PET scan.
9.1.2
Secondary efficacy endpoint

Change from baseline to Week 4 in physical limitation as assessed by SAQ-PL.
9.1.3
Exploratory endpoints

Rate of diary angina episodes at baseline and Week 4.

Rate of diary angina episodes requiring use of short-acting nitrates at baseline and 
Week 4.

Change from baseline to Week 4 in the other dimensions of the SAQ.

Change from baseline to Week 4 in the SAQ-7 score.

Patients’ perceptions of treatment and symptoms assessed at baseline and Week 4.

 
9.1.4
Assessment methods and activity parameters
9.1.4.1
13N-ammonia or 82Rubidium PET scan
Coronary Flow Reserve is assessed by PET scan in the morning at baseline (Day 1 or up to 14 
days prior to first day of study drug administration and up to 4 weeks before in patients diagnosed 
with MVA and stable angina without previous PCI and whose coronary angiogram or CCTA was 
not performed in the previous 24 months but between 24 months to 5 years) and end of treatment 
Day 29 visit (or up to Day 31), approximately one or two hours after last IMP intake.
PET scan CFR procedure is described hereafter. Details on the procedure are contained in the 
imaging acquisition guidelines (IAG).
9.1.4.1.1 Positron emission tomography (PET):
Regional and global MBF will be assessed using PET imaging in accordance with the study-
specific acquisition protocol (see IAG). PET scans will be performed using a whole body PET
scanner. 
Anti-hypertensives, beta-blockers and calcium channel blockers will be withheld 24 hours prior to 
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PET scan. Patients will be allowed to continue using sublingual nitroglycerin as needed. Studies
will be performed after 4 hours of fasting and 24 hours of abstinence from caffeine-containing 
products. The PET scan will take approximately 2.5 hours, including patient preparation. 
Myocardial blood flow (MBF) will be measured at rest and during maximal hyperemia using 
adenosine or regadenoson infusion, and using 13N-ammonia or 82Rubidium as the flow tracer. 
After transmission imaging and beginning with the intravenous (IV) administration of the flow 
tracer, list mode images are acquired. Then, patients will undergo a standard infusion of adenosine
or bolus injection regadenoson. At peak hyperemia, a second dose of the flow tracer will be 
injected IV, and images recorded in the same manner. The heart rate, BP, and 12-lead ECG will 
be recorded at baseline and throughout the infusion of adenosine or regadenoson, and at recovery. 
All PET scans will be done for research (non-clinical) purposes only. For safety reasons, all PET 
scans will be reviewed at the sites by site investigators for clinically important findings. No 
reports or analyses will be provided to sites from the PET core laboratory and studies will not be 
assessed in real-time.
9.1.4.1.2 Risks and discomforts from the PET scans
The risks and discomforts to the patients associated with the PET scan include those associated 
with administration of the vasodilator and potentially aminophylline that may be utilized to 
reverse the side effects due to vasodilator administration. Also, there are radiation risks related to 
the procedure and the radioactive flow tracers. These risks are detailed in the patient consent 
form.
9.1.4.2
Analysis of rest and stress myocardial perfusion PET images
A complete analysis of rest and stress myocardial perfusion PET images will be performed. It will 
include:

Quantitative analysis of all PET studies will be performed at the central core laboratory.
The following analyses will be performed:

Semi-Quantitative Analysis:
1. Total Perfusion Deficit (TPD): it measures the total left ventricular perfusion deficit at rest 
(reflecting scarred myocardium) and during stress (reflecting both scarred + ischemic 
myocardium), as well as the difference between stress and rest (reflecting ischemic 
myocardium). TPD scores will be processed using standard software (CSI software, 
Cedars Sinai Medical Center, Los Angeles, CA). 
2. For each patient, the following variables will be obtained at baseline and during the 
follow-up scans: 
1. Rest TPD
2. Stress TPD
3. Difference TPD 

Quantification of left ventricular function: rest and post-stress left ventricular ejection 
fraction (LVEF) will be calculated from the gated myocardial perfusion images using 
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commercially available software (Corridor4DM, INVIA Medical Imaging Solutions, Ann 
Arbor, MI). 
For each patient, the following variables will be obtained at baseline and during the follow-up 
scans: (1) rest LVEF, and (2) post-stress LVEF

Quantification of myocardial blood flow and CFR: Absolute myocardial blood flow 
(MBF, in mL/g/min) will be computed from the dynamic rest and stress imaging series 
using commercially available software (Corridor4DM; Ann Arbor, MI) and previously 
validated methods (30, 31, 32). Automated regions of interest will be used to generate 
blood pool (arterial input function) and tissue time-activity curves. A validated 
2-compartment tracer kinetic model for 13N-ammonia or 82Rubidium will be used to 
quantify absolute MBF at rest and during peak hyperemic-stress. Per-patient regional and 
global CFR will be calculated as the ratio of absolute MBF at stress over that at rest. 
Finally, a regional and global index of coronary vascular resistance (CVR) will be 
generated by dividing the mean arterial pressure by MBF (both at rest and during peak 
hyperemic-stress). 
For each patient, the following variables will be obtained at baseline and during the follow-up 
scans: 
1. Rest MBF: individual values will be obtained for each of the coronary vascular territories 
(left anterior descending, LAD; left circumflex, LCX; and right coronary artery, RCA) and 
also for the entire LV (global rest MBF).
2. Peak hyperemic-stress MBF: individual values will be obtained for each of the coronary 
vascular territories (LAD, LCX, and RCA) and also for the entire LV (global stress MBF).
3. Coronary flow reserve (CFR): individual values will be obtained for each of the coronary 
vascular territories (LAD, LCX, and RCA) and also for the entire LV (global CFR).
4. Rest CVR: individual values will be obtained for each of the coronary vascular territories 
(LAD, LCX, and RCA) and also for the entire left ventricle, LV (global rest CVR).
5. Peak hyperemic-stress CVR: individual values will be obtained for each of the coronary 
vascular territories (LAD, LCX, and RCA) and also for the entire LV (global stress CVR).
9.1.4.3
Angina episodes and short-acting nitrates:
A diary is provided to the patient to collect the number and severity (requiring short-acting nitrate
intakes) of angina episodes that he/ she will experience in between site’s visits. This patient’s 
diary will be reviewed by the investigator or designee at each on-site visit.
9.1.4.4
Patient Reported Outcomes

Change from baseline to end of study treatment/Week 4 in the other dimensions of the 
SAQ (see Appendix C).

Change from baseline to end of study treatment/Week 4 in the SAQ-7 score.
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
Change from baseline to end of study treatment/Week 4 in Patients’ perception of 
treatment and symptoms.
Assessment of the other dimensions of the SAQ

Angina stability: measures whether angina has changed in frequency when patient 
performs his or her most strenuous level of activity (1 question).

Angina frequency: measures frequency of angina over the previous 4 weeks (2 questions).

Treatment satisfaction: measures patient satisfaction with current angina treatment 
(4 questions).

Disease perception: measures concern about angina in relation to quality of life and 
possibility of death (3 questions).
Each SAQ dimension is scored from 0-100 with higher scores better (as per the SAQ-PL; 
see Section 4.4). A change of 10 points is considered to be clinically important for any dimension.
Assessment of the SAQ-7 (29)
An SAQ summary score, called the SAQ-7, can be derived using the “best” 7 items from the three 
dimensions that directly measure patients’ current health status: Physical Limitation, Angina 
Frequency, and Disease Perception (“best” defined as the items that had the highest levels of 
concordance with the overall domain score). Scores for each of the three dimensions were 
calculated using methodology analogous to that of the full SAQ, so that scores ranged from 0 to 
100 for each dimension (although the number of items is smaller). The SAQ-7 score is derived as 
the average of the three domain scores.
Patient’s perception of treatment and symptoms
The patient qualitative self-assessment aims to better understand the patient’s views on their 
treatment and symptoms at baseline and at the end of the treatment. Three questions assessing the 
patient’s perception will be asked and a free-text box will be provided for patients to give 
qualitative answers. This assessment should take between 5-10 minutes, and the text will later be 
analyzed using qualitative data analysis software to perform content analysis using text mining. 
The patient will be asked to complete these three questions. The questions are:

Day 1 and at the end of study treatment visit/Day 29: “Please think back over the past 
week. In your own words, please describe the symptoms you have experienced because of 
your angina without obstructive coronary artery disease.

End of study treatment visit/Day 29 only: “Please think about the study you have been part 
of. In your own words, please list the pros and cons of study treatment”.

End of study treatment visit/Day 29 only: “Please give your overall thoughts on the study 
treatment you have received as part of this study”.
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Resources utilization
To assess the economic burden of MVA and/or persistent stable angina despite angiographically 
successful PCI, health care resources will be collected retrospectively at baseline within the year 
before study inclusion:

Number of out-patients visits by type (cardiologists, general practitioner, other).

Working status (activity, number of day off).
9.1.4.5
Coronary computed tomography angiography
A CCTA will be performed only in patients without previous PCI and whose coronary angiogram
or CCTA was not performed in the previous 24 months but between 24 months to 5 years in 
whom screening PET scan results and CFR < 2.0 qualify for the study. This additional 
investigation will be performed according to common practice.
9.2
SAFETY ENDPOINTS
9.2.1
Adverse events
Refer to Section 10.4 to Section 10.7 for details.
Adverse events, serious adverse events, and adverse events of special interest: spontaneously 
reported to the Investigator (see Section 10.4) will be collected from signed informed consent 
until the End of Study at Day 36.
To ensure the continuing safety of patients in this study, an independent DMC will be responsible 
for reviewing the safety data on a periodic basis throughout the course of the study as outlined in 
Section 6.4.1.
9.2.2
Physical examination
Physical examination including smoking habits and vital signs will be performed at Screening, 
Day 1 and Day 29.
In addition:

Body weight (kg) will be measured at Screening, Day 1 and Day 29 by using the same 
calibrated scale.

Body temperature (°C) will be measured using the same method for a given patient 
(oral/rectal/ tympanic) at Day 1 and Day 29.
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9.2.3
Laboratory safety variables
The clinical laboratory data are collected in accordance with the study schedule (Section 1.3 and 
Section 1.4) and consist of:

Blood count: red blood cell count (RBC - with morphology if blood cell count is 
abnormal), hematocrit (Hct), hemoglobin (Hb), white blood cell count (WBC) with 
differential (neutrophils, eosinophils, basophils, monocytes and lymphocytes), platelets.

Serum Biochemistry:
-
Plasma/serum electrolytes: glucose, sodium, potassium, chloride, calcium, bicarbonate, 
BUN, creatinine (with estimated glomerular filtration rate), uric acid, total protein, 
albumin, creatine phosphokinase (CPK), LDH and cystatin C,
-
Lipid profile: total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides,
-
Liver function: AST, ALT, alkaline phosphatases, gamma-glutamyl transferase (GGT), 
total and conjugated bilirubin.

Urinalysis: dipstick for proteins, glucose, blood, leucocytes, ketone bodies, pH, bilirubin, 
urobilinogen, nitrite, specific gravity. If positivity of this test, microscopic analysis has to 
be considered.
Clinical laboratory values will be analyzed after conversion into standard international units. 
International units will be used in all listings and tables.
Decision trees for the management of some laboratory abnormalities are provided in Appendix A.
9.2.4
Vital signs
Vital signs include: heart rate (HR), systolic and diastolic BP. The measurements will commence 
after 10 minutes have elapsed in seated resting position and continue at Minute 3 and Minute 5 in 
standing position. 
9.2.4.1
Technical aspects
Blood pressure will be measured using an electronic device (ie, Omron® or equivalent, if possible, 
with the same device for a selected patient applied consistently throughout the study). The BP
cuff should be placed over the arm at the heart level with the patient's arm extended and supported 
comfortably on a table or arm rest (for seated measurements) or the arm should be supported by 
the site staff (during standing measurements). A standard bladder (12-13 cm width and 35 cm 
long) or larger or smaller depending on the patient’s arm circumference should be used. Blood 
pressure should be measured in the seated position after at least 10 minutes of wait. Heart rate
will be measured concomitantly with BP measurements using the electronic device, if available or 
with the same methodology applied consistently throughout the study.
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9.2.4.2
Screening visit (determination of reference arm)
Blood pressure will be measured seated in both arms to detect possible differences. The arm with 
the higher value will be used as a reference and all subsequent BP measurements will occur on 
this arm. 
9.2.4.3
Measurements for assessing presence or not of orthostatic hypotension
In seated position, three BP measurements spaced 1-2 min apart should be done, if an automated 
device is available preferably in absence of the investigator. The average of the 3 readings is 
considered the seated BP value for comparison with standing BPs. The investigator or designee 
will be present. The patient will be instructed to stand and then a single BP and HR measurement 
will be obtained at Minute 3 and Minute 5 in the standing position. The lower BP value of the two 
standing BP values, regardless of whether at Minute 3 or Minute 5, will be used for assessing any 
orthostatic effect. Symptoms will not be elicited but rather spontaneously reported by the patient
during this time. The Vital signs data are collected in accordance with the study schedule 
(Section 1.3 and Section 1.4).

Heart rate and BP to check for orthostatic hypotension will be performed by the 
investigator or designee before morning administration on visit days except on Day 1 
which requires before morning administration, at T1h and T3h.
Of note:
-
No increase and maintenance of the dose at the same level in case of asymptomatic
orthostatic hypotension with SBP decreases at Minute 3 or Minute 5 between seated
and standing position ≥30 mmHg,
-
Decrease of the dose to the previous level in case of symptomatic orthostatic 
hypotension with SBP decreases at Minute 3 or Minute 5 between seated and standing 
position ≥20 mmHg or hypotension with SBP <90 mmHg. If the starting dose of 5 mg 
BID is not tolerated, based on investigator’s judgment, the dose could be decreased to 
2.5 mg BID dose,
-
If 2.5 mg BID dose is not tolerated, the study drug will be discontinued.
9.2.5
Electrocardiogram variables
Electrocardiogram data will be assessed by the Investigator.
Twelve-lead ECGs recorded after at least 10 minutes rest will be performed in accordance with 
the study schedule (Section 1.3 and Section 1.4).
Measurements of ECG parameters are initially made automatically by a computerized 
electrocardiograph and further interpreted by the investigator. 
The printout includes the date, time, initials and patient number as well as an automatic 
measurement of heart rate in beats per minute, PR interval (msec), QRS interval (msec), QT 
interval (msec), and QTc interval (msec) corrected for heart rate using Fridericia’s (QTcF) 
formula. If the printout doesn’t include either one of the corrected QT, it will be calculated by the 
investigator using Fridericia’s formula. 
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Note: Any abnormal ECG parameter is immediately rechecked for confirmation before making a 
decision of permanent discontinuation of IMP for the concerned patient. ECG parameters include: 
heart rate, PR, QRS, QT, QTc automatic correction evaluation (by the ECG device).
Please note that due to different scenarios related to the visit window of the D1 PET assessment, 
the following ECG schedule should be followed:

If PET assessment done at D1 visit: 
-
ECG recorded prior PET (T-3H) and monitored during the PET (up to the end of PET 
[T-0H30]).

If PET assessment done during screening period and not at  D1 visit:
-
ECG recorded prior PET and monitored during the PET (up to the end of PET [T-
0H30]).
-
ECG recorded on D1 prior 1st dosing (could be repeated just before dosing according 
to creatinine results availability).
Please note that the following ECG schedule should be followed on Day 29 or Day 30 or Day 31:

ECG recorded at arrival on site (before dosing) and monitored during the PET (up to the 
end of PET [T-0H30]).
9.3
PHARMACOKINETIC ENDPOINT
9.3.1
Pharmacokinetics
9.3.1.1
Sampling time
A total of seven pharmacokinetic samples will be collected in all patients as follow: 1 hour and 
3 hours post-dose on Day 1, pre-dose on Day 8, Day 15 and Day 22, and pre-dose and 1 to 3 hours 
post-dose on Day 29 (see Section 1.3). In case of premature study drug discontinuation a 
pharmacokinetic blood sample will be collected as soon as possible and no later than 3 days after 
the last study drug intake.
9.3.1.2
Pharmacokinetics handling procedure
Special procedures for collection, storage and shipping of plasma will be described in a separate 
laboratory manual.
9.3.1.3
Bioanalytical method
Concentrations of SAR407899 in plasma samples will be measured using a validated liquid 
chromatography method coupled with tandem mass spectrometry (LC-MS/MS) with a lower limit 
of quantification of 1 ng/mL (DOH1425) under the responsibility of Covance Laboratories.
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9.3.1.4
Pharmacokinetics parameters
Observed SAR407899 concentrations will be reported in the clinical study report.  A population 
pharmacokinetic analysis may be conducted and will be reported in a separated report.
9.3.2
Pharmacogenetic assessment
9.3.2.1
Drug metabolizing enzymes DNA sample 
Not applicable.
9.3.2.2
Optional stored DNA sample
For those patients who signed the optional pharmacogenetic informed consent form, a blood 
sample will be collected at the study visit as specified in the study flow chart and this sample will
be stored for up to 15 years after completion of the final study report of the main clinical trial. 
This sample may be used to determine a possible relationship between genes and response to 
treatment with SAR407899, how the body processes SAR407899, and possible side effects to 
SAR407899. Genes that may be studied include those related to ROCK pathway and/or 
endothelial dysfunction. This blood sample will be transferred to a site that will, on behalf of 
Sanofi, extract DNA from the sample and that is managed by Covance.
This blood sample, and the DNA that is extracted from it, will be assigned a second number, a 
genetic ID (deidentification code) that is different from the patient ID. This “double coding” is 
performed to separate a subject’s medical information and DNA data.
The clinical study data (coded by subject ID) will be stored in the clinical data management 
system (CDMS), which is a distinct database in a separate environment from the database 
containing the pharmacogenetic data (coded by genetic ID). The key linking subject 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.
Special procedures for storage and shipping of pharmacogenetic samples are described in a 
separate laboratory manual and in Appendix B.
 
 
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9.4.1
Sampling / handling procedures
Table 1 - Summary of sampling/handling procedures for 
Sample volume
10 mL blood
Matrix
Serum
Anticoagulant
None 
Handling procedures
See laboratory manual
Aliquot split
4 aliquots with 1 mL serum for the first three aliquots, at each timepoint
Storage conditions
-20C
Shipment conditions
In dry ice
Table 2 - Summary of sampling/handling procedures for 
Sample volume
10 mL blood
Matrix
Serum
Anticoagulant
None 
Handling procedures
See laboratory manual
Aliquot split
4 aliquots with 1 mL serum for the first three aliquots, at each timepoint
Storage conditions
-20C
Shipment conditions
In dry ice
Special procedures for collection, storage and shipping of blood/plasma/serum will be described 
in a separate laboratory manual.
9.4.2
Biomarker assay methods
The methods are still under development. Methods will be described in a separate laboratory 
manual.
9.5
FUTURE USE OF SAMPLES FOR BIOMARKER SAMPLES
Table 3 - Summary of sampling/handling procedures for future use of samples 
Sample volume
4 mL blood
Matrix
Serum
Anticoagulant
None 
Handling procedures
See laboratory manual
Aliquot split
8 aliquot of 0.250 mL serum at each timepoint
Storage conditions
-20C
Shipment conditions
In dry ice
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For patients who have consented to it, one sample will be collected at the visits specified in the 
study flow chart and these samples will be stored for up to 15 years after completion of the final 
study report. These samples may be used for other research purposes (excluding genetic analysis) 
related to endothelial dysfunction and/or microvascular angina.
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 than the one used during the study 
(ie, subject 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 subject confidentiality and personal data.
Special procedures for storage and shipping are described in a separate laboratory manual.
9.6
SAMPLE BLOOD VOLUME
Sample blood volume is presented in the table below.
Table 4 - Sampled blood volume
Type
Volume per sample
Sample number
Total
Laboratory
5 mL
7
35 mL
10 mL
1
10 mL
10 mL
1
10 mL
Future use of sample
2.5 mL
1
  2.5 mL
Pharmacogenetics 
6 mL
1
  6 mL
Pharmacokinetics
2 mL
7
14 mL
Total for male patient
Approximately up 
to 80 mL
FSH
10 mL
1
10 mL
Total for female 
patient
Approximately up 
to 90 mL
9.7
APPROPRIATENESS OF MEASUREMENTS 
Please refer to Section 4.
Primary endpoint:
Change from baseline to end of study treatment/Week 4, in uncorrected global CFR assessed by 
13N-ammonia or 82Rubidium PET scan will be the primary endpoint as CFR represents the 
increase in blood flow to the myocardium in response to metabolic or pharmacological 
stimulations, the critical factor in angina. CFR is the endpoint with the most abundant clinical data 
in MVA patients. An abnormal CFR is <2.0.
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The standard deviation and the mean of the placebo group of a study published by (1), using a 
noninvasive measures of coronary flow reserve based on rest/stress PET in 2783 patients with 
known or suspected coronary artery disease, were used in sample size calculation. 
Secondary endpoints:
Change from baseline to end of study treatment/Week 4 in physical limitation as assessed by the 
SAQ-PL will be the secondary endpoint as it relates to patients’ physical activity. The Seattle 
Angina Questionnaire (SAQ) is widely used to understand patients’ perceptions of cardiovascular 
disease and symptoms. It was used in pilot MVA studies. Although data will be collected on 
multiple dimensions of the SAQ, the physical limitation (PL) dimension is the most relevant for 
defining treatment benefit in this population.
SAR407899 peak and trough concentrations will also be assessed as secondary endpoint as no 
data on microvascular angina patient and/or persistent stable angina despite angiographically 
successful PCI population are available with this compound.
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10
STUDY PROCEDURES
10.1
VISIT SCHEDULE
10.1.1 Visit 0: Screening visit
The screening visit has to be performed 4 weeks to one day before scheduled (first) dosing 
(Day 1) and up to 6 weeks in patients before scheduled (first) dosing with CCTA during 
screening.
Informed Consent
Information on the study will be given to and discussed with the patient. The patient will sign the 
informed consent for the current trial before any procedure. When the consent has been obtained, 
full identification of patient and personal physician will be recorded for the Investigator’s record, 
and a subject number will be assigned as described in Section 8.3.
Also the informed consents have to be obtained for the optional DNA banking and future use of 
samples for possible later further analyses.
Collection of adverse events has to be started from the time of signing informed consent. The 
patient has to be registered with the IVRS/IWRS.
After the inform consent has been signed, the following measurements have to be performed:

Call IVRS/IWRS to assign patient number.

Demographic information.

Collection of prior/concomitant medications.

Begin AEs reporting.

Medical/surgical history.

Data of previous (if done 24 months prior to screening) coronary artery angiography or 
CCTA.

Data of previous (if done between 24 months and 5 years prior to screening) coronary 
artery angiography or CCTA.

Data of previous (if done 24 months prior to screening) CFR assessment whatever the 
method.

Assessment of inclusion and exclusion criteria.

Physical examination (including smoking habits).

Body weight and height.

Vital signs, resting 12 lead-ECG.
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Patients who do not met inclusion criteria and/or met at least one exclusion criterion will be 
considered a screening failure and will not perform the following measurements:

Blood sampling for hematology, biochemistry and plasma FSH (For 
post-menopausal female patients not treated with HRT).

Blood sampling for renal function (blood creatinine and cystatin C).

Collection of urine for urinalysis.

A patient diary will be dispensed to the eligible patients in order to record their angina 
episodes and the short-acting nitrates intakes.

Patients who meet all the inclusion criteria and none of the exclusion will be potentially 
eligible for inclusion into the study depending on PET scan CFR value assessed at baseline 
visit or if not otherwise possible up to 14 days prior to Day 1 (except for patients described 
below where PET scan will be performed up to 4 weeks prior to Day 1). A visit within the 
next 4 weeks will be scheduled.
In patients diagnosed with MVA and stable angina without previous PCI, who did not have 
coronary angiogram or CCTA in the previous 24 months but within 5 years, a CCTA will be 
performed during screening period provided that:

These patients meet all inclusion criteria including qualifying PET scan and CFR<2.0 up 
to 4 weeks before Day 1 visit. If not, the patient will be screen failed and will not have 
CCTA.
The Investigator will call the patient to confirm the date for CCTA, to be performed in order to 
have the results before Day 1 visit to ascertain the absence of obstructive coronary arteries.
At the end of the screening visit, the patient should be informed and follow restriction rules for 
PET scan investigation: methylxanthines (eg, caffeine) will be forbidden 24 hours prior to the test 
otherwise PET scan should be re-scheduled one day after. All site visits whereby the PET 
assessment is not performed on the same day as the site visit will not require fasting or other 
dietary / medication restrictions.
Screening failure
If the patient is not eligible after this visit and after all reports are available, this information has
to be entered into the IVRS/IWRS by a screening failure call.
In case the PET scan cannot be performed in the allowed time window for logistical reasons, the 
patient can be re-screened after consultation with the sponsor.
10.1.2 Visit 1: Baseline / Randomization / Day 1
The patient has to go on Day 1 morning to the investigational site for his / her visit.
Patients diagnosed with MVA and stable angina without PCI, who did not have a coronary 
angiogram or CCTA in the previous 24 months but between 24 months to 5 years, need to have 
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the PET assessment followed by the CCTA during the screening period. Other patients will have 
their PET scan up to 14 days before Day 1 visit or on Day 1 visit.
For the PET assessment, the patient should be in fasting state (at least 4 hours) and well hydrated 
and should avoid, in the following timely manner (whenever possible), the intake of:

24 hours before CFR assessment :
-
Anti-hypertensive drugs,
-
Beta blockers,
-
Calcium channel blockers,
-
Methylxanthines including caffeinated coffee, tea or other caffeinated beverages, 
caffeine-containing drug products.

At least 4 hours before CFR assessment:
-
Nicotine,
-
Short acting nitrate.
If not, this visit should be re-scheduled one day after with the restrictions re-explained to the 
patient.
The following assessments are to be completed at Day 1 as follows:

Quality of life questionnaires should be filled in prior any other assessment and without 
any help:
-
Seattle Angina Questionnaire,
-
Patients’ perceptions of treatment and symptoms.

Resources utilization.
Prior any IMP administration, the following assessments will be performed:

Assessment of part of inclusion and exclusion criteria.

Physical examination (including smoking habits).

Patient diary evaluation: angina episodes with severity (intake of short-acting nitrate).

Body weight.

Body temperature.

DNA blood sample (provided appropriate consent has been obtained).

Blood sampling for future use of samples (provided appropriate consent has been 
obtained).

Blood sampling for renal function (blood creatinine and cystatin C).

Blood sampling for hematology, biochemistry.
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
Collection of urine for urinalysis.

Vital signs including orthostatic BP measurements and resting 12 lead-ECG.

Coronary Flow Reserve assessed by vasodilator stress PET scan with NIMPs 
administration (can be performed up to 14 days prior to Day 1).

AEs collection.

Concomitant treatments reporting.
One hour before dosing, a standard meal can be given to the patient.
Just before the study drug administration, 12 lead-ECG and vital signs assessments will be 
performed (only if PET scan is done at Day 1 or according to creatinine results availability if PET 
scan done prior to Day 1).
If the patient is still eligible after all assessments, the investigator or designee will call the 
IVRS/IWRS to randomize the patient and obtain a treatment number assigned by IVRS/IWRS.
If the patient is not eligible after these assessments, this information has to be entered into the 
IVRS/IWRS by a screening failure call.
Then the 1st IMP intake has to be given on Day 1.
After dosing the following assessments have to be performed according to the period flow chart 
(see at Section 1.4):

Evaluation of AEs and concomitant medication.

Vital signs at T1h and T3h post IMP intake.

Resting 12 lead ECG.

Collection of PK sample (T1h and T3h).
If no clinically relevant findings have been detected from all safety examinations until then, the
patient can leave the unit in the evening or earlier depending on the investigator’s judgment of 
Day 1. 
Day 1 discharge time:

Before the patient leave the unit, he/she will be given sufficient study drug (packaged in a 
Wallet) for 1 treatment week (±2 days).

At home, the patient will take the IMP twice a day (morning and bedtime) and will report 
on his patient diary IMP information and the angina episodes that will occur and short-
acting nitrate intakes.

In case a patient does not tolerate a dose, he/she should call the investigator to have an 
on-site visit. Based on the tolerability assessed at this visit, the investigator could decide to 
stop or modify study drug dose (the IVRS/IWRS will be called in that cases).
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10.1.3 Visits 2, 3, and 4: Days 8, 15, and 22 (+/- 2 days) 
During the titration phase, patient’s visits are performed at the clinical site. The following 
assessments have to be performed before the administration:

Physical examination may be symptoms driven at the investigator’s discretion.

Collection of information about concomitant medication/concomitant treatment reporting.

AEs collection.

Vital signs (BP & heart rate measurements including search of hypotension) and resting 12 
lead-ECG before study drug administration.

Collection for PK samples (pre-dose).

Collection for renal function (blood creatinine and cystatin C).

Collection for hematology (except at D15 and D22), biochemistry.

Patient diary (one per week) review & dispensation.

Call IVRS/IWRS to obtain the treatment kit code after specifying the chosen titration.

After these assessments, the IMP morning administration could be done.

In case a patient does not tolerate a dose, he/she should call the investigator to have an on-
site visit. Based on the tolerability assessed at this visit, the investigator could decide to 
stop or modify study drug dose.

Before the patient leave the unit, he/she will be given sufficient study drug (packaged in a 
Wallet) for 1 treatment week (±2 days).

At home, the patient will take the IMP twice a day (morning and bedtime) and will report 
on his patient diary IMP information and the angina episodes that will occur and short-
acting nitroglycerin intakes.
10.1.4 Visit 5: End of treatment: Day 29 (or up to 2 days after at the latest) even in case of
early IMP discontinuation
The patient arrives to the clinical site in the morning on Day 29 (or up to 2 days after at the latest) 
and should be in fasting state (at least 4 hours) and well hydrated and should avoid, in the 
following timely manner (whenever possible), the intake of as it relates to the PET assessment:

24 hours before CFR assessment :
-
Anti-hypertensive drugs,
-
Beta blockers,
-
Calcium channel blockers,
-
Methylxanthines including caffeinated coffee, tea or other caffeinated beverages, 
caffeine-containing drug products.

At least 4 hours before CFR assessment :
-
Nicotine,
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-
Short acting nitrate.
IMP administration should be continued until the visit to the site.
The following assessments have to be performed:

Quality of life questionnaires should be filled in prior any other assessment and without 
any help:
-
Seattle Angina Questionnaire,
-
Patients’ perceptions of treatment and symptoms.

Physical examination (including smoking habits).

Patient diary collection.

Body weight.

Body temperature.

Vital signs including search of orthostatic BP measurements and resting 12 lead-ECG.

Blood sampling for renal function (blood creatinine and cystatin C).

Blood sampling for hematology, biochemistry.

Collection of urine for urinalysis.

Collection of PK samples (pre-dose).

AEs collection.

Collection of information about any concomitant medications.
After IMP intake:

Coronary flow reserve assessed by vasodilator stress PET scan with NIMPs 
administration, is performed approximately 1 to 2 hours after IMP intake.

Collection of PK samples (1-3h post-dose).

Call IVRS/IWRS to declare the end of treatment for this patient, except if patient has delay 
in end-of-treatment PET scan.
If no clinically relevant findings have been detected from all safety examinations until then, the 
patient can be discharged from the unit in the evening or earlier depending of the investigator’s 
judgment.
Approximately seven days after the last study drug intake, the investigator will prescribe if needed 
anti-anginal drugs (ie, nitrates) and/or PDE 5 inhibitor.
Only if PET scan performed after Day 29 visit, at home, the patient will take the IMP twice a day 
(morning and bedtime) and will report on his patient diary IMP information and the angina 
episodes that will occur and short-acting nitroglycerin intakes.
In case of early IMP discontinuation: 
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-
Within the first 2 weeks of study treatment patients are to be assessed as soon as 
possible after study drug stop, using the procedures (except PET scan) planned for the 
D29/end of treatment visit, including a pharmacokinetic sample (to be collected no 
later than 3 days after the last study drug intake).
-
With at least 2 weeks of study treatment patients are to be assessed as soon as possible 
after study drug stop, using the procedures planned for the D29/end of treatment visit, 
including a pharmacokinetic sample (to be collected no later than 3 days after the last 
study drug intake). PET scan can be performed up to 3 days after study drug 
discontinuation.
10.1.5 Visit 6: End of study: Day 36 (+/- 2 days) 
Visit at clinical site:

Patient’s diary review.

Vital signs (BP & heart rate measurements including search of hypotension) and resting 
12 lead ECG.

Blood sampling for hematology, biochemistry.

Blood sampling for renal function (blood creatinine and cystatin C).

AEs collection.

Collection of information about any concomitant medications.
Study restriction(s)
There is no restriction of meals with regard to contents or time schedule.
This visit is not mandatory in case of premature treatment discontinuation.
10.2
DEFINITION OF SOURCE DATA
All evaluations listed below that are reported in the CRF must be supported by appropriately
signed identified source documentation related to:

Patient identification.

Medical/surgical history.

Dates and times of visits and assessments.

Physical examination, cardiological examination.

Vital signs, body weight and height, body temperature.

Resting 12-lead ECGs results.

Laboratory result.

Pharmacokinetic & Biomarker time points.
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
Adverse events.

IMP administration.

Previous/concomitant medication, including start of medication and time of change in
dosing regimen.

SAQ.

PET scan CFR reports of assessments performed during the patient’s study participation.

CCTA results if any.

Coronary artery angiography results if any.

Patient’s diaries.

Patient perceptions of treatment and symptoms.

Resources utilization.
10.3
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION 
The IMP should be continued whenever possible. Permanent IMP discontinuation should be a last 
resort. Any IMP discontinuation should be fully documented in the CRF. In any case, the patient 
should remain in the study as long as possible.

Pregnancy will lead to definitive treatment discontinuation in all cases.

Additional stopping rules described in Appendix A and Section 8.1 should be applied, 
if applicable. 
10.3.1 Temporary treatment discontinuation with investigational medicinal product(s)
Not applicable.
10.3.2 Permanent treatment discontinuation with investigational medicinal product(s)
Permanent treatment discontinuation is any treatment discontinuation associated with the 
definitive decision from the Investigator or the patient not to re-expose the patient to the IMP at 
any time. 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 
e-CRF.
IMP may be permanently discontinued in case of the following events. The list is not intended to 
be exhaustive:

Severe symptomatic orthostatic hypotension or postural dizziness (defined as requiring 
medical intervention or hospitalization) (see Section 10.4.5).
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
Any serious or severe Grade 3 related adverse event will lead to permanent treatment 
discontinuation.

Adverse events of lesser grade should be evaluated in the context of concomitant clinical 
and laboratory findings and, in the judgment of the Investigator, may be cause of
permanent discontinuation of treatment for an individual subject.

Symptoms of severe hypersensitivity or anaphylactic reactions.

If 
 dose is not tolerated.

Significant laboratory abnormalities (see Section 10.4.6 and Appendix A):
-
Confirmed ALT >5 ULN or confirmed ALT >3 ULN and total bilirubin >2 ULN 
(unless the patient has Gilbert’s disease documented by genetic testing),
-
Confirmed neutrophil count <1500/mm3 with or without signs of infection,
-
Suspected rhabdomyolysis with confirmed CPK >10 ULN,
-
Confirmed platelet count <100,000 cells/mm3 with or without spontaneous bleeding,
-
Confirmed decline in total white blood cell count of >50% compared to baseline and 
white blood cell count Grade 1  (<LLN -3000/mm3),
-
Confirmed decline in hemoglobin of >3 g/dL compared to baseline and hemoglobin 
level Grade 1 (< LLN -10g/dL) or higher of CTCAE terminology,
-
Confirmed QTc >500 ms.

Pregnancy.

Any adverse events, per Investigator’s judgment, that may jeopardize the patient’s safety.

Any code breaking requested by the Investigator will lead to permanent treatment 
discontinuation.

At the specific request of the Sponsor.
Any abnormal laboratory value or ECG parameter will be immediately rechecked for 
confirmation before making a decision of permanent discontinuation of the IMP for the concerned 
patient.  All efforts should be made to reassess in a clinically relevant timeframe, the clinical 
significance of lab abnormalities and corrective actions before making a decision of permanent 
discontinuation of the IMP for the concerned patient.
10.3.3 Handling of patients after permanent treatment discontinuation
Patients will be followed-up and every effort should be done to have the end of study 
treatment/Day 29 visit completed 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 should be recorded by the Investigator in the 
appropriate pages of the e-CRF when considered as confirmed.
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10.3.4 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. 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 records check. Patients requesting withdrawal should be informed 
that withdrawal of consent for follow-up may jeopardize the public health value of the study.
Every effort should be made to convince the patients to perform the end of study treatment/D29
with assessment of primary and secondary endpoints including blood samples and 
pharmacokinetic samples. The end of study visit (D36) one week later should be done. This visit 
is not mandatory in case of premature study drug discontinuation.
Patients who withdraw should be explicitly asked about the contribution of possible AEs to their 
decision to withdraw consent, and any AE information elicited should be documented. Preferably 
the patient should withdraw consent in writing and, if the patient or the patient’s representative 
refuses or is physically unavailable, the site should document and sign the reason for the patient’s 
failure to withdraw consent in writing. 
All study withdrawals should be recorded by the Investigator in the appropriate screens of the 
e-CRF 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.
For patients who fail to return to the site, unless the patient withdraws consent for follow-up, the 
investigator should make the best effort to re-contact 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). The statistical analysis plan will specify how these patients 
inevaluable for their primary endpoints will be considered.
Patients who have withdrawn from the study cannot be re-randomized (treated) in the study. Their 
inclusion and treatment numbers must not be reused. 
10.4
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING
10.4.1 Definitions of adverse events 
10.4.1.1 Adverse event
An adverse event (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.
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Intensity of an AE is defined as:

Mild: no modification of daily activities and does not require mandatory 
corrective/symptomatic treatment.

Moderate: hinders normal daily activities and/or requires mandatory 
corrective/symptomatic treatment.

Severe: prevents daily activities and requires mandatory corrective/symptomatic treatment.
10.4.1.2 Serious adverse event
A serious adverse event (SAE) is any untoward medical occurrence that at any dose:

Results in death, or,

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).

ALT >3 x ULN + total bilirubin >2 x ULN or asymptomatic ALT increase >5 x ULN.

Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling).

Bullous cutaneous eruptions.
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10.4.1.3 Adverse event of special interest
An adverse event of special interest (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.

Pregnancy of a female subject entered in a study as well as pregnancy occurring in a 
female partner of a male subject entered in a study with IMP:
-
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 participant, IMP should be discontinued,
-
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined.

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.

Increase in alanine transaminase (ALT)>3xULN (see Appendix A of the protocol).

QTc ≥500ms.

Hypotension/orthostatic hypotension symptomatic or not defined as: 
-
Asymptomatic orthostatic hypotension with SBP decrease at Minute 3 or Minute 5
between seated and standing position ≥30 mmHg,
-
SBP <90 mmHg,
-
Symptomatic orthostatic hypotension with SBP decrease at Minute 3 or Minute 5
between seated and standing position ≥20 mmHg,
-
Symptoms of hypotension (either orthostatic or non-postural) include: presyncope, 
including any symptoms of dizziness, faintness or lightheadedness appearing while 
standing up and possibly caused by a drop in BP and/or appearing while standing up,
-
Whenever possible, concomitant medications, BP and heart rate measurements in 
seated and standing positions, plasma glucose level and ECG will be collected at or 
near the time of the event or per the investigator’s clinical judgment,
-
For any such event, the appropriate AESI eCRF screen must be filled out.
Note: the following non-pharmacological measures will be encouraged by discussing with the 
patient: If a patient experiences faint-headedness or unusual dizziness, he or she will assume a 
seated position and, if still dizzy, either lie down or, while seated, place the head between the 
knees until dizziness has passed; the patient will be recommended to drink at least 12 ounces 
(375 mL) of fluid.
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10.4.2 Serious adverse events waived from expedited regulatory reporting to regulatory 
authorities
Not applicable.
10.4.3 General guidelines for reporting adverse events

All AEs, regardless of seriousness or relationship to IMP/NIMP, 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/NIMP 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. Patients who experience an ongoing SAE or an 
AESI, at the prespecified study end-date, should be followed until resolution, 
stabilization, or death and related data will be collected,
-
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 or ECG 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.
Instructions for AE reporting are summarized in Table 5.
10.4.4 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 e-CRF; the system will automatically send a notification to the monitoring team after 
approval of the Investigator within the e-CRF or after a standard delay.
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
SEND (preferably by fax or e-mail) a photocopy of all examinations carried out and the 
dates on which these examinations were performed, to the representative of the monitoring 
team whose name, fax number, and email address appear on the clinical trial protocol. 
Care should be taken to ensure that the patient's identity is protected and the patient's 
identifiers in the clinical trial are properly mentioned on any copy of a source document 
provided to the Sponsor. For laboratory results, include the laboratory normal ranges.

All further data updates should be recorded in the e-CRF 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 
e-CRF 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.
10.4.5 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 10.4.4, even if not fulfilling a seriousness criterion, 
using the corresponding pages of the CRF (to be sent) or screens in the e-CRF. Instructions for 
AE reporting are summarized in Table 5.
10.4.6 Guidelines for management of specific laboratory abnormalities
Decision trees for the management of certain laboratory abnormalities by Sanofi are provided in 
Appendix A. 
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.
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Table 5 - Summary of adverse event reporting instructions
Event 
category
Reporting 
timeframe
Specific events in this category
Case Report Form completion
AE form
Safety 
Complementary 
Form
Other 
specific 
forms
Adverse Event 
(non-SAE, 
non-AESI)
Routine
Any AE that is not SAE or AESI
Yes
No
No
Serious Adverse 
Event (non-AESI 
or AESI)
Expedited 
(within 24 hours)
Any AE meeting seriousness criterion per 
Section 10.4.1.2
Yes
Yes
No
Adverse Event of 
Special Interest 
Expedited 
(within 24 hours)
Pregnancy
Yes
Yes
Yes
Symptomatic overdose with IMP
Yes
Yes
No
ALT increase as defined in the protocol
Yes
Yes
Yes
QTc ≥500ms
Yes
Yes
No
Hypotension/orthostatic hypotension 
(asymptomatic and symptomatic)
Yes
Yes
No 
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 investigator’s brochure.
Any other AE not listed as an expected event in the Investigator’s Brochure or in this protocol 
will be considered unexpected.
For regulatory purposes, the treatment code will be unblinded at Sponsor Pharmacovigilance 
department level for reporting to the Health Authorities of any suspected unexpected adverse drug 
reaction (SUSAR) and reasonably associated with the use of the IMP according to either the 
judgment of the Investigator and/or the Sponsor. Apart from Sponsor Pharmacovigilance 
department, within the company and associated organizations, the results of this unblinding will 
remained undisclosed.
The Sponsor will report all safety observations made during the conduct of the trial in the clinical 
study report.
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10.6
SAFETY INSTRUCTIONS
In case of signs or symptoms suggestive of hypotension or orthostatic hypotension occur, physical 
examinations will include respiratory, cardiovascular systems; clinical management of this 
hypotension should be undertaken by the investigator. If the event persisted, decision of IMP
discontinuation should be discussed with the Sponsor.
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
The sample size calculations are based on the primary efficacy variable of uncorrected global
CFR assessed by 13N-ammonia or 82Rubidium PET scan change from baseline to Week 4.
Assumptions for sample size calculation:

A large study of 2783 patients referred for rest/stress positron emission tomography
suggested a SD 0.65 for CFR at baseline. With the hypothesis of correlation of 
0.6 between baseline assessment and Week 4 assessment the SD for the change of baseline 
to week for could be estimated at 0.58

A t-test at a 1-sided 5% significance level.
Based on the above assumptions, 35 evaluable patients per arm are needed for this study to detect 
a treatment effect of 0.35 with 80% of power. 10% more patients will be randomized in each 
group. Thus, approximately 78 patients will be randomized in this study, 39 per arm.
Calculations were made using East 6.3.
11.2
DISPOSITION OF PATIENTS
Screened patients are defined as any patient who originally met the inclusion criteria and signed 
the informed consent. 
Randomized patients consist of all screened patients with a double-blind treatment kit number 
allocated and recorded in the IVRS/IWRS database, 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. The safety experience of patients treated and not randomized 
will be reported separately, and these patients will not be in the safety 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.
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11.3
ANALYSIS POPULATIONS
11.3.1 Efficacy populations
11.3.1.1 Modified intent-to-treat population
The primary population for analysis will be the modified ITT (mITT) population: all randomized 
patients analyzed according to the treatment group allocated by randomization, who received at 
least a dose or part of a dose of the IMP and with an evaluable primary efficacy endpoint. The 
primary efficacy endpoint will be considered evaluable when the baseline CFR assessment is 
available.
11.3.2 Safety population
The safety population will be the as-treated population, defined as randomized population who did 
actually receive at least one dose or part of a dose of IMP and analyzed according to the treatment 
actually received.
In addition: 

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 active group if at least one active dose or part 
of a dose was taken.  
11.3.3 Pharmacokinetic and biomarker analysis population
The population for all PK analyses will be all randomized and treated patients (safety population) 
having at least one sample.
The population for BM analysis will be randomized and treated patients from selected sites having 
at least a baseline and a post-baseline biomarker assessment.
11.4
STATISTICAL METHODS
11.4.1 Extent of study treatment exposure and compliance
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. 
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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, above-planned and under-planned dosing percentages will be summarized 
descriptively (N, mean, SD, median, min, and max). The percentage of patients with compliance 
<80% will be summarized. In addition, the number and percentage of patients with at least 
1 above-planned dosing administration will be given, as well as the number and percentage of 
patients with 0, (0, 20%], and >20% under-planned dosing administrations.
11.4.2 Analyses of efficacy endpoints
11.4.2.1 Analysis of primary efficacy endpoint
Model assumptions for normality will be explored prior to the analysis testing.
Assuming that the change in CFR from baseline to Week 4 distribution is normal, an analysis of 
covariance (ANCOVA) model including the two following fixed categorical effect: treatment 
group (pooled SAR407899 doses versus placebo) and the presence of angiographically successful 
PCI (YES/NO) as well as a continuous fixed covariate of baseline CFR will be fitted. The 
interaction factors will be explored. The final model will provide adjusted least-squares means 
(LS means) estimates of the change from baseline to Week 4 in both treatment groups with their 
corresponding 95% confidence intervals (CIs). The difference of these estimates will be tested at 
the 1-sided 5% level using an appropriate contrast statement and the 95% confidence interval of 
the difference will be provided.
Let μ0 and μ1 be the population means of the change from baseline to Week 4 in CFR under 
placebo and SAR407899, respectively. The null hypothesis that will be tested is: 
H0: μ0 = μ1 versus H1: μ0 ≠ μ1.
Robustness of this statistical method will be assessed via sensitivity analyses detailed in the 
Statistical Analysis Plan (SAP), including different methodologies for missing data (multiple 
imputation and potentially pattern mixture modeling).
In this primary analysis, the mITT population is considered and the Week 4 assessments will be 
used regardless of whether the patient has previously discontinued the treatment. 
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11.4.2.2 Analyses of secondary efficacy endpoints 
The score of the SAQ-Physical Limitation scale will be derived according to the SAQ scoring 
instructions.
Assuming that the change from baseline to Week 4 in SAQ-Physical Limitation score distribution 
is normal, a similar model as primary analysis will be fitted. The interaction factors will be 
explored. The final model will provide adjusted least-squares means (LS means) estimates of the 
change from baseline to Week 4 in both treatment groups with their corresponding 
95% confidence intervals (CIs). The difference of these estimates will be tested at the 1-sided 
10% level using an appropriate contrast statement and the 95% confidence interval of the 
difference will be provided.
In this analysis, the mITT population is considered and the Week 4 assessments will be used 
regardless of whether the patient has previously discontinued the treatment.
11.4.2.3 Multiplicity considerations
Results of secondary analysis are considered informative ONLY if the primary analysis is 
positive, therefore the study overall type I error does not need to be adjusted for multiplicity.
For secondary and exploratory efficacy endpoints, p-values will be provided for descriptive 
purpose only.
11.4.3 Analyses of safety data 
The summary of safety results will be presented by treatment group on the basis of the safety 
population. 
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 randomization. 

The analysis of the safety variables will be essentially descriptive and no hypothesis 
testing is planned.
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. 
PCSA criteria will determine which patients had at least 1 PCSA during the TEAE period, taking 
into account all evaluations performed during the TEAE period, including unscheduled or 
repeated evaluations. The number of all such patients will be the numerator for the PCSA 
percentage. 
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Observation period

The TEAE observation period is defined as the time from the first dose of IMP up to 
7 days after the last dose of IMP.

The on-study period is defined as the time from randomization until the end of the study 
(see definition in Section 6.2.1).
11.4.3.1 Adverse events
Treatment-emergent AEs, treatment-emergent SAEs, TEAEs leading to treatment discontinuation 
and treatment-emergent AESIs will be summarized for each treatment group based on MedDRA 
coding of verbatim terms reported by investigators.
Analysis of TEAEs
Treatment emergent adverse event incidence tables will be presented 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, the number (n) and
percentage (%) of patients experiencing at least one TEAE. 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.
Analysis of all treatment-emergent SAEs
All treatment-emergent SAEs will be presented by primary SOC, HLGT, HLT, and PT, showing 
number (%) of patients with at least 1 serious TEAE, sorted by SOC internationally agreed order. 
The order levels (HLGT, HLT, PT) will be presented in alphabetical order. Listings will be 
provided for all SAEs by treatment group and patient with flags indicating on-treatment status.
Analysis of all TEAEs leading to permanent treatment discontinuation
TEAEs leading to treatment discontinuation will be presented by primary SOC, HLGT, HLT, and 
PT, showing number (%) of patients with at least 1 TEAE leading to permanent treatment 
discontinuation, sorted by SOC internationally agreed order. The order levels (HLGT, HLT, PT) 
will be presented in alphabetical order. Listings will be provided for all TEAE leading to 
permanent treatment discontinuation by treatment group and patient.
Analysis of treatment-emergent AESI:
Treatment-emergent AESI, by AESI category and PT, will show number (%) of patients overall, 
sorted by decreasing incidence of PT within each AESI category. The AESIs include, but are not 
limited to, the following categories and details of the MedDRA coding will be provided in the 
SAP: (see AESI list in Section 10.4.1.3): AESIs include hypotension/orthostatic hypotension 
symptomatic or not.
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Analysis of Deaths
The following deaths summaries will be generated:

Number (%) of patients who died by study period (TEAE, on-study) and reasons for death 
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 CRF page as reported by the 
Investigator) by primary SOC , HLGT, HLT and PT showing number (%) of patients 
sorted by internationally agreed order of SOC and alphabetic order of HLGT, HLT, and 
PT. 
11.4.3.2 Laboratory data
The summary statistics (including number, mean, median, Q1, Q3, standard deviation, minimum 
and maximum) of all laboratory variables will be calculated for each visit or study assessment 
(baseline, each post-baseline time point, endpoint) by treatment group. Listings will be provided 
with flags indicating the out of range values as well as the PCSA values. 
The incidence of PCSA at any time will be summarized by treatment group for each laboratory 
parameter. Shift tables showing changes with respect to the baseline status will be provided.
11.4.3.3 Potential drug-induced liver injury
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 
post-baseline visit by baseline status will be displayed by treatment group for each parameter. The 
proportion of patients with PCSA values at any post-baseline 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: never normalized, normalized after 
permanent discontinuation of study drug. Note that a patient will be counted only under the 
maximum elevation category. 
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.
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11.4.3.4 Vital signs data
The summary statistics (including number, mean, median, Q1, Q3, standard deviation, minimum 
and maximum) of all vital signs variables with a focus on BP and orthostatic BP will be calculated 
for each visit or study assessment (baseline, each post-baseline time point, endpoint) by treatment 
group. Listings will be provided with flags indicating the out of range values as well as the PCSA 
values. The incidence of PCSA at any time will be summarized by treatment group for each vital 
signs variable. Shift tables showing changes with respect to the baseline status will be provided.
11.4.3.5 Electrocardiogram data
The summary statistics (including number, mean, median, Q1, Q3, standard deviation, minimum 
and maximum) of all ECG variables will be calculated for each visit or study assessment 
(baseline, each post baseline time point, endpoint) by treatment group.
The incidence of PCSA at any during the TEAE period will be summarized by treatment group 
for each ECG variable. Shift tables showing changes with respect to the baseline status will be 
provided. Listings will be provided with flags indicating the PCSA values.
11.4.4 Analyses of pharmacokinetic and pharmacodynamic variables
PK data will summarized by treatment arm and timepoint using descriptive statistics (number of 
patients, arithmetic mean, standard deviation, geometric mean, coefficient of variation, minimum 
and maximum).
A population pharmacokinetic analysis may be conducted and will be reported in a separated 
report.
Correlation analysis may be conducted to explore the PK/PD relationship.
11.5
INTERIM ANALYSIS
Safety
A DMC will review the clinical safety data on a regular basis in an unblinded manner. The first 
analysis will occur once 19 patients (irrespective of treatment group) have completed the 
 
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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 participants 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 copy of the signed and dated written informed consent form will 
be provided to the patient. 
Prior to collection of blood for pharmacogenetics, the optional pharmacogenetic informed consent 
form (written) should be signed, name filled in, and personally dated by the patient and by the 
person who conducted the informed consent discussion. A copy of the signed and dated written 
optional informed consent form will be provided to the subject.
The informed consent form and the optional pharmacogenetic 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.
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, Investigator’s Brochure, 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 Investigator’s Brochure 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 and in countries where applicable by local legislation and 
regulations to Health Authorities 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 CRF, 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 CRFs. 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. Source document requirements
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According to the ICH GCP, the monitoring team must check the CRF entries against the source 
documents, except for the pre-identified source data directly recorded in the CRF. 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 CRFs (eg, patient's medical file, 
appointment books, original laboratory records, etc). 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).
13.3
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST
It is the responsibility of the Investigator to maintain adequate and accurate CRFs (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 CRFs 
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 e-CRF 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 e-CRF.
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 e-CRF.
13.4
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 and Investigator study files.
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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 confidential all study documentation, and take measures to 
prevent accidental or premature destruction of these documents.
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.
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 CRFs, the Investigator's Brochure 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.
Subject’s race or ethnicity (eg, Caucasian/white, Black, Asian/Oriental, others) will be collected 
in this study because these data are required by several regulatory authorities (eg, on afro 
American population for FDA).
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. 
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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.

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.
In any case the Sponsor will notify the Investigator of its decision by written notice.
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14.8.2 By the Investigator
The Investigator may terminate his/her participation upon thirty (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 twelve (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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BIBLIOGRAPHIC REFERENCES
1. Murthy VL, Naya M, Foster CR, Hainer J, Gaber M, Di Carli G, Blankstein R, Dorbala S, 
Sitek A, Pencina MJ, Di Carli MF. Improved cardiac risk assessment with noninvasive 
measures of coronary flow reserve. Circulation. 2011;124:2215-24.
2. Marzilli M, Huqi A and Morrone D.  Persistent Angina The Araba Phoenix of Cardiology. Am 
J Cardiovasc Drugs. 2010;10 Suppl.1:27-32.
3. Focardi M, Capati E, Affinito S, Urselli R and Marzilli M. Persistent angina after myocardial 
revascularization: a case report. Heart Metab. 2006; 31:27–9.
4. Patel M.R, Peterson E.D, Dai D,  Brennan J.M, Redberg R.F, Anderson H.V et al. Low 
Diagnostic Yield of Elective Coronary Angiography. N Engl J Med. 2010;362:886-95.
5. Radico F, Cicchitti V, Zimarino M, De Catherina R. Angina pectoris and myocardial ischemia 
in the absence of obstructive coronary artery disease: practical considerations for diagnosis 
tests. J Am Coll Cadiol Intv. 2014;7:453-63.
6. Olson MB, Kelsey SF, Matthews K, Shaw LJ, Sharaf BL, Pohost GM, et al. Symptoms, 
myocardial ischaemia and quality of life in women: results from the NHLBI-sponsored WISE 
Study. Eur Heart J. 2003;24:1506-14.
7. Merz CN, Kelsey SF, Pepine CJ, Reichek N, Reis SE, Rogers WJ et al. The Women’s 
Ischemia Syndrome Evaluation (WISE) study: protocol design, methodology and feasibility 
report. J Am Coll Cardiol. 1999;33:1453–61.
8. Bugiardini R, Pozzati A, Ottani F, Morgagni GL, Puddu P. Vasotonic angina: a spectrum of 
ischemic syndromes involving functional abnormalities of the epicardial and microvascular 
coronary circulation. J Am Coll Cardiol. 1993;22:417–25.
9. Shaw LJ, Bairey Merz CN, Pepine CJ, Reis SE, Bittner V, Kelsey SF et al. Insights from the 
NHLBI-Sponsored Women’s Ischemia Syndrome Evaluation (WISE) Study: Part I: gender 
differences in traditional and novel risk factors, symptom evaluation, and gender-optimized 
diagnostic strategies. J Am Coll Cardiol. 2006;47:S4–S20.
10.Suzuki H. Different definition of microvascular angina. Eur J Clin Invest. 2015;45(12):1360-6.
11. Izzo P, Macchi A, De Gennaro L, Gaglione A, Di Biase M and Brunetti N.D. Recurrent 
angina after coronary angioplasty: mechanisms, diagnostic and therapeutic options.  European 
Heart Journal: Acute Cardiovascular Care. 2012;1(2):158–69.
12. Opherk D, Zebe H, Weihe E, Mall G, Dürr C, Gravert B et al. Reduced coronary dilatory 
capacity and ultrastructural changes of the myocardium in patients with angina pectoris but 
normal coronary arteriograms. Circulation. 1981;63(4):817–25.
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13. Chauhan A, Mullins PA, Taylor G, Petch MC, Schofield PM. Both endothelium-dependent 
and endothelium-independent function is impaired in patients with angina pectoris and normal 
coronary angiograms. Eur Heart J. 1997;18:60–8.
14. Sestito A, Lanza GA, Di Monaco A, Lamendola P, Carreri G, Tarzia P et al. Relation between 
cardiovascular risk factors and coronary microvascular dysfunction in cardiac syndrome X. J 
Cardiovasc Med (Hagerstown). 2011;12:322–7.
15. Egashira K, Inou T, Hirooka Y, Yamada A, Urabe Y, Takeshita A. Evidence of impaired 
endothelium-dependent coronary vasodilation in patients with angina pectoris and normal 
coronary angiograms. N Engl J Med. 1993;328:1659–64.
16. Shimokawa H, Satoh K. 2015 ATVB Plenary Lecture: translational research on rho-kinase in 
cardiovascular medicine Arterioscler Thromb Vasc Biol. 2015;35(8):1756-69.
17. Kanda T, Wakino S, Hayashi K, Homma K, Ozawa Y, Saruta T. Effect of fasudil on Rho-
kinase and nephropathy in subtotally nephrectomized spontaneously hypertensive rats. Kidney 
Int. 2003;64:2009-19.
18. Sawada N, Itoh H, Ueyama K, Yamashita J, Doi K, Chun TH, et al. Inhibition of rho-
associated kinase results in suppression of neointimal formation of balloon-injured arteries. 
Circulation. 2000;101(17):2030-3.
19. Kataoka C, Egashira K, Inoue S, Takemoto M, Ni W, Koyanagi M, et al. Important role of 
Rho-kinase in the pathogenesis of cardiovascular inflammation and remodeling induced by 
long-term blockade of nitric oxide synthesis in rats. Hypertension. 2002;39:245-50.
20. Do e Z, Fukumoto Y, Takaki A, Tawara S, Ohashi J, Nakano M, et al. Evidence for Rho-
Kinase activation in patients with pulmonary arterial hypertension. Circ J. 2009;73:1731-9.
21. Hata T, Goto C, Soga J, Hidaka T, Fujii Y, Idei N, et al. Measurement of Rho-associated 
kinase (ROCK) activity in humans: Validity of leukocyte p-MBS/t-MBS in comparison with 
vascular response to fasudil. Atherosclerosis. 2011;214:117-21.
22. Kikuchi Y, Yasuda S, Aizawa K, Tsuburaya R, Ito Y, Takeda M, et al. Enhanced Rho-Kinase 
activity in circulating neutrophils of patients with vasospastic angina. A Possible Biomarker 
for Diagnosis and Disease Activity Assessment. J Am Coll Cardiol. 2011;58:1231-7.
23. Löhn M, Plettenburg O, Ivashchenko Y, Kannt A, Hofmeister A, Kadereit D, Schaefer M, 
Linz W, Kohlmann M, Herbert JM, Janiak P, O'Connor SE, Ruetten H. Pharmacological 
characterization of SAR407899, a novel rho-kinase inhibitor. Hypertension. 2009;54(3):676-
83.
24. Shimokawa H, Sunamura S, Satoh K. RhoA/Rho-Kinase in the Cardiovascular System. Circ 
Res. 2016;118(2):352-66.
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25. Ming-Jui Hung, Wen-Jin Cherng. Clinical Applications of Transthoracic Doppler 
Echocardiographic Coronary Flow Reserve. Measurements in the Left Anterior Descending 
Coronary Artery. Journal of Medical Ultrasound. 2011;19:115-21.
26. Montalescot G, Sechtem U, Achenbach S, Andreotti F, Arden C, Budaj A et al. 2013 ESC 
guidelines on the management of stable coronary artery disease:The Task Force on the 
management of stable coronary artery disease of the European Society of Cardiology. Eur 
Heart J. 2013;34(38):2949-3003.
27. Berry C. Fractional flow reserve, coronary flow reserve and the index of microvascular 
resistance in clinical practice. Radcliffe Cardiology. 2014;1-6.
28. Spertus JA, Winder JA, Dewhurst T, Deyo R, Prodzinski J, McDonell M, et al. Development 
and evaluation of the Seattle Angina Questionnaire: a new functional status measure for 
coronary artery disease. J Am Coll Cardiol. 1995;25:333-41.
29. Chan PS, Jones PG, Arnold SA, Spertus JA. Development and validation of a short version of 
the Seattle angina questionnaire. Circ Cardiovasc Qual Outcomes. 2014;7:640-7. 
30. El Fakhri G, Kardan A, Sitek A, Dorbala S, Abi-Hatem N, Lahoud Y et al. Reproducibility 
and accuracy of quantitative myocardial blood flow assessment with (82)Rb PET: comparison 
with (13)N-ammonia PET. J Nucl Med. 2009;50:1062-71.
31. El Fakhri G, Guerin G, Sitek A, Curillova Z, Agnostopoulos C, Dorbala S et al. Absolute 
myocardial blood flow quantification in Rb-82 cardiac PET using generalized factor and 
compartment analysis: a reproducibility study. Eur J Nucl Med Molec Imaging. 2006;33:S217.
32. Murthy VL, Lee BC, Sitek A, Naya M, Moody J, Polavarapu V, Ficaro EP and Di Carli MF. 
Comparison and prognostic validation of multiple methods of quantification of myocardial 
blood flow with 82Rb PET. J Nucl Med. 2014;55:1952-8.
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APPENDICES
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Appendix A
General guidance for the follow-up of laboratory abnormalities by 
Sanofi 
Neutrophils < 1500/mm3 or according to ethnic 
group
NEUTROPENIA
Repeat immediately a full blood count if value 
close to 1500/mm3
Neutrophils < 1500/mm3 confirmed 
with signs of infection  
Neutrophils < 1500/mm3 confirmed 
with no signs of infection  
1.
DISCONTINUE
Investigational Medicinal 
Product, hospitalization 
should be considered
2.
PERFORM biological 
investigations for infection
1.
DISCONTINUE
Investigational 
Medicinal Product
2.
INVESTIGATE for 
infection
In both situations
3.
INFORM the local monitor
4.
INVESTIGATE previous treatments particularly long-term, even a long time ago, 
exposure to toxic agents, e.g., benzene, X-rays, etc.
5.
PERFORM and collect the following investigations (results): 
•
RBC and platelet counts
•
Serology: EBV, (HIV), mumps, measles, rubella
6.
DECISION for bone marrow aspiration: to be taken in specialized unit
7.
COLLECT/STORE one sample following handling procedures described in PK 
sections (for studies with PK sampling) and freeze one serum sample (5 mL) on 
Day 1 (cessation of investigational medicinal product) and Day 5 (for further 
investigations)
8.
MONITOR the leukocyte count 3 times per week for at least one  week, then twice a 
month until it returns to normal
Note: 
•The procedures described in the above flowchart are to be discussed with the patient only in case 
the event occurs. If applicable (according to local regulations), an additional consent (e.g., for 
HIV testing) will only be obtained in the case the event actually occurs.
•For individuals of African descent, the relevant value of concern is <1000/mm3
Neutropenia is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting adverse events in Section 10.4.3 is met.
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Platelets < 100 000/mm3 (rule out EDTA – induced 
pseudo-thrombocytopenia)
THROMBOCYTOPENIA
Repeat immediately the count (rule out EDTA 
anticoagulant in the sample)
Platelets  < 100 000/mm3 confirmed 
with bleeding  
Platelets  < 100 000/mm3 confirmed 
with no bleeding
1.
DISCONTINUE
Investigational Medicinal 
Product
2.
HOSPITALIZATION
should be considered
1.
DISCONTINUE
Investigational Medicinal 
Product
2.
INVESTIGATE for 
bleeding
In both situations
3.
INFORM the local Monitor
4.
QUESTION about last intake of quinine (drinks), alcoholism, heparin administration
5.
PERFORM or collect the following investigations: 
•
Complete blood count, schizocytes, creatinine
•
Bleeding time and coagulation test (fibrinogen, INR or PT, aPTT), Fibrin 
Degradation Product
•
Viral serology: EBV, HIV, mumps, measles, rubella
6.
COLLECT/STORE one sample following handling procedures described in PK 
sections (for studies with PK sampling) and freeze one serum sample (5 mL) on 
Day 1 (cessation of investigational medicinal product) and Day 5 (for further 
investigations)
7.
DECISION for bone marrow aspiration: to be taken in specialized unit
•
On Day 1 in the case of associated anemia and/or leukopenia
•
On Day 8 if platelets remain < 50 000/mm3
8.
MONITOR the platelet count every day for at least one week and then regularly 
until it returns to normal
Note: 
The procedures above flowchart are to be discussed with the patient only in case described in the 
the event occurs. If applicable (according to local regulations), an additional consent (e.g., for 
HIV testing) will only be obtained in the case the event actually occurs.
Thrombocytopenia is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting adverse events in Section 10.4.3 is met.
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ALT > 3 ULN
Monitor LFTs every 72 hours
ALT ≤ 5 ULN
ALT > 3 ULN &
Total Bilirubin > 2 ULN 
Permanent Discontinuation of IMP
ALT > 5 ULN 
In ANY CASE, FOLLOW the instructions listed in the box below: 
1.
INFORM the Site Monitor who will forward the information to the Study Manager
2.
INVESTIGATE specifically for malaise with or without loss of consciousness, dizziness, and/or 
hypotension and/or episode of arrhythmia in the previous 72 hours; rule out muscular injury
3.
PERFORM the following tests:
- LFTs: AST, ALT, alkaline phosphatase, total and conjugated bilirubin and prothrombin time / INR
- CPK, serum creatinine, complete blood count
- Anti-HAV IgM, anti-HBc IgM, (HBV-DNA if clinically indicated), anti-HCV and HCV RNA, anti-
CMV IgM and anti-HEV IgM antibodies
- Depending on the clinical context, check for recent infection with EBV, herpes viruses, and toxoplasma
- Hepatobiliary ultrasonography (or other imaging investigations if needed)
4.
CONSIDER Auto-antibodies: antinuclear, anti-DNA, anti-smooth muscle, anti-LKM
5.
CONSIDER consulting with hepatologist
6.
CONSIDER patient hospitalisation if INR>2 (or PT<50%) and/or central nervous system disburbances 
suggesting hepatic encephalopathy
7.
MONITOR LFTs after discontinuation of IMP:
- As closely as possible (or every 48 hours) until stabilization, then every 2 weeks until return to 
normal/baseline or clinical resolution.
8.
FREEZE serum sample (5ml x 2)
9.
In case of SUSPICION of GILBERT Syndrome, a DNA diagnostic test should be done
COMPLETE the specific CRF forms 
for „ALT Increase” and inform the 
Monitoring Team within 24 hours
Confirm ALT > 3 ULN
Retest within 72 hours of initial sample*
IMP administration can be continued as 
long as – under close monitoring –
conditions for permanent 
discontinuation or temporary 
interruption per protocol are not met
INCREASE IN ALT
*If unable to retest in 72 hours, use original lab results to decide on further reporting/monitoring/discontinuation. 
Note:

“Baseline” refers to ALT sampled at baseline visit; or if baseline value unavailable, to the latest ALT sampled before the 
baseline visit. The algorithm does not apply to the instances of increase in ALT during screening.
See Section 10.4 for guidance on safety reporting.

Normalization is defined as ≤ ULN or baseline value, if baseline value is >ULN.
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Rapid increase in serum creatinine over 150 µmol/L 
or rapid decrease in creatinine clearance below
50 mL/mn
ACUTE RENAL FAILURE
Can be rapidly reversed:
• By volume repletion
• Or relief of urinary tract 
obstruction (according to etiology)
Cannot be rapidly reversed: 
• Occurrence/aggravation of life 
threatening symptoms of ARF: anemia, 
hyperkalemia, hyperuricemia, metabolic 
acidosis, cardiac insufficiency, 
pulmonary edema, arrhythmia, DIC, etc.
• And/or predominant elimination of 
Investigational Medicinal Product by 
renal route
1.
Investigational Medicinal 
Product may be continued
2.
MONITOR serum creatinine 
until return to baseline level
1.
INFORM the local monitor
2.
DISCONTINUE
Investigational Medicinal Product 
administration
3.
HOSPITALIZATION should be 
considered and seek for nephrologic  
advice
4.
PERFORM the following 
examinations: 
•
BP, HR, hydration status, ECG
•
Blood count
•
Liver function tests + CPK
•
Biochemistry, including urea
•
Urinalysis
5.
COLLECT/STORE one sample 
following handling procedures 
described in PK sections (for studies 
with PK sampling) and freeze one 
serum sample (5 mL) on Day 1 
(cessation of investigational 
medicinal product)
6.
MONITOR renal function until 
return to baseline level (every day at 
the beginning, then every week)
Acute renal failure is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting adverse events in Section 10.4.3 is met.
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If Increase in CPK (expressed in ULN)
> 3 ULN
Repeat immediately the count.
If confirmed, inform the local monitor and
INVESTIGATE for the origin:
- PERFORM:
•
ECG
•
CPK-MB -MM 
•
Troponin
•
Creatinine
•
Iono (k+, Ca2+)
•
Transaminases + Total and conjugated bilirubin
•
Myoglobin (serum and urines)
- COLLECT/STORE one sample following handling procedures described in PK sections (for 
studies with PK sampling) and freeze one serum sample (5 mL) on Day 1 (cessation of 
investigational medicinal product). 
- INTERVIEW the patient about a recent intensive muscular effort, trauma, convulsions, electrical 
injury, injury or stress to the skeletal muscle, multiple intramuscular injections, recent surgery, 
concomitant medications, consumption of alcohol, morphine, cocaine.
- SEARCH for alternative causes to cardiac or muscular toxicity, ie: stroke, pulmonary infarction, 
dermatomyositis or polymyositis, convulsions, hypothyroidism, delirium tremens, muscular 
dystrophies.
If either the cardiac origin or the 
rhabdomyolysis is confirmed or if CPK 
> 10 ULN:
1. DISCONTINUE Investigational 
Medicinal Product administration
2. MONITOR CPK every 3 days for the 
first week then once weekly until return 
to normal or for at least 3 months
3. HOSPITALIZATION should be 
considered
If the cardiac origin or the rhabdomyolysis is 
ruled out and if CPK 10 ULN:
MONITOR CPK every 3 days for the first week 
then once weekly until return to normal or for 
at least 3 months
Muscular symptoms (myalgia, pain, weakness, 
dark urines)
Systematic CPK assessment as per 
protocol
Perform CPK
SUSPICION OF RHABDOMYOLYSIS
Suspicion of rhabdomyolysis is to be recorded as an AE only if at least 1 of the criteria in the 
general guidelines for reporting adverse events in Section 10.4.3 is met.
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Appendix B
Procedure for collection, handling, storage, and shipment of 
SAR407899 specimens for pharmacogenetic samples
1.
SUMMARY OF HANDLING AND SUPPLIES FOR PHARMACOGENETIC 
SAMPLES 
1.1
Sampling Supply Description
Pharmacogenetic specimens
Collection/Storage Tube: 2 vacutainer BECTON Dickinson 6 mL K2 EDTA with 
HEMOGARD closure, 
1.2
Summary of handling procedures for pharmacogenetic samples
Sample type(s)
Pharmacogenetic
Blood sample volume
6 mL 
Collection tube
a 6 mL Becton Dickinson K2 EDTA VACUTAINER™ Plus tubes with HEMOGARD™ closure 
(PN367863/4) sterile tubes 
Anticoagulant 
K2 EDTA
Blood handling procedures 
Keep blood on ice and frozen within 30 minutes of sampling time. DO NOT CENTRIFUGE 
BLOOD
Storage conditions
-70°C or colder
2.
COLLECTION/HANDLING/PROCESSING OF SAMPLES
The analytical methods used are extremely sensitive. All sampling procedures must be 
followed accurately.
2.1
Blood pharmacogenetic samples for DNA storage

Collection schedule: Per protocol.

Procedure:
-
Using a waterproof pen, write subject ID on label in space provided,
-
Collect 6 mL of blood, using the 6 mL Vacutainer Becton Dickinson K2 EDTA with 
HEMOGARD Closure provided, and gently invert tube 10-15 times permitting the 
specimen to mix with the anticoagulant,
-
Under no circumstances should the tube be centrifuged,
-
Ensure the sample tube is clearly and appropriately labeled as described above and in 
detail in Covance laboratory manual,
-
Immediately freeze and maintain the blood in an upright position at -70°C or colder. 
Samples must be stored on dry ice if a freezer is not immediately available,
-
Complete the laboratory requisition form (provided by Covance) for each sample.
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
Labeling of specimens:
-
Each sample tube should have attached to it the label provided by Covance,
DNA Subject ID:XXX-001-YYY
ACT14656 / SAR407899 (preprinted)
Bar code (preprinted)
Accession number (preprinted)
-
In the event of damage or loss of the provided labels, a new label should be 
immediately requested from Covance.

Storage
-
Samples must be kept at -70 ºC or colder, organized in a rack in numeric order 
according to the subject ID, until ready for packaging and shipping. 
3.
PACKAGING AND SHIPMENT OF DNA PHARMACOGENETIC ANALYSIS
3.2
DNA for pharmacogenetic analysis sample
3.2.1
Packaging and shipment 
-
Samples and accompanying documents should be packaged according to the detailed 
instructions in Covance laboratory manual provided at the initiation of the study.
-
Samples must be packaged according to IATA Dangerous Goods Regulations, Packing 
Instructions 650, using the packing materials provided by Covance.
-
In the event that the packaging materials or instructions are lost, please contact the 
study Sponsor.
-
Ship samples on dry ice to Covance as described in the Global Study Schedule, using 
the shipping materials provided.
Note: Additional detailed information can be found in Covance laboratory manual, provided at 
the beginning of the study. This includes additional details regarding:
-
Sample collection kits.
-
Sample collection procedures.
-
Documentation procedures.
-
Packing and shipping instructions.
-
Sample kit resupply.
-
How to get help.
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4.
SHIPMENT CONTACT NAMES AND ADDRESSES
Pharmacogenetic specimens for DNA storage:
Use for the Americas: USA and Canada, as well as Latin America and the Islands (Dominican 
Republic, etc):
Covance CLS Indianapolis
8211 SciCor Drive
Indianapolis, IN
46214-2985 USA
Tel. 
(local calls)
Tel: 
Fax: 
Use for Europe, the Middle East, and Africa:
Covance CLS Genève
Rue Moïse-Marcinhes 7
1217 Meyrin/Genève-CH
Tel: 
Fax: 
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ELECTRONIC SIGNATURES 
 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ACT14656 Amended Protocol 03
Clinical Approval
19-Apr-2018 19:24 GMT+0200
Clinical Approval
19-Apr-2018 20:41 GMT+0200

SAP_001.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning direct 
or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: QSD-002928 VERSION N°4.0 (06-JUL-2016) 
Page 1 
STATISTICAL TECHNICAL DOCUMENT 
A randomized, double-blind, placebo-controlled parallel arm dose titration study to 
assess the effects of SAR4907899 in patients with microvascular angina and/or 
persistent stable angina despite angiographically successful percutaneous 
coronary intervention 
SAR407899-ACT14656 
STATISTICIAN: 
  
DATE OF ISSUE: 03-Oct-2018 
Total number of pages: 
16 
(electronic 1.0)
NCT Number: NCT03236311


Statistical Technical Document  
03-Oct-2018 
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Page 2 
TABLE OF CONTENTS 
STATISTICAL TECHNICAL DOCUMENT......................................................................................................1 
TABLE OF CONTENTS..................................................................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ..........................................................................3 
1 
STATISTICAL AND ANALYTICAL PROCEDURES .......................................................................4 
1.1 
INTRODUCTION..............................................................................................................................4 
1.2 
MODIFICATIONS FROM THE STATISTICAL SECTION OF THE PROTOCOL............................4 
1.3 
DATA HANDLING CONVENTIONS.................................................................................................5 
2 
SOFTWARE DOCUMENTATION....................................................................................................7 
3 
LIST OF APPENDICES ...................................................................................................................8 
APPENDIX A 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES (PCSA) CRITERIA............9 
APPENDIX B 
SCORING AND INTERPRETING THE SAQ.......................................................................15 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
AESI: 
Adverse Event of Special Interest 
CFR: 
Coronary Flow Reserve 
DBP: 
Diastolic Blood Pressure 
HR: 
Heart Rate 
PCSA: 
Potentially Clinically Significant Abnormality 
PD: 
Pharmacodynamic 
PK: 
Pharmocokinetics 
PL: 
Physical Limitation 
SAE: 
Serious Adverse Event 
SAQ: 
Seattle Angina Questionnaire 
SBP: 
Systolic Blood Pressure 
TEAE: 
Treatment Emergent Adverse Event 
 
 
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1 
STATISTICAL AND ANALYTICAL PROCEDURES 
1.1 
INTRODUCTION 
The purpose of this document is to provide additional technical details. 
A comprehensive and detailed description of strategy and statistical technique used to perform the 
analysis of data was provided in Section 11 of the protocol (amended clinical trial protocol no 03 
dated 18-Apr-2018). 
Adverse events will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA version 21.0). 
Previous and concomitant medication records will be coded according to the World Health 
Organization Drug Dictionary (WHO-DD version 2018 MARCH 1).  
1.2 
MODIFICATIONS FROM THE STATISTICAL SECTION OF THE PROTOCOL 
At the time of the early study termination decided by the sponsor, only 10 patients were 
randomized in the study, and only 8 patients have a post baseline CFR assessed (primary efficacy 
endpoint) . The number of patients initially planned to be randomized in the study was 78, 
therefore with such few patients finally enrolled in the study, no formal statistical analysis will be 
performed. The analysis will be only descriptive, with few summary tables and some additional 
listings.  
The following table gives the changes to the protocol statistical section. 
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Table 1 – Statistical analysis changes 
Protocol version 
Section number 
Description of statistical changes 
Amended no 03 
11.4.1.2 Compliance 
No summary table on compliance will be done. Instead listing with 
individual treatment intake, and compliance by visits interval will 
be provided. 
 
11.4.2.1 Analysis of primary 
efficacy endpoint 
No model will be built. Only descriptive table and listing with 
information on the uncorrected global CRF will be provided 
 
11.4.2.2 Analysis of secondary 
efficacy endpoint 
No model will be built for the SAQ-PL. Only descriptive table and 
listing will be provided 
 
11.4.2.3 Multiplicity 
considerations 
Not applicable. All results presented are considered informative 
only. 
 
11.4.3.1 Adverse events 
Incidence tables will be provided as planned. Only one listing will 
be provided for the treatment emergent adverse events with flag 
to identify SAE, TEAE leading to treatment discontinuation, AESI. 
 
11.4.3.2 Laboratory data 
No summary statistics will be provided since only local laboratory 
data are retrieved in this study. Only the incidence of PCSA will 
be provided, as well as standard listings of patients with PCSAs 
 
11.4.3.4 Vital signs data 
No summary statistics will be provided. Only the incidence of 
PCSA will be provided, as well as standard listings. In addition 
Individual graphs for SBP and HR could be provided if necessary 
 
11.4.3.5 Electrocardiogram data 
No summary statistics will be provided. Only the incidence of 
PCSA will be provided, as well as standard listings 
 
11.4.4 Analysis of 
pharmacokinetic and 
pharmacodynamic variables 
No PK nor PK/PD analysis will be performed 
 
1.3 
DATA HANDLING CONVENTIONS 
This section describes the rules and conventions used in the presentation and analysis of data.  
In the statistical appendices the following treatment label will be used: 
SAR407899 or Placebo. 
For parameters with possible several evaluations before administration, only the last observation 
will be used as baseline in descriptive statistics and derivations.  
For clinical laboratory parameters with nonnumeric values, the imputed values used for the flags 
of PCSA will be determined by considering the following rules: 
• 
If database value is ‘< X’, the value used will be X/2 
• 
If database value is ‘> X’, the value used will be X 
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Descriptive statistics for quantitative parameters will be provided using number of observations 
(N), mean, standard deviation (SD), standard error of the mean (SEM), minimum, maximum and 
median.  
Descriptive statistics for qualitative parameters will be provided using frequencies (N) and  
percent (%).   
For vital signs parameters, the mean value of the three measures by time-points for the sitting 
SBP, DBP and HR will be used to determine the PCSA. 
Windows for time points for vital signs 
Vital signs analyzed by time point will be summarized using the time windows given below. If 
multiple valid values of a variable exist within a time window, the nearest from the targeted time 
point will be used. In case the time of the drug intake the day of the vital sign assessment is not 
reported in eCRF (possible when the vital sign assessment did not occur the first day or the last 
day of the kit number assigned), then the theoretical time will be used. 
Table 2 – Time windows definition for vital signs 
Time point 
Targeted time 
Time windows 
T0H 
Just before drug intake 
6H00 to 0H00 before drug intake 
T1H 
1 hour after drug intake 
0H30 to 2H00 after dug intake 
T3H 
3 hours after drug intake 
2H01 to 6H00 after drug intake 
 
Handling missing data for adverse events 
In case of missing or inconsistent information, an adverse event will be counted as a treatment-
emergent adverse event, unless it can clearly be ruled out that it is not a treatment-emergent 
adverse event (eg, by partial dates or other information). 
Rules to derive SAQ summary scores 
The rules used to derive the secondary endpoint SAQ-PL, and other summary SAQ summary 
scores are detailed in appendix B. 
Angina episodes and short-acting nitrate intakes frequency 
The weekly rate of angina episode and short-acting nitrate intakes will be derived as follows: 
(Nb of angina episodes (respectively nb of short-acting nitrate intakes) reported during the recall 
period / duration of the recall period) * 7 
For baseline, only the 7 days before randomization will be taken into account as recall period. 
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2 
SOFTWARE DOCUMENTATION 
The analysis of clinical data will be performed under the responsibility of Sanofi Biostatistics 
Department, using SAS® (SAS Institute, NC USA).   
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3 
LIST OF APPENDICES 
Appendix A: Potentially clinically significant abnormalities (PCSA) criteria 
Appendix B: Scoring and interpreting the SAQ 
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Appendix A 
Potentially clinically significant abnormalities (PCSA) criteria 
 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
 
Parameter 
PCSA 
Comments 
Clinical Chemistry 
ALT 
By distribution analysis : 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Enzymes activities must be expressed in ULN, not in 
IU/L.  
Concept paper on DILI – FDA draft Guidance Oct 2007.
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning 
zero can be deleted. 
AST 
By distribution analysis : 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Enzymes activities must be expressed in ULN, not in 
IU/L.  
Concept paper on DILI – FDA draft Guidance Oct 2007.
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning 
zero can be deleted. 
Alkaline 
Phosphatase 
>1.5 ULN 
Enzymes activities must be expressed in ULN, not in 
IU/L. 
Concept paper on DILI – FDA draft Guidance Oct 2007.
Internal DILI WG Oct 2008. 
Total Bilirubin 
>1.5 ULN 
>2 ULN 
Must be expressed in ULN, not in µmol/L or mg/L. 
Categories are cumulative. 
Concept paper on DILI – FDA draft Guidance Oct 2007.
Internal DILI WG Oct 2008. 
Conjugated Bilirubin >35% Total Bilirubin and TBILI>1.5 ULN 
Conjugated bilirubin dosed on a case-by-case basis. 
ALT and Total 
Bilirubin 
ALT>3 ULN and TBILI>2 ULN 
Concept paper on DILI – FDA draft Guidance Oct 2007.
Internal DILI WG Oct 2008. 
To be counted within a same treatment phase, 
whatever the interval between measurement. 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
 
Parameter 
PCSA 
Comments 
CPK 
>3 ULN 
>10 ULN 
FDA Feb 2005. 
Am J Cardiol April 2006. 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning 
zero can be deleted. 
CLcr (mL/min) 
(Estimated 
creatinine clearance 
based on the 
Cokcroft-Gault 
equation)  
<15 (end stage renal disease) 
≥15 - <30 (severe decrease in GFR) 
≥30 - < 60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥ 90 (normal GFR) 
FDA draft Guidance 2010 
Pharmacokinetics in patients with impaired renal 
function-study design, data analysis, and impact on 
dosing and labeling 
eGFR 
(mL/min/1.73m2) 
(Estimate of GFR 
based on an MDRD 
equation)  
 
<15 (end stage renal disease) 
≥15 - <30 (severe decrease in GFR) 
≥30 - < 60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥ 90 (normal GFR) 
FDA draft Guidance 2010 
Pharmacokinetics in patients with impaired renal 
function-study design, data analysis, and impact on 
dosing and labeling 
Creatinine 
≥150 µmol/L (Adults) 
≥30% change from baseline 
≥100% change from baseline 
Benichou C., 1994. 
 
Uric Acid 
Hyperuricemia  
Hypouricemia  
 
>408 µmol/L 
<120 µmol/L  
Harrison- Principles of internal Medicine 17th Ed., 2008. 
Blood Urea Nitrogen ≥17 mmol/L 
 
Chloride 
<80 mmol/L 
>115 mmol/L 
 
Sodium 
≤129 mmol/L 
≥160 mmol/L 
 
Potassium 
<3 mmol/L 
≥5.5 mmol/L 
FDA Feb 2005. 
Total Cholesterol 
≥7.74 mmol/L  
Threshold for therapeutic intervention. 
Triglycerides 
≥4.6 mmol/L 
Threshold for therapeutic intervention. 
Lipasemia 
≥3 ULN 
 
Amylasemia 
≥3 ULN 
 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
 
Parameter 
PCSA 
Comments 
Glucose 
Hypoglycaemia 
Hyperglycaemia 
 
≤3.9 mmol/L and <LLN 
≥11.1 mmol/L (unfasted); ≥7 mmol/L (fasted) 
 
ADA May 2005. 
ADA Jan 2008. 
HbA1c 
>8% 
 
Albumin 
≤25 g/L 
 
CRP 
>2 ULN or >10 mg/L (if ULN not provided) 
 FDA Sept 2005. 
Hematology 
WBC 
<3.0 Giga/L (Non-Black); <2.0 Giga/L (Black) 
≥16.0 Giga/L 
Increase in WBC: not relevant. 
To be interpreted only if no differential count available. 
Lymphocytes 
>4.0 Giga/L 
 
Neutrophils 
<1.5 Giga/L (Non-Black);<1.0 Giga/L (Black) 
International Consensus meeting on drug-induced 
blood cytopenias, 1991. 
FDA criteria. 
Monocytes 
>0.7 Giga/L 
 
Basophils 
>0.1 Giga/L 
 
Eosinophils 
>0.5 Giga/L or >ULN (if ULN≥0.5 Giga/L) 
Harrison- Principles of internal Medicine 17th Ed., 2008. 
Hemoglobin 
≤115 g/L (Male); ≤95 g/L (Female) 
≥185 g/L (Male); ≥165 g/L (Female) 
 
Decrease from Baseline ≥20 g/L 
Criteria based upon decrease from baseline are more 
relevant than based on absolute value. Other 
categories for decrease from baseline can be used 
(≥30 g/L, ≥40 g/L, ≥50 g/L). 
Hematocrit 
≤0.37 v/v (Male) ; ≤0.32 v/v (Female) 
≥0.55 v/v (Male) ; ≥0.5 v/v (Female) 
 
RBC 
≥6 Tera/L 
Unless specifically required for particular drug 
development, the analysis is redundant with that of Hb. 
Otherwise, consider FDA criteria. 
Platelets 
<100 Giga/L 
≥700 Giga/L 
International Consensus meeting on drug-induced 
blood cytopenias, 1991. 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
 
Parameter 
PCSA 
Comments 
Urinalysis 
pH 
≤4.6 
≥8 
 
Vital signs 
HR 
≤50 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline≥20 bpm 
To be applied for all positions (including missing) 
except STANDING. 
SBP 
≤95 mmHg and decrease from baseline ≥20mmHg 
≥160 mmHg and increase from baseline ≥20 mmHg 
To be applied for all positions (including missing) 
except STANDING. 
DBP 
≤45 mmHg and decrease from baseline ≥10 mmHg 
≥110 mmHg and increase from baseline ≥10 mmHg 
To be applied for all positions (including missing) 
except STANDING. 
Orthostatic 
Hypotension 
Orthostatic SDB 
Orthostatic DBP 
 
 
≤-20 mmHg 
≤-10 mmHg 
 
Weight 
≥5% increase from baseline  
≥5% decrease from baseline 
FDA Feb 2007. 
(electronic 
 
 
 
1.0)


Statistical Technical Document  
03-Oct-2018 
SAR407899-ACT14656  
 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 13 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
 
Parameter 
PCSA 
Comments 
ECG 
Ref.: ICH E14 guidance (2005) and E14 Q&A (2012), 
and Cardiac Safety Research Consortium White Paper 
on PR and QRS (Nada et al. Am Heart J. 2013; 165(4) 
: 489-500) 
HR 
<50 bpm 
<50 bpm and decrease from baseline ≥20 bpm 
<40 bpm 
<40 bpm and decrease from baseline ≥20 bpm 
<30 bpm 
<30 bpm and decrease from baseline ≥20 bpm 
 
>90 bpm 
>90 bpm and increase from baseline ≥20bpm 
>100 bpm  
>100 bpm and increase from baseline ≥20bpm 
>120 bpm  
>120 bpm and increase from baseline ≥20 bpm 
Categories are cumulative 
 
 
 
 
 
 
Categories are cumulative 
 
PR 
>200 ms 
>200 ms and increase from baseline ≥25% 
> 220 ms 
>220 ms and increase from baseline ≥25% 
> 240 ms 
> 240 ms and increase from baseline ≥25% 
Categories are cumulative 
 
QRS 
>110 ms 
>110 msec and increase from baseline ≥25% 
>120 ms 
>120 ms and increase from baseline ≥25% 
Categories are cumulative 
QT 
>500 ms 
 
(electronic 
 
 
 
1.0)


Statistical Technical Document  
03-Oct-2018 
SAR407899-ACT14656  
 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 14 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
 
Parameter 
PCSA 
Comments 
QTc 
 
Absolute values (ms) 
 
 
>450 ms 
>480 ms 
>500 ms 
 
Increase from baseline 
Increase from baseline ]30-60] ms 
Increase from baseline >60 ms 
To be applied to any kind of QT correction formula.  
Absolute values categories are cumulative 
 
QTc >480 ms and ∆QTc>60 ms are the 2 PCSA 
categories to be identified in individual 
subjects/patients listings. 
 
 
(electronic 
 
 
 
1.0)


Statistical Technical Document  
03-Oct-2018 
SAR407899-ACT14656  
 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 15 
 
 
 
 
 
(electronic 
 
 
 
1.0)


Statistical Technical Document  
03-Oct-2018 
SAR407899-ACT14656  
 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 16 
 
 
(electronic 
 
 
 
1.0)